European Journal of Cardiovascular Medicine

COVID-19, caused by the SARS-CoV-2 virus, has led to widespread morbidity and mortality worldwide [1]. While initial research focused on acute respiratory complications, emerging evidence highlights significant long-term cardiovascular implications [2]. SARS-CoV-2 has been linked to persistent endothelial dysfunction, chronic inflammation, and direct myocardial injury, leading to an increased incidence of cardiovascular diseases (CVDs) in recovered individuals [3]. Given the widespread impact of COVID-19, understanding its long-term effects on cardiovascular health is crucial for developing preventive and therapeutic strategies [4].

Mechanism of Cardiovascular Impact

The virus is thought to enter endothelial cells through the ACE2 receptor, leading to vascular inflammation, oxidative stress, and microvascular dysfunction, lasting for months or years after the initial infection [5]. Endothelial dysfunction with increased arterial stiffness contributes to hypertension and atherosclerosis, while chronic systemic inflammation increases the risk for thrombosis and myocardial infarction [6]. The relationship between viral-mediated injury and the host immune response aggravates the cardiovascular injury, leaving patients vulnerable to, long-term sequelae including heart failure, arrhythmias, and microvascular dysfunction [7].

Epidemiology and Prevalence

These post-COVID cardiovascular sequelae create a significant burden on the healthcare systems globally, which supports the need for better screening protocols as well as follow-up for those who have been infected [8]. Pre-existing cardiovascular conditions further exacerbate the risk of severe complication from SARS-CoV-2 infection [9]. Additionally, the effects of the COVID-19 pandemic on cardiovascular health are further aggravated by lifestyle changes during the pandemic such as decreased physical activity, dietary modifications, and mental health challenges, which in turn affect long-term cardiac outcomes [10]. According to epidemiological studies, cardiovascular involvement occurs in up to 30% of hospitalized patients with COVID-19 and even mild cases will demonstrate at least some degree of cardiac involvement [11].

What is the Risk Factors for Cardiovascular Complications After COVID-19?

There are multiple reasons for the increased cardiovascular sequelae risk seen in post-COVID patients:

• Pre-existing Conditions: People who suffer from hypertension, diabetes, or previous heart disease, face a higher risk of complications [12].
• Severity of Initial Infection: There is a greater incidence of long-term cardiovascular complications in patients with severe COVID-19 disease, especially among those who received intensive care or mechanical ventilation [13].
• Demographic Attributes: Older, male, and obese individuals are the key high-risk groups [14].
• Inflammatory Response: Prolonged cardiovascular dysfunction associated with sustained elevation of inflammatory markers like IL-6 and C-reactive protein (CRP) [15].
• Viral Persistence and Immune Dysregulation: Studies suggest that SARS-CoV-2 may cause long-lasting immune activation, contributing to myocardial inflammation and fibrosis [16].

Pathophysiology of Post-COVID Cardiovascular Disease

The underlying mechanisms of post-COVID cardiovascular disease include:

• Myocardial Injury: SARS-CoV-2 can directly infect cardiac cells, leading to myocarditis, myocardial necrosis, and fibrosis [17].
• Thrombogenesis and Hypercoagulability: Persistent endothelial activation results in an increased risk of deep vein thrombosis, pulmonary embolism, and stroke [18].
• Autonomic Dysfunction: COVID-19 has been linked to postural orthostatic tachycardia syndrome (POTS) and dysautonomia, affecting heart rate and blood pressure regulation [19].
• Microvascular Dysfunction: Damage to the small blood vessels may contribute to ischemic heart disease and chronic heart failure [20].

Clinical Manifestations of Post-COVID Cardiovascular Complications

Post-COVID cardiovascular symptoms vary in severity and may persist for months or even years after the initial infection. Common manifestations include:

• Chest Pain and Dyspnea: Often linked to myocarditis or pericardial inflammation [21].
• Palpitations and Arrhythmias: Atrial fibrillation, ventricular arrhythmias, and conduction abnormalities have been frequently reported [22].
• Exercise Intolerance and Fatigue: Many post-COVID patients experience significant reductions in exercise capacity due to cardiovascular and autonomic dysfunction [23].
• Hypertension and Vascular Stiffness: Persistent endothelial dysfunction may contribute to increased blood pressure and arterial stiffness [24].
• Increased Risk of Sudden Cardiac Events: Studies have documented a higher incidence of sudden cardiac death in individuals with previous severe COVID-19 infection [25].

