Chronic hepatitis C and the risk for atherosclerotic and cardiomyopathic heart disease

Abstract

Hepatitis C virus (HCV) infection has been increasingly associated with cardiovascular complications, particularly atherosclerosis and cardiomyopathy, in addition to its primary hepatic effects. Studies indicate a higher prevalence of carotid atherosclerosis in patients with chronic hepatitis C infection, with viral load and steatosis emerging as independent risk factors. HCV-related atherosclerosis appears to develop through complex processes involving endothelial dysfunction, inflammation, oxidative stress, and immune dysregulation. Key cytokines, including tumor necrosis factor-alpha and interleukin-6, increase inflammatory responses, while oxidative stress markers, such as malondialdehyde, are associated with an increased risk of atherogenesis. In addition, HCV infection has been linked to cardiomyopathy. Direct viral effects, including HCV replication within cardiomyocytes and cytotoxicity induced by viral proteins, lead to myocardial injury and functional decline. Indirectly, HCV triggers immune-mediated damage, with heightened pro-inflammatory cytokines exacerbating cardiomyocyte apoptosis and fibrosis. Furthermore, HCV infection promotes a procoagulant imbalance, as evidenced by elevated factor VIII levels and thrombin potential, contributing to the increased cardiovascular risk. While substantial evidence indicates a relationship between HCV and cardiovascular disease, further research is needed to establish causality and guide therapeutic interventions.

Key Words: Hepatitis C virus; Chronic hepatitis C; Cardiovascular disease; Carotid atherosclerosis; Cardiomyopathy; Immune dysregulation; Myocarditis

Core Tip: Hepatitis C virus (HCV) infection has been shown to contribute to cardiovascular complications, extending beyond its liver-related effects. This review highlights the link between HCV and various examples of these complications, such as atherosclerosis and cardiomyopathy, emphasizing the roles of chronic inflammation, oxidative stress, immune dysregulation, and coagulation imbalance. Understanding these mechanisms may help guide future research and improve cardiovascular risk assessment and management in patients with chronic HCV infection.

INTRODUCTION

Chronic hepatitis C (CHC) is a significant global health burden, affecting millions of people worldwide. In the United States, an estimated 2.7 to 3.9 million people have CHC, with approximately 17000 new cases reported each year. Alarmingly, up to 75% of individuals with CHC are unaware of their infection[1].

CHC is primarily known for its devastating effects on the liver, with a 2019 report estimating 540000 deaths and 15.3 million disability-adjusted life years (DALYs)[2]. However, emerging evidence highlights a concerning association between CHC and cardiovascular disease (CVD)[3,4]. This connection is multifaceted, involving both direct and indirect mechanisms that contribute to increased cardiovascular risk in individuals with CHC.

Atherosclerosis, characterized by the buildup of plaques in arterial walls, poses a critical threat to cardiovascular health and is linked to increased morbidity and mortality in hepatitis C virus (HCV)-infected populations. Studies have demonstrated that HCV infection is linked to an increased prevalence of carotid plaques and CVD, suggesting that the virus may play a role in the pathogenesis of vascular disease through mechanisms such as chronic inflammation and altered lipid metabolism. Similarly, cardiomyopathy has been identified in patients with chronic HCV infection, raising concerns about the long-term cardiac health of these individuals. The potential for HCV to induce direct myocardial damage or exacerbate existing cardiac conditions underscores the need for comprehensive cardiovascular assessment in individuals with CHC[5,6].

The effect of HCV on the heart remains a controversial topic, with strong opinions on both sides[7]. Two major cardiovascular conditions with emerging evidence of association with CHC are atherosclerotic heart disease and cardiomyopathy. This review focuses on understanding these associations, their epidemiology, pathogenetic mechanisms, clinical presentation, and treatment options to improve patient outcomes and guide future research.

THE ASSOCIATION OF HCV AND ATHEROSCLEROSIS

Atherosclerosis has been found to occur more frequently in patients with HCV infection. Adinolfi et al[8] explored the relationship between HCV infection and carotid atherosclerosis (CA) in a cohort of 803 individuals. The study included 326 treatment-naïve CHC patients and 477 matched controls. The study found a significantly higher prevalence of CA in CHC patients compared to controls (53.7% vs 34.3%). Younger CHC patients (< 50 years) also showed a greater risk.

The study provides novel insights into the role of serum HCV RNA levels and steatosis in the development of atherosclerosis, identifying associations between HCV RNA and both early (intima-media thickness) and advanced atherosclerotic plaques. It also provides a valuable comparison between CHC patients with HCV-related steatosis and patients with non-alcoholic fatty liver disease (NAFLD). The finding that HCV-related steatosis poses a higher risk for atherosclerosis compared to NAFLD patients contributes to the ongoing debate about the relative risks posed by these liver conditions.

