Personalizing Risk Stratification for Sudden Death in Dilated Cardiomyopathy: The Past, Present, and Future

Abstract

Results from the DANISH Study (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality) suggest that for many patients with dilated cardiomyopathy (DCM), implantable cardioverter-defibrillators do not increase longevity. Accurate identification of patients who are more likely to die of an arrhythmia and less likely to die of other causes is required to ensure improvement in outcomes and wise use of resources. Until now, left ventricular ejection fraction has been used as a key criterion for selecting patients with DCM for an implantable cardioverter-defibrillator for primary prevention purposes. However, registry data suggest that many patients with DCM and an out-of-hospital cardiac arrest do not have a markedly reduced left ventricular ejection fraction. In addition, many patients with reduced left ventricular ejection fraction die of nonsudden causes of death. Methods to predict a higher or lower risk of sudden death include the detection of myocardial fibrosis (a substrate for ventricular arrhythmia), microvolt T-wave alternans (a marker of electrophysiological vulnerability), and genetic testing. Midwall fibrosis is identified by late gadolinium enhancement cardiovascular magnetic resonance imaging in ≈30% of patients and provides incremental value in addition to left ventricular ejection fraction for the prediction of sudden cardiac death events. Microvolt T-wave alternans represents another promising predictor, supported by large meta-analyses that have highlighted the negative predictive value of this test. However, neither of these strategies have been routinely adopted for risk stratification in clinical practice. More convincing data from randomized trials are required to inform the management of patients with these features. Understanding of the genetics of DCM and how specific mutations affect arrhythmic risk is also rapidly increasing. The finding of a mutation in lamin A/C, the cause of ≈6% of idiopathic DCM, commonly underpins more aggressive management because of the malignant nature of the associated phenotype. With the expansion of genetic sequencing, the identification of further high-risk mutations appears likely, leading to better-informed clinical decision making and providing insight into disease mechanisms. Over the next 5 to 10 years, we expect these techniques to be integrated into the existing algorithm to form a more sensitive, specific, and cost-effective approach to the selection of patients with DCM for implantable cardioverter-defibrillator implantation.

Keywords: cardiomyopathy, dilated; death, sudden, cardiac; defibrillators, implantable.

Figure 1

Flow chart of the potential techniques that may be used to improve risk stratification. This is accompanied by the main characteristic of the condition assessed by each technique and the interaction of these characteristics with either the risk of sudden cardiac death or non-sudden death. (ECG – electrocardiogram; LGE-CMR – late gadolinium enhanced cardiovascular magnetic resonance; MIBG – metaiodobenzylguanidine; MTWA – microvolt T wave alternans; NYHA – New York Heart Association; SCD – sudden cardiac death; SHFM – Seattle Heart Failure Model)

Figure 2

(A) Late gadolinium enhancement cardiovascular magnetic resonance image of a mid-ventricular short-axis slice in a healthy control; (B) Native T1 map of a mid-ventricular short-axis slice in a healthy control with a mean myocardial T1 of 1240ms; (C) Late gadolinium enhancement image of a mid-ventricular short axis slice in a patient with dilated cardiomyopathy demonstrating linear mid-wall enhancement; (D) Native T1 map of a mid-ventricular short-axis slice in a patient with dilated cardiomyopathy with a mean myocardial T1 of 1375ms; Scans performed on Siemens Skyra 3T (Erlangen, Germany); (E) Microscopic examination of a sample taken from the septum of an explanted heart post-transplant demonstrating the presence of replacement fibrosis (blue arrow) and peri-cellular interstitial fibrosis (yellow arrow). (DCM – dilated cardiomyopathy)

Figure 3

Figure demonstrating the acquired and genetic insults implicated in the aetiology of dilated cardiomyopathy followed by the common genetic mutations associated with DCM (incidence of mutations in cases of idiopathic DCM followed by the protein encoded by the gene) and data on disease outcomes. (Abs – antibodies; HIV – human immunodeficiency virus; phaeo – phaeochromocytoma)