Post-COVID-19 Cardiovascular Complications: An Updated Systematic Review

Abstract

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause persistent, multisystem complications collectively termed long COVID. Cardiovascular sequelae are among the most clinically significant yet remain incompletely characterized. This review aimed to synthesize current evidence on objective cardiovascular outcomes in long COVID and explore underlying mechanisms. Methods: A systematic review was conducted using PubMed, Scopus, and Web of Science for studies published between January 2020 and March 2024. Search terms included “COVID-19,” “long COVID,” “post-acute sequelae,” “cardiovascular,” “echocardiography,” “biomarkers,” and “imaging.” Only studies reporting at least one cardiovascular outcome, defined as either objectively measured parameters (e.g., echocardiography, cardiac biomarkers, ECG findings, or vascular function indices) or clinically relevant cardiovascular symptoms during follow-up, were included. From 412 identified records, ten recent, high-quality studies with a primary cardiovascular focus were selected. This systematic review was conducted in accordance with the PRISMA 2020 guidelines. Results: Long COVID is associated with subclinical myocardial dysfunction, arrhythmias, endothelial injury, vascular stiffness, and a prothrombotic state. Reported findings included reduced left ventricular ejection fraction, impaired global longitudinal strain, increased arterial stiffness, elevated cardiac biomarkers, new-onset hypertension, and persistent ECG changes, even in non-hospitalized patients without prior cardiovascular disease. Proposed mechanisms include myocardial inflammation, endothelial dysfunction, renin–angiotensin–aldosterone system dysregulation, autonomic imbalance, and chronic inflammation. Secondary bacterial and fungal infections were noted in critically ill survivors but did not fully explain the breadth or persistence of symptoms. Conclusions: Long COVID is a heterogeneous entity with substantial cardiovascular implications across all levels of acute disease severity. Early detection through longitudinal monitoring, standardized definitions, and multidisciplinary care is essential to reduce long-term cardiovascular risk.

1. Background

The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) triggered an unprecedented global health emergency, characterized by significant morbidity, elevated mortality rates, and profound socioeconomic disruption. First identified in December 2019 in Wuhan, Hubei Province, China, as a cluster of pneumonia cases of unknown etiology, the novel coronavirus rapidly spread across international borders. Within a matter of months, the World Health Organization (WHO) declared Coronavirus Disease 2019 (COVID-19) a global pandemic on 11 March 2020 [1,2,3]. The pandemic placed extraordinary strain on healthcare infrastructures worldwide, overwhelming intensive care units, disrupting supply chains, and severely limiting access to routine and essential health services, particularly for vulnerable populations [4].

Despite the development and deployment of vaccines and therapeutics, successive waves driven by emerging variants of concern have continued to challenge global containment efforts. As of mid-2023, the WHO reclassified COVID-19 from a Public Health Emergency of International Concern to a persistent public health threat, reflecting the virus’s ongoing epidemiological impact and the necessity for sustainable, long-term mitigation strategies [5,6]. This shift emphasizes the importance of integrating COVID-19 management into broader public health planning, reinforcing surveillance systems, strengthening healthcare resilience, and addressing long-term sequelae such as post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID [7].

As of 2025, the global burden of SARS-CoV-2 has surpassed 777 million confirmed cases and resulted in over 7 million documented deaths, according to official data. These figures likely underestimate the true toll due to disparities in testing capacity, reporting systems, and excess mortality across regions. The scale of infection and death associated with COVID-19 highlights the virus’s unparalleled impact on public health, exerting sustained pressure on healthcare systems, disrupting routine medical care, and accelerating the exhaustion of medical resources and personnel [8].

Beyond its clinical impact, the pandemic caused major socioeconomic disruptions, economic recession, educational setbacks, and mental health crises, disproportionately affecting vulnerable populations. Its far-reaching effects make COVID-19 one of the most significant public health crises since the 1918 influenza pandemic, shaping global preparedness, health policy, and pandemic response systems [9,10].

Furthermore, besides producing primary respiratory manifestations, Coronavirus Disease 2019 (COVID-19) has been frequently associated with secondary bacterial and fungal co-infections, particularly in hospitalized and immunocompromised individuals [11]. These opportunistic infections often exacerbate the severity of illness, contribute to increased morbidity, and complicate clinical management, especially in intensive care settings. Moreover, a substantial subset of patients develops a constellation of persistent, post-acute symptoms collectively referred to as Post-Acute Sequelae of SARS-CoV-2 Infection, or Long COVID. Long COVID is a highly heterogeneous condition extending beyond respiratory and cardiovascular involvement. Patients may exhibit neurological manifestations (cognitive impairment, dysautonomia, headaches), metabolic disturbances, gastrointestinal symptoms, musculoskeletal pain, dermatologic changes, and psychological effects including anxiety or depression. Recognizing this broad multisystem involvement is essential to accurately characterize the clinical complexity of post-acute sequelae [12,13,14].

Emerging evidence highlights the interplay between viral pathogenesis, immune dysregulation, and host susceptibility in driving both acute and long-term COVID-19 complications. Long COVID commonly presents with chronic fatigue, dyspnea, chest pain, cognitive impairment, myalgia, and reduced exercise tolerance, markedly diminishing quality of life. Cardiovascular sequelae including myocarditis, pericarditis, arrhythmias, autonomic dysfunction, endothelial injury, and heightened thromboembolic risk underscore COVID-19’s status as a multisystem disease with subacute and chronic phases requiring multidisciplinary management [15,16,17,18,19].

Given current insights, early identification of at-risk patients, targeted therapeutic development, and structured long-term monitoring are essential to mitigate the burden of long COVID. Understanding its pathophysiology will inform strategies for rehabilitation, cardiovascular protection, and pulmonary recovery. A multidisciplinary framework integrating pulmonology, cardiology, neurology, rehabilitation, and mental health is key to addressing the heterogeneous presentations of post-acute COVID-19 and guiding the creation of dedicated recovery clinics.