However, the study design, which focuses on treatment-naïve patients, prevents it from establishing causality and limits generalizability. Without follow-up, it is unclear whether the observed atherosclerosis leads to clinical cardiovascular events, such as heart attacks or strokes.

Another case-control study investigated the prevalence of CA in 174 biopsy-proven CHC patients compared with 174 control patients. The study found a significantly higher prevalence of carotid plaques in cases vs controls (41.9% vs 22.9%). Additionally, CHC patients had greater intima-media thickness measurements. Severe hepatic fibrosis was identified as an independent risk factor for atherosclerosis, particularly in younger patients[9].

Pathophysiology of atherosclerosis among HCV patients

The development of atherosclerosis in HCV-infected patients involves several stages: (1) Endothelial damage: This occurs due to factors like systemic inflammation; (2) Inflammation and oxidative stress: Immune cells are attracted to injury sites, leading to fatty streak formation and plaque buildup; and (3) Plaque formation: Plaques can rupture, leading to obstructed blood flow.

The process of plaque formation and subsequent rupture, depending on the site, can cause obstructed blood flow to the tissue or organ upstream[10,11].

Several clinical studies have identified the most common cytokines reported in HCV-affected patients. Th1 cytokines and Th2, which are responsible for the activation of cell-mediated and humoral immune systems respectively, suggesting a mixed immune reaction, through tumor necrosis factor-alpha (TNF-α), interferon-gamma, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10. These cytokines modulate the inflammatory response either in a protective or causative role[12,13].

HCV disrupts endothelial function, particularly nitric oxide production, leading to vasoconstriction and turbulent blood flow, which promotes lipoprotein infiltration into the arterial walls. Pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8 are elevated in HCV patients, promoting plaque formation[13-16]. In contrast, antiatherogenic cytokines like IL-4, IL-5, and IL-10 are downregulated, reducing protection against plaque formation. Table 1 summarizes these cytokines and effects[17-20].

Table 1 Overview of the cell types, cytokines with their actions on target cells.

Cytokine	T helper cell type	Target cell	Action	Net effect on plague formation
TNF-α	Th1	Macrophages, endothelial cells	Promotes atherogenesis by increasing the expression of adhesion molecules on endothelial cells, leading to the recruitment of inflammatory cells into the arterial wall	Proatherogenic
IFN-γ	Th1	Macrophages, CD8, T cells, NK cells	Despite its antiviral effects, it increases adhesion molecules expression	Proatherogenic
IL-2	Th1	T cell	B cell clonal expansion and T cell development	Proatherogenic (less well-established)
IL-4	Th2	T and B cells	Promotes T cell development, upregulate pro-inflammatory mediators	Antiatherogenic (less well-established)
IL-5	Th2	B cell	B cell activation and production of protective natural immunoglobulin M antibodies against oxidation-specific antigens	Antiatherogenic (less well-established)
IL-6	Macrophages	Macrophages, Th1	Increase adhesion molecule expression	Proatherogenic
IL-8	Th2	Neutrophils	Releasing reactive oxygen species and promoting inflammation	Proatherogenic
IL-10	T reg cell	Macrophages, B cells	Suppresses activation of Th1 cells and macrophages	Antiatherogenic

TNF-α: Tumor necrosis factor-alpha; IL: Interleukin-6; IFN-γ: Interferon-gamma; NK: Natural killer.

Another key to pathogenesis is oxidative stress, an important factor in changing the accumulated lipoproteins which attracts the attention of the macrophages. The source of the reactive oxygen species is mitochondria and rough endoplasmic reticulum. This is a physiological process, and it is swiftly eliminated by cellular responses to keep a fine balance between oxidation and anti-oxidation state. If this balance is offset, pathological processes like inflammation, metabolic dysfunction, and neural damage occur[21].

Many markers were investigated to better understand the pathological process and limit it pharmacologically. Biomarkers like malondialdehyde and oxidative stress index are elevated in HCV patients, supporting the link between HCV and oxidative stress[22].

HCV proteins are responsible for inducing oxidative damage in the tissues, namely core, E1, E2, NS3, NS4B, and NS5A. These proteins overwhelm the glutathione system’s ability to protect cells from damage, leading to endothelial dysfunction on vessel walls[21].

Furthermore, oxidative stress is also responsible for carcinomas and other extra-hepatic disorders such as diabetes, lymphoproliferative disorders, neuropathy, and embolic strokes[23,24].

