Hepatitis C virus-associated cardiomyopathy: A review of pathogenesis

Abstract

BACKGROUND

Hepatitis C virus (HCV) affects millions of individuals globally and is linked to dilated cardiomyopathy and hypertrophic cardiomyopathy via complex direct viral, immune, and metabolic mechanisms, often exacerbated by cirrhosis, increasing cardiovascular morbidity.

AIM

To review the pathogenesis of cardiomyopathy in patients infected with HCV and investigate its clinical implications.

METHODS

A narrative literature review (PubMed, Scopus, Google Scholar; 1990–2024) focused on English-language studies examining the HCV–cardiomyopathy link, pathophysiology, and treatment. The findings were qualitatively synthesized.

RESULTS

HCV drives cardiomyopathy through direct viral toxicity, immune damage, genetic factors, and apoptosis. The associated cirrhosis contributes via cirrhotic cardiomyopathy mechanisms. Clinically, HCV increases cardiovascular events. Direct-acting antivirals (DAAs) generally improve cardiovascular outcomes by reducing adverse events and enhancing cardiac function.

CONCLUSION

HCV is a significant cardiomyopathy risk factor involving diverse pathways, including cirrhosis. DAA therapy offers cardiovascular benefits. Further research on the underlying mechanisms, biomarkers (e.g., M2BPGi, Ang-2), and global DAA access is warranted.

Key Words: Hepatitis C virus; Cardiomyopathy; Direct-acting antivirals; Cirrhosis; Cardiotropic

Core Tip: Chronic hepatitis C virus (HCV) infection is emerging as a significant contributor to cardiomyopathy, including dilated, hypertrophic, and arrhythmogenic subtypes. This review synthesizes evidence outlining complex pathogenic mechanisms: Direct viral toxicity via HCV core protein-mediated cytokine release (e.g., tumor necrosis factor alpha), immune-mediated damage, genetic predispositions, apoptotic pathways, and cirrhotic cardiomyopathy from HCV-induced liver disease. Notably, direct-acting antiviral (DAA) therapies not only achieve high cure rates but also improve cardiac function, although potential cardiotoxic effects require vigilance. The study underscores the need for further research into mechanistic insights, biomarker validation, and expansion of global DAA access to mitigate cardiovascular risks and improve patient outcomes.

INTRODUCTION

Viral cardiomyopathies are a well-established cause of congestive heart failure, with studies reporting a mean survival rate of 30%–40% in affected individuals[1]. Traditionally, these conditions were primarily associated with enteroviruses, particularly Coxsackievirus B. However, increasing evidence suggests that hepatitis C virus (HCV), a single-stranded RNA virus within the Flaviviridae family, which affects approximately 170 million individuals globally, plays a significant role in the pathogenesis of various cardiomyopathies, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (Table 1)[2]. The prevalence of cardiomyopathies is difficult to estimate owing to limited data and discrepancies in testing; however, it has been estimated to be around 1/250 to 500 for HCM and 1/2000 to 5000 for arrhythmogenic right ventricular cardiomyopathy. The estimates for DCM are unclear, although it has been estimated to be twice as prevalent as HCM[3].

Table 1 An overview of selected studies examining the link between hepatitis C virus infection and various forms of cardiomyopathy.