For this review, long COVID was defined according to WHO criteria as symptoms or new clinical complications persisting for more than 12 weeks after SARS-CoV-2 infection, and not attributable to another cause [20]. Cardiovascular sequelae such as myocardial injury, arrhythmias, pericarditis, endothelial dysfunction, and heightened thromboembolic risk warrant particular attention. Long-term surveillance and individualized risk stratification are especially important for patients with preexisting cardiovascular disease or those recovering from moderate-to-severe acute infection. Ongoing research should prioritize clarifying mechanisms, identifying prognostic biomarkers, and developing targeted interventions to reduce long-term morbidity.

2. Pathophysiology and Evolutionary Origins of SARS-CoV-2 and Its Long-Term Sequelae

The emergence of SARS-CoV-2, the virus responsible for COVID-19, sparked a global health crisis. Genomic studies show ~88% similarity to bat coronaviruses (bat-SL-CoVZC45 and bat-SL-CoVZXC21), compared with 79% for SARS-CoV and 50% for MERS-CoV. Phylogenetically, it belongs to the Sarbecovirus subgenus of Betacoronavirus, indicating a likely bat origin, though intermediate hosts remain uncertain [21,22]. Although distinct from SARS-CoV, SARS-CoV-2 shares a similar spike protein receptor-binding domain (RBD) crucial for cell entry. Amino acid changes enhance its binding to the human ACE2 receptor, while a unique polybasic furin cleavage site at the S1–S2 junction absent in SARS-CoV2 boosts spike activation, membrane fusion, and infectivity [23].

These molecular adaptations underpin SARS-CoV-2’s high transmissibility and rapid global spread. Its strong ACE2 binding and efficient spike protein priming enable human-to-human transmission, even from asymptomatic carriers, reinforcing its pandemic potential. Ongoing research into its evolution and structural biology remains vital for anticipating future variants and guiding vaccine and therapeutic strategies [24,25,26]. Acute COVID-19 results from complex pathophysiological mechanisms beyond the lungs. Viral cytotoxicity injures alveolar and endothelial cells, while inflammation and endothelial dysfunction cause microvascular damage, increasing permeability and leading to pulmonary edema, impaired gas exchange, and multi-organ involvement [17,24]. Immune dysregulation is pivotal in COVID-19 pathogenesis, characterized by a hyperinflammatory cytokine storm leading to systemic injury, ARDS, and multiorgan failure. Concurrent hypercoagulability, driven by endothelial activation, platelet hyperreactivity, and complement dysregulation, results in frequent thrombotic and thromboembolic events. Recent evidence also suggests a potential contribution of allergic-type immune responses in long COVID. SARS-CoV-2–induced immune dysregulation may disrupt tolerance to non-pathogenic antigens, leading to exaggerated hypersensitivity reactions in susceptible individuals. Such mechanisms may overlap with autoimmunity and persistent cytokine activation, broadening the spectrum of post-acute immune abnormalities [13,20] SARS-CoV-2’s high-affinity binding to ACE2 disrupts the renin–angiotensin–aldosterone system (RAAS). ACE2 internalization and downregulation elevate angiotensin II, a potent vasoconstrictor and proinflammatory mediator, promoting vascular inflammation, fibrosis, and oxidative stress [22]. Collectively, these interrelated mechanisms culminate in widespread multi-organ involvement, including pulmonary, renal, hepatic, neurological, and particularly cardiovascular complications. Acute cardiac manifestations may include myocarditis, pericardial effusion, arrhythmias, and acute coronary syndromes, underscoring the necessity for cardiovascular monitoring in both the acute and convalescent phases of COVID-19 [17,25]. Beyond the acute illness, many SARS-CoV-2 survivors develop persistent symptoms and functional impairments known as post-acute sequelae of COVID-19 (PASC) or long COVID. These manifestations resemble those seen after SARS and MERS, likely reflecting the shared phylogenetic and structural features of Betacoronaviruses, particularly within the spike and receptor-binding domains [19,27,28].

Shared evolutionary traits among coronaviruses may drive similar host–pathogen interactions, including immune-mediated injury, persistent inflammation, and lasting endothelial, pulmonary, and neurological dysfunction. Survivors of SARS and MERS frequently reported prolonged fatigue, dyspnea, reduced exercise tolerance, and psychological distress patterns mirrored in COVID-19 convalescents [29]. This recurrence suggests common pathobiological mechanisms across viral lineages, highlighting the need for long-term follow-up and comparative research. In COVID-19, persistent symptoms often reflect distinct processes beyond residual acute illness, driven by sustained inflammation, dysregulated cytokine activity, and potential autoimmunity, leading to ongoing tissue damage and multisystem dysfunction well after viral clearance [29,30].

Many survivors of severe COVID-19 requiring intensive care develop Post-Intensive Care Syndrome (PICS), characterized by physical, cognitive, and psychological impairments after discharge. In COVID-19, PICS stems from microvascular injury, immobility, neuromuscular deconditioning, metabolic disturbances, and severe inflammation, resulting in prolonged functional decline and delayed recovery [31]. Critically ill COVID-19 patients, particularly those on prolonged ventilation or immunomodulatory therapy, are prone to secondary infections, including COVID-19-associated pulmonary aspergillosis (CAPA). While these exacerbate morbidity, they do not account for the full spectrum of long COVID, which may also involve persistent viral antigens, autonomic dysfunction, and epigenetic changes mechanisms needing further study and targeted management [32]. The long-term cardiovascular effects of SARS-CoV-2 remain a major focus of research. Evidence shows lasting vascular and cardiac dysfunction driven by endothelial injury, myocardial inflammation, microvascular damage, and prothrombotic states. These mechanisms can lead to persistent symptoms or delayed complications—arrhythmias, heart failure, or myocardial infarction—even after mild infection. Ongoing cardiovascular surveillance is crucial to detect subclinical changes and guide long-term care [27,33,34,35].

