|Year : 2020 | Volume
| Issue : 2 | Page : 57-64
COVID-19, hypertension, and cardiovascular disease
HK Chopra1, RR Kasliwal2, A Muruganathan3, Mohsin Wali4, C Venkata S Ram5
1 Moolchand Medcity, New Delhi, India
2 Division of Clinical and Preventive Cardiology, Medanta Heart Institute, New Delhi, India
3 A. G. Hospital, Tirupur, Tamil Nadu, India
4 Sir Gangaram Hospital, New Delhi, India
5 Apollo Institute for Blood Pressure Management, Apollo Medical College and Hospitals, Hyderabad, Telangana, India
|Date of Submission||09-May-2020|
|Date of Acceptance||20-May-2020|
|Date of Web Publication||24-Jun-2020|
Dr. C Venkata S Ram
Apollo Institute for Blood Pressure Management, Apollo Blood Pressure Clinics, Apollo Medical College and Hospitals, Hyderabad, Telangana.
Source of Support: None, Conflict of Interest: None
The coronavirus disease-2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular (CV) health of patients, although the respiratory disease is the predominant clinical sign of COVID-19. The presence of comorbidities such as hypertension, diabetes, and CV disease (CVD) increases the risk of morbidity and mortality due to CVD. Numerous patients with COVID-19 have basic CV ailments or develop severe heart injury due to the disease. Severe CV injury characterized by a huge rise of heart troponins is the most commonly seen effect on the heart. This happens in approximately 8%–12% of all patients. Direct myocardial injury because of viral association of cardiomyocytes and the effect of systemic inflammation appear to be the most common mechanisms responsible for the cardiac injury. The presence of preexisting CV disease and/or development of acute cardiac injury is associated with significantly worse outcomes in patients with COVID-19. Most of the current reports on COVID-19 have only briefly described CV manifestations in these patients. Given the significant adverse prognostic impact of cardiac involvement, further studies are needed on the incidence, mechanisms, clinical presentation, and outcomes of various CV manifestations in patients with COVID-19.
Keywords: Cardiovascular disease, coronavirus disease-2019 (COVID-19), hypertension, type 2 diabetes
|How to cite this article:|
Chopra H, Kasliwal R R, Muruganathan A, Wali M, Ram C V. COVID-19, hypertension, and cardiovascular disease. J Diabetol 2020;11:57-64
| Introduction|| |
We are now engulfed in the outbreak of a pandemic caused by severe acute respiratory syndrome considered by a novel coronavirus (SARS-CoV-2), which causes an extremely serious disease, coronavirus disease-2019 (COVID-19), which was first reported in Wuhan, China, in December 2019. At the time of writing this article, the number of COVID-19 cases is steadily increasing all over the world including India. The disease is highly contagious and transmits easily to anyone, and thus is termed an equal opportunity killer.
Coronaviruses are large, wrapped, and positive-stranded ribonucleic acid (RNA) viruses. They have the largest genome among all RNA viruses. The genome is stuffed inside a helical capsid framed by the nucleocapsid protein and further encompassed by an envelope. Related with the viral envelope are three auxiliary proteins: the film protein, the envelope protein, and the spike protein. It is believed that the latter is responsible for the virus entry into host cells. In addition to mediating virus entry, the spike protein is a basic determinant of viral host response and tissue tropism and a significant inducer of host immune responses.
The clinical, epidemiological, and therapeutic aspects of COVID-19 have been extensively published. It has been noted that certain comorbidities increase the risk of lung injury and death. These include but are not limited to hypertension (27%–30%), diabetes (20%), and cardiovascular disease (CVD) (8%) [Figure 1]. This article will focus on CVD and hypertension in patients with COVID-19.
| Coronavirus Disease-2019 and Cardiovascular disease|| |
There could be a bidirectional relationship between COVID-19 and CVD. COVID-19 infection may affect the CV systems. Conversely, the previous CVD may predispose an individual to COVID-19 infection. Those with CVD who are infected by this virus have an increased risk of adverse events and poorer outcomes.,, In addition, COVID-19 disease may have various effects on the CV system. Moreover, if large numbers of individuals are infected, it may affect the treatment of CVD patients without COVID-19. Finally, also as it is an intensive care unit (ICU) setting, the cardiologist treating the COVID-19 may develop this infection.
