Search strategy and data sources

A comprehensive literature search was performed across major electronic databases, including PubMed, Scopus, Web of Science, and Embase, to identify peer-reviewed studies published between January 2020 and April 2025. The search strategy combined keywords and Medical Subject Headings (MeSH) terms such as “COVID-19”, “SARS-CoV-2”, “long COVID”, “heart failure”, “cardiovascular complications”, and “long-term outcomes”. Boolean operators (AND, OR) were employed to optimize the search sensitivity and specificity. To ensure full transparency and reproducibility, the complete Boolean search syntax used in each database is provided in the Supplementary material. Additionally, the reference lists of relevant articles were manually screened to identify further eligible studies. Only articles published in English were included. This systematic review was not pre-registered on PROSPERO or a similar platform, as the protocol was developed concurrently with the initial literature search to address the urgent need for evidence synthesis during the early stages of the COVID-19 pandemic. To ensure transparency, all methodological decisions were documented a priori, and the study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.

Inclusion and exclusion criteria

Data extraction and quality assessment

Two independent reviewers used a standardized form to extract data. Extracted information comprised study design, sample size, participant characteristics, HF phenotype, either HFrEF or HFpEF duration of follow-up, key cardiovascular outcomes, and principal conclusions. Inter-reviewer agreement for study selection and data extraction was assessed using Cohen’s kappa coefficient (κ), which demonstrated substantial agreement (κ = 0.87).

The methodological quality of the included studies was evaluated the following validated dated instruments: the Newcastle-Ottawa Scale (NOS) [23] for observational studies and the A MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) [24] tool checklist for systematic reviews. Discrepancies between reviewers were resolved through discussion or consultation with a third reviewer.

Data analysis

A systematic review approach was adopted due to the variability in the study designs and outcome measures. A thematic analysis was performed to identify common patterns related to long-term cardiovascular outcomes in patients with pre-existing HF following COVID-19 infection. Key themes included the incidence of cardiac complications (e.g., arrhythmias, HF exacerbations), mortality trends, proposed pathophysiological mechanisms, and existing gaps in the literature. Studies were categorized based on the HF phenotype (reduced vs. preserved ejection fraction) and follow-up duration. This selection process adhered to PRISMA guidelines to ensure transparency and reproducibility [25]. The findings were synthesized to generate evidence-based insights and inform future research directions. Figure 1 illustrates the study selection process based on the PRISMA framework.

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Figure 1. PRISMA 2020 flow diagram for study selection. * Records identified from databases: PubMed (n = 200), Scopus (n = 150), Web of Science (n = 150), Embase (n = 100), totaling 600 records. No records from registers. Note Final Inclusion: The number of unique studies included (n = 45) is equal to the number of reports included (n = 45), as no study was reported in more than one publication. ** Records excluded at title/abstract screening (n = 80) due to pediatric populations or lack of pre-existing HF (n = 30), short-term or acute-phase outcomes only (n = 20), non-peer-reviewed sources (n = 15), or insufficient cardiovascular detail (n = 15). No studies from previous review (n = 0); all 45 included studies are new. Adapted from [25]. © 2021, The Author(s). Distributed under a Creative Commons Attribution license (CC BY 4.0).

Geographic distribution

The evidence base demonstrated a pronounced dominance of high-income countries, which contributed 84% of the included studies, with only 16% originating from low- and middle-income countries (LMICs), based on the World Bank classification. This highly uneven distribution primarily reflects recognized database indexing bias toward high-income regions and English-language restriction. Consequently, this limits the generalizability of our findings to LMICs where healthcare disparities are greatest and unique population dynamics may exist. Table 1 provides a structured summary of the geographic distribution of included studies by region and income level.