Ref.	Year	Study type	Population studied	Key findings
Matsumori et al[77]	1995	Case-control/observational	36 patients with dilated cardiomyopathy vs 40 controls with ischemic heart disease (Japan)	Significantly higher HCV antibody prevalence (16.7% vs 2.5%) in patients with dilated cardiomyopathy. HCV RNA detected in the heart tissue of some patients
Omura et al[15]	2005	Animal study (transgenic mice)	Mice transgenic for the HCV-core gene vs wild-type mice	HCV-core gene expression led to cardiac dysfunction, hypertrophy, and fibrosis consistent with cardiomyopathy, suggesting a direct pathogenic role of the viral protein
Matsumori[78]	2005	Review/commentary	Review of studies (primarily Japanese) on patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, and arrhythmogenic right ventricular cardiomyopathy	Summarizes evidence linking HCV to various cardiomyopathies. HCV antibodies were found in 10.6% of patients with hypertrophic cardiomyopathy and 6.3% of patients with dilated cardiomyopathy in a large Japanese study. HCV RNA found in the heart tissue
Dos Reis et al[79]	2006	Systematic review	Review of published studies on idiopathic dilated cardiomyopathy patients	The role of HCV in idiopathic dilated cardiomyopathy pathogenesis remains controversial. Significant association found in only 2 reviewed papers (same author, Japan); methodological limitations noted
Tsui et al[80]	2009	Cohort study analysis	Patients with stable coronary heart disease from the Heart and Soul Study	HCV-positive status is associated with higher tumor necrosis factor-α and increased risk of death and heart failure-related hospitalizations. HCV remained independently associated with heart failure events after adjustment
Younossi et al[81]	2013	Cross-sectional (NHANES)	United States population data (NHANES 1999–2010)	Chronic HCV is independently associated with insulin resistance, type 2 diabetes, hypertension, and congestive heart failure (but not ischemic heart disease or stroke)
Petta et al[9]	2015	Meta-analysis	22 observational studies comparing HCV-positive vs HCV-negative individuals	HCV infection is associated with increased cardiovascular disease-related mortality and subclinical carotid atherosclerosis
Poller et al[82]	2018	Review/perspective	General review focusing on chronic HCV, heart failure, and the impact of direct-acting antivirals	Known association between HCV and cardiomyopathy, but causality is unclear. HCV may aggravate existing heart issues via immune mechanisms. New direct-acting antivirals offer a way to study this

HCV: Hepatitis C virus.

The pathophysiology of HCV-related cardiomyopathy is complex, involving both direct viral myocarditis and indirect mechanisms such as systemic inflammation and metabolic dysregulation[4]. HCV can replicate within vascular tissues, promoting a pro-atherogenic environment through chronic inflammation, endothelial dysfunction, and insulin resistance[5]. Chronic HCV infection is associated with increased severity of coronary artery disease, higher rates of heart failure, and subclinical cardiac abnormalities, thereby positioning HCV as an independent risk factor for cardiovascular morbidity[6]. The risk is particularly elevated in older patients with comorbid conditions such as hypertension and diabetes mellitus. Additionally, HCV-infected individuals have a higher prevalence of carotid intima–media thickening and carotid plaques, which are markers of atherosclerosis[6]. Despite growing evidence, significant gaps remain in understanding the precise mechanisms linking HCV and cirrhosis to cardiovascular dysfunction, the impact of early HCV treatment on cardiovascular outcomes, and the potential for targeted therapeutic interventions. This review seeks to offer a comprehensive understanding that can serve as a foundation for future research and facilitate the development of practical solutions to these major global health issues.

MATERIALS AND METHODS

Search strategy

A comprehensive narrative literature review was conducted to evaluate the relationship between hepatitis C and cardiomyopathies using major databases, including PubMed, Scopus, and Google Scholar. The search employed a combination of keywords such as “hepatitis C”, “cardiomyopathy”, “dilated cardiomyopathy”, “hypertrophic cardiomyopathy”, “cirrhosis”, and “antiviral therapies”, along with Boolean operators (AND, OR) and Medical Subject Headings terms to refine results and ensure relevance.

The search was restricted to English-language articles published between January 1990 and December 2024 to highlight recent advancements and compare them with contemporary perspectives. Inclusion criteria encompassed studies, review articles, and meta-analyses focusing on the relationship between hepatitis C and cardiomyopathy, diagnostic approaches, treatment modalities, and articles exploring the pathophysiological mechanisms linking hepatitis C to cardiomyopathy. Exclusion criteria included non-English publications, studies unrelated to hepatitis C, studies focusing solely on non-cardiac manifestations of hepatitis C, conference abstracts, editorials, and opinion pieces.

