Risk Factors for Malignant Ventricular Arrhythmias in Lamin A/C Mutation Carriers

Rijsingen, I. A. W. Van; Arbustini, Eloisa; Elliott, Perry; Mogensen, Jens; Ast, J.F. Hermans-van; Kooi, Anneke J. van der; Tintelen, J. Peter van; Berg, Maarten P. van den; Pilotto, Andrea; Pasotti, Michele; Jenkins, Sharon; Rowland, Camilla; Aslam, Uzma; Wilde, Arthur A.M.; Perrot, Andreas; Pankuweit, Sabine; Zwinderman, Aeilko H.; Charron, Philippe; Pinto, Yigal M.

doi:10.1016/j.jacc.2011.08.078

Cited by 471 publications

(373 citation statements)

References 27 publications

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“…In this series of patients, who were implanted with a defibrillator in 59% of cases, male sex, non-missense mutations, and left ventricular dysfunction were associated with development of sustained ventricular tachyarrhythmias, while no relationship was found with the mode of presentation (with isolated or combination of clinical features) [24]. These findings are in line with a previous multicentre study, where a series of risk factors emerged as predictors of the occurrence of ventricular tachyarrhythmias (male gender, non- sustained ventricular tachycardia, left ventricular ejection fraction <45% and non-missense mutation), thus providing an important clinical guide for the decision to implant an ICD [53] (Table 2) [4,6,23,24,27,43,44,47,51–62]…”

Section: Ventricular Tachyarrhythmias and Sudden Cardiac Deathsupporting

confidence: 81%

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Boriani

Biagini

Ziacchi

et al. 2018

Nucleus

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Lamin A/C gene mutations can be associated with cardiac diseases, usually referred to as ‘cardiolaminopathies’ characterized by arrhythmic disorders and/or left ventricular or biventricular dysfunction up to an overt picture of heart failure. The phenotypic cardiac manifestations of laminopathies are frequently mixed in complex clinical patterns and specifically may include bradyarrhythmias (sinus node disease or atrioventricular blocks), atrial arrhythmias (atrial fibrillation, atrial flutter, atrial standstill), ventricular tachyarrhythmias and heart failure of variable degrees of severity. Family history, physical examination, laboratory findings (specifically serum creatine phosphokinase values) and ECG findings are often important ‘red flags’ in diagnosing a ‘cardiolaminopathy’. Sudden arrhythmic death, thromboembolic events or stroke and severe heart failure requiring heart transplantation are the most dramatic complications of the evolution of cardiolaminopathies and appropriate risk stratification is clinically needed combined with clinical follow-up. Treatment with cardiac electrical implantable devices is indicated in case of bradyarrhythmias (implant of a device with pacemaker functions), risk of life-threatening ventricular tachyarrhythmias (implant of an ICD) or in case of heart failure with wide QRS interval (implant of a device for cardiac resynchronization). New technologies introduced in the last 5 years can help physicians to reduce device-related complications, thanks to the extension of device longevity and availability of leadless pacemakers or defibrillators, to be implanted in appropriately selected patients. An improved knowledge of the complex pathophysiological pathways involved in cardiolaminopathies and in the determinants of their progression to more severe forms will help to improve clinical management and to better target pharmacological and non-pharmacological treatments.

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Section: Ventricular Tachyarrhythmias and Sudden Cardiac Deathsupporting

confidence: 81%

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Boriani

Biagini

Ziacchi

et al. 2018

Nucleus

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“…AR‐DCM phenotype was diagnosed by the presence of 1 of the following: (1) unexplained syncope (likely due to ventricular tachyarrhythmia),2, 14, 15, 16 (2) rapid nonsustained ventricular tachycardia (NSVT) defined as ≥5 consecutive ventricular beats,17 lasting <30 seconds, with a rate ≥150/min on 24‐hour Holter monitoring,18 (3) ≥1000 premature ventricular contractions (PVCs) in 24 hours1 or (4) ≥50 couplets in 24 hours 19. ICD implantation had been performed for primary prevention in selected patients with DCM considered at high risk for SCD (ie, persistent LV dysfunction with LVEF ≤35% and New York Heart Association class II or III while being treated with optimal medical therapy).…”