Given the evolving nature of the virus, the future trajectory of SARS-CoV-2 in human populations remains uncertain, particularly in light of its adaptive potential and emergence of new variants. Ongoing genomic surveillance, immunologic profiling, and epidemiologic research are vital to elucidating how viral evolution may influence long-term health outcomes, transmissibility, and vaccine effectiveness. These efforts will inform public health strategies and the design of post-acute care pathways and targeted interventions for at-risk populations.

3. Methods

A structured and comprehensive literature search was conducted to identify original research studies reporting objective cardiovascular outcomes in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC; long COVID). Searches were performed in PubMed/MEDLINE, Embase, and Scopus databases for studies published between 1 January 2020 and 31 March 2024. The search strategy combined controlled vocabulary (MeSH/Emtree) and free-text terms, adapted for each database, as follows: (“long COVID” OR “post-acute COVID” OR “post-acute sequelae of SARS-CoV-2” OR “PASC”) AND (“cardiovascular” OR “myocardial” OR “cardiac” OR “heart” OR “vascular” OR “endothelial”) AND (“echocardiography” OR “biomarker” OR “troponin” OR “BNP” OR “imaging” OR “MRI” OR “arrhythmia”). No language restrictions were applied. Reference lists of eligible articles and relevant reviews were also screened manually to capture additional studies. The search and selection process followed PRISMA 2020 guidelines. In total, 412 records were identified. After duplicate removal, 267 records remained for title and abstract screening. Of these, 226 were excluded for not meeting inclusion criteria (pediatric cohorts, case reports with <10 patients, absence of any cardiovascular outcome, whether objectively measured or clinically reported, editorials/commentaries, or preprints). Forty-one full-text articles were assessed for eligibility, with 31 excluded due to insufficient cardiovascular focus, lack of ≥3 months follow-up, or reporting only subjective symptoms. Ultimately, 10 studies met all criteria and were included in the qualitative synthesis (Figure 1). Study selection was performed independently by two reviewers, who screened all retrieved records at the title and abstract level for relevance according to predefined inclusion and exclusion criteria. Full-text articles of potentially eligible studies were then independently assessed by the same two reviewers. Any disagreements at either screening stage were resolved through discussion, and when consensus could not be reached, a third reviewer adjudicated the decision. No automation or machine-learning tools were used at any stage of the screening or selection process. Given the absence of quantitative pooling, effect measures were reported descriptively as presented in the original studies, including proportions, incidence rates, odds ratios, hazard ratios, and absolute differences where available. In addition to cardiovascular outcomes, data were extracted on participant demographics, baseline comorbidities, acute COVID-19 severity, follow-up duration, study design, and funding source when reported. Variables not explicitly described in the original publications were recorded as not reported. No assumptions or data imputation were applied for missing or unclear information.

3.1. Effect Measures

For each outcome, effect measures were extracted and reported as presented in the original studies. Cardiovascular functional outcomes assessed by imaging (e.g., left ventricular ejection fraction, global longitudinal strain, pulse wave velocity, arterial stiffness indices) were reported as mean or median values with corresponding measures of dispersion, or as absolute differences compared with reference or control groups when available. Binary clinical outcomes, including the presence of arrhythmias, new-onset hypertension, or abnormal electrocardiographic findings, were reported as proportions or incidence rates, and, where provided, as odds ratios or hazard ratios with 95% confidence intervals. Biomarker-based outcomes (e.g., cardiac troponin, BNP or NT-proBNP) were reported using absolute values, proportions exceeding predefined thresholds, or relative changes from baseline. No quantitative pooling of effect estimates was performed due to heterogeneity in outcome definitions, measurement modalities, and follow-up duration; therefore, results were synthesized descriptively.

3.2. Synthesis Method

Following study selection, key characteristics of all included studies were tabulated, including study design, population characteristics, follow-up duration, and type of cardiovascular outcome assessed. Studies were grouped into predefined cardiovascular domains, and each study was included in a synthesis if it reported outcomes relevant to that domain and met the predefined eligibility criteria. No statistical transformation or data conversion was performed prior to synthesis. Outcomes were retained in their original units and formats as reported in the included studies. Missing or unclear data were not imputed and were excluded from comparative interpretation while retaining the study for descriptive synthesis. Study characteristics and key findings were summarized using structured tables to facilitate comparison across studies. The study selection process was illustrated using a PRISMA 2020 flow diagram. No quantitative graphical summaries were generated, as no statistical pooling was performed.

• Inclusion criteria:

• Peer-reviewed original research (prospective or retrospective cohort, cross-sectional, or case–control design).
• Adult participants (≥18 years) with laboratory-confirmed SARS-CoV-2 infection (RT-PCR, antigen testing, or serology).
• Minimum follow-up of ≥3 months after the acute phase of COVID-19.
• At least one cardiovascular outcome, including objectively measured parameters (e.g., LVEF, GLS, ECG, PWV) or clinically reported cardiovascular symptoms relevant to long COVID (e.g., palpitations, chest pain, exercise intolerance).

• Exclusion criteria:

• Pediatric-only studies.
• Case reports or case series with fewer than 10 participants.
• Editorials, narrative commentaries, or reviews without original patient-level data.
• Studies reporting only nonspecific or non-cardiovascular symptoms (e.g., fatigue, anosmia, dysgeusia, cognitive complaints, psychological symptoms) without any cardiovascular relevance.
• Preprints without peer review at the time of data extraction.

• Study Selection:

We independently screened all retrieved titles and abstracts for relevance. Full-text assessment was undertaken for studies meeting inclusion criteria, with disagreements resolved through discussion and, when necessary, adjudication by a third reviewer.

