A Review of Heart Failure in Patients with COVID-19

Abstract

The interplay of COVID-19 and heart failure is complex and involves direct and indirect effects. Patients with existing heart failure develop more severe COVID-19 symptoms and have worse clinical outcomes. Pandemic-related policies and protocols have negatively affected care for cardiovascular conditions and established hospital protocols, which is particularly important for patients with heart failure.

Key points

• •The COVID-19 pandemic has led to a wide range of direct and indirect consequences in patients with heart failure.
• •Complications of COVID-19 infection affecting the cardiovascular system include mild myocardial injury to more severe conditions such as myocardial infarction, heart failure, and cardiogenic shock.
• •Patients with existing heart failure develop more severe COVID-19 symptoms and have worse clinical outcomes.
• •Pandemic-related policies and protocols have negatively affected patients with heart failure.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has significantly affected the public health on a global scale. It was first reported in Wuhan, China, in December 2019¹ and has since spread globally, infecting more than 651 million people and causing more than 6.65 million deaths as of December 2022.² Although the most well-known complication of COVID-19 is respiratory failure, the infection can also lead to dysfunction in multiple organ systems, including the cardiovascular system; this can range from mild myocardial injury to more severe conditions such as myocardial infarction, heart failure (HF), and cardiogenic shock, potentially leading to cardiovascular death.3, 4, 5

COVID-19 infection has been linked to the development of HF via myocardial infarction, myocarditis, microthrombi, and stress cardiomyopathy.⁶ There are several potential mechanisms by which SARS-CoV-2 may lead to these conditions through direct viral or immune-mediated effects.⁷ Patients with COVID-19 and myocardial infarction are at an increased risk for cardiogenic shock. Although the direct effects of COVID-19 on the cardiovascular system have received significant attention, the pandemic has also significantly affected HF systems of care (Fig. 1 ).⁸

Fig. 1.

Direct and indirect impact of COVID-19 on heart failure.

(Created with BioRender.com.)

This review explores the impacts of COVID-19 on individuals with preexisting HF, the incidence and risk factors for subsequent HF in patients with COVID-19, the relationship between COVID-19 and cardiogenic shock, and the indirect impacts of COVID-19 on HF care.

COVID-19 and pre-existing heart failure

HF is a common preexisting condition among patients with COVID-19 and can lead to poor prognoses. Studies found that between 4.9% and 13% of hospitalized patients with COVID-19 also had HF.9, 10, 11, 12, 13, 14 These patients tended to have higher levels of certain biomarkers, such as troponin and BNP and were at increased risk of needing mechanical ventilation and having a longer stay in the intensive care unit.^{12 , 13} In addition, the risk of in-hospital mortality increased in patients with COVID-19 with concomitant HF compared with those without the condition after adjusted for confounders (Fig. 2 ).^{13 , 14}

Fig. 2.

Preexisting HF is an independent risk factor for intensive care unit stay, intubation, and in-hospital mortality after adjusted for confounding factors in patients with COVID-19 infection.

(Adapted from Alvarez-Garcia J, Lee S, Gupta A, et al. Prognostic Impact of Prior Heart Failure in Patients Hospitalized With COVID-19. J Am Coll Cardiol. 2020;76(20):2334-2348.)

There was also initial concern about the potential effects of certain medications, used to treat HF, on the risk of SARS CoV-2 infection, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs).¹⁵ Some preclinical data suggested that ACEIs and ARBs might upregulate ACE2 receptors, which increases the risk of SARS-CoV-2 infection. As a result, there was a shift toward using fewer ARBs or ACEIs for these conditions. However, multiple subsequent studies found no relationship between the use of ACEIs or ARBs and the severity of COVID-19 infection, and a meta-analysis of 11 randomized controlled trials suggested no difference in the risk of all-cause mortality.¹⁶ Overall, despite longer length of stay and higher short-term mortality in patients with HF and concomitant COVID-19 infection, adherence to HF quality measures such as sustained to minimally increased prescription of guideline-directed medical therapies was largely maintained during the pandemic.¹⁷ In terms of withdrawing from guideline-directed medical therapy (GDMT) and mortality rates, discontinuing the GDMT medications prescribed during hospitalization was significantly associated with an increased risk of in-hospital mortality.¹²

However, overall HF care has been affected by the pandemic in various ways. There is evidence that the number of acute HF hospitalizations decreased significantly during the pandemic, with a 27% reduction in daily admissions observed in a large German study during the early months of the pandemic compared with the previous year.¹⁷ This decrease was thought to be related to the implementation of social distancing measures, increased use of telemedicine, and changes in health care–seeking behavior.¹⁷