Section: Methodsmentioning

confidence: 99%

“…Specifically, SCD was defined as witnessed sudden cardiac death with or without documented ventricular fibrillation (VF) or death within 1 hour of acute symptoms or nocturnal death with no antecedent history of immediate worsening symptoms. Ventricular arrhythmias were defined as sustained (≥30 seconds, hemodynamically symptomatic) ventricular tachycardia (SVT), VF, appropriate SVT or VF treatment with implantable cardioverter‐defibrillator (ICD) (shock or antitachycardia pacing for termination of SVT ≥185 bpm), cardiopulmonary resuscitation after cardiac arrest, or SCD 14. The secondary end point was death due to heart failure (excluding SCD) or heart transplantation.…”

Section: Methodsmentioning

confidence: 99%

Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life‐Threatening Arrhythmias

Spezzacatene

Sinagra

Merlo

et al. 2015

JAHA

109

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BackgroundPatients with dilated cardiomyopathy (DCM) may present with ventricular arrhythmias early in the disease course, unrelated to the severity of left ventricular dysfunction. These patients may be classified as having an arrhythmogenic DCM (AR‐DCM). We investigated the phenotype and natural history of patients with AR‐DCM.Methods and ResultsTwo hundred eighty‐five patients with a recent diagnosis of DCM (median duration of the disease 1 month, range 0 to 7 months) and who had Holter monitoring at baseline were comprehensively evaluated and followed for 107 months (range 29 to 170 months). AR‐DCM was defined by the presence of ≥1 of the following: unexplained syncope, rapid nonsustained ventricular tachycardia (≥5 beats, ≥150 bpm), ≥1000 premature ventricular contractions/24 hours, and ≥50 ventricular couplets/24 hours, in the absence of overt heart failure. The primary end points were sudden cardiac death (SCD), sustained ventricular tachycardia (SVT), or ventricular fibrillation (VF). The secondary end points were death from congestive heart failure or heart transplantation. Of the 285 patients, 109 (38.2%) met criteria for AR‐DCM phenotype. AR‐DCM subjects had a higher incidence of SCD/SVT/VF compared with non–AR‐DCM patients (30.3% vs 17.6%, P=0.022), with no difference in the secondary end points. A family history of SCD/SVT/VF and the AR‐DCM phenotype were statistically significant and cumulative predictors of SCD/SVT/VF.ConclusionsOne‐third of DCM patients may have an arrhythmogenic phenotype associated with increased risk of arrhythmias during follow‐up. A family history of ventricular arrhythmias in DCM predicts a poor prognosis and increased risk of SCD.

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“…If such a mutation is discovered in a patient, the threshold for recommending an implantable cardiac defibrillator to a patient should be decreased. LMNA mutation carriers have an increased occurrence of malignant (potentially life‐threatening) ventricular arrhythmias and sudden cardiac death 32. Other examples are TNNT2 33 and DES 34 mutation carriers, who also present with a high arrhythmia risk.…”

Section: Clinical Consequences Of Genetic Findings In Heart Failure Pmentioning

confidence: 99%

Genetic determinants of heart failure: facts and numbers

2018

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The relevance of gene mutations leading to heart diseases and hence heart failure has become evident. The risk for and the course of heart failure depends on genomic variants and mutations underlying the so‐called genetic predisposition. Genetic contribution to heart failure is highly heterogenous and complex. For any patient with a likely inherited heart failure syndrome, genetic counselling is recommended and important. In the last few years, novel sequencing technologies (named next‐generation sequencing – NGS) have dramatically improved the availability of molecular testing, the efficiency of genetic analyses, and moreover reduced the cost for genetic testing. Due to this development, genetic testing has become increasingly accessible and NGS‐based sequencing is now applied in clinical routine diagnostics. One of the most common reasons of heart failure are cardiomyopathies such as the dilated or the hypertrophic cardiomyopathy. Nearly 100 disease‐associated genes have been identified for cardiomyopathies. The knowledge of a pathogenic mutation can be used for genetic counselling, risk and prognosis determination, therapy guidance and hence for a more effective treatment. Besides, family cascade screening for a known familial, pathogenic mutation can lead to an early diagnosis in affected individuals. At that timepoint, a preventative intervention could be used to avoid or delay disease onset or delay disease progression. Understanding the cellular basis of genetic heart failure syndromes in more detail may provide new insights into the molecular biology of physiological and impaired cardiac (cell) function. As our understanding of the molecular and genetic pathophysiology of heart failure will increase, this might help to identify novel therapeutic targets and may lead to the development of new and specific treatment options in patients with heart failure.

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Risk Factors for Malignant Ventricular Arrhythmias in Lamin A/C Mutation Carriers

Abstract: Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD.

Cited by 471 publications

References 27 publications

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life‐Threatening Arrhythmias

Genetic determinants of heart failure: facts and numbers

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