Rheumatic valve disease and acceleration of cardiac aging in Africa: next-generation answers for an old, orphan problem

Rheumatic valve disease (RVD), the chronic outcome of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), remains a major determinant of cardiovascular morbidity and mortality in Africa. While nearly eradicated in high-income countries, such as in Europe and North America, RHD persists in low- and middle-income areas, disproportionately affecting socio-economically disadvantaged populations. Sub-Saharan Africa bears approximately a quarter of the global RVD burden, where the condition is a leading cause of heart failure and often diagnosed at advanced stages.1 Despite global improvements in age-standardized mortality from rheumatic valve disease, declining by 47% from 1990 to 2015, sub-Saharan Africa has seen little to no progress. According to the Global Burden of Disease study, the region continues to report some of the world’s highest RHD-related mortality and prevalence worldwide.2 In certain African countries, the prevalence among school-aged children may reach 3%, often remaining undetected until symptomatic valve dysfunction develops. RVD in Africa predominantly affects children and young adults, with devastating long-term consequences. Multi-valve involvement is common and often leads to progressive heart failure, arrhythmias, stroke, and premature death. Surgery remains inaccessible for most, and medical management is often delayed or suboptimal due to systemic limitations, including weak primary care, lack of routine echocardiographic screening, and inconsistent supply of secondary prophylaxis.1 In summary, the epidemiology of RVD in Africa highlights important opportunities to address health disparities by improving living conditions, expanding access to quality healthcare, and investing in stronger public health infrastructure. In high-income areas, cardiac fibrosis and calcification of the cardiac valves are prevalent in elderly populations, and this has been classically linked to age as an unmodifiable risk condition together with inflammation, lipid accumulation, and other modifiable factors3 (Figure 1A). Despite the basic epidemiological conditions favouring the progression of the disease are known, the pathology remains relatively poorly understood mechanistically, and effective treatments to halt its progression are not yet available.4 Discrimination between the most commonly accepted determinants of cardiac valves calcific disease (here represented in an aortic valve) in elderly individuals from high-income countries (e.g. USA and Europe) (A) vs the here proposed new RVD determinant, possibly occurring in young Africans due to group A streptococcus infection and acute rheumatic fever, represented by increased DNA methylation and variation in the histone marks, and the resulting effect on epigenetic age acceleration and cellular senescence (B). While the transition of valve interstitial cells to a pathological status (activated valve interstitial cells) might be initiated in both populations by common determinants (e.g. inflammation), the absence of direct comparisons and robust molecular investigations hinders accurate assessment of these pathologies across these contexts, limiting effectiveness of therapies worldwide. Image created with Biorender (https://app.biorender.com/illustrations/6811fe1be70db6f6e1c121f0?slideId=e3ee1af7-66df-49a6-8212-6d0b6473d3d9), licensed to Centro Cardiologico Monzino, IRCCS In recent years, evidences have indicated that the ‘chronological aging’ process, occurring as a consequence of the progression in age, does not reflect linearly in progressive organ failure. In fact, the ‘biological aging’, resulting from the combination of genomic instability, alterations in metabolism, and stress conditions, exposes cells and tissues to enhanced cellular senescence in an organ-specific manner. The speed of biological aging is measurable through quantifications of epigenetic markers (e.g. methylation of age-sensitive CpG islands) using different epigenetic ‘clocks’, and this makes possible to understand the deviation of the biological aging from the chronological aging in a personalized fashion.4 Reports showed that the heart is particularly susceptible to acceleration of this biological clock and that the speed of cardiac aging seems to be faster than in other districts like, e.g. the blood of the same individuals.5 While it is emerging that cardiac pathologies (e.g. subclinical atherosclerosis) are established by risk factor-dependent epigenetic age acceleration (EAA) before clinical manifestations,6 experience with HIV, HCV, SARS-CoV-2, and other viral infections suggests that chronic infections can also contribute to EAA, and that this acceleration can enhance cardiovascular pathologies.7,8 Whether or not chronic infections by group A streptococcus (GAS), the primary cause of ARF, lead to EAA in cardiac fibroblasts, valve interstitial cells (VICs) and infiltrating immune cells, causing acceleration of biological age, have never been directly assessed and require intensive research. On the other hand, reports from China showed that RHD and RVD are associated to variations in DNA methylation status with possible consequences for chronic activation of downstream inflammatory pathways.9 Extrapolating the findings of these studies to the sub-Saharan Africa strongly suggests that ARF plays a major role in accelerating premature cardiac aging across large segments of the population. The most immediate and severe consequence appears to be a pandemic-level risk of multi-valvular heart disease among young individuals (Figure 1B). The unacceptably high incidence of ARF and its immediate consequences RHD and RVD in Africa demands an integrated approach combining classic public health interventions with cutting-edge molecular research. The benefits of this approach are expected to extend beyond the African continent, contributing to the promotion of healthy cardiovascular aging worldwide, for example by addressing the interplay between molecular determinants of the pathology, such as the acceleration of the epigenetic clock, and socio-economic factors. Indeed, EAA and increased cardiovascular risk have been consistently observed in populations exposed to social stressors even in high-income countries. Groups like ethnical minorities, individuals with low socio-economic status, and those living in disadvantaged neighbourhoods or exposed to chronic psychosocial stress are subjected to acceleration of the epigenetic clock and increased cardiovascular risk.10 When this concept is applied to Africa, where there is one of the most unequal distributions of living resources globally along with widespread social inequalities, an additional and alarming dimension emerges, compounding the impact of the already significant biological determinants. To respond to the growing burden of this modern and neglected injustice, it is in our opinion necessary to put in place a multilevel strategy leveraging the solid research capacity of the high-income countries in collaboration with the rising potential of the new generations of doctors and scientists in the African continent, empowering them to lead translational research initiatives directly on ground. This will require, at first, to tailor the cardiovascular risk of the African population by integrating the traditional risk factors defined for the economically advanced environments with the molecular indicators of GAS infection and the socio-economic conditions that contribute to accelerate cardiac aging across the continent. The ability to establish regional biobanks, high-quality clinical registries, and molecular profiling programmes in Africa is a second factor that will enable the collection and preservation of biological samples from the still limited number of RVD treatment centres and perform next-generation omics. This will help to establish meaningful associations between the pathology determinants and predictive biomarkers for advanced patient stratification and assessment. Third, it is crucial to tailor current preventive therapies to the specific molecular determinants of the disease. For example, treatments aimed at inhibiting calcification considered very valuable for calcific degenerative disease in elderly populations at high latitudes may be ineffective against the fibrotic processes predominant in RHD. Conversely, targeting epigenetic regulators or inflammatory cytokines may hold promise for patients with RHD, given the likely susceptibility of the African populations to extreme acceleration of cardiac aging as a pathological driver. Fourth and finally, we believe that only by building an autonomous African-based research capacity specifically focused on this need, it will be possible to advance the knowledge on aspects of cardiac aging that remains poorly understood even in high-income countries. This perspective highlights Africa not merely as a continent historically neglected in its health necessities, but as a potential new driver of global public health innovation and economic value creation.