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Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy.

To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA).Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with the Medical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events.Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed.Our findings suggest a positive effect of clenbuterol on SBMA disease progression.This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA.

Introduction: Transgenic mice overexpressing mutated NEBL, encoding the cardiac-specific Z-disk protein nebulette, develop severe cardiac phenotypes. Since cardiomyopathies are commonly familial and because mutations in a single gene may result in variable phenotypes, we tested the hypothesis that NEBL mutations are associated with cardiomyopathy. Material and methods: We analyzed 389 patients, including cohorts of patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction cardiomyopathy (LVNC). The 28 coding exons of the NEBL gene were sequenced. Further bioinformatic analysis was used to distinguish variants. Results: In total, we identified six very rare heterozygous missense mutations in NEBL in 7 different patients (frequency 1.8%) in highly conserved codons. The mutations were not detectable in 320 Caucasian sex-matched unrelated individuals without cardiomyopathy and 192 Caucasian sex-matched blood donors without heart disease. Known cardiomyopathy genes were excluded in these patients. The mutations p.H171R and p.I652L were found in 2 HCM patients. Further, p.Q581R and p.S747L were detected in 2 DCM patients, while the mutation p.A175T was identified independently in two unrelated patients with DCM. One LVNC patient carried the mutation p.P916L. All HCM and DCM related mutations were located in the nebulin-like repeats, domains responsible for actin binding. Interestingly, the mutation associated with LVNC was located in the C-terminal serine-rich linker region. Conclusions: Our data suggest that NEBL mutations may cause various cardiomyopathies. We herein describe the first NEBL mutations in HCM and LVNC. Our findings underline the notion that the cardiomyopathies are true allelic diseases.

Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent α-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.European Journal of Human Genetics advance online publication, 2 May 2012; doi:10.1038/ejhg.2012.71

Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory. Method and results The authors used their custom DNA resequencing array which interrogates all possible single-nucleotide variants on both strands of all exons (n=160), splice sites and 5′-untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1 . Conclusions Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy.

Objective Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. Methods A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. Results Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). Conclusions We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.

Background Mutations in the cardiac myosin binding protein C ( MYBPC3 ) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis. Methods and results Mutation screening of MYBPC3 gene was performed in 97 HCM probands. Nineteen (19.5%) resulted to be carriers of the founder p.F305Pfs*27 mutation and other 45 mutation carriers were identified during the evaluation of 14 families. Eleven (38%) mutation carriers were diagnosed between ages 30 years and 40 years. Disease penetrance was incomplete (64.4%), age-related and was greater in men than women (85% vs 48%, p=0.009). Probands carrying the founder mutation exhibited highest prevalence of non-sustained ventricular tachycardia (63% vs 22%, p=0.003; 63% vs 23%, p=0.01) and implantable cardioverter-defibrillator (58% vs 17%, p=0.001; 58% vs 18%, p=0.005) when compared with probands without MYBPC3 mutations or carrying other MYBPC3 mutations. Reduced survival due to sudden cardiac death (SCD) or aborted SCD occurred more frequently after the fourth decade of life in probands carrying p.F305Pfs*27 mutation than those without MYBPC3 mutations (32% vs 15%, p=0.01). Conclusions p.F305Pfs*27 mutation carriers have a high probability to develop the disease between ages 30 years and 40 years with a significant major risk if they are men. This founder mutation is associated with an increase of SCD/aborted SCD events after the fourth decade of life.These findings are of relevant importance for management and clinical decision-making in patients with HCM.

Arrhythmogenic cardiomyopathy (ACM) and Hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. The population of the study included 2 families with recurrence of ACM and HCM. ACM and HCM were diagnosed according to the revised 2010 Task Force

We report here for the first time the case of a symptomatic DMD carrier, who had a heart transplant for a severe dilated cardiomyopathy. Dystrophin immunohistochemistry, western blot and analysis of X-chromosome inactivation on leucocytes, and skeletal and cardiac muscle biopsies on the explanted heart were performed. The patient was a heterozygote for exons 50-52 deletion in the dystrophin gene. The number of dystrophin-deficient fibres in the heart was much higher than in skeletal muscle. On the other hand, the explanted heart showed a non-skewed pattern of X-chromosome inactivation, as in leukocytes and skeletal muscle. The adverse cardiac course may be explained by the absence of regeneration among cardiomyocytes.

