Autophagy, telomerase, and endothelial dysfunction in COVID-19–induced cardiac injury: an evidence-graded genetic and epigenetic synthesis

Abstract

Background:

Cardiac injury is a frequent and severe complication of COVID-19, yet the molecular mechanisms driving myocardial involvement remain incompletely understood. Dysregulated autophagy, telomerase/telomere biology, and endothelial dysfunction have emerged as biologically plausible and potentially interconnected contributors to COVID-19-associated cardiac injury.

Methods:

We conducted a narrative, evidence-graded review of literature retrieved from PubMed and EMBASE, with Google Scholar used selectively as a supplementary source to capture emerging or cross-disciplinary studies. Eligible studies included human investigations and relevant animal models reporting genetic, epigenetic, or molecular alterations in autophagy, telomerase, or endothelial pathways with cardiovascular relevance. Non-English publications, studies lacking primary data, and reports unrelated to cardiovascular or systemic disease mechanisms were excluded. Evidence was stratified as Level I (direct evidence in COVID-19-associated cardiac injury), Level II (COVID-19 systemic or vascular evidence with plausible cardiac relevance), and Level III (non-COVID cardiovascular or systemic disease; hypothesis-generating).

Findings:

Across viral, cardiovascular, and systemic contexts, key candidate genes, including ATG5, ATG7, Beclin-1, TERT, ICAM1, and eNOS-emerged as potential mediators of COVID-19–related cardiac injury. While endothelial activation is supported by relatively consistent clinical and molecular evidence, direct cardiac-tissue data linking autophagy and telomerase pathways to COVID-19-associated myocardial injury remain limited. These gaps highlight substantial uncertainty regarding causal mechanisms and inter-individual susceptibility.

Conclusion:

Autophagy dysregulation, telomere attrition, and endothelial dysfunction represent convergent and biologically plausible mechanisms contributing to COVID-19–associated cardiac injury; however, current evidence remains largely indirect and derived from systemic or vascular compartments rather than cardiac tissue. Cardiac-specific, longitudinal genetic and epigenetic studies are required before these pathways can be considered for biomarker development or therapeutic targeting.

1 Introduction

Cardiac injury ranks among the most frequent and serious complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can precipitate both acute and sustained cardiovascular damage extending beyond the respiratory phase of illness. Clinical manifestations include myocarditis, arrhythmias, heart failure, ischemic events, and microvascular dysfunction. Individuals with pre-existing cardiovascular disease, as well as those who develop acute cardiac injury during COVID-19, are at substantially elevated risk of adverse short- and long-term outcomes.

Endothelial dysfunction has emerged as a central feature of COVID-19 pathophysiology. SARS-CoV-2 disrupts endothelial homeostasis through multiple mechanisms, including reduced nitric oxide bioavailability, oxidative stress, increased vascular permeability, glycocalyx shedding, inflammation, and endothelial-to-mesenchymal transition (EndoMT) (1). These alterations promote microvascular injury, thrombosis, and impaired myocardial perfusion and have been implicated in both acute cardiac injury and post-acute cardiovascular sequelae (2).

Beyond individual molecular pathways, genetic and epigenetic regulation has emerged as a critical determinant of COVID-19 pathogenesis and cardiovascular outcomes. SARS-CoV-2–induced changes in DNA methylation, histone modifications, and microRNA expression can influence inflammatory signaling, endothelial activation, thrombosis, and cellular stress responses. Genetic polymorphisms and epigenetic remodeling of key regulatory pathways may therefore contribute to inter-individual variability in susceptibility to cardiac injury and recovery trajectories following infection.

At the molecular level, autophagy is a fundamental cellular quality-control and recycling process essential for cardiomyocyte survival and endothelial integrity under stress conditions. Dysregulated autophagy has been linked to viral infection, inflammation, and cardiovascular disease. Experimental evidence suggests that SARS-CoV-2 interferes with autophagic flux, potentially amplifying oxidative stress, cytokine signaling, and tissue damage (3).

In parallel, telomere biology reflects cellular replicative capacity and biological aging. Several studies have reported accelerated telomere attrition and epigenetic age acceleration in patients with severe COVID-19 (4), while longer telomere length has been associated with improved clinical outcomes, including reduced need for intensive care and mechanical ventilation (5). However, meta-analyses reveal substantial heterogeneity and inconsistent findings across populations (6), underscoring unresolved uncertainty.

