Treating and diagnosing post-COVID19 infection induced heart failure

Introduction

Coronavirus disease 2019 (COVID-19), a viral illness caused by the novel coronavirus SARS-CoV-2 has resulted in significant morbidity and mortality across the world. COVID-19 is primarily a respiratory illness however, based on the broad-spectrum clinical manifestations associated with the involvement of multiple organs in patients infected with SARS-CoV-2, COVID-19 is now considered a systemic illness. Multiorgan effects of COVID-19 include clinical manifestations pertaining to the cardiovascular, pulmonary, renal, and neuropsychiatric organ systems (1). Several studies have shown that people with COVID-19 exhibited increased risks and 12-month burdens of incident cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, pericarditis, myocarditis, ischemic and non-ischemic heart disease, thromboembolic disease, heart failure (HF) and other cardiac disorders (1-4). The risks of cardiac complications are evident regardless of age, race, sex and other cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease and hyperlipidemia.

Heart failure is one of the main complications of COVID-19, to this regard, few studies have investigated the risk of heart failure during the post-acute phase of COVID-19. In the article published by Zuin et at. (5) it is demonstrated that COVID-19 recovery subjects had an additional 90% risk of developing HF within 9 months from the acute infection. The risk of developing HF is directly influenced by age and previous history of hypertension and resulted higher in the early post-acute phase of the infection.

Biomarkers such as natriuretic peptides have been suggested to be useful in determining the severity of disease and prognosis of clinical outcomes in patients with HF (6). B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are peptides secreted by the cardiac ventricles in response to volume expansion and pressure load. The release of BNP is increased in heart failure, as ventricular cells are recruited to secrete BNP in response to the high ventricular filling pressures (7). Increasing serum BNP and NT-pro-BNP levels grossly correlate with the severity of left ventricle dysfunction and predict the mortality risk in patients with HF. BNP levels are also valuable as a screening tool of HF. BNP tests help to detect patients at high risk of overt heart failure and may help to prevent its progression (8).

Farxiga (dapagliflozin) is the first SGLT2 inhibitor proven to significantly reduce the risk of cardiovascular death and hospitalization for heart failure (9). Farxiga is a sodium glucose co-transporter 2 (SGLT2) inhibitor indicated in adults for Type 2 Diabetes Mellitus, chronic kidney disease and heart failure (10). Farxiga improves heart failure via several mechanisms, including inducing the kidneys to excrete sodium and improving the way the heart contracts and relaxes. It also reduces the elevated activity of the sympathetic nervous system that is associated with heart failure. In light of the above, we hypothesize that with close monitoring of BNP and NT-pro-BNP levels in post-covid patients, the development of heart failure can be identified at an early stage and subsequent treatment with farxiga can help prevent its progression. To prove this hypothesis a comprehensive literature review was conducted in which a description, summary, and critical evaluation of published articles concerning this topic is provided.

Methods

A comprehensive exploration of available literature was performed using electronic databases such as MEDLINE, PubMed, and EMBASE. The exploration was carried out by combining Medical Subject Headings (MeSH) terms and keywords associated with COVID-19, cardiovascular disease, heart failure, biomarkers, natriuretic peptides, and pharmacological agents. The timeframe for the search was limited to English language articles published between January 2020 and December 2022. To supplement the search, relevant articles were manually examined and cross-referenced. The studies included in this analysis were identified by the following references: 1-5 for COVID-19 and cardiovascular disease, 6-8 for heart failure biomarkers, and 9-10 for pharmacological agents in heart failure.

Results and discussion

Several recent publications have drawn attention to the heightened likelihood of cardiovascular issues stemming from COVID-19. In one such report, Farshidfar et al. comprehensively explored the cardiovascular complications arising from COVID-19 infection, which may include myocardial injury, myocarditis, heart failure, arrhythmias, and thrombotic events (1). Several studies have focused on the underlying pathophysiology relating COVID-19 to cardiovascular disease (2). However the exact pathophysiological mechanism underlying the higher risk of HF in COVID-19 survivors has not yet been completely established. Putative mechanisms include lingering damage from direct viral invasion of cardiomyocytes and subsequent cell death, endothelial cell infection and endotheliitis, complement activation and complement-mediated coagulopathy and microangiopathy, downregulation of ACE2 and dysregulation of the renin–angiotensin–aldosterone system, autonomic dysfunction and elevated levels of pro-inflammatory cytokines (11-13). These mechanistic pathways might explain the range of post-acute COVID-19 cardiovascular sequelae and the immunohistochemical analysis of endomyocardial biopsy in post-COVID patients which has shown severe intramyocardial inflammation with increased perforin-positive cells, macrophages, T lymphocytes, CD45R0 T memory cells and cell adhesion molecules(CAM) (14).