A meta-examination of six investigations involving 1527 patients with COVID-19 looked at the effects on CVD and showed the prevalence of hypertension, CVD, and diabetes to be 17.1%, 16.4%, and 9.7%, respectively. Increased fatality rates were reported in a study of 44,672 confirmed COVID-19 cases from Wuhan, China. The mortality rates were as follows: CVD (10.5%), diabetes (7.3%), and hypertension (6.0%), all of which were higher than the overall case-fatality rate in individuals without these comorbidities, which was 2.3%. Several smaller cohort studies have yielded comparable outcomes showing proposing higher hazard for adverse events in patients with CVD who contract COVID-19.,[8-13]
| Pathogenic Mechanisms|| |
Although the respiratory tract is the primary target for SARS-CoV-2, the CV system may get involved in several different ways. The following are the common mechanisms responsible for CV complications in COVID-19.,
- Direct myocardial injury: SARS-CoV-2 enters human cells by binding to angiotensin-converting enzyme 2 (ACE2), a membrane-bound aminopeptidase which is highly expressed in the heart and lungs. ACE2 plays an important role in neurohumoral regulation of the CV system in normal health as well as in various disease conditions. The binding of SARS-CoV-2 to ACE2 can result in alteration of ACE2 signaling pathways in the form of dysregulation and reducing the activity of ACE2 leading to increased Angiotensin-II resulting in acute myocarditis, myocardial, and lung injury.,
- Systemic inflammation: More severe forms of COVID-19 are characterized by acute systemic inflammatory response and cytokine storm, which can result in injury to multiple organs leading to multiorgan failure. Studies have shown high circulatory levels of pro-inflammatory cytokines in patients with severe/critical COVID-19.,
- Altered myocardial demand-supply ratio: Increased cardiometabolic demand associated with the systemic infection coupled with hypoxia caused by the acute respiratory illness can impair myocardial oxygen demand–supply relationship and lead to acute myocardial injury.
- Plaque rupture and coronary thrombosis: Systemic inflammation as well as increased shear stress due to increased coronary blood flow can precipitate plaque rupture resulting in acute myocardial infarction (MF), pro-thrombotic milieu created by systemic inflammation, and further increases the risk of an acute MI.
- Cardiac microvascular damage: This is because of perfusion defect, vessel hyperpermeability, and angiospasm.
- Adverse effects of various therapies: Various antiviral drugs, corticosteroids, and other therapies aimed at treating COVID-19 can also have deleterious effects on the CV system.
- Electrolyte imbalances: Electrolyte imbalances can occur in any critical systemic illness and precipitate arrhythmias, especially, in patients with an underlying cardiac disorder. There is particular concern about hypokalemia in COVID-19, due to the interaction of SARS-CoV-2 with renin–angiotensin–aldosterone system (RAAS). Hypokalemia increases the vulnerability to various tachyarrhythmias.
| Role of Cardiovascular Disease Comorbidities|| |
A meta-analysis of six published studies from China including 1527 patients with COVID-19 reported 9.7%, 16.4%, and 17.1% prevalence of diabetes, cardio-cerebrovascular disease, and hypertension, respectively. Although the prevalence of diabetes and hypertension in this cohort was the same as in the Chinese general population, the prevalence of cardio-cerebrovascular disease was considerably higher. More importantly, the presence of diabetes, cardio-cerebrovascular disease, and hypertension was associated with a twofold, threefold, and twofold greater risk of severe disease or requiring ICU admission, suggesting a prognostic impact of these comorbidities. A small report including 21 patients from Washington, USA showed that comorbidities were common in this cohort, with diabetes present in 33.3% and congestive heart failure in 42.9%. Acute cardiac dysfunction occurred in 33.3% of patients and 52.4% of patients died.
| Cardiovascular Conditions Associated with Coronavirus Disease-2019|| |
Myocardial injury, myocarditis, and acute coronary syndromes
Myocardial injury is repeatedly an increase in troponin-I level and can occur due to myocardial ischemia or nonischemic myocardial processes, including myocarditis.,, With severe respiratory infection and hypoxia in the setting of severe infection and ARDS due to COVID-19, a number of patients will likely develop such injury. In a meta-analysis of four studies including a total of 341 patients, the standardized mean difference of cardiac troponin levels was significantly higher in those with severe COVID-19-related illness compared to those with nonsevere disease.
Reports have also suggested that acute cardiac injury––which includes not only elevation of cardiac biomarkers (D-dimer, cardiac myoglobin, troponin I, ferritin, interleukin-6 [IL-6], and lactate dehydrogenase [LDH]) to > 99th percentile of the upper reference limit, but also electrocardiographic and echocardiographic abnormalities is highly prevalent in patients with COVID-19 and is associated with more severe disease and worse prognosis. Cohort studies from hospitalized patients in China estimate that such injury that occurs in 7%–17% of hospitalized patients with the disease,, is significantly more common in patients admitted to the ICU (22.2% vs. 2.0%, P < 0.001) and among those who died (59% vs. 1%, P < 0.0001)., Some patients can present with myocarditis including a severe fulminant myocarditis due to cytokine storm with regional ST elevation, with elevation in N-terminal-pro hormone BNP (NT-pro-BNP), marked troponin release, and ventricular dysfunction. Others may present with acute coronary syndrome ST-segment elevation myocardial infarction (STEMI) or non-STEMI because of both micro- and macro-vessel obstruction.