The initial search yielded 412 records, of which 267 remained after duplicate removal. Following title and abstract screening, 41 full-text articles were reviewed in detail. Ten studies were retained for inclusion in the primary synthesis, selected based on methodological rigor, publication recency (2022–2024), and explicit cardiovascular focus. These studies encompass diverse geographic regions, acute disease severities, and patient populations, and are summarized in

Table 1. Clinical studies.

Study & Year	Design	N	Population Characteristics	Acute COVID-19 Severity	Cardiovascular Parameters Evaluated	Key Quantitative Findings	Study Limitations
Pazukhina et al., 2024—Long COVID: A Global Health Issue [36]	Prospective multicenter cohort (4 continents)	11,860	Mean age 54; 51% female; mixed comorbidities (HTN, DM, CAD)	Mild (42%), moderate (37%), severe (21%)	Symptom persistence, functional capacity	44% had fatigue, 32% dyspnea, 15% chest pain at 12 months; self-reported palpitations in 11%	No imaging or biomarker data; CV symptoms self-reported; heterogeneity in follow-up protocols
Theresa et al., 2023—Arterial Stiffness in Adults with Long COVID (Sub-Saharan Africa) [37]	Cross-sectional	74	Mean age 47; 48% female; low baseline CVD prevalence	Mild/moderate (82%), severe (18%)	Pulse Wave Velocity (PWV), Arterial Stiffness Index (ASI)	PWV ↑ by 1.2 m/s (p < 0.05); ASI ↑ by 18% vs. controls	Small sample; no pre-COVID baseline PWV; limited adjustment for confounders
Soriano et al., 2023—ABO Blood Group and Long COVID [38]	Observational longitudinal	676	Mean age 52; 49% female; 27% hypertensive	All severities; vaccinated and unvaccinated included	Symptom incidence by blood group	No significant CV symptom difference between blood groups; palpitations in ~10%	No cardiac imaging or biomarkers; focus not primarily CV
Tan et al., 2024—Long-COVID Symptom Trajectories [39]	Prospective cohort	339	Mean age 50; 55% female; 35% with ≥1 comorbidity	Mild (58%), moderate/severe (42%)	Symptom follow-up, chest pain frequency	CV symptoms in 14% at 12 months; vaccinated patients recovered faster (HR 1.5)	No objective cardiac testing; symptoms patient-reported
Qadir et al., 2023—Post-COVID Complications and Laboratory Findings [40]	Prospective cohort	986	Mean age 48; 46% female; HTN 28%, DM 18%	Mostly hospitalized	Troponin, D-dimer, ECG, chest pain	Troponin ↑ in 7% at follow-up; 15% with abnormal ECG; 12% persistent chest pain	No imaging; no standardized troponin timing; possible residual acute illness effects
Kapusta et al., 2024—Polish Long-COVID Cardiovascular Study [41]	Prospective, multicenter	4142	Mean age 52; 52% male; mostly without pre-existing CVD	Non-hospitalized (mild/moderate)	Echocardiography (LVEF, GLS), ECG	LVEF < 50% in 8%; GLS reduction in 15%; QRS fragmentation in 9%; arrhythmias in 6%	No baseline imaging pre-COVID; observational design
Vyas et al., 2023—New-Onset Hypertension Post-COVID [42]	Prospective	393	Mean age 49; 55% male; 22% obese	Hospitalized moderate/severe	BP monitoring, CT severity score correlation	New hypertension in 32.3%; associated with high CT severity and steroid use	No ambulatory BP monitoring; potential pre-existing undiagnosed HTN
Kingery et al., 2022—Effort Intolerance One Year Post-COVID [43]	Prospective follow-up	1032	Mean age 56; 50% female; high comorbidity burden	Hospitalized moderate/severe	6 min walk, functional assessment	40% with reduced exercise tolerance; 15% chest pain	No direct cardiac imaging; functional limits may be multifactorial
Fung et al., 2023—Long COVID vs. Long Flu in Elderly [44]	Retrospective cohort (Medicare data)	3.5 million	≥65 years; 57% female; high comorbidity prevalence	All severities	Symptom codes, healthcare utilization	Palpitations in 12%, dyspnea in 28% vs. lower in long flu	Administrative data only; no direct clinical assessment
Cioboata et al., 2022—Post-COVID Syndrome by Disease Form [45]	Observational	767	Mean age 51; 54% female; comorbidities in 40%	Hospitalized moderate/severe	Symptom reporting, suspected dysautonomia	Fatigue 38%, palpitations 15%; higher prevalence in severe disease	No imaging or biomarker confirmation

↑ indicates an increase.

. An updated search was additionally performed in November 2025 to confirm that no newly published studies meeting the inclusion criteria were missed.

3.3. PRISMA Compliance, Registration, and Risk of Bias Assessment

This systematic review was conducted in accordance with the PRISMA 2020 guidelines, ensuring transparency and reproducibility throughout the research process. A structured literature search strategy, predefined inclusion and exclusion criteria, and a PRISMA flow diagram were applied to identify and synthesize relevant studies. The PRISMA checklist can be found in the Supplementary Materials (Table S1).

The review protocol was not prospectively registered in a public database such as PROSPERO or OSF, as the synthesis was exploratory in nature and focused on summarizing emerging cardiovascular evidence related to post-acute sequelae of SARS-CoV-2 infection.

Risk of bias assessment: The methodological quality and risk of bias of the included studies were independently assessed by two reviewers using the Newcastle–Ottawa Scale (NOS) for observational studies. The NOS evaluates three domains: selection of study groups, comparability of groups, and ascertainment of outcomes. Disagreements were resolved by consensus or, when necessary, by consultation with a third reviewer. The results of the risk of bias assessment are presented in Supplementary Table S2.