Objectives Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by a CAG repeat expansion within the androgen receptor (AR) gene. Toxic nuclear accumulation of mutant AR has been observed in tissues other than nervous system including cardiac muscle. Moreover, CAG polymorphism length within AR has been associated with an increased risk of heart disease. Materials and methods To test the hypothesis of the presence of cardiomyopathy in SBMA, a full cardiac protocol was applied to 25 SBMA patients. Results Patients' age ranged between 32 and 75 years. Cardiologic examination, 12-lead ECG, and echocardiography showed no abnormalities other than those consistent with hypertensive heart disease. One patient showed frequent supraventricular premature beats in absence of other significant arrhythmias at the 24-h ECG Holter. Conclusions Our findings do not support the hypothesis of a primary cardiomyopathy in SBMA.

Intensiveathleticconditioningisassociatedwithphysiologiccardiacremodeling (known as “athlete's heart”), consisting of augmented leftventricular (LV) mass due to increase of both cavity dimension andwall thickness, which are re flected on the electrocardiogram (ECG)mostfrequentlyasanincreaseofQRSvoltages[1,2].Becauseofthepar-tialoverlapofECGsignsofLVhypertrophy,athlete'sheartisofteninthedifferentialdiagnosiswithhypertrophiccardiomyopathy(HCM),whichis the leading cause of sports-related cardiac arrest in young athletes.Patients with HCM have a variety of ECG abnormalities, includingatrial enlargement, QRS left axis deviation, increase of QRS amplitudes,ST-segment and/or T-wave abnormalities, and pathologic Q waves [3].AccordingtotherecommendationsoftheEuropeanSocietyofCardiology,the ECG changes due to cardiac adaptat ion to physical exertion, predom-inantly the physiologic increase of QRS voltages, should not cause alarmand the athlete should be allowed to participate in competitive sportswithout additional evaluation [1]. Although this ECG interpretationapproach offers the potential to lower the traditional high number offalse-positives, whether and to what extent the increased speci ficityalter the ECG sensitivity for HCM remains to be established.The present study compared the ECG abnormalities associated withthe LV remodeling of HCM (nondilated, hypertrophic LV) and that ofathlete's heart (augmented LV mass due to increase of both cavity di-mensionandwallthickness),withparticularreferencetotheprevalence,clinicalsignificance,andrelevancetoscreeningoftheECGpatternofiso-lated increase of QRS voltages. The main study objective was to evaluatethe risk to miss a diagnosis of HCM by interpreting as normal the ECGpattern of isolated increase of QRS amplitude in highly trained athletes.The HCM population included 247 consecutive patients (181 males;age 39 ± 14 years, range 15–65 years). The diagnosis of HCM wasbased on the presence of a hypertrophied and nondilated left ventriclein the absence of other diseases that could produce the magnitude ofhypertrophy evident. Echocardiographic criteria for diagnosis were amaximal LV wall thickness (LVWT) ≥ 15 mm in adult index patientsand ≥13 mm in adult relatives [4,5]. The athlete's population includeda series of 133 Caucasian healthy, highly trained athletes (116 males;age 27 ± 6 years, range 15 –65 years) who fulfilled the echocardio-graphic criteria for augmented LV mass de fined according to Devereuxet al. as ≥134 g/m

