Predictores de riesgo en una cohorte española con cardiolaminopatías. Registro REDLAMINA

Introduction and objectivesAccording to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) < 45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria.MethodsThe relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure.ResultsWe identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF < 45% (P = .001) and NSVT (P < .001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF < 45% (P < .001).ConclusionsIn the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF < 45%. Therefore, female carriers of missense variants with either NSVT or LVEF < 45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosisFull English text available from:www.revespcardiol.org/en     

Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy

The familial form of dilated cardiomyopathy (DCM) occurs in about 20%–50% of DCM cases. It is a heterogenous genetic disease: mutations in more than 20 different genes have been shown to cause familial DCM. LMNA, encoding the nuclear membrane protein lamin A/C, is one of the most inportant disease gene for that disease. Therefore, we analyzed the LMNA gene in a large cohort of 73 patients with familial DCM. Clinical examination (ECG, echocardiography, and catheterization) was followed by genetic characterization of LMNA by direct sequencing. We detected five heterozygous missense mutations (prevalence 7%) in five different families characterized by severe DCM and heart failure with conduction system disease necessitating pacemaker implantation and heart transplantation. Four of these variants clustered in the protein domain coil 1B, which is important for lamin B interaction and lamin A/C dimerization. Although we identified two novel mutations (E203V, K219T) besides three known ones (E161K, R190Q, R644C), it was remarkable that four mutations represent LMNA hot spots. DCM patients with LMNA mutations show a notable homogenous severe phenotype as we could confirm in our study. Testing LMNA in such families seems to be recommended because genotype information in an individual could definitely be useful for the clinician. Returned for 1. Revision: 18 February 2008 1. Revision received: 12 August 2008 Returned for 2. Revision: 20 August 2008 2. Revision received: 21 August 2008     

Mutations in the cardiac troponin T gene show various prognoses in Japanese patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder resulting from mutations in genes for at least 15 various sarcomere-related proteins including cardiac β-myosin heavy chain, cardiac myosin-binding protein C, and cardiac troponin T. The troponin T gene (TNNT2) mutation has the third incidence of familial HCM, and the genotype–phenotype correlation of this gene still remains insufficient in Japanese familial HCM. Therefore, in the present study, we focused on screening the TNNT2 mutation in 173 unrelated Japanese patients with familial HCM, and found three reported mutations and a new mutation of TNNT2 in 11 individuals from four families. In these families, two individuals from one family had double mutations, Arg130Cys and Phe110Ile, six individuals from two other families had an Arg92Trp mutation, and one individual of another family had a new mutation, Ile79Thr, of TNNT2. The phenotype of each family was often different from reported cases, even if they had the same genetic mutation. In addition, families with the same genetic mutation showed a similar trend in the phenotype, but it was not exactly the same. However, sudden death in youth was observed in all of these families. Although the type of genetic mutation is not useful for predicting prognosis in HCM, the possibility of sudden cardiac death remains. Therefore, the prognosis of individuals bearing the TNNT2 mutation with familial HCM should be more carefully observed from birth.     

Genetic testing for dilated cardiomyopathy in clinical practice

BackgroundFamilial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations.Methods and ResultsWe studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, and LDB3), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7, LMNA, or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing.ConclusionsUsing rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.     

Genetic variants identified by target next-generation sequencing in heart transplant patients with dilated cardiomyopathy

Introduction and ObjectivesDilated cardiomyopathy (DCM) is a myocardial disease that can progress to a terminal stage, requiring heart transplantation. In this work we aim to contribute to knowledge of genetic variants in adult patients undergoing heart transplantation due to end-stage DCM, reporting the results obtained in our single-center tertiary hospital series using target next-generation sequencing (NGS).Methods and ResultsGenetic variants were screened in 15 genes, preselected based on variants previously identified in DCM patients. Thirteen unrelated patients were included, nine (69%) male, mean age at diagnosis 33±13 years, eight (62%) with familial DCM. Nine genetic variants were identified in six (46%) patients: five in LMNA, two in LBD3, one in TNNT2 and one in TCAP. These variants were new in most patients. The majority were classified as of uncertain significance. Two patients were double and triple heterozygotes in the LBD3 and LMNA genes, respectively.ConclusionOur results highlight the potential of NGS in the genetic characterization of DCM patients. LMNA is one of the most frequently mutated genes and should be included in all target gene assessments of end-stage DCM patients until more data are available.     