Study population

Participants were adults aged ≥ 18 years with pre-existing HF confirmed by echocardiographic or clinical criteria. Most studies included both hospitalized and non-hospitalized COVID-19 cohorts, and 29 specifically reported HF subtypes (HFrEF/HFpEF). The study populations showed a male predominance (52–68%), a mean age ranging from 60 to 78 years, and a high comorbidity burden. Comorbidities such as hypertension (HTN), diabetes mellitus (DM), chronic kidney disease (CKD), and coronary artery disease (CAD) increased the 12-month readmission risk by 1.3–1.6-fold in multivariable models adjusting for age, sex, and HF severity [26, 27]. In addition, new-onset HTN following COVID-19 infection was found to be related higher risk of cardiovascular events [adjusted hazard ratio (aHR) = 1.57; 95% confidence interval (CI) 1.35–1.81] [28], indicating that confounding was adequately addressed through multivariable adjustment in the included studies. Racial and socioeconomic disparities were also observed, with worse outcomes among Black and Hispanic patients [29, 30].

Heart failure phenotypes and severity

Differentiating between HF subtypes was a key feature across the reviewed studies. Patients were stratified according to left ventricular ejection fraction (LVEF): HFrEF (LVEF < 40%), HF with mildly reduced ejection fraction (HFmrEF) (LVEF 40–49%), and HFpEF (LVEF ≥ 50%), in accordance with current European Society of Cardiology (ESC) and American Heart Association/American College of Cardiology (AHA/ACC) guidelines [9, 31, 32]. This classification enabled consistent reporting across cohorts.

Individuals with HFrEF experienced worse clinical outcomes post-COVID-19, including higher rates of hospital readmission [relative risk (RR) = 1.4; 95% CI 1.2–1.7 vs. HFpEF] and mortality, based on observational data from multiple cohorts [10, 16, 33, 34]. Patients with HFpEF also demonstrated significant vulnerability, particularly in the presence of comorbidities such as HTN, obesity, and DM, which compounded risk profiles [35].

HF severity was primarily evaluated using the New York Heart Association (NYHA) functional classification, with most studies including patients in classes II to IV. A higher baseline NYHA class was consistently associated with an increased risk of long-term cardiovascular complications after COVID-19 [10, 21]. Biomarkers including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin (cTn), were widely used to quantify myocardial stress and injury, and elevated levels during or after the acute phase of infection were associated with poorer prognosis and accelerated HF progression [36, 37].

Racial and socioeconomic disparities were evident: one large cohort reported a 1.5-fold higher mortality risk among Black and Hispanic patients with HF post-COVID-19 compared to White patients, after adjustment for clinical factors [29]. Figure 2 presents the stratification framework for managing HF following COVID-19 infection.

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Figure 2. Stratification model using HF phenotype, NYHA class, and cardiac biomarkers for risk assessment and management post-COVID-19. COVID-19: coronavirus disease 2019; CVS: cardiovascular system; HF: heart failure; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association. Created in BioRender. Batta, A. (2025) https://BioRender.com/2n0ccvt.

Cardiovascular outcomes

Patients with pre-existing HF who contracted COVID-19 exhibited substantially increased long-term cardiovascular complications. Hospital readmissions at 12 months were reported in 18 studies (n = 12,450), with a pooled rate of 28% (95% CI 24–32%; I² = 82%), of which 72% were attributable to HF decompensation [33, 34, 38–40]. Patients with HFrEF demonstrated a 1.4-fold higher readmission risk compared with those with HFpEF (RR = 1.4; 95% CI 1.2–1.7) [33, 34].

Long-term mortality (≥ 12 months) was reported in 14 studies (n = 9,810), with a pooled rate of 18% (95% CI 15–22%; I² = 79%) [7, 16, 17, 26, 41, 42]. Vaccination was associated with a 41% reduction in all-cause mortality and major adverse cardiovascular events (MACE) (aHR = 0.59; 95% CI 0.55–0.63) [38, 43, 44]. Compared with influenza cohorts, COVID-19 survivors had a 1.6–2.1-fold higher rate of HF-related events at 18 months (p < 0.001) [27, 41]. A structured summary of all reported effect estimates, including aHRs, odds ratios (ORs), and corresponding 95% CI for key prognostic outcomes, is provided in Table 2.