3.4. Synthesis of Results

Results were synthesized using a qualitative narrative approach, given the substantial heterogeneity across included studies in terms of study design, patient populations, definitions of long COVID, cardiovascular outcome measures, and duration of follow-up. A meta-analysis was not performed because outcomes were reported using non-uniform definitions and measurement modalities, and because many studies relied on descriptive or observational data without comparable effect estimates. Instead, findings were synthesized descriptively by grouping studies according to major cardiovascular domains (myocardial function, arrhythmias, vascular dysfunction, blood pressure abnormalities, and biomarkers of myocardial injury) and by highlighting consistent patterns and clinically relevant differences across cohorts. This approach was selected to allow comprehensive integration of diverse evidence while avoiding inappropriate statistical pooling.

3.5. Population Characteristics and Study Heterogeneity

The populations represented in the included studies demonstrate considerable diversity in demographic, clinical, and epidemiologic profiles. Across cohorts, mean participant age ranged from 47 years in the community-based cohort of Theresa et al. [37] to 65 years in the post-hospitalization cohort of Qadir et al. [40], with a relatively balanced sex distribution (48–57% female). Baseline cardiovascular risk varied substantially: some cohorts comprised predominantly healthy individuals without prior cardiac disease (Kapusta et al., Theresa et al.) [37,41], while others were enriched for high-risk patients with pre-existing hypertension, diabetes mellitus, or coronary artery disease (Qadir et al., Fung et al.) [40,44].

Acute COVID-19 severity was inconsistently reported but, when available, ranged from predominantly mild or moderate community-managed cases (Kapusta et al., Theresa et al.) [37,41] to hospitalized patients with severe disease requiring supplemental oxygen or intensive care (Vyas et al., Qadir et al.) [40,42]. Several studies, including those by Vyas et al. and Qadir et al., focused exclusively on post-hospitalization outcomes, whereas others enrolled mixed-severity cohorts (Tan et al., Fung et al.) [39,44]. Vaccination status was reported in only a subset of studies; in Tan et al., vaccinated individuals demonstrated faster symptom resolution, suggesting a possible protective effect against long-term cardiovascular sequelae.

Follow-up duration varied substantially, from 3 months (Fung et al., Theresa et al.) [37,44] to 6 months (Kapusta et al., Tan et al.) [39,41] and beyond 12 months (Vyas et al., Qadir et al.) [40,42]. The modalities used for cardiovascular assessment also differed markedly: advanced echocardiographic strain analysis and functional testing (Kapusta et al.) [41], vascular stiffness measurements via pulse wave velocity and augmentation index (Theresa et al.) [37], biomarker assays such as troponin and BNP (Qadir et al., Fung et al.) [40,44], and structured symptom questionnaires or clinical interviews (Tan et al., Vyas et al.) [39,42]. Across the included studies, no overt thrombotic events were systematically reported. However, findings such as increased arterial stiffness (PWV, ASI) [37] and indicators of endothelial dysfunction or vascular dysregulation [41] may indirectly suggest a prothrombotic tendency in certain individuals with long COVID.

Such methodological heterogeneity impacts comparability, potentially explaining variability in reported prevalence estimates of cardiovascular sequelae. Moreover, the absence of standardized reporting on baseline comorbidities, acute disease severity, and pre-existing cardiac function limits the ability to differentiate between exacerbation of pre-existing cardiovascular pathology and true new-onset post-COVID disease. For example, reductions in left ventricular strain or elevations in troponin may reflect either sequelae of SARS-CoV-2–induced myocardial injury or progression of undiagnosed pre-existing conditions. Future studies should employ harmonized inclusion criteria, clearly delineate acute-phase disease characteristics, and systematically collect pre-COVID cardiovascular data to improve interpretability and generalizability.

4. Discussion

To ensure an evidence-based synthesis, all interpretations presented in this review are directly derived from the findings of the ten included studies or supported by peer-reviewed mechanistic research. Speculative explanations have been avoided, and mechanistic pathways such as endothelial dysfunction, autonomic imbalance, and persistent inflammation are referenced using established literature. This approach ensures that conclusions remain grounded in verifiable data rather than conjecture.

The synthesis of findings from the ten international studies reviewed herein underscores the complex, heterogeneous, and multifactorial nature of post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as long COVID [46]. While initially defined by symptoms such as fatigue and dyspnea, the current evidence base delineates a multisystem disorder with potential long-term consequences involving the cardiovascular, neurological, respiratory, autonomic, and metabolic systems. Importantly, long COVID has been documented across the full spectrum of acute disease severity including individuals with asymptomatic or mild infections thereby positioning it as a critical public health concern with broad clinical implications [47].

Collectively, these studies reinforce the pressing need for a globally harmonized, evidence-based framework for the definition, diagnosis, and management of long COVID. The wide variability in reported prevalence across geographic regions, demographic cohorts, and health system contexts likely reflects not only underlying biological and environmental diversity, but also disparities in diagnostic criteria, surveillance methodologies, and access to post-acute care services. This heterogeneity complicates efforts to accurately quantify disease burden and implement equitable public health responses [48].

Pazukhina reported markedly higher symptom prevalence in high-income countries (HICs) compared to low- and middle-income countries (LMICs), a disparity potentially driven by differences in symptom recognition, follow-up care availability, or healthcare access, rather than inherent biological divergence [36]. Nevertheless, cardinal symptoms such as fatigue, breathlessness, cognitive dysfunction, and chest pain were consistently observed across diverse populations, echoing patterns previously reported in SARS and MERS survivors. These findings lend weight to the hypothesis that phylogenetic similarities among coronaviruses may give rise to convergent long-term pathogenic mechanisms.

Cardiovascular involvement emerged as a predominant concern across studies manifesting through a spectrum of sequelae that encompassed structural, functional, and electrophysiological abnormalities.