Vascular and immune-mediated mechanisms

The adhesion of circulating leukocytes is an essential step in vasculitis and the migration of these immune cells into the tissues in the inflammation process. HCV infection increases the expression of adhesion molecules on endothelial cells, promotes local vascular inflammation, and enhances the production of proinflammatory cytokines and free radicals by macrophages, all of which accelerate atherosclerosis. A family of surface molecules is responsible for this exact step, mainly intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and integrins on lymphocytes such as lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) and very late antigen-4 (VLA-4, CD49/CD29). LFA-1 and VLA-4 are found mainly on monocytes and T cells but not neutrophils. These surface molecules interact with each other to bind, arrest, and promote the migration of monocytes and T cells. Some adhesion molecules are essential in the process of atherosclerosis and the subsequent myocardial infarction[25,26].

Analyzing HCV core antigen isolated from liver, kidney, heart, and bone marrow samples by immunohistochemistry found CD68-positive macrophages. HCV core and NS4 antibodies stained mostly infiltrating cells in the heart. These results suggest that macrophages play a role in directly attacking cardiac myocytes[27].

The relationship between HCV infection and endothelial surface markers is evident especially after eradication of disease, with a notable improvement in endothelial function. For example, liver transplant (LT) recipients with history of HCV infection showed significantly higher levels of endothelial activation markers such as soluble E-selectin, soluble ICAM-1, and soluble VCAM-1 compared to LT recipients without HCV infection. Furthermore, these markers are crucial indicators of endothelial dysfunction, which is associated with an increased risk of CVD. E-selectin, ICAM-1, and VCAM-1 play a role in recruiting white blood cells to endothelial cells, promoting inflammation and atherogenesis. The higher levels of these markers in LT+/HCV+ patients suggest that HCV infection contributes to endothelial activation, likely exacerbating the risk of atherosclerosis and subsequent cardiovascular complications post-transplant[28].

Another important marker is MMP-9 which is involved in extracellular matrix remodeling and is linked to the progression of atherosclerosis and plaque destabilization. Interestingly, LT+/HCV+ patients have lower levels of MMP-9 compared to the non-HCV group. These findings suggest that HCV infection plays a key role in endothelial dysfunction and could heighten cardiovascular risk in LT recipients. The fact that inflammatory and endothelial activation markers were significantly elevated in the HCV-infected group (while insulin resistance remained similar) points to HCV’s direct involvement in vascular damage, rather than through metabolic pathways alone. The lower MMP-9 Levels in HCV-infected patients add complexity to the understanding of how HCV impacts vascular health, potentially indicating differences in how the disease affects the stability of arterial plaques. It is worth noting that the study suffers from a small sample size and lack of pre-intervention assessment for atherosclerosis[28,29].

Another key mechanism of HCV infection is triggering an immune response characterized by elevated levels of GM-CSF and IgG, particularly in cirrhotic patients. This suggests an overactive yet ineffective immune response to the virus, contributing to cardiovascular complications[22].

HCV is lymphotropic and can infect immune cells such as B cells and monocytes, in addition to hepatocytes, via receptors including CD81, scavenger receptor class B type I, claudin 1 and occludin. This direct infection of immune cells leads to altered immune function, chronic immune activation, and the production of autoantibodies and immune complexes, which are implicated in extrahepatic manifestations such as mixed cryoglobulinemia and vasculitis. These immune-mediated processes contribute to vascular inflammation and endothelial dysfunction, key steps in the pathogenesis of atherosclerosis and cardiovascular events[30-32]. The literature reviewed in the New England Journal of Medicine by Cacoub and Saadoun[33] highlights that HCV-induced chronic antigenic stimulation reduces the threshold for B-cell activation, promotes clonal B-cell expansion, and leads to immune complex deposition in small vessels.

The literature reviewed in the New England Journal of Medicine by Cacoub and Saadoun[33] highlights that HCV-induced chronic antigenic stimulation reduces the threshold for B-cell activation, promotes clonal B-cell expansion and leads to immune complex deposition in small vessels.

Procoagulant imbalance influences cardiovascular damage

HCV-infected patients (without cirrhosis) demonstrate a significant procoagulant imbalance characterized by elevated FVIII levels, higher FVIII/protein C ratios and increased thrombin potential. This imbalance contributes to an increased risk of cardiovascular damage and atherosclerosis, as indicated by the association between elevated FVIII/PC ratio and increased carotid intima-media thickness (CIMT), a marker of early atherosclerosis and cardiovascular risk[34].

Symptoms of atherosclerosis

Atherosclerosis reduces oxygen-rich blood supply leading to a variety of symptoms that affect quality of life. These symptoms depend on which arteries are affected and the extent of blood flow obstruction. When the coronary arteries are affected, it can result in chest pain (angina), cold sweats, dizziness, extreme fatigue, heart palpitations, shortness of breath, nausea, and general weakness, all of which are common signs of coronary artery disease.