Despite growing evidence of endothelial injury and systemic inflammation, the molecular determinants of differential cardiac vulnerability remain poorly understood. Genetic and epigenetic variation in autophagy, telomerase/telomere maintenance, and endothelial function may act as key modifiers of SARS-CoV-2–induced cardiac injury, yet these mechanisms have not been systematically integrated (Figure 1).

Figure 1

The objective of this review is to synthesize and critically evaluate current evidence on genetic and epigenetic alterations in autophagy, telomerase/telomere biology, and endothelial activation in COVID-19–related cardiac injury. Specifically, we aim to (i) map mechanistic links among these pathways, (ii) identify candidate biomarkers of increased cardiovascular risk, and (iii) highlight priorities for future mechanistic and translational research.

Importantly, these pathways are not independent. Oxidative stress and inflammatory signaling induced by SARS-CoV-2 can simultaneously suppress autophagic flux, accelerate telomere shortening, and activate endothelial inflammatory programs. This convergence provides a mechanistic framework linking cellular stress responses to endothelial dysfunction and myocardial vulnerability, potentially explaining inter-individual heterogeneity in COVID-19–related cardiac injury.

2 Methodological framework and evidence grading

This review is a narrative, evidence-graded synthesis rather than a systematic review or meta-analysis; therefore, a PRISMA flow diagram was not included. The aim was a critical appraisal and stratification of existing evidence linking autophagy, telomerase biology, and endothelial dysfunction to COVID-19–associated cardiac injury.

Published literature was retrieved from PubMed, EMBASE, and Google Scholar. Inclusion criteria comprised studies on humans or relevant animal models, reporting genetic, epigenetic, or molecular alterations in autophagy, telomerase, or endothelial pathways with potential relevance to cardiac injury. Exclusion criteria included studies lacking primary data, non-English publications, and reports unrelated to cardiovascular or systemic disease mechanisms.

3 Role of autophagy in COVID-19–induced cardiac injury

3.1 Autophagy in cardiac homeostasis and viral stress

Autophagy is a conserved lysosomal degradation pathway essential for maintaining cellular homeostasis through the removal of damaged organelles and misfolded proteins. In the cardiovascular system, basal autophagy supports cardiomyocyte survival, limits oxidative stress, and preserves endothelial integrity, particularly under conditions of ischemia, inflammation, and metabolic stress (7, 8).

In the context of viral infection, autophagy serves a dual role by contributing to antiviral defense while also being susceptible to viral subversion. SARS-CoV-2 infection has been associated with myocardial injury manifesting as myocarditis, arrhythmias, heart failure, and microvascular dysfunction (9, 10). Experimental and clinical observations suggest that dysregulated autophagy in cardiomyocytes and endothelial cells may exacerbate inflammation, oxidative stress, and apoptotic signaling, thereby amplifying cardiac injury in COVID-19 (11, 12).

3.2 Mechanisms of autophagy dysregulation in COVID-19 cardiac injury

Autophagy is regulated by a coordinated network of autophagy-related genes and signaling pathways, including ATG5, ATG7, Beclin-1, LC3 (MAP1LC3A), and the AMPK–mTOR axis, which integrates cellular energy status with stress responses (13, 14). In cardiomyocytes, efficient autophagy—particularly mitophagy-is critical for limiting reactive oxygen species (ROS) accumulation and maintaining contractile function. In endothelial cells, autophagy supports barrier integrity and regulates inflammatory activation.

SARS-CoV-2 disrupts autophagy through several convergent mechanisms. Viral proteins have been shown to interact with key autophagy regulators, including Beclin-1 and LC3, impairing autophagosome formation and lysosomal fusion. In parallel, infection-associated metabolic stress promotes mTOR hyperactivation, suppressing autophagic flux and exacerbating cardiomyocyte injury (12). Impaired clearance of damaged mitochondria and protein aggregates results in heightened oxidative stress, inflammatory cytokine release, endothelial dysfunction, and apoptotic cell death. Collectively, these alterations may contribute to myocardial injury, microvascular thrombosis, and fibrotic remodeling observed in severe COVID-19.