COVID-19 and new-onset heart failure

There are several potential mechanisms to account for the cardiotoxic effects of SARS-CoV-2, including direct viral and immune-mediated damage, leading to inflammation with subsequent myocardial injury, edema, and myocarditis; demand ischemia due to respiratory failure and hypoxemia; and postviral autoimmune reactions.¹⁸ Possible factors that may worsen HF in patients with COVID-19 include increased oxygen demand, myocarditis, stress-induced cardiomyopathy, ischemia, increased pulmonary pressure, and venous thromboembolism.¹⁹

COVID-19 has been implicated in vascular endothelial damage. Systemic inflammation caused by SARS-CoV-2 leads to significant platelet activation. The increased levels of proinflammatory interleukins on the surface receptors of platelets as well as the reduction of endothelial nitric oxide are what causes this phenomenon. The increased levels of proinflammatory interleukins on the surface receptors of platelets and neutrophils as well as the reduction of endothelial nitric oxide, are what causes platelet aggregation. These mechanisms, along with endothelial damage, lead to aggravation of the thromboinflammatory pathway of COVID-19.²⁰ Hence, COVID-19 has led to abnormal activation of immune responses during infection, leading to suboptimal myocardial repair with increased incidence of HF.²¹ Myocardial infarction have been shown to increase the incidence of HF; a study of patient older than 65 years showed that 76% of patient who survived their first acute myocardial infarction developed HF in the next 5 years.²²

Another potential mechanism of COVID-19–induced HF include endothelial injury coupled with microthrombi, which could damage the endocardium. Several reports showed that the endothelium of organs contains ACE2 receptors and invasion of receptors by SARS-CoV-2, resulting in an immediate inflammatory response with activation of the complement and thrombin system. All of these pathophysiological reactions lead to the development of coagulopathy with elevated D-dimer and fibrin products, leading to subsequent development of microthrombi.^{23 , 24} In patients who died of COVID-19, inflammation of the capillaries with microthrombi was observed in the early disease course. Large thrombi, microangiopathy, and signs of disseminated intravascular coagulation were observed in the more chronic and serious cases of COVID-19.²⁵ This coagulopathy and microthrombosis dysfunction of vascular endothelium in patients with COVID-19 is associated with development of myocardial injury and HF. Other studies show that endothelial injury may lead to increased vascular permeability and low nitric oxide level in the internal layer of the capillary.²⁶ All of these components could lead to severe cardiac injury, causing HF.

Early cases of COVID-19 in the United States revealed that cardiomyopathy developed in a significant proportion of patients. However, it is unclear whether the high rates of cardiomyopathy were a direct cardiac complication from SARS-CoV-2 infection or a result of critical illness.²⁷ Pathogenesis of COVID-19 cardiomyopathy is related to previously described inflammatory cytokines, leading to diastolic dysfunction and increased myocardial wall stiffness facilitated by interleukin-6 (IL-6) and myocardial fibrosis induced by IL-1β and tumor necrosis factor α.²⁸ In Wuhan, of 191 hospitalized patients, HF was found in half of the fatal cases and in 12% of survivors.²⁹ These observations were later confirmed in a second Chinese study of 799 hospitalized patients with COVID-19. In addition, 49% of 113 deceased patents with COVID-19 had complications of acute HF during their clinical course.³⁰ Furthermore, elevated NT-pro-BNP at the time of admission for COVID-19 hospitalization was associated with an increased risk of inpatient mortality. NT-pro-BNP elevations independently predicted a 2 to 7 times increased rate of mortality based on a large nationwide cohort.³¹ Hospital mortality rates in patients with acute HF and COVID-19 were extremely high, up to 44% at the height of the pandemic.