When the peripheral arteries are involved, particularly in the legs, individuals may experience pain, aching, heaviness, or cramping when walking or climbing stairs. These symptoms typically subside after a period of rest and are indicative of peripheral artery disease. Furthermore, when the vertebral arteries are compromised, early symptoms may include problems with thinking and memory, weakness or numbness on one side of the body or face, and vision difficulties. If the condition progresses, it can lead to more serious outcomes, such as a transient ischemic attack.

Mesenteric artery ischemia, affecting the intestines, causes severe pain after eating, unintended weight loss and diarrhea. Additionally, erectile dysfunction (ED) can serve as an early warning sign of atherosclerosis and its complications, as it may indicate plaque buildup in the arteries. Men experiencing ED are advised to consult their healthcare providers to assess their risk of CVD[10].

TEMPORAL ONSET OF CVD IN HCV

HCV-associated heart disease and cardiovascular complications typically develop after a period of chronic infection, not concurrently with acute HCV infection. The literature consistently shows that the increased risk of atherosclerosis, coronary artery disease, stroke, and other cardiovascular events is associated with chronic HCV infection, which is usually defined as infection persisting beyond six months after exposure. Most extrahepatic manifestations, including CVD, are linked to the chronic inflammatory state, metabolic disturbances, and direct vascular effects that accumulate over years of persistent infection rather than during the acute phase.

There is evidence that subclinical atherosclerosis, such as increased CIMT and coronary artery plaque, can be detected in HCV-infected individuals before overt cardiovascular events occur, suggesting a gradual process rather than an immediate complication[30,35-38]. The risk of cardiovascular events is higher in those with active viremia (detectable HCV RNA), and the risk increases with age and the presence of comorbidities such as diabetes and hypertension[30,39].

The risk of cardiovascular events is higher in those with active viremia (detectable HCV RNA), and increases with age and the presence of comorbidities such as diabetes and hypertension[33,36,40].

SCREENING AND DIAGNOSTIC APPROACHES FOR CVD AND ATHEROSCLEROSIS IN HCV PATIENTS

Accurately diagnosing atherosclerosis in patients with HCV is essential, given their increased cardiovascular risk. Both invasive and noninvasive diagnostic techniques play crucial roles in detecting the disease and assessing its severity. There are no specific guideline-recommended screening protocols for early detection of heart disease unique to HCV-infected individuals. However, the medical literature supports vigilant assessment of traditional cardiovascular risk factors and consideration of subclinical atherosclerosis screening (e.g., carotid ultrasound, coronary calcium scoring) in patients with chronic HCV infection, especially those with additional risk factors. Early antiviral treatment with direct-acting antivirals is associated with improvement in cardiovascular risk markers and may reduce the incidence of cardiovascular events. Standard cardiovascular risk reduction strategies (blood pressure, lipid, and glucose control; smoking cessation) remain essential[33,37-42].

Invasive techniques

Coronary Arteriography remains the gold standard for assessing coronary atherosclerosis. It provides detailed images of the arterial lumen, allowing direct visualization of blockages[43,44].

Angiography offers a comprehensive view of the coronary tree; angiography is helpful in identifying stenosis or blockages[43,44].

Noninvasive techniques

Ultrasound and magnetic resonance imaging are methods that allow visualization of atherosclerotic plaques, particularly by assessing fibrous cap integrity and necrotic core size, key indicators of plaque stability. However, these techniques may struggle to detect smaller or less pronounced plaques[44,45].

CIMT: CIMT is an ultrasound-based method used to measure the thickness of the intima and media layers of the carotid artery. This technique is useful for detecting early atherosclerosis, especially in high-risk populations such as HCV patients. CIMT has been shown to correlate with the presence of coronary atherosclerosis and is widely used for risk stratification in CVD[45].

CIMT is often elevated in HCV-infected patients, particularly those with cirrhosis. CIMT values exceeding 0.9 mm or falling above the 75^th percentile are considered diagnostic for atherosclerosis. CHC is associated with significantly increased CIMT compared to non-cirrhotic HCV patients, indicating an intensified risk of vascular disease progression in those with liver damage[46,47].

Electron-beam computed tomography and Ankle-Brachial index: Electron-beam computed tomography is used to measure coronary calcium, which is an indicator of atherosclerotic burden, while Ankle-Brachial index is useful for detecting peripheral artery disease. Both methods help identify early atherosclerosis but have limitations in terms of sensitivity and specificity[48].

HCV’s contribution to atherosclerosis is further supported by the detection of HCV RNA in carotid plaques of anti-HCV-positive patients, establishing a direct viral presence in atherosclerotic lesions. This local viral infection may drive plaque formation and instability, contributing to vascular dysfunction. Additionally, patients with CHC exhibit increased aortic stiffness, a marker of early arterial changes that precede overt atherosclerosis. This stiffness occurs independent of traditional cardiovascular risk factors like lipid profile or HCV-RNA levels, suggesting alternative mechanisms-likely mediated by chronic inflammation and immune activation-that contribute to vascular remodeling and stiffness[49].

