Myocardial fibrosis in rheumatic heart disease (RHD) has been well described in previous studies (1–3). We previously relied solely on myocardial biopsies to diagnose myocardial fibrosis. However, it has a significant rate of sampling error and render the prevalence of myocardial fibrosis difficult to evaluate. With the advance of cutting-edge technology, myocardial fibrosis may now be easily detected with high accuracy and precision (4). The existence of myocardial fibrosis is essential in understanding the development of RHD (3). Myocardial fibrosis in RHD is noteworthy because its presence poses more risk to the patients. Myocardial fibrosis is mainly responsible for left ventricular (LV) dysfunction in RHD (5). Myocardial fibrosis is also associated with poor outcomes after mitral valve surgery in RHD (6). On the other hand, it might play an important role in several therapeutic aspects. The presence of myocardial fibrosis, which is associated with LV dysfunction, might require adjustments to patients' medication (5, 7). Myocardial fibrosis also has a significant role in predicting the outcome of interventions. This modifies our understanding of selecting the best course of treatment for the patients (6). It is also predicted to be an important indicator to evaluate medication therapy (8).

Myocardial fibrosis in RHD was noticed decades ago (1, 2). However, its role in clinical settings has not been explored sufficiently (8). Research progress surrounding this area of expertise is relatively slow compared to other cardiovascular problems such as coronary artery disease or heart failure. This deduction is inferred from the significantly decreased number of published materials regarding RHD over the years (9). In addition, the known clinical significance of myocardial fibrosis in RHD is currently based on observational studies (5–7). Accordingly, examinations for myocardial fibrosis in RHD have not yet been recommended by any guidelines or expert opinions (10). This review aims to compile what is known about myocardial fibrosis in RHD and its future perspective in order to ignite more progress in this field.

Although it is no longer prevalent in developed countries, RHD is nevertheless recognized as a global significant cardiovascular burden (11–13). The prevalence of RHD varies across the world. It is commonly known that RHD can be found prevalently in developing Asian and African countries (13–17). RHD is found at a rate of 5.7 per 1,000 individuals in Sub-Saharan African countries and 1.8 per 1,000 individuals in Northern Africa (18). The prevalence of RHD in Indonesia is 5.3 per 1,000 individuals (19). It is crucial to acknowledge that these prevalence figures are derived from clinical screening in the population (15, 18, 19). When systematic echocardiography is used as a screening tool, the prevalence rates increase to 21.5–30.4 per 1,000 individuals as reported in Cambodia and Mozambique (15, 16). On the other hand, the prevalence of RHD in high-income countries (HIC) is rapidly decreasing and has been recorded at as low as 0.5 per 1,000 individuals (11, 15). Moreover, RHD cases in developing countries have been associated with severe valve disease at a much younger age (16, 20). Discrepancy in epidemiological data between developing and developed countries are reportedly due to better quality of life and access to healthcare resulting in a lower transmission rate of Group A Streptococcus (GAS) bacterial infection, the causative agent of RHD. This epidemiologic discrepancy is the reason why most publications and studies regarding this topic are relatively old and originated primarily from Asia and Africa (9, 12).

Rheumatic heart disease has been recognized for more than two centuries. Scientists had previously attempted to establish a link between manifestations of rheumatic fever (RF) and the presence of RHD. Unfortunately, the technology was not enough to properly investigate the pathophysiology concept of the disease. In 1904, Aschoff presented the first description of a distinct RHD lesion (21, 22). He was the first to report the pathological aspects of RHD by describing a nodule identified in the heart of patients with RHD, which would be later known as the Aschoff body. Given that the Aschoff body is derived from lymphatic vessels of the heart, he stated that the damage to the myocardium was secondary to the specific lesion in the connective tissue rather than due to destruction by what was previously described as rheumatic poison (21). This updated understanding confirmed the pathophysiology theory that RHD is the result of an exaggerated immune response to specific bacterial epitopes (21, 22).

