key: cord-0699530-d9ho8uxu authors: Çalışkan, Mustafa; Baycan, Ömer Faruk; Çelik, Fatma Betül; Güvenç, Tolga Sinan; Atıcı, Adem; Çağ, Yasemin; Konal, Oğuz; İrgi, Tuğçe; Bilgili, Ümmühan Zeynep; Ağırbaşlı, Mehmet Ali title: Coronary microvascular dysfunction is common in patients hospitalized with COVID‐19 infection date: 2022-05-03 journal: Microcirculation DOI: 10.1111/micc.12757 sha: 09ffe656da32f5d14f21fa7b98477b8f833ca907 doc_id: 699530 cord_uid: d9ho8uxu BACKGROUND AND AIMS: Microvascular disease is considered as one of the main drivers of morbidity and mortality in severe COVID‐19, and microvascular dysfunction has been demonstrated in the subcutaneous and sublingual tissues in COVID‐19 patients. The presence of coronary microvascular dysfunction (CMD) has also been hypothesized, but direct evidence demonstrating CMD in COVID‐19 patients is missing. In the present study, we aimed to investigate CMD in patients hospitalized with COVID‐19, and to understand whether there is a relationship between biomarkers of myocardial injury, myocardial strain and inflammation and CMD. METHODS: 39 patients that were hospitalized with COVID‐19 and 40 control subjects were included to the present study. Biomarkers for myocardial injury, myocardial strain, inflammation, and fibrin turnover were obtained at admission. A comprehensive echocardiographic examination, including measurement of coronary flow velocity reserve (CFVR), was done after the patient was stabilized. RESULTS: Patients with COVID‐19 infection had a significantly lower hyperemic coronary flow velocity, resulting in a significantly lower CFVR (2.0 ± 0.3 vs. 2.4 ± 0.5, p < .001). Patients with severe COVID‐19 had a lower CFVR compared to those with moderate COVID‐19 (1.8 ± 0.2 vs. 2.2 ± 0.2, p < .001) driven by a trend toward higher basal flow velocity. CFVR correlated with troponin (p = .003, r: −.470), B‐type natriuretic peptide (p < .001, r: −.580), C‐reactive protein (p < .001, r: −.369), interleukin‐6 (p < .001, r: −.597), and d‐dimer (p < .001, r: −.561), with the three latter biomarkers having the highest areas‐under‐curve for predicting CMD. CONCLUSIONS: Coronary microvascular dysfunction is common in patients with COVID‐19 and is related to the severity of the infection. CMD may also explain the “cryptic” myocardial injury seen in patients with severe COVID‐19 infection. SARS-COV-2 is a novel betacoronavirus that have infected over 177 million individuals and claimed 3.9 million lives globally. 1, 2 Cardiac involvement in patients with moderate-to-severe COVID-19 infection ranges from asymptomatic myocardial damage to overt myocarditis and myocardial infarction secondary to epicardial coronary artery disease (CAD). [3] [4] [5] [6] [7] Myocardial damage is somewhat common in patients hospitalized for COVID-19. While some cases can be explained with histologically proven myocarditis or epicardial CAD, in most instances the origin of this damage is uncertain. 8 Coronary microvascular dysfunction has been suggested as a possible cause of myocardial injury in COVID-19 patients, as studies have suggested presence of microvascular dysfunction in other vascular beds and there is histologic evidence for SARS-COV-2-associated endotheliitis in specimens obtained from heart, lung, kidney, liver, and other tissues. 9, 10 However, this is an indirect assumption as there are no data so far to suggest coronary microvascular dysfunction (CMD) in COVID-19 patients. Cardiac microvascular dysfunction could be investigated with several invasive or non-invasive methods. [11] [12] [13] [14] Coronary flow velocity reserve (CFVR), which can be obtained by comparing velocities obtained before and after administration of a vasodilator agent, is the primary method of assessing CMD with echocardiography. Importantly, echocardiography allows making bedside measurements, which is usually the optimal method for assessing CMD in most patients. In the present study, we aimed to understand whether patients hospitalized with COVID-19 had echocardiographically demonstrable CMD as compared to healthy individuals, and whether CMD is related to other pathophysiological processes such as myocardial injury, fibrin turnover, or inflammation. Present study is a cross-sectional case-control study performed in a single academic center. Patients aged between 20 and 60 years that were diagnosed with COVID-19 infection and hospitalized with this diagnosis were included. Patients that were past or current smokers, those with known coronary artery disease or diabetes, those with a history of heart failure due to any cause and patients on any kind of vasoactive drugs that might affect CFVR measurements were excluded. In addition, patients with a suboptimal image quality on echocardiography or patients with a condition that contraindicates administration of dipyridamole (such as asthma) were excluded. 50 COVID-19 patients were initially screened but 11 patients were excluded after applying these exclusion criteria. 