A novel lamin A/C mutation in a family with dilated cardiomyopathy,prominent conduction system disease,and need for permanent pacemaker implantation

Background The LMNA gene, which encodes the nuclear envelope protein lamin A/C, is thought to be the most common of 8 autosomal disease genes implicated in familial dilated cardiomyopathy (FDC). Each family reported to date has a unique mutation and variable degrees of cardiac conduction system, dilated cardiomyopathy, or skeletal muscle disease. Methods and Results Coding regions of the LMNA gene were screened in 12 biological members of a family with dilated cardiomyopathy and conduction system disease. A novel missense mutation (Leu215Pro) in exon 4 was identified in 8 subjects. Disease was manifested as brady- and tachyarrhythmias, often necessitating permanent pacemaker implantation, and later onset of dilated cardiomyopathy and heart failure. No features of skeletal muscle disease were noted. The high percentage of affected individuals who needed pacemaker therapy (88%) was a unique characteristic of this family compared with other FDC families with LMNA mutations. Conclusions Careful examination of clinical data in families with FDC and LMNA mutations may reveal subtle genotype-phenotype correlations. Knowledge of such correlations may help to further define the mechanisms of disease in LMNA-associated FDC and can assist in the monitoring of disease for at-risk family members. (Am Heart J 2002;144:1081-6.)     

Lamin A/C mutation is independently associated with an increased risk of arterial and venous thromboembolic complications

Background

Lamin A/C (LMNA) mutation carriers suffer from a variety of clinical phenotypes, including dilated cardiomyopathy (DCM). Although it has been suggested that carriers are at risk for thromboembolic complications, it is unknown whether this risk is higher than can be expected from the underlying cardiac abnormalities. The purpose of this study was to determine whether a LMNA mutation is associated with an increased risk of thromboembolic complications.

Methods

We compared a cohort of 76 LMNA mutation carriers with a cohort of 224 idiopathic DCM patients without a LMNA mutation, with respect to the prevalence of arterial and venous thromboembolic complications. Furthermore, we carried out a case–control study to explore whether a prothrombotic phenotype was present in LMNA mutation carriers without DCM or atrial tachyarrhythmias (n = 14) and compared this with mutation negative relatives (n = 13).

Results

The prevalence of thromboembolic complications was higher in the cohort of LMNA mutation carriers than in DCM patients (22 vs 11%; p < 0.05), after respectively mean follow-up of 42 ± 12 and 49 ± 12 years. After adjustment for possible confounders, including atrial tachyarrhythmias and left ventricular ejection fraction, LMNA mutation carriership was independently associated with an increased risk of thromboembolic complications (HR 4.8, 95% CI: 2.2–10.6). The results of the case–control study suggested a prothrombotic phenotype in LMNA mutation carriers, as reflected by an altered platelet function and increased thrombin generation.

Conclusions

LMNA mutation is independently associated with an increased risk of arterial and venous thromboembolic complications. Laboratory research in LMNA mutation carriers without severe cardiac abnormalities suggests a prothrombotic phenotype.     

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

Mutations in the lamin A/C (LMNA) gene, which encodes nuclear membrane proteins, cause a variety of human conditions including dilated cardiomyopathy (DCM) with associated cardiac conduction system disease. To investigate mechanisms responsible for electrophysiologic and myocardial phenotypes caused by dominant human LMNA mutations, we performed longitudinal evaluations in heterozygous Lmna^+/− mice. Despite one normal allele, Lmna^+/− mice had 50% of normal cardiac lamin A/C levels and developed cardiac abnormalities. Conduction system function was normal in neonatal Lmna^+/− mice but, by 4 weeks of age, atrioventricular (AV) nodal myocytes had abnormally shaped nuclei and active apoptosis. Telemetric and in vivo electrophysiologic studies in 10-week-old Lmna^+/− mice showed AV conduction defects and both atrial and ventricular arrhythmias, analogous to those observed in humans with heterozygous LMNA mutations. Isolated myocytes from 12-month-old Lmna^+/− mice exhibited impaired contractility. In vivo cardiac studies of aged Lmna^+/− mice revealed DCM; in some mice this occurred without overt conduction system disease. However, neither histopathology nor serum CK levels indicated skeletal muscle pathology. These data demonstrate cardiac pathology due to heterozygous Lmna mutations reflecting a 50% reduction in lamin protein levels. Lamin haploinsufficiency caused early-onset programmed cell death of AV nodal myocytes and progressive electrophysiologic disease. While lamin haploinsufficiency was better tolerated by non-conducting myocytes, ultimately, these too succumbed to diminished lamin levels leading to dilated cardiomyopathy, which presumably arose independently from conduction system disease.     

