Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e578 Marvin A. Konstam, MD, Chair Michael S. Kiernan, MD, MS, FAHA, Co-Chair Daniel Bernstein, MD Biykem Bozkurt, MD, PhD, FAHA Miriam Jacob, MD Navin K. Kapur, MD Robb D. Kociol, MD, MS Eldrin F. Lewis, MD, MPH, FAHA Mandeep R. Mehra, MD Francis D. Pagani, MD, PhD, FAHA Amish N. Raval, MD, FAHA Carey Ward, MD On behalf of the American Heart Association Coun- cil on Clinical Cardiology; Council on Cardiovas- cular Disease in the Young; and Council on Cardiovascular Surgery and Anesthesia © 2018 American Heart Association, Inc. Circulation http://circ.ahajournals.org BACKGROUND AND PURPOSE: The diverse causes of right-sided heart failure (RHF) include, among others, primary cardiomyopathies with right ventricular (RV) involvement, RV ischemia and infarction, volume loading caused by cardiac lesions associated with congenital heart disease and valvular pathologies, and pressure loading resulting from pulmonic stenosis or pulmonary hypertension from a variety of causes, including left-sided heart disease. Progressive RV dysfunction in these disease states is associated with increased morbidity and mortality. The purpose of this scientific statement is to provide guidance on the assessment and management of RHF. METHODS: The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through September 2017. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or reference to contemporary clinical practice recommendations. RESULTS: Chronic RHF is associated with decreased exercise tolerance, poor functional capacity, decreased cardiac output and progressive end-organ damage (caused by a combination of end-organ venous congestion and underperfusion), and cachexia resulting from poor absorption of nutrients, as well as a systemic proinflammatory state. It is the principal cause of death in patients with pulmonary arterial hypertension. Similarly, acute RHF is associated with hemodynamic instability and is the primary cause of death in patients presenting with massive pulmonary embolism, RV myocardial infarction, and postcardiotomy shock associated with cardiac surgery. Functional assessment of the right side of the heart can be hindered by its complex geometry. Multiple hemodynamic and biochemical markers are associated with worsening RHF and can serve to guide clinical assessment and therapeutic decision making. Pharmacological and mechanical interventions targeting isolated acute and chronic RHF have not been well investigated. Specific therapies promoting stabilization and recovery of RV function are lacking. CONCLUSIONS: RHF is a complex syndrome including diverse causes, pathways, and pathological processes. In this scientific statement, we review the causes and epidemiology of RV dysfunction and the pathophysiology of acute and chronic RHF and provide guidance for the management of the associated conditions leading to and caused by RHF. AHA SCIENTIFIC STATEMENT Evaluation and Management of Right-Sided Heart Failure A Scientific Statement From the American Heart Association Endorsed by the Heart Failure Society of America and International Society for Heart and Lung Transplantation Key Words: AHA Scientific Statements ◼ causality ◼ disease management ◼ heart failure ◼ ventricular dysfunction, right D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e579 CLINICAL STATEM ENTS AND GUIDELINES O ver the years, there have been intermittent surges in interest in and investigation of the right ven- tricle (RV). One such period was the early 1980s, with the emergence of novel imaging techniques, ad- vanced surgical approaches, enhanced understanding of RV infarction and ischemia, and intense physiological in- vestigation of right-sided hemodynamics and ventricular interdependence. Now, once again, we enjoy intense in- terest in this area, owing in large part to advanced phar- macology for managing pulmonary hypertension (PH) and a mushrooming of both diagnostic techniques and durable and temporary mechanical circulatory support (MCS) devices, yielding expanded treatment options and enhanced outcomes in patients with acute and chronic disorders of the right side of the heart. RV dysfunction (RVD), defined here as evidence of ab- normal RV structure or function, is associated with poor clinical outcomes independently of the underlying mecha- nism of disease: across the spectrum of left ventricular (LV) ejection fraction (EF) in patients with acute and chronic heart failure (HF), after cardiac surgery, acute myocardial infarction (MI), congenital heart disease (CHD), and PH. To distinguish right-sided HF (RHF) from structural RVD, we define RHF as a clinical syndrome with signs and symp- toms of HF resulting from RVD.1 RHF is caused by the inability of the RV to support optimal circulation in the presence of adequate preload. This scientific statement provides evidence-based guidance in the following areas: pathophysiology of RVD, assessment and evaluation of RV function, epidemiology and prognosis of RHF, medical and surgical management of acute (ARHF) and chronic RHF (CRHF), and proposed areas for future investigation. The recommendations and suggestions/considerations listed in this document are, whenever possible, evidence based. An extensive literature review was conducted through May 2017, with references selected as appropri- ate. Searches were limited to studies, reviews, and other evidence conducted in human subjects and published in English. In addition, the committee reviewed documents related to the subject matter previously published by clini- cal practice guideline task forces from the American Heart Association (AHA) and American College of Cardiology. References selected and published in this document are representative but not all inclusive. To provide clinicians with a representative evidence base, whenever deemed appropriate or when published, it was felt that critical appraisal of the quality of study be maintained and, whenever possible, robust statistical data be provided. ORGANIZATION OF THE WRITING COMMITTEE The committee was composed of physicians with a broad knowledge base in the epidemiology and patho- physiology of HF with expertise in the evaluation, care, and management of patients with RHF. The authors’ expertise included general cardiology, advanced HF and transplantation cardiology, cardiac surgery, interven- tional cardiology, PH, and CHD; physicians with meth- odological expertise also were included. The committee included representatives from the AHA Council on Clini- cal Cardiology, Council on Cardiovascular Disease in the Young, and Council on Cardiovascular Surgery and An- esthesia; the Heart Failure Society of America; and the International Society of Heart and Lung Transplantation. DOCUMENT REVIEW AND APPROVAL This document was reviewed by 5 official reviewers, each nominated by the AHA. All information on review- ers’ relationships with industry was distributed to the writing committee and is published in this document. This document was approved for publication by the governing bodies of the AHA. SUGGESTIONS/CONSIDERATIONS AND REFERENCE TO CLINICAL PRACTICE GUIDELINE RECOMMENDATIONS To make certain that this document is aligned with the appropriate guideline statements but does not preempt those guidelines, the authors have opted to reference evidence-based clinical practice recommendations only and to refer the reader to the most recently published clinical practice guideline statement for more specific alignment with extant guidelines. Suggestions/con- siderations are included when the evidence does not warrant recommendations but there is still a desire to provide some guidance to the community. SCOPE OF THIS SCIENTIFIC STATEMENT WITH REFERENCE TO OTHER RELEVANT GUIDELINES OR STATEMENTS This scientific statement focuses on the evaluation and management of RHF. Some topics may have been reviewed in other clinical practice guidelines and scientific statements published by other working groups, including the Ameri- can College of Cardiology/AHA task forces. The writing committee saw no need to reiterate the recommendations contained in those guidelines but chose instead to provide current suggestions or considerations for clinical practice and to clarify previous discrepancies if present. ANATOMY AND EMBRYOLOGY OF THE RV Several developmental and anatomic features distin- guish the RV from the LV.2,3 The RV and RV outflow D ow nloaded from http://ahajournals.org by on A pril 5, 2021 May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e580 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Konstam et al Evaluation and Management of Right-Sided Heart Failure tracts originate from cells of the secondary (anterior) heart field, whereas the LV and left atria originate from the primary heart field.4 The identification of the sec- ondary heart field has provided new insight into the development of congenital heart defects and may lead to discoveries identifying distinct intercellular signaling pathways and transcriptional regulation in response to injury by the RV in contrast to the LV.5–8 Beginning in the third week of embryonic development, the primi- tive heart tube begins beating and undergoes a series of twisting and folding movements to generate a sin- gle primitive ventricle that receives blood from a single atrium and ejects blood through a common outflow tube known as the truncus arteriosus (Figure  1).9 By the end of the fourth week, a muscular ventricular sep- tum emerges from the floor of the primitive ventricle to form the earliest signs of distinct RVs and LVs. Between the fifth and eighth weeks, ridges within the truncus ar- teriosus grow into the aorticopulmonary septum, which fuses with the endocardial cushions and muscular inter- ventricular septum to form the membranous septum. At the end of the eighth week, distinct pulmonary and systemic circulations exist. For the remainder of fetal development, the RV will account for ≈60% of total cardiac output (CO), which provides systemic perfusion via the foramen ovale and the ductus arteriosus. At birth, the LV becomes the dominant systemic ventricle while the RV adapts to provide flow through the pul- monary circulation alone, assuming that the foramen ovale and ductus arteriosus close appropriately. Anatomically, the RV free wall is thin (2–3 mm) and compliant and forms a hemi-ellipsoid shape that ad- heres to the LV3 (Figure 2). A large sinus for venous in- flow and a tubular outflow tract provide a funnel-like configuration to the heavily trabeculated RV. Unlike the shared annulus of the aortic and mitral valves, the crista supraventricularis is a muscle bridge that is unique to the RV and separates the RV inflow (tricuspid annulus) from the outflow tract (pulmonic annulus). The crista supraventricularis shares muscle fibers with the inter- ventricular septum and the RV free wall and serves to contract the orifice of the tricuspid valve (TV) while pull- ing the RV free wall toward the interventricular septum during systole.10,11 PHYSIOLOGY OF THE RV Normal RV function is governed by systemic venous return, PA load (RV afterload), pericardial compliance, and native contractility of the RV free wall and inter- ventricular septum. Generating RV output requires one sixth the energy expenditure of the LV because much of RV stroke work maintains forward momentum of blood flow into a highly compliant, low-resistance pul- monic circulation. This difference is exemplified by the RV pressure-volume (PV) loop, which lacks isovolumic Figure 1. Cardiac embryogenesis. During embryogenesis, the primary heart field is formed by early cardiac progenitor cells in the anterior mesoderm. The sec- ondary heart field is derived from the pharyngeal mesoderm located medial and anterior to the primary heart field. Cells from the primary heart field migrate to the midline to form a linear heart tube, serving as a scaffold for subsequent heart growth. The heart tube is expanded posteriorly and anteriorly with cells migrating from the secondary heart field, giving rise to the arterial and venous poles. The linear heart tube undergoes a rightward looping, leading to the formation of primitive ventricles and atria. As a result, the venous pole moves anteriorly, positioning the future cardiac chambers for proper development. Heart maturation involves septation formation in the ventricles and atria, as well as valve formation. The primary heart field contributes to the left ventricle and right and left atria. The secondary heart field contributes to the right ventricle, outflow tract, and right and left atria. Cardiac neural crest cells migrating from the dorsal neural tube into the arterial pole participate in separation of the outflow tract. Reprinted by permission from Macmillan Publishers Ltd. Adapted from Xin et al.9 Nature Reviews Molecular Cell Biology. Copyright © 2013, Macmillan Publishers Ltd. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e581 CLINICAL STATEM ENTS AND GUIDELINES phases of contraction and relaxation during systole and diastole, has a lower peak systolic pressure, and exists at a higher steady-state volume compared with the LV.12 In contrast to the LV, peak RV pressure occurs before the end of systolic ejection, which leads to a more trap- ezoid-appearing RV PV loop (Figure 3).13–15 Afterload is a primary determinant of normal RV function, and RVEF is inversely proportional to pulmo- nary artery (PA) pressure (PAP).16 The RV has a shal- lower end-systolic PV slope than the LV, which results in lesser change in end-systolic pressure, generating greater change in end-systolic volume.17,18 Accordingly, RV systolic function is highly sensitive to changes in afterload, with minor increases in afterload causing large decreases in stroke volume (SV)19 (Figure 4).20 As dictated by the law of LaPlace, wall stress (afterload) is directly proportional to intracavitary pressure and to internal ventricular diameter and inversely related to ventricular wall thickness. However, regional wall stress may vary widely as a result of the nonspherical RV shape. RV afterload is most appropriately defined as the RV wall stress during systolic ejection estimated by the summation of the resistive and pulsatile com- ponents of blood flow.21,22 Commonly used measures of RV afterload, including PA systolic pressure (PASP) and pulmonary vascular resistance (PVR), provide an inadequate description of RV afterload because they do not account for contributions of pulsatile loading.22 As blood ejects from the RV into the lungs, antegrade flow away from the pulmonic valve (PV) encounters waves of retrograde flow generated by multiple bifur- cations throughout the pulmonary vasculature. This retrograde impedance wave reduces antegrade flow and increases peak PASP.23 In the setting of left-sided heart (LH) disease, eleva- tions in left atrial pressures lead to lower PA compliance than would be anticipated from elevated PVR alone.24,25 Similarly, lowering of pulmonary capillary wedge pres- sure (PCWP) increases PA compliance more than would be anticipated from a fall in PVR alone.26 Thus, elevated LH filling pressures directly increase RV afterload, sec- ondarily reduce PA compliance, and increase PA resis- tance through acute vasoconstriction and chronic vas- cular remodeling.22 Under steady-state conditions, optimal ventricu- lar efficiency is achieved if end-systolic elastance (Ees) is matched by vascular load, defined by arterial elas- tance16,27–31 (Figure 5). The ratio of Ees to arterial elas- tance is known as ventriculo-arterial coupling, a frame- work to consider contractility in the context of load. The optimal mechanical coupling of RV function to afterload corresponds to a ratio of Ees to arterial elas- tance of 1.0, with uncoupling occurring below a ratio of 0.6 to 1.0.16,29,30 When PASP increases acutely, RV SV decreases significantly and arterial elastance increases out of proportion to Ees. As a result, RV function be- comes inefficient, and more energy is expended to maintain adequate RV output. In contrast, an increase in aortic systolic pressure results in smaller decreases in LV SV, thereby maintaining a near-normal ventriculo- arterial coupling ratio. Unlike the predominantly diastolic coronary flow of the LV, normal RV coronary perfusion occurs during both systole and diastole. The pressure-overloaded RV is at increased risk for developing ischemia as a result of decreased perfusion pressure in the setting of in- creased RV intramural pressure and decreased system- ic arterial pressure.32,33 Any process that increases RV Figure 2. Right ventricular (RV) geometry in health and disease. Three-dimensional reconstructions of the RV illustrating its complex shape in a normal subject (A). RV remodeling in diseased hearts can result in profound shape change with RV dilation caused by chronic volume or pressure overload (B). The red mesh surface is the left ventricle (LV), and the solid blue surface is the RV. P indicates pulmonary valve; and T, tricuspid valve. Reprinted from Sheehan and Redington3 with permission from BMJ Publishing Group, Ltd. Copyright © 2008, BMJ Publishing Group, Ltd. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e582 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES end-diastolic pressure leads to decreased RV coronary blood flow and has the potential to induce subendo- cardial ischemia. PATHOPHYSIOLOGY OF RHF Acute RHF ARHF can occur because of abruptly increased RV af- terload (pulmonary embolus, hypoxia, acidemia) or de- creased RV contractility (RV ischemia, myocarditis, post- cardiotomy shock). Each condition represents a unique hemodynamic challenge for the RV. The RV is coupled to the high-compliance, low-resistance pulmonary cir- culation and is suited to adapt to changes in volume rather than pressure.2 In a healthy individual, PVR is <1/10th of the systemic vascular resistance. In contrast, the LV is coupled to the lower-compliance, higher-re- sistance systemic arterial circulation and adapts better to changes in pressure than volume. Thus, an acute in- crease in RV afterload such as can result from a large pulmonary embolism (PE) may abruptly decrease RV SV, with minimal increase in RV systolic pressure. Acute reductions in RV contractility may also be caused by direct myocardial injury from mechanisms such as myocardial inflammation (myocarditis) and ischemia. Reduced RV SV results in RV dilation, which promotes tricuspid regurgitation (TR), exacerbates RV dilation, and drives a ventricular-interdependent effect on LV filling. Ventricular interdependence is defined as the forces directly transmitted from one ventricle to the other through the myocardium and pericardium.16 Mechanical flattening with a leftward shift of the inter- ventricular septum increases LV end-diastolic pressure, reduces LV transmural filling pressure, and impedes LV diastolic filling, contributing to systemic hypoperfusion18 (Figure 6). Diastolic interaction is described as ventricu- lar competition for diastolic distension/filling within an acutely confined pericardial space. Systolic interactions also exist because it is estimated that 20% to 40% of RV systolic pressure results from LV contraction.3,34 Elevated filling pressures of the right side of the heart also cause coronary sinus congestion, which re- duces coronary blood flow and can provoke RV isch- emia.35,36 High right-sided filling pressure with systemic Figure 3. Right ventricular (RV) pressure-volume (PV) loops. RV PV loops obtained by a conductance catheter. White solid lines reflect the end-systolic PV relationships (ESPVR) of a series of loops generated by varying the loading conditions. The slope of ESPVR line reflects the RV end-systolic elastance (Ees). A steeper slope represents higher Ees. Loop a depicts a normal RV PV loop. A lower proportion of RV stroke work goes to pressure generation, with a higher proportion going to blood momentum. In the normal state, in contrast to the left ventricle (LV), there is a relative absence of RV isovolemic periods. The high momentum of blood ejecting from the RV into the low-pressure pulmonary circulation results in con- tinued RV ejection after LV systolic ejection has ended into RV relaxation. Loop b represents a compensated, chronically hypertensive RV. Loop c is obtained from a decompensated hypertensive RV. Note the decrease in RV Ees from the com- pensated RV depicted in loop b to the decompensated RV depicted by loop c. Reproduced from Friedberg and Reding- ton13 with permission. Copyright © 2014, American Heart Association. Figure 4. Relationship of right ventricular (RV) and left ventricular (LV) stroke volumes to increases in after- load. Response of the RV and LV to an experimental increase in afterload. Note the comparatively steep decline in stroke volume associated with increases in pressure compared with the smaller reductions seen in LV stroke volume associated with similar pressure increments. Reprinted with permission of the American Thoracic Society. Copy- right © 2018, American Thoracic Society. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease: part one. Am J Respir Crit Care Med. 1994;150:883–852.20 The American Journal of Respira- tory and Critical Care Medicine is an official journal of the American Thoracic Society. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e583 CLINICAL STATEM ENTS AND GUIDELINES venous congestion also negatively affects hepatic and renal function, aggravating further fluid retention and worsening RHF. Chronic RHF CRHF most commonly results from gradual increases in RV afterload caused by PH most frequently from LH failure (LHF), although chronic volume overload from right-sided lesions such as TR can also lead to its development (Figure  7). Long-standing pressure or volume overload imposed on the RV initially pro- motes compensatory myocyte hypertrophy and fibro- sis analogous to the remodeling that occurs in LHF. If the load persists, then the RV transitions from a compensated to decompensated phenotype charac- terized by myocyte loss and replacement/fibrosis.37 During the initial compensated phase, the hyper- trophied RV begins to develop isovolumic phases of contraction and relaxation with increased RV systolic pressure and higher end-diastolic volume (Figure  3). In the decompensating phase, there is a concomitant rise in PVR and right atrial (RA) pressure (RAP). While PVR remains persistently elevated, CO subsequently declines, followed by a reduction in PAP18,38 (Figure 8). Declining PAP in the setting of high PVR is an ominous clinical finding. In the presence of an intact pericardium, RV dila- tion eventually compresses the LV cavity, impeding LV filling and equalizing biventricular diastolic pressures (Figure 6). Although it is true that patients with CRHF may require higher RV end-diastolic pressure (preload), reduced LH filling is more likely caused by RV dilation and ventricular interdependence than reduced RV for- ward output.39 That is, increased transmural pressure caused by RV dilation with pericardial constraint impairs LV filling (preload). The combination of RV systolic and biventricular diastolic dysfunction reduces CO, impairs coronary blood flow, and exacerbates peripheral and abdominal congestion. EPIDEMIOLOGY AND PATHOGENESIS OF RHF HF With Reduced EF Progressive RHF was first described as a component of the HF clinical syndrome in 1910.40 Regardless of pathogenesis, RVD increases in prevalence with more advanced LHF. In this setting, RVD may occur second- ary to increased RV afterload from postcapillary PH, vol- ume overload, arrhythmias, or the underlying myocar- dial disease process affecting the LV (Table 1). The last factor may contribute to the higher prevalence of RVD observed in nonischemic dilated cardiomyopathy com- pared with ischemic cardiomyopathy, especially given the possible genetic predisposition in many of these patients. The overall prevalence of RVD in HF with re- duced EF (HFrEF) varies widely with distinct differences in varied populations, but its presence is universally associated with increased mortality.41 The prevalence of RVD in a meta-analysis of patients with HFrEF was 48%.41 In a small cohort of patients with dilated car- diomyopathy, RVD was seen in ≈60% of patients and was associated with greater mitral regurgitation and TR, more rapid progression of clinical HF, and decreased survival.42 Likewise, in a separate series, patients with nonischemic dilated cardiomyopathy had a higher pro- portion of RVD than those with an ischemic pathogen- esis: 65% versus 16%.43 Among patients with HFrEF who underwent echocardiography during acute HF hospitalization, 48% had RVD. These patients had a 2.4-fold increased risk of mortality, urgent transplanta- Figure 5. Pressure-volume (PV) loop. Right ventricular–pulmonary arterial (RV-PA) coupling. The PV loop is a comprehensive description of the relationship between pressure and volume during the cardiac cycle. The area within the loop defines the stroke work of the RV, with the width of the loop representing stroke volume (SV). End-systolic elastance (Ees), a load-independent measure of contractility, is determined by a tangent fitted on the end-systolic portions of a family of PV. RV afterload is determined by dividing the end-systolic pressure by the SV, providing the effective arterial elastance (Ea). Ea is measured as the slope of a straight line drawn from the end-systolic to end-diastolic PV relationship (to end-diastolic volume [EDV] at P=0). The relationship of these 2 parameters (Ees:Ea) provides a ratio defining RV-PA coupling, which reflects contractility in the context of afterload. Determinations of Ees and Ea require instantaneous measurements of RV pres- sure and volume to generate sequential PV loops obtained by a decrease of venous return via stepwise inflation of an inferior vena cava balloon or a Valsalva maneuver. Reprinted from Guazzi and Naeije16 with permission from Elsevier. Copyright © 2017, Elsevier. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e584 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Konstam et al Evaluation and Management of Right-Sided Heart Failure tion, or urgent LV assist device (LVAD) placement at 90 days compared with those without RVD.44 RVD is also associated with decreased exercise ca- pacity measured by peak oxygen consumption and worse New York Heart Association functional class.45 In a study of 97 patients with HFrEF, RV exercise con- tractile reserve and RV-PA coupling were assessed with tricuspid annular plane systolic excursion (TAPSE) ver- sus PASP and the slope of mean PAP versus CO.46 Pa- tients were grouped according to whether their rest- ing TAPSE was ≥16 mm. Those with TAPSE <16 mm were further subdivided by whether TAPSE at peak Figure 6. Ventricular interdependence in right-sided heart failure. Pathological increases in right ventricular (RV) filling pressures are transmitted to the interventricular septum. As the RV is constrained by the pericardium (arrows), these forces result in leftward shift of the septum, altering left ventricular (LV) ge- ometry. These changes contribute to reduced cardiac output by decreasing LV distensibility, preload, and ventricular elastance, adversely affecting LV diastolic filling. Leftward septal shift secondary to pericardial constraint from elevated RV end-diastolic pressure distorts the normal geometric ventricular relationship, also impairing RV contractile function. Adapted from Haddad et al18 with permission. Copyright © 2008, American Heart Association. Figure 7. Pathophysiology of right-sided heart failure. LV indicates left ventricular; LVEDP, left ventricular end-diastolic pressure; RAP, right atrial pressure; RV, right ventricle; and RVEDD, right ventricular end-diastolic dimension. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e585 CLINICAL STATEM ENTS AND GUIDELINES exercise was ≥15.5 mm. Although patients had similar baseline profiles of biventricular function, those with higher TAPSE in response to exercise demonstrated improved RV contractile reserve and some degree of favorable RV-PA coupling in contrast to those patients with persistently low TAPSE. Thus, many patients with resting RVD can have residual contractile reserve with the ability to improve RV-PA coupling during exercise. Data directly linking RVD to reduced performance on structured health-related quality of life (HRQoL) ques- tionnaires are sparse. HF With Preserved EF RV function is equally important in patients with HF with preserved EF (HFpEF). In this population, however, it is difficult to distinguish primary RV pathology from that resulting from secondary PH, given the afterload dependency of RV function.47 Nevertheless, several small cohort studies have evaluated the prevalence of concomitant RV systolic dysfunction in the setting of HFpEF. In a Mayo Clinic cohort, 33% of patients with HFpEF had RVD defined as RV fractional area change (RVFAC) <35%.48 In a separate study of 51 patients, depending on the criteria used, RVD was present in 33% to 50% of patients with HFpEF in contrast to 63% to 76% of those with HFrEF.49 Other groups have reported similar findings.50 A meta-analysis including 4835 patients reported varied prevalence depending partly on the modality used to assess RV function: 31% by TAPSE, 26% by RV S’, and 13% by RVFAC.47 Approximately 70% of these patients with HFpEF with RVD had concomitant PH at rest. More novel indexes of RV function have led to higher prevalence estimates. RV longitudinal systolic strain abnormalities were iden- tified in 75% of 208 patients with HFpEF, whereas RV- FAC <35% was seen in only 28%.51 Compared with patients with HFpEF without RVD, those with RVD were more likely to be male, to have more renal impair- ment, and to have a higher prevalence of atrial fibrilla- tion and coronary artery disease.48,51 Analogous to outcomes in HFrEF populations, RVD is associated with increased morbidity and mortality in HFpEF populations.51 Two-year mortality in 1 study was ≈45% for patients with RVD compared with 7% Figure 8. Hemodynamics in progressive pulmonary vascular disease. A decrease in pulmonary arterial pressure (PAP) in patients with pulmonary hypertension may be a sign of low cardiac output (CO) and severe right ventricular dysfunction. MPAP indicates mean PAP; PCWP, pulmonary artery capil- lary wedge pressure; PVR, pulmonary vascular resistance; and RAP, right atrial pressure. Adapted from Haddad et al18 with permission. Copyright © 2008, American Heart Association. Table 1. Causes of RHF Decreased RV Contractility RV Volume Overload RV Pressure Overload Acute Sepsis Acidosis LVAD support Hypoxia RVMI Excessive transfusion PE Myocarditis ARDS Perioperative injury/ischemia (postcardiotomy) Positive pressure ventilation Chronic RV cardiomyopathy LH disease ARVC Single ventricle Ebstein anomaly Pericardial disease PR PAH TGA Chronic thromboembolic PH TR PS Left-sided valvular heart disease Restrictive cardiomyopathy ARDS indicates acute respiratory distress syndrome; ARVC, arrhythmogenic right ventricular cardiomyopathy; LH, left- sided heart disease; LVAD, left ventricular assist device; PAH, pulmonary arterial hypertension; PE, pulmonary embolism; PH, pulmonary hypertension; PR, pulmonary regurgitation; PS, pulmonary stenosis; RHF, right-sided heart failure; RV, right ventricular; RVMI, right ventricular myocardial infarction; TGA, transposition of the great arteries; and TR, tricuspid regurgitation. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e586 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES in those without RVD.48 Exercise intolerance is com- mon in people with HFpEF, and those with evidence of RVD have lower New York Heart Association classifica- tion.51 In an exercise comparison between 50 patients with HFpEF and 24 control subjects, those with HF- pEF had impaired RV systolic and diastolic functional enhancement measured by invasive cardiopulmonary exercise testing and simultaneous echocardiogra- phy.52 Increased left- and right-sided filling pressures and limitations in CO reserve correlated with abnor- mal augmentation in biventricular mechanics during stress, suggesting limited RV reserve with RV-PA un- coupling during. Myocarditis Inflammatory myocardial disease has varied clinical presentations and outcomes. The focus of myocarditis studies has been predominantly on characterization of LV function. RV involvement, however, may reflect a greater burden of inflammation, preexisting vulnerabil- ity to an acute process, or increased afterload caused by LHF. When treatment options are considered, the presence of RVD, depending on the severity, may dic- tate the need for biventricular support. In 174 patients with active or borderline myocarditis, RVD was pres- ent in 39% of patients with anti-heart autoantibodies compared with 17% of those without anti-heart auto- antibodies.53 The presence of RVD by cardiac magnetic resonance imaging (MRI) in a study of patients with myocarditis was associated with a hazard ratio of 3.4 for death or heart transplantation and was the stron- gest predictor of death.53 RV Myocardial Infarction Acute RVMI is prevalent in ≈50% of patients with an acute inferior MI.54 A functionally-relevant acute RVMI generally requires disruption of blood flow to both the RV free wall and a portion of the interventricu- lar septum. It typically occurs when a dominant right coronary artery is occluded proximally to the major RV branch(es), leading to reduced RV systolic function and acute RV dilation. A smaller proportion of patients have RVMI resulting from circumflex coronary artery occlusion in a left-dominant coronary system and rare- ly in association with left anterior descending coronary artery occlusion, in which this artery supplies collater- als to an otherwise underperfused anterior portion of the RV free wall. RVMI is associated with hemodynamic compromise in 25% to 50% of patients presenting with this infarct pattern.55 Early mortality is highest among patients with evidence of hemodynamic compromise.56,57 Patients with RVMI have a greater burden of arrhythmias, con- tributing to mortality.57 Most patients recover RV func- tion within days to weeks after the infarct.58 One-year mortality after RVMI is reported to be 18% in patients with isolated right coronary artery lesions compared to 27% in the presence of combined right and left coro- nary artery disease. In long-term follow-up, mortality beyond the first year remains at an additional 2%/y to 3%/y through year 10.59 In 1 series, mortality among patients with inferior MI with RVMI was 25% to 30% compared with 6% in patients without RVMI.60 Similar- ly, among 666 patients with acute MI undergoing per- cutaneous coronary intervention, excluding those with cardiogenic shock on admission, electrocardiographic (ST-segment elevation of 0.1 mV in lead V 3 R or V 4 R) and echocardiographic evidence of RVMI (RV free wall motion abnormalities or RV dilatation) was associated with higher in-hospital and 1- and 6-month mortality compared with patients with either anterior or inferior MI without evidence of RVMI (although findings at 6 months were not statistically significant).56 Although patients with inferior MI have, in general, a better prognosis than those with anterior MI, the presence of RV involvement increases the risk of death, shock, and arrhythmia.61 Among patients with MI complicated by cardiogenic shock enrolled in the SHOCK trial (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock), 5% had a picture of predominant RHF and the remainder had a shock syndrome charac- terized by LHF.62 Despite some favorable clinical charac- teristics among the patients with RHF, the mortality rate was similar between these 2 groups. Postsurgical ARHF ARHF may occur during or after noncardiac surgery as a result of the development of acute PH or intraopera- tive myocardial ischemia.63 The prevalence of RHF after noncardiac surgery is difficult to determine. There is the potential for a survival bias whereby patients with more profound RHF die before full cardiac evaluation. Furthermore, preexisting HF may make the diagnosis of ARHF more challenging to differentiate. During cardiac surgery, ARHF can be caused by hy- poxia/myocardial ischemia, microemboli, air emboli leading to MI, arrhythmias, and excessive volume load- ing.64,65 Furthermore, there is a disruption in the na- tive RV contractile pattern after cardiothoracic surgery. Although overall RV function remains preserved, the combination of cardiopulmonary bypass and pericardi- otomy leads to a reduction in longitudinal contraction and an increase in transverse shortening.66 In the nor- mal RV, longitudinal shortening accounts for ≈80% of RV function.67 Whether release of pericardial constraint after complete pericardiotomy predisposes the at-risk RV to the development of ARHF remains uncertain. RVD is frequently seen within 5 days of cardiac surgery and may persist despite improvements in LV function.68 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e587 CLINICAL STATEM ENTS AND GUIDELINES Postoperative ARHF is associated with increased mor- tality, prolonged length of stay, and increased resource use.69 In a cohort of patients undergoing coronary ar- tery bypass graft surgery, most patients did not dem- onstrate a significant postoperative change in RV func- tion, although modest decreases in longitudinal strain were noted.70 After Cardiac Transplantation Primary graft dysfunction (PGD) affects ≈7% or more of patients after cardiac transplantation and is the lead- ing cause of early mortality.71,72 PGD may be classified as PGD of the LV, which includes biventricular dysfunc- tion, versus PGD of the RV alone. Diagnosis of PGD of the RV alone requires both (1) RAP >15 mm Hg, PCWP <15 mm Hg, and cardiac index <2.0 L·min−1·m−2 and (2) transpulmonary gradient <15 mm Hg and PASP <50 mm Hg or (3) the need for an RV assist