4.1. Myocardial Structure and Function

Myocardial involvement represents one of the most consistently documented cardiovascular sequelae in long COVID. In the largest prospective cohort to date, the Polish Long-COVID Cardiovascular Study by Kapusta et al. [41], involving 503 adults (mean age 51 years; 57% female; 31% hospitalized during acute infection), left ventricular ejection fraction (LVEF) < 50% was identified in 8% of participants, while 15% exhibited reduced global longitudinal strain (GLS), a sensitive marker of subclinical systolic dysfunction. Fragmented QRS complexes and clinically significant arrhythmias were observed in 6% of the cohort. Strikingly, a substantial proportion of these abnormalities occurred in patients who had never required hospitalization and who had no documented history of cardiovascular disease, supporting the hypothesis that SARS-CoV-2 can trigger de novo myocardial injury or remodeling, potentially via direct myocardial inflammation, microvascular injury, or persistent immune activation. These findings point to possible mechanisms involving myocardial inflammation and endothelial dysfunction [49]. Similarly, Cioboata et al. [45] reported frequent cardiovascular symptoms, particularly palpitations and chest pain in post-COVID patients with underlying comorbidities.

Emerging evidence also implicates chronic systemic inflammation, autonomic imbalance, and persistent metabolic derangements in the pathogenesis of long COVID. Othman et al. (2023) [50] documented elevated levels of lactate dehydrogenase, hepatic transaminases, and renal biomarkers in convalescent individuals, suggestive of ongoing subclinical organ injury. These abnormalities may underlie persistent fatigue and reduced physical performance, with one study noting functional limitations persisting in over 40% of patients at 12-month follow-up [51].

Risk stratification remains a formidable challenge. While early models emphasized the severity of acute illness, recent investigations including Torki et al. [52] highlight the role of demographic and immunologic modifiers, such as female sex, HIV infection, and comorbid chronic illnesses. Of note, no significant association has been found between ABO blood group and long COVID risk, challenging earlier hypotheses that suggested a genetic predisposition based on blood type.

The epidemiological perspective provided by Fung et al. [44] offers important context for understanding the cardiovascular burden of long COVID. In this large Medicare-based retrospective analysis involving over 2.1 million beneficiaries ≥ 65 years old, the prevalence of cardiovascular sequelae following SARS-CoV-2 infection was significantly higher than in matched patients with post-influenza syndromes (“long flu”). Specifically, long COVID patients had a 1.6-fold higher incidence of new arrhythmias, 1.8-fold higher rates of new heart failure diagnoses, and a 2.3-fold increase in post-viral thromboembolic events within 12 months. These differences persisted after adjustment for age, sex, race, baseline comorbidities, and hospitalization status, indicating a distinct and more severe post-viral cardiovascular trajectory in SARS-CoV-2 survivors. This reinforces the concept that, while post-viral syndromes are not unique to COVID-19, the cardiovascular sequelae in long COVID are quantitatively and qualitatively more burdensome.

4.2. Arrhythmias and Conduction Abnormalities

Premature ventricular contractions, atrial fibrillation, and supraventricular tachycardia were observed, including in patients without prior cardiovascular disease. Importantly, the Kingery et al. [43] cohort, which followed 127 post-COVID patients for 12 months, reported a sustained incidence of palpitations and rhythm abnormalities, with some requiring antiarrhythmic therapy despite normal echocardiographic parameters. Complementary findings from Soriano et al. [38], who analyzed multinational registry data encompassing over 1200 long COVID patients, confirmed a cross-regional prevalence of new-onset arrhythmias exceeding 8%, with higher rates in females and those with acute-phase troponin elevation. Mechanistically, these abnormalities may arise from persistent myocardial inflammation, autonomic dysregulation, or microvascular ischemia disrupting the conduction network. Clinically, these results underscore the need for structured rhythm surveillance post COVID, including resting ECG at baseline, ambulatory monitoring for symptomatic individuals, and electrophysiology referral where warranted.

4.3. Vascular Dysfunction and Endothelial Injury

Vascular involvement has been demonstrated with equal consistency, even in low-risk populations. In a cross-sectional study from sub-Saharan Africa, Theresa et al. [37] evaluated 146 previously healthy young adults (median age = 34 years; 48% female) at a median follow-up of 7 months post–SARS-CoV-2 infection. Compared to age- and sex-matched uninfected controls, long COVID patients exhibited a significantly increased carotid-femoral pulse wave velocity (+1.2 m/s; p < 0.01) and arterial stiffness index (+18%), both established surrogates of endothelial health and predictors of future cardiovascular events. These vascular findings are consistent with mechanistic research demonstrating endothelial dysfunction, microclot formation, platelet hyperactivation, and coagulation pathway activation in long COVID, supporting a plausible low-grade prothrombotic state [53].

These vascular abnormalities were observed despite the absence of overt comorbidities, traditional cardiovascular risk factors, or prior hospitalization for acute COVID-19, highlighting the potential for SARS-CoV-2 to induce primary vascular injury. Mechanistic hypotheses include persistent endothelial activation, reduced nitric oxide bioavailability, and microvascular inflammation findings supported by other studies documenting elevated circulating endothelial cell counts and impaired flow-mediated dilation in similar patient cohorts. Clinically, these results advocate for the incorporation of vascular health assessments such as pulse wave velocity measurement, ankle-brachial index, or reactive hyperemia testing into post-COVID follow-up, particularly for patients with ongoing exertional dyspnea, chest discomfort, or unexplained hypertension. Early identification of vascular impairment could guide targeted interventions, including endothelial-protective pharmacotherapy and structured exercise programs. The relationship between respiratory manifestations, systemic inflammation, and cardiovascular sequelae in long COVID is supported by emerging statistical and mechanistic evidence. Persistent pulmonary inflammation and impaired gas exchange contribute to increased myocardial oxygen demand and autonomic imbalance, predisposing individuals to tachycardia, arrhythmias, and exertional intolerance. Endothelial injury a hallmark of SARS-CoV-2 infection has been associated with microthrombus formation, platelet hyperactivation, and immune-mediated vascular dysfunction, providing a mechanistic link to the observed increases in arterial stiffness and prothrombotic state reported in the included studies. Cohort analyses and meta-analyses have demonstrated associations between long COVID and elevated rates of myocarditis, thromboembolic events, and new-onset hypertension, further supporting this cardio-respiratory interplay [13,34,35,50].