Key Cardiovascular Complications of Long-Term COVID-19

Importance of Early Detection and Prevention

Due to the significant impact of COVID-19 on cardiovascular health, early detection and preventive strategies are crucial. Routine screening for cardiovascular markers in recovered COVID-19 patients is recommended to identify high-risk individuals [26]. Preventive strategies include:

• Regular Cardiovascular Monitoring: Follow-up electrocardiograms (ECG), echocardiograms, and cardiac biomarkers help detect abnormalities early [27].
• Pharmacological Interventions: The use of anticoagulants, beta-blockers, and ACE inhibitors may mitigate cardiovascular risks in post-COVID patients [28].
• Lifestyle Modifications: Encouraging physical activity, a heart-healthy diet, and stress management techniques can improve cardiovascular outcomes [29].
• Targeted Rehabilitation Programs: Cardiac rehabilitation programs focusing on gradual physical activity resumption have shown benefits in post-COVID patients experiencing exercise intolerance [30].

This systematic review aims to comprehensively evaluate the long-term cardiovascular effects of COVID-19, offering insights into pathophysiological mechanisms, risk factors, and potential treatment approaches.

Search Strategy

A systematic review including a comprehensive search across several scientific databases (PubMed, Scopus, Web of Science, and Google Scholar) was performed for peer-reviewed papers published between 2020 and 2024. This was further delimited to literature discussing the long-term cardiovascular sequelae of COVID-19, using search terms including “COVID-19 and cardiovascular health, “long-term effects of COVID-19 on the heart,” “post-COVID myocardial injury, “COVID-19 and arrhythmias” and “thromboembolism post-COVID.” Boolean operators (AND, OR) were applied to focus the results of the search, and reference lists of chosen articles were hand-searched to capture all relevant literature.

Inclusion and Exclusion Criteria

To maintain the relevance and accuracy of the study, specific inclusion and exclusion criteria were applied.

Inclusion Criteria:

• Studies that investigated the long-term cardiovascular outcomes in post-COVID-19 patients.
• Randomized controlled trials, observational studies, meta-analyses, and systematic reviews.
• Research focusing on pathophysiological mechanisms, clinical manifestations, and therapeutic strategies.
• Studies published in English between 2020 and 2024.

Exclusion Criteria:

• Studies focusing only on acute cardiovascular events during active COVID-19 infection.
• Non-human studies and preclinical laboratory research.
• Opinion articles, editorials, and non-peer-reviewed literature.

Data Extraction and Quality Assessment

A structured form was used to extract data to maintain consistency in evaluation. Data extraction was conducted covering study design, sample size, characteristics of the population, cardiovascular outcomes, duration of follow-up, and intervention strategies. Risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies.

PRISMA Flowchart

The study selection process followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure a transparent and systematic review methodology. The flowchart below outlines the steps of the study selection process:

Cardiovascular Manifestations Post-COVID-19

Recent studies have identified a range of cardiovascular complications among COVID-19 survivors, emphasizing the persistent and multifactorial nature of the disease [30]. Long-term manifestations include myocarditis, arrhythmias, thromboembolic events, and endothelial dysfunction, all of which contribute to an increased burden of cardiovascular morbidity and mortality [31].

• Myocarditis and myocardial injury: Multiple cohort studies have revealed that post-COVID-19 myocarditis may last for months after acute infection, resulting in impaired cardiac function and greater risk for heart failure [32]. MRI data from post-COVID-19 adults have shown late gadolinium enhancement consistent with persistent myocardial inflammation, even in patients who were asymptomatic or had a mild course of infection [33].

• Arrhythmias and Conduction Abnormalities: They are largely reported among post-COVID-19 patients, comprising atrial fibrillation, ventricular tachycardia (VT), and QT interval prolongation [34]. These arrhythmias have pathophysiological mechanisms of autonomic dysfunction, fibrosis, and ischemic injury to the myocardium that may contribute to sudden cardiac death in affected individuals [35].

• Thromboembolic Events: Hypercoagulability has been significantly associated with COVID-19, prolonging the risk of venous thromboembolism, pulmonary embolism, and ischaemic stroke among the recovered patients [36]. It is a fact that persistent endothelial dysfunction and increased inflammatory responses lead to prolonged clotting abnormalities and the need for long-term anticoagulation therapy in patients at high risk [37].