An exaggerated immune response is responsible for the development of RHD. Streptococcal infection in the throat, skin, or mucosa is the gateway for GAS to the body (23, 24). These first contacts of GAS activate innate immune responses involving neutrophils, dendritic cells, and macrophages (24, 25). Multiple inflammatory mediators excreted during this process, including cytokines and interleukins (IL), facilitate phagocytosis in order to eliminate the invading organisms (25). Furthermore, these inflammatory mediators (IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ) promote the differentiation of T cells and B cells (25, 26). B cells and T cells develop the ability to recognize GAS antigens through the amino acid sequence and its structural conformations (27, 28). This process triggers a mechanism known as molecular mimicry (12, 23, 24). M protein in GAS antigen shares a close resemblance to γ-helical coils structure found in both cardiac valvular and myocardial structures. N-Acetyl-β-D-glucosamine (GlcNAc) and myosin in the myocardium are the main targets of this cross-reactivity (23, 26, 29, 30). The Anti-GlcNAc and Anti-myosin complex is cytotoxic in nature and enhances both inflammation and fibrosis (3, 23, 26, 29). This causes T cells to induce cross-reactivity to both cardiac valvular and myocardial structures and generates the formation of autoantibodies (23). In healthy cardiac tissue, both GlcNAc and myosin are difficult to be accessed by the immune system (31). Anti-myosin leads to inflammation in the valve through its cross-reactivity with valve proteins laminin and vimentin (23, 26, 28, 30, 31). Cross-reactivity to these cell surface targets and extracellular matrix proteins (Collagens IV) is responsible for the infiltration of inflammatory mediators and antibodies to cardiac tissue (31). Furthermore, infiltration of these autoantibodies is enhanced with the activation of Vascular Cell Adhesion Molecule-1 (VCAM-1) (23, 26). These infiltrates can be detected further into the papillary muscle that contains myosin within its cardiomyocytes (26). This mechanism reinforced the long-held belief that the chordae tendineae are the most vulnerable cardiac structures to be affected by cross-reactivity antibodies (23). Excessively produced autoantibodies also upregulate inflammatory mediators, worsening inflammation specifically at the heart. This inflammation is granulomatous in nature and can be detected as Aschoff Body (26). Aschoff bodies are collections of interstitial inflammatory substances including lymphocytes, macrophages, B cells, Giant cells, and collagen necrosis (30). Recurrent GAS infection will recycle this process with a more pronounced inflammatory response, resulting in both valvular and myocardial dysfunction (Figure 1).

The repeated inflammatory process of cross-reactivity between streptococcal antigen and tissue of the heart eventually leads to pathological dysfunction. This involves valve tissue, chordae tendineae, and myocardium. Repeated inflammation that occurred during multiple exposures to RF disrupts the shape and function of the valves (24). Cross-reactivity of antibodies generates inflammation at valve tissue incurring edema, cellular infiltration, and fibrinous vegetations (23). The initial lesion of the valve is typically characterized by annular dilatation and chordal elongation, leading to inadequate coaptation of the leaflets (23, 24, 26). Subsequently, It may be possible to identify tiny nodules at the coaptation sections of the valve leaflets (30, 32). Over time, the leaflets thicken with eventual deposition of fibrin on the cusps until the valves cannot maintain their physiological function (23). Parts of valves that are pathologically altered are leaflet commissures, leaflet cusps, and chordae tendineae (32). Commissural fusion and chordal shortening occur as a result of recurrent RF with repetitive valve scarring (23). Leaflet thickening and calcification are primarily due to the stress of chronic turbulence through a deformed valve (32). Mitral regurgitation (MR) is the first valve abnormality that appears shortly after RF presentation. Repeated RF incidents will accelerate the RHD progression over time. Mitral valve abnormalities will gradually develop into mitral stenosis (MS) (Figure 2) (23, 32). It is commonly accepted that it takes several years after the initial attack of RF for MS to manifest and it can take decades for MS to become visible in certain circumstances (32). This occurrence corresponds to epidemiological studies that revealed that rheumatic MR is dominant in younger patients and rheumatic MS becomes more prevalent with increasing age (12). The mitral valves are the most commonly afflicted valves in RHD, followed by the aortic valve (30). Valves with more hemodynamic stress, represented by their transvalvular pressure gradient, are more prone to acute valvulitis during RF presentation and may progress to RHD. This is mediated by tumor growth factor β-1 (TGF β-1), which epigenetically alters cells to promote more fibrosis and accelerate the advancement of RHD lesions (33, 34). Chronic overexpression of TGF β-1 in RHD cases stimulates fibroblasts to proliferate and creates pathological extracellular matrix components generating fibrosis in both valves and myocardium (34). Despite its predominance in valvular tissue, RHD is characterized pathologically by the involvement of all layers of the heart, including the pericardium, myocardium, and endocardium (23). The terms used to describe how RHD affects the heart are pancarditis, involving Aschoff bodies in the myocardium, fibrinous pericarditis, and valvulopathy (30). This pathological change is primarily responsible for fatal morbidities associated with RHD, such as heart failure, atrial fibrillation, stroke, and death (3).