Temporal Relationship of Conduction System Disease and Ventricular Dysfunction in LMNA Cardiomyopathy

BackgroundLMNA cardiomyopathy presents with electrocardiogram (ECG) abnormalities, conduction system disease (CSD), and/or arrhythmias before the onset of dilated cardiomyopathy (DCM). Knowing the time interval between the onset of CSD and its progression to DCM would help to guide clinical care.Methods and ResultsWe evaluated family members from 16 pedigrees previously identified to carry LMNA mutations for the ages of onset of ECG abnormalities, CSD, or arrhythmia and of left ventricular enlargement (LVE) and/or systolic dysfunction. Of 103 subjects, 64 carried their family LMNA mutation, and 51 (79%) had ECG abnormalities with a mean age of onset of 41.2 years (range 18–76). Ventricular dysfunction was observed in 26 with a mean age of onset of 47.6 years (range 28–82); at diagnosis 9 had systolic dysfunction but no LVE, 5 had LVE but no systolic dysfunction, and 11 had DCM. Of 16 subjects identified with ECG abnormalities who later developed ventricular dysfunction, the median ages of onset by log-rank analyses were 41 and 48 years, respectively.ConclusionsECG abnormalities preceded DCM with a median difference of 7 years. Clinical surveillance should occur at least annually in those at risk for LMNA cardiomyopathy with any ECG findings.     

Ventrikuläre Tachykardien

Dilative cardiomyopathy (DCM) has an incidence of 5–8/100,000 inhabitants, and hypertrophic cardiomyopathy an incidence of 1/500 inhabitants. Depending on specific risk factors both conditions have an increased risk for sudden cardiac death (SCD): in DCM reduced left ventricular ejection fraction and reduced physical capacity; and in HCM SCD in family members, left ventricular septum? >?30 mm, unclear syncope, non-sustained ventricular tachycardia (VT) on holter-ECG and inadequate blood pressure response on ergometer. Especially patients with intermediary risk factors are insufficiently classified, and the lifesaving implantation of a cardioverter-defibrillator (ICD) often leads to a significant number of device-related complications. In this area additional methods like late enhancement imaging with cardio MRI, identification of genetic variation and ECG characteristics could help improve risk stratification in these patients.     

Prophylactic implantable defibrillators in dilated cardiomyopathy

Arrhythmia risk stratification with regard to prophylactic implantable cardioverter?Cdefibrillator (ICD) therapy was investigated in the Marburg Cardiomyopathy Study, which revealed left ventricular ejection fraction to be the only significant independent arrhythmia risk predictor in a relatively large dilated cardiomyopathy (DCM) patient population. Based of the favorable results of the SCD-HeFT Trial, prophylactic ICD therapy became a class?I indication for patients with DCM, NYHA class?II or III heart failure and a left ventricular ejection fraction ???35% despite optimized medical therapy. In addition, prophylactic ICD therapy combined with cardiac resynchronization became standard treatment in DCM patients with complete left bundle branch block and an ICD indication according to SCD-HeFT criteria. Unresolved issues of prophylactic ICD therapy in DCM include a high number to treat in order to save one patient from sudden death due to difficult arrhythmia risk stratification which is largely based on reduced left ventricular ejection fraction. Second, optimal timing of prophylactic ICD implant remains difficult, because a significant but unpredictable number of DCM patients show a marked improvement of left ventricular function during follow-up, thus, averting the need prophylactic ICD therapy. Finally, prophylactic ICD therapy is associated with a considerable complication rate with painful inappropriate shocks and lead-related problems being the most frequent complications during long-term follow-up.     