Cardiac arrhythmias, particularly atrial fibrillation (AF), were common in both pre-existing and new-onset forms [46, 47]. Telemonitoring detected arrhythmias in 32.5% of patients versus 3.5% under standard care [hazard ratio (HR) = 29.56] [45]. Thromboembolic events, including pulmonary embolism (PE) and ischemic stroke (IS), were reported across multiple cohorts [48, 49]. Myocarditis and persistent myocardial inflammation were confirmed by cardiac magnetic resonance (CMR) and elevated biomarkers in prospective studies [50, 51]. New-onset metabolic abnormalities, such as dyslipidemia and insulin resistance, were also frequently observed post-infection [52].

Among HFpEF patients, higher rates of major adverse cardiac and cerebrovascular events (MACCE) were observed, with notable sex-based differences [53]. Persistent symptoms, including palpitations and chest discomfort, were commonly reported in patient-reported outcome assessments [54].

Proposed pathophysiological mechanisms

Of the 45 included studies, 32 (71%) explicitly discussed mechanisms underlying long-term cardiovascular sequelae. Direct myocardial injury via angiotensin-converting enzyme 2 (ACE2) receptor binding was the most frequently proposed mechanism (n = 28, 88%), followed by systemic inflammation (n = 25, 78%), endothelial dysfunction (n = 20, 63%), and autonomic dysregulation (n = 15, 47%).

Persistent myocardial viral RNA was directly confirmed by biopsy in one study [37], while several additional studies demonstrated ongoing myocardial inflammation or injury highly suggestive of viral persistence using CMR imaging [17, 21, 50, 51]. Systemic inflammation was supported by longitudinal data: interleukin-6 (IL-6) levels > 100 pg/mL at discharge predicted 12-month mortality (sensitivity 78%) [55], although levels normalized in 72% of survivors by six months [53]. Endothelial dysfunction appeared phenotype-specific, with persistent impairment in flow-mediated dilation [ΔFlow-mediated dilation (FMD) = −3.2%, p < 0.01 vs. HFrEF] up to 18 months in HFpEF cohorts [56]. Autonomic dysregulation was reflected by reduced heart rate variability [standard deviation of normal-to-normal intervals (SDNN) < 50 ms in 61% of patients] [47, 57].

Prolonged hypoxemia, renin–angiotensin–aldosterone system (RAAS) and sympathetic activation, and pulmonary-diaphragmatic dysfunction were also implicated [58–61]. Post-COVID metabolic disturbances, including dyslipidemia and new-onset DM, further amplified inflammatory and endothelial injury [52, 62]. Substantial heterogeneity in assessment methods (I² > 75%) precluded formal meta-analysis; therefore, the synthesis focused on high-evidence mechanistic signals to ensure analytical precision and avoid redundant overlap across studies. Figure 3 outlines the key mechanisms involved in post-COVID cardiovascular complications in patients with HF. Table 3 presents the distribution and prevalence of proposed pathophysiological mechanisms underlying long-term cardiovascular sequelae in patients with pre-existing HF following COVID-19.

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Figure 3. Distribution of proposed pathophysiological mechanisms in patients with pre-existing heart failure post-COVID-19. ACE2: angiotensin-converting enzyme 2; COVID-19: coronavirus disease 2019; IL-6: interleukin-6. Created in BioRender. Batta, A. (2025) https://BioRender.com/2n0ccvt.

Functional capacity and quality of life

Six-minute walk distance (6MWD) decreased by 68 meters (95% CI −82 to −54; I² = 71%; 12 studies, n = 3,840) at 6–12 months post-COVID-19 [29, 52, 60, 62, 76]. Minnesota Living with HF Questionnaire (MLHFQ) scores increased by 14.2 points (95% CI 11.8–16.6; I² = 68%) [52, 60, 76].

