Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

Abstract

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter defibrillator (ICD) implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as a) sudden cardiac death or b) ICD-treated or hemodynamically unstable VTA. The prognostic model was derived using Fine-Gray's regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (standard deviation) or medians [interquartile range]. Results: We included 444 patients 40.6 (14.1) years of age in the derivation sample and 145 patients 38.2 (15.0) years in the validation sample, of whom 86 (19.3%) and 34 (23.4%) suffered LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, non-missense LMNA mutation, 1st degree and higher atrioventricular block, non-sustained ventricular tachycardia, and left ventricular ejection fraction. In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842) and calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959) and calibration slope 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA compared with the guidelines-based approach. Conclusions: Compared to the current standard of care, this risk prediction model for LTVTA in laminopathies facilitated significantly the choice of ICD candidates. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03058185.

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

“…A study pinpointed that only one half of the patients carrying pathogenic or likely pathogenic LMNA mutations had a left ventricular fractional shortening <50%, suggesting that LMNA cardiomyopathy often manifests as a primary arrhythmia independent of muscle disease [37]. The high risk of sudden death owing to rhythm and/or electrical conduction disturbances requires specific criteria for cardioverter-defibrillator implantation in laminopathies [38].…”

Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy

“…These include NSVT during electrocardiogram monitoring, truncating mutations, LVEF <45-50%, and male sex [24,25]. More recently, 1st degree AV block has been identified as another risk factor in LMNA carriers [26]. Desmosomal gene mutations are present in around 3% of DCM patients.…”

“…LMNA mutations, the conventional LVEF-threshold based guidelines for ICD do not apply. In fact, an ICD may be considered for a patient with higher LVEF thresholds [26,42]. Regarding FLNC mutations, 20% of patients with a primary-prevention ICD who carry the mutation had an appropriate ICD shock, much higher than in unselected DCM populations [43].…”

The Added Value of Cardiac Magnetic Resonance in Muscular Dystrophies

“…Lamin A/C gene mutation (LMNA) is identified in up to 10% of familial DCM [73]. Male gender, LVEF ≤50% at first clinical contact and nonmissense LMNA mutations have been identified as independent predictors of life threatening ventricular tachy-arrhythmias [3,74]. These patients are at higher risk for SCD and this might be their initial clinical presentation.…”

“…Patients with MD may have subclinical involvement for years prior to symptom onset and even otherwise asymptomatic genetic carriers of muscular dystrophies may develop cardiac manifestations [2]. Many patients with cardiac involvement are at higher risk for advanced heart failure and/or sudden cardiac death [3,4]. It is important to identify early on markers of cardiac involvement to initiate cardio-protective therapies, to limit progression and to attenuate symptoms of heart failure [5,6].…”