Familial Dilated Cardiomyopathy Secondary to Dystrophin Splice Site Mutation

BackgroundIdiopathic dilated cardiomyopathy (DCM) encompasses a heterogeneous group of disorders, posing significant diagnostic challenges. Genetic etiologies underlie an important subset of DCM, including 20 genes and 5 X-linked disorders to date. We report a family with a rare dystrophin gene alteration, identified after evaluation of asymptomatic children whose extended family history included cardiomyopathy, premature cardiac death, or cardiac transplantation.Methods and ResultsRecord review, clinical evaluations, and DNA samples were obtained from members of a 5-generation pedigree with early onset DCM. Five of 6 affected males experienced death or cardiac transplant in their second or third decades. No affected individuals had skeletal muscle weakness before acute cardiac decompensation. Dystrophin gene analysis of an affected family member revealed sequence alteration at the conserved 5′ splice site of exon 1 of the muscle-specific isoform of dystrophin (IVS1 +1 G>T) and co-segregated with cardiac disease in this family.ConclusionsYoung males presenting with apparent isolated cardiomyopathy or acute myocarditis may harbor dystrophin mutations without overt skeletal muscle pathology. The etiology of familial risk was not evident in this pedigree before retrospective cardiovascular genetics assessment, highlighting ongoing diagnostic challenges and limitations of standardized screening panels (which do not include dystrophin) in patients with “idiopathic” DCM.     

Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption

Major nuclear envelope abnormalities, such as disruption and/or presence of intranuclear organelles, have rarely been described in cardiomyocytes from dilated cardiomyopathy (DCM) patients. In this study, we screened a series of 25 unrelated DCM patient samples for (a) cardiomyocyte nuclear abnormalities and (b) mutations in LMNA and TMPO as they are two DCM-causing genes that encode proteins involved in maintaining nuclear envelope architecture. Among the 25 heart samples investigated, we identified major cardiomyocyte nuclear abnormalities in 8 patients. Direct sequencing allowed the detection of three heterozygous LMNA mutations (p.D192G, p.Q353K and p.R541S) in three patients. By multiplex ligation-dependant probe amplification (MLPA)/quantitative real-time PCR, we found a heterozygous deletion encompassing exons 3–12 of the LMNA gene in one patient. Immunostaining demonstrated that this deletion led to a decrease in lamin A/C expression in cardiomyocytes from this patient. This LMNA deletion as well as the p.D192G mutation was found in patients displaying major cardiomyocyte nuclear envelope abnormalities, while the p.Q353K and p.R541S mutations were found in patients without specific nuclear envelope abnormalities. None of the DCM patients included in the study carried a mutation in the TMPO gene. Taken together, we found no evidence of a genotype–phenotype relationship between the onset and the severity of DCM, the presence of nuclear abnormalities and the presence or absence of LMNA mutations. We demonstrated that a large deletion in LMNA associated with reduced levels of the protein in the nuclear envelope suggesting a haploinsufficiency mechanism can lead to cardiomyocyte nuclear envelope disruption and thus underlie the pathogenesis of DCM.     

Sarcomeric hypertrophic cardiomyopathy: Genetic profile in a Portuguese population

BackgroundSarcomeric hypertrophic cardiomyopathy has heterogeneous phenotypic expressions, of which sudden cardiac death is the most feared. A genetic diagnosis is essential to identify subjects at risk in each family. The spectrum of disease-causing mutations in the Portuguese population is unknown.MethodsSeventy-seven unrelated probands with hypertrophic cardiomyopathy were systematically screened for mutations by PCR and sequencing of five sarcomeric genes: MYBPC3, MYH7, TNNT2, TNNI3 and MYL2. Familial cosegregation analysis was performed in most patients.ResultsThirty-four different mutations were identified in 41 (53%) index patients, 71% with familial hypertrophic cardiomyopathy. The most frequently involved gene was MYBPC3 (66%) with 22 different mutations (8 novel) in 27 patients, followed by MYH7 (22%), TNNT2 (12%) and TNNI3 (2.6%). In three patients (7%), two mutations were found in MYBPC3 and/or MYH7. Additionally, 276 relatives were screened, leading to the identification of a mean of three other affected relatives for each pedigree with the familial form of the disease.ConclusionsDisease-associated mutations were identified mostly in familial hypertrophic cardiomyopathy, corroborating the idea that rarely studied genes may be implicated in sporadic forms. Private mutations are the rule, MYBPC3 being the most commonly involved gene. Mutations in MYBPC3 and MYH7 accounted for most cases of sarcomere-related disease. Multiple mutations in these genes may occur, which highlights the importance of screening both. The detection of novel mutations strongly suggests that all coding regions should be systematically screened. Genotyping in hypertrophic cardiomyopathy enables a more precise diagnosis of the disease, with implications for risk stratification and genetic counseling.     