The study selection process involved title and abstract screening to assess relevance, followed by full-text review to confirm alignment with study objectives. Data were systematically extracted using a predefined framework, and findings were summarized qualitatively, focusing on key themes such as pathophysiology; the impact of hepatitis C on cardiomyopathy, morbidity, and mortality; and emerging research gaps and opportunities.

Epidemiology

The global prevalence of HCV varies from 0.5% to 2.5%, with higher rates in Asia, Eastern Europe, and parts of Africa[7]. An estimated 1.5 to 1.75 million new HCV infections still occur per year worldwide (roughly 23.7 per 100000 population). Regional variations in HCV-related cardiomyopathy rates may be influenced by differences in HCV genotype distribution across regions[2]. For instance, genotype 1 is predominant in the Americas and Europe, genotype 4 in Egypt, and genotype 3 in South Asia (Figure 1). North America has relatively lower HCV prevalence (around 1% of adults in the United States are chronically infected), but certain subpopulations (e.g., people who inject drugs, baby boomers) have higher rates[8]. While it is challenging to measure the precise worldwide prevalence of cardiomyopathy among patients infected with HCV, studies indicate that HCV confers an elevated risk. A 2016 meta-analysis of 22 studies reported that HCV-positive individuals have about 20%–30% higher odds of experiencing cardiovascular events (including conditions such as myocardial infarction, stroke, and heart failure) compared to HCV-negative controls[9]. In a large national cohort from Taiwan, the incidence of heart failure (a clinical outcome of cardiomyopathy) in untreated patients with chronic HCV was about 1.5 per 1000 person-years, which was significantly higher than the observed incidence in patients who received antiviral therapy[10]. There is limited direct surveillance of “HCV-related cardiomyopathy” in North America; however, research indicates that HCV-infected individuals are at elevated cardiovascular risk[8]. Other studies support a higher-than-expected occurrence of cardiomyopathy in patients with HCV. For instance, up to 5%–7% of idiopathic (unexplained) cardiomyopathy cases worldwide have been linked to underlying HCV infection[11].

Figure 1 Global epidemiology of hepatitis C virus infection and its cardiovascular implications. Worldwide, hepatitis C virus (HCV) prevalence is estimated at 2.5%-5%, with an annual incidence of approximately 23.7 cases per 100000 population. Chronic HCV infection increases cardiovascular risk by 20%-30%, with an incidence of cardiomyopathy of 1.5 per 1000 person-years. HCV: Hepatitis C virus; MI: Myocardial infarction; HF: Heart failure.

HCV is linked to multiple forms of cardiomyopathy. The strongest association is observed with DCM and myocarditis[2]. HCV RNA has been detected in the heart tissue of patients with myocarditis/DCM, suggesting direct viral involvement. HCV is also associated with HCM. One study showed HCV antibodies in 22.5% of hypertrophic cardiomyopathy cases (18 of 80 patients)—a rate far higher than the rate observed in matched controls[1]. The association with arrhythmogenic right ventricular cardiomyopathy and restrictive cardiomyopathy is less well-established and warrants further investigation[12].

RESULTS

Pathophysiology

The relationship between HCV infection and cardiomyopathy is complex and multifaceted, involving both direct and indirect mechanisms that lead to cardiac dysfunction (Figure 2).

Figure 2 Proposed pathogenesis of hepatitis C virus-induced cardiomyopathy. Chronic hepatitis C virus infection contributes to myocardial injury through both direct viral invasion and indirect mechanisms. Direct effects include immunomodulation and apoptosis, while indirect pathways involve cytokine release, inducible nitric oxide synthase activation, altered calcium channel function, and reduced beta-adrenergic response, ultimately decreasing myocardial contractility. NO: Nitric oxide; iNOS: Inducible nitric oxide synthase; IL-1β: Interleukin-1β; TNF-α: Tumor necrosis factor-alpha.