• Endothelial dysregulation and arterial stiffness: Multiple studies have pointed out that SARS-CoV-2 produces a persistent endothelial dysfunction that is accompanied by augmented arterial stiffness and systemic hypertension [38]. Despite these limitations, longitudinal studies have shown that recovery from COVID-19 is characterized by impaired vascular reactivity and enhanced early-onset atherosclerosis when compared to non-infected controls [39].

Risk Stratification and Biomarker Analysis

The identification of high-risk individuals remains a critical component of cardiovascular surveillance in post-COVID-19 patients. Emerging biomarkers, such as troponin, D-dimer, and inflammatory markers (IL-6, CRP), have been associated with an increased risk of adverse cardiovascular outcomes in recovered patients [40].

Therapeutic Approaches and Interventions

Given the increasing recognition of post-COVID cardiovascular complications, management strategies must address both acute and chronic disease processes. Current therapeutic recommendations emphasize the importance of multidisciplinary care, integrating cardiologists, hematologists, and infectious disease specialists [41].

Pharmacological Therapies: Data from real-world studies have shown a decrease in the                 incidence of cardiovascular events with long-term anticoagulation, beta-blockers, and ACE inhibitors for the management of post-COVID patients who are deemed at high risk for thrombosis and myocardial dysfunction [42].

Cardiac Rehabilitation Programs: Diagnostic tests to identify pre-existing heart conditions in COVID-19 patients, as well as • Cardiac Rehabilitation Programs: Participating in a structured rehabilitation program that emphasizes a gradual and closely monitored reintroduction to physical activity level has been shown to improve cardiovascular outcomes and reduce functional fatigue in this post-COVID myocarditis patient population [43].

Lifestyle Modifications: There is growing evidence that a heart-healthy diet, effective stress management, and regular cardiovascular screenings are critical in reducing post-COVID cardiovascular risks [44].

Longitudinal Studies and Areas for Further Research

• However, large, descriptive longitudinal studies are needed to define appropriate causality in the recognized relationship between COVID-19 infection and the etiology of chronic cardiovascular pathophysiology. Countermeasures against COVID-19 have historically been limited, however, ongoing clinical studies assessing new therapies, including anti-inflammatory agents directed against IL-6 and medications targeting endothelial protection, can shed light on management strategies for post-COVID cardiovascular disorders [45].

• Cohort Studies: Several multinational registries are actively tracking cardiovascular outcomes in COVID-19 survivors to assess the long-term disease trajectory [46].
• Clinical Trials: Trials evaluating the efficacy of anti-fibrotic agents in preventing myocardial remodeling post-COVID are currently underway [47].
• Genetic and Immunological Research: Studies exploring genetic susceptibility to severe cardiovascular sequelae following COVID-19 may identify at-risk populations and inform personalized treatment approaches [48].

Summary of Findings

The findings of this systematic review emphasize the significant burden of long-term cardiovascular complications among COVID-19 survivors. While risk stratification and early intervention remain paramount, ongoing research will be essential in developing targeted therapies to mitigate the impact of SARS-CoV-2 on cardiovascular health [49].

The Burden of Cardiovascular Complications in Post-COVID-19 Patients

The long-term sequelae of COVID-19 on cardiovascular health is posing an increasing burden on global health care [50]. SARS-CoV-2 infection has remained associated with cardiovascular sequelae, including myocarditis, arrhythmias, and thromboembolic events, as demonstrated in several studies. Dysregulation of the immune system, inflammation, and damage to the endothelium have all played a role in the long-term sequelae, which affect morbidity and mortality.

For example, recent cohort studies have reported an excess of cardiovascular disease in patients post-COVID-19 relative to non-infected individuals. Ongoing cardiac involvement after acute infection is indicated by the persistence of symptoms like palpitations, dyspnea, and chest discomfort. These findings underline the need for ongoing monitoring and cardiovascular screening in COVID-19 survivors.

Post-COVID Cardiovascular Disease Pathophysiology

The underlying mechanisms behind cardiovascular dysfunction in post-COVID patients are shown to be multiple. Several pathophysiological processes have been implicated, including the following:

• Direct Viral Myocardial Invasion: SARS-CoV-2 has been shown to infect myocardial cells inducing inflammatory responses, myocardial fibrosis, and long-term functional impairment.