Diagnostic markers

Emerging diagnostic biomarkers are playing an increasingly important role in understanding the complex mechanisms behind atherosclerosis, particularly in high-risk groups like HCV patients. These biomarkers offer new avenues for early detection, risk stratification, and therapeutic monitoring.

Inflammatory markers

Inflammation plays a central role in atherosclerosis, particularly in the context of chronic infections such as HCV. Biomarkers like VCAM-1 and P-selectin have gained attention for their involvement in plaque vulnerability. These markers are indicators of endothelial activation and leukocyte adhesion, which are critical in the development and progression of atherosclerotic plaques. Targeting VCAM-1 and P-selectin provides insights into the inflammatory processes driving plaque instability and cardiovascular events, helping clinicians assess the risk of acute coronary syndromes[50].

A study investigated the relationship between HCV infection, its markers, and the risk of atherosclerosis in patients with CHC. The results demonstrate that both HCV infected patients with steatosis have a higher prevalence of CA. Additionally, higher HCV viral load is linked to increased levels of inflammatory markers, mainly serum CRP and fibrinogen levels, and a greater risk of atherosclerosis[8].

Metabolic tracers

Advanced biological tracers are being developed to evaluate the metabolic state of atherosclerotic plaques, further refining risk prediction and treatment strategies. These tracers offer real-time insights into plaque activity by highlighting metabolic changes, such as increased glucose uptake, that often precede clinical events. This enhanced understanding allows for better risk stratification and more tailored therapeutic interventions, particularly in patients with HCV, who are at increased risk of accelerated atherosclerosis[51].

Treatment modalities

The management of atherosclerosis in patients with HCV, particularly those with advanced fibrosis or cirrhosis, poses unique challenges. Historically, patients with advanced liver disease were considered “difficult-to-treat” due to the limited efficacy and high toxicity of peginterferon and ribavirin combination therapies. However, the introduction of direct-acting antiviral agents (DAAs) has revolutionized the treatment landscape, offering higher efficacy and fewer adverse effects[52].

First-generation DAAs like boceprevir and telaprevir, used in combination with peginterferon and ribavirin, significantly improved sustained virological response rates in HCV genotype 1 infections. However, these treatments were less effective in patients with cirrhosis and prior non-responders, and they were associated with a high incidence of adverse events, particularly in patients with advanced liver disease. Due to these limitations, these regimens are no longer recommended in current treatment guidelines[52].

Next-generation DAAs, including second-generation HCV NS3/4A protease inhibitors, HCV NS5A inhibitors, and HCV NS5B inhibitors, offer more promising options for HCV patients with atherosclerosis. These agents are highly effective and have a lower toxicity profile, allowing for their use in interferon-free regimens, with or without ribavirin. Interferon-free regimens are especially beneficial for patients with cirrhosis or those intolerant to interferon. Clinical trials have demonstrated that these regimens can achieve similar efficacy and safety in both cirrhotic and non-cirrhotic patients[52].

For HCV patients with atherosclerosis and advanced liver disease, prioritizing antiviral therapy is crucial to prevent liver-related complications such as decompensation and hepatocellular carcinoma, while simultaneously reducing the systemic inflammatory burden that contributes to atherosclerotic progression[53].

Recent studies highlight the role of HMG CoA reductase inhibitors, commonly known as statins, in modulating hepatic steatosis and fibrosis. Statins have shown promising antiviral and antifibrotic effects in CHC patients, adding another layer of therapeutic potential for managing both liver disease and cardiovascular risk[53].

Lifestyle management is fundamental to prevent atherosclerotic CVD, and its importance is highlighted by all major guidelines. Key aspects of lifestyle modification include smoking cessation, weight loss, dietary improvements, increased physical activity, and stress management[54].

HCV AND PREVALENCE OF CARDIOMYOPATHY

HCV appears to contribute to the development of multiple cardiomyopathy phenotypes, including dilated, hypertrophic, and restrictive forms. Studies have demonstrated a higher prevalence of HCV antibodies in patients with hypertrophic (10.6%) and dilated (6.3%) cardiomyopathies compared to the general population. Over a 10-year period, approximately 9.9% of patients with dilated cardiomyopathy (DCM) were found to have evidence of HCV infection, significantly higher than in patients with ischemic heart disease[55].

A population-based cohort study from 1998 to 2020 further highlighted the prevalence of cardiovascular complications among HCV patients. HCV was identified as the third most prevalent liver disease (6.0 per 100000 person-years), following NAFLD and alcoholic liver disease. The study also revealed that the age group most affected by HCV infection was 40-49 years, indicating that middle-aged individuals are more susceptible to developing HCV-related complications, including cardiomyopathy. Additionally, the study examined 17 types of CVD, with atrial fibrillation being the most common and hypertrophic cardiomyopathy the least prevalent. Table 2 shows a summary of study designs, findings and limitations[56].

