Author + information
- Received June 7, 2016
- Revision received August 12, 2016
- Accepted August 23, 2016
- Published online November 29, 2016.
- Saurabh Kumar, BSc(Med)/MBBS, PhDa,
- Samuel H. Baldinger, MDb,
- Estelle Gandjbakhch, MD, PhDc,
- Philippe Maury, MDd,
- Jean-Marc Sellal, MDe,f,g,h,
- Alexander F.A. Androulakis, MDi,
- Xavier Waintraub, MDc,
- Philippe Charron, PhDc,j,k,
- Anne Rollin, MDd,
- Pascale Richard, PhDl,
- William G. Stevenson, MDa,
- Ciorsti J. Macintyre, MDa,
- Carolyn Y. Ho, MDa,
- Tina Thompson, RNm,
- Jitendra K. Vohra, MDn,
- Jonathan M. Kalman, MBBS, PhDn,
- Katja Zeppenfeld, MDi,
- Frederic Sacher, MDe,f,g,
- Usha B. Tedrow, MD, MSca and
- Neal K. Lakdawala, MDa,∗ ()
- aCardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- bDepartment of Cardiology, Inselspital, Bern University Hospital, Bern, Switzerland
- cHôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux De Paris (AP-HP), Department of Cardiology, Paris, France
- dToulouse University Hospital, Rangueil, Toulouse, France
- eHôpital Cardiologique du Haut-Lévêque (CHU), Bordeaux-Pessac, France
- fL’Institut de Rythmologie et Modélisation Cardiaque (LIRYC), Bordeaux, France
- gInstitut Hospitalo-Universitaire (IHU), Bordeaux, France
- hCentre Hospitalier Universitaire de Nancy, Nancy, France
- iDepartment of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands
- jCentre de Référence Maladies Cardiaques Héréditaires, Institute for Cardiometabolism and Nutrition (ICAN), Paris, France
- kUniversité de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt, France
- lCardiomyogenetics, Department of Biochemistry and INSERM U582, University Hospital Pitié-Salpêtrière, AP-HP, Paris, France
- mDepartment of Genetic Medicine, The Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia
- nDepartment of Cardiology, Division of Medicine, The Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia
- ↵∗Reprint requests and correspondence:
Dr. Neal K. Lakdawala, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Background Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural history studies of LMNA-associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain.
Objectives This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype.
Methods The incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined.
Results The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death.
Conclusions LMNA-related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.
- atrial fibrillation
- complete atrioventricular block
- heart failure
- ventricular tachycardia
Dominant mutations in LMNA, which encodes the nuclear envelope protein lamin A/C, cause a type of arrhythmogenic cardiomyopathy characterized by age-dependent penetrance that approaches 100% by the seventh decade (1), and it is the culprit for ∼5% of dilated cardiomyopathy cases (2). Clinical expression of pathogenic LMNA mutations is variable; however, progressive conduction abnormalities, atrial arrhythmias (AAs), and ventricular arrhythmias (VAs) are highly prevalent and may precede or supersede systolic dysfunction, with associated risks for stroke and sudden death (1,3–8). Detailed natural history studies of LMNA-associated arrhythmic and nonarrhythmic outcomes are limited (1,4,6,7,9). Moreover, there has been a limited examination of the interrelationship of arrhythmic and nonarrhythmic events in follow-up. In this multicenter retrospective study, we sought to examine the presentation, progression, and interrelationship of arrhythmic and nonarrhythmic events and long-term outcomes of patients with pathogenic LMNA mutations. Furthermore, we examined whether the mode of clinical presentation (with either isolated or combination of clinical features) as a marker of mutation expression and disease severity was associated with adverse outcomes.
A chart review was performed in all patients (probands and available relatives) with a pathogenic or likely pathogenic LMNA mutation followed by cardiovascular genetics clinics of 5 international referral centers (in Boston, Massachusetts; Bordeaux, Paris, and Toulouse, France; Melbourne, Australia; and Leiden, the Netherlands). Genetic diagnosis was made between 1998 and 2015. Persons with a previously published pathogenic LMNA mutation with cardiac involvement and persons with a newly identified LMNA mutation with clinical or family evidence of laminopathy with possible cardiac involvement were included (6). Of 132 patients screened (92 families), 10 patients (5 families) were excluded because of incomplete follow-up (n = 7) or when the LMNA variant was deemed benign (n = 1) or was considered to be a variant of unknown significance (n = 2).