• Persistent Systemic Inflammation: Elevated inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), have been associated with prolonged cardiac dysfunction.
• Endothelial Dysfunction and Hypercoagulability: SARS-CoV-2 infection is linked to endothelial injury, leading to thromboembolic complications such as deep vein thrombosis (DVT) and pulmonary embolism.
• Autonomic Dysregulation: Many post-COVID patients experience autonomic dysfunction, manifesting as postural orthostatic tachycardia syndrome (POTS) and exercise intolerance.

Clinical Manifestations and Diagnosis

The clinical presentation of post-COVID cardiovascular disease varies widely. Common manifestations include:

• Myocarditis: Characterized by chest pain, arrhythmias, and reduced ejection fraction, post-COVID myocarditis has been detected in up to 10% of recovered individuals via cardiac MRI.
• Arrhythmias: Atrial fibrillation and ventricular tachycardia are frequently reported, with increased incidence among hospitalized COVID-19 survivors.
• Heart Failure: Persistent myocardial dysfunction contributes to heart failure, necessitating long-term medical management.
• Hypertension and Vascular Stiffness: Endothelial dysfunction may lead to hypertension and increased arterial stiffness in post-COVID individuals.

The diagnosis of post-COVID cardiovascular complications requires a combination of laboratory biomarkers, imaging modalities, and functional assessments. Elevated troponin levels, abnormal ECG findings, and evidence of cardiac fibrosis on MRI are critical indicators of ongoing cardiac involvement.

Management Strategies

Given the diverse nature of cardiovascular complications associated with COVID-19, a multidisciplinary approach to management is essential. Recommended strategies include:

• Pharmacological Interventions:
• Anticoagulation therapy for high-risk thromboembolic patients.
• Beta-blockers and ACE inhibitors for arrhythmias and heart failure management.
• Anti-inflammatory therapies targeting persistent cytokine activation.
• Cardiac Rehabilitation: Structured rehabilitation programs have demonstrated improved outcomes in post-COVID patients with cardiovascular involvement.
• Lifestyle Modifications: Regular physical activity, a heart-healthy diet, and stress management are essential components of long-term cardiovascular care.
• Follow-Up Monitoring: Periodic echocardiograms and biomarker assessments can aid in early detection of disease progression.

Future Research Directions

While substantial progress has been made in understanding the cardiovascular implications of COVID-19, several gaps in knowledge remain. Areas requiring further research include:

• Longitudinal Studies: Large-scale prospective studies are needed to assess long-term cardiovascular outcomes beyond the first year of recovery.
• Role of Genetic Susceptibility: Investigating genetic predisposition to severe cardiovascular outcomes may aid in risk stratification.
• Novel Therapeutics: Development of targeted therapies aimed at mitigating endothelial injury and myocardial fibrosis.
• Impact of Vaccination: Assessing whether vaccination reduces the incidence and severity of post-COVID cardiovascular complications.

Public Health and Policy Implications

The burden of post-COVID cardiovascular disease has significant implications for healthcare systems worldwide. Strategies to mitigate this impact should include:

• Incorporating Cardiovascular Screening into Post-COVID Care: Standardized screening protocols should be established for early detection and management.
• Healthcare Infrastructure Development: Resources should be allocated for specialized post-COVID cardiovascular clinics to manage long-term complications.
• Public Awareness and Education: Increasing awareness about cardiovascular risks in COVID-19 survivors can promote early medical intervention.

COVID-19 long-term cardiovascular consequences are now a major public health challenge requiring continued research, monitoring and prevention. The interdisciplinary approach towards care, early detection methods and therapeutic innovations shall prove essential in alleviating the burden of CV complications in survivors of COVID-19.

The protracted cardiovascular impact of COVID-19 presents a definite challenge to global healthcare, requiring immediate investigation, monitoring, and management. Ongoing myocardial inflammation, endothelial dysfunction, arrhythmias, and thromboembolic risks warrant the necessity of multidisciplinary strategies in post-COVID care. Early screening, targeted therapies, lifestyle interventions, and structured rehabilitation programs play a key role in reducing disease burden. Further studies are warranted to elucidate the underlying molecular mechanisms of cardiovascular complications, as well as refine treatment approaches and assess the effectiveness of vaccination in mitigating long-term cardiovascular risk. Initiatives of public health, such as raising global awareness about the role of CV comorbidities in COVID severity and implementing post-COVID CV care units, will be urgently needed in the management of the long-term costs of the pandemic and in improving patient prognosis.

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