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Teer, E.;  Dominick, L.;  Mukonowenzou, N.C.;  Essop, M.F. Human Immunodeficiency Virus-Related Myocardial Fibrosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/27574 (accessed on 06 December 2024).
Teer E,  Dominick L,  Mukonowenzou NC,  Essop MF. Human Immunodeficiency Virus-Related Myocardial Fibrosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/27574. Accessed December 06, 2024.
Teer, Eman, Leanne Dominick, Nyasha C. Mukonowenzou, M. Faadiel Essop. "Human Immunodeficiency Virus-Related Myocardial Fibrosis" Encyclopedia, https://encyclopedia.pub/entry/27574 (accessed December 06, 2024).
Teer, E.,  Dominick, L.,  Mukonowenzou, N.C., & Essop, M.F. (2022, September 26). Human Immunodeficiency Virus-Related Myocardial Fibrosis. In Encyclopedia. https://encyclopedia.pub/entry/27574
Teer, Eman, et al. "Human Immunodeficiency Virus-Related Myocardial Fibrosis." Encyclopedia. Web. 26 September, 2022.
Human Immunodeficiency Virus-Related Myocardial Fibrosis
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This entry is adapted from the peer-reviewed paper 10.3390/cells11182825

Chronic inflammation is a characteristic feature of cardiovascular diseases (CVD) and considered a contributor to diastolic dysfunction, heart failure, and sudden cardiac death. This can trigger downstream effects that result in the increased release of pro-coagulant, pro-fibrotic, and pro-inflammatory cytokines. Subsequently, this can lead to an enhanced thrombotic state (by platelet activation), endothelial dysfunction, and myocardial fibrosis. Of note, Studies have revealed that myocardial fibrosis is emerging as a mediator of human immunodeficiency virus (HIV)-related CVD. Together, such factors can eventually result in systolic and diastolic dysfunction, and an increased risk for CVD.

HIV myocardial fibrosis platelets chronic inflammation sudden cardiac death heart failure cardiovascular diseases

1. Introduction

There are currently ~38.4 million human immunodeficiency virus (HIV)-infected individuals globally, with ~28.7 million receiving combination antiretroviral therapy (cART) [1]. Increased access to cART has significantly improved the lifespan of people living with HIV (PLHIV). It has also attenuated viral replication and ensured a relatively well-maintained immune system, together with lowered opportunistic infections and associated mortalities [2]. The main cause of death in PLHIV has therefore shifted from acquired immunodeficiency disease (AIDS)-related immunocompromised states to non-AIDS age-related complications, such as cardiovascular diseases (CVD). In support, the proportion of global deaths due to CVD in PLHIV has increased from 2.5% to 4.6% during the past decade [3][4]. Although HIV-positive patients present with a variety of heart and vascular co-morbidities, certain cardiac disorders manifest with a greater frequency and display geographic variations. For example, in developed countries, PLHIV usually present with metabolic syndrome, hypertension, coronary artery disease, and atherosclerosis [4][5][6]. In contrast, complications such as hypotension, heart failure (HF)/sudden cardiac death (due to HIV-associated cardiomyopathy), and tuberculosis-associated pericarditis are far more prevalent in the sub-Saharan African region [7][8][9][10].
Despite this burgeoning health threat, the underlying mechanisms driving HIV-mediated CVD onset are still being elucidated. Of note, the role of chronic immune activation (despite cART) as a significant mediator in HIV-mediated CVD onset and progression is increasingly being highlighted [11][12]. In agreement, the researchers' laboratory recently found a strong interplay between immune activation, coagulation, and lipid subclass alterations in South African HIV-positive patients [9]. This data also revealed a robust negative correlation between either immune activation or coagulation, and diastolic blood pressure [9]. Chronic inflammation is a characteristic feature of various CVD and is regarded as a key contributor to diastolic dysfunction, HF, and sudden cardiac death [13]. HIV-mediated immune dysregulation can trigger downstream effects that lead to an enhanced release of pro-coagulant, pro-fibrotic, and pro-inflammatory cytokines [14]. This can subsequently result in an increased thrombotic state, endothelial dysfunction, and myocardial fibrosis [15][16]. The culmination of the interplay of such mediators can eventually lead to systolic and diastolic dysfunction and an increased risk for CVD.
While the pathogenesis of HIV-mediated CVD onset and progression is multi-factorial in nature, myocardial fibrosis is emerging as a key mediator underlying the manifestation of systolic and diastolic dysfunction [17]. In support, research findings have revealed prognostic associations between diffuse myocardial fibrosis and left ventricular (LV) remodeling in PLHIV [18][19].