Table 2 A summary table for key studies and their conclusions.

Ref.	Year	Study design	Findings	Limitations
Wang et al[74]	2024	Cross-sectional study	HCV group without metabolic syndrome had higher odds ratio of 2.75	While CT is a widely used method, it primarily detects advanced atherosclerosis (calcified plaques) and may miss earlier stages of the disease
Chang et al[56]	2022	Population-based cohort	HCV patients have a high incidence of CVD, though it is lower than that of ALD and NAFLD	The findings may not be directly generalizable
Petta et al[9]	2011	Case-control	Severe hepatic fibrosis is associated with a high risk of early carotid atherosclerosis in G1 CHC patients	Selection bias in the recruitment of the control population and limited generalizability
Lee et al[72]	2019	Systematic review and meta-analysis	Patients with HCV had 28% higher risk compared to those without HCV infection	Limited generalizability on global scale, and significant heterogeneity
Wen et al[75]	2019	Systematic review and meta-analysis	The overall RR of 1.25 in the cohort studies, higher OR of 1.94 in these studies suggests a stronger association between HCV and CAD compared to the cohort studies	Small sample size between studies and different criteria for diagnosing CHC
Badawi et al[76]	2018	Survey analysis	HCV infection was significantly associated with a 25%-3.5% absolute risk increases of 10-year CVD after adjusting for sociodemographic and cardiometabolic risk factors	Confounding variables such as alcohol use, and drug use were not controlled
Roed et al[65]	2014	Cross-sectional study	Higher carotid intima media thickness in CHC patients with small difference of means	Confounding variables such as physical activity, diet, medication use, family history of CAD, and genetic predisposition were not controlled

HCV: Hepatitis C virus; CHC: Chronic hepatitis C; CAD: Coronary artery disease; NAFLD: Non-alcoholic fatty liver disease; ALD: Alcoholic liver disease; CT: Computed tomography.

Pathogenesis of myocarditis and cardiomyopathy

HCV has been implicated in the pathogenesis of myocarditis and cardiomyopathy, contributing to both inflammatory and structural damage in the myocardium. Myocarditis, an acute inflammation of the heart muscle, is often associated with viral infections and has been linked to HCV in various studies. The virus can directly invade cardiac tissue, triggering an immune response that results in myocardial injury. In patients with CHC, diastolic dysfunction has been observed, characterized by reduced left ventricular end-diastolic volume and increased myocardial fibrosis. Significant morbidity and mortality are still reported, primarily due to cardiogenic shock and arrhythmia[57].

The cardiotropic nature of HCV is further evidenced by its association with cardiomyopathy, particularly dilated and hypertrophic forms. Studies have demonstrated the presence of HCV antibodies in a significant proportion of patients with idiopathic cardiomyopathy, supporting the virus's role in the disease’s development. Additionally, HCV-related insulin resistance has been shown to contribute to left ventricular hypertrophy, indicating that metabolic dysfunction may exacerbate the virus's impact on cardiac structure[58].

Several studies have implicated HCV infection in the development of cardiomyopathy. Ngu et al[59] found that patients with CHC and histological analyses have confirmed the presence of HCV genomes in the myocardium of patients with myocarditis, suggesting a direct viral effect on cardiac cells. The results demonstrated diastolic dysfunction, characterized by lower left ventricular end-diastolic volume, stroke volume, and increased diffuse myocardial fibrosis. Importantly, these changes occurred in the absence of overt heart failure.

Direct viral effects

The direct impact of the HCV on cardiomyocytes plays a significant role in the development of cardiomyopathy. HCV has been shown to replicate within cardiac tissues, which leads to significant cellular damage and contributes to cardiac dysfunction. Studies have detected HCV RNA in myocardial tissues, confirming that the virus can infect heart cells directly. This viral replication can cause necrosis and apoptosis of the heart muscle cells (myocytes), leading to the development of conditions like DCM and other related cardiac disorders[60,61].

Moreover, the HCV core protein exerts a cytotoxic effect on myocytes by disrupting essential cellular structures and interferes with calcium handling, a critical process for muscle contraction. This disruption can result in ventricular dilation and reduced contractility, which are key features of DCM[6,62].

Infected cardiomyocytes also trigger local inflammatory responses. The presence of the virus leads to the recruitment of immune cells to the heart muscle, causing chronic inflammation and further damage to the cardiac tissue. Additionally, HCV infection induces the release of pro-inflammatory cytokines such as TNF-α and IL-6, which can exacerbate myocardial injury and contribute to the development of heart failure[6,62].