40 age-and gender-matched subjects without a previous history of COVID-19, no active symptoms and had a negative nasopharyngeal swab for COVID-19 were enrolled as controls. Demographic, clinical and laboratory parameters were recorded with direct interviews and with using institutional electronic medical database. The study was conducted according to the 1975 Helsinki and its subsequent revisions. All patients gave their informed consent, and the study was approved by a local ethics committee. All echocardiographic examinations were performed with an ultrasound platform equipped with a matrix-array transducer (X5-1, Philips Epiq 7, Philips Healthcare). Chamber quantification and other measurements were done according to the relevant international guidelines. For coronary flow measurements, distal part of the left anterior descending artery (LAD) was visualized using high ultrasound beam frequency (5) (6) (7) . The color Doppler gain was optimized using conventional techniques, and the Nyquist limit was set to 0.16-0.50 m/s. After visualization of the distal part of the LAD, pulse-wave Doppler cursor was placed to measure coronary flow velocity and measurements were done before and after dipyridamole infusion (0.84 mg/kg for 6 min). Patients were monitored during the procedure, and heart rate and blood pressure data were recorded at baseline, during infusion, and after the procedure. Coronary flow velocity reserve was calculated as the ratio of the hyperemic peak flow velocity to the resting peak flow velocity. Patients with a CFVR <2.0 were accepted as having CMD. 13, 15 We have previously reported interobserver and intraobserver variability values for our laboratory. 16, 17 All echocardiographic examinations, including CFVR measurements, were performed immediately after the stabilization of the patient. For patients that needed intubation or intensive unit care due to any cause, echocardiographic examinations were delayed until the patient was transferred to the ward. Theophylline and similar drugs, as well as caffeine-containing beverages, were discontinued for 24 h before the procedure. All patients included in the present study had: i) A positive nasopharyngeal swab for COVID-19, ii) thoracic CT findings compatible with COVID-19 pneumonia, and iii) hospitalized due to COVID-19 infection. Patients fulfilling one or more of the following criteria were accepted as severe COVID-19 infection: i) A respiratory rate >30 breaths/minute signifying respiratory distress, ii) a resting oxygen saturation 93% or less, iii) ratio of partial arterial oxygen saturation to the fraction of inspired oxygen <300 mmHg, and iv) respiratory failure or a critical life-threatening complication of COVID-19 necessitating admission to intensive care unit. Patients who did not fulfill these criteria were accepted as having a moderate COVID-19 infection. Subjects within the control group had a negative nasopharyngeal swab for COVID-19, with or without a negative CT scan for COVID-19 pneumonia. Nasopharyngeal swabs were obtained at admission, and COVID-19 infection was diagnosed with real-time reverse-transcription PCR using Coronex COVID-19 rt-qPCR detection kit (Gensutek Inc). For all other tests, blood samples were obtained immediately after the diagnosis of COVID-19 was ascertained with a positive PCR test and a thorax CT scan compatible with COVID-19 pneumonia. Interleukin-6 concentration was determined with electrochemiluminescence immunoassay method, using Elecsys IL-6 biochemical analysis kits and Roche Cobas 6000 analysis device (Roche Diagnostics). Other laboratory analyses were done with conventional methods. Data for continuous parameters were given as mean ± SD or median and interquartile range, depending on the distribution of the data. Demographic, clinical and laboratory characteristics of the study groups were summarized in Table 1 . COVID-19 (+) patients had a higher systolic and diastolic blood pressure and a lower oxygen saturation, as well as higher fibrinogen, ferritin, and d-dimer concentrations at baseline. To note, there were no significant differences between patients in terms of age, gender, obesity, or other evaluated risk factors for atherosclerosis. Echocardiographic characteristics and coronary flow measurements of the study groups were summarized in Table 2 . Conventional echocardiographic measurements were not different between groups, except for a significantly higher left atrial diameter in the COVID-19 (+) group. Basal diastolic peak flow velocity (DPFV) was similar between groups, but hyperemic DPFV was significantly lower in patients with COVID-19, leading to a statistically significant difference for CFVR between groups. Both basal and hyperemic heart rates were higher in the COVID-19 (+) group, but both findings did not reach statistical significance. Patients with severe COVID-19 infection were more likely to have a higher respiratory rate, lower oxygen saturation, and higher fibrinogen concentration as compared to patients with moderate COVID-19 infection and controls (Table 3) , and both BNP and troponin concentrations were higher in patients with severe COVID-19 infection as compared to those with moderate disease (Table S1 ). Despite these differences, conventional echocardiographic parameters of left ventricular structure or systolic/diastolic functions were not different between groups ( Table 4) . Patients with severe COVID-19 had a significantly