2. HIV Treatment and Cardiovascular Complications

Prior to cART, CVD manifestations of HIV infection included myocardial and peripheral disease, due to the direct effects of HIV, coinfections, and concomitant chronic inflammation [20]. The introduction of cART improved lifespans by viral load reduction and immune system restoration, but also came with side-effects, due to drug-toxicity and metabolic changes (e.g., dyslipidemia, altered glucose handling) [21][22][23]. Furthermore, there are variations between different antiretroviral classes and divergent responses within drug class types [22]. Older generation protein inhibitors, such as lopinavir/ritonavir, and nucleoside reverse transcription inhibitors, such as abacavir, stavudine and zidovudine, can induce dyslipidemia to increase CVD risk [23][24][25][26]. Moreover, body fat distribution changes are still evident years after cessation of antiretroviral use [27][28]. Earlier work, therefore, reported the occurrence of early-onset and aggressive coronary artery disease in PLHIV compared to uninfected individuals [29]. Currently, integrase inhibitors and C-C chemokine receptor 5 antagonists have replaced protease inhibitors as the first line therapy and appear to elicit negligible CVD toxicity, although there are concerns regarding the weight gain associated with their use and hence the need to assess their long-term effects in this context [30].
cART-treated HIV is associated with an increased incidence of myocardial fibrosis [31], as well as both systolic and diastolic LV dysfunction [32], and an up to two-times higher risk of HF [33]. Results from the Veterans Aging Cohort Study [34] showed that this manifests in various forms, such as HF with preserved ejection fraction, borderline HF with preserved ejection fraction, and those with a reduced ejection fraction. Furthermore, the occurrence of such HF subtypes occurs at an earlier stage in the PLHIV population versus uninfected individuals. However, the direct relationship between myocardial inflammation and fibrosis in HIV has been less well studied [13]. For PLHIV who are virally suppressed on cART, the risk of sudden cardiac death levels out to the risk observed in the general population [35]. Moreover, a Taiwanese study found that no specific cART class was associated with increased HF risk [36]. Meanwhile, a relatively small US study on virally suppressed women living with HIV (on integrase strand transfer inhibitors and nucleoside reverse transcription inhibitors) showed increased myocardial fibrosis and lowered diastolic function compared to HIV-negative women [37].

3. Immune Activation and Chronic Inflammation

HIV infection activates the innate and adaptive immune systems, which can result in a state of chronic infection that forms the basis of ongoing immune activation and immunodeficiency [14]. Inflammation is crucial in resolving infections, tissue damage, and maintaining a state of hemostasis [38]. While some degree of immune cell activation is essential to promote suitable responses to injury and activation of tissue repair processes, uncontrolled activation may lead to excess fibrosis and offset its beneficial effects [39].
The innate immune system consists of granulocytes (neutrophils, basophils, eosinophils), mast cells, and antigen presenting cells (macrophages and dendritic cells) [40]. Pathogen-associated molecular patterns and damage-associated molecular patterns can bind to cell surface toll-like receptors, which subsequently results in their activation [14][41]. The activated cells of the innate immune response produce pro-inflammatory cytokines, to further amplify the inflammatory response [38]. The acute inflammatory response starts rapidly, becomes more severe over short periods of time, and usually lasts for a few days [38].
However, if the pathogen-induced stimulation persists, the inflammatory process then acquires new characteristics that are more typically associated with chronic inflammation [38]. This is a slow, long-term state of inflammation that can last for prolonged periods and is induced by cytokines such as interferon-gamma (IFN-γ) that can promote activation of the adaptive immune system [41]. Here, T-cells play a significant role and differentiate into either CD4 (helping to orchestrate immune responses) or CD8 (destroying infected cells) cells [14][41]. Such cells, together with macrophages and natural killer cells, are key players for cell-mediated immunity, while B-cells produce antibodies and are responsible for humoral immunity [40]. Thus, the inflammatory response is the result of a complex interplay between multiple immune cells in the body.
Persistent immune activation and chronic inflammation occur during HIV-infection, despite cART adherence and suppressed viremia [41]. Chronic and persistent CD8+ T-cell activation (the marker of immune activation) rests on three important factors: (1) the persistent detection of HIV-specific effector cytotoxic T cells, (2) the presence of cell surface protein receptors that differentiate naïve T cells into differentiated effector phenotypes [42], and (3) an acute/active cytokine profile detected in serum. Ongoing immune activation and resulting inflammation can lead to immune-related perturbations [43]. Moreover, circulating monocytes and tissue macrophages are both susceptible targets of HIV-1 infection, and the early host response determines whether the infection becomes pathogenic or not. For example, monocytes and macrophages can contribute to the HIV reservoir (and viral persistence) and influence the initiation/extension of immune activation and chronic inflammation, despite cART [44]. Here, the inflammatory response is attenuated (when not required) and becomes chronic if there is a persistent source of activation and/or due to defective control mechanisms [45]. The harmful consequences of persistent immune activation and inflammation during HIV-infection have been extensively reviewed in the previously published literature [13][45][46].