Immune-mediated mechanisms

The immune response to HCV infection is another critical factor in the progression of cardiomyopathy. Both the innate and adaptive immune systems are involved in this process. Upon infection, the innate immune system is activated, leading to the production of inflammatory cytokines by immune cells like macrophages and natural killer (NK) cells. This response causes tissue damage not only in the liver but also in the heart, contributing to the deterioration of cardiac function[63].

Chronic HCV infection can also result in the formation of autoantibodies against myocardial proteins such as troponin I. These autoantibodies further promote inflammation in the heart and exacerbate myocardial dysfunction, thereby worsening cardiac outcomes. Additionally, the immune response often results in an imbalance between pro-inflammatory and anti-inflammatory cytokines. Elevated levels of TNF-α, for example, are linked to impaired cardiac function, as this cytokine disrupts calcium currents in heart cells, compromising their ability to contract properly[60,61].

Molecular mimicry is another mechanism by which HCV infection contributes to cardiomyopathy. In this process, the structural similarity between viral proteins and host myocardial proteins triggers an autoimmune response, leading to further damage to the heart muscle. Persistent inflammation caused by ongoing viral replication also contributes to myocardial fibrosis and remodeling, both of which are key factors in the progression toward heart failure in HCV-infected individuals. Figure 1 shows the 3 possible mechanisms of HCV infection on the cardiovascular system[60,61].

Figure 1 Overview of the pathogenesis of chronic hepatitis C and how it contributes to atherosclerosis and cardiomyopathy. HCV: Hepatitis C virus; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin-6.

HCV proteins and cardiovascular risk

HCV proteins play a crucial role in modulating immune responses and can significantly impact cardiovascular health. One notable protein, NS5A, disrupts innate immune signaling pathways, particularly those involving Toll-like receptors. This disruption can lead to chronic inflammation, a condition recognized as a risk factor for various cardiovascular complications. The chronic inflammatory state induced by HCV can create an environment conducive to the development of CVD, including atherosclerosis and coronary artery disease[64].

Additionally, NS5A impairs the function of NK cells, further exacerbating inflammatory responses. NK cells are essential for the innate immune response and play a vital role in controlling viral infections. The dysfunction of these cells due to HCV can promote heightened inflammation and contribute to the progression of cardiovascular complications[64].

The envelope proteins of HCV, specifically E1 and E2, also contribute to cardiovascular risk. These proteins can induce endothelial dysfunction and promote inflammation, which are critical processes in the development of atherosclerosis. The interplay between HCV proteins and the immune response highlights the intricate mechanisms through which HCV infection can adversely affect cardiovascular health[65,66].

Symptoms of cardiomyopathy

One of the most common signs is shortness of breath, which may occur during physical exertion or even at rest as the heart struggles to pump efficiently. Fatigue is another common symptom, where individuals experience unexplained tiredness despite adequate rest. Swelling, known as edema, may appear in the ankles, legs, abdomen, or neck veins due to fluid retention caused by impaired cardiac function[67].

Other symptoms include dizziness and light-headedness, sometimes leading to fainting, particularly during physical activity. Arrhythmias, or irregular heartbeats, may feel like rapid or fluttering sensations in the chest. Some patients experience chest pain, especially after physical exertion or large meals, while bloating in the abdominal area and coughing when lying down can also indicate worsening heart function. These symptoms tend to progress as the condition advances, greatly impacting a patient’s daily life and quality of life[68].

Diagnostics

An electrocardiogram is often one of the first diagnostic tools used, as it can detect abnormalities in the heart’s electrical activity due to chamber hypertrophy or dilatation, which are common in cardiomyopathy.

An echocardiogram is a key imaging tool used to visualize the heart’s structure and function. It provides valuable information about heart chamber size, wall motion abnormalities, and whether the heart is functioning normally in terms of systolic and diastolic function. A chest X-ray may also be performed to check for signs of heart enlargement (cardiomegaly) or fluid accumulation in the lungs, though it is not specific for diagnosing cardiomyopathy.

More invasive diagnostic techniques, such as cardiac catheterization, may be used to measure the pressures within the heart chambers and evaluate blood flow. This test often includes coronary angiography to rule out any blockages in the coronary arteries that might contribute to heart dysfunction. In certain cases, a myocardial biopsy may be performed to remove and examine a small sample of heart tissue, which can help identify specific types of cardiomyopathies[67-69].

Novel markers for cardiomyopathy in HCV patients

MicroRNA-21 has gained attention as a promising biomarker in the study of HCV-related conditions, particularly due to its involvement in various pathological processes such as inflammation and cardiac remodeling. Increased levels of microRNA-21 have been associated with cardiac hypertrophy and fibrosis. Notably, microRNA-21 Levels show a strong correlation with serum markers of myocardial fibrosis, indicating its value in tracking cardiac involvement and disease progression in HCV-infected individuals[70].

