Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine

Abstract

Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. Despite improvements in the prognosis of patients with DCM in the past decade, this condition remains a leading cause of heart failure and premature death. Conventional treatment for DCM is based on the foundational therapies for heart failure with reduced ejection fraction. However, increasingly, attention is being directed towards individualized treatments and precision medicine. The ability to confirm genetic causality is gradually being complemented by an increased understanding of genotype-phenotype correlations. Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the 'two-hit' hypothesis). The roles of common genetic variants in the general population and of gene modifiers in disease onset and progression are also discussed. Finally, areas for future research are highlighted, particularly novel therapies, such as small molecules, RNA and gene therapy, and measures for the prevention of arrhythmic death.

Fig. 1 ∣. Complex interactions in the pathophysiology of dilated cardiomyopathy.

Multiple interactions occur between environmental (red boxes) and genetic (yellow boxes) factors, with monogenic or polygenic architectures. Titin-truncating variants (TTNtv) are a model of the ‘two-hit’ hypothesis, whereby genetic predisposition to dilated cardiomyopathy can mediate different responses depending on environmental factors and, reciprocally, that environmental exposure might influence gene expression. Solid lines indicate strong evidence, whereas dashed lines indicate areas still to be explored.

Fig. 2 ∣. Genotype–phenotype correlations in dilated cardiomyopathy.

Late gadolinium enhancement (LGE) on cardiac MRI and electrocardiographic findings in four different genotypes of dilated cardiomyopathy. a, A carrier of a pathogenic variant in FLNC, with a typical subepicardial ring-like pattern of LGE on MRI, as well as low voltages on peripheral leads and inferolateral negative T waves on the electrocardiogram. b, A carrier of a pathogenic variant in TTN, with no specific LGE distribution and minor, non-specific repolarization electrocardiographic abnormalities. c, A carrier of a pathogenic variant in DSP, with a typical subepicardial ring-like pattern of LGE on MRI, as well as low voltages on peripheral leads, ventricular ectopic beat, QRS fragmentation and flat lateral T waves on the electrocardiogram. d, A carrier of a pathogenic variant in LMNA, with transmural septal LGE on MRI as well as first-degree atrioventricular block, intraventricular conduction delay and multiple ventricular ectopic beats on the electrocardiogram.

Fig. 3 ∣. Life-threatening ventricular arrhythmias and HF-related events in DCM.

Graphs showing survival free from sudden cardiac death (SCD) or major ventricular arrhythmias (MVA) (panel a) and heart failure-related (HF) death or heart transplantation (HT) (panel b) for the four genotypes of dilated cardiomyopathy (DCM) in the Trieste, Italy, and Denver, USA, genetic cardiomyopathy registries: DSP, FLNC, LMNA and TTN. The risk of SCD or MVA is similar in DSP, FLNC and LMNA variant groups and lower in the TTN variant group. Carriers of LMNA variants have the highest risk of HF-related death or HF. Data extracted from ref. .

Fig. 4 ∣. Cascade screening in DCM.

Flow chart proposal for genetic testing and subsequent management of probands with dilated cardiomyopathy (DCM) and their first-degree relatives. Genetic testing and clinical assessment also apply to first-degree relatives of each affected individual or carrier of a pathogenic or likely pathogenic variant within the family.

Fig. 5 ∣. Simplified mechanisms of inflammation in dilated cardiomyopathy.

Damage-associated molecular patterns (DAMPs; endogenous molecules) and pathogen-associated molecular patterns (PAMPs; exogenous microbial products), acting via specific receptors and pathways, can trigger and promote inflammatory responses related to the activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in cardiomyocytes. This mechanism triggers an excessive inflammatory response (the IL-1 cascade), mediated by innate and adaptive immune cells, contributing to an increase in cardiac fibrosis, the progression of ventricular dilatation and a decline in cardiac function. In turn, the haemodynamic overload, oxidative stress and endothelial dysfunction seen in dilated cardiomyopathy lead to an overwhelming inflammatory response for tissue repair, thereby creating a ‘vicious cycle’. BCR, B cell receptor; CD40L, CD40 ligand; MHC II, major histocompatibility complex class II; TCR, T cell receptor; TLR, Toll-like receptor.