Left ventricular noncompaction associated with a pathogenic mutation in the MYH7 gene: Known mutation,different phenotype

Left ventricular noncompaction (LVNC) is a genetically heterogeneous cardiomyopathy, with familial and sporadic forms, but genetic testing only identifies a pathogenic mutation in a minority of cases. The main complications are heart failure, embolism and dysrhythmias. Herein we report a familial case of LVNC associated with a mutation in the MYH7 gene and review the literature regarding controversies in LVNC. A 50-year-old woman was referred to the cardiology clinic for palpitations. She underwent echocardiography and cardiac magnetic resonance imaging that revealed mild left ventricular systolic dysfunction and LVNC criteria. She had several episodes of non-sustained ventricular tachycardia and received an implantable cardioverter-defibrillator (ICD). Genetic testing revealed the c.1003G>C (p.Ala335Pro) mutation in the MYH7 gene. Familial screening showed clear genotype-phenotype cosegregation, which provided strong evidence for the pathogenic role of this mutation. To the best of our knowledge, this is the first report of LVNC associated with the p.Ala335Pro mutation in the MYH7 gene. This mutation has been described in hypertrophic cardiomyopathy, suggesting that the same pathogenic sarcomere mutation may be associated with different cardiomyopathies. This case also highlights the current difficulties regarding decisions on ICD implantation for primary prevention of sudden cardiac death in LVNC.     

Pediatric cardiomyopathy: importance of genetic and metabolic evaluation

BackgroundCardiomyopathy is a heterogeneous disease with a strong genetic component. A research-based pediatric cardiomyopathy registry identified familial, syndromic, or metabolic causes in 30% of children. However, these results predated clinical genetic testing.Methods and ResultsWe determined the prevalence of familial, syndromic, or metabolic causes in 83 consecutive unrelated patients referred for genetic evaluation of cardiomyopathy from 2006 to 2009. Seventy-six percent of probands (n = 63) were categorized as familial, syndromic, or metabolic. Forty-three percent (n = 18) of hypertrophic cardiomyopathy (HCM) patients had mutations in sarcomeric genes, with MYH7 and MYBPC3 mutations predominating. Syndromic (17%; n = 7) and metabolic (26%; n = 11) causes were frequently identified in HCM patients. The metabolic subgroup was differentiated by decreased endocardial shortening fraction on echocardiography. Dilated cardiomyopathy (DCM) patients had similar rates of syndromic (20%; n = 5) and metabolic (16%; n = 4) causes, but fewer familial cases (24%; n = 6) compared with HCM patients.ConclusionsThe cause of cardiomyopathy is identifiable in a majority of affected children. An underlying metabolic or syndromic cause is identified in >35% of children with HCM or DCM. Identification of etiology is important for management, family-based risk assessment, and screening.     

Malignant and benign mutations in familial cardiomyopathies: Insights into mutations linked to complex cardiovascular phenotypes

Cardiomyopathies, familial or sporadic, have become recognized as one of the leading cardiac threats. Hypertrophic cardiomyopathy (HCM) affects 0.2% of the population and is the leading cause of sudden death in young adults. Dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) are associated with sudden death as well as heart transplantations. Ventricular noncompaction cardiomyopathy (VNCM) is associated with heart failure and arrhythmias. Currently, more than 630 mutations in 10 sarcomeric genes associated with cardiomyopathy have been identified. HCM is associated with more than 550 mutations, whereas DCM, RCM and VNCM are associated with 52, 14 and 17 mutations, respectively. In many cases, the genes affected present a varying range of phenotypic and pathological severity. Recent data suggest that at least two main genetic determinants are involved in the pathogenesis and phenotypic variability within families afflicted by the same disease-linked gene. Individuals that are homozygous for a mutation or heterozygous for two or more mutations often show more severe phenotypes. Secondly, genetic modifiers are present in some cardiomyopathy patients and are associated with a poorer prognosis. At the protein level, changes in protein-protein interactions may also be important in determining the type of cardiomyopathy caused by different mutations. This review provides insight into the complex cardiovascular phenotypes and genetic variability associated with HCM, DCM, RCM and VNCM.     

