Professor Stephane Heymans (Maastricht University Medical Centre, Netherlands), Chair of the HFA Board’s Basic Science Section, provides his insight into some of the latest developments in the diagnosis and treatment of dilated cardiomyopathy (DCM).
“Non-ischaemic DCM is a multifactorial and complex disease that is driven by different pathophysiological processes. The phenotype of DCM results from interactions between the genotype (mono-genetic mutations and epigenetics) and disease modifiers or acquired diseases, such as chemotherapy, alcohol, viral triggers, pregnancy, autoimmune diseases, diabetes and hypertension. As such, multi-level diagnosis is important.
Cardiac sampling is extremely valuable – biopsies allow us to examine the extent and nature of the pathophysiological processes, such as the presence of viruses, inflammation, storage diseases, metabolic diseases or fibrosis. As in oncology, performing DNA or RNA sequencing in samples helps to investigate new molecular targets and profiles. Major metabolic disturbances occur in most genetic DCM hearts. Truncating titin variants (TTNtv) are the most prevalent genetic cause of DCM and our recent work shows that titin mutations are especially associated with strong metabolic alterations.1
Combining clinical and laboratory data, genetic analysis and information from imaging allow us to define DCM phenotypes. Currently, distinct phenotypes are being identified (unpublished data). Two of these phenotypes relate to cardiac function, others to the presence of autoimmune diseases or arrhythmias. Classical heart failure therapies are not effective in around one-third to one half of patients with DCM, especially in genetic cardiomyopathies – this reflects the heterogeneity of the disease and highlights a considerable need to find more selective treatments that are targeted towards phenotypes and also to individual patient’s pathophysiology.
Patients with a proven pathogenic genetic mutation respond particularly poorly to current treatments and new treatment approaches are being sought. We have shown that TTNtv lead to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias.2 Furthermore, arrhythmias have been found to be particularly prominent in patients with TTNtv who experience an additional environmental trigger, e.g. virus infection, cardiac inflammation, systemic disease or toxic exposure. Patients with TTNtv with strong alterations in glucose metabolism, carbon metabolism and oxidative stress in their cardiac samples may benefit from drugs such as sodium-glucose cotransporter-2 (SGLT2) inhibitors. It has also been shown that there is an association between loss-of-function TTNtvs and early onset atrial fibrillation in the general population.3 This finding suggests an overlapping pathophysiological mechanism that warrants further investigation to uncover more about atrial fibrillation and DCM.
Mutations in the LMNA gene, encoding lamin A/C, are responsible for laminopathies, and DCM is a major cause of mortality and morbidity in laminopathies. LMNA mutations cause severe cardiac fibrosis and myocardial apoptosis in preclinical models, and it has been recently shown that the DNA damage response (DDR)/TP53 pathway may be involved in the molecular pathogenesis of LMNA mutations.4 These results indicate that the DDR/TP53 pathway may be a potential therapeutic target for certain patients.
Over the recent years, it has become clear that detecting the underlying dominant cause and the ongoing downstream pathophysiological processes is the key to targeted treatment strategies for DCM. The ultimate goal is to link the key disease‐driving mechanisms in individual patients with specific therapies, for example, the choice can be made between selecting immunosuppressive, antifibrotic therapies or treatments to reverse metabolic alterations. In the future, for genetic DCM, there is also the hope that we may be able to silence the mutated allele for the ultimate targeted treatment.”
- Verdonschot JAJ, et al.J Card Fail2020;26:212–222.
- 2.Verdonschot JAJ, et al.Eur Heart J 2018;39:864–873.
- 3.Choi SH, et al.JAMA 2018;320:2354–2364.
- Chen SN, et al.Circ Res2019;124:856–873.
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Universal definition of heart failure