The Clinical and Biochemical Effects of Atrial Fibrillation on Heart Failure with Reduced Ejection Fraction

Abstract

Background: The increasing burden of non-communicable diseases in Sub-Saharan Africa has led to an increased prevalence of heart failure with reduced ejection fraction (HFrEF), often complicated by atrial fibrillation (AF). However, most evidence informing HF management is derived from high-income countries, overlooking the specific epidemiology, clinical and biomarker profiles, and genetic backgrounds of African populations. Aim: This thesis aimed to characterise the clinical, echocardiographic, biochemical, and genetic characteristics of South African patients with HFrEF, both with and without concomitant AF, and to and to identify determinants of all-cause mortality in this population. Methods: A prospective, single-centre observational cohort study was conducted among HFrEF adults attending a dedicated HF clinic as well as those admitted in cardiac admission wards at a tertiary hospital in Johannesburg. Patients with HFrEF were phenotyped using comprehensive clinical assessment, advanced echocardiography including 2D-speckle tracking, measurement of standard and novel biomarkers (NT-proBNP, sST2, IL-6, GDF-15, galectin-3, cathepsin-D, cTnT), and β1-adrenergic receptor Arg389Gly single nucleotide polymorphism genotyping. The outcome of all-cause mortality was assessed after a follow-up period of 3 years. Predictors of all-cause mortality were identified through multivariable regression models. Results: Among 136 HFrEF patients, the prevalence of AF was 21%. HFrEF-AF patients were older, had more advanced structural heart disease, poorer functional status, and higher mortality compared to those in sinus rhythm. Notably, prescription rates and achievement of optimal guideline-directed medical therapy (GDMT) were suboptimal among HFrEF-AF patients, with fewer patients achieving target doses across drug classes. Similarly, oral anticoagulation (OAC) use was lower than guideline standards, despite elevated thromboembolic risk. Biomarker profiling revealed a distinct fibrotic and inflammatory signature in HFrEF-AF, with elevated sST2, GDF-15, and IL-6 correlating with clinical severity and quality of life. Echocardiographic analysis confirmed greater left atrial dysfunction and advanced right sided remodeling in HFrEF-AF. Independent predictors of all- cause mortality included worsening diastolic dysfunction, higher heart rate, prior stroke, poorer quality of life, and right ventricular dysfunction. Pharmacogenomic analysis demonstrated a predominance of the Arg389 allele, with the Gly389 loss-of-function variant notably absent in HFrEF-AF, diverging from other African populations. Conclusions: This thesis provides the first comprehensive multimodal characterisation of HFrEF-AF in South Africa. The findings xv highlight that AF marks a more advanced and severe HFrEF phenotype, underpinned by inflammatory and fibrotic pathways and distinctive genetic profiles. Suboptimal GDMT and OAC implementation highlight significant care gaps. These data underscore the need for context-specific risk stratification and management strategies, and lay the groundwork for future precision medicine initiatives in this high-risk population