This study aimed to describe myocardial involvement, respiratory impairment and pulmonary blood flow abnormalities in advanced-stage Duchenne muscular dystrophy (DMD). Twenty-one wheelchair-bound patients, aged from 10 to 24 yr, underwent electrocardiographic and echocardiographic examination, conventional spirometry, diurnal arterial blood gas analysis, and nocturnal polysomnography (SaO2 monitoring). Diagnosis was confirmed by neurological examination, dystrophin analysis at protein and DNA level. Patients were classified into two groups: group A normoxemic (14 cases) and group B with nocturnal hypoxemia (seven cases). Group A was further split into two subgroups, one without, and one with, left ventricular dilation (A1 = nine patients, end diastolic volume (EDV) = 51 ml m-2, ejection fraction (EF) = 56 per cent; A2 = five patients, EDV = 112 ml m-2, EF = 32 per cent; P < 0.05). Left ventricular regional wall motion abnormalities were found in 55, 40, and 43 per cent of groups A1, A2, and B patients respectively. Analysis of pulsed Doppler pulmonary data highlighted a significant reduction in corrected time to peak velocity in group B patients, when compared with control, A1, and A2 groups respectively. In group A, we observed a direct correlation between ejection fraction and corrected time-to-peak velocity. Two patterns of cardiac involvement may be recognized in advanced-stage DMD: left ventricular wall motion abnormalities and dilated cardiomyopathy. Doppler data which could suggest pulmonary hypertension may be observed in patients with dilated cardiomyopathy, and in patients with nocturnal hypoxemia. Therefore, in the management of advanced-stage DMD, a careful diagnosis of the heart-lung relationship should be performed, and both conventional treatment of heart failure and ventilatory therapy are necessary to improve the quality of life and survival in these patients.

Recent studies have suggested that interlead QT variability on the surface electrocardiogram, defined as QT dispersion, may reflect regional variations in myocardial recovery of excitability.1-4 The finding of a decreased QT dispersion in patients with different heart diseases treated with class III agents, sotalo13 and amiodarone,5T6 further supports this theory. A significant QT dispersion was found both in patients with congenital and acquired long QT interva12,5,7%s and in patients with myocardial infarction. 2,3,g~10 In hypertrophic cardiomyopathy (HC), the presence of electrical instability is a potentially important determinant of sudden death.“-l3 The pathologic substrate of the disease may create the conditions for QT interval prolongation and nonhomogeneous recovery of excitability.14 Dritsas et all5 recently showed a prolonged corrected QT interval (QTc) and increased QTc dispersion in 24 patients with HC compared with normal subjects, but a comparison between patients with and without ventricular arrhythmias was not done. This study assesses QT dispersion in HC patients with and without documented serious ventricular arrhythmias and sudden death. Twenty-six patients with NC (19 males and 7 females, mean age 37 t- 13 years, range 8 to 57) attending our institution for outpatient follow-up evaluation, or referred for risk stratification

Between January 1968 and December 1989, 280 patients underwent conservative surgical treatment for pure mitral stenosis. Closed commissurotomy was utilized in 134 patients, with a mean age of 38 +/- 11 years and a mean valve area of 1.0 +/- 0.29 cm2. Open commissurotomy was performed in 146 older patients (mean age 44 +/- 11 years) with a mean valve area of 0.9 +/- 0.3 cm2. The perioperative mortality was 3% in closed procedures and 3.4% in open procedures. Surviving patients were evaluated by questionnaires or phone interviews, and 129 patients were examined by two-dimensional echocardiography with the purpose of analyzing long-term results. Follow-up was 95% complete (Grunkemeier-Starr method), with a median of 18 years in patients with closed commissurotomy and 6.6 years in patients with open commissurotomy. The actuarial survival at 21 years was 60.8% (70% confidence limits 55% to 66%) in patients having closed commissurotomies and 60.6% (70% confidence limits 49% to 71%) at 22 years in patients having open commissurotomies. The "effective palliation" rate, defined by clinical and echocardiographic criteria, was 47% at 15 years and 15% at 20 years. We conclude that mitral commissurotomy is the procedure of choice in pure mitral valve stenosis and should be applied early. When performed in patients aged less than 40 years, a 78% (70% confidence limits 72% to 84%) survival at 18 years and 67% "effective palliation" at 15 years were observed. The closed valvotomy results of our study support the present trend toward use of percutaneous balloon valvotomy.