Data were collected from the patient’s first-ever clinical contact with any cardiologist to the time of last clinical contact. Baseline clinical, echocardiographic, electrocardiographic, Holter, implanted device diagnostic, and genetic data were collected. Details of clinical events occurring at first clinical contact and in follow-up (including the timing of events) were collected. Events characterized were as follows: development of any form of atrioventricular block ([AVB] including first degree, Mobitz II, and complete AVB); AA lasting >30 s (including atrial fibrillation [AF], atrial flutter, and atrial tachycardia); sustained VA (10) (including sustained ventricular tachycardia [VT] lasting >30 s, ventricular fibrillation [VF], or cardiac arrest); heart failure (HF) or left ventricular systolic dysfunction (LVD); type of arrhythmia device implanted (pacemaker, implantable cardioverter-defibrillator [ICD], or cardiac resynchronization therapy [CRT]), thromboemboli ([TE] arterial and/or venous); end-stage HF; and overall mortality.
Cardiac arrest was defined as witnessed sudden cardiac death with or without documented VF or death within 1 h of acute symptoms or nocturnal deaths with no antecedent history of worsening symptoms (11). HF was defined according to published guidelines (12). LVD was defined as left ventricular ejection fraction (LVEF) <50%. End-stage HF was defined as treatment with continuous inotropic infusion, mechanical circulatory support, or cardiac transplantation. Where possible, both composite and individual subtypes of clinical events (e.g., any form of AVB) were reported. Mode of presentation was defined as a phenotype with isolated clinical features (e.g., AVB alone, AA alone) or a combination of clinical features (e.g., AVB and AA) at first clinical contact. A subset of subjects with LMNA mutations who were evaluated because of their family history had no clinical, electrocardiographic, or echocardiographic abnormalities at first contact, and thus these subjects were categorized as phenotype negative.
Deoxyribonucleic acid sequence analysis was performed through the participating institutions. LMNA mutation pathogenicity and type of mutation (missense vs. nonmissense) was confirmed by the investigators using publicly available resources in 120 of 122 patients (ClinVar and the UMD-LMNA mutations databases). Criteria for gene mutation pathogenicity were applied as described previously (6).
SPSS Version 23 (IBM Corp., Armonk, New York) was used for analysis, and Prism Version 6 (GraphPad Software Inc., La Jolla, California) was used for graphic presentation. Continuous variables were expressed as mean ± SD if normally distributed; median and interquartile range (IQR) of 25% to 75% were used if the data were skewed. Categorical variables were reported as counts (percentages) and were compared using the Fisher exact test, where applicable. Clinical events were described both as raw number of events and percentages (percentage of events/total number of patients × 100; reported as prevalence) and as cumulative event rates using the Kaplan-Meier method. Follow-up started at first-ever clinical contact and ended at the last available physician visit.
Cox regression analysis was used to identify whether independent clinical factors at presentation (including mode of presentation) predicted sustained VA and a composite endpoint of end-stage HF and overall mortality in follow-up. Variables reaching p < 0.20 at univariable analysis were included in the multivariable model. Where relevant, 2-sided p values <0.05 were considered statistically significant.
The study cohort comprised 122 patients with LMNA mutations from 87 families (range 1 to 10 subjects per family) with 87 probands and 35 relatives. At first evaluation, 18 relatives were phenotype negative and 17 were phenotype positive. Baseline characteristics are shown in Table 1, and a list of mutations is presented in Online Table 1. Median follow-up from first clinical contact until last follow-up was 7 years (IQR: 3 to 12 years). Data for the occurrence of arrhythmic and nonarrhythmic events were present in all patients except for AVB, which were unavailable in 5 patients.