Apical hypertrophic cardiomyopathy: A case series at a Brazilian referral center with a maximal follow-up of 15 years

BackgroundApical hypertrophic cardiomyopathy (AHCM) is a rare cardiomyopathy, in which hypertrophy occurs predominantly in the ventricular apex, and in some cases with a high risk of sudden cardiac death.ObjectiveThe aim of this paper is to present a case series of patients with AHCM and describe their main clinical, echocardiographic and electrocardiographic characteristics, the recommendation for an implantable cardioverter-defibrillator (ICD) and the frequency of sudden cardiac death (SCD).MethodsA retrospective case series was conducted at the referral center of a federal teaching hospital, between the years 2005 to 2020, involving patients with an echocardiographic diagnosis of AHCM. The parameters of the American College of Cardiology and the European Society of Cardiology were used to assess the risk of SCD.ResultsA total of 11 individuals were assessed with a mean age of 55.3 years, mean follow-up of 41.2 months, most of whom were symptomatic at diagnosis (72.7%). The most frequent symptom was dyspnea (27.3%). A family history of SCD was described in 45.5% of cases. Due to a high risk of SCD, four patients received ICDs. One patient presented sudden cardiac death after having refused the ICD.ConclusionsSymptoms and alterations in the imaging exams are significant factors in the clinical and prognostic assessment of patients with AHCM.     

Sudden death in a patient with lamin A/C gene mutation and near normal left ventricular systolic function

Mutations in the lamin A/C gene seem to be important aetiological factors in familial DCM. Heart disease caused by lamin A/C gene mutations is characterised by conduction system disorders with the need for permanent pacemaker implantations, atrial fibrillation, severe heart failure, and increased risk for sudden cardiac death. We described an asymptomatic 28-year-old man with a R190W lamin A/C gene mutation and mild left ventricular enlargement and near normal left ventricular ejection fraction who suffered from sudden cardiac death during sleeping. His electrocardiogram did not show conduction system disease and the most remarkable finding was a progressive decrease in voltage, which may be a marker of disease progression. The case study's mother had a similar phenotype to this and also had died suddenly. Sudden cardiac death in some lamin A/C gene mutations may occur even before the development of severe left ventricular dysfunction and implantable cardioverter-defibrillator should be early considered.     

Short QT syndrome: clinical findings and diagnostic-therapeutic implications.

AIMS: Clinical presentation, occurrence of sudden infant death, and results of the available therapies in the largest group of patients with short QT syndrome (SQTS), studied so far, are reported. METHODS AND RESULTS: Clinical history, physical examination, electrocardiogram (ECG), exercise stress testing, electrophysiological study, morphological evaluation, genetic analysis and therapy results in 29 patients with SQTS and personal and/or familial history of cardiac arrest are reported. The median age at diagnosis was 30 years (range 4-80). In all subjects, structural heart disease was excluded. Eighteen patients were symptomatic (62%): 10 had cardiac arrest (34%) and in 8 (28%) this was the first clinical presentation. Cardiac arrest had occurred in the first months of life in two patients. Seven patients had syncope (24%); 9 (31%) had palpitations with atrial fibrillation documented even in young subjects. At ECG, patients exhibited a QT interval < or = 320 ms and QTc < or = 340 ms. Fourteen patients received an implantable cardioverter-defibrillator (ICD) and 10 hydroquinidine prophylaxis. At a median follow-up of 23 months (range 9-49), one patient received an appropriate shock from the ICD; no patient on hydroquinidine had sudden death or syncope. CONCLUSION: SQTS carries a high risk of sudden death and may be a cause of death in early infancy. ICD is the first choice therapy; hydroquinidine may be proposed in children and in the patients who refuse the implant.