Two brothers, 25 and 19 years old, were affected by asymmetrical hypertrophic cardiomyopathy. The older brother had waddling gait and weakness of the proximal girdle muscles, while the younger had a broad-based gait and weakness of selected limb girdle muscles. EMG exam was myopathic. Serum enzyme, CPK and aldolase were elevated. Histochemical reactions in muscle revealed "core-like" areas, subsarcolemmal rims of mitochondria and lipid accumulation. Succinatedehydrogenase stain showed a lack of activity in both biopsies, with the exception of intrafusal fibers. Microphotometric quantitative measurements confirmed the defect in both biopsies. Biochemical measurements of several mitochondrial enzymes in muscle showed a reduced activity of succinate-dehydrogenase (33%) and succinate-cytochrome C reductase (36-47%) which are both components of complex II. On myocardial biopsy lipid and mitochondrial abnormalities were found. This mitochondriopathy represents a new phenotype of partial complex II defect.

Cardiac involvement (CI) in congenital muscular dystrophies (CMDs) has been only rarely investigated so far. By means of a systematic literature search we reviewed the literature about CI in CMD and found that CI is apparently absent in Ullrich CMD or CMD with integrin deficiency and only mild in Bethlem CMD. CI in merosin deficiency includes dilated cardiomyopathy and systolic dysfunction. CI in dystroglycanopathies seems most prevalent among all CMDs and includes dilated cardiomyopathy, systolic dysfunction, and myocardial fibrosis in Fukuyama CMD. Among the nonspecified dystroglycanopathies, CI manifests as dilated cardiomyopathy, hypertrophic cardiomyopathy (CMP) or systolic dysfunction. With CMD type 1C, as well as with limb-girdle muscular dystrophy 2I, up to half of the patients develop dilated cardiomyopathy. In rigid-spine syndrome, predominantly the right heart is affected secondary to thoracic deformity. In patients who carry LMNA mutations, CI may manifest as dilated cardiomyopathy, hypertrophic cardiomyopathy, or fatal ventricular arrhythmias. Overall, CI in patients with CMD varies considerably between the different CMD types from absent or mild CI to severe cardiac disease, particularly in merosin deficiency, dystroglycanopathies, and laminopathies. Patients with CMD with CI require regular cardiologic surveillance so that severe, treatable cardiac disease is not overlooked.

Aims Hypertrophic cardiomyopathy (HCM) is an important cause of heart failure-related disability over a wide range of ages. Profiles of severe progressive heart failure symptoms and death, or heart transplantation deserve more complete definition within large patient cohorts. Methods and results Clinical and morphological features of heart failure were assessed in 293 consecutive HCM patients over a median follow-up of 6 (inter-quartile range 2–11) years. Gross and histopathological features were analysed in 12 patients for whom the heart was available for inspection. Of the 293 patients, 50 (17%) developed severe progressive heart failure, including 18 who died or were transplanted. Three profiles of heart failure were identified predominantly associated with: (i) end-stage systolic dysfunction (ejection fraction

Objective Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adults. DM1 is a multisystem disorder also affecting the heart with an increased incidence of sudden death, which has been explained with the common impairment of the conduction system often requiring pacemaker implantation; however, the occurrence of sudden death despite pacemaker implantation and the observation of major ventricular arrhythmias generated the hypothesis that ventricular arrhythmias may play a causal role as well. The aim of the study was to assess the 2-year cumulative incidence and the value of noninvasive and invasive findings as predictive factors for sudden death, resuscitated cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia and severe sinus dysfunction or high-degree atrioventricular block. Methods/design More than 500 DM1 patients will be evaluated at baseline with a clinical interview, 12-lead ECG, 24-h ECG and echocardiogram. Conventional and nonconventional indications to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implantation have been developed. In the case of an indication to electrophysiological study, pacemaker, implantable cardioverter defibrillator or loop recorder implant at baseline or at follow-up, the patient will be referred for the procedure. At the end of 2-year follow-up, all candidate prognostic factors will be tested for their association with the endpoints. Trial registration ClinicalTrials.gov ID NCT00127582. Conclusion The available evidence supports the hypothesis that both bradyarrhythmias and tachyarrhythmias may cause sudden death in DM1, but the course of cardiac disease in DM1 is still unclear. We expect that this large, prospective, multicenter study will provide evidence to improve diagnostic and therapeutic strategies in DM1.