Cardiac arrhythmia and cardiac arrest
Cardiac arrhythmia is another common CV event, described in patients with COVID-19 infection. Nonspecific, heart palpitations were part of the presenting symptomology in 7.3% of patients in a cohort of 137 patients admitted for COVID-19. In hospitalized patients with COVID-19, cardiac arrhythmia was noted in 16.7% of 138 patients in a Chinese cohort and was more common in ICU patients compared to nonICU patients (44.4% vs. 6.9%). High prevalence of arrhythmia might be, in part, attributable to metabolic disarray, hypoxia, neurohormonal, or inflammatory stress in the setting of viral infection in patients with or without prior CVD.
Cardiomyopathy and heart failure
Zhou et al. reported that heart failure was observed in 23.0% of patients with COVID-19 presentations. Notably, heart failure was more commonly observed than acute kidney injury in this cohort and was more common in patients who did not survive the hospitalization compared to those who did survive (51.9% vs. 11.7%). Whether heart failure is most commonly due to exacerbation of preexisting left ventricular dysfunction vs. new cardiomyopathy (either due to myocarditis or stress cardiomyopathy) remains unclear. Right heart failure and associated pulmonary hypertension should be also considered, particularly in the context of severe parenchymal lung disease and acute respiratory distress syndrome (ARDS).
Cardiogenic and mixed shock
The predominant clinical presentation of COVID-19 is an acute respiratory illness, which may lead to ARDS which manifests as ground-glass opacities on chest imaging and hypoxemia. However, similar features may be seen in the case of de novo or coexisting cardiogenic pulmonary edema. As such, it is important to consider cardiogenic or mixed cardiac plus primary pulmonary causes of respiratory manifestations in COVID-19.
Venous thromboembolic disease
COVID-19-infected patients are likely at increased risk of venous thromboembolism (VTE). Although there are no published case series thus far, there are reports of abnormal coagulation parameters in hospitalized patients with severe COVID-19 disease., In a multicenter retrospective cohort study from China, elevated D-dimer levels (>1g/L) were strongly associated with in-hospital death, even after multivariable adjustment (odds ratio [OR] 18.4 95% confidence interval [CI] 2.6–128.6, P = 0.003). In another study comparing COVID-19 survivors to nonsurvivors, nonsurvivors had significantly higher D-dimer and fibrin degradation products (FDP) levels and 71.4% of nonsurvivors met clinical criteria for disseminated intravascular coagulation (DIC) duringthe course of their disease. In addition to DIC, critically ill patients with prolonged immobilization are inherently at high risk for VTE. Vascular inflammation may also contribute to the hypercoagulable state and endothelial dysfunction in such patients.
Rheumatic heart disease
Rheumatic heart disease (RHD) continues to be a major cause of disease burden among children, adolescents, and young adults in low-income countries and even in some high-income countries with socioeconomic inequalities. The major determinant of the persistent burden of RF/RHD in developing countries is because of poor standards of living conditions and overcrowding. Similarly, COVID-19 also spreads fast due to poor hygiene and lack of social distancing as reported by World Health Organization (WHO). Hence, COVID-19 may worsen RHD.
| Coronavirus Disease-2019 and Hypertension|| |
Although hypertension has been recognized as a frequent accompaniment of COVID-19, it is unclear whether it is causal or coincidental finding. From the published reports, it is not yet clear about the duration of hypertension or how the diagnosis of blood pressure control was made among these patients. For example, it is more likely uncontrolled hypertension is a factor for worsening COVID-19, but not well-controlled hypertension. It is reasonable, therefore, that leading global organizations have emphasized the importance of blood pressure control. From the published studies, it is impossible to ascertain how the blood pressure was measured in the COVID-19, although we can assume that in the ICU setting, intra-arterial blood pressure was measured. It should be noted that in some studies the age difference between survivors and nonsurvivors from COVID-19 was as much as 20 or more years,, again implying a greater chance of having hypertension due to the older age group. The same explanation applies to other Covid-19 comorbidities like diabetes and CVD. One unifying hypothesis is that the mortality from COVID-19 is worsened by increasing age which by itself carries a higher prevalence of hypertension.