Direct viral effects

HCV has been identified as a cardiotropic virus, capable of direct viral invasion and replication within cardiac tissue[13]. HCV invasion of cardiac myocytes leads to an inflammatory response and the production of cytokines, which contribute to the pathogenesis of myocarditis. HCV core protein directly injures the myocardium, with tumor necrosis factor alpha (TNF-α) identified as a key mediator[14,15]. Studies have shown a correlation between elevated levels of interleukin-1β (IL-1β) and TNF-α, and depressed myocardial function[14]. Cardiac myocytes themselves contribute to this pathology by producing TNF-α in response to viral infections[16]. Myocardial dysfunction occurs when TNF-α binds to its specific receptors (TNFR1 and TNFR2) on cardiac myocytes, leading to negative inotropic effects[14]. Mechanistically, TNF-α disrupts intracellular calcium signaling by reducing L-type calcium channel currents, thereby limiting calcium influx into the cell. Furthermore, TNF-α impairs calcium reuptake into the sarcoplasmic reticulum via SR Ca²⁺/Mg²⁺ ATPase[14,17]. This dual impact on calcium handling profoundly affects both the contraction and relaxation phases of myocardial activity, ultimately leading to compromised cardiac performance.

In addition, the inflammatory microenvironment and cytokines induce the production of nitric oxide (NO) by stimulating inducible nitric oxide synthase[18]. Elevated NO levels attenuate beta-adrenergic responsiveness and depress myocardial contractility[19]. The enhanced NO production and conversion of nitric oxide to peroxynitrite by inflammatory cells lead to intracellular damage of myocytes[20,21]. Inflammatory mediators also increase myocardial oxidoreductases, such as xanthine oxidoreductase and NADPH oxidoreductase, amplifying oxidative stress[22]. HCV proteins, particularly the NS3/4A serine protease, interfere with critical components of the cellular immune response. NS3/4A has been shown to cleave signaling molecules such as mitochondrial antiviral signaling and TRIF (TIR domain-containing adapter inducing interferon-β), disrupting RIG-I-like receptor and toll-like receptor pathways required for activating type I IFN and its downstream signaling pathways. This interference results in decreased production of interferon-stimulated genes, which are vital for controlling viral replication[23]. Additionally, HCV induces the expression of suppressor of cytokine signaling (SOCS) proteins such as SOCS3, which inhibit the JAK-STAT signaling pathway that mediates the effects of interferons on target cells[24].

Immune-mediated mechanism

The immune-mediated mechanisms underlying HCV-induced cardiomyopathy are characterized by the formation of antigen–antibody complexes that contribute to cardiac damage and dysfunction. The innate immune system serves as the first line of defense against HCV infection, responding rapidly to viral presence[25]. However, HCV has developed various strategies to evade this innate immune response, which can result in inadequate clearance of the virus and persistent infection[26,27]. Antigenic variation represents a key mechanism by which HCV evades the host immune response. The virus exhibits a high mutation rate, particularly within hypervariable regions such as the E2 envelope protein, which encodes critical neutralizing epitopes. This genetic diversity gives rise to a population of viral quasispecies capable of escaping recognition by host-derived neutralizing antibodies[28]. Additionally, glycan shielding on the HCV envelope proteins conceals conserved immunogenic regions from neutralizing antibodies, further impairing immune recognition. The ongoing evolution of these variants contributes to a shifting antigenic profile, thereby complicating the development of effective and sustained immune responses[29]. Evidence suggests that specific mutations can generate escape variants with diminished immunogenicity, allowing them to evade immune surveillance and persist within the host, ultimately undermining treatment efficacy[30]. Collectively, these strategies illustrate the sophisticated immune evasion tactics employed by HCV, which not only facilitate viral persistence but also hinder the host’s ability to mount a robust antiviral response.

The adaptive immune response, particularly T cell responses, is vital for the clearance of HCV. However, chronic infection can result in T cell exhaustion, characterized by impaired function and the inability to effectively combat the virus[26,31]. Similarly, B cell responses, although not protective in the context of HCV, can contribute to lymphoproliferative disorders and further complicate the clinical picture[32]. Recent studies suggest that even after successful HCV treatment with direct-acting antivirals (DAAs), some immune alterations may persist, including only partial recovery of T cell functionality and potential persistence of B cell activation, which can have long-term consequences for both immune regulation and cardiac health[31,32]. The immunologic mechanism of cell damage is further supported by a study that reported the isolation of serum antibodies that specifically targeted cardiac myocytes in three cases of HCV-associated myocarditis in which the individuals did not have any other cardiotropic viral infections and responded positively to immunosuppressive treatments[33].