Notably, impaired autophagy in endothelial cells may exacerbate leukocyte adhesion and microvascular thrombosis, whereas defective mitophagy in cardiomyocytes promotes ROS accumulation and contractile dysfunction, highlighting cell-type–specific consequences of autophagy dysregulation. Collectively, dysregulation of core autophagy mediators such as ATG5, ATG7, and Beclin-1 represents a critical upstream event linking SARS-CoV-2 infection to oxidative stress, endothelial dysfunction, and myocardial injury. The molecular mechanisms underlying SARS-CoV-2–mediated disruption of autophagic flux in cardiomyocytes and endothelial cells are illustrated in Figure 2.

Figure 2

3.3 Genetic and epigenetic regulation of autophagy pathways

Genetic variation in autophagy-related genes has been associated with cardiometabolic traits and cardiovascular disease susceptibility in non-COVID contexts, suggesting a potential role as modifiers of COVID-19–related cardiac injury. Variants in ATG7, ATG5, ATG4C/D, AMBRA1, ATG13, ATG16L1, and MAP1LC3A have been linked to coronary artery disease, lipid metabolism, insulin signaling, and blood pressure regulation (15). However, direct evidence connecting these variants to myocardial injury in COVID-19 remains limited.

Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA-mediated regulation, further influence autophagy gene expression and stress responsiveness. SARS-CoV-2–induced inflammatory and oxidative environments may alter epigenetic control of autophagy pathways, thereby contributing to inter-individual variability in cardiac injury severity (Tables 1–3).

Selected single-nucleotide polymorphism (SNP) in autophagy-related genes associated with cardiometabolic and cardiovascular traits are summarized in Supplementary Table S1; however, their relevance to COVID-19–associated cardiac injury remains untested.

3.4 Translational implications and future directions

Autophagy-related pathways represent attractive but currently unvalidated targets for mitigating COVID-19–associated cardiac injury. Importantly, pharmacological modulation of autophagy remains experimental, and inappropriate activation or inhibition may be deleterious in the setting of acute viral infection. Therefore, clinical translation should be deferred until cardiac-specific safety and efficacy data are available.

Future research priorities include systematic profiling of autophagy-related genes and epigenetic markers in myocardial tissue, functional studies of SARS-CoV-2 interactions with autophagy machinery, and carefully designed clinical trials evaluating autophagy modulators for cardioprotection.

4 Telomerase and telomere biology in COVID-19–induced cardiac injury

4.1 Mechanistic role of telomerase

Telomerase is an RNA-dependent DNA polymerase that preserves chromosomal integrity by adding repetitive TTAGGG sequences to telomeres, with TERT encoding the catalytic subunit and TERC serving as the RNA template. While telomerase activity is robust in germline and stem cells, it is low or absent in most somatic tissues, rendering cells susceptible to progressive telomere shortening under conditions of replicative stress, inflammation, and oxidative injury.

SARS-CoV-2 infection induces systemic inflammation, oxidative stress, and excessive reactive oxygen species (ROS) production, all of which accelerate telomere attrition in proliferative cell populations, including leukocytes and endothelial cells (16, 17). Critically short telomeres activate DNA damage response pathways, including p53/p21 signaling, leading to cellular senescence, apoptosis, and the senescence-associated secretory phenotype (SASP), and thereby amplifying inflammation and tissue injury. Epidemiological studies have consistently associated reduced leukocyte telomere length with increased risk of myocardial infarction, stroke, and cardiovascular mortality (18).

Emerging transcriptomic and epigenetic studies suggest reduced expression of telomerase-related genes (TERT, TERC, DKC1, NOP10, NHP2) and shelterin complex components (POT1, TRF1, TRF2, TIN2, TPP1, RAP1) in patients with severe COVID-19 and systemic inflammation (19). Importantly, most available evidence derives from circulating immune cells or systemic tissues rather than myocardial samples (Tables 1–3 and Figure 3). Although telomere shortening is consistently observed in severe COVID-19, direct evidence linking telomerase dysfunction to cardiomyocyte injury remains sparse, and causality cannot currently be inferred. Under sustained inflammatory and oxidative stress conditions, reduced TERT activity may accelerate telomere attrition, thereby promoting endothelial and cardiomyocyte senescence and increasing susceptibility to COVID-19–associated cardiac injury.