A 43-year-old woman with progressive external ophthalmoplegia developed a bifascicular block and dilatation of the right ventricle during 4 years of follow-up. Histochemical and electron microscopy studies detected mitochondrial abnormalities in ocular, skeletal muscle and cardiac biopsies. This case registers disease progression from the external ocular to the skeletal and cardiac muscles. Mitochondrial DNA was deleted in relation to the morphological abnormality.

Recurrent myocardial ischemia has been recognized as playing an important role in the pathophysiology of hypertrophic cardiomyopathy (HCM) and cardiovascular magnetic resonance (CMR), with or without gadolinium, is a promising method of evaluating fibrosis, edema and hypoperfusion. The aim of this study is to evaluate the interrelationship between late enhancement (LE) and other signs of ischemia, such as edema and perfusion defects, and to relate them to clinical data in order to describe the stage of the disease.Forty-four patients were evaluated by CMR cine images, T2-weighted sequences for edema and LE sequences. First-pass perfusion study was obtained in 37 patients. Acute-subacute ischemic events were clinically defined as the presence of chest pain or new onset of ST-segment depression, end-stage phase by left ventricular ejection fraction50% and maximal left ventricular wall thickness25 mm.Intramural patchy LE was found in 35/44 (80%) patients; extensive LE in 4/44 (9%). Edema was present in 24/44 (54%) patients and perfusion defects in 17/37 (46%). Simultaneous presence of patchy LE, edema and hypoperfusion in corresponding segments, was significantly associated to acute-subacute ischemic-phase parameters (p=0.02; RR 1.99, 95% C.I. 0.77-5.02). Extensive LE and perfusion defects in the absence of edema were significantly related to end-stage HCM (p0.001; RR 13.7, 95% C.I. 1.83-102.05).Using CMR in patients with HCM, we found focal tissue abnormalities consistent with regional ischemia at various stages. CMR provides important, clinically relevant information on the acuity, extent and functional relevance of ischemic injuries in HCM.

Objective: To determine the efficacy of pharmacological treatment in the prevention of sudden cardiac death in hypertrophic cardiomyopathy (HCM). Design: Clinical outcome was assessed retrospectively in 293 patients with HCM, including 173 who were taking cardioactive medications. Setting: Department of Cardiology, University of Padua, Padua, Italy; a tertiary HCM Centre. Interventions: Medical treatment with β blockers, verapamil, sotalol and amiodarone. Main outcome measure: HCM-related sudden cardiac death. Results: 17 of 173 (10%) patients died suddenly or had aborted cardiac arrest, while being treated continuously with drugs having antiarrhythmic properties, over a period of 62 (56) months. Sudden death occurred in 20% of patients administered amiodarone (6/30), 9% each of patients taking verapamil (4/46) or β blockers (7/76), and 0% of those taking sotalol (0/21). Patients taking cardioactive drugs (n = 173) and those without pharmaceutical therapy (n = 120) did not differ with respect to sudden death mortality. Conclusion: Medical treatment is not absolutely protective against the risk of sudden death in HCM. The present data inferentially support the use of the implantable defibrillator as the primary treatment choice for prevention of sudden death in high-risk patients with HCM.

Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of nine unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified three novel families (including one affected mother) with unreported LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes, and fibroblasts. LAMP-2 protein deficiency was detectable in various tissues, including leukocytes, explaining the multisystem clinical involvement. Skeletal muscle immunopathology showed that mutant protein was not localized in the Golgi complex, vacuolar membranes expressed sarcolemmal-specific proteins, and the degree of muscle fiber vacuolization correlated with clinical muscle involvement. In our female patient, muscle histopathology and LAMP-2 protein analysis was inconclusive, indicating that diagnosis in females requires mutation identification. The random X-chromosome inactivation found in muscle and leukocytes excluded the possibility that selective involvement of some tissues in females is due to skewed X-chromosome inactivation. Therefore, biochemical analysis of leukocytes might be used for screening in male patients, but genetic screening is required in females.