Genetic susceptibility

Genetic variations in host immune systems, particularly within the human leukocyte antigen (HLA) and non-HLA systems, play a crucial role in the presentation of viral antigens to immune cells and have been implicated in modulating the immune response to HCV and the subsequent risk of developing cardiomyopathy[34]. HLA class I and II alleles determine the efficiency of antigen presentation to T lymphocytes, thereby shaping the quality and magnitude of the antiviral immune response and the risk of autoimmune or inflammatory sequelae in extrahepatic tissues, including the myocardium[35]. The pathogenesis likely involves molecular mimicry, immune complex deposition, and chronic inflammation, with HLA molecules facilitating the presentation of viral or cross-reactive self-antigens to T cells, thereby promoting myocardial damage in susceptible hosts[13,35]. Specific HLA-DP alleles—such as DPB104:01 and DPB109:01—have been associated with an elevated risk of HCV-related hypertrophic cardiomyopathy. These alleles may contribute to a progressive cardiomyopathic phenotype in individuals with chronic HCV infection. The observed gene–dose effect disparity suggests that certain HLA-DP molecules, through their antigen-binding properties specific to HCV peptides, may facilitate disease progression.

Chronic HCV infection is associated with marked disruptions in natural killer (NK) cell function. These alterations manifest primarily through changes in the expression patterns of various receptors on NK cell surfaces. Specifically, there is a notable decrease in the expression of activating receptors, particularly NKp30 and NKp46, which are essential for NK cell-mediated cytotoxicity and cytokine production. Concurrently, an increase in the expression of inhibitory receptors, such as NKG2A, is observed. This shift in the balance between activating and inhibitory signals, along with the activation of STAT1 and STAT4 pathways, impairs the NK cells’ ability to effectively recognize and eliminate virus-infected cells. Furthermore, HCV E2 glycoprotein is known to induce CEACAM1 expression on infected hepatocytes, which subsequently suppresses NK cell activity[36]. In addition, the CD56-dim subset, which is primarily responsible for cytolytic activity, is decreased, whereas the CD56-bright subset, which is more involved in cytokine secretion, exhibits increased expression of inhibitory receptors[37]. These alterations impair NK cell cytotoxicity and cytokine production, facilitating viral persistence and contributing to progressive hepatic injury.

HCV-associated dilated cardiomyopathy (HCV-DCM) appears to be more strongly linked to non-HLA genes located within the MHC class III–class I boundary region, rather than to classical HLA genes. However, certain HLA and non-HLA haplotypes have been linked to increased TNF-α production and immune dysregulation, making some individuals more prone to developing HCV-associated cardiomyopathy[38]. In a gene mapping study, Shichi et al[39] identified a locus of susceptibility to HCV-DCM within a non-HLA gene region extending from the NFKBIL1 to the MICA gene loci, situated at the MHC class III-class I boundary. Their findings indicated a stronger association of HCV-DCM with alleles of non-HLA genes compared to HLA genes. Furthermore, polymorphisms in apoptosis-related genes such as TRAIL and FasL have been associated with increased susceptibility to HCV infection and higher viral loads, suggesting a genetic predisposition to HCV-induced cardiomyopathy[40].

HCV itself exhibits extensive genetic variation, characterized by its high mutation rate and the ability to generate quasispecies[41]. This variability not only affects the virus’ ability to evade the host immune system but also influences the clinical outcomes of the infection[42]. Specifically, the presence of certain HCV genotypes and subtypes, particularly genotype 2 and its recombinants, may play a critical role in the pathogenesis of HCV-associated conditions, including cardiomyopathy[2]. Additionally, the continuous generation and selection of resistant viral variants within the quasispecies spectrum may further complicate the host’s ability to mount an effective immune response, leading to increased susceptibility to complications such as cardiomyopathy[43]. Thus, genetic determinants of both the host and the virus are implicated in the pathophysiology of HCV-associated cardiomyopathy.

