Early‐stage myocardial changes are not aggravated by Western diet or ageing in Mybpc3 c.2373insG heterozygous mice

Hypertrophic cardiomyopathy (HCM) caused by heterozygous pathogenic gene variants is characterized by highly variable disease phenotypes. Ageing and systemic metabolic disruption are thought to act as additional ‘second hits’ that modulate this genotype–phenotype relationship. To define mechanisms through which metabolic and ageing‐related stressors may trigger development of HCM, we investigated whether Western diet (WD) feeding or ageing (3, 8.5 and 18 months) could trigger and/or aggravate cardiac hypertrophy and dysfunction in targeted knock‐in mice harbouring the Dutch heterozygous (HET) c.2373InsG mutation in Mybpc3 encoding cardiac myosin‐binding protein C (cMyBP‐C). Using cardiac magnetic resonance imaging we revealed impaired relaxation in absence of left ventricular hypertrophy in HET compared to WT mice. Mybpc3 transcript levels were reduced by approximately 50%, but no cMyBP‐C haploinsufficiency was observed. Both WD‐feeding and ageing did not trigger cardiac hypertrophy or haploinsufficiency in HET Mybpc3 c.2373insG mice. Ageing induced cardiac remodelling and peripheral vascular remodelling, which coincided with enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation capacity and increased myocardial perfusion. Noteworthy both mitochondrial function and myocardial perfusion were significantly higher in HET compared to WT mice at a younger age. This study shows that the HET Mybpc3 c.2373insG mice represent a model for early‐stage HCM, characterized by impaired relaxation, preserved cMyBP‐C protein levels despite reduced Mybpc3 transcripts and early ‘ageing’‐related myocardial changes in energy supply. As WD‐feeding and ageing did not trigger hypertrophy or haploinsufficiency, our HET mouse model most likely requires a combination of additional disease stressors to elicit a more severe cardiac phenotype. image Key points Heterozygous (HET) Mybpc3 c.2373insG mice displayed an early‐stage HCM phenotype characterized by impaired diastolic function, early mitochondrial alterations and cardiac remodelling, without developing left ventricular hypertrophy; cMyBP‐C protein levels were preserved. Cardiac magnetic resonance imaging sensitively detected impaired diastolic dysfunction in HET mice. Western diet–induced metabolic stress did not trigger cardiac hypertrophy, worsen dysfunction or impair mitochondrial function in HET mice. Ageing induced systemic, vascular and mitochondrial adaptations, but did not exacerbate cardiac pathology. The heterozygous Mybpc3 mutation induced earlier onset of ageing‐related myocardial changes in absence of cMyBP‐C haploinsufficiency.