4. Persistent Immune Activation, Chronic Inflammation, and Cardiac Fibrosis

Chronic inflammation and immune dysfunction increase the risk of cardiovascular morbidities and mortalities through endothelial dysfunction, hypercoagulation, and myocardial fibrosis [41][47][48][49][50]. The persistent activation of the innate and adaptive immune systems (monocytes/macrophages and T cells, respectively) results in increased circulating pro-inflammatory and pro-fibrotic cytokines (Figure 1) [12][48][51][52][53][54]. Higher circulating cytokine levels can contribute to hypercoagulation, endothelial dysfunction, and fibrotic remodeling, which increase the risk of CVD onset in PLHIV [31][49][55][56][57][58]. Fibrotic remodeling due to immune dysfunction is an important area of research, due to its detrimental effects on cardiac function, and its links to HF and sudden cardiac death in PLHIV [59]. Myocardial fibrosis is a contributor to sudden cardiac deaths especially in PLHIV that are receiving cART [13][60]. More recently, studies have shown that persistent activation of the innate and adaptive immune responses leads to myocardial fibrosis in PLHIV (Figure 1) [31][58]. Some studies explored subclinical cardiovascular imaging changes using cardiac magnetic resonance and found that HIV-infected patients displayed changes in myocardial function and higher rates of subclinical myocardial inflammation and fibrosis, which worsened with increased severity of the disease [36].
Figure 1. The role of myocardial fibrosis in CVD pathogenesis. The inflammatory hypothesis is considered a main driver of CVD complications in HIV-positive individuals. Persistent immune activation leads to a chronic inflammatory state that includes relatively high levels of inflammatory and pro-fibrotic cytokines (IL-10, TGF-β), together with RAAS activation. This subsequently enhances pro-fibrotic pathways (increased collagen I and III deposition), while also lowering collagen degradation. The increased collagen leads to LV stiffness and diastolic dysfunction (early sign of myocardial fibrosis). Myocardial fibrosis is a contributor to diastolic and systolic dysfunction, HF, and sudden cardiac death. LV: left ventricle, RAAS: renin-angiotensin aldosterone system, ROS: reactive oxygen species, IL: interleukin, and TGF: transforming growth factor.