The aforementioned autoimmunity cascade affected by GAS raises critical questions about the prevalence of RHD. If molecular mimicry is sufficient to initiate an autoimmune cascade, RHD prevalence should be significantly greater than the present estimate. Yet, only 1 individual out of 5,000 with GAS infections develops RF (31). This prevalence is actually an underestimated number because GAS infection is not easily detected even by various methods of examination. Children with reported detectable GAS infections do not account for all those with the disease. Nevertheless, this phenomenon denotes unique individual susceptibility to develop RHD when exposed to GAS infections. Individual genetic susceptibility and familial tendency to RHD have been widely studied (35). Approximately 14% of the population possess genes associated with an increased risk of RHD (31). Human Leukocyte-associated Antigen (HLA) class II genes located at chromosome 6 are believed to play a role in the development of both RF and RHD. This finding does not contradict the current understanding that these genes are responsible for regulating the immune response. Among these genes, HLA-DR7, DR4, and DR9 are the alleles that have consistently been found in the development of RHD (35).

Myocardial fibrosis is currently acknowledged to be a common finding in RHD. Multiple studies have identified the presence of myocardial fibrosis in patients with RHD. The first was published in 1968 by Shaper AG et al. This necropsy study found that 26 cases from 213 RHD patients were complicated by myocardial fibrosis (1). Another study was performed by Perennec et al. in 1980 in a different subset of population. Eleven samples of LV myocardial biopsies were studied from patients with isolated rheumatic MS who had corrective surgery. Four patients were identified with a moderate degree of myocardial fibrosis (36). Various degrees of myocardial fibrosis may develop in rheumatic MS. In 1999, Saraiva et al. observed extensive myocardial fibrosis in rheumatic MS with the fibrosis penetrating far into the myocardium (2).

The prevalence of myocardial fibrosis in RHD has not been established consistently, likely due to varying methods utilized to identify myocardial fibrosis. Older publications were using necropsy or myocardial biopsy samples, which are susceptible to sampling errors (1, 36). Recent use of cardiac MRI to identify myocardial fibrosis generates a relatively higher prevalence of myocardial fibrosis in RHD cases (5, 6). Nonetheless, the quality of the MRI image and the experience of the center were valid concerns for the possibility of bias. In Table 1, we present the prevalence of myocardial fibrosis in patients with RHD obtained from previous studies.