After the acute phase, COVID-19 may be responsible for HF as a long-term cardiovascular complication, but further clinical studies are needed.⁶ In a study, they observed more than 3000 patients with confirmed COVID-19 infections and followed them for 30 days. They found that 77 patients, about 2.5%, developed symptoms of acute HF during this study period. Echocardiographic examinations were available for 31 patients with some degree of left ventricular systolic dysfunction. Seventeen patients had other findings, such as valvular heart disease, pericardial effusion, or right ventricular dysfunction.¹² Echocardiography performed within the first 24 hours in 100 patients with COVID-19 showed predominantly an initial deterioration of right ventricular function by dilation and dysfunction, followed by the development of left ventricular dysfunction, and worsening left ventricular systolic dysfunction in 10% of patients.³² Right ventricular dysfunction was present in large proportions of hospitalized patients with predictive value for poor outcomes.³³ Intensive care unit level patients with severe COVID-19 requiring persistent ventilation can lead to increased RV afterload from elevated positive pressures, thus inducing additional strain in the ventricle and further reducing the already impaired cardiac output.³⁴

Viruses are known to stimulate a cell-mediated immune response, which causes myocarditis and may progress to dilated cardiomyopathy.³⁵ Previous case reports of myocarditis in patients with COVID-19 provided evidence of cardiac inflammation, with inflammatory infiltrates leading to regions of cardiomyocyte necrosis leading to myocarditis.³⁶ Proposed mechanisms include specific infectious causes that alter the myocyte membrane, which trigger an immune response, which consists of predominate macrophage and lymphocyte infiltration of myocardial tissue. A large recent review of postmortem histopathologic data showed a high prevalence of myocardial necrosis and edema without myocarditis, due to a lack of inflammatory infiltrates; this may be related to the microthrombi described earlier.³⁷ In most patients, after the initial viral infection, the immune response clears the pathogen, and usually the inflammation resolves. However, for a group of patients with altered immune reactivity, they can develop an autoimmune reactivation, leading to acute myocardial disease and cardiac dysfunction.³⁸ The incidence of COVID-19 myocarditis is uncertain. A recent systemic review revealed that the prevalence of definite acute myocarditis among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations and that number was increased to 4.1 per 1000 to include possible acute myocarditis.³⁹ In a study of 100 patients who had recovered from severe COVID-19 infection, it was found that 78% of them had an evidence of cardiac involvement as seen on cardiac MRI, and 60% of them had ongoing myocardial inflammation, regardless of preexisting conditions, severity, and course of their acute illness. MRI injury patterns included a raised myocardial native T2, nonischemic myocardial late gadolinium enhancement (LGE), pericardial enhancement, and an ischemic pattern LGE.⁴⁰

Stress-induced cardiomyopathy with apical ballooning was also documented in patients with COVID-19. In a case report, a patient with COVID-19 without a history of cardiovascular diseases developed and recovered from clinical stress cardiomyopathy.⁴¹ A retrospective cohort study found a significant incidence of stress-induced cardiomyopathy during the COVID-19 pandemic compared with prepandemic periods. Of note, all of these patients tested negative for COVID-19 during the pandemic period. The psychological, social, and economic distress accompanying the pandemic likely led to an increased risk of stress-induced cardiomyopathy, rather than direct viral involvement.⁴² Stress-induced cardiomyopathy may lead to left ventricular dysfunction, cardiogenic shock, dynamic left ventricular tract obstruction, pericardial effusion, and death.⁴³

COVID-19 and cardiogenic shock

COVID-19 has been linked to a variety of cardiovascular complications, ranging from mild myocardial injury to devastating cardiogenic shock that can lead to cardiovascular death. Several studies have been conducted to better understand the relationship between COVID-19 and cardiogenic shock. In a large registry of patients hospitalized for COVID-19 infection (n = 15,208), 12% developed some form of shock (cardiogenic, distributive, or mixed), with 0.7% experiencing cardiogenic shock.⁴⁴ These individuals were more likely to be men, have diabetes, a history of myocardial infarction or HF, higher troponin levels, and lower left ventricular ejection fraction compared with those without shock.⁴⁴ Approximately 20% of those with cardiogenic shock had a myocardial infarction (including demand-related events) during the hospitalization.⁴⁴

Myocardial infarction is a known risk factor for developing cardiogenic shock, particularly ST-segment elevation myocardial infarction (STEMI). In the North American COVID-19 Myocardial Infarction (NACMI) registry, 18% of patients with STEMI with concomitant COVID-19 infection developed cardiogenic shock during the early phase of the pandemic,⁴⁵ which decreased to 13% later in the pandemic.⁴⁶ Multiple mechanisms may increase the risk of cardiogenic shock in patients with STEMI, including delayed presentation, prolonged ischemic time, proinflammatory and prothrombotic effects, and cytokine storms.⁴⁷ The prognosis for these patients was poor, with in-hospital mortality risk being significantly higher in those with cardiogenic shock compared with those without shock in the American Heart Association COVID-19 CVD Registry (63% vs 10.3%, P < .001).⁴⁴ Similarly, cardiogenic shock increased the risk of in-hospital mortality by more than 4-fold in patients with STEMI with concomitant COVID-19 infection in the NACMI registry.⁴⁸

