SARS-CoV-2 is the virus responsible for the ongoing COVID-19 outbreak. The virus uses ACE2 receptor for viral entry. ACE2 is part of the counter-regulatory renin-angiotensin-aldosterone system and is also expressed in the lower respiratory tract along the alveolar epithelium. There is, however, significant controversy regarding the role of ACE2 expression in COVID-19 pathogenesis. Some have argued that decreasing ACE2 expression would result in decreased susceptibility to the virus by decreasing available binding sites for SARS-CoV-2 and restricting viral entry into the cells. Others have argued that, like the pathogenesis of other viral pneumonias, including those stemming from previous severe acute respiratory syndrome (SARS) viruses, once SARS-CoV-2 binds to ACE2, it downregulates ACE2 expression. Lack of the favourable effects of ACE2 might exaggerate lung injury by a variety of mechanisms. In order to help address this controversy, we conducted a literature search and review of relevant preclinical and clinical publications pertaining to SARS-CoV-2, COVID-19, ACE2, viral pneumonia, SARS, acute respiratory distress syndrome and lung injury. Our review suggests, although controversial, that patients at increased susceptibility to COVID-19 complications may have reduced baseline ACE2, and by modulating ACE2 expression one can possibly improve COVID-19 outcomes. Herein, we elucidate why and how this potential mechanism might work.

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The heart and the kidneys are closely interconnected, and disease in one organ system can lead to disease in the other. This interdependence is illustrated in heart failure with reduced ejection fraction (HFrEF), where worsening heart failure can lead to renal dysfunction and vice versa. Further complicating this situation is the fact that drugs that serve as guideline directed medical therapy (GDMT) for HFrEF can affect renal function. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of medication with an evolving role in heart failure (HF) and chronic kidney disease (CKD). Initially found to have benefits in diabetics, new research established potential cardiovascular and renal benefits in patients with HF independent of their diabetic status and in populations with CKD. This has been established by landmark trials such as EMPEROR-Reduced, EMPA-TROPISM, CREDENCE, DAPA-CKD, DAPA-HF, and DEFINE-HF. Multiple mechanisms responsible for these benefits have been suggested by clinical and non-clinical studies, and involve cardiac and renal energetic efficiency, cardiac remodeling, preservation of renal function, immunomodulation, changes in hematocrit, and control of risk factors. As such, SGLT2 inhibitors have tremendous potential to improve outcomes in populations with HF and CKD. The purpose of this review is to discuss the current evidence and underlying mechanisms for the cardio-renal benefits of SGLT2 inhibitors in patients with HFrEF.

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