Myocardial fibrosis is characterized by pathological manifestations of extracellular matrix (ECM) remodeling (37). It is marked by an increased collagen type I deposition and cardiac fibroblast activation (38). Regardless of the etiology, myocardial fibrosis leads to myocardial stiffness thereby causing cardiac dysfunction (38, 39). In RHD, myocardial fibrosis develops primarily due to an immunologic cascade triggered by cross-reactivity. Immunologic cascade, described as molecular mimicry, causes the upregulation of autoantibodies that exacerbate inflammation (24). This cascade involves autoantibodies and complement activation. Autoantibodies developed by cross-reactivity are the cornerstone of pathways leading to myocardial fibrosis. These autoantibodies develop a mechanism by overexpressing transforming growth factor β (TGF-β). Autoantibodies can directly cause injury at the endothelium and in the heart cell environment underneath (29). Consequently, the autoreactive innate immune system exacerbates tissue degradation, inflammation, neovascularization, and fibrosis in a negative cycle (3, 40). Angiotensin II has long been recognized as the primary stimulator of cardiac fibrosis (Figure 1) (41, 42). Angiotensin II generates fibrosis by stimulating TGF-β (41–44). This process is also observed in RHD (3). Angiotensin II also stimulates the soluble ST2 (sST2) decoy receptor, causing increased phosphorylation in the mitogen-activated protein kinase (MAPK) pathway. MAPK is a protein kinase that functions as a second messenger in response to extracellular stimuli. The MAPK pathway regulates gene expression, metabolism, cell proliferation, growth, differentiation, and survival (3, 45, 46). Activation of the MAPK pathway by TGF-β enhances ECM remodeling (37, 44, 46). Uncontrolled activity of TGF-β and the MAPK pathway will result in pathogenic fibrosis (43, 46).

There are several modalities we can use to detect myocardial fibrosis. Endomyocardial biopsy was the only available method to assess myocardial fibrosis prior to the development of more advanced techniques. Despite the advent of numerous novel diagnostic techniques, myocardial biopsies continue to be the gold standard for diagnosing myocardial fibrosis (4, 38). Its disadvantages include its invasive nature and a significant likelihood of sampling error in detecting localized fibrosis (4, 47). Cardiac MRI is a relatively recent modality used to detect fibrosis using the late gadolinium enhancement (LGE) protocol (4, 47, 48). LGE can easily detect and accurately analyze the extension of myocardial fibrosis in various diseases including RHD (4, 47, 49). The physiological basis of the LGE for identifying myocardial fibrosis is the combination of an increased volume of distribution for the contrast agent and a prolonged washout due to the decreased capillary density within the cardiac fibrotic tissue (4, 47). Description of myocardial fibrosis by LGE in patients with RHD is unique by its nature. It is frequently described as a patchwork pattern of myocardial fibrosis in the mid-myocardial part across every segment of the left ventricle (6, 50). Its appearance reflects the occurrence of myocardial fibrosis, which resulted from a non-ischemic condition (4, 50). T1 mapping is another novel protocol of cardiac MRI. This protocol is currently being developed and calibrated in recent studies (47, 48). Publications regarding the use of T1 mapping protocol in patients with RHD are still scarce (47, 48, 51). Another approach for detecting myocardial fibrosis is the ST2 biomarker. Soluble ST2 is a member of the IL 1 receptor family and it plays an important role in both the inflammatory response and the fibroproliferative mechanism. Its role as a decoy receptor for IL-33 attenuates its counterpart's (ST2 ligand) beneficial effect of reducing fibrosis. A higher level of soluble ST2 serum level is associated with increased myocardial fibrosis (3, 52). Other potential laboratory biomarkers for myocardial fibrosis are galectin-3 and procollagen (52).

Evolving research regarding myocardial fibrosis in the field of RHD encourages clinicians to adopt a more comprehensive approach to treating RHD. Utilizing recent discoveries with significant clinical impact in our daily practice will benefit patients with RHD. Further advantages can be gained when more research for clinical benefit is conducted in this area of expertise. Future research can guide both medical and surgical programs for the patients (Figure 4).

Speckle tracking echocardiography is used to analyze subtle changes in LV performance before LVEF is compromised (7, 59). It was commonly thought that inflammatory insult had little effect on the left ventricle in RHD (54, 60). As a result, there was little interest in assessing LV function thoroughly beyond the LVEF measurement. Recent studies on myocardial fibrosis in patients with RHD have provided clinicians with additional evidence of the limitations of LVEF measurement in reflecting LV function. It has been established that global longitudinal strain rates from speckle tracking echocardiography are worse in patients with RHD than in a normal population (7, 59, 62). A larger area of myocardial fibrosis is likewise associated with a worse global longitudinal strain rate (7). The clinical significance of a worse global longitudinal strain rate in RHD patients has not yet been determined. Hence, there is currently no recommendation to routinely perform speckle tracking echocardiography in RHD other than to confirm subtle changes in LV function. Such a recommendation might be proposed when its clinical impact is discovered. It is to be expected that future investigations will be focusing on the clinical value of a poor strain rate from speckle tracking echocardiography. Information regarding the long-term progression of the disease based on strain rate findings would give a crucial perspective on the timing of valve surgery.

The prognostic implications of myocardial fibrosis in RHD had been established in patients planned for surgery. More extensive myocardial fibrosis, as measured by LGE from cardiac MRI, significantly leads to worse postoperative morbidity (6). This insight might be used to guide the decision for mitral valve surgery for certain patients with RHD. In patients with ischemic heart disease, LGE findings from cardiac MRI were utilized to determine the risk and benefits of surgical treatment (68, 78). The degree of transmurality determined by the LGE protocol can be used to establish the viability of specific regions of the left ventricle and whether or not the patient requires revascularization procedures (78–80). Transmurality quantification is not appropriate for quantifying myocardial fibrosis in RHD due to the fact that it is not subendocardial in nature (6, 50). The degree of myocardial fibrosis in RHD is based on the extension of its volume and it can be classified as less than 5% and ≥5%. Less than 5% myocardial fibrosis implies a more favorable improvement of LV geometry after mitral surgery (50). However, its association with long-term prognosis has not been explored yet. Information about long-term morbidity and mortality after valve surgery in RHD based on myocardial fibrosis findings is necessary to firmly determine recommendations regarding decisions to perform surgery. This issue needs more validation and confirmation before being implemented in daily clinical practice.

Medications for RHD recommended by current guidelines reside in treating the congestion nature of the disease (10). The presence of myocardial fibrosis in RHD uncovers a new perspective on drug therapy. Unfortunately, medications specifically targeted to treat myocardial fibrosis in RHD have not been explored. This is due to the fact that myocardial fibrosis in RHD is a relatively new concept. The antifibrosis property of some medications may be advantageous in the treatment of RHD (3, 8, 75). ACE inhibitors are debatable medications for treating myocardial fibrosis in RHD due to concerns about their safety (75, 77). Ongoing randomized controlled trials are being conducted to assess the efficacy of ACE inhibitors in reducing myocardial fibrosis (8). The impact of treatment on myocardial fibrosis in RHD is unclear without the result of such research. The results may significantly alter the fundamental treatment for RHD.

Myocardial fibrosis is a common finding in patients with RHD. It is fundamentally generated by an exaggerated immune response to the GAS antigen because of its cross-reactivity with cardiac valvular and myocardial structures. The presence of myocardial fibrosis and its impact on patients with RHD have been confirmed by multiple studies. Myocardial fibrosis appears to be important in various clinical aspects. Myocardial fibrosis is responsible for LV dysfunction in RHD cases. It also plays a significant role in predicting clinical outcomes of interventions in patients with RHD. The presence of myocardial fibrosis uncovers different approaches to medication therapy for RHD. Medications with antifibrotic properties such as ACE inhibitors might hold a potential role in the treatment of RHD. Future perspective regarding this issue requires additional research to determine its clinical utility in daily practice.