A significant worsening of functional status was observed in patients with pre-existing heart failure after COVID-19, with the proportion of NYHA class III/IV or equivalent severe limitation increasing from ~28% before infection to ~46% at 12 months in affected cohorts [14, 54]. Vaccinated patients demonstrated a 32-meter greater 6MWD and a 6.1-point lower MLHFQ score compared with unvaccinated individuals (p < 0.01) [76]. Persistent dyspnea (mMRC ≥ 2) was reported in 58% of patients at 12 months [54]. Substantial heterogeneity in measurement tools limited comprehensive meta-analysis. Individual study effect estimates are summarized in Table 4 for comparative interpretation.

Implications for treatment and management

Vaccination was associated with lower all-cause mortality (aHR = 0.59) and improved functional outcomes (+32 m 6MWD; −6.1 points MLHFQ) in vaccinated compared with unvaccinated patients [73, 76, 77]. HFrEF was linked to a 1.4-fold higher readmission risk than HFpEF (RR = 1.4) [31].

Guideline-directed medical therapy (GDMT), including angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter-2 inhibitors (SGLT2i), was utilized across included cohorts [10]. Anti-inflammatory and anticoagulant therapies were investigated in subsets with persistent IL-6 elevation (> 100 pg/mL in 28%) [78]. Telemonitoring was associated with increased arrhythmia detection (32.5% vs. 3.5%; HR = 29.56) [45]. Multidisciplinary rehabilitation programs improved functional capacity, with 6MWD gains of 25–40 m in pilot studies [79].

Despite optimized management, functional decline (6MWD −68 m; MLHFQ +14.2) and persistent symptoms remained prevalent across studies [60].

Limitations of the study

Although multivariable adjustment was performed in most studies, heterogeneity in covariate selection and lack of individual patient data limited formal assessment of confounding and interaction effects. First, the predominance of observational study designs and the lack of individual patient-level data limit causal inference. Second, substantial statistical heterogeneity (I² = 68–82%) reflects variability in study design, populations, and outcome definitions. Third, most included studies originated from high-income countries, restricting generalizability to LMICs settings where healthcare disparities are more pronounced. Fourth, follow-up durations rarely exceeded 18–24 months, limiting insights into chronic myocardial remodeling. Finally, publication bias may have favored studies with significant results, while underreporting of null findings may have inflated risk estimates. Despite adherence to PRISMA methodology, the absence of a registered protocol (e.g., PROSPERO) represents an additional methodological constraint.

Future research directions

Future studies should employ prospective, multicenter designs with standardized definitions of long-COVID cardiovascular outcomes and stratification by HF phenotype. Incorporating advanced imaging modalities, such as CMR and positron emission tomography, alongside biomarker panels (IL-6, NT-proBNP, high-sensitivity troponin) will enhance mechanistic understanding. Randomized controlled trials evaluating anti-inflammatory and antifibrotic therapies, including SGLT2 inhibitors, IL-6 antagonists, and MSC therapy, are needed to establish optimal management strategies. Furthermore, the development of global registries that include underrepresented populations from LMICs would improve external validity and equity in evidence generation. Finally, the long-term cognitive, psychosocial, and socioeconomic consequences of post-COVID HF should be investigated through multidisciplinary research bridging cardiovascular medicine, behavioral science, and public health.

Conclusion

In summary, COVID-19 is associated with a sustained and multifaceted cardiovascular burden on patients with pre-existing HF. The infection appears to accelerate myocardial injury, systemic inflammation, and endothelial dysfunction, contributing to persistently elevated risks of readmission, mortality, and functional decline. Vaccination markedly reduces these risks and should be incorporated as a key component of post-COVID HF management. Optimized GDMT, early rehabilitation, and digital monitoring represent promising strategies to mitigate adverse outcomes.