At first clinical contact, 104 patients were phenotypically affected (including electrocardiographic manifestations such as first-degree AVB). Of these patients, 42% presented with an isolated clinical finding and 58% with a combination of clinical findings. Isolated clinical findings included AA (11.5%), AVB (13.5%), HF or LVD (10.6%), neuromuscular manifestation (4.8%), or VA alone (1.9%). Patients with a combination of clinical findings could be broadly grouped into the following categories: those with AVB in addition to 1 or more of AA, VA, HF or LVD, or neuromuscular symptoms (38.5%); or HF in addition to 1 or more of AA, VA, or neuromuscular symptoms (17.3%); or AA in addition to neuromuscular manifestations (1.9%).
Figure 1 shows the age at which arrhythmic and nonarrhythmic clinical events occurred during follow-up. Notably, the median age of patients with clinical events exhibited a stepwise increment from AVB, AA, and TE events (44 to 46 years) to HF or LVD and sustained VA (48 to 50 years) to end-stage HF and death (56 years). The Central Illustration and Figure 2 summarize the prevalence of arrhythmic and nonarrhythmic events at presentation and at last follow-up. Any clinical event (arrhythmic or nonarrhythmic) was experienced by 82 ± 4% by median follow-up of 7 years. The Central Illustration (panel B) summarizes the rate of new clinical events (incident) after excluding patients who had experienced these events at presentation. Notably, among patients with any clinical manifestations on presentation, only 17% remained free of VA, HF or LVD, or death.
Arrhythmias, conduction disorders, and thromboembolic events
The prevalence of any and all forms of AVB increased from first clinical contact to last follow-up (Central Illustration, Figure 2). The cumulative event estimate for AVB was 57 ± 5% at 7 years. New complete AVB occurred in 16 ± 5% of patients at 7 years. Demographic features and subsequent clinical events experienced by patients who had AVB on presentation are summarized Table 2 and are notable for a substantial incidence of subsequent AA, VA, and end-stage HF or death events in follow-up. In patients with AVB (excluding patients with second- or third-degree AVB), mean PR interval on presentation increased from 261 ± 50 ms at first clinical contact to 309 ± 55 ms at last follow-up (p = 0.03).
The prevalence of any and all subtypes of AA increased from first clinical contact to last follow-up (Figure 2, Online Figure 1). The cumulative event estimate for AA was 63 ± 5% at 7 years. Among patients without AA at first evaluation, new AF, atrial flutter, and atrial tachycardia occurred in 33 ± 7%, 14 ± 5%, and 14 ± 5% of patients, respectively.
Of patients with AF on presentation, progression of AF (e.g., paroxysmal to persistent or persistent to permanent) occurred in 45% of patients. In patients with AF that developed during follow-up, AF coexisted with HF or LVD in 57% of patients, occurred before HF or LVD in 24% of patients, and occurred without future HF or LVD in 19% of patients.
Demographic features and subsequent clinical events experienced by patients who had AA on presentation are summarized in Table 2 and are notable for the high incidence of subsequent AVB, VA, HF or LVD, and end-stage HF or death in follow-up.
There was an increase in TE events from baseline to follow-up (Central Illustration, Figure 2), and these events included 10 strokes. Two of the 10 patients with strokes had no documented AAs at any point in follow-up. At last follow-up, 56% of patients were receiving oral anticoagulant therapy.
The prevalence of any and all forms of sustained VA increased from presentation to last follow-up (Figure 2, Online Figure 2). The cumulative event estimate for VA was 34 ± 5% at 7 years. New sustained VT occurred in 19 ± 5% of patients, and VF occurred in 8 ± 3% of patients at median follow-up. Median time from first clinical contact to sustained VA was 4 years (IQR: 0 to 9 years).
At the time of sustained VA, some form of AVB was present in 75% of patients (complete AVB in 34%). At least 1 episode of AA was experienced by 60% of patients with VA. Mean LVEF at time of sustained VA was 42 ± 15% (range 19% to 66%). Among patients with VAs, 27% of patients had preserved systolic function (LVEF >50%), and 56% had an LVEF >35%.