Figure 3

4.2 Therapeutic considerations and biomarker potential

Potential telomere-preserving strategies—including antioxidants, anti-inflammatory agents, and experimental telomerase activators (e.g., cycloastragenol)—have been proposed to mitigate inflammation-driven telomere erosion. However, these approaches remain hypothesis-generating, and their safety and efficacy in COVID-19-related cardiac injury are unproven. Proposed telomere-preserving strategies should be regarded as hypothesis-generating, as no interventional studies have demonstrated cardioprotective efficacy in COVID-19.

4.3 Translational implications

Telomere length and telomerase activity may serve as indirect biomarkers of biological aging and vulnerability to severe COVID-19 outcomes, particularly in older adults and individuals with pre-existing cardiovascular disease. Validation in cardiac-specific, longitudinal cohorts is essential before translational application.

5 Endothelial dysfunction in COVID-19–induced cardiac injury

5.1 Role of endothelial activation

Endothelial cells regulate vascular tone, growth, thrombogenicity, and inflammation. SARS-CoV-2 interacts with endothelial cells via ACE2, leading to receptor internalization, angiotensin II–mediated vasoconstriction, oxidative stress, and microvascular thrombosis (20, 21).

Endothelial activation is characterized by upregulation of adhesion molecules (ICAM1, VCAM1, E-selectin), inflammatory mediators (IL-6, TNF-α), and extracellular matrix–remodeling enzymes (MMP-7, MMP-9), promoting thrombosis, vascular leakage, and myocardial injury (22, 23). Circulating biomarkers such as endoglin (CD105) and serum amyloid A (SAA) reflect early endothelial stress and vascular inflammation (24, 25). Persistent upregulation of ICAM1 reflects endothelial activation and facilitates leukocyte adhesion, microvascular inflammation, and thrombosis, key pathological features of COVID-19–associated cardiac injury.

5.2 Molecular and epigenetic insights

SARS-CoV-2 modulates endothelial gene expression through epigenetic mechanisms. The viral E protein interacts with BRD2/BRD4, inducing chromatin remodeling and dysregulated inflammatory gene transcription (26, 27). Epigenetic regulators, including DNMT1/3, H3K9 histone modifications, and SIRT1, govern adhesion molecule expression, nitric oxide signaling, and endothelial homeostasis. Dysregulation of these mechanisms contributes to sustained endothelial activation and chronic cardiovascular sequelae following COVID-19 (28, 29).

Comprehensive profiling of endothelial markers (ACE2, IFN-γ, eNOS, VCAM1) alongside epigenetic regulators may aid early detection of vascular and cardiac involvement in COVID-19 (Tables 1–3, Figure 4). Through BRD2/BRD4-mediated chromatin remodeling, SARS-CoV-2 may amplify inflammatory endothelial transcriptional programs, thereby indirectly promoting myocardial injury via microvascular dysfunction rather than direct cardiomyocyte infection.

Figure 4

5.3 Clinical implications and therapeutic opportunities

• High-Risk Populations: Older adults and individuals with pre-existing cardiovascular disease, hypertension, or diabetes are particularly vulnerable to endothelial-mediated cardiac injury.

• Biomarker Monitoring: Soluble ICAM1, VCAM1, endocan, SAA, and MMP-9 may facilitate early detection of endothelial activation, pending validation in longitudinal cohorts.

• Potential Therapeutics (Experimental): BET inhibitors, ACE2 pathway modulators, antioxidants, and anti-inflammatory agents represent investigational strategies targeting endothelial dysfunction.

5.4 Summary and translational relevance

• Mechanistic Insights: Endothelial activation and dysfunction drive inflammation, microthrombosis, and myocardial damage in COVID-19.

• Genetic/Epigenetic Contributions: BRD2/BRD4, DNMTs, SIRT1, and H3K9 modifications modulate endothelial gene expression and stress responses.

• Translational Implication: While endothelial dysfunction is strongly supported by vascular and clinical evidence, direct causal links between specific endothelial genetic or epigenetic alterations and myocardial injury remain incompletely established, underscoring the need for cardiac-specific validation studies.

6 Cross-Pathway convergence of autophagy, telomerase, and endothelial dysfunction in COVID-19–induced cardiac injury

Rather than acting as independent pathogenic processes, emerging evidence suggests that autophagy dysregulation, telomere/telomerase dysfunction, and endothelial activation form a convergent and interdependent network driving COVID-19–associated cardiovascular injury. This integrative framework represents a shift from descriptive pathway cataloging toward a systems-level model in which disruption of one axis amplifies dysfunction in the others.

