Bridging gaps in prognostic stratification of cardiomyopathies

Cardiomyopathies are a heterogeneous group of myocardial disorders characterised by structural and functional abnormalities of the heart muscle in the absence of coronary artery disease, hypertension, valvular disease, or congenital heart disease sufficient to cause the observed abnormality. Despite recent advancements in screening, diagnosis, and therapeutic strategies, these diseases still carry a substantial burden of morbidity and mortality worldwide, being associated with a significant risk of heart failure, arrhythmias, and sudden death (SD). Hence, there is a need for continuous investigation, particularly in prognostic stratification, to enable clinicians to tailor therapeutic and preventive strategies for patients with cardiomyopathies. This doctoral thesis brings together a series of studies aimed at identifying improved prognostic markers in cardiomyopathies. The thesis consists of five main chapters: the first three chapters explore the role of coronary microvascular dysfunction (CMD) in patients with dilated cardiomyopathy (DCM), the fourth chapter focuses on the impact of a specific variant of troponin T 2 (TNNT2) on the prognosis of patients with hypertrophic cardiomyopathy (HCM), and the last chapter looks for a correlation between the onset of cardiological manifestation and neurological ones in patients with type 1 myotonic dystrophy (DM1). The first chapter provides a comprehensive review of the role of CMD in patients with heart failure with reduced ejection fraction (HFrEF), especially in those with non-ischaemic DCM. In recent years, evidence of CMD as a pathophysiological hallmark of heart failure has been accumulating, and it is emerging as a potentially crucial contributor to disease progression and adverse outcomes. This chapter discusses current evidence and highlights how impaired microvascular function may serve as a prognostic determinant beyond traditional markers. In the second chapter, we evaluated whether angiography-derived resting coronary flow (rCF) correlated with resting coronary perfusion assessed by continuous thermodilution in patients with HFrEF and whether it was associated with adverse outcomes in a prospective cohort of patients with non-ischemic DCM. Significantly, abnormally increased rCF (≥ 2.32) was associated with impaired microvascular resistance reserve, a lower likelihood of left ventricular reverse remodelling despite guideline-directed medical and a higher occurrence of long-term adverse clinical outcomes. In the third chapter, we aimed to determine the prevalence of CMD and to characterise CMD endotypes across different left ventricular ejection fractions (LVEF) in a prospective cohort of patients with a new diagnosis of DCM and systolic dysfunction. Notably, CMD correlated with adverse remodelling markers at initial evaluation and with lower rates of echocardiographic recovery after six months of GDMT, further suggesting the idea that CMD may contribute to disease progression in patients with DCM with LVEF ≤ 40% and might serve as a marker of adverse cardiac remodelling. In the fourth chapter, we described clinical phenotype, penetrance, and major adverse cardiovascular events during follow-up of a retrospective cohort of patients with the p.Arg92Trp (c.304C>T) variant in the TNNT2 gene. Of note, this variant was associated with a non-obstructive HCM phenotype with a frequent evolution to left ventricular (LV) dysfunction, high incidence of SD, and adverse events. However, significant phenotypic variability was also observed, suggesting that outcomes could depend on factors other than the variant position. Finally, the fifth chapter aimed to describe neuromuscular and cardiac involvement, as well as clinical predictors during long-term follow-up of a large, retrospective cohort of patients with DM1. Interestingly, advanced delays in cardiac conduction were significant predictors of device implantation; atrial fibrillation and flutter predicted adverse outcomes. In conclusion, this thesis illustrates the complex nature of prognostic stratification of cardiomyopathies, highlighting the limitations of the current one-size-fits-all approach. Prognosis stems from the dynamic interaction of diverse factors, which- if correctly identified and integrated- might help improve patients’ outcomes by allowing for the earlier identification of high-risk individuals and tailoring therapeutic interventions.