| Renin-angiotensin-aldosterone-system Blockers and Coronavirus Disease-2019|| |
A substantial number of patients with COVID-19 have preexisting CVD and therefore may be on RAAS blocker such as ACE inhibitors or angiotensin receptor blockers (ARBs). These drugs may increase ACE2 receptors. It has been suggested that increased levels of ACE2 expression may enhance the coronavirus entry into the cell [Figure 2] and thus conceivably worsen the lung function in patients with COVID-19.,It has been proposed that RAAS blockers may worsen the lung injury., On the other side of the coin, ACE2 has been proven to protect from lung injury. ACE2 forms angiotensin 1–7 from angiotensin-II; increased levels of angiotensin 1–7 which may reduce the systemic and lung inflammation. Therefore, RAAS blockers may interrupt the progression to ARDS and myocardial injury. Increased levels of soluble ACE2 could reduce the viral load and attachment to the tissue. So, the paradox is that although RAAS blockade associated increase in the ACE2 levels may be harmful for lung function on the one hand, ACE2 may actually prevent lung injury on the other.,,, The panic concerning RAAS blockade (and COVID-19) started with the information that ACE2 is the receptor for SARS-CoV-2. This fear is unfounded, as a large portion of ACE2 is membrane bound and thus an increase in the blood levels of ACE2 would not have a biological effect. In this context, it must be noted that ACE2 expression decreases with aging. This raises a paradox––how can a natural decline in ACE2 levels in older persons predispose then to greater severity of COVID-19?
|Figure 2: Possible experimental description of ACE2/Corona Virus interaction|
Click here to view
Taken together, the totality of the experimental (not human) data suggests that upregulation of ACE2 by ARBs would not be sufficient to facilitate the viral entry into the cell. Moreover, as most of ACE2 is tissue bound, its blood level is not likely to make any meaningful effect on the substrate load. With acute lung injury (ARDS), alveolar levels of ACE2 are downregulated. Hence, enhancing the tissue ACE2 by ARBs may indeed be protective. At present, there is no clinical evidence to indicate whether the RAAS blockade is either detrimental or beneficial in patients with COVID-19. Future randomized studies will yield evidence-based much-needed information on this subject.
There is no clear evidence to suggest hypertension either predisposes to COVID-19 or worsens its prognosis. It is more likely that hypertension is a bystander; and the elderly (who are vulnerable to COVID-19 complications) have a high prevalence of hypertension. It is also possible as pointed out earlier that the high prevalence of hypertension in patients with COVID-19 is an accompaniment to the aging process.
At present, there is no valid reason to implicate any connection between RAAS blockers and COVID-19. There is a concern that RAAS blockade may increase to ACE2 expression in animal models, and there are no human data in this regard. Therefore, there is no need for the practitioners to alter the treatment of hypertension particularly the RAAS blockers. Despite the paucity of data in humans, it is imperative at present to develop guidance to protect our patients. The therapeutic benefits of RAAS blockers outweigh any theoretical concerns from the animal models. As per the statement of the American Heart Association (ACC/AHA statement, 3/2020), “Be advised not to add or remove RAAS-related treatments beyond actions based on clinical practice”. Effective control of hypertension is always recommended whether or not the patients have COVID-19. In conclusion, hypertension is likely to be more common in patients with COVID-19 because of older age being a principal factor. There is no corroborative evidence to incriminate RAAS blockers in the natural history of COVID-19. The ongoing randomized clinical trials and collection of global data will provide the information needed to prevent and manage COVID-19 and comorbidities based on demonstrable evidence.
In the absence of compelling data, regarding ACE inhibitor (ACEi) and ARBs it is very much prudent to follow the guidance by various international agencies as shown in [Table 1].
|Table 1: Recommendations of various societies regarding the management of hypertension in patients with COVID-19,,,,,|
Click here to view
| Cardiac-specific Preparedness Recommendations for Coronavirus Disease?-2019|| |
The overall management principles for patients presenting with COVID-19 who develop CV complications or who have preexisting CVD are the same as for any other patient without COVID-19. However, there are a few important points that need consideration:-
- As caregivers, the utmost responsibility is to protect themselves from getting infected while managing these patients. Therefore, all health-care personnel engaged in the care of patients with COVID-19 must take the utmost precautions at all times. All of them should be trained in donning, usage, and doffing of the personal protective equipment in accordance with the existing practice guidelines.
- The hospital systems need to ensure preparedness for dealing with a large volume of patients with COVID-19, many of whom would need ICU care and/or acute cardiac care. Appropriate protocols for rapid diagnosis, triage, isolation, and management of COVID-19 patients with CV complications should be developed and well-rehearsed. Rapid triaging and management of these patients is crucial, not only to allow efficient utilization of healthcare resources but also to minimize exposure to caregivers. There are already reports highlighting delays in delivering acute cardiac care due to extra precautions that need to be observed in view of COVID-19. Efforts should be made to minimize such delays
- Strong emphasis should be placed on avoiding unwarranted diagnostic tests (e.g., cardiac troponin and echocardiography) in these patients. This is required to minimize unwarranted downstream diagnostic/therapeutic procedures which would further strain the already stretched healthcare resources and would also subject caregivers to the added risk of exposure to the infection. The American College of Cardiology (ACC) has released an advisory discouraging random measurement of cardiac biomarkers such as troponins and natriuretic peptides. It urges all the clinicians to reserve these assays for circumstances in which they would actually meaningfully add to the management of the patients with COVID-19. The American Society of Echocardiography (ASE) has also issued a similar advisory regarding the use of echocardiography in these patients.
- For the confirmed or suspected COVID-19 patient with STEMI presenting within 12h and with no contraindications, thrombolysis is the prudent option to avoid time delay and for protection of cardiac catheterization laboratory (CCL) personnel, especially if the patient is hemodynamically stable., The individual hospitals may also have to reconsider the risk–benefit ratio of primary percutaneous intervention vs. fibrinolysis in patients with COVID-19 who present with ST-segment elevation MF
- There has been a concern regarding the safety of ACEi and ARBs during the ongoing COVID-19 pandemic. These agents upregulate the expression of ACE2 in various tissues, including on cardiomyocytes. As SARS-CoV-2 binds to ACE2 to gain entry into human cells, there is a potentially increased risk of developing COVID 19 or developing the more severe disease in patients who are already on background treatment with ACEi/ARB. However, to date, no experimental or clinical data have emerged to support these concerns. At the same time, the risks of discontinuing these therapies are well known. Therefore, several leading professional societies have strongly urged to not discontinue clinically-indicated ACEi/ARB therapy in the event the patient develops COVID-19.,
| Precautions if Using Hydroxychloroquine|| |
Recently, chloroquine/hydroxychloroquine and azathioprine have been proposed as potential therapeutic options, based on preliminary evidence. Both these drugs are known to prolong QT interval and due caution must be exercised when prescribing these agents. Their combination is best avoided and even when using chloroquine/hydroxychloroquine alone, daily electrocardiogram for monitoring QT interval is warranted, especially in patients with hepatic or renal dysfunction and in those receiving another drug with the potential to prolong QT interval. Possible interaction of Amiodarone (if prescribed) with Hydroxychloroquine/Chloroquine as well as the antiretroviral (ARV) drugs lopinavir/ritonavir, regular monitoring of QT interval is required to minimize risk of torsades de pointes. Being a potent liver enzyme CYP3A4 inhibitor, lopinavir/ritonavir also has potential drug interaction with antiplatelets, anticoagulants, and statins.
| Conclusions and Future Directions|| |
Although the respiratory illness is the dominant clinical manifestation of COVID-19, the shear burden of the illness implies that a large number of patients with COVID-19 would present with preexisting CVD or develop new-onset cardiac dysfunction during the course of the illness. Considering this, the current understanding of the interplay between CVD and COVID-19 is grossly inadequate. It is therefore highly desirable that future studies on COVID-19 specifically describe the incidence, mechanisms, clinical presentation and outcomes of various CV manifestations in these patients. The diagnostic and therapeutic challenges posed by the concurrence of these two illnesses also need to be adequately studied. The CV community will play a key job in the administration and treatment of patients influenced by this ailment, and also in giving congruity of care to noninfected patients with basic CVD. They can consider using handheld ultrasound (point care) which can be easily disinfected and would be more useful to diagnose wall motion abnormality and as a lung ultrasound. Arterial blood gas (ABG) is more reliable than pulse oximetry. The use of extracorporeal membrane oxygenation (ECMO) should be planned with sufficient precaution as it involves the risk of exposure to many staff.
In the coming months, endeavors toward assessing new treatments will be essential to the treatment of this infection, and as this procedure grows, further appreciation of the intricate interplay between COVID-19, CVD, and the various stakeholders involved including patients, health-care workers, and health-care systems will be crucial to improving outcomes in at-risk and infected patients. It is of utmost importance to do a long-term follow-up of the recovered patients and monitor their cardiac health.
We thank Dr. Ishita Sengupta from Eris Lifesciences for help with writing this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]