HCV RNA has been detected in myocardial tissues, supporting the possibility that the virus can replicate within the heart muscle itself. Research has shown that around 19.4% of patients with DCM had detectable levels of HCV RNA in their heart tissue. This presence of the virus correlates with the severity of cardiac symptoms such as heart failure and arrhythmias. As a result, HCV RNA detection in heart tissue could serve as a direct marker for assessing myocardial involvement in patients with cardiomyopathy[6].

Elevated levels of atrial and brain natriuretic peptides have been observed in HCV-infected patients who develop cardiomyopathy. These peptides are typically markers of heart failure, as they rise in response to increased cardiac stress and dysfunction[6].

Another interesting marker is cardiac troponin T, which is a widely recognized biomarker for detecting myocardial injury, and it has been used in patients with HCV-related cardiomyopathy to assess heart muscle damage. Elevated levels of troponin T can indicate ongoing myocardial injury and are often monitored alongside other cardiac markers to provide a more comprehensive understanding of a patient’s cardiac health. In the context of HCV infection, elevated troponin levels serve as a critical marker for cardiac involvement and damage[6].

Cardiomyopathy management

Treatment of cardiomyopathy, particularly in the context of HCV-related disease, focuses on both managing symptoms and addressing the underlying cause.

Antiviral therapies such as DAAs have revolutionized the management of HCV infection, which can indirectly contribute to cardiomyopathy. These antivirals help reduce systemic inflammation and may limit the progression of cardiomyopathy by addressing the viral cause.

Historically, interferon-based regimens were used in HCV treatment, but their lower efficacy in patients with cirrhosis, combined with significant side effects, have led to their decline in favor of DAAs[52].

For managing cardiomyopathy symptoms directly, beta-blockers and calcium channel blockers are often used to manage heart rate and improve overall cardiac function, though specific evidence for their efficacy in HCV-related cardiomyopathy remains limited. Symptomatic treatment in these patients is aimed at improving quality of life and reducing the risk of cardiac complications[71].

QUALITY OF LIFE

A systematic review and meta-analysis (SR/MA) examined the relationship between HCV infection and CVD on a global scale. The SR/MA estimated 1.5 million DALYs lost annually due to HCV-associated CVD. The highest burden of HCV-associated CVD was observed in low-income and middle-income countries, with regions such as South Asia, eastern Europe, north Africa, and the Middle East accounting for two-thirds of all DALYs. This highlights the disproportionate impact of HCV infection on these regions and underscores the need for targeted interventions to address the burden of CVD in these populations[72].

Despite the large sample size in this study, most of the studies included in the meta-analysis originate from high-income countries, particularly in North America and Western Europe. This limits the generalizability of their results on a global scale. Furthermore, the study observed significant heterogeneity in the risk ratio estimates, likely due to the diverse patient populations, varying viremic statuses, differences in healthcare systems, access to treatment, and geographical locations of the studies. Finally, the study's burden estimation may have been limited by the inability to assess the impact of angina and peripheral artery disease, conditions that are often diagnosed in outpatient settings and less likely to be captured by electronic health records[72].

A study, by Hallsworth et al[73] found that those who engaged in regular physical activity reported significantly higher health-related quality of life (HRQoL) scores across various domains of the Short-Form 36v2 compared to their inactive counterparts. Despite these differences in HRQoL, no significant differences were observed in metabolic and cardiovascular characteristics between the groups when stratified by physical activity or exercise status.

The study also examined the Exercise Benefits/Barriers Scale (EBBS) and found that while overall scores were similar between active and inactive participants, active patients scored significantly higher on the psychological outlook and social interaction subscales. Furthermore, significant associations were observed between EBBS scores and HRQoL, suggesting that psychological and social factors might play a role in enhancing quality of life through regular physical activity, even if direct metabolic or cardiovascular improvements were not detected[73-76].

CONCLUSION

CHC infection is now recognized as a significant contributor to CVD, extending its clinical impact beyond hepatic pathology. This minireview summarizes current evidence linking HCV to both atherosclerotic and cardiomyopathic heart disease, highlighting the multifaceted mechanisms by which the virus influences cardiovascular risk. The interplay of direct viral effects, immune activation, oxidative stress, and metabolic disturbances emphasizes the increased risk of atherosclerosis and cardiomyopathy in affected individuals. Early diagnosis, comprehensive cardiovascular risk assessment, prompt initiation of antiviral therapy, and aggressive management of modifiable risk factors are essential strategies to reduce the burden of CVD in patients with CHC. Further research is needed to elucidate the different pathways, refine risk stratification, and optimize therapeutic approaches for this high-risk population.