Correlation between structural heart disease and cardiac SARS-CoV-2 manifestations

Abstract

Background: The prognosis of COVID-19 patients with cardiac involvement is unfavorable and it remains unknown which patients are at risk. The virus enters cells via its receptor angiotensin-converting enzyme 2 (ACE2). Myocardial ACE2 expression is increased in structural heart disease (SHD). We, therefore, aimed to analyze correlations between structural heart disease and cardiac SARS-CoV-2 manifestation.

Methods: The clinical course of COVID-19 in patients with structural heart disease was assessed in a prospective cohort of 152 patients. The primary endpoints consisted of hospitalization and survival. Cardiac tissue of 23 autopsy cases with lethal COVID-19 course was obtained and analyzed for (a) the presence of SHD, (b) myocardial presence of SARS-CoV-2 via RT,-PCR, and (c) levels of ACE2 expression using immunofluorescence staining.

Results: Structural heart disease is found in 67 patients, of whom 56 (83.60%) are hospitalized. The myocardium is positive for SARS-CoV-2 in 15 patients (65%) in 23 autopsy cases of lethal COVID-19. Moreover, most hearts with evidence of myocardial SARS-CoV-2 have structural heart disease [11 (91,67%) vs. 1 (8,33%), p = 0.029]. Myocardial presence of SARS-CoV-2 is correlated with a significant downregulation of ACE2 compared to negative control hearts (6.545 ± 1.1818 A.U. vs. 7.764 ± 2.411 A.U., p = 0.003). The clinical course of patients with cardiac SARS-CoV-2 manifestation is unfavorable, resulting in impaired survival (median, 12 days and 4.5 days, respectively, HR 0.30, 95% CI, 0.13 to 0.73, p = 0.0005) CONCLUSIONS: We provide evidence for a correlation between SHD, altered ACE2 receptor expression, and cardiac SARS-CoV-2 manifestation. Consequently, structural heart disease may be considered a distinct risk factor for a severe clinical course after infection with SARS-CoV-2.

Registration number local irb: Ethics Committee of Northwestern and Central Switzerland ID 2020-00629; Ethics Committee of the Medical University Innsbruck EK Nr: 1103/2020.

Gov number: NCT04416100.

Fig. 1. Relationship between structural heart disease and hospitalization rates upon SARS-CoV-2 infection.

A significant relationship between pathological echo findings and hospitalization rate in 152 patients who tested positive for SARS-CoV-2 could be found (p < 0.0002, Chi-square test).

Fig. 2. Histopathological signs of cardiac hypertrophy in correlation to SARS-CoV-2 infections.

A Patients suffering from structural heart disease showed higher rates of cardiac SARS-CoV-2 infections. (p = 0.0289, Chi-square test). B Representative histopathological images of Hematoxylin/Eosin stained tissue sections from hypertrophic and non-hypertrophic hearts.

Fig. 3. Altered ACE2 expression upon cardiac SARS-CoV-2 infection.

A Cardiac ACE2 staining intensity was significantly downregulated in hearts with cardiac SARS-CoV-2 viral load (p = 0.003, Unpaired t-test, n = 5 high-power fields per section). B Representative immunofluorescence images of ACE2 and alpha-actinin stained tissue sections from hearts without and with cardiac SARS-CoV-2 infections.

Fig. 4. Cardiac ACE2 and cytokine expression levels correlate with cardiac viral load.

A Increased SARS-CoV-2 spike protein RNA expression is significantly correlated with reduced gene expression levels of ACE2 and increased cytokine expression levels of B TNFa, C IL6, and D IFNa (Spearman’s rank correlation, regression slopes are represented by black lines, grey area represents 95% CI, n = 9).

Fig. 5. Short-term survival of 23 COVID-19 fatalities.

Cardiac SARS-CoV-2 infection (blue line, n = 12) correlated with significantly shorter survival (Log-Rank-Test p = 0.005) compared to patients without cardiac viral load (green line, n = 10).