Of the 52 patients experiencing sustained VA, 25 patients were managed with catheter ablation, and 27 patients were managed with antiarrhythmic drugs or beta-blockers. Twenty-two patients (18%) experienced arrhythmic storm (VT, n = 21; VF, n = 1) that was managed with catheter ablation (n = 17), antiarrhythmic drugs (n = 4), or urgent cardiac transplantation after multiple ablations failed (n = 1).
Implanted arrhythmia devices
The presence of an arrhythmia device increased from 41% of patients at presentation to 73% in follow-up (Figure 3). The most notable increase was in the proportion of ICDs and CRTs, paralleling the increasing incidence of new HF or LVD and complete AVB events (Figure 3). Notably, 59 of 122 patients (48%) received a new implant (n = 39) or required a device upgrade (n = 20). In follow-up, an ICD was placed for primary prevention of sudden cardiac death in 46 patients and for sustained VA in 8 patients. Three patients received a new pacemaker for sinus node dysfunction or AVB with preserved ventricular function, and 2 patients received a device upgrade from a secondary preventive ICD to a CRT-defibrillator for new HF or LVD.
There were no sudden deaths in the 20 patients with a pacemaker. Sudden death occurred in 3 patients who had CRT-defibrillators but developed refractory VAs and in 1 patient whose sudden death was the initial disease presentation. There were 58 patients with primary preventive ICDs (12 implanted shortly after presentation and 46 during follow-up); 29 (50%) of these patients experienced an appropriate ICD intervention for sustained VAs.
Data on device complications and inappropriate shocks were available in 24 patients. No patients received inappropriate shocks for AA or experienced device infection. Two patients received inappropriate shocks caused by lead malfunction.
HF, LVD, and mortality
HF or LVD increased from presentation to last follow-up (Figure 2A). The cumulative event estimate was 57 ± 5% at 7 years. At last follow-up, 27 patients (22%) had end-stage HF; the cumulative event estimate was 19 ± 4% at 7 years. Of these, 10 patients underwent cardiac transplantation, and 8 underwent ventricular assist device implantation; additionally, 6 patients were awaiting cardiac transplants without ventricular devices, and 3 patients were receiving long-term inotrope infusions because they were declined for other advanced HF therapies.
In patients who had preserved LV function (LVEF >50%) and no HF at presentation, new HF or LVD events occurred in 24 ± 6%, and end-stage HF occurred in 7 ± 4% of patients at 7 years (Central Illustration, panel B).
Demographic features and subsequent clinical events experienced by patients who had HF on presentation are summarized Table 2; there is a notably high incidence of subsequent AVB, AA, VA, and end-stage HF or death.
During follow-up, 22 patients died (18%), predominantly of HF (n = 8) or of complications related to cardiac transplantation or ventricular assist devices (n = 9), sudden death (n = 4), and stroke (n = 1) (Online Table 2). The cumulative estimate for mortality was 13 ± 4% at 7 years.
Predictors of adverse events
Male sex (hazard ratio [HR]: 3.2; 95% confidence interval [CI]: 1.3 to 8.0; p = 0.01), LVEF ≤50% at first clinical contact (HR: 3.4; 95% CI: 1.5 to 8.1; p = 0.004), and nonmissense mutations (HR: 2.5; 95% CI: 1.1 to 6.0; p = 0.03) were independently associated with new sustained VA in follow-up (Online Table 3). Among patients with none, 1, 2, or 3 of these features at first clinical contact, event rates for VA at median follow-up were 9 ± 6%, 28 ± 8%, 47 ± 9%, and 69 ± 16%, respectively. LVEF ≤50% at first clinical contact was the only factor independently associated with a composite endpoint of new end-stage HF or death during follow-up (HR: 4.8; 95% CI: 1.9 to 12.1; p = 0.001) (Online Table 4). In addition to LVEF ≤50% at first clinical contact (HR: 3.1; 95% CI: 1.1 to 8.5), nonmissense mutation (HR: 3.7; 95% CI: 1.4 to 10.1; p = 0.009) and male sex (HR: 2.7; 95% CI: 0.9 to 7.8; p = 0.07) were factors independently associated with death in follow-up (Online Table 5). Mode of presentation (with isolated clinical finding versus a combination of findings) did not independently predict new sustained VA or the composite endpoint of end-stage HF or death or death alone (Online Tables 3 to 5). Patients with rapid disease progression from first clinical contact to end-stage HF or death within 5 years (n = 20) could not be differentiated from patients with long interval to end-stage HF or death (n = 11) on the basis of clinical or genetic factors.