Apoptotic pathways

HCV infection is significantly associated with the induction of apoptosis through both intrinsic (i.e., mitochondrial) and extrinsic (i.e., death receptor-mediated) pathways[44]. The intrinsic pathway involves mitochondrial dysfunction, with the HCV core protein identified as a potent inducer of apoptosis, triggering Bax activation, leading to mitochondrial membrane potential disruption, cytochrome c release, and caspase 3 activation[45,46]. This pathway is further amplified by the ROS/JNK signaling pathway, which upregulates pro-apoptotic proteins such as Bim, facilitating Bax activation and subsequent apoptosis[47]. The extrinsic pathway involves the activation of death receptors such as Fas and TNF alpha, leading to caspase 8 activation and downstream caspase 3 activation[44,48]. HCV protein disrupts the activation of important signaling pathways such as p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular signal-regulated kinase[49]. This dual activation of apoptotic pathways results in significant myocardial cell death, contributing to the development of cardiomyopathy.

Daussy et al[50] documented the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the setting of HCV infection. NLRP3 expression is upregulated in hepatocytes during HCV infection, in correlation with the intracellular levels of HCV NS3 protein and viral RNA. This upregulation is initiated by a priming phase involving NF-κB activation, which is followed by inflammasome assembly. The assembled complex activates caspase-1, leading to the maturation and secretion of pro-inflammatory cytokines, notably IL-1β, which plays a pivotal role in recruiting inflammatory cells and promoting cardiac extracellular matrix remodeling[51]. Therefore, NLRP3-mediated pyroptosis contributes to tissue damage by fostering a highly inflammatory milieu that may lead to the loss of cardiomyocytes and cardiac fibroblasts, thereby exacerbating myocardial injury.

Cirrhosis and cardiomyopathy

Chronic HCV infection is the leading cause of cirrhosis, with a substantial number of infected individuals progressing to chronic liver disease and eventually cirrhosis[52]. The relationship between HCV liver cirrhosis and cardiomyopathy is primarily characterized by the development of cirrhotic cardiomyopathy, defined as chronic cardiac dysfunction in patients with cirrhosis. Cirrhotic cardiomyopathy is characterized by impaired contractile responsiveness to stress and altered diastolic relaxation, leading to elevated cardiac output and hyperdynamic circulation[53]. Wong et al[54] studied how cirrhosis affects heart function during exercise. They tested 39 patients with cirrhosis and 12 healthy volunteers, measuring heart performance and oxygen consumption before and after exercise. Patients with pre-ascites (without fluid buildup) demonstrated better exercise tolerance, with 71% achieving their predicted workload, while those with ascites (with fluid buildup) showed markedly impaired performance, with only 41% meeting their expected workload. Patients with cirrhosis showed a smaller increase in cardiac output, reducing their oxygen use[54]. This suggests that cirrhosis weakens the cardiovascular response to physical activity.

The proposed mechanisms of systolic dysfunction in cirrhosis primarily involve decreased responsiveness of the cardiac beta-adrenergic system, leading to impaired chronotropic and inotropic response to stressors[53]. Excessive splanchnic vasodilation and the ensuing hypotension lead to persistent stimulation of the sympathetic nervous system and the renin–angiotensin–aldosterone system. This chronic stimulation leads to downregulation of beta-adrenergic receptors and impaired signaling, characterized by decreased cAMP production[55,56]. Furthermore, sympathetic overactivity directly causes myocyte injury and fibrosis[57]. The second important pathophysiological mechanism of cardiac dysfunction is the effect of endogenous cannabinoids such as anandamide on cardiac function. Anandamide exerts its effect through the G protein-coupled cannabinoid-1 receptor and suppresses cardiac responsiveness to sympathetic stimulation[58]. Elevated levels of NO and carbon monoxide also exert similar effects on cardiac myocytes, thereby leading to cirrhotic cardiomyopathy[59].