5. Myocardial Fibrosis: Role in the Pathogenesis of Heart Failure and Sudden Cardiac Death

The modification of the cardiac microenvironment after injury results from the crosstalk between a variety of players such as fibroblasts, endothelial cells, inflammatory and immune cells, soluble factors, and components of the extracellular matrix (ECM) [61]. It is established that cardiac fibrosis is associated with inflammation, exemplified by continuous innate and adaptive immune responses. Myocardial fibrosis is characterized by ECM remodeling, resulting in abnormal matrix composition and leading to impairments in cardiac contractility and function. At first, ECM deposition is defensive and important for wound healing, but unnecessary or prolonged deposition can lead to impairments in tissue function. Fibrosis leads to a stiffer and less compliant heart, eventually contributing to the progression of HF and sudden cardiac death [31].
Of concern, myocardial fibrosis is emerging as a growing cardiac complication in PLHIV. For example, HIV infection (±cART) is linked to an increased incidence of myocardial fibrosis, together with systolic and diastolic LV dysfunction [60][62][63]. Some researchers found that HIV-positive patients exhibited greater evidence of myocardial fibrosis than their negative counterparts, despite relatively normal ejection fractions [31], while others showed a significantly higher prevalence of myocardial fibrosis in PLHIV who suffered mortality due to sudden cardiac deaths [64][65]. Furthermore, a study on HIV-positive patients on cART versus uninfected controls (no CVD history) found that HIV-positive patients displayed a six-fold higher rate of patchy myocardial fibrosis after controlling for age, gender, and coronary artery [60]. In addition, others evaluated associations between HIV serostatus and cardiovascular magnetic resonance imaging and demonstrated that HIV seropositivity was independently associated with greater diffuse non-ischemic fibrosis and a larger left atrial volume [66].
In terms of mechanistic insights, there is some evidence that chronic inflammation can trigger fibrosis, ECM formation, proliferation, and activation of myofibroblasts [13][61]. Activated fibroblasts and myofibroblasts are central effectors in cardiac fibrosis, by functioning as the main source of matrix proteins. Furthermore, the activation of myofibroblasts require the co-operation of growth factors and specialized matrix proteins, which signal through cell surface receptors to activate intracellular signaling pathways that can lead to the synthesis of contractile proteins and the transcription of matrix macromolecules [67]. Several cell types, such as macrophages, mast cells, and lymphocytes (infiltrating the remodeled heart), play an important role in fibroblast activation by secreting a wide range of bioactive mediators, including cytokines such as transforming growth factor (TGF)-β1 and IL-10, and matricellular proteins [61]. Furthermore, the activation of the renin-angiotensin aldosterone system stimulates fibroblast proliferation and ECM protein synthesis in the infarcted and remodeled myocardium, by activation of the angiotensin type 1 receptor or through mineralocorticoid receptor signaling [68]. Although cardiomyocyte death is usually the cause of activation of fibrogenic signals, certain stimuli such as inflammation or pressure overload may activate pro-fibrotic remodeling of the heart [61]. However, despite some progress regarding identification of the underlying mechanisms responsible for the development of myocardial fibrosis during HIV-infection, the associated risk factors and clinical consequences of such pathology still require further elucidation.
Ventricular myocytes are tightly arranged and coupled together, with adjacent layers separated by clefts [61][69][70]. Advanced proteomic methods have revealed that ~90% of the cardiac ECM comprises 10 different proteins, with serum albumin, collagens (collagens I, III, and IV), non-collagenous glycoproteins (fibronectin and laminin), proteoglycans, glucosaminoglycans, and elastins being the most common [71]. The fibrillar collagenous matrix is essentially comprised of type I (>80%) and type III (>10%) collagens [61][70][72]. Fibroblasts regulate collagen turnover by controlling the synthesis and degradation of matrix proteins [73]. As the ECM forms a link between intracellular cytoskeletal proteins and intercellular ones, this allows for the transmission of biochemical signals by mechanosensation [74]. The latter also plays a significant role in activating and differentiating myofibroblasts [74].
There are two types of myocardial fibrosis, namely reactive and replacement. Reactive fibrosis is characterized by excessive extracellular matrix deposition in interstitial or perivascular spaces and is associated with pathological conditions [61]. For example, cardiac structural abnormalities (e.g., HF, arrhythmia, and coronary artery disease) can occur due to the dysregulation of collagen metabolism (synthesis and degradation) [75]. Such structural abnormalities can cause the disruption of myocardial excitation and contraction, thereby leading to impaired systolic and diastolic function (Figure 1) [61][75]. Ventricular dysfunction is the most common cause of HF, including left-sided HF with preserved ejection fraction and reduced ejection fraction with HIV infection [76]. Excessive fibrosis can also cause mechanical stiffness, which may result in the impairment of electric conduction (forming a physical barrier between cardiomyocytes) and lead to impaired cardiac systolic function [61]. Fibrosis can also cause sliding displacement of cardiomyocytes and decrease the number of muscular layers in the ventricular wall, leading to left ventricular dilation [77]. In contrast, replacement fibrosis occurs when there is acute myocardial injury/infarction in the setting of accelerated atherosclerosis associated with HIV. This occurs due to the loss of viable myocardium and results in scar formation and LV remodeling [61][78]. Thus, a balance between replacement and reactive fibrosis is required to prevent cardiac dysfunction [77][78]. As myocardial fibrosis can elicit profound effects on myocardial function and potentially lead to HF and sudden cardiac death, understanding its pathogenesis may help identify promising targets for therapeutic interventions. For example, a recent postmortem study revealed increased rates of sudden cardiac death and myocardial fibrosis in HIV-positive persons versus non-infected individuals [64].

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Eman Teer
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