Managing acute myocardial infarction–associated cardiogenic shock regardless of COVID-19 status is challenging, with standardized protocols including early revascularization and initial stabilization with or without mechanical circulatory support.⁴⁹ However, the evidence for the use of mechanical circulatory support in patients with COVID-19, particularly extracorporeal membrane oxygenation (ECMO), is limited to observational studies. In the NACMI registry, intraaortic balloon pumping was the most common form of mechanical circulatory support (62%), followed by Impella (28%) and ECMO (7%).⁵⁰ Despite using these strategies, the in-hospital mortality rate was still 60%. A large international registry of the Extracorporeal Life Support Organization also found that using ECMO for circulatory support was associated with in-hospital mortality risk of 89% in patients with COVID-19 infection.⁵¹

It is clear that COVID-19 infections can lead to severe illness, including cardiogenic shock, particularly in individuals with underlying cardiac conditions or those who have experienced a myocardial infarction. Although the exact mechanisms by which COVID-19 may increase this risk are not fully understood, the management of COVID-19–associated cardiogenic shock is challenging, and the use of mechanical circulatory support has demonstrated inconclusive results. Further research is needed to fully understand the relationship between COVID-19 and cardiogenic shock and to appropriate risk-stratify and identify effective therapeutic strategies.

COVID-19 and indirect impacts

There are indirect effects of the COVID-19 pandemic that can contribute to or exacerbate HF. Because of the widespread use of “shelter in place” and “stay at home” orders, patients with various cardiovascular (CV) conditions tended to present later in the course of the disease, which contributed to worse outcomes. Furthermore, a meta-analysis noted that all cardiovascular conditions, such as acute coronary syndrome (ACS) and HF, had an increased risk of in-hospital mortality for patients admitted for CV conditions but not infected with SARS-CoV-2.^{52 , 53} In addition, overall cardiac catheterization laboratory STEMI activations in the United States were reduced by 38% during the early phase of the COVID-19 pandemic.⁵⁴ Similar reductions were seen throughout the world.⁵⁵ Patients who were admitted to the hospital with elevated troponins during the pandemic often waited longer for revascularization and were reported to have double the risk of all-cause mortality and a 20-fold increase in the risk of being hospitalized for HF at 6 months.⁵³ There was also an increase in out-of-hospital cardiac arrest. It is likely that many of these patients had their ACS at home or presented to the hospital late, which may explain the increase in cardiac arrest.⁵⁶

Compared with the year before, the number of primary diagnoses of HF and ACS were reduced by 43%. In addition, there was an incremental decline in daily hospitalization rate by 6% per day in March 2020.⁵⁷ The reasons patients have delayed care are likely multifactorial and complex. The intense media coverage may have unintentionally driven patients from healthy respect for COVID-19 into fear. Delaying care until symptoms were critical could theoretically have led to fewer admissions but a higher severity of the disease in patients seeking treatment.⁵⁸ The arrival and general use of more available communication methods between patients and their providers, for example, telemedicine, may have prevented particular hospitalizations in less severe cases. There is evidence that patients with HF, knowing they are at high risk of developing complications from COVID-19, may have been afraid to go to the hospital and possibly get exposed to infection.⁵⁹ Moreover, some patients may have died of ACS during the COVID-19 pandemic without seeking medical attention. A study in London describing the long-term outcomes of patients admitted with HF in 2020 compared with patients in the previous year observed an increase in all-cause mortality even after discharge. The authors suggested these results from overextended HF resources, and fewer patients were managed in the hospital, as this was associated with an increased all-cause mortality postdischarge.⁶⁰ In addition, medical resources used to prioritize patients with COVID-19 may have left other patients without the care they need. Patients with HF with less urgent conditions may have been subjected to suboptimal and delayed treatments.⁶¹

Summary

The interplay of COVID-19 and HF is complex and involves direct and indirect effects. Patients with existing HF develop more severe COVID-19 symptoms and have worse clinical outcomes. Pandemic-related policies and protocols have negatively affected care for CV conditions and established hospital protocols, which is particularly important for patients with HF. When caring for patients with HF during the pandemic, all these factors should be considered.

Clinics care point

• •When caring for patients with HF during the pandemic, all indirect and direct factors should be considered.

Disclosure

The authors have nothing to disclose.