Another mechanism involves amphiregulin (ARG), a member of the epidermal growth factor family, which has been linked to a greater risk of cardiomyopathy in patients with cirrhosis[60]. This connection is primarily owing to ARG’s role in promoting fibrosis and early diastolic dysfunction. A study involving 87 individuals with HCV-related cirrhosis divided participants into two groups: 52 patients with left ventricular diastolic dysfunction and 35 with normal diastolic function. The results showed that ARG levels were notably higher in the group experiencing left ventricular dysfunction and were independently linked to early signs of extracellular matrix remodeling, such as carboxyterminal propeptide of type I collagen, amino-terminal propeptide of type III procollagen, and tissue inhibitor of matrix metalloproteinase-1[60]. Furthermore, markers related to ventricular remodeling, such as N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin-T, were also elevated in the diastolic dysfunction group, supporting the findings of the study.

DISCUSSION

Clinical implications

The management of hepatitis C and its potential complications, such as cardiomyopathy, involves a multifaceted approach that prioritizes treatment adherence, lifestyle modifications, and effective communication with healthcare providers. Chronic HCV is a major public health burden; however, the advent of DAA medications, which achieve cure rates of more than 90%, has transformed the management of chronic hepatitis[61]. While DAA-induced cardiomyopathy is not recognized in the medical literature, its cardiovascular implications could be both positive and negative[62]. For instance, a study by Ahmad et al[63] highlighted cardiac dysfunction associated with a nucleotide polymerase inhibitor, BMS-986094, which was subsequently withdrawn owing to cardiotoxicity. This study found that some patients experienced significant reductions in left ventricular ejection fraction and required hospitalization for suspected cardiotoxicity. A study by Lam et al[64] researching the impact of DAA agents on cardiac disease reported reduced risk of peripheral arterial disease and other cardiovascular outcomes in patients with advanced fibrosis. However, it was also associated with an increased risk of arrhythmias and conduction disorders, especially within the first year of initiation[64].

Conversely, other studies have shown beneficial cardiovascular effects of DAA therapy. DAAs such as sofosbuvir, ledipasvir, daclatasvir, and velpatasvir are highly effective in achieving sustained virologic response in HCV patients, which in turn leads to a reduction in major adverse cardiovascular events, including heart failure and acute coronary syndrome, by improving endothelial function and reducing systemic inflammation[62,65]. For example, Roguljic et al[62] reported a 43% reduction in cardiovascular events in patients with chronic HCV treated with DAAs. Moreover, DAA therapy has also been associated with improvements in cardiac function and structure, with a recent study demonstrating decreased right heart dimensions and improved left ventricular function, suggesting a favorable effect on cardiac remodeling[66]. However, patients with pre-existing cardiovascular disease, diabetes mellitus, advanced liver disease, and older adults remain at increased risk for developing cardiomyopathy when treated for HCV infection[64,67]. Certain DAA regimens are more suited for patients with pre-existing cardiovascular disease. The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend the use of glecaprevir/pibrentasvir as a first-line treatment option for HCV for patients with cardiovascular comorbidities, as it is well tolerated and has fewer drug–drug interactions[68,69].

In contrast to DAAs, antiviral regimens based on peginterferon alpha (Peg IFN-α) combined with ribavirin have been associated with cardiotoxicity, including rare cases of cardiomyopathy. A case report documented fatal cardiomyopathy in a patient treated with this combination, highlighting the need for caution in patients with pre-existing cardiac conditions[70]. The mechanisms through which Peg IFN-α and ribavirin induce cardiac toxicity are complex and not yet fully understood. Factors such as mitochondrial dysfunction and changes in erythrocyte function due to ribavirin accumulation may contribute to myocardial complications[71]. Additionally, the biological activity of PEGASYS, a preservative-free solution administered subcutaneously, derived from recombinant human interferon α-2a, is linked to its binding to the human type 1 interferon receptor, which activates multiple intracellular signaling pathways, including the JAK/STAT pathway. This receptor activation has diverse effects on various cell types, potentially influencing cardiovascular responses[72]. While cardiac toxicity is uncommon, current guidelines recommend pre-treatment cardiac evaluations, including electrocardiograms, in individuals with risk factors[68].