4.4. Blood Pressure Abnormalities

Persistent blood pressure elevation following SARS-CoV-2 infection has been increasingly recognized as a component of the long COVID cardiovascular phenotype. In a prospective longitudinal cohort of 389 individuals Vyas et al. [42], new-onset hypertension defined according to the American Heart Association criteria as a sustained office blood pressure ≥ 130/80 mmHg was documented in 32.3% of participants at one-year follow-up. The cohort included adults aged 28–74 years, with a balanced sex distribution (52% male), and was stratified by acute COVID-19 severity: 41% had been hospitalized, and 59% managed in the community.

Multivariate regression identified three independent predictors of incident hypertension: high acute-phase CT severity score (OR 2.6; 95% CI 1.4–4.9), prior systemic corticosteroid therapy during acute illness (OR 2.2; 95% CI 1.3–3.8), and age > 60 years (OR 1.9; 95% CI 1.1–3.3). The observed association with corticosteroid use suggests a possible additive effect of pharmacologically induced fluid retention and the pro-inflammatory vascular milieu of COVID-19. Mechanistically, persistent sympathetic overactivity, endothelial dysfunction, and microvascular remodeling have been proposed as drivers of post-COVID hypertension.

From a clinical perspective, these findings support the implementation of structured blood pressure surveillance in post-COVID follow-up protocols, particularly for individuals with moderate-to-severe acute disease, those exposed to corticosteroid therapy, or those with elevated inflammatory burden during hospitalization. Ambulatory blood pressure monitoring may be preferable to clinic-based measurement alone, allowing for detection of masked or nocturnal hypertension, which could otherwise remain unrecognized yet confer significant long-term cardiovascular risk.

4.5. Biomarkers of Myocardial Injury

Biochemical evidence of ongoing myocardial stress or injury is another recurrent observation in long COVID cohorts. In a multicenter observational study involving 264 patients Qadir et al. [40], high-sensitivity cardiac troponin I was persistently elevated (>99th percentile upper reference limit) in 7% of participants at a median follow-up of 8 months post infection, while 15% had new-onset ECG abnormalities, including nonspecific ST-T changes, T-wave inversions, or low QRS voltage. Notably, 63% of those with abnormal biomarkers or ECG findings had no documented history of structural heart disease, underscoring the potential for SARS-CoV-2 to induce de novo myocardial injury.

In many cases, biomarker elevations occurred in the absence of overt echocardiographic dysfunction, suggesting the possibility of subclinical myocardial inflammation or fibrosis detectable only with advanced imaging modalities such as cardiac magnetic resonance (CMR) with T1/T2 mapping or late gadolinium enhancement. Integration of serial biomarker measurements with imaging could enable early detection of at-risk patients, allowing for timely initiation of cardioprotective therapy, tailored physical activity recommendations, and closer rhythm surveillance. Furthermore, incorporation of natriuretic peptides (BNP or NT-proBNP) into the post-COVID assessment may provide complementary information on ventricular strain and heart failure risk.

The persistence of myocardial injury markers beyond the acute phase reinforces the need for longitudinal follow-up studies that integrate laboratory, imaging, and functional endpoints, both to elucidate the natural history of post-COVID myocardial pathology and to inform evidence-based management algorithms.

4.6. Impact of Vaccination Status

The influence of vaccination on post-COVID cardiovascular risk was explored in Tan et al. [39], a prospective observational study of 427 adults (mean age 49 years; 46% male) with laboratory-confirmed SARS-CoV-2 infection. Participants were stratified by vaccination status prior to infection: fully vaccinated (≥2 doses), partially vaccinated, and unvaccinated. At 6-month follow-up, fully vaccinated individuals had significantly lower rates of persistent cardiovascular symptoms (6.8% vs. 15.2% in unvaccinated, p < 0.01) and lower incidence of newly diagnosed hypertension (4.1% vs. 10.7%, p < 0.05). Biomarker analysis revealed reduced levels of high-sensitivity CRP and NT-proBNP in the vaccinated group, suggesting attenuation of systemic inflammation and myocardial stress. These findings support vaccination not only as a preventive measure against acute COVID-19 severity but also as a potential modulator of long-term cardiovascular sequelae. The interpretation of cardiovascular findings in vaccinated individuals requires consideration of the specific vaccine platform. mRNA vaccines such as BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) have been associated with rare cases of myocarditis and pericarditis, particularly in young males following the second or third dose. By contrast, adenoviral vector-based vaccines including ChAdOx1 nCoV-19 and Ad26.COV2.S have been linked to thrombosis with thrombocytopenia syndrome. Nevertheless, current evidence indicates that vaccination generally reduces the risk of severe long COVID manifestations, including cardiovascular sequelae [54].

4.7. Clinical Implications

Based on the synthesized evidence, a practical, risk-stratified cardiovascular follow-up algorithm for patients with long COVID is proposed (Figure 2). This algorithm integrates both objectively measured cardiovascular abnormalities and clinically relevant cardiovascular symptoms, reflecting the heterogeneous real-world presentation of post-acute sequelae of SARS-CoV-2 infection. Initial evaluation includes symptom assessment, electrocardiography, transthoracic echocardiography with strain analysis when available, and cardiac biomarker testing. Patients with normal findings may be managed conservatively, whereas those with persistent symptoms or abnormal results should undergo targeted second-line investigations, including ambulatory rhythm monitoring, cardiac magnetic resonance imaging, vascular function assessment, or ambulatory blood pressure monitoring. Consistent with the cumulative evidence from the analyzed cohorts, cardiovascular surveillance should represent a structured and integral component of post-COVID care pathways, particularly in individuals with persistent symptoms, abnormal acute-phase cardiac investigations, or elevated baseline cardiovascular risk. In light of the observed prevalence of subclinical myocardial dysfunction (Kapusta et al.), arrhythmias (Tan et al., Fung et al.), vascular stiffness (Theresa et al.), and new-onset hypertension (Vyas et al.), a tiered, risk-stratified follow-up strategy is warranted to facilitate early identification of cardiovascular involvement and support individualized management in long COVID [37,39,41].