device (RVAD).71 The pathogenesis of PGD is complex and likely multifac- torial. Contributing causes consist of donor, procedur- al, and recipient-level factors, including inflammatory mediators resulting from brain death, elevated PVR, and ischemia/reperfusion injury associated with pres- ervation issues.73,74 Although management of ARHF is discussed elsewhere, a decision on the need for right- sided MCS should be made before leaving the opera- tive room, pending the initial response to medical inter- ventions.74,75 After LVAD Twenty percent or more of patients undergoing isolated LVAD implantation experience ARHF, which is a lead- ing cause of premature morbidity and mortality.76–78 Rates of RHF associated with LVAD insertion may be partially dependent on the underlying cause of myopa- thy. Patients with a history of chemotherapy-associated cardiomyopathy appear to be at higher risk than those with other forms of nonischemic or ischemic disease.79 The physiology of ARHF after LVAD implantation is com- plex. From a hemodynamic perspective, activation of an LVAD increases venous return, potentially overwhelm- ing a functionally impaired RV, leading to RV dilatation, TR, leftward shift of the interventricular septum, and decline in RV SV. As RV output falls and the septum shifts leftward, LV preload and LVAD flows are reduced. The RV is dependent on the LV for a significant portion of its contractile function, and leftward septal shift re- sulting from LV unloading can have a direct, detrimental effect on RV contraction.27,80 Furthermore, anchoring of the LVAD to the LV apex may alter the normal twisting contractile pattern of the heart. Whether the direction of apical deformation (ie, apical pull versus push, de- pending on device configuration and placement) alters the risk of RVD remains uncertain. LV unloading with mechanical support may improve RV contractility via a reduction in PAP after the acute decline in PCWP associated with LVAD activation.80,81 PH, however, is a risk factor for the development of ARHF in LVAD recipients,82,83 and residual, fixed PH likely contributes to RV-PA uncoupling when other intraoperative complications are encountered. Even if compensated for in the preoperative period, a chroni- cally dysfunctional RV coupled to a fixed and elevated pulmonary afterload may not be able to tolerate intra- operative insults such as ischemia and volume loading, which then precipitate ARHF. In addition, it is possible that a reduction in systemic afterload after insertion of rotary blood pumps leads to a decline in LV contractility with a resultant second- ary decline in RV contractility. The Anrep effect is the physiological consequence whereby increases in arterial afterload lead to increases in ventricular contractility. Although this relationship remains somewhat hypo- thetical in the LVAD-supported circulation, the converse of this is also true: Reductions in afterload may lead to reduced contractility. Late RHF in the LVAD recipients, after initial hospital discharge, occurs in ≈10% of patients and is similarly associated with reduced survival and lower HRQoL and functional capacity.84,85 The development of ventricular and atrial tachyarrhythmias may be a significant factor contributing to the development of late RHF. PE With ARHF Acute PE can lead to acute RV strain as a result of pres- sure overload within minutes of occlusion of a major PA segment and is a common cause of ARHF.33,63 Physi- cal presentation often includes initial syncope or right- sided atrial arrhythmias. The prevalence of ARHF in the setting of acute PE ranges from 25% to 60%.86,87 Predictors of RVD include >50% of the PA tree oc- cluded by thrombus.88 Patients with evidence of RVD have a 2.4- to 3.5-fold increase in mortality compared with those without RVD.86,87 Given the poor prognosis, guidelines on the management of acute PE recommend early detection of RVD to guide risk stratification and therapeutic decision making. Arrhythmogenic RV Cardiomyopathy Arrhythmogenic RV cardiomyopathy (ARVC) is a dis- ease of the cardiac myocytes caused by impaired des- mosome function.89 Desmosomes are intercellular junctions that provide adhesion between cells. Muta- tions in desmosomal proteins such as plakophilin and desmoplakin decrease the ability of the cells to toler- ate mechanical stress, resulting in myocyte detachment and cell death. The inflammation that accompanies this process manifests as fibrofatty infiltration, causing ven- D ow nloaded from http://ahajournals.org by on A pril 5, 2021 May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e588 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Konstam et al Evaluation and Management of Right-Sided Heart Failure tricular irritability and arrhythmias and eventually ven- tricular dysfunction. In affected patients, this process shows a predilection for the thinnest portions of the RV where mechanical stress is greatest. However, the LV also is often affected in advanced disease.90 The prevalence of ARVC is estimated to be 1 in 2000 to 5000, and ARVC affects men more frequently than women. A familial component is identified in >50% of patients.91 Transmission is autosomal dominant with in- complete penetrance. Diagnosis of ARVC can be diffi- cult, so standardized criteria have been developed that are based on family history, ventricular dysfunction, tissue characterization, electrocardiographic changes (Figure 9A), and history of arrhythmias.93 The sensitivity of electrocardiographic criteria alone (Table  2) for the diagnosis of ARVC is low. Diagnosis requires a specific combination of major and minor criteria from the ECG, RV imaging, and family history that are reviewed in detail elsewhere.93 Genetic screening, although not re- quired, may be helpful when screening family members of a recently diagnosed patient.93,94 Recommendations for the role of genetic testing of probands and first- degree relatives have been published.94 ARVC is more often associated with arrhythmia than isolated RVD. In Italy, where young athletes undergo detailed screening before participation in sports, ARVC was a cause of sudden cardiac death (SCD) in >20%.95 In a registry of SCDs in athletes from the United Kingdom, ARVC was detected in 13% of 357 subjects.96 Among 100 US patients diagnosed with ARVC, the median age at presentation was 29 years, but age at presentation varied widely, from 2 to 70 years.97 Thirty-one patients experienced SCD, and 6 patients progressed to RHF, one of whom died while awaiting cardiac transplantation. Figure 9. ECGs in patients with right-sided heart disease. A, ECG from a patient with arrhythmogenic right ventricular cardiomyopathy. ECG from a patient with T-wave inversion in V 1 through V 4 and prolongation of the terminal activation of a 55-millisecond duration measured from the nadir of the S wave to the end of the QRS complex in V 1 . Reproduced with permission from Marcus et al.92 Copyright © 2010, American Heart Association. B, ECG with right ventricular hypertrophy. ECG demonstrating the changes of right ventricular hypertrophy. Long arrow indicates dominant R wave in V 1 ; short arrow, right-axis deviation; black arrowhead, right atrial abnormality; and open arrowhead, secondary ST-T changes. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e589 CLINICAL STATEM ENTS AND GUIDELINES More than 90% of patients had a life-threatening ar- rhythmia at some point during follow-up.97 This statistic is, of course, influenced by selection bias because the presence of ventricular arrhythmia increases the prob- ability of ascertaining the diagnosis of ARVC. Indica- tions for implantable cardioverter-defibrillator therapy in ARVC are available.98 Tricuspid Regurgitation TR is a common echocardiographic finding, and mild TR is present in 80% to 90% of individuals. Although less common, moderate to severe TR affects >1 mil- lion people in the United States.99 TR can be related to 2 principal types: primary valvular TR and secondary functional TR. Functional changes of the TV related to annular dilation and leaflet tethering in the setting of RV remodeling caused by pressure and volume over- load are the most common causes of significant TR, ac- counting for 85% of cases.100 In contrast, primary TR is secondary to lesions of the valve structure itself such as endocardial cushion abnormalities, Ebstein anomaly, endocarditis, and carcinoid heart disease. The severity of TR affects prognosis even when con- trolling for LV dysfunction or PH. In a study of 5223 pa- tients at 3 Veterans Affairs medical centers, 1-year sur- vival rates were 92%, 90%, 79%, and 64% in patient groups with no, mild, moderate, or severe TR, respec- tively.101 Moderate or greater TR was associated with increased mortality regardless of PASP or LVEF. Severe TR, older age, lower LVEF, inferior vena cava dilation, and moderate or greater RV enlargement were associ- ated with worse survival. PV Disease Pulmonary stenosis (PS) occurs in ≈10% of children with CHD. PS can be encountered as part of tetralogy of Fallot (TOF), the incidence of which is 6 in 20 000 live births,102,103 or other complex CHDs such as trans- position of the great arteries (TGA), ventricular septal defect, and PS or an isolated valve abnormality. PV atre- sia can be seen in patients with TOF but can also be encountered in those with an intact ventricular septum. PS can also be seen in patients with Noonan syndrome, in whom it can be isolated or seen in combination with cardiomyopathy. PV disease can be found in the setting of endocarditis, especially in intravenous drug users, or in carcinoid heart disease.104,105 Patients with isolated PS do quite well, usually treated with balloon valvuloplasty alone. When treated, long-term survival of patients with PS is not different from that in individuals without PS.106 The development of RHF in patients with isolated PS is rare. Pulmonary insufficiency is most often a consequence of balloon valvuloplasty or surgical repair of congeni- tal abnormalities and is commonly seen after complete repair of TOF.107 The highest-risk group is made up of patients with a small PV annulus, in whom surgical re- pair involves placement of a transannular patch, leav- ing the patient with an incompetent PV. Historically, surgeons have attempted to make this patch as large as possible to relieve PS; however, more contemporary techniques use a smaller transannular patch, recogniz- ing that a small degree of residual PS is preferable for preservation of long-term RV function than wide-open pulmonary insufficiency. MRI studies have shown RV fibrosis in 99% of patients with repaired TOF and LV fibrosis in 53%.108 In 10% to 15% of patients, pulmo- Table 2. Revised Task Force Criteria for Electrocardiographic Diagnosis of ARVC Repolarization abnormalities Major Inverted T waves in right precordial leads (V 1 –V 3 ) or beyond in individuals >14 y of age (in the absence of complete right bundle-branch block QRS ≥120 ms) Minor Inverted T waves in leads V 1 and V 2 in individuals >14 y of age (in the absence of complete right bundle-branch block) or in V 4 , V 5 , or V 6 Inverted T waves in leads V 1 –V 4 in individuals >14 y of age in the presence of complete right bundle-branch block Depolarization/conduction abnormalities Major Epsilon wave (reproducible low-amplitude signals between end of QRS complex and onset of the T wave) in the right precordial leads (V 1 –V 3 ) Minor Late potentials by SAECG in ≥1 of 3 parameters in the absence of a QRS duration ≥110 ms on the standard ECG Filtered QRS duration ≥114 ms Duration of terminal QRS <40 V (low-amplitude signal duration) 38 ms Root-mean-square voltage of terminal 40 ms ≤20 μV Terminal activation duration of QRS ≥55 ms measured from the nadir of the S wave to the end of the QRS, including R, in V 1 , V 2 , or V 3 , in the absence of complete right bundle- branch block ARVC indicates arrhythmogenic right ventricular cardiomyopathy; and SAECG, signal-averaged ECG. Adapted from Marcus et al92 with permission. Copyright © 2010, American Heart Association. Table 3. Classification of PH PH Category Characteristics Clinical Group Precapillary MPAP ≥25 mm Hg PCWP ≤15 mm Hg WHO class 1, 3–5 Postcapillary MPAP ≥25 mm Hg PCWP >15 mm Hg WHO class 2, 5 Isolated postcapillary PH DPG <7 mm Hg and/ or PVR ≤3 WU Combined precapillary and postcapillary PH DPG ≥7 mm Hg and/ or PVR >3 WU DPG indicates diastolic pulmonary gradient; MPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; WHO, World Health Organization; and WU, Woods units. Reproduced from Galiè et al109 with permission. Copyright © 2016, Oxford University Press. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e590 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES nary insufficiency leads to progressive RV dilatation and dysfunction and may require PV replacement later in life.103,107 Left unrepaired, RV dilatation and dysfunction can lead to ventricular arrhythmias with a rate of SCD in this population estimated to be 0.3%/y.103 PULMONARY HYPERTENSION The evaluation of a patient with RVD includes an as- sessment for increased RV afterload. PH is characterized by alterations in the pulmonary vasculature leading to increased PVR and ultimately RVD. The increased after- load on the RV leads to RV hypertrophy, dilation, and systolic dysfunction. PH is defined as a mean PAP ≥25 mm Hg and when present is associated with impaired survival. PH is found in isolation and as a consequence of other diseases as detailed below. Patients are catego- rized on the basis of the mechanism of disease (Table 3). Group 1: Pulmonary Arterial Hypertension Pulmonary arterial hypertension (PAH) describes a group of disorders characterized hemodynamically by the presence of precapillary PH, defined by a PCWP ≤15 mm Hg and a PVR >3 Woods units in the absence of other causes of precapillary PH such as chronic lung disease.109,110 Initial PH screening is typically performed with echocardiography, but right-sided heart catheter- ization is required for definitive diagnosis. The incidence for all group 1 PAH is 2.3 cases per 1 million adults with an overall prevalence of 12.4 per 1 million adults.111 Group 1 includes those patients with idiopathic PAH; hereditary PAH; PAH caused by drugs and toxins; PAH associated with connective tissues disease, portal hy- pertension, HIV, CHD with persistent pulmonary-to- systemic shunt, Eisenmenger physiology, and schisto- somiasis; persistent PAH of the newborn; pulmonary veno-occlusive disease; and pulmonary capillary hem- angiomatosis.112 Patients with PAH benefit from care provided in cen- ters with expertise in this condition. Despite the intro- duction of new pulmonary vasodilator therapies, group 1 PH continues to be associated with high morbidity and mortality. In a US cohort of patients in the REVEAL registry (Registry to Evaluate Early and Long-Term Pul- monary Arterial Hypertension Disease Management), 1- and 5-year survival rates were 85% and 57%, respec- tively.113 PAH secondary to connective tissue disease or portopulmonary hypertension is associated with a worse prognosis. The presence of RVD in patients with PAH is a strong predictor of adverse outcomes and more closely associated with clinical outcomes than the PAPs.114 Hemodynamic and echocardiographic mark- ers of RVD associated with increased mortality include RA and RV dilation, elevated RAP, RV systolic dysfunc- tion, the presence of a pericardial effusion, decreased PA capacitance, and reduced CO.110,113,115 Assessment of RV strain may add prognostic value to traditional markers of RVD in the assessment of PAH.116,117 There is significant variability in the timing of the onset of RHF among patients, including those with similarly elevated PAP.18,114,118,119 Other variables associated with reduced survival include lower functional class, lower blood pressure (BP), higher heart rate, increased BNP (B-type natriuretic peptide), reduced diffusion capacity of the lung for carbon monoxide, and reduced 6-minute walk distance.120 In the subset of patients with elevated RV pressure secondary to Eisenmenger syndrome or con- genital PS, chronic RV pressure overload can be reason- ably well tolerated for decades.121–123 Pulmonary veno-occlusive disease represents a small subgroup of group 1 PAH associated with a particularly poor prognosis.124 In contrast to other forms of PAH, pulmonary veno-occlusive disease results in postcapil- lary PH. Vasodilatory therapy can lead to clinical wors- ening in patients with pulmonary veno-occlusive dis- ease, and these patients should be considered for lung transplantation. Group 2: LH Disease Chronically elevated left-sided filling pressures from LV systolic and diastolic dysfunction or significant left-sid- ed valvular heart disease can lead to PH.125 A study of 1063 patients with HF found that 68% of those with HFrEF and 54% with HFpEF had PH.25 The definition of group 2 PH requires a mean PAP ≥25 mm Hg with a PCWP >15 mm Hg or LV end-diastolic pressure ≥18 mm Hg.110 Most patients with HF have postcapillary PH, characterized by low PVR (<3 Woods units) and low transpulmonary gradient (≤12 mm Hg). Others, howev- er, have elevation of PVR and transpulmonary gradient, historically described as out-of-proportion or mixed PH. The commonly used measures of out-of-proportion PH include transpulmonary gradient, PVR, and the diastolic pulmonary gradient (diastolic pulmonary gradient=PA diastolic pressure–PCWP).16 A diastolic pulmonary gra- dient ≥7 mm Hg suggests pulmonary vascular disease superimposed on left-sided pressure elevation.126 Clas- sification of postcapillary PH in the 2015 European Society of Cardiology guidelines for the diagnosis and treatment of PH identified patients as having either isolated postcapillary PH, defined by a diastolic pul- monary gradient <7 mm Hg, or combined precapillary or postcapillary PH (Cpc-PH) with diastolic pulmonary gradient ≥7 mm Hg and concomitantly elevated PVR >3 Woods units (Table  3).109 In 1 study, Cpc-PH was observed in 12% of patients with HF with an equal prevalence in HFrEF and HFpEF.25 Predictors of Cpc-PH included younger age, coexistent chronic obstructive D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e591 CLINICAL STATEM ENTS AND GUIDELINES pulmonary disease, and valvular heart disease. Com- pared with isolated postcapillary PH, Cpc-PH was asso- ciated with increased mortality. RV–pulmonary vascular coupling is poor in Cpc-PH and has been proposed as an explanation for poor outcomes associated with this syndrome.25,127,128 Group 3: Chronic Lung Disease and Hypoxia PH caused by chronic obstructive pulmonary disease or interstitial lung disease is usually mild to moder- ate in severity.129 The small number of patients with severe PH in this category may have an additional underlying pathogenesis for an elevated PVR. PH is seen in ≈20% of patients with obstructive sleep ap- nea.130,131 Obesity hypoventilation syndrome is similarly associated