Background Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene ( FKRP ). FKRP encodes a putative glycosyltransferase protein that is involved in α-dystroglycan glycosylation. Objectives To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotype-phenotype correlations. Design Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high-performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes. Results Thirteen patients with limb-girdle muscular dystrophy type 2I (6% of all patients tested) were identified by FKRP mutation analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826C>A nucleotide change was a common mutation, present in 35% of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant intrafamilial and interfamilial clinical variability was observed. Conclusions FKRP mutations are a frequent cause of limb-girdle muscular dystrophies. The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involvement. The finding of 2 asymptomatic patients with FKRP mutations suggests that modulating factors may ameliorate the clinical phenotype.

Sarcoglycan gene mutations cause various limb-girdle muscular dystrophies. The sarcoglycans are expressed both in skeletal and cardiac muscle but, surprisingly, so far only a few sarcoglycanopathy patients have had documented cardiomyopathy. We studied six patients with β-sarcoglycanopathy. Immunohistochemical and immunoblot analysis performed on skeletal muscle biopsies from five patients, showed the loss of all sarcoglycans in three cases and marked reduction in two patients. Non-invasive cardiac examinations revealed that three patients had cardiac involvement: one had a severe Duchenne-like dystrophy, lethal dilated cardiomyopathy, and shared the same mutation reported in another cardiomyopathic patient; the other two patients had limb-girdle dystrophy and moderate cardiac involvement (one of them has a novel gene mutation). Given the age profile of the patients studied, the 50% cardiac involvement found in our LGMD2E patients is likely to be a conservative estimate. Careful cardiac monitoring should be carried out in β-sarcoglycanopathy patients who are at high risk of developing cardiomyopathy.

CARDIAC involvement in patients with inherited myopathies is well described in the literature. In dystrophinopathies (Duchenne muscular dystrophy [DMD], Becker muscular dystrophy [BMD], and DMD/ BMD carriers), dilated cardiomyopathy (DCM) has been reported in association with muscular dystrophy. In addition, in cases with particularly mild skeletal muscle involvement, cardiomyopathy may be the primary clinical feature and the main clinical problem. In mitochondrial myopathies, cardiac conduction defects have been described in many patients, whereas both hypertrophic (HCM) and DCM have been reported infrequently. In desminopathies, cardiomyopathy with conduction abnormalities is frequently associated with myopathy and may predominate. Up to now, end-stage cardiomyopathy resulting from dystrophinopathies, desminopathies, and mitochondrial myopathies have been accepted for heart transplantation (HTx) with reluctance because of a high perioperative risk caused by physical disability and restrictive respiratory failure. Moreover, a suspected rapid onset of cardiomyopathy of the transplanted heart is a further concern. Here we report five cases of end-stage cardiomyopathy with mild to moderate myopathies, who successfully underwent heart transplantation and were followed up for 72 months after surgery.

We describe a 47-year-old man affected with hypertrophic cardiomyopathy and frequent episodes of syncope. During ambulatory Holter monitoring and head-up tilt test, a syncopal attack was associated with sinus arrest and hypotension. This case suggests an additional mechanism of syncope in hypertrophic cardiomyopathy.

