Expression of the SARS-CoV-2 receptorACE2 in human heart is associated with uncontrolled diabetes, Obesity, and activation of the Renin Angiotensin system - The 68th Annual Conference of the Israel Heart Society in association with the Israel Society of Cardiothoracic Surgery

Tali Guetta ¹ Michal Herman-Edelstein ^1,5 Amir Barnea ^1,2 Maayan Waldman ^1,2 Naomi Ben-Dor ^1,5 Yaron Barak ^1,2 Ran Kornowski ^1,3 Michael Arad ⁴ Edith Hochhauser ^1,2 Dan Aravot ^1,2

¹Cardiac Research Laboratory, Felsenstein Medical Research Center and Sackler School of Medicine Tel-Aviv University,, Israel
²Departments of Cardiothoracic Surgery, Rabin Medical Center, Israel
³Departments of Cardiothoracic Surgery and Cardiology, Rabin Medical Center, Israel
⁴Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Israel
⁵Nephrology Department, Rabin Medical Center, Israel

Background: Diabetic and obese patients are at higher risk of severe cardiac injury in corona virus 2 (SARS-CoV-2) infections. Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in the heart. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the heart and whether treatment with renin-angiotensin system inhibitors or receptor blockers (ACEi and ARBs), or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We aimed to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice.

Methods: ACE2 mRNA and protein expression in heart tissue and serum biopsies collected from 79 patients that underwent Coronary Artery Bypass Graft surgery were tested and compared with clinical risk factors: diabetes, obesity and different anti-hypertensive or anti-diabetic therapies. WT or db/db mice were infused with Angiotensin II (ATII), treated with different anti-diabetic drugs (Metformin, GLP1A or SGLT2i) were also tested.

Results: ACE2 gene expression was increased in diabetic hearts compared to non-diabetic hearts and was positively correlated with HbA1c, body mass index (BMI), and activation of the Renin Angiotensin System (RAS), and negatively correlated with ejection fraction. ACE2 was not differentially expressed in patients who were on ACEi or ARBs. We found no correlation between plasma free ACE2 and cardiac tissue ACE2 expression. Transmembrane serine protease 2 (TMPRSS2), metalloprotease ADAM10 and ADAM17 that facilitate viral-ACE2 complex entry and degradation were increased in diabetic hearts. ACE2 expression in mice was increased with ATII infusion and attenuated following anti-diabetic drugs treatment.

Conclusion: Patients with uncontrolled diabetes or obesity with RAS activation have higher ACE2 expressions therefore are at higher risk for severe infection. Since ACEi or ARBs show no effect on ACE2 expression in the heart further support their safety.