with a high prevalence of PH and RVD132–134 and a high rate of overlap among patients with these 2 diagnoses. Group 4: Chronic Thromboembolic Disease When PH is identified, exclusion of chronic thrombo- embolic PH is required, given that surgical interven- tion can alter the natural history of this disease. A significant proportion of patients without a history of PE are ultimately diagnosed with chronic thromboem- bolic PH. Ventilation/perfusion scan is standard in the evaluation of newly diagnosed PH.109,110 Among pa- tients undergoing pulmonary endarterectomy at expe- rienced centers, 3-year survival is as high as 90%, and 10-year survival is 72%.135 Limited data from obser- vational studies describe a potential role for percuta- neous balloon angioplasty in patients with inoperable disease.136–138 Group 5: Miscellaneous Group 5 PH is characterized by diseases with multiple or unclear mechanisms contributing to the develop- ment of PH. This group includes systemic illnesses such as sarcoidosis, chronic hemolytic disorders, and chronic kidney disease. Myocardial depression during sepsis is a well-known phenomenon, and RHF can occur inde- pendently of PH or respiratory status.139 RVD can oc- cur in isolation or concomitantly with LV dysfunction. A combination of reduced RV contractility and decreased preload caused by systemic vasodilation can impair circulation. Acute respiratory distress syndrome and mechanical ventilation are associated with increased PVR, which can also precipitate RVD. In a small study of septic patients evaluated with radionuclide imaging, patients with worsening respiratory status and PH were less likely to have recovery of RV function.140 CONGENITAL HEART DISEASE CHD affects nearly 1% of births per year.141,142 Because of improved surgical techniques and advances in the medical care of patients with CHD, the prevalence of congenital heart defects in adult patients has grown substantially over the past decade. As of 2003, the esti- mated 1.4 million adults in the United States living with CHD exceeded the number of children with CHD.143 Many patients with CHD have significant RV involve- ment because of right-sided valvular lesions, intracar- diac shunting, or the presence of a systemic RV. The prognosis for each lesion of CHD is dependent on the severity of the residual hemodynamic abnormalities and other associated defects. Atrial Septal Defect There are 3 types of atrial septal defects (ASDs): ostium secundum (most common), ostium primum, and sinus venosus.102,144 Larger ASDs pose little or no resistance to intra-atrial flow, yielding equalization or near equaliza- tion of left atrial pressure and RAP. In the absence of pulmonary vascular obstructive disease (Eisenmenger physiology), the magnitude of the left-to-right shunt in unrestrictive ASDs relates primarily to the relative com- pliance characteristics of the 2 ventricles. The shunt poses a volume load on the RV, dilating this chamber, as well as the pulmonary vasculature and left atrium, but if not complicated by additional anomalies or PH, it seldom results in RHF in early life. RV volume overload is associated with LV dysfunction secondary to altered chamber geometry and decreased myofiber preload, which is immediately reversible after ASD closure and reflective of the ventricular interdependence.145 Across multiple disease types, in the absence of primary RV pathology, RVEF tends to correlate with PAP. However, because of increased preload associated with an ASD, RVEF is higher than would otherwise be expected for any degree of RV contractile dysfunction or afterload.146 ASDs do not close spontaneously, and in developed countries, they are generally surgically corrected in childhood. Left uncorrected, they are associated with pulmonary vascular obstructive disease and Eisen- menger physiology in a small percentage of cases. Eisenmenger syndrome is characterized by progressive PVR, PH, reversal (or bidirectionality) of the intracardiac shunt, cyanosis, and RV hypertrophy and failure. The frequency of this syndrome is much lower with an ASD than a ventricular septal defect because in the latter case increased pulmonary blood flow is accompanied by increased pressure caused (effectively) by direct LV ejection into the pulmonary circulation, impeded only by the resistance posed by the intracardiac defect it- self. When ASDs are allowed to persist into late adult life, in the absence of Eisenmenger physiology, an in- D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e592 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES creased rate of morbidity and mortality may be driven by an increased magnitude of the left-to-right shunt, the result of progressive LV stiffness caused by system- ic hypertension or aging.121,144 In these cases, RHF may ensue as a result of the increase in both volume and pressure load, the latter generally driven more by the increased magnitude of pulmonary flow than obstruc- tive pulmonary vascular disease. Therefore, if the ASD is missed or ignored in childhood, it is not unusual for the patient to present symptomatically for the first time in late life. Ebstein Anomaly In Ebstein anomaly, ≥1 leaflets of the TV are adherent to the RV wall, leading to atrialization of a portion of the RV chamber with varying degrees of TR.102 In neonates, severe Ebstein anomaly can lead to profound cyanosis caused by the inability of the RV to eject into the pul- monary circulation. In older patients with milder forms, it can lead to cyanosis with exercise caused by shunting across a foramen ovale or an ASD. The degree of long- term RHF depends on the degree of RV hypoplasia or the success of TV reparative surgery. Transposition of the Great Arteries L-TGA is commonly referred to as corrected transposi- tion. In this lesion, the morphological RV serves as the systemic ventricle and is coupled to the high-pressure systemic circulation. The majority of patients with L- TGA have other significant cardiac defects, most com- monly including ventricular septal defect and PS. The TV is almost always abnormal, frequently with Ebstein- like displacement, leading to TR and RV volume over- load. RHF occurs in up to 50% of patients with L-TGA by middle age, with the risk increased by the presence of associated lesions such as TV disease.147 D-TGA results in cyanosis in the newborn period. Be- fore the 1980s, surgical repair involved placement of an atrial baffle (atrial switch, Mustard or Senning pro- cedure) to redirect venous return, leaving the RV as the systemic ventricle. Analogous to patients with L-TGA, the RV in these patients is at increased risk of dilatation and failure. The arterial switch operation involves tran- section of both great arteries and translocation of the vessels to the opposite root, creating ventriculoarterial concordance, and has become the standard corrective procedure for this lesion.148 Single-Ventricle (RV) Physiology There are various forms of single-ventricle morphology. In the most severe forms of CHD involving hypopla- sia or total absence of the LV (ie, hypoplastic LH syn- drome), surgical palliative procedures result in the RV being used as the systemic ventricle, coupled to the high-resistance systemic circulation. In these patients, pulmonary blood flow is achieved by connecting the vena cavae directly to the pulmonary arteries (Glenn and Fontan operations). There are a number of long- term complications in patients with a single ventricle, including protein-losing enteropathy, plastic bronchitis, and hepatic fibrosis. However, systemic RV dilation, TR, and RHF become increasingly common as patients en- ter their third and fourth decades. Patients with a sys- temic RV are at greater risk of developing HF than pa- tients with a systemic LV.149 Fibrosis is present in >25% of patients with a Fontan operation.150 CLINICAL MANIFESTATIONS OF RHF Acute RHF ARHF is generally characterized by acute RV dilation, a ventricular-interdependent effect limiting LV fill- ing, reduced RV forward flow, and elevated systemic venous pressure. Patients with ARHF typically show signs of hypoperfusion and hypotension, including diaphoresis, listlessness, cyanosis, cool extremities, hypotension, and tachycardia.151 Although chest aus- cultation may point to underlying lung pathology, the finding of pulmonary edema is not consistent with isolated ARHF. Instead, if pulmonary edema is pres- ent, it suggests ARHF combined with or secondary to LHF. In this setting, many of the common clinical findings of CRHF (see Chronic RHF) such as peripheral Table 4. Manifestations of RHF Clinical manifestations of RHF Increased mortality Fatigue/decreased functional capacity Cardiorenal abnormalities Cardiohepatic abnormalities Protein malnutrition Coagulopathy Cachexia Signs and symptoms Elevated jugular venous pressure with prominent V wave Peripheral edema Bloating/early satiety/abdominal discomfort Ascites and hepatomegaly Pleural effusion Prominent S 2 (P 2 ) (PH) Right-sided S 3 gallop Holosystolic murmur LLSB (TR) RV parasternal heave LLSB indicates left lower sternal border; PH, pulmonary hypertension; RHF, right-sided heart failure; RV, right ventricular; and TR, tricuspid regurgitation. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e593 CLINICAL STATEM ENTS AND GUIDELINES edema may initially be less prominent or absent al- together. Besides systemic hypoperfusion, prominent clinical findings in ARHF include shortness of breath resulting from diminished peripheral oxygen deliv- ery, as well as atrial and ventricular arrhythmias. On clinical examination, signs of ARHF include increased jugular venous pressure with a prominent v wave, prominent midprecordial cardiac impulse, right-sided third heart sound, and holosystolic murmur of TR. Hepatomegaly, ascites, and peripheral edema may be present when ARHF is superimposed on CRHF. Right upper quadrant discomfort may be caused by stretch of the hepatic capsule by hepatic congestion. If a pat- ent foramen ovale is present (≈15% of adults), right- to-left shunting at the atrial level can lead to systemic hypoxemia and cyanosis. Chronic RHF Peripheral edema is often the most prominent clinical feature in patients with CRHF63 (Table 4). Although pa- tients with early stages of CRHF may initially have mild symptoms, as RV function worsens, the reduction in CO leads to progressive exercise intolerance and fatigue. Atrial tachyarrhythmias are common in the setting of elevated RAP and can lead to hemodynamic deteriora- tion in CRHF.152 Ventricular tachycardia and heart block are additional electrophysiological complications and common causes of SCD in this population. In patients with PH, CRHF closely correlates with increased morbid- ity and mortality.114,153 The hemodynamic constellation driving the del- eterious effects of CRHF on end-organ function dif- fers between CRHF and primary LHF, the former rep- resenting a combination of increased central venous pressure (CVP) and reduced LV filling resulting from ventricular interdependence as a consequence of RV dilation.18,63 Recent studies have also suggested a pri- mary role for elevated CVP in the pathophysiology of end-organ dysfunction occurring in the setting of pri- mary LHF.39 In the later stages of CRHF when systemic output is reduced, impaired end-organ function may be caused by both elevated central venous filling pres- sure and reduced CO (Figure  7). Increased systemic venous pressure impedes lung lymphatic drainage, decreasing lung fluid clearance and exacerbating pul- monary edema and the development of pleural effu- sions in the setting of concomitant postcapillary PH.18 The organs most affected in CRHF are the kidneys and liver, with recent studies implicating the gastrointesti- nal tract.154,155 Cardiorenal Syndrome In patients with RHF, the increase in CVP and conse- quent rise in renal vein pressure worsen renal function, even in the absence of decreased CO (Figure 10).157 In- creased CVP has been identified as an independent risk factor for impaired renal function in patients with HF of diverse origins.39,157 Clinical features include decreased urine output, worsening fluid retention, and increased diuretic requirements.63 Laboratory abnormalities in- clude increased blood urea nitrogen and creatinine.63 Elevated and worsening levels of serum creatinine and blood urea nitrogen are independent predictors of ad- verse outcomes, unless they are accompanied by signif- icant decongestion in the setting of acute HF.158 These findings, connoting worsening renal function, may be causally linked to adverse outcomes or may, in part, represent epiphenomena connoting worsening HF and cardiac function. Furthermore, these findings may limit the clinician’s aggressiveness in pursuing diuresis and using guideline-directed medical therapy, includ- ing renin-angiotensin-aldosterone system–inhibiting agents, and may promote the use of inotropic agents with their associated deleterious effects. Considerable efforts to identify treatments that simultaneously re- solve congestion, improve clinical HF, and preserve or improve renal function have had limited success.159–161 Continued investigation into the interdependency of right-sided heart function and the cardiorenal syn- drome is warranted. Increasing evidence of acute kidney injury in the set- ting of elevated right-sided filling pressures may moti- vate clinicians to erroneously reduce loop diuretic ther- apy. However, this action may be deleterious because there is a proverbial “hump” one must get over to im- prove hemodynamics sufficiently that diuresis becomes increasingly effective. If the volume status is unclear or there is concern that the clinical presentation represents isolated RHF, then placement of a PA catheter may be informative. Cardiohepatic Syndrome The term congestive hepatopathy is a misnomer be- cause it generally results from a combination of he- patic congestion and reduced hepatic perfusion. Over time, congestive hepatopathy can lead to the devel- opment of cardiac cirrhosis.155,162 The most prominent laboratory abnormalities include markers of cholesta- sis (elevated bilirubin, γ-glutamyl transpeptidase, and alkaline phosphatase) and altered synthetic function (prolonged prothrombin time). These laboratory ab- normalities are more commonly encountered than el- evations in transaminases.163,164 Severity of TR has been found to be closely associated with liver function ab- normalities,165 and markers of cholestasis are indepen- dently associated with mortality among patients with HF.163,164 Likewise, hyperbilirubinemia is a risk factor for poor outcomes in patients with PH.166 In the set- ting of these abnormalities, patients being considered for advanced HF therapies such as cardiac transplan- tation may require a liver biopsy to exclude cirrhosis, D ow nloaded from http://ahajournals.org by on A pril 5, 2021 May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e594 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Konstam et al Evaluation and Management of Right-Sided Heart Failure particularly if hepatic imaging is also abnormal.167 Furthermore, patients with end-stage liver disease are at risk for the developing portopulmonary hyperten- sion, which is associated with worse outcomes after liver transplantation.168 Isolated and markedly elevated transaminases are more commonly caused by severely reduced CO/cardiogenic shock and respond better to inotropes than diuretic therapy. Increased serum am- monia is also associated with adverse prognosis in de- compensated HF.169 Gastrointestinal Involvement Gastrointestinal tract function can be impaired by RHF as a consequence of increased CVP and reduced CO, leading to reduced absorption and malnutrition.155,169 Splanchnic venous congestion with deficient abdominal Figure 10. Pathophysiology of cardiorenal disease: acute decompensated heart failure leading to kidney injury. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin-2 receptor blocker; CO, cardiac output; CVP, central venous pressure; GFR, glomerular filtration rate; LVEDP, left ventricular end-diastolic pressure; NSAID, nonsteroidal anti- inflammatory drug; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; and SV, stroke volume. Reproduced with permission from Kiernan MS, Udelson JE, Sarnak M, Konstam M. Cardiorenal syndrome: definition, preva- lence, diagnosis, and pathophysiology. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate.156 Accessed on January 30, 2018. Copyright © 2017, UpToDate, Inc. For more information, visit www.uptodate.com. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e595 CLINICAL STATEM ENTS AND GUIDELINES lymph flow causes interstitial edema with ensuing in- creases in intra-abdominal pressure that may contribute to RHF-induced renal failure.155,170 Visceral edema also impairs the barrier function of the intestine, allowing entrance of toxins produced by microorganisms in the gut lumen into the bloodstream, which can further sup- press cardiac and renal function and contribute to sys- temic inflammation.154,171 Protein-losing enteropathy, a complication most commonly associated with single- ventricle physiology, is also less commonly seen with other forms of RHF, including severe TR.172,173 Labora- tory abnormalities include reduced serum albumin and increased stool α 1 -antitrypsin. EVALUATION OF RHF Physical Examination Patients with severe RHF may appear emaciated, tachy- pneic, and cyanotic. Patients with significant RHF typically have elevated jugular venous pressure with a prominent V wave from TR. Atrial fibrillation is common. Those in sinus rhythm may have a prominent A wave caused by RV diastolic abnormalities. Increased jugular venous pressure with inspiration (Kussmaul sign) may also be seen with a noncompliant RV. The abdomino- jugular reflex test, defined as a sustained rise of >3 cm in the jugular venous pressure for at least 15 seconds with calm spontaneous respiration, may unmask subtle venous hypertension.174 A precordial RV heave, hepa- tomegaly and ascites, and lower extremity or presacral edema may be observed. For patients with RHF second- ary to PH, a prominent pulmonic component of the sec- ond heart sound (P 2 ) may be heard on auscultation. In contrast, for those with CHD, P 2 may be soft or even absent in cases when there is a structural or postsurgi- cal abnormality of the PV. A low-amplitude holosystolic murmur of TR may be present. An increase in the ampli- tude of the systolic murmur during inspiration (Carvallo sign) may distinguish TR from mitral regurgitation. For patients with CHD such as repaired TOF, there may be a to-and-fro murmur of combined PS and insufficiency at the upper left sternal border, with radiation to the lungs. Electrocardiographic Evaluation CRHF is often associated with right-axis deviation, R:S amplitude ratio of >1 in lead V 1 , R wave >0.5 mV in V 1 , and p-wave amplitude of >2.5 mm in II, III, aVF or >1.5 mm in V 1 indicative of RA enlargement (Figure  9B). ARHF may be associated with sinus tachycardia and a qR pattern in lead V 1 .175,176 An initial S deflection in I, initial Q deflection in III, and inverted T in III (SI, QIII, TIII) may point to acute RV strain such as in the case of large PE (high specificity, low sensitivity). Atrial arrhythmias, especially atrial flutter, are common. Serum Markers In CRHF, the transaminases may be normal or mini- mally elevated; however, in ARHF, transaminase levels are commonly high.177 In advanced CRHF, liver synthetic function may be impaired as evidenced by reduced al- bumin and elevated international normalized ratio. In- creased bilirubin can be related to passive congestion or cholestasis or could suggest the onset of fibrosis and cirrhosis. In more severe cases, venous congestion com- bined with systemic hypoperfusion can lead to renal insufficiency characterized by an elevation in the blood urea nitrogen and creatinine.39 Echocardiography Guidelines on the echocardiographic assessment of the RV are available elsewhere.178 There are limitations to the quantification of RV function by 2-dimensional echocardiography because of the complex geometry and retrosternal position of the RV, significant intrao- bserver variability, and load and angle dependence of standard imaging parameters, including TAPSE, RVFAC, and tricuspid annular systolic velocity by tissue Dop- pler.179 Although strain and strain rate are indepen- dent of ventricular morphology and angle independent when obtained by speckle tracking, these measures are intrinsically load dependent.180 RV strain imaging is be- coming an increasingly popular tool in the evaluation of PH and, when performed in experienced hands, is in- dependently prognostic.116,117 However, given the high variability in addition to a current lack of standardiza- tion and normative data, the American Society of Echo- cardiography does not yet recommend tissue Doppler imaging for this purpose.178 RV Size Compared with volumetric MRI, 2-dimensional mea- surements of RV size can be erroneous because of the complex shape of the RV.181 RV enlargement is suggest- ed if the RV area dimension is larger than the LV area in end diastole in the apical 4-chamber view. A linear RV basal dimension of >4.2 cm also suggests significant enlargement. RV end-diastolic wall thickness of >5 mm in the subcostal view indicates hypertrophy.178 RV Function RV motion is restricted mainly to longitudinal (base to apex) shortening and systolic thickening. Longitudi- nal shortening of the RV may be measured by TAPSE (normal reference limit ≥1.7 cm). TAPSE reflects systolic motion of a single point of tricuspid annulus, disregard- ing the contribution of mid, apical, and free wall seg- ments.178 Motion of the TV annulus is affected by prior cardiac surgery, which may render TAPSE less useful in this population. Additional measures of RV systolic dys- function include RVFAC <35% and RV tissue Doppler S’ D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e596 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES velocity <10 cm/s at the plane of the tricuspid annulus. Three-dimensional echocardiography is emerging as a potential alternative, perhaps more accurate, method of evaluating RV size and contractility.182,183 Close corre- lation exists between 3-dimensional echocardiography and MRI for RV size in patients with PH and CHD.184,185 RV diastolic dysfunction may be measured with tis- sue Doppler early diastolic myocardial velocity at the tricuspid lateral annulus (E) and early diastolic tricuspid inflow (E’) ratio (E/E’) as demonstrated in patients with PH.186,187 An estimate of PASP can be made by Doppler inter- rogation of TR, assuming an adequate Doppler enve- lope. PASP is calculated as the Doppler gradient across the TV plus estimated RAP. PASP may be underestimat- ed with poor ultrasound alignment and overestimated if the patient is anemic, as well as in cases when RAP is severely elevated. The TAPSE/PASP ratio has recently been proposed as a potential marker of RV-PA coupling because TAPSE reflects RV contractile function and PASP serves as a surrogate of afterload.188 This ratio was lower in sub- jects who died with a similar distribution in the HFrEF and HFpEF populations. The inferior vena cava diameter and collapsibility with respiration can be used to estimate RAP as a mark- er of volume status. Hepatic vein flow reversal indicates severe TR, whereas leftward interatrial septal bowing also indicates RAP or volume overload. Although vol- ume overload and pressure overload frequently occur simultaneously, diastolic septal flattening is associated with a volume-overloaded state, whereas systolic flat- tening is more consistent with pressure overload. Cardiac MRI Cardiac MRI offers 3-dimensional, tomographic imaging of the entire heart and has become the gold standard for quantitative noninvasive measurement of RV vol- ume, mass, and EF, including patients with CHD.189–193 Delayed gadolinium enhancement methods can iden- tify areas of RV fibrosis, although given the thinner wall of the RV, this may be more challenging compared with use for quantification of LV fibrosis. Dynamic real-time imaging during deep inspiration and expiration has been developed to detect RV volume changes and in- termittent interventricular septal flattening.194 Velocity- encoded methods also measure CO. Multidetector Computed Tomography Similar to cardiac MRI and 3-dimensional echocar- diography, multidetector computed tomography provides volumetric information about RV size and function.195,196 The high spatial resolution of contrast- enhanced computed tomography, combined with its rapid scan sequence, makes it an appealing modality for RV assessment. Limitations with computed tomog- raphy include the need to bolus potentially nephrotoxic iodinated contrast material and the need for ionizing radiation, which is a problem for radiosensitive patient populations, including children, and for serial surveil- lance studies. Although the patient must be able to lie flat and perform a breath hold, the scan process occurs over a shorter period compared with cardiac MRI. Fur- thermore, implanted devices do not prevent the use of computed tomography, and claustrophobia is rarely an issue given the short bore length. Radionuclide Imaging Radionuclide imaging can be used for the assessment of RV size, function, and infiltration.144 It is less fre- quently used for these purposes in the contemporary era given its poorer spatial resolution compared with other imaging modalities and the need for ionizing radiotracers. However, radionuclide ventriculography can be more accurate than echocardiography in mea- suring RV volumes given its reliance on count density rather than on geometric assumptions, which may be stymied by complex RV geometry. Increased RV uptake of [11F]-2-fluoro-2-deoxy-d-glucose has been described in cases of PH, including its potential utility in tracking response to pulmonary vasodilator therapy.197,198 Tech- netium pyrophosphate imaging is a sensitive means of detecting certain infiltrative processes, particularly car- diac involvement by transthyretin amyloidosis. It is most frequently used via ventilation/perfusion scan to screen for chronic thromboembolic PH in patients with PH and RV enlargement detected by other imaging modalities. Chest Radiograph In cases of significant RV enlargement, the cardiac sil- houette on a chest radiograph will have a globular ap- pearance. Loss of the retrosternal airspace on a lateral projection also indicates RV enlargement. Rightward displacement of the cardiac silhouette, well beyond the spine, almost always represents RA enlargement (the alterative being a giant left atrium). With coexisting PH, the main PA will be enlarged and the distal PA branches may have a “pruned” appearance.199,200 Elevated CVP may sometimes be recognized by an enlarged azygous vein. Pulmonary vascular redistribution, increased inter- stitial markings, and Kerley lines are signs of pulmonary venous hypertension, evidence of which often dimin- ishes as pulmonary vascular obstructive disease pro- gresses and signs of RHF dominate those of LHF in the presence of chronic biventricular failure. Pleural effu- sions are frequent in the presence of severe HF, particu- larly when pulmonary and systemic venous pressures are both elevated. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e597 CLINICAL STATEM ENTS AND GUIDELINES Hemodynamic Assessment of RV Function Several hemodynamic variables have been identified as risk factors for the development of RHF, predominantly after LVAD surgery (Table  5).77 As with imaging pa- rameters of RV function, hemodynamic correlates are largely inconsistent across studies. Elevated RAP, par- ticularly when this elevation is disproportionate relative to the rise in PCWP, is a marker of RVD.83,201 A normal RA/PCWP ratio is ≈0.5; higher ratios imply RVD.209,210 A preoperative RA/PCWP ratio >0.63 is associated with RHF after LVAD surgery.76 PA pulsatility is another po- tential correlate of RHF.203,204 PA pulse pressure index, defined as the ratio of PA pulse pressure (PASP minus PA diastolic pressure) to RAP, was recently proposed as a sensitive marker of disproportionate RVD and a pre- dictor of post-VAD RHF.203 This metric, however, has also yet to be validated in larger, prospective cohorts. RV stroke work index [(mean PAP−RAP)×SV index] is an established marker of RV function. SV index is calcu- lated by dividing cardiac index by heart rate. RV stroke work index is influenced by preload, however, and its calculation is dependent on multiple measured param- eters susceptible to acquisition error.201,211–213 Risk Models of RHF Durable mechanical circulatory assist devices are increas- ingly offered to patients with advanced HF as a bridge to transplantation or as long-term destination therapy.214 Despite technological advances in the use of continuous- flow LVADs, RHF remains a major cause of morbidity and mortality after LVAD implantation.179,215 Postoperative RHF can occur immediately, before the patient leaves the operating room, whereas in other cases, it may develop over weeks, months, or even years as a result of the pro- gression of underlying myocardial disease, worsening TR, or PH.84 Several clinical prediction scores have been developed to facilitate preoperative identification of pa- tients at risk for post-LVAD RHF.76,78,83,201,205,207,216 Age, vital signs, invasive hemodynamic metrics, echocardio- graphic parameters, indexes of end-organ function, and the need for cardiorespiratory support have been used to identify high-risk individuals. Although these scores perform well in their derivation cohorts, they perform less well in external validation studies.217 The complex physiology of RHF complicates accurate prediction of postoperative events, and these scores are unable to in- corporate intraoperative parameters or events that can precipitate ARHF. Such events include volume loading from transfusions and short-term increases in PVR sec- ondary to hypoxia, acidemia, or increases in airway pres- sure from mechanical ventilation.77 Furthermore, predic- tion models cannot model RV-LVAD interactions and the direct impact of LVAD hemodynamics on RV function, including volume loading of the right-sided circulation and geometric changes in the contractile pattern of the interventricular septum that affect RV SV.27 Other limita- tions of risk scores include the heterogeneity of popu- lations studied and the variability in definitions of RHF used.217 The overall clinical profile of the patient tends to be the strongest correlate of the failing RV, with greater acuity of illness being associated with more severe RHF. Severe RHF with diminished systemic perfusion is com- monly characterized by a state of vasodilation, inter- stitial fluid leakage, and systemic inflammation, poten- tially with fever in the absence of infection.218 Profound vasodilation can be present and should not be mistaken for alternative causes of distributive shock. Refractory cardiogenic shock is generally accompanied by severe biventricular dysfunction.219 Given the known limita- tions of echocardiographic and hemodynamic variables, no parameter in isolation can adequately identify clini- cally significant RHF with a high sensitivity or specificity. The assessment of RV function requires a multimodal- ity approach with careful evaluation of trends across hemodynamic, hematologic, and imaging parameters. Confidence in the clinical diagnosis of RHF increases when multiple parameters across modalities collectively suggest a state of RVD. Biomarkers to Assess RV Function There has been much interest in identifying biomarkers such as NT-proBNP (N-terminal pro-BNP) to help guide Table 5. Hemodynamic Assessment of RH Function Hemodynamic Parameters Associated With RV Function Variable Calculation Thresholds Associated With Clinical Events in Specific Populations RAP RAP (or CVP) >15 mm Hg (RHF after LVAD)83,201 Right-to-left discordance of filling pressures RAP:PCWP >0.63 (RHF after LVAD)76 >0.86 (RHF in acute MI)202 PA pulsatility index (PASP−PADP)/RAP <1.0 (RHF in acute MI)203 <1.85 (RHF after LVAD)204 RV stroke work index (MPAP−CVP)×SVI <0.25–0.30 mm Hg·L/m2 (RHF after LVAD)205,206 PVR (MPAP−PCWP)/CO >3.6 WU (RHF after LVAD)207 PA compliance SV/(PASP−PADP) <2.5 mL/mm Hg (RHF in chronic HF, RV-PA coupling in PAH)26,115 CO indicates cardiac output; CVP, central venous pressure; LVAD, left ventricular assist device; MI, myocardial infarction; MPAP, mean pulmonary artery pressure; PA, pulmonary artery; PADP, pulmonary artery diastolic pressure; PAH, pulmonary artery hypertension; PASP, pulmonary artery systolic pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RH, right-sided heart; RHF, right-sided heart failure; RV, right ventricular; SV, stroke volume; SVI, stroke volume index (SVI=cardiac index/heart rate); and WU, Woods units. Adapted with permission from Kapur et al.208 Copyright © 2017, American Heart Association. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e598 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Konstam et al Evaluation and Management of Right-Sided Heart Failure the identification and management of patients with HF. The focus, however, has historically been on iden- tifying patients with LV dysfunction.220 NT-proBNP may also be useful in patients with predominantly RHF but is relatively nonspecific.118,221 Likewise, elevated BNP is observed in both LH and right-sided heart dysfunction and is not a reliable marker to distinguish the level of dysfunction within each ventricle.222,223 BNP, however, has emerged as a useful marker of prognosis in RHF ac- companying PAH.224 The reliability of other biomarkers such as creatine phosphokinase-MB and troponins is less well established in the setting of RHF.225–227 Elevated BNP and troponin have adverse prognostic implications in the setting of acute PE.228,229 Several small, predominantly exploratory studies have examined RV-specific gene expression patterns, microRNAs, exosomes, and proteins associated with RHF, primarily in patients with CHD and PH.230–238 One study used unbiased RNA sequencing to identify several differentially expressed genes in patients with RVD.239 Of these, STEAP4, SPARCL1, and VSIG4 were differentially expressed between the RV and LV, suggesting their role as RV-specific biomarkers. Lewis et al240 identified 21 metabolites that were closely related to hemodynamic indexes of RVD using mass spectrometry–based meth- ods in 11 subjects with PH. Similarly, early animal stud- ies have identified unique microRNAs associated with RV but not LV failure.238,241 Identifying novel RV-specific biomarkers may lead to targeted therapies for RHF.242 MEDICAL MANAGEMENT OF ARHF Management of ARHF focuses on management of volume and preload, myocardial contractility, and RV afterload with pharmacotherapy and, if needed, MCS (Figure 11).243,244 Abnormalities in the pulmonary circu- lation and LV filling should be identified as targets for reducing RV afterload and augmenting RV function. Volume Management Volume management is a critical consideration in ARHF, and the volume status of the patient should be deter- mined on initial examination.245 A primary goal should be a reduction in left atrial pressure with an aim of reducing congestion and pulsatile RV loading.16 In the absence of gross volume overload, evident by findings such as pe- ripheral edema, careful inspection of the jugular venous pulsation should allow the clinician in most cases to de- termine the presence or absence of elevated CVP. This examination may be confounded by the large A waves of atrial contraction against a poorly compliant RV and large V waves caused by a poorly compliant RA or significant TR. Hemodynamic monitoring with a central venous cath- eter or PA catheter can be informative if the volume status is uncertain or if a patient has hemodynamic instability or worsening renal function in response to therapy.210,245 The teaching that ARHF is a preload-dependent condition requiring volume loading is overly simplistic. Figure 11. Management of acute right-sided heart failure. All management must be undertaken with an awareness of the patient’s hemodynamic status. If this status is not clear clini- cally, then invasive assessment/monitoring should be undertaken. Hemodynamic targets provide rough guidelines for tai- lored therapy. AV indicates atrial-ventricular; CI, cardiac index; CVP, central venous pressure; CVVHF, continuous venovenous hemofiltration; DCCV, direct current cardioversion; IV, intravenous; LV, left ventricular; MAP, mean arterial pressure; NS, normal saline; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PM, pacemaker; RAP, right atrial pressure; RHC, right-sided heart catheterization; RV, right ventricular; UF, ultrafiltration; and UOP, urine output. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e599 CLINICAL STATEM ENTS AND GUIDELINES Although it may be reasonable to consider a small in- travenous fluid bolus in the setting of ARHF compli- cated by hypotension, excess RV preload can lead to further clinical deterioration if it results in increased RV dilation, TR, RV afterload, and myocardial wall ten- sion causing ischemia.18,246–248 As the RV dilates, the interventricular septum is pushed leftward in diastole. Limits of pericardial compliance result in RV constraint, causing impaired LV filling and a reduction in CO. This ventricular-interdependent effect is often more impor- tant than impaired RVEF in reducing CO. If the CVP exceeds 8 to 12 mm Hg, the patient will likely benefit from decongestion to restore more favorable intraven- tricular loading conditions and normalized interventric- ular interaction.249 Invasive hemodynamic monitoring is very useful to help determine the optimal RAP needed to maintain appropriate preload. Decongestion leads to RV decompression, reduced ventricular interdepen- dence, downward displacement of the effective LV dia- stolic PV curve, improved LV filling, and augmentation of SV, CO, and BP. Diuretics Diuretic resistance can be a significant barrier to ef- fective therapy in the setting of acute decompensa- tion.250,251 Patients may not respond to high doses of intravenous loop diuretics because of a combination of factors, including elevated CVP and renal venous congestion, hypotension, low CO, and oliguric acute kidney injury.252 Although efficacy has not been clear- ly demonstrated, there is mounting evidence for the safety of an early, aggressive high-dose diuretic strat- egy, with rapid titration in patients failing to respond to initial interventions159,160 (Table 6253). It is reasonable to consider adding a thiazide diuretic to augment natri- uresis with intravenous loop diuretics.160,254 Aldosterone antagonists may help to maintain potassium homeo- stasis from potassium losses, although a trial of high- versus low-dose spironolactone in acute HF did not lead to improved clinical outcomes.255 Likewise, carbonic anhydrase inhibitors can improve the hypochloremic metabolic alkalosis resulting from aggressive loop and thiazide diuresis. Diuretics should not be held in a hypotensive patient who is clearly volume-overloaded. Hypotension in this setting is a marker of a critically ill patient, and mea- sures should be taken to support the BP with vasoactive therapies while concomitantly attempting to improve clinical congestion with diuretic or renal replacement therapies. Hypotension requiring vasoconstrictors and persistent poor hemodynamics should prompt strong consideration for MCS. Renal Replacement Therapies Among patients who fail to respond to escalating di- uretics therapy, continuous veno-venous hemofiltration or ultrafiltration may be needed to mechanically re- move intravascular volume.245,254 Care should be taken not to remove fluid at a rate that exceeds the ability of the body to shift extravascular fluid into the intravas- cular space (the plasma refill rate) because such an ex- cess is likely to result in new or worsening acute kidney dysfunction or injury.249 Markers of hemoconcentration include increases in hemoglobin, hematocrit, serum al- bumin, and total serum protein levels.158,256 Ultrafiltration, which refers to the removal of isoton- ic fluid from the venous compartment via filtration of plasma across a semipermeable membrane, has been evaluated for the treatment of acute HF in multiple tri- als, although not specifically targeting subjects with RHF. The UNLOAD trial (Ultrafiltration Versus IV Diuret- ics in Patients Hospitalized for Acute Decompensated Table 6. Stepped Pharmacological Care: Treatment Algorithm From the CARRESS-HF Trial Stepped Pharmacological Care Treatment Algorithm UO goals to be assessed daily from randomization to 96 h UO >5 L/d→reduce current diuretic regimen if desired UO 3–5 L/d→continue current diuretic regimen UO <3 L/d→see diuretic grid 24-h assessment UO recommendations as above Advance to next step on grid if UO <3 L/d 48-h assessment UO recommendations as above Advance to next step on grid if UO <3 L/d Consider dopamine or dobutamine at 2 μg·kg−1·h−1 if SBP <110 mm Hg and EF <40% or RV systolic dysfunction Consider nitroglycerin or nesiritide if SBP >120 mm Hg (any EF) and severe symptoms 72- and 96-h assessments UO recommendations as above Advance to next step on grid if UO <3 L/d Consider dopamine or dobutamine at 2 μg·kg−1·h−1 if SBP <110 mm Hg and EF <40% or RV systolic dysfunction Consider nitroglycerin or nesiritide if SBP >120 mm Hg (any EF) and severe symptoms Consider hemodynamic-guided IV therapy, LVAD, dialysis, or ultrafiltration crossover Diuretic Grid Suggested Dose Current Dose Daily Loop Dose Thiazide A <80 mg 40 mg IV bolus 5 mg/h None B 81–160 mg 80 mg IV bolus+10 mg/h 5 mg metolazone once daily C 161–240 mg 80 mg IV bolus+20 mg/h 5 mg metolazone twice daily D >240 mg 80 mg IV bolus+30 mg/h 5 mg metolazone twice daily CARRESS-HF indicates Cardiorenal Rescue Study in Acute Decompensated Heart Failure; EF, ejection fraction; IV, intravenous; Loop, loop diuretic dose in furosemide equivalents; LVAD, left ventricular assist device; RV, right ventricular; SBP, systolic blood pressure; and UO, urine output. Reproduced from Bart et al253 with permission. Copyright © 2012, Elsevier. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e600 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Congestive Heart Failure) showed that early ultrafiltra- tion produced greater weight and fluid loss compared with intravenous diuretics.257 The subsequent CARRESS- HF trial (Cardiorenal Rescue Study in Acute Decompen- sated Heart Failure), however, failed to demonstrate a benefit of ultrafiltration compared with a prescribed stepwise escalation of diuretic therapy based on uri- nary response in patients with acute HF and worsen- ing kidney function.253 The diuretic algorithm (Table 6) included high doses of loop diuretics via both bolus and continuous infusion, the addition of thiazide diuret- ics, and selected intravenous inotrope and vasodilatory therapy. The AVOID-HF trial (Aquapheresis vs Intrave- nous Diuretics and Hospitalizations for Heart Failure) was designed to clarify the role of ultrafiltration in the management of acute HF but was terminated prema- turely after the sponsor withdrew financial support.258 Whereas ultrafiltration may be helpful for fluid removal, available evidence does not support ultrafiltration as a first-line therapy for acute HF, and its use should be re- served for patients with persistent congestion refrac- tory to escalation of diuretic therapies. Vasoactive Therapies Vasoactive medical therapy plays an important role in the management of ARHF. Global goals of therapy in- clude reducing RV afterload, enhancing forward flow, and augmenting RV perfusion. There are few clinical trials to guide selection of vasoactive agents for ARHF, and most available data are from observational se- ries.248,259,260 Medication choice relies on clinician experi- ence, expert consensus opinion, and a firm understand- ing of the mechanism of action of chemotherapeutics and cardiovascular physiology. If a patient remains re- sistant to therapy, a PA catheter may be helpful to mea- sure biventricular filling pressures and CO.245 Afterload Reduction Correcting reversible causes of elevated PVR such as hy- poxia and acidosis is a primary consideration. By relax- ing vascular tone, vasodilators decrease systolic stress, enabling more effective systolic contraction. Nonselec- tive vasodilators, including intravenous nitroglycerin and sodium nitroprusside, decrease both PVR and sys- temic vascular resistance, augmenting RV and LV SV and facilitating decongestion of the pulmonary and systemic circulations.261–263 Conceptually, vasodilator therapy may also relieve renal venous congestion and augment renal perfusion, although this strategy has not had positive results when studied in patients with acute HF and cardiorenal disease.161 Both nitroglycerin and sodium nitroprusside have short half-lives, which is advantageous in the event of hypotension. Partially selective pulmonary vasodilators provide cli- nicians another option to decrease PVR in an effort to improve RV SV.261 For appropriately selected patients, available agents include inhaled and parenteral epo- prostenol and nitric oxide.260 When long-term use of pulmonary vasodilatory therapy is being considered, it should be recognized that adverse effects have been observed in patients with LH disease.264 Inhaled agents have the advantage of avoiding systemic hypotension and worsening ventilation/perfusion mismatch. In pri- marily observational studies, short-term use of inhaled nitric oxide resulted in lower PVR, increased RV ejection, less RV distension, and improved oxygen consumption in patients with PH,265–267 RVMI, or PE268,269 and after LVAD implantation.270–272 In chronic HF, however, aug- mented RV CO from inhaled nitric oxide administration can precipitate acute pulmonary edema caused by an abrupt increase in the filling of an already volume-over- loaded or poorly compliant LV.273 Oral agents include the phosphodiesterase-5 inhibi- tors (PDE5is). There are anecdotal reports of the ben- eficial impact of this class of medications on persistent PH after LVAD implantation complicated by ARHF,274 al- though these findings have been inconsistent.274,275 Augment Contractility In broad terms, inotropes augment myocardial con- tractility and augment failing RV SV while reducing RV end-diastolic volume and pressure. If the CO and BP are inadequate, inotropes should be considered to increase forward flow and possibly renal perfusion, recognizing the potential for inducing ischemia and ar- rhythmia.276 Milrinone and dobutamine have combined inotropic and vasodilator properties.277–279 Therefore, they can precipitate or worsen hypotension, although this is less likely if LV preload is adequate, and their use results in improved CO. Overall, direct comparisons of dobutamine and milrinone have shown similar clinical outcomes, including similar hemodynamic efficacy and arrhythmogenic potential.280,281 Compared with dobutamine, milrinone leads to greater reductions in RV and LV end-diastolic pressure because of its potent pulmonary and systemic vasodi- latory properties.282,283 In addition, milrinone less com- monly causes tachycardia and may be considered a more rational choice in the setting of concomitant β-blocker therapy. Patients are also less likely to develop drug toler- ance during prolonged infusions of milrinone. However, milrinone is more likely than dobutamine to provoke hypotension, particularly during bolus administration, which is subsequently less easily reversed by discontinua- tion of therapy. Given the long half-life, vasopressor sup- port may be necessary to counteract vasoplegia in this setting. In addition, milrinone is partially renally cleared, and the estimated glomerular filtration rate must be con- sidered in the determination of appropriate dosing. Dobutamine has the advantage of a short half-life with rapid onset and offset of effect when discontin- D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e601 CLINICAL STATEM ENTS AND GUIDELINES ued. It has only a modest direct vasodilator effect, me- diated through β 2 -adrenergic peripheral vasodilation and thus a lower propensity for causing hypotension. Accordingly, it also has less effect on RV and LV after- load. In rare cases, dobutamine can cause an eosino- philic myocarditis, which may result in further deterio- ration of cardiac function.284 Although short-term administration of inotropic agents leads to hemodynamic improvement, long-term administration is associated with increased myocardial oxygen consumption and possibly increased mortal- ity.276,285–288 Clinical guidelines recommend against the routine use of these agents in hospitalized patients with acute HF.245 Maintain Perfusion In cases of hypotension, a drug with combined ino- tropic and vasopressor properties may be necessary to maintain adequate perfusion. Studies comparing out- comes of vasoactive agents are limited.289 Given the inherent inotropic properties and a dose-dependent vasopressor effect from α 1 agonism, dopamine, nor- epinephrine, and epinephrine are useful adjuncts to augment contractility in the setting of significant hy- potension (systolic BP <80–90 mm Hg).290,291 Norepi- nephrine, for example, is a potent α 1 -receptor ago- nist with weaker β-receptor activity. Its administration leads to vasoconstriction with less prominent inotropic and chronotropic effects. Recognizing the downside of increasing ventricular afterload, cases of refractory hypotension caused by peripheral vasodilation not responding to initial inter- ventions may require the use of more pure vasopres- sors such as arginine vasopressin or phenylephrine.292 Arginine vasopressin causes peripheral vasoconstric- tion with less impact on PVR and has beneficial effects supporting glomerular filtration via selective efferent arteriole constriction.292,293 These agents can aug- ment mean arterial pressure to improve coronary ar- tery perfusion and to reduce the risk of RV myocardial ischemia. Furthermore, supportive care with arginine vasopressin may be beneficial to limit the arrhythmo- genic properties of catecholamines. Attempts should be made to wean off these treatments as rapidly as possible. MEDICAL MANAGEMENT OF CRHF Diuretics and Sodium Restriction Similar to ARHF, diuretics remain the mainstay of ther- apy to treat congestion in CRHF.109,245 The intensity of diuretic therapy needed may vary according to the pathogenesis and severity of RHF, in addition to other factors such as coexisting renal disease. Because pa- tients with RHF can have normal or low LV filling pres- sures, clinical monitoring is necessary to prevent the development of prerenal azotemia and worsening re- nal function. Akin to ARHF, the goals of volume man- agement in CRHF are to maintain sufficient preload for adequate cardiac filling while providing relief from RV volume overload, ventricular interdependence, and congestion. Patients with CRHF frequently require large diuretic doses because of neurohormonal activation, includ- ing upregulation of the renin-angiotensin-aldosterone system axis, resulting in fluid and sodium retention.294 Congestion leads to increased volume of distribution, visceral edema causing impaired drug absorption and tubular drug delivery, and rebound sodium absorp- tion in the hypertrophied distal nephron resulting from chronic Na-K-2CL blockade.252,295 Combination therapy including loop diuretics with thiazides may be helpful to augment natriuresis via sequential nephron blockade of sodium reabsorption.160 Compared with furosemide, torsemide has more consistent absorption, especially during decompensation, and may be a preferred loop diuretic in CRHF.295,296 According to the AHA/American College of Cardiol- ogy HF practice guidelines, sodium restriction is consid- ered reasonable for patients with symptomatic HF to re- duce symptoms of congestion.245 This recommendation is applicable to patients with symptomatic biventricu- lar failure or isolated RHF, but it should be noted that no large-scale studies have demonstrated the safety or efficacy of sodium restriction in these populations. Clinicians should consider some degree (ie, <3 g/d) of sodium restriction in patients with symptomatic CRHF, although insufficiency of data and inconsistency of rec- ommendations across guidelines make it difficult to provide precise recommendations.245,297 Similarly, fluid restriction (1.5–2 L/d) is considered reasonable in pa- tients with refractory congestion and hyponatremia.245 Renin-Angiotensin-Aldosterone System Inhibitors, β-Blockers, and Hydralazine Patients with biventricular dysfunction should be man- aged according to current practice guidelines for the management of chronic HF.245,298 In contrast to clear guidelines available for the management of HFrEF, less evidence is available to guide therapy of predominant RHF syndromes. Small-scale, single-center studies sup- port the use of β-blockers,299–307 renin-angiotensin-al- dosterone system inhibitors,308–311 and hydralazine,312 although results are inconsistent and vary across popu- lations, depending on the pathogenesis of RHF.313–315 Early studies with systemic vasodilators, including hy- dralazine, produced inconsistent hemodynamic benefits in patients with PH.312,316,317 These agents were also fre- quently associated with serious adverse events.318–320 At present, the use of angiotensin-converting enzyme in- hibitors, angiotensin-2 receptor blockers, and β-blockers D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e602 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES is not recommended in patients with PH regardless of RHF,321 unless associated with hypertension, coronary artery disease, or LHF.109 Prospective trials are also not available on the role of mineralocorticoid antagonists, including spironolactone, in the setting of RHF caused by PH. Digoxin Few studies have evaluated the use of digoxin use for CRHF. In early small studies, digoxin administration was associated with acute increases in CO or RVEF when ad- ministered to patients with PH and RVD.322–324 In other studies, digoxin in subjects with severe chronic airflow obstruction and RVD did not improve exercise capacity or RVEF.325 Likewise, a meta-analysis did not find digox- in to be associated with improvement in RVEF, exercise capacity, or New York Heart Association class.326 The clinical efficacy of digoxin remains unknown when ad- ministered long term in patients with RHF.327 Pulmonary Vasodilators RHF is the final common pathway of PH, and vasodilator therapy relieving RV afterload has led to improved out- comes among group 1 patients with RHF.109,110 Medical therapy is also now available for treatment of refractory group 4 disease because riociguat, a soluble guanylate cyclase stimulator, has been shown to improve exercise capacity and PVR in patients with persistent chronic thromboembolic PH after pulmonary endarterectomy or in patients with inoperable disease.328 Although some trials have investigated pulmonary vasodilator therapy in patients with LH disease (group 2), these tri- als have not specifically targeted patients with evidence of PH. Comprehensive guidelines for the treatment of PH are available elsewhere.109 The SOPRANO trial (Clini- cal Study to Assess the Efficacy and Safety of Maciten- tan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation; NCT02554930) is actively investigating the potential for macitentan to lower PVR after LVAD. Prostacyclin Analogs The role of pulmonary vasodilators with prostacyclin analogs has been extensively studied in patients with group 1 PH, a significant proportion of whom have RVD. Among patients with PAH, intravenous epopro- stenol has long-term clinical benefits, including im- proved survival and functional capacity.329,330 Compared with epoprostenol, other prostacyclin analogs, includ- ing treprostinil and iloprost, are more easily adminis- tered, have longer half-lives, and are able to be admin- istered subcutaneously or by inhalation, with similar pharmacological actions and comparable hemodynam- ic effects. These agents also improve exercise tolerance and HRQoL in group 1 PH.331–336 Parenteral prostanoids, however, remain the first-line therapy for patients with advanced disease.109,329 In contrast, epoprostenol resulted in increased mor- tality when used to treat patients with LHF. A study of patients with severe HFrEF was terminated early because of a strong signal of decreased survival in patients treat- ed with epoprostenol, despite increases in cardiac index and decreases in PCWP.264 Similarly, epoprostenol was not associated with improvement in distance walked or HRQoL in this population. The use of prostacyclin ana- logs is not recommended