The mechanism underlying cardiac arrest in patients with hypertrophic cardiomyopathy (HC) is intriguing. In the clinical setting, myocardial ischemia has long been incriminated, particularly in the young. Among 274 cardiovascular sudden deaths in the young (< or = 35 years), 19 (7.0%), 14 males and 5 females, median age 23 years, had HC. Familial occurrence of HC was ascertained in 3 (16%). SD occurred on effort in 6 (31%). Previous syncope occurred in 5 and palpitations in 3. Basal electrocardiogram (ECG) was abnormal in 7 of 8 available cases. Hypertrophy was septal asymmetric in 14. Gross examination showed large isolated or multiple septal scars in 11 (58%); at histomorphometry, the mean percent area of fibrosis of the septal myocardium was 18.6 +/- 6. Four showed a deep intramyocardial course of the left anterior descending coronary artery. At histology, myocardial disarray involved 30 +/- 16% of the septal myocardium; evidence of acute-subacute myocardial necrosis was present in 14 (74%), 1 of them with a regional acute myocardial infarction. By comparing hearts with (n = 11) and without (n = 8) areas of scar-type fibrosis, we found a statistically significant difference in terms of age (25.5 +/- 5.4 v 15.5 +/- 12.4 years, P = .04), septal thickness (25.4 +/- 5.4 v 15.4 +/- 4.9 mm, P < .001), percent increase of septal thickness versus normal value for age and sex (46.2 +/- 15 v 25.2 +/- 13.6%, P < .01) and mean score of small vessel disease (1.7 +/- 0.4 v 1.2 +/- 0.4, P = .04). Linear regression analysis showed a positive correlation of percent area of replacement fibrosis with septal thickness (P = .01) and with mean score of small vessel disease (P < .01). In conclusion, our pathologic findings of ischemic damage, either acute-subacute or in the form of fibrotic scars, support the clinical evidence that ischemia occurs in the natural history of HC and may contribute to life-threatening electrical instability.

The spontaneous up-regulation of utrophin, observed in dystrophin-deficient skeletal muscle fibers, may decrease the susceptibility of such fibers to necrosis. It has been reported that the utrophin-rescued double-mutant mdx mouse always develops a lethal cardiomyopathy. We report two patients with severe dilated cardiomyopathy due to dystrophin gene mutations: the first was a manifesting Duchenne muscular dystrophy carrier and the second a patient affected with moderate Becker muscular dystrophy. We studied their explanted heart specimen and/or endoImyocardial biopsies by immunohistochemistry and Western blot for both dystrophin and utrophin. Utrophin was found to be over-expressed in these specimens. Our results suggest that in these patients the up-regulation of utrophin in dystrophin-deficient cardiomyocytes was unable to prevent the development of life-threatening myocardial dysfunction. These findings seem to dampen the enthusiasm raised by the prospect of DMD treatment by utrophin rescue in skeletal muscle fibers, as the myocardium would still remain severely affected.

Mutations in the sarcoglycan genes cause autosomal-recessive muscular dystrophies. Because sarcoglycan genes and their protein products are highly expressed both in skeletal and cardiac muscle, patients with these mutations might be expected to be at risk to develop dilated cardiomyopathy. We therefore studied 13 patients with α-, β-, γ-sarcoglycan gene mutations by thorough cardiological assessment. Electrocardiographic or echocardiographic abnormalities were observed in about 30% of cases showing a severe course of muscular dystrophy. No correlation was found between the presence of cardiac abnormalities and the type of mutation or sarcoglycan gene involved. The cardiac involvement was never severe, but it may be detected in early stages of the muscle disease. The absence of overt cardiac dysfunction may be due to lower sarcoglycan protein expression in cardiac than skeletal muscle or to less sarcolemmal instability at the myocardial level, possibly related to the different distribution of forces generated by contraction of the myocardium with respect to proximal limb-girdle muscles. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 473–479, 1999.

A15-year-old boy underwent successful cardiac transplantation for severe congestive heart failure. His sister had died at the age of 9 years of undefined congenital heart disease. At the age of 10 years, during a school medical screening, the patient was diagnosed with a cardiomyopathy. At cardiac catheterization, the right ventricle disclosed an increased trabecular pattern, …