The risk of cardiac complications are increased in patients with older age, obesity, hypertension, diabetes, previous cardiovascular disease, cerebrovascular disease, immobility, and chronic respiratory disease. Chung et al. provided insight into the clinical manifestations and treatment of COVID-19-associated cardiovascular complications. The most frequently reported cardiovascular symptoms include chest pain, dyspnea, and palpitations (3). Additionally, Di Toro et al. discussed the emerging concept of "long COVID" which describes a condition characterized by the persistence of symptoms for at least 12 weeks after the onset of COVID-19. Additionally they report the potential long-term impacts of long COVID in cardiovascular health (4). In a meta-analysis, Zuin et al. examined the risk of heart failure following COVID-19 recovery, concluding that COVID-19 recovery subjects had an additional 90% risk of developing HF within 9 months from the acute infection (5). In addition, Lee et al. reported that heart failure was observed in 23% of 191 SARS-Cov-2-positive inpatients. Later it was found that nearly half of the patients had HF as a complication of COVID-19 (15). These findings provide preliminary comprehensive evidence regarding the higher risk of HF in COVID-19 survivors. The HF risk is not limited just to the acute phase of the infection but extends in the medium/long-term period, indicating the need to prevent the infection and to consider the implementation of specific clinical follow-up for these subjects to prevent long-term cardiovascular consequences.

Brain natriuretic peptide (BNP) and N-terminal pro-BNP are frequently utilized biomarkers for diagnosing heart failure and monitoring disease progression. Kinnunen et al. have demonstrated that myocardial stretching can cause BNP release, while Hobbs et al. have confirmed the dependability of the N-terminal pro-BNP assay in diagnosing heart failure among different populations (7,8). Patients with COVID-19 often demonstrate significant elevation of BNP or NT-proBNP. Accordingly, this peptide may theoretically be used as an indicator of clinical severity for SARS-CoV-2 infection. A large nationwide observational cohort study of the American Heart Association’s COVID-19 Cardiovascular Disease Registry showed that elevations in NT-pro BNP on admission to the hospital for COVID-19 predict worse clinical outcomes, including increased risk of death and major cardiovascular complications (16). Given the frequency and non-specific nature of abnormal natriuretic peptide results among patients with COVID-19 infection, clinicians should be advised to measure natriuretic peptides if the diagnosis of acute MI or heart failure are being considered on clinical grounds. In particular, if a highly elevated level of NT-proBNP is found, this may suggest the need to admit the patient or perform a more precise cardiac evaluation, to exclude direct or indirect myocardial involvement (17). Furthermore, the evaluation of NT-proBNP can represent a substitute for invasive monitoring in a context of scarce resources and support the adaptation and early initiation of medical therapy to prevent disease progression and complications.

New medications such as dapagliflozin have demonstrated encouraging results in enhancing outcomes for patients with heart failure and reduced ejection fraction, as demonstrated in the DAPA-HF trial (10). The US Food and Drug Administration has approved dapagliflozin for heart failure treatment among patients with reduced ejection fraction. While the literature indicates that COVID-19 is linked to an elevated risk of cardiovascular issues, current treatment options for COVID-19-induced heart failure remain consistent.

Clinical Hesitancies

The use of Farxiga to treat heart failure has raised some clinical hesitancies. Although Farxiga has shown promising results in improving heart failure outcomes in clinical trials, some concerns have been raised regarding its potential adverse effects. For instance, Farxiga may lead to dehydration, low blood pressure, and an increased risk of diabetic ketoacidosis, which may exacerbate heart failure symptoms. Additionally, some clinicians are concerned about the long-term effects of Farxiga on renal function, particularly in patients with pre-existing renal impairment. These clinical hesitancies highlight the importance of careful patient selection and monitoring during Farxiga treatment.

In addition, the use of BNP peptide as a diagnostic tool for heart failure has also been met with some clinical hesitancies. While BNP is widely used to diagnose heart failure and monitor disease progression, its clinical utility may be limited in certain patient populations. For instance, BNP levels may be elevated in patients with pulmonary disease, renal dysfunction, and obesity, which may confound the diagnosis of heart failure. Additionally, BNP levels may not accurately reflect the severity of heart failure symptoms in all patients. These clinical hesitancies have led some clinicians to rely on multiple diagnostic tests and clinical assessments to diagnose heart failure and monitor disease progression.

Conclusion

In conclusion, COVID-19 has been shown to cause multiorgan effects, with increased risk and burden of incident cardiovascular diseases, including heart failure (HF). Post-COVID-19 recovery subjects had a 90% higher risk of developing HF within 9 months from the acute infection, influenced by age and history of hypertension. Biomarkers such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) can be useful in identifying the severity of disease and prognosis of clinical outcomes in patients with HF. Farxiga (dapagliflozin), a sodium glucose co-transporter 2 (SGLT2) inhibitor, has shown to reduce the risk of cardiovascular death and hospitalization for heart failure. The literature review conducted in this article suggests that with close monitoring of BNP and NT-pro-BNP levels in post-COVID-19 patients, the development of heart failure can be identified at an early stage, and subsequent treatment with farxiga can help prevent its progression. While these tools can be effective in diagnosing and treating heart failure after a COVID-19 infection, they are not replacements for other treatments that may better suit the patient.

References

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Chung, M. K. et al. COVID-19 and cardiovascular disease. Circ. Res. 128, 1214–1236 (2021).

Di Toro, A. et al. Long COVID: long-term effects? Eur. Heart J. Suppl. 23, E1–E5 (2021).

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