to treat group 2 PH.109 Phosphodiesterase-5 Inhibitors Oral PDE5is, including sildenafil and tadalafil, are estab- lished, effective, and well-tolerated therapy in patients with group 1 PH, either alone or as combination thera- py with other vasodilators.337–340 PDE5is are associated with improvements in pulmonary vascular remodeling, improvements in RV contractility, and antiproliferative effects. They are also associated with improvements in exercise capacity and reduced rates of clinical events in patients with group 1 PH.337–345 These trials did not specifically select patients with RHF. In smaller studies, PDE5i treatment has been dem- onstrated to improve exercise capacity, exercise hemo- dynamics, and HRQoL in patients with HFrEF and sec- ondary PH (group 2)346–349; however, these results await validation in large-scale multicenter randomized clinical trials. A multicenter trial of PDE5i treatment in patients with HFpEF failed to demonstrate improvement in exer- cise capacity or clinical status.350 This trial did not specif- ically select patients with evidence of PH or RHF. These agents are well tolerated and generally not associated with clinically significant reductions in BP, although decreases in BP may be accentuated by concomitant medications such as nitrates. This combination is specif- ically contraindicated. Although treatment with PDE5is is beneficial in patients with group 1 PH, their role in patients with isolated RHF or PH caused by LH disease remains uncertain. Endothelin Receptor Antagonists Endothelin-1, a potent vasoconstrictor, is implicated in the pathogenesis of PAH, and endothelin receptor an- tagonists targeting endothelin receptors type A and B have been extensively studied in group 1 PH. Whereas these studies did not explicitly select patients with PH with RHF, endothelin receptor antagonists are nonethe- less associated with improvements in HF symptoms, exercise capacity, hemodynamics, and time to clinical worsening in group 1 patients.351–357 Phase II studies of endothelin receptor antagonist administration in patients with HFrEF have documented short-term hemodynamic benefits.358,359 Unfortunately, phase III HFrEF trials failed to demonstrate improve- ments in morbidity or mortality in this population, D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e603 CLINICAL STATEM ENTS AND GUIDELINES and increases in hepatic aminotransferases were re- ported.360,361 Because of hepatic congestion commonly seen in RHF, monitoring of liver function should be per- formed routinely in patients receiving endothelin recep- tor antagonist therapy. Management of CRHF in CHD Despite the significant contribution of RHF to prema- ture morbidity and mortality in the acute CHD popula- tion, no adequately powered clinical trials have been completed to elucidate the role of medical therapies in this population. Furthermore, although many patients with acute CHD have RHF, these patients have typically been excluded from adult HF clinical trials. Thus, most standard HF therapies must be regarded as LV specific until proven otherwise. RHF resulting from pressure and volume loading may be seen after repair of TOF, pul- monary atresia, Ebstein anomaly, and pulmonary val- votomy for congenital PS.14 A thorough evaluation at a center specializing in HF of patients with CHD is recom- mended to identify and correct any hemodynamically- significant lesions contributing to RHF.362 Specific pop- ulations of patients with CHD with RHF are reviewed briefly, including those with systemic RVD (in whom the RV is subaortic) in patients with a 2-ventricle circulation, those with a single-ventricle Fontan palliation circula- tion in whom the single ventricle is of RV morphology, and patients with a subpulmonary RV who are at risk for RV failure resulting from chronic PS or insufficiency. Comprehensive guidelines for the management of CHD are available elsewhere.363,364 Patients with a systemic RV generally include those who have D-TGA that has been corrected with an atrial switch (Mustard or Senning) procedure or those with congenitally corrected L-TGA. A major determinant of survival in patients with a systemic RV is progressive systolic dysfunction of the systemic ventricle, which is often associated with progressive atrial-ventricular (tricuspid) valve regurgitation.147 Worsening atrial- ventricular regurgitation can lead to deterioration in systemic ventricular function.365,366 Atrial-ventricular valve repair or replacement can improve the course of disease, particularly if performed before a decline in systemic RVEF.364,367,368 Cardiac resynchronization therapy has also been proposed in patients with CHD and systemic RVD.369–371 These preliminary studies have demonstrated markers of clinical improvement and improvement in RV function, although larger, longer-term studies are necessary. Few studies have addressed the role of standard HF therapies in this population. Given the physiological and anatomic dif- ferences in the RV, the response of the RV to standard HF therapies remains uncertain. A number of small single-center reports suggest a potential clinical benefit of β-blockade in patients with systemic RV, including improvement in symptoms and functional capacity, less systemic atrial-ventricular valve regurgitation, and potential beneficial effects of reverse RV remodeling.301,372,373 However, in the largest clinical trial to date, carvedilol did not improve HF outcomes or echocardiographic measures of ventricular function in a randomized, double-blind, placebo-controlled study of children with systolic HF, including those with a sys- temic RV.374 Indeed, there was instead a nonsignificant trend toward worsening of ventricular function in those patients who had a systemic RV and were treated with the β-blocker. Unfortunately, this study was not pow- ered to fully address this question. Thus, routine use of β-blocker therapy cannot at this time be recommended in patients with systemic RVD375 and, if used, should be done so with caution. Furthermore, given an increased risk of sinus node dysfunction after atrial switch proce- dures in patients with D-TGA and a risk of heart block in those with L-TGA, β-blocker use requires close obser- vation in these populations.362 There have been a number of small prospective ran- domized trials of angiotensin-2 receptor blocker311,376 and angiotensin-converting enzyme inhibitor309,315,377 administration in patients a systemic RV secondary to D-TGA or L-TGA. These trials have demonstrated mixed results and generally have not demonstrated a clear benefit or renin-angiotensin-aldosterone system inhi- bition in this population.362 In a study of 26 patients with atrial switch repair for D-TGA, randomization to eplerenone was not associated with improvement in MRI parameters or RV function, although there was a trend toward improvement in biomarkers of collagen turnover.378 Patients with a single-ventricle circulation in whom the single ventricle is of RV morphology are at greater risk of HF than patients whose single ventricles are of LV morphology.379 Manifestations of a failing Fontan cir- cuit are variable and may include systemic venous con- gestion, protein-losing enteropathy, plastic bronchitis, and cirrhosis. It is important to evaluate for potentially reversible conditions of HF in patients with a Fontan op- eration such as a correctable mechanical obstruction.362 Even small pressure gradients in the low-pressure Fon- tan circuit can be deleterious to the single-ventricle circulation. Diuretics remain the mainstay therapy. In a multicenter randomized trial in infants with a single ventricle, enalapril did not improve ventricular func- tion, HF severity, or somatic growth, although the duration of follow-up was too short to assess longer- term benefits.380 Similarly, a randomized, double-blind, placebo-controlled crossover trial of enalapril did not demonstrate improvement in functional capacity or he- modynamic measurements.381 A crossover trial of oral sildenafil in patients with a Fontan circulation likewise did not lead to increased maximal oxygen consump- tion, although ventilatory efficiency was improved.382 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e604 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Small series of patients with protein-losing enteropathy report a benefit of mineralocorticoid receptor antago- nism with high-dose spironolactone.383,384 In a separate report, short-term therapy with spironolactone led to evidence of improved endothelial function and im- provement in cytokine profiles in patients with a Fontan operation.385 Data, however, remain limited. Finally, in patients with a pulmonary RV and CHD, for example, those after repair of TOF with a transan- nular patch or after repair of pulmonary atresia with an RV-PA conduit, the risk of RV dilation and RV failure persists. Few studies have shown definitive efficacy of any of the standard heart rate therapies in this patient population. In a study of adults with repaired TOF, the β-blocker bisoprolol did not improve echocardiographic or MRI parameters of RV size and function,386 and in a randomized trial of the angiotensin-converting enzyme inhibitor ramipril in repaired TOF and pulmonary regur- gitation, RVEF was not increased, although in a sub- group of patients with restrictive RV physiology, ramipril decreased LV end-systolic volume index and increased LVEF.387 In summary, current data do not support the rou- tine administration of standard HF drug therapies to patients with CHD with either a single RV or systemic RV or in patients with a pulmonary RV at risk for RV failure. Patients with CHD and HF should be cared for by clinicians with specific expertise in HF in the set- ting of CHD. Select patients may be considered for a trial of these LV-specific HF therapies with close moni- toring in these settings.238,388,389 Ultimately, many ap- propriately selected patients with refractory symptoms require consideration for heart or heart-lung trans- plantation.363 MCS AND TRANSPLANTATION FOR RHF MCS is reserved for patients refractory to optimal medi- cal management of acute or chronic RHF.327 Appropri- ate timing of intervention to prevent delays in institut- ing MCS therapy is critical to its success in optimizing patient outcomes and preventing unnecessary morbid- ity and mortality. MCS is used for bridge to recovery; bridge to heart, lung, or heart-lung transplantation; or, in unique cases, as destination therapy (ie, permanent use). Recent literature suggests that 42% to 75% of patients with acute forms of RHF may recover sufficient function to allow MCS device explantation.390–392 Thus, appropriate application of MCS is essential to maximize the possibility of myocardial recovery. The appropri- ate type of MCS device used for RHF is determined by whether the pathogenesis is a primary RV insult or is the result of disease of the pulmonary vasculature or LV (Figure  12). Typically, primary pathogeneses of the RV lend themselves to application with temporary implant- able or percutaneous VADs. ARHF secondary to obstructive diseases of the pul- monary vasculature may be more appropriately treated with extracorporeal membrane oxygenation (ECMO) as opposed to an RVAD because increased pulmonary blood flow from an RVAD will further increase PAP.393 There is a risk that when PH is present, excessive fur- ther increase in PAP could precipitate pulmonary hem- orrhage. ARHF caused by LHF is often more suitably treated with temporary or durable MCS support of the LV, alongside temporary or durable RV support if need- ed (biventricular assist device support). Not all patients with biventricular dysfunction need biventricular sup- port. However, determining which patients can be ade- quately supported by isolated LV support is challenging Figure 12. Mechanical circulatory support options based on the pathogenesis of right ventricular (RV) failure. A challenge in the management of patients with biventricu- lar dysfunction is discriminating between patients who have primary RV involvement necessitating true biventricular sup- port and those with right-sided heart failure caused primar- ily by left-sided heart disease. Among this latter group, left ventricular (LV) mechanical circulatory support alone may provide adequate cardiac support given secondary unloading of the RV after LV decompression. Clinician experience and estimations of the probability of recovery guide decisions on the need for durable vs temporary support devices. The pres- ence of pulmonary disease also influences device selection. BiVAD indicates biventricular assist device; ECMO, extracor- poreal membrane support; LVAD, left ventricular assist device and RVAD, right ventricular assist device. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e605 CLINICAL STATEM ENTS AND GUIDELINES and requires the expert review of a multidisciplinary HF team experienced with MCS. Patients with biventricu- lar dysfunction who receive isolated LV support should be closely monitored for clinical deterioration. Evidence of worsening RHF should lead to rapid deployment of RV mechanical support. Common indications for right- sided MCS use in ARHF include ARHF after LVAD, heart transplantation, RVMI, and myocarditis. Temporary Support Temporary MCS device options include newer percuta- neous devices designed specifically for RV support and include the Impella RP (Abiomed Inc, Danvers, MA)394 and TandemHeart pVAD395–397 with the PROTEK Duo398 cannula (TandemLife, Inc, Pittsburgh, PA) (Figure  13). The Impella RP is a microaxial temporary extracorporeal VAD that is placed percutaneously through the femoral vein and positioned with the distal tip in the PA. The microaxial pump positioned within the catheter drains blood from the RA and pumps it into the PA. The ef- ficacy and safety of this device were investigated in RECOVER RIGHT (The Use of Impella RP Support System in Patients With Right Heart Failure: A Clinical Safety and Probable Benefit Study), a prospective, multicenter, single-arm outcomes trial.394 Two groups of patients with RHF were enrolled, the first after LVAD placement and the second consisting of a mixture of patients af- ter cardiotomy, after transplantation, and with acute MI. The primary outcome was a combined end point of either survival at 30 days or hospital discharge or survival to next therapy (ie, transplantation or surgical RVAD). Thirty patients were enrolled with 73% survival to discharge. The major complication was postopera- tive bleeding, which occurred in 36.6% of patients. The PROTEK Duo398 cannula is a dual-lumen coaxial cannula positioned, via the internal jugular vein, with its distal tip in the PA and connected to an extracorpo- real centrifugal blood pump. Because of its internal jug- ular cannulation site, this configuration allows ambula- tion during support. These devices provide an option for MCS because of the ease of device insertion and removal, and they obviate the need for surgical ster- notomy. These devices have corresponding variations designed specifically to support the LV so that biventric- ular assist device support can be achieved completely with a percutaneous option.399,400 ECMO represents a viable alternative for acute MCS for ARHF that is either caused by primary RVD or is a consequence of PA disease, including in the presence of systemic oxygen desaturation.401 There has been a sig- nificant adoption of ECMO in adults.402 The benefits of ECMO are that it can be applied percutaneously at the bedside for initiation of emergent support, it provides biventricular support, and it addresses pathogeneses of the pulmonary system that are not addressed with isolated RV support. The more typical support configu- ration includes femoral venous drainage and arterial outflow to the femoral artery. This configuration can be achieved either percutaneously or by surgical pro- cedure. Other configurations, including internal jugular cannulation for venous drainage and arterial outflow to the axillary artery, are also feasible to facilitate am- bulation.401 An RVAD-like configuration with RA inflow to PA outflow with an oxygenator has also been de- scribed. The complications of ECMO have been well chronicled in the literature.401,403 Intermediate Support Surgical options of intermediate-term RV support re- main important, particularly for patients experiencing postcardiotomy failure to wean from cardiopulmo- nary bypass after open heart surgery, including heart transplantation, or for ARHF after implantation of a durable LVAD.76,216,392,404,405 Surgical implantation of an RVAD involves cannulation of the RA or RV for venous drainage and PA for arterial outflow. The cannulas are Figure 13. Mechanical circulatory support options for acute right ventricular (RV) support. LA indicates left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RVAD, right ventricular assist device; and VA- ECMO, veno-arterial extracorporeal membrane oxygenation. Adapted with permission from Kapur et al.208 Copyright © 2017, American Heart Association. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e606 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES connected to an extracorporeal centrifugal flow pump such as the CentriMag (Abbott Medical, Abbott Park, IL).392,406 Numerous reports detailing the use of a surgi- cally implanted temporary RVAD after LVAD have dem- onstrated that this strategy is effective in supporting the patient through severe ARHF during the postop- erative period. However, patients requiring RVAD af- ter implantation of a durable LVAD have consistently worse outcomes related to bleeding complications and hepatic and renal dysfunction compared with those who do not need an RVAD.76,205,214 Although effective, a surgical RVAD typically requires a repeat sternotomy if not placed at the same time as the LVAD, and a sec- ond surgery is usually required to remove the device at the time of RV recovery. Long-Term Support Long-term, durable MCS device options for irrecover- able forms of RHF are limited, and destination therapy for chronic advanced RHF is not well studied.407 Wheth- er MCS with newer, durable, implantable continuous- flow VADs could be of benefit in patients with refrac- tory CRHF with a contraindication to transplantation is unknown. The off-label use of durable MCS devices in the setting of RHF caused by chronic PH is controver- sial, and rigorous data on its efficacy in this setting are lacking. Typically, durable devices used for long-term or per- manent RV support have been designed for LV support, and their use for the RV represents an off-label or un- approved indication. The most frequently used durable VAD for chronic RV support has been the HeartWare HVAD (Medtronic, Inc, Minneapolis, MN), which is a small, continuous-flow centrifugal device with mag- netic and hydrodynamic levitation of the internal im- pellor.408 Small, single-center observational series have demonstrated successful application of this device for long-term RV support. Typically, the durable RVAD has been used in conjunction with a durable LVAD. The in- flow cannula of the device has been positioned within the diaphragmatic surface of the RV, anterior surface of the RV, or RA, with outflow connected to the PA. However, the use of durable continuous-flow rotary pumps for RV support raises many issues of feasibility, including the increased risk of thrombus generated in the venous system and embolizing to the pump. The total artificial heart (TAH) represents an alter- native therapy for biventricular support for the failing RV and LV. The most used TAH is the Syncardia TAH- t (Syncardia Systems, LLC, Tucson, AZ).408,409 The Syn- cardia TAH-t is a pneumatically-driven pulsatile device currently approved for bridge to transplantation in the United States. The device is available in 50- and 70-cm sizes and is being investigated for destination therapy indication. The use of the TAH may be advantageous over biventricular assist device support options in clini- cal situations such as ARVC, restrictive cardiomyopa- thies, biventricular failure with significant intraventricu- lar thrombus burden, very large body size, and failed transplantation.408 Transplantation In patients with advanced refractory CRHF, transplan- tation can be considered after the exclusion of all re- versible causes of CRHF and careful assessment of comorbidities, including cachexia, cardiac cirrhosis, chronic kidney disease, protein malnutrition, and other potential contraindications to transplantation. In pa- tients with PH and CRHF (RAP >15 mm Hg and a cardi- ac index <2.0 L·min−1·m−2), prognosis is generally poor, and referral for transplantation should be considered. In carefully selected patients with CRHF from severe pulmonary vascular disease, heart-lung or double-lung transplantation can be considered.18,110,363,410,411 Outcomes for isolated heart transplantation are generally excellent, and 1-year survival is ≈90% in the most recent era for all patients according to registry data.410,412 However, the presence of RVAD support be- fore heart transplantation is associated with a relative mortality hazard of 3.03 after transplantation.410 Simi- larly, outcomes have improved after lung transplanta- tion, with a 1-year survival of ≈84% for all patients re- ported in the most recent era.411 Palliative Interventions Balloon atrial septostomy (BAS) represents a percuta- neous option to treat RHF caused by severe PH, creat- ing a surgical right-to-left shunt to unload the RV. The associated decrease in systemic oxygenation must be outweighed by the increased oxygen delivery mediated by the increased CO. BAS is typically used as a bridge to lung transplantation or as a palliative measure in refrac- tory PH.413 Preoperative optimization of filling pressures is crucial, and periprocedural inotropic support may be necessary. BAS is contraindicated in severe RHF and should not be offered to patients with RAP >20 mm Hg, significant hypoxemia (<90% on room air), or PVR in- dex >4400 dynes·s·cm−5/m2. Surgical shunt placement between the left PA and descending aorta (Potts shunt) has also been described as a palliative intervention for refractory PH.414 SURGICAL MANAGEMENT OF VALVULAR LESIONS TV Surgery TR is a common valve disorder; however, data clarify- ing indications for interventions or outcomes after TV D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e607 CLINICAL STATEM ENTS AND GUIDELINES repair or replacement are less robust compared with disorders of the aortic or mitral valves. Severe TR (ef- fective regurgitant orifice >0.4 cm2) can result in sig- nificant symptoms and mortality but remains under- treated.101,415,416 Despite the morbidity and mortality associated with significant TR, patients are rarely re- ferred for isolated surgical intervention, and most sur- geries of the TV are performed in the context of other planned cardiac procedures. Patients with severe TR and signs or symptoms of CRHF are classified as having stage D TV disease.415 Recent data have demonstrated that isolated TV surgery can be performed with accept- able risk if patients undergo intervention before the onset of advanced HF or severe RVD.417 Patients with RHF caused by severe TR from implantable cardiovert- er-defibrillator or pacemaker leads should also be con- sidered for surgical evaluation.418 In the setting of concomitant valve disease, severe TR of either a primary or functional nature may not improve after treatment of the left-sided valve lesions and reduction of RV afterload.416 The addition of TV re- pair during surgery for left-sided valve disease does not add appreciable risk, whereas reoperation for severe, isolated TR after left-sided valve surgery is associated with a perioperative mortality rate of up to 25%.416 These observations have prompted clinicians toward a higher rate of TV intervention during surgery for left- sided valve disease. Moderate or even mild degrees of functional TR left uncorrected at the time of left-sided valve surgery may progress over time in approximately a quarter of patients and result in reduced long-term functional outcome and survival.419 Risk factors for per- sistence or progression of TR include TV annular dila- tation >40 mm or 21 mm/m2 on transthoracic echo- cardiogram, significant RVD or dilatation, significant tricuspid leaflet tethering, atrial fibrillation or PH at the time of left-sided valve surgery, rheumatic or functional origin of the mitral disease, or history of RHF.419 The overwhelming majority of cases requiring sur- gery for TR are amenable to repair. Singh et al420 demon- strated that TV repair is associated with improved peri- operative, midterm, and event-free survival compared with TV replacement for patients with organic tricuspid disease. Repair was associated with greater recurrence of TR, although reoperation rates and functional class were similar. Thus, repair should be pursued whenever possible.420 Repair should include an annuloplasty ring because it is associated with improved survival and event-free survival compared with other techniques not using an annuloplasty ring (eg, De Vega technique).421 The durability of TV repair may be limited, even in cir- cumstances when an annuloplasty ring is used, because of increased preoperative TV leaflet tethering height and area, low LVEF, and increased RV pressure. These factors are associated with a greater degree of TR dur- ing follow-up.421 Patients with significant tethering, sig- nificant distortion of the TV, significant RVD, or severe PH may require TV replacement to avoid long-term fail- ure of repair and worse clinical outcome. Percutaneous options for TV replacement may become available in the future.99,422 Although the impact of concomitant TV repair at the time of LVAD implantation on long-term outcomes remains poorly defined, anecdotally, most operators err toward addressing moderate or worse TR at the time of LVAD surgery.423–425 Recommendations from the AHA/American College of Cardiology guide- line for TV surgery are provided in Figure 14.415 Tricuspid Stenosis Surgery for severe tricuspid stenosis (TS) is generally performed in conjunction with surgery for left-sided valve disease, most commonly mitral valve stenosis. TS is usually caused by rheumatic heart disease; car- cinoid disease is a less common cause. TV surgery for relief of symptomatic TS is preferred over percutane- ous balloon tricuspid commissurotomy because most cases of severe TS have important concomitant TR (rheumatic, carcinoid, or congenital). Indications for surgery for TS include stage C or D TS characterized by T1/2 ≥190 milliseconds and valve area <1.0 cm2 with or without the presence of symptoms.415 Repair for primary TS is feasible but has a higher rate of need for reoperation. Pulmonary Insufficiency Significant PV regurgitation (PR) is uncommon but is most typically observed after surgery for TOF or other congenital lesions. Residual PR after repair of TOF is initially well tolerated but eventually contributes to RV enlargement, RVD, decreased exercise tolerance, in- creased incidence of arrhythmias, and increased risk of sudden death.363,426,427 PR is less commonly seen in association with infective endocarditis or carcinoid syndrome. Secondary PR after long-standing PH and annular dilation is uncommon. Primary treatment of PR in this setting should focus on the cause(s) of elevated PAP. Surgery for PR is considered when symptoms or signs of RVD have occurred and PR is severe. Surgery is generally recommended for asymptomatic severe PR in the setting of severe RV dilation or dysfunction (car- diac MRI–derived RV end-diastolic volume index >150 mL/m2, RV end-systolic volume index >80 mL/m2, RVEF <47%) or symptomatic atrial and ventricular arrhyth- mias.363,426,427 Current guidelines support surgery for se- vere PR along with (1) moderate to severe RVD (Class IIa; Level of Evidence B), (2) moderate to severe RV enlargement (Class IIa; Level of Evidence B), (3) symp- tomatic or sustained atrial and ventricular arrhythmias (Class IIa; Level of Evidence C), or (4) moderate to se- D ow nloaded from http://ahajournals.org by on A pril 5, 2021 May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e608 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Konstam et al Evaluation and Management of Right-Sided Heart Failure vere TR (Class IIa; Level of Evidence B). Transcatheter PV replacement is also now possible. In patients with concomitant severe TR undergoing transcatheter PV re- placement, transcatheter PV replacement resulted in a clinically relevant reduction in TR that persisted over 5 years of follow-up.428 Pulmonic Stenosis PS is typically caused by CHD. Acquired types are less common and include carcinoid disease or obstructing vegetations from endocarditis or obstructing tumors. PS may be treated with either percutaneous balloon PV commissurotomy or valve replacement. Surgical ther- apy, as opposed to percutaneous therapies, is recom- mended for patients with severe PS and associated hy- poplastic pulmonary annulus, severe PR, subvalvular PS, or supravalvular PS. Surgical therapy is also generally preferred for a dysplastic PV or when there is associated severe TR or the need for a surgical Maze procedure (Class I; Level of Evidence C).363 CONCLUSIONS AND FUTURE DIRECTIONS We must continue to enhance our understanding of pathophysiology. It is remarkable how misunderstood are some basic concepts of right-sided heart dysfunc- tion among practicing clinicians and the impact that such misunderstanding can have on appropriate pa- tient management. Acute right-sided heart syndromes such as acute RV infarction or acute PE must be rec- ognized principally as syndromes of impaired LH filling caused by direct ventricular interdependence to avoid excessive volume administration and to turn more rapidly to RV mechanical unloading and support. Like- wise, central and renal venous engorgement must be recognized as at least as important as impaired for- ward output in the pathogenesis of the cardiorenal syndrome. Our management of these conditions remains subop- timal, and new therapies, pharmacological and device based, should be sought. For example, as we continue to grow in our understanding of the interdependency of LH function, right-sided heart function, and renal he- modynamics, it may be possible to develop drugs and devices tailored to alleviation of diuretic resistance and the cardiorenal syndrome. Ultimately, however, it may be time that matters most because unrecognized and undertreated RHF inevitably results in sequelae of end- organ damage caused by chronic congestion and acute malperfusion. Early identification is critical to improve care targeting this complex syndrome, which remains frequently misjudged given the diverse pathways and pathological processes leading to its condition. Figure 14. Indications for surgery for tricuspid regurgitation (TR). Tricuspid annular (TA) dilation is defined by >40 mm on transthoracic echocardiography (>21 mm/m2) or >70 mm on direct intraoperative measurement. LV indicates left ventricular; PHTN, pulmonary hypertension; RV, right ventricular; TV, tricuspid valve; and TVR, tricuspid valve replacement. Reproduced with permission from Nishimura et al.415 Copyright © 2014, American Heart Association. D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e609 CLINICAL STATEM ENTS AND GUIDELINES We should improve our ability to distinguish among RHF caused by LHF, pulmonary vascular obstructive dis- ease, and intrinsic RV pathology through novel hemody- namic indexes and biomarkers of load-dependent and load-independent forms of RHF. Although we currently define pulmonary vascular obstruction as either fixed or reversible, perhaps the notion of fixed pathology mere- ly connotes our pathophysiological naiveté. Improved understanding of the pathobiology of pulmonary mi- crovascular disease will lead us to novel approaches for reversing fixed pathology. Although we have come a long way in RV imag- ing, more advances are warranted, particularly in re- lating measures of systolic and diastolic performance to indexes of load. Although we have made enormous strides in advanced MCS, we continue to struggle with patients who have biventricular disease. There is room for considerable advance in biventricular support tech- nologies, particularly durable devices with applicability to broader patient populations. We have seen progressive advances in our under- standing and managing of RHF, but we have much more to learn. The future holds many diagnostic and therapeutic advances that will markedly expand our ability to tackle these many complex clinical challenges. ARTICLE INFORMATION The American Heart Association makes every effort to avoid any actual or po- tential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on October 27, 2017, and the American Heart Association Executive Committee on December 11, 2017. A copy of the document is available at http://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The American Heart Association requests that this document be cited as follows: Konstam MA, Kiernan MS, Bernstein D, Bozkurt B, Jacob M, Kapur NK, Kociol RD, Lewis EF, Mehra MR, Pagani FD, Raval AN, Ward C; on behalf of the American Heart Association Council on Clinical Cardiology; Council on Car- diovascular Disease in the Young; and Council on Cardiovascular Surgery and Anesthesia. Evaluation and management of right-sided heart failure: a scientific statement from the American Heart Association. Circulation. 2018;137:e578– e622. DOI: 10.1161/CIR.0000000000000560. The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements. Select the “Guide- lines & Statements” drop-down menu, then click “Publication Development.” Permissions: Multiple copies, modification, alteration, enhancement, and/ or distribution of this document are not permitted without the express permis- sion of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright-Permission- Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page. Disclosures Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers’ Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Marvin A. Konstam Tufts Medical Center None None None None None None None Michael S. Kiernan Tufts Medical Center None None None None None Abbott*; Medtronic* None Daniel Bernstein Stanford University Department of Defense (grant to explore mechanisms of defective angiogenesis in right ventricular failure)† None None None Regencor* None None Biykem Bozkurt Baylor College of Medicine and MEDVAMC None None None None None None None Miriam Jacob Cleveland Clinic Foundation Heart and Vascular Institute None None None None None None None Navin K. Kapur Tufts Medical Center None Abiomed†; Cardiac Assist†; St. Jude (preclinical research)†; Maquet (translational research)† Abiomed†; Heartware*; Maquet*; St. Jude* None None Abiomed*; Cardiac Assist*; Maquet*; St. Jude* None Robb D. Kociol Beth Israel Deaconess Medical Center DCRI (steering committee– connect–HF)* HFSA (executive board, speaker at meeting) * AHA spotlight series–HF* None None None None Eldrin F. Lewis Brigham & Women’s Hospital Amgen†; Novartis†; Sanofi† None None None None Novartis† None (Continued ) D ow nloaded from http://ahajournals.org by on A pril 5, 2021 mailto:kelle.ramsay@wolterskluwer.com May 15, 2018 Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560e610 CL IN IC AL S TA TE M EN TS AN D GU ID EL IN ES Konstam et al Evaluation and Management of Right-Sided Heart Failure Mandeep R. Mehra Brigham and Women’s Hospital and Harvard Medical School None Heart Failure Society of America (president)*; International Society for Heart and Lung Transplantation (editor- in-chief of the Journal of Heart and Lung Transplantation)† None None NuPulse, Inc† Abbott*; Johnson and Johnson (Janssen)*; Medtronic*; Mesoblast*; Portola* None Francis D. Pagani University of Michigan Health System Cardiac Surgery None None None None None None None Amish N. Raval University of Wisconsin None None None None None None None Carey Ward Duke University None None None None None None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. *Modest. †Significant. Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers’ Bureau/ Honoraria Expert Witness Ownership Interest Consultant/Advisory Board Other Robert P. Frantz Mayo Clinic None None None None None Actelion (unpaid)*; Arena Pharmaceuticals*; Bayer (unpaid)*; Abbott*; Novartis*; United Therapeutics (unpaid)* None Jason N. Katz University of North Carolina None None None None None None None Robert L. Kormos University of Pittsburgh None None None None None None None Gregory D. Lewis Massachusetts General Hospital NHLBI (investigation of markers of right ventricular dysfunction)†; NHLBI (evaluation of metabolic disease in relation to pulmonary hypertension in heart failure)* Bayer (clinical trial research)† None None None Ironwood* None Myung Park Houston Methodist DeBakey Heart & Vascular Center None None Bayer* None None Actelion*; Bayer* None This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. *Modest. †Significant. Writing Group Disclosures Continued Writing Group Member Employment Research Grant Other Research Support Speakers’ Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other D ow nloaded from http://ahajournals.org by on A pril 5, 2021 Konstam et al Evaluation and Management of Right-Sided Heart Failure Circulation. 2018;137:e578–e622. DOI: 10.1161/CIR.0000000000000560 May 15, 2018 e611 CLINICAL STATEM ENTS AND GUIDELINES REFERENCES 1. Mehra MR, Park MH, Landzberg MJ, Lala A, Waxman AB; International Right Heart Failure Foundation Scientific Working Group. Right heart failure: toward a common language. J Heart Lung Transplant. 2014;33: 123–126. doi: 10.1016/j.healun.2013.10.015. 2. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. 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