Aims: This study aims to comprehensively explore the genetics and imaging characteristics of heart failure with preserved ejection fraction (HFpEF) to improve understanding of this condition. The study has three primary objectives: compile a comprehensive list of single-nucleotide polymorphisms (SNPs) associated with cardiac imaging traits; conduct a systematic literature review of genetic studies related to cardiac imaging traits; and lastly to perform genome-wide association studies (GWAS) to identify genetic locis associated with high-risk of HFpEF and cardiac fibrosis and use enrichment analyses to identify the overlap between the GWAS results and the biological pathways present in the compiled list of SNPs.
Methods: The systematic literature review was conducted following the PRISMA guidelines, highlighting significant advancements in understanding the genetic determinants of cardiac structure and function through various GWAS. Then, we performed GWAS utilizing data from the UK Biobank, to identify genetic variants associated with high risk of HFpEF and cardiac fibrosis.
Results: The review uncovered specific correlations between genetic markers and cardiac imaging phenotypes, as assessed by echocardiography and MRI, which offered profound insights into the genetic factors influencing heart anatomy and function. We identified a comprehensive set of 775 SNPs associated with HFpEF, linked to over 56 distinct cardiac traits, including left ventricular mass (LVM), ejection fraction (EF), aortic root size, ventricular volumes, and wall thickness measures. Notably, specific regions on chromosomes 17, 6, and 12 exhibited the highest concentrations of variants, suggesting these regions may play crucial roles in the genetic predisposition to HFpEF. Enrichment analysis further confirmed that these genetic variants are involved in key biological pathways such as metabolic regulation, inflammation, and myocardial fibrosis.
Conclusion: Our findings highlight the potential of integrating genetic data with cardiac imaging to better understand the complex mechanisms of HFpEF. The identification of significant genetic loci and their roles in metabolic regulation, inflammation, and myocardial fibrosis, highlights the importance of genetic factors in HFpEF pathophysiology. This integrated approach could lead to improved diagnostic and therapeutic strategies tailored to individual genetic profiles, ultimately enhancing patient care and clinical outcomes. Understanding the epidemiology and underlying pathophysiological mechanisms of HFpEF remains challenging due to its current definition encompassing multiple etiologies. However, this study highlights the potential of imaging genetics to characterize and identify subtypes of HFpEF and possible novel preventive, diagnostic, and therapeutic strategies for this condition.