Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers

Kumar, Saurabh; Baldinger, Samuel H.; Gandjbakhch, Estelle; Maury, Philippe; Sellal, Jean‐Marc; Androulakis, Afa; Waintraub, Xavier; Charron, Philippe; Rollin, Anne; Richard, P.; Stevenson, William G.; MacIntyre, Ciorsti; Ho, Carolyn Y.; Thompson, T.; Vohra, Jitendra K.; Kalman, Jonathan M.; Zeppenfeld, Katja; Sacher, Frédéric; Tedrow, Usha B.; Lakdawala, Neal K.

doi:10.1016/j.jacc.2016.08.058

Cited by 236 publications

(229 citation statements)

References 24 publications

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“…The most common clinical manifestations are dizziness, syncope, palpitations, or even ischemic stroke due to cardioembolism (in the case of atrial fibrillation or atrial standstill) but also ventricular tachyarrhythmias and sudden death and/or worsening heart failure may occur, the latter usually at a later stage in the course of the disease [4,21–24]. We will describe the clinical characteristics of these symptoms, focusing on the need for a disease-oriented decision-making.…”

Section: Cardiac Manifestations Of Laminopathies and Clinical Decisiomentioning

confidence: 99%

“…Bradyarrhythmias and supraventricular tachyarrhythmias are common features in laminopathies and often anticipate by decades the development of heart failure due to dilated cardiomyopathy [4,24]. Supraventricular arrhythmias include atrial flutter, atrial fibrillation, and atrial tachycardia, and may be associated with sinus node dysfunction (i.e.…”

Section: Bradyarrhythmias Atrial Fibrillation and Atrial Fluttermentioning

confidence: 99%

“…In the series of cases recently reported by Kumar et al [24] during a median follow up of 7 years, 24% of patients without left ventricular dysfunction at baseline developed new left ventricular dysfunction and 7% developed end-stage heart failure. Left ventricular dysfunction (ejection fraction <50%) was associated with end-stage heart failure or death, but the mode of presentation (with isolated or combination of clinical features) did not predict end-stage heart failure or death.…”

Section: Dilated Cardiomyopathymentioning

confidence: 99%

“…A detailed review of all the literature published on the risk of ventricular tachyarrhythmias, and on device activations in carriers of an implantable cardioverter defibrillators (ICDs) are shown in Table 2, in relationship to the series of patients with laminopathies reported in Table 1 [4,6,23,24,27,43,44,47,51–62]. In the largest observational study, reported by Kumar et al [24], the cumulative occurrence of sustained ventricular tachyarrhythmias was 34% at 7 years, and among patients with no history of ventricular tachyarrhythmias the incidence was 22% during a 7-year follow-up.…”

Section: Ventricular Tachyarrhythmias and Sudden Cardiac Deathmentioning

confidence: 99%

“…In the largest observational study, reported by Kumar et al [24], the cumulative occurrence of sustained ventricular tachyarrhythmias was 34% at 7 years, and among patients with no history of ventricular tachyarrhythmias the incidence was 22% during a 7-year follow-up. In the same series, appropriate ICD activations occurred in 50% of patients with an ICD implanted for primary prevention of sudden cardiac death, with a rate of appropriate interventions (3% to 7%/year) comparable to appropriate ICD interventions occurring in high-risk patients with idiopathic or post-infarction dilated cardiomyopathy.…”

Section: Ventricular Tachyarrhythmias and Sudden Cardiac Deathmentioning

confidence: 99%

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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: Cardiac Manifestations Of Laminopathies and Clinical Decisiomentioning

confidence: 99%

Section: Bradyarrhythmias Atrial Fibrillation and Atrial Fluttermentioning

confidence: 99%

Section: Dilated Cardiomyopathymentioning

confidence: 99%

Section: Ventricular Tachyarrhythmias and Sudden Cardiac Deathmentioning

confidence: 99%

Section: Ventricular Tachyarrhythmias and Sudden Cardiac Deathmentioning

confidence: 99%

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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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Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure

et al. 2021

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IMPORTANCETruncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.OBJECTIVE To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). DESIGN, SETTING, AND PARTICIPANTSThis cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. MAIN OUTCOMES AND MEASURESThe primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. RESULTSIn total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (Ն500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF Յ35%) LVSD (HR, 1.29 [95% CI,]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI,]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). CONCLUSIONS AND RELEVANCEThe high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

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Genotype–phenotype correlation of LMNA variants involving the Arg541 residue: a case report with multimodality imaging and literature review

et al. 2020

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We present a case of atypical LMNA cardiomyopathy associated with the pathogenic variant p.Arg541Ser. The patient had early-onset severe ventricular arrhythmias but atrioventricular conduction was normal. Segmental motion abnormalities and a large transmural scar, mainly apical and lateral, were found at cardiac magnetic resonance, corresponding to areas of severe wall thinning at computed tomography and of low voltages at electroanatomic mapping. Ventricular tachycardia ablation was successful in controlling ventricular arrhythmias. Few other cases described patients with pathogenic variants in the Arg541 residue, and they displayed similar atypical features, suggesting a genotype-phenotype correlation which may have specific prognostic and therapeutic implications.

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Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers

Cited by 236 publications

References 24 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

Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure

Genotype–phenotype correlation of LMNA variants involving the Arg541 residue: a case report with multimodality imaging and literature review

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