Characteristics and outcomes of relatives versus probands
Phenotypic expression was absent (phenotype negative) in 18 of the 35 mutation-positive relatives at initial evaluation (Online Table 6). Phenotype-negative relatives were younger (age 31 ± 16 years) compared with phenotype-positive relatives (age 44 ± 12 years; p = 0.009) and probands (age 43 ± 14 years; p = 0.002), with a shorter duration of follow-up (median 1.5 years). However, 3 (17%) initially phenotype-negative relatives experienced phenotypic expression during follow-up (AA at 5 years, first degree AVB at 8 years, and complete AVB at 17 years). Event rates in phenotype-positive relatives (new complete AVB, 21%; new AA, 24%; new VA, 24%; and end-stage HF or death, 24%) were comparable to those observed in probands (new complete AVB, 27%; new AA, 28%; new VA, 32%; and end-stage HF or death, 31%) (Online Table 6).
Mutations in LMNA are relatively rare but important causes of arrhythmogenic cardiomyopathy (Central Illustration). This multicenter study adds to the existing literature highlighting the adverse outcomes associated with this disease and emphasizes the value of a gene-based diagnosis. Here we have catalogued the spectrum of arrhythmic and nonarrhythmic disease manifestations among 122 LMNA mutation carriers with detail and a robust duration of follow-up (median 7 years). Furthermore, our dataset was comprehensive, with complete data on event rates present for all patients except for AVB (94% complete). Previous studies provided critical insights into natural history but included limited numbers of affected persons (4,5,7), had a shorter or comparable duration of follow-up (1,13), lacked a detailed assessment of specific nonarrhythmic or arrhythmic events (e.g., limited to VA), or focused principally on identifying risk factors of malignant VAs (1,4–6).
We confirm the proclivity of LMNA mutation carriers to malignant VAs (1,4,9,14). The cumulative event estimate for VA was 34% at 7 years. In patients who did not present with VA, 22% experienced new sustained VAs by 7-year follow-up. Moreover, 50% of patients with an ICD implanted for the primary prevention of sudden cardiac death experienced an appropriate ICD intervention by last follow-up. These event rates (∼3% to 7%/year) are higher than or comparable to appropriate ICD interventions experienced by high-risk patients without a previous history of VA who received a prophylactic ICD for the following indications: nonischemic dilated cardiomyopathy with severe systolicdysunction (LVEF ∼25%) and symptomatic HF (∼2% per year) (15); arrhythmogenic right ventricular cardiomyopathy (∼5% per year) (16); hypertrophic cardiomyopathy ∼2% per year (17); and high-risk patients with ischemic cardiomyopathy (∼7% to 8% per year) (18).
Moreover, as previously recognized (3,19), up to one-third of LMNA mutation carriers who manifested sustained VA had preserved ventricular function (LVEF >50%), and 56% did not meet conventional criteria for ICD implantation because they had LVEF >35% at the time of first sustained VA. This finding emphasizes the limitations of traditional risk stratification on the basis of systolic function and HF among patients with LMNA mutations and the value of a gene-based diagnosis in clinical management. Notably, malignant VA and sudden death events in the absence of an ICD occurred in 7% of patients (1 sudden death, 8 sustained VA episodes in pacemaker recipients), which was a lower rate than that reported in previous studies of 31% to 46% of patients (9,20). It is plausible that fewer sudden deaths reflected increasing tendencies to implant an ICD rather than a permanent pacemaker in LMNA-related heart disease because physicians recognize the VA risk; that 59% of patients underwent implantation of a new ICD or had an ICD upgrade from a pacemaker supports this point (21,22). The common coexistence of AV conduction disease with AAs in LMNA-related heart disease may reduce the risk of inappropriate shocks (23). Indeed, no patient reported here experienced inappropriate shocks for AA, in marked contrast to patients with other inherited cardiomyopathies and arrhythmia syndromes in which inappropriate shocks outnumber appropriate shocks (21). As previously reported, male sex and nonmissense mutations were associated with sustained VA (6). Nevertheless, the high VA event rate, the occurrence of VA with preserved ventricular function, the lack of robust predictive factors to identify a truly low-risk cohort, and the low rate of inappropriate shocks suggested that decisions regarding ICD use could be a matter of timing of implantation, rather than patient selection.