Within this model, impaired autophagic flux-mediated by dysregulation of ATG5, ATG7, and Beclin-1-may function as an upstream event that promotes oxidative stress and accelerates telomere attrition. Telomere shortening and reduced TERT activity, in turn, favor endothelial and cardiomyocyte senescence, increasing vulnerability to inflammatory signaling, apoptosis, and microvascular injury. Endothelial activation, reflected by sustained ICAM1 expression, emerges as both a downstream consequence and an amplifying node that reinforces inflammation, thrombosis, and myocardial damage.

Importantly, this convergence model generates testable hypotheses, including the prediction that modulation of autophagy will influence telomere integrity and endothelial function, and that combined assessment of autophagy, telomerase, and endothelial markers will outperform single-pathway indicators in predicting cardiovascular outcomes in COVID-19. Together, these interactions position autophagy–telomere–endothelial cross-talk as a unifying mechanistic axis underlying disease heterogeneity and cardiovascular risk (Figure 5).

Figure 5

7 Clinical and translational implications

While these pathways provide mechanistic insight into COVID-19–associated cardiac injury, none currently meet criteria for validated clinical biomarkers or therapeutic targets. As summarized in Table 4, altered autophagic signaling involving Beclin-1, ATG5, ATG7, and LC3-II reflects impaired cellular stress adaptation and may represent modifiable pathways through AMPK–mTOR or SIRT1-targeted interventions aimed at limiting myocardial inflammation and metabolic dysfunction.

Markers of telomere attrition and reduced expression of TERT/TERC, primarily derived from circulating or systemic tissues, suggest accelerated cellular aging and senescence in severe COVID-19. While direct cardiomyocyte-specific evidence remains limited, these alterations highlight potential therapeutic avenues involving antioxidant strategies, anti-inflammatory modulation, or experimental approaches targeting telomere stability.

Endothelial activation and dysfunction, reflected by elevated ICAM1, VCAM1, E-selectin, endocan, IL-6, MMP-9, and CRP, represent the most clinically tractable pathway, given the availability of vascular biomarkers and established cardiovascular therapies. Interventions targeting ACE2–angiotensin signaling, nitric oxide bioavailability, and endothelial inflammation (e.g., statins or anti-inflammatory agents) may offer potential cardioprotective benefits in high-risk COVID-19 populations.

Collectively, cross-pathway convergence driven by oxidative stress, inflammation, and epigenetic remodeling supports the development of integrated multi-omic panels, rather than single biomarkers, for improved risk stratification and precision cardiovascular management (Table 4, Figure 6).

Figure 6

8 Conclusion and future directions

In conclusion, COVID-19–associated cardiac injury arises from an intricate interplay of cellular stress pathways rather than isolated molecular events. SARS-CoV-2 infection induces oxidative stress and inflammatory signaling that concurrently suppress autophagic flux in cardiomyocytes and endothelial cells, accelerate telomere attrition, and promote endothelial activation. These processes are mechanistically interconnected: impaired autophagy leads to the accumulation of damaged organelles and reactive oxygen species, which in turn exacerbate telomere shortening and endothelial senescence, while telomere dysfunction further increases cellular susceptibility to apoptosis and inflammatory signaling. Endothelial activation, amplified by both autophagy impairment and telomere attrition, contributes to microvascular dysfunction, thrombosis, and subsequent myocardial injury.

This integrated network positions autophagy, telomerase/telomere maintenance, and endothelial function as convergent modifiers of disease severity, providing a unified mechanistic framework to explain inter-individual variability in COVID-19–related cardiac outcomes. Importantly, much of the current evidence remains indirect and is largely derived from systemic or vascular compartments, underscoring the need for cardiac-resolved, longitudinal, multi-omic studies to validate these mechanistic links.

From a translational perspective, this convergence model supports the development of multi-omic biomarker panels integrating autophagy markers (e.g., Beclin-1, ATG5, ATG7), telomere/telomerase indicators (e.g., TERT, TERC, telomere length), and endothelial activation markers (e.g., ICAM1, VCAM1, eNOS) to improve risk stratification and precision cardiovascular management in COVID-19. Future studies should prioritize experimental validation to determine whether targeting one pathway, such as autophagy modulation, can beneficially influence telomere integrity and endothelial function, thereby providing mechanistic and therapeutic insight into this interconnected network.

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