lower CFVR as compared to both moderate COVID-19 group and controls. As compared to the controls, patients with severe COVID-19 had a significantly lower hyperemic DPFV (Table 4 ). In contrast, post hoc comparisons between patients with moderate and severe COVID-19 did not show a statistically significant difference for either basal or hyperemic DPFV, although there was a trend toward higher basal DPFV in the latter subgroup (p = .07 in the pairwise comparison). While there was also a trend toward lower hyperemic DPFV in patients with moderate COVID-19 as compared to the control group, this finding did not reach statistical significance (p = .15 in the pairwise comparison). Coronary flow velocity reserve showed a significant negative correlation with proinflammatory biomarkers, as well as with B-type natriuretic peptide (BNP), d-dimer, and troponin. Of those, CFVR had a weak to moderate correlation with C-reactive protein (p < .001, In the overall study population, saO 2 correlated with hyperemic DPFV (r = .295, p = .01) and CFVR (r = .532, p < .001) but not with basal DPFV (Figure 3 ). However, after adjustment for the presence of COVID-19, neither hyperemic DPFV nor CFVR had a statistically significant correlation with saO 2 (p = .47 and p = .06, respectively). In contrast, COVID-19 positivity remained as a statistically significant predictor of CFVR after adjusting for saO 2 (p = .002 and p < .001, respectively). In the subgroup of patients with COVID-19, saO2 correlated with both basal DPFV (r = −.398, p = .012) and CFVR (r = .69, p < .001), but not with hyperemic DPFV (Figure 4) . However, after adjusting for the severity of the COVID-19, both correlations lost their statistical significance (p = .81 for basal DPFV and p = .94 for CFVR). Similar to the previous analysis, the association between the severity of COVID-19 infection and basal DPFV/CFVR remained significant after adjusting for saO 2 (p = .04 and p < .001, respectively). It has been suggested that COVID-19 is a disorder of the microvasculature. Given that microvascular dysfunction is seen in the subcutaneous and retinal vasculature in COVID-19 patients, several investigators have speculated that the same should also be true for the coronary microvasculature, but direct evidence was missing so far. [18] [19] [20] [21] Present study supports the validity of this latter hypothesis, since our findings indicate that CFVR, which is a measure of CMD, is lower in COVID-19 patients. Moreover, these findings also indicate a relationship between several biomarkers (including troponin) and is widely though as the cause of hypercoagulability that is typically seen in COVID-19. 18, 27 It may also underlie CMD in COVID-19 given that microvascular thrombosis and obstruction reduce recruitable capillaries, which in turn leads to microvascular dysfunction. 27, 28 Finally, overactivation of inflammatory pathways with accompanying "cytokine storm," which is somewhat common in patients with severe COVID-19, can exacerbate endothelial dysfunction by either worsening endothelial inflammation or by activating prothrombotic cascades. 18, 29 Probably not a single pathway is responsible for the Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BNP, brain natriuretic peptide; CRP, C-reactive protein; DAP, diastolic arterial pressure; DM, diabetes mellitus; GFR, glomerular filtration rate; HDL, high-density lipoprotein; HT, hypertension; LDL, low-density lipoprotein; RR, respiratory rate; saO 2 , blood oxygen saturation; SAP, systolic arterial pressure; TC, total cholesterol; WBC, white blood cell. unethical. As such, present results were obtained from the best time frame that CMD can be evaluated without harming a patient. Our study had several limitations. This is a single-center study with a small sample size and a cross-sectional design. While controls did not have active infection at the time of echocardiographic evaluation, past asymptomatic infections (which might or might not affect microvascular function) cannot be excluded. As correlation does not imply causality, present findings do not show that inflammation or prothrombotic milieu causes CFVR or CFVR leads to myocardial injury but rather suggest an association between them. Also, elevation of an inflammatory/ thrombotic biomarker does not show an organ-specific condition but rather reflects an overall inflammatory or prothrombotic state. Thus, present findings should be interpreted in this context. Patients with COVID-19, particularly those with severe infection, have a reduced hyperemic coronary flow and CFVR indicating the presence of CMD. The degree of CMD correlates with biomarkers of inflammation, fibrin turnover, myocardial injury, and myocyte stretch, though it remains to be determined whether these associations represent causal relationships between inflammation, thrombosis, microvascular dysfunction, and finally myocardial injury. Further work is needed to understand the clinical importance of these findings, as well as therapeutic approaches to prevent or treat CMD in COVID-19 patients. Not applicable. The data are available from the corresponding author upon reasonable request. 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