Another important finding of this study was the inexorable progression to end-stage HF (57% at 7 years). Indeed, among patients without LVD or HF at presentation, 24% developed new HF or LVD, and 7% reached end-stage HF at a median of 7 years of follow-up. Critically, the mode of clinical presentation (whether isolated or a combination of clinical manifestations) did not predict subsequent VA, end-stage HF, or death. Indeed, only 21% of patients with any clinical manifestations at the index evaluation were at low risk of VA, HF or LVD, or death.
The final important message from this study was the ubiquitous presence of AAs in LMNA-related heart disease (63% at 7 years), the high rate of AF progression from paroxysmal to persistent or permanent forms (45%), and the accompanying high incidence of TE events (10% at 7 years). AA likely contributes to an underrecognized burden of disease morbidity in LMNA-related heart disease. Further work is needed to elucidate the mechanism of LMNA-related atriopathy.
These findings have important implications. We believe that early recognition of lamin-related heart disease with a high index of clinical suspicion and early use of genetic testing is critical. Our findings also highlight the need to maintain heightened vigilance for disease progression with early consideration of adjunctive therapies such as CRT and support the need for trials of novel drugs, such as mitogen-activated protein kinase inhibitors to slow disease progression (24). Furthermore, at-risk relatives require careful longitudinal follow-up for detection and management of phenotypic expression.
The sample size was modest because of the seeming rarity of the disease, which likely reflects the incomplete use of genetic testing in contemporary practice beyond select referral centers. Similarly, there is the potential for referral bias toward more severely affected patients, given that patients were drawn from academic centers with expertise in complex arrhythmia management.
LMNA heart disease has a malignant course; most patients experience AAs and VAs, heart block, embolic events, or HF within 7 years of diagnosis. Although the disease is rare, the malignant course warrants a high index of suspicion in patients with familial cardiomyopathy and cardiomyopathies characterized by prominent arrhythmias and conduction disease to enable careful surveillance and prevention of complications.
COMPETENCY IN MEDICAL KNOWLEDGE: During long-term follow-up, patients with LMNA mutations exhibit high rates of atrioventricular conduction block, AAs, sustained VAs, ventricular dysfunction, and HF and frequently require upgrade of implanted cardiac electrical devices to provide defibrillation or resynchronization functionality.
TRANSLATIONAL OUTLOOK: Larger studies are needed to identify lower- or higher-risk subsets of patients with LMNA mutations and assess the therapeutic impact of drugs such as mitogen-activated protein kinase inhibitors on disease progression and related clinical outcomes.
For supplemental figures and tables, please see the online version of this article.
Dr. Kumar is a recipient of the Neil Hamilton Fairley Overseas Research scholarship co-funded by the National Health and Medical Research Council and the National Heart Foundation of Australia; and the Bushell Travelling Fellowship funded by the Royal Australasian College of Physicians. Dr. Lakdawala has received support from the O’Hare Family Foundation directed toward research on cardiolaminopathy. Dr. Gandjbakhch has received consultant fees from Sorin, Medtronic, Boston Scientific, and Bayer. Dr. Stevenson has intellectual property and a patent for needle ablation consigned to Brigham and Women’s Hospital. Dr. Sacher has received speaker honoraria from St. Jude Medical. Dr. Tedrow is on the faculty of St. Jude Medical and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial arrhythmia
- atrial fibrillation
- atrioventricular block
- cardiac resynchronization therapy
- implantable cardioverter-defibrillator
- gene-encoding lamin A/C
- left ventricular systolic dysfunction
- ventricular arrhythmia
- ventricular fibrillation
- ventricular tachycardia
- Received June 7, 2016.
- Revision received August 12, 2016.
- Accepted August 23, 2016.
- American College of Cardiology Foundation
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