Background Several cases of Becker's muscular dystrophy (BMD) have been reported, which showed mild or subclinical skeletal muscle involvement with an overt dilated cardiomyopathy. Here, for the first time, a group of 28 patients with BMD who had a subclinical or benign myopathy have been studied through a thorough cardiological assessment. Methods and Results Each patient underwent ECG and echocardiographic examinations. Molecular analyses of the dystrophin gene and protein were performed. An unexpectedly high incidence of myocardial involvement was observed among patients affected with subclinical (72%) or benign (60%) BMD. The cardiac involvement appears to develop early from the right ventricle. Both the increase in left ventricular end-diastolic volume and the reduction in the ejection fraction appeared to be age related. Severe left ventricular dilation with reduced ejection fraction, which could be complicated by life-threatening arrhythmias, may occur. Contrary to previous reports, which indicated the involvement of 5′-end mutations in cardiomyopathies as a result of dystrophin gene alterations, this study shows that despite the apparent concentration of deletions in two regions (5′-end and exons 47 through 49), no general conclusions can be drawn regarding the involvement of specific gene mutations in the development of cardiomyopathy. Conclusions Cardiomyopathy is the main clinical feature and complication in patients affected by subclinical or mild BMD. The cardiac manifestation is characterized by early right ventricular involvement and is later associated with left ventricular impairment. In mild BMD, myocardial damage may develop because the patients, who are unaware of a possible cardiac involvement, are still able to perform strenuous muscle exercise and, through pressure or volume overload, may induce mechanical stress, which is harmful for dystrophin-deficient myocardial cells.

One hundred twenty five patients from 105 families were considered, showing in-frame intragenic deletion or duplication of the dystrophin gene and/or abnormal dystrophin on muscle biopsy. According to clinical status of patients, the affection was classified as subclinical, benign, moderate or severe. Significant decrease of dystrophin abundance was observed with increasing clinical severity (p < 0.05). Detailed clinical data were available in 68 patients in whom a long-term follow-up (6-39 years) was obtained. Functional performance at different ages and disease endpoints were recorded in order to analyze the rate of disease progression. We identified three different disease courses: stable, slow and rapid progression. We observed a significantly lower level of dystrophin and immunohistochemical score (p < 0.05 vs. the other courses) in patients with rapid course. Deletion or duplication in the 5' end of the gene was associated with poor prognosis. Prognosis was substantially better, showing a stable course, in patients with large deletions or duplications in the proximal rod region. These subjects often suffered from a cramps/myalgia syndrome or experienced rhabdomyolisis. Cardiac involvement was detected in 65% of cases. A significant increase of right ventricular volume was seen in all clinical groups (p < 0.05). A left ventricular dilation was observed in 25% and a decreased ejection fraction in 29% of our patients. The reduction of ejection fraction and the increase of left ventricular volume were age-related. Since sudden death may occur as a consequence of cardiomyopathy, severe left ventricular dysfunction in dystrophinopathic patients is another important adverse prognostic factor, although not always directly correlated with skeletal muscle impairment.

We studied long-term variability of QT-dispersion in three patients with hypertrophic cardiomyopathy (Maron III) and ventricular fibrillation. Late potentials were absent on signal-averaged electrocardiogram. ST-segment depression was recorded in all three patients at Holter monitoring, and in two during exercise stress testing, nonsustained ventricular tachycardia was present in only one patient. The maximal correct QT-interval and corrected QT-dispersion (QTcd) were measured retrospectively, both off-drug and under treatment with amiodarone and beta-blocker (two patients), or sotalol alone (one patient). Ten age- and sex-matched normal subjects, and 13 hypertrophic cardiomyopathy patients without ventricular arrhythmias formed the control groups. QTcd-values in the control groups never exceeded 80 ms and mean values of 30.1 +/- 10.1 ms and 44.1 +/- 7.9 ms respectively, were found. During long-term follow-up, QTcd increased progressively in two of the three patients with ventricular fibrillation, and at the time of the event all showed a value > 100 ms. Sotalol, but not the amiodarone reduced QTcd. QTcd seems to be a powerful predictor of ventricular electrical instability in the absence of other specific markers, and a promising guide for effective pharmacological therapy.

Objectives . The purpose of this study was to assess the incidence of myocardial involvement and the relation of cardiac disease to the molecular defect at the deoxyribonucleic acid (DNA) or protein level in Becker muscular dystrophy. Background . Dystrophin gene mutations produce clinical manifestations of disease in the heart and skeletal muscle of patients with Becker muscular dystrophy. Methods . Thirty-one patients underwent electrocardiographic and echocardiographic examination and 24-h Holter monitoring. The diagnosis was established by neurologic examination, dystrophin immunohistochemical assays or Western blot on muscