Titin's role in diastolic heart function across species

BackgroundCardiac diastolic function and blood pressure are physiologically tightly interconnected. While diastolic function is regulated by post-translational modifications of sarcomeric genes, including titin (TTN), isolating its genetic determinants from those influencing blood pressure is challenging due to variable in vivo loading conditions. We aimed to genetically map diastolic function to the rat genome to prioritise human gene orthologs for genotype-phenotype studies of cardiac function and clinical outcomes. MethodsHigh-fidelity cardiac phenotyping using ex vivo Langendorff preparation in an F2 cross of inbred rat strains included evaluation of left ventricular contractility (LV) (dP / dtmax) and relaxation (dP/dtmin), while controlling loading conditions. In UK Biobank, whole exome sequencing was performed and cardiovascular image-derived phenotypes and outcomes were compared in adult rare variant carriers and genotype-negative participants. ResultsIn rats, quantitative trait locus analysis identified a single locus on chromosome 3 that reached genome-wide significance for LV relaxation (dP/dtmin), which was also associated with variation in LV contractility (dP/dtmax) but not blood pressure. The Ttn gene, which encodes varied non-synonymous single-nucleotide polymorphisms of parental strains, is encoded at the peak of linkage. In humans, the prevalence of rare titin truncating variants (TTNtv) (allele frequency < 0.00004) in 454,756 UK Biobank participants was 0.37% (n = 1,672). Carrying a TTNtv was associated with an increased risk of death or major adverse cardiac events compared to genotype negative controls (hazard ratio: 1.94; 95% confidence interval [CI]: 1.78-2.12; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 3.76; 95% CI: 3.30-4.29; P < 0.001). In 33,988 participants with both cardiac magnetic resonance imaging and whole exome sequencing, TTNtvs were associated with reduced diastolic function, even in participants with normal systolic function and no ventricular dilatation. ConclusionsThese studies demonstrate for the first time in rats, that naturally occurring variations in Ttn are associated with diastolic function, independently of blood pressure, and in humans TTNtv cause impaired cardiac relaxation and adverse outcomes before overt cardiomyopathy develops.