Future directions

The introduction of DAAs has significantly improved the prognosis for patients with HCV, including those with extrahepatic manifestations such as cardiomyopathy[6]. Current evidence indicates that DAAs not only clear the HCV infection but also significantly mitigate cardiovascular risks and improve cardiac outcomes[5,73]. Continued research is needed to further elucidate the long-term cardiovascular benefits of HCV eradication and establish standardized treatment protocols for managing HCV-related cardiomyopathy[74]. Furthermore, understanding the mechanisms by which HCV contributes to cardiomyopathy is crucial. As established above, HCV has been identified as a cardiotropic virus, exerting both direct and indirect effects on the myocardium. The pathogenesis involves a complex interplay of direct viral injury, immune-mediated mechanisms, genetic susceptibility, oxidative stress, and apoptotic pathways[5,13,62]. Future research should aim to clarify these mechanisms to develop targeted therapies (Figure 3).

Figure 3 Future research directions in hepatitis C virus-related cardiomyopathy. Research priorities include elucidating pathogenic mechanisms to enable the development of targeted therapies, validating early-detection biomarkers (e.g., Mac-2 binding protein glycan isomer, Angiopoietin-2), and ultimately improving global access to direct-acting antiviral agents. These strategies align with the World Health Organization’s goal of eliminating viral hepatitis as a public health threat by 2030. Ang2: Angiopoietin-2; DDA: Direct-acting antiviral agent; M2BPGi: Mac-2 binding protein glycan isomer; WHO: World Health Organization.

The identification of biomarkers for early detection and monitoring of HCV-related cardiomyopathy is essential. M2BPGi (Mac-2 binding protein glycosylation isomer) and Ang-2 have shown promise as potential biomarkers in this context[75]. M2BPGi is a glycoprotein associated with liver fibrosis progression in patients with HCV infections, while Ang-2 is involved in vascular remodeling and inflammation. Early identification of high-risk patients would facilitate the implementation of preventive measures, such as lifestyle modifications, closer monitoring, or more aggressive antiviral therapy. Additionally, these biomarkers could be used to track the effectiveness of treatments and interventions over time, providing a more comprehensive understanding of disease progression and treatment response. Further research is needed to validate the clinical utility of M2BPGi and Ang-2, as well as to identify other potential biomarkers that could enhance the accuracy and reliability of risk assessment in HCV-related cardiomyopathy.

Expanding access to DAA therapy for HCV, particularly in developing nations, is of paramount importance in the global fight against HCV-related cardiovascular diseases. Its availability remains limited in many parts of the world owing to factors such as high costs, lack of healthcare infrastructure, and insufficient awareness among both healthcare providers and patients. Addressing these barriers through initiatives such as price negotiations with pharmaceutical companies, strengthening healthcare systems, and implementing targeted education programs can significantly increase access to treatment. Broader availability of DAAs can support the World Health Organization’s goal of eliminating viral hepatitis as a major public health threat by 2030[76].

CONCLUSION

HCV infection represents a significant risk factor for developing both dilated and hypertrophic cardiomyopathy. The underlying pathophysiology is intricate, involving direct viral cardiotoxicity, complex immune-mediated damage, genetic predispositions, apoptotic pathways, and the distinct entity of cirrhotic cardiomyopathy stemming from HCV-induced liver disease. While the advent of highly effective DAAs has revolutionized HCV treatment and demonstrated benefits in reducing cardiovascular events, thereby potentially improving cardiac function, vigilance regarding potential cardiotoxicity, especially with older regimens or specific agents, remains necessary. Future efforts must focus on fully elucidating the precise mechanisms linking HCV to cardiac dysfunction, validating reliable biomarkers like M2BPGi and Ang-2 for early detection and risk stratification, and critically, expanding global access to DAA therapy. Addressing these challenges is essential not only for managing individual patient outcomes but also for achieving the broader public health goal of mitigating the extensive cardiovascular burden associated with chronic HCV infection worldwide.