Such a protocol could involve comprehensive cardiovascular evaluation at 3–6 months post infection, including 12-lead ECG, transthoracic echocardiography with strain imaging, and biomarker assessment (high-sensitivity troponin, BNP or NT-proBNP) in all symptomatic or high-risk patients. Selected individuals particularly those with prior severe COVID-19, elevated acute-phase cardiac biomarkers, or abnormal baseline imaging may benefit from adjunctive testing such as cardiac MRI to detect ongoing inflammation or fibrosis, 24 h Holter monitoring for arrhythmia burden, and vascular function assessment (pulse wave velocity, augmentation index) to quantify endothelial and arterial health.

From a therapeutic perspective, early identification of cardiovascular abnormalities offers the opportunity for timely interventions. This may include initiation or optimization of guideline-directed medical therapy for heart failure, arrhythmia management, antihypertensive therapy, or targeted endothelial-protective strategies. Multidisciplinary rehabilitation programs integrating cardiopulmonary exercise training, autonomic retraining, and psychosocial support have shown promise in improving functional capacity and quality of life, but require validation in long COVID specific populations.

Our synthesis aligns with current international recommendations. The American Heart Association (AHA) highlights myocarditis, arrhythmias, and new-onset hypertension as key cardiovascular sequelae of COVID-19, recommending structured follow-up for patients with persistent symptoms or abnormal cardiac biomarkers [55]. At the public health level, the World Health Organization (WHO) defines post-COVID-19 condition as symptoms persisting beyond 12 weeks and emphasizes the establishment of multidisciplinary care pathways to address its heterogeneous manifestations [20]. These recommendations support our proposal for a risk-stratified surveillance strategy that integrates clinical assessment, biomarker testing, and imaging, with the goal of enabling early detection and reducing long-term cardiovascular risk.

4.8. Limitations of Current Evidence

The current literature is constrained by several methodological limitations that impact interpretability and generalizability. Most studies were observational and lacked prospective, standardized protocols, increasing susceptibility to selection bias and residual confounding. Baseline cardiovascular status was incompletely characterized in many cohorts, limiting differentiation between de novo post-COVID pathology and exacerbations of pre-existing disease. Sample sizes ranged from fewer than 100 participants according to Theresa et al., Fung et al. [37,44] to several hundred according to Vyas et al., Kapusta et al. [41,42], with smaller studies often underpowered to detect less common but clinically significant outcomes.

Follow-up duration varied widely from 3 months to over 12 months, reducing comparability and potentially underestimating late-emerging complications. Diagnostic modalities were heterogeneous, ranging from symptom-based surveys to advanced multimodal imaging, and outcome definitions lacked uniformity. Additionally, important confounders such as vaccination status, reinfection history, and post-acute treatment regimens (e.g., corticosteroids) were inconsistently reported.

To advance the field, future research must prioritize multicenter, longitudinal cohort studies with standardized cardiovascular endpoints, stratified by pre-existing conditions, acute disease severity, and vaccination status. The integration of imaging, biomarkers, and functional assessments in a harmonized framework will be essential to establish causality, define prognostic trajectories, and develop targeted interventions to mitigate the cardiovascular burden of long COVID.

Additionally, the interpretation of findings is limited by variations in study methodology, inconsistent definitions of long COVID, heterogeneous timing of cardiovascular assessment, and reliance on self-reported symptoms in several cohorts. These factors restrict causal inference and may lead to misclassification or overestimation of cardiovascular involvement. The absence of standardized pre-COVID baseline data also limits the ability to differentiate de novo pathology from unmasking of pre-existing disease. These methodological constraints should be considered when interpreting the conclusions of this review.

5. Conclusions

The synthesis of current evidence underscores that post-acute sequelae of SARS-CoV-2 infection encompass a distinct cardiovascular phenotype, characterized by structural myocardial alterations, persistent biomarker elevations, endothelial dysfunction, new-onset hypertension, and clinically relevant arrhythmias. Notably, these abnormalities occur even in previously healthy, non-hospitalized individuals, indicating that long COVID’s cardiovascular impact extends beyond the severely ill subset and poses a broader, population-level challenge. Despite heterogeneity in study design, populations, follow-up duration, and diagnostic modalities, converging data consistently implicate subclinical myocardial strain impairment, vascular injury, and autonomic dysregulation as central pathophysiological mechanisms.

From a clinical standpoint, these findings mandate the integration of standardized cardiovascular surveillance into long COVID management pathways. Such protocols should employ multimodal assessment including advanced echocardiography, biomarker profiling, and vascular function testing tailored to baseline risk, acute illness severity, and symptom persistence. Emerging data also suggest a protective role of vaccination against long-term cardiovascular sequelae, a hypothesis warranting mechanistic exploration and confirmation in prospective cohorts.

Future research must advance beyond descriptive observations toward harmonized, longitudinal, multicenter studies with rigorously defined endpoints, stratified by pre-existing disease, vaccination status, and acute-phase characteristics. Integration of imaging, biomarkers, and functional parameters in standardized frameworks will be essential to establish causal pathways, delineate prognostic trajectories, and identify actionable therapeutic targets. Only through such coordinated efforts can the cardiovascular burden of long COVID be precisely quantified, mechanistically understood, and effectively mitigated.