Cardiomyopathies (CMP) are a diverse group of myocardial diseases that cause structural, functional, and pathological changes to the heart. Alterations at the molecular level associated with the clinical phenotype and progression of CMPs cannot be solely explained by the genetic mutations, even in inherited cardiomyopathies. Epigenetics and environmental factors are likely to significantly modify the clinical manifestations of CMPs, resulting in variable clinical expression and different age-related penetrance. This review examines the role of dysfunctional DNA methylation, histone modifications, chromatin remodelling, and noncoding RNAs in the development and exacerbation of CMPs, highlighting their potential as diagnostic markers and therapeutic targets, including the use of histone deacetylase inhibitors. Additionally, it explores how environmental exposures can influence epigenetic changes and potentially be used for preventive strategies and personalized care in CMP patients. Monozygotic twin studies and intergenerational studies are discussed as valuable tools for understanding the interplay between genetics, epigenetics, and environmental factors. Lastly, this review addresses current challenges and future perspectives, such as the need for greater specificity in epigenetic therapies, minimizing off-target effects, and investigating sex differences in CMP research and treatment.

Ascending aortic (AoAsc) dilatation can lead to acute aortic syndromes and has been described in various familial cardiac diseases. Its prevalence and clinical significance in patients with noncompaction cardiomyopathy (NCCM) are however unknown. Establishing the prevalence can facilitate recommendations on routine screening in NCCM. In this cross-sectional cohort study based on the Rijnmond Heart Failure/Cardiomyopathy Registry, the patient were enrolment between 2014 and 2021. All NCCM patients (n = 109) were age and sex matched with 109 dilated cardiomyopathy (DCM) patients as controls. The aortic diameters were measured through the parasternal long-axis transthoracic echocardiographic view at the sinuses of valsalva (SoV-Ao), sinotubular junction (STJ) and ascending aorta (AscAo). Dilatation was defined using published criteria adjusted for body surface area (BSA), sex, and age. Median age of age-sex matched NCCM and DCM patients was 45[31–56] vs. 45 [31–55] years with 53% males in both groups. NCCM patients had more familial hereditary patterns and genetic variants (55% vs. 24%, p < 0.001). DCM patients had more heart failure and left ventricular dysfunction (ejection fraction 34 ± 11 vs. 41 ± 12, p = 0.001). Ascending aortic dilatation was present in 8(7%) patients with NCCM and 5(5%) patients with DCM (p = 0.46). All dilatations were classified as mild. In conclusion, in this cross-sectional cohort study the prevalence of ascending aortic dilatation in NCCM patients was 7%, which were only mild dilatations and not significantly different from an age-sex matched cohort of DCM patients. Routine aortic dilatation screening therefore does not seem warranted in patients with NCCM.

Abnormal aortic elasticity serves as a marker for cardiovascular mortality and has a negative impact on the left ventricular (LV) afterload. Noncompaction cardiomyopathy (NCCM) is characterized by hypertrabeculation of the LV endomyocardial wall, with an underdeveloped endocardial helix. This may result in absence of LV twist, disturbed aortic elasticity, LV dysfunction, and ultimately premature heart failure (HF). This study compared the aortic stiffness and clinical outcome in patients with NCCM to that of a control group with dilated cardiomyopathy (DCM). Sixty NCCM patients, matched by age and sex, were compared with 60 DCM controls. Transthoracic echocardiography was performed to measure the systolic (SD) and diastolic diameters (DD) of the ascending aorta. These measurements, along with systolic (SBP) and diastolic blood pressure (DBP), were utilized to calculate the aortic stiffness index defined as ln(SBP/DBP)/[(SD-DD)/DD]. This index was then compared to clinical features and outcome. The mean age was 49 ± 16 years (55% males) in the NCCM group and 49 ± 16 years (55% male) in the DCM group. Aortic stiffness index (ASI) was significantly higher in the NCCM group than in the DCM group (7.0 [5.8–10.2] vs. 6.2 [4.8–7.7], p = 0.011). This difference remained statistically significant after adjustment for established risk factors associated with aortic stiffness (β = 1.771; 95% CI [0.253–3.289], p = 0.023). Patients with NCCM demonstrated increased aortic stiffness when compared to those with DCM, which may reflect the underlying pathophysiological processes. Additional research is necessary to evaluate the impact of aortic stiffness on the advancement of LV dysfunction, the onset of heart failure, and long-term outcomes.