COVID-19 and Hypertension: What We Know and Don't Know

Introduction to COVID-19

Coronavirus disease 2019 (COVID-19) emerged in December 2019 likely as a result of zoonotic transmission from wild animals linked to a large wet market in Wuhan, China.1 The responsible virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1 is a novel coronavirus that belongs to the same family as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Due to its high transmissibility, COVID-19 spread quickly and escalated into a global pandemic. As of June 18, 2020 there were over 8 million documented cases and 450,000 deaths worldwide, including more than 2 million cases and 118,000 deaths in the United States (US).2

Early reports from major COVID-19 epicenters including Wuhan and Lombardy, Italy revealed higher morbidity and mortality rates among patients with a history of hypertension, coronary artery disease, diabetes mellitus, chronic kidney disease, and obesity. Since SARS-CoV-2 infects human cells via the angiotensin-converting enzyme II (ACE2) receptor that acts on the renin-angiotensin-aldosterone system (RAAS), a key regular of blood pressure, questions have been raised about a possible link between hypertension and severe COVID-19 infection. This paper will explore the current state of our understanding of this association and review recently published studies evaluating outcomes of hypertensive COVID-19 patients treated with RAAS inhibitors.

Link between Hypertension and COVID-19

Hypertension, defined by the American College of Cardiology (ACC) and American Heart Association (AHA) as a systolic blood pressure (BP) ≥130 or diastolic BP ≥80 mm3, is a primary modifiable risk factor associated with atherosclerotic cardiovascular disease.3 The prevalence of hypertension in US adults is around 50% and higher rates correlate directly with advancing age.3 According to the Centers for Disease Control (CDC), 63% of adults over the age of 60 are hypertensive,4 a number that will continue to rise as our population ages. Approximately 50% of US patients with hypertension are prescribed angiotensin converting enzyme inhibitors (ACE-I), aldosterone receptor blockers (ARB) and aldosterone antagonists, collectively called RAAS inhibitors, and are among the most frequently prescribed anti-hypertensive medications.5

Initial reports from COVID-19 hot spots, including Wuhan,6,7 Lombardy,8,9 and New York City,10 identified higher rates of hypertension among severely ill, hospitalized COVID-19 patients. A large US study of 5,700 hospitalized patients revealed an overall hypertension rate of 56%,10 similar to hypertension rates reported from China11 and Italy9 (50% and 49%, respectively). Despite these observations, the link between hypertension and COVID-19 is unclear. Severity of COVID-19 illness is skewed towards the elderly population who have a higher prevalence of hypertension. The median age of hospitalized patients in Lombardy and New York City was 63 years old9,10 and the percentage with a hypertension diagnosis is consistent with the percentage observed in the general population. While there is an overrepresentation of hypertension among hospitalized and critically ill COVID-19 patients, it is uncertain whether this relationship is causal or confounded by age and other co-morbidities associated with hypertension including obesity, diabetes mellitus, and chronic kidney disease.

SARS-CoV-2 and Interaction with the Renin-Angiotensin Aldosterone System

ACE2 is a modulator of the RAAS, a critical neurohormonal pathway that regulates blood pressure and fluid balance.12 The end product of the RAAS, angiotensin II, is a key vasoactive hormone that binds to angiotensin II receptor type 1 (AT1) located in the heart, lungs, blood vessels, kidneys, and adrenal glands, and it plays a central role in myocardial hypertrophy and fibrosis, inflammation, vascular remodeling, and atherosclerosis.13 ACE2 is expressed in many human tissues including the nasal epithelium, heart, kidneys, and lungs, and inactivates angiotensin II diminishing its vasoconstrictive and myoproliferative effects.14

SARS-CoV-2 binds to the ACE2 receptor via its spike (S) protein to allow entry into host cells. This complex is endocytosed leading to down-regulation of ACE2 and resulting in local accumulation of angiotensin II. Severe respiratory illness is a hallmark of COVID-19 and a primary cause of morbidity- and mortality-local activation of the RAAS is proposed as a mechanism for severe lung injury.14

Impact of RAAS Inhibitors on COVID-19 Patient Outcomes

Given the overrepresentation of hypertension among critically ill COVID-19 patients, concerns have been raised about the potential risk associated with RAAS inhibitors. Recent discussions have debated whether ACE-Is and ARBs upregulate ACE2 expression thereby facilitating COVID-19 infection or contributing to more severe infection.15 Findings from animal studies have revealed inconsistent effects of RAAS inhibitors on ACE2 levels and tissue activity with some showing upregulation of ACE2,16 while others demonstrating no change.17 While there is a paucity of human data, in cross-sectional studies of patients exposed to long term RAAS inhibitor therapies, plasma ACE2 activity was not higher in treated subjects.18,19

Due to concerns about the theoretical risk of RAAS inhibition in COVID-19 patients, some clinicians have recommended discontinuation of these antihypertensive agents. Currently, there is no compelling evidence that withdrawal of ACE-Is or ARBs prevents infection or impacts clinical outcomes.20,21 Many cases of myocardial infarction, myocarditis22 and cardiomyopathy23 have been reported among COVID-19 patients and interruption of cardioprotective medications, including RAAS inhibitors, could lead to clinical decompensation.14 A retrospective Chinese study of 1,128 hospitalized, hypertensive patients found that inpatient use of ACE-Is or ARBs was associated with a lower risk of all-cause mortality when compared to non-users.24 A recent case control data of 6,272 patients from Lombardy considered disease severity based on ACE-I or ARB use. This study demonstrated that neither ARBs nor ACE-Is had a significant association with COVID-19 cases or fatal outcomes.25 Reynolds et al. reported no interaction between any antihypertensive medication classes, including RAAS inhibitors, and risk of COVID-19 infection.26 Most of the peer-reviewed studies published to date have not found higher rates of infection, greater severity of disease, or increased mortality among patients with treated with RAAS inhibitors (Table 1). Of note, no studies have addressed the safety of initiating RAAS inhibitor therapy for disease-specific indications such as congestive heart failure. Recent statements by major medical societies have only commented on continuation or cessation of RAAS inhibitors for guideline-directed indications but have not provided guidance on initiation of therapy in COVID-19 patients.27

Table 1: RAAS Inhibitors and COVID-19 Patient Outcomes

Table 1

Conclusion

The COVID-19 pandemic has taken an enormous toll on human life and efforts to better understand how to prevent and reduce severity of the disease are paramount. While overrepresentation of hypertension has been observed among critically ill COVID-19 patients, our current knowledge is skewed by observational studies that demonstrate an association but do not establish causation. The ACC, AHA, and Heart Failure Society of America released a joint statement advising against discontinuation of RAAS inhibitors where clinically indicated.27 This position is also supported by major international scientific societies including the International Society of Hypertension, European Society of Hypertension, European Society of Cardiology, Canadian Cardiovascular Society, and Canadian Heart Failure Society.28 The ACC recently created a COVID-19 Hub29 to provide clinical COVID-19 guidance to the cardiovascular team and includes information on RAAS inhibitors30 for hypertension management.31

Studies are underway to explore whether hypertension is an independent risk factor for COVID-19. Given the theoretical risks of RAAS inhibition, randomized trials have been initiated to evaluate clinical outcomes for COVID-19 patients treated with ACE-Is or ARBs (Table 2). Until more information is available, it is important to treat hypertensive patients to target based on current clinical practice guidelines.

Table 2: Current Clinical Trials- Use of RAAS Inhibitors and COVID-19 Outcomes

Table 2

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Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Heart Failure and Cardiac Biomarkers

Keywords: Primary Prevention, Secondary Prevention, COVID-19, Pandemics, Coronavirus, Coronavirus Infections, severe acute respiratory syndrome coronavirus 2, Antihypertensive Agents, SARS Virus, Mineralocorticoid Receptor Antagonists, Blood Pressure, Renin-Angiotensin System, Angiotensin-Converting Enzyme Inhibitors, Aldosterone, Peptidyl-Dipeptidase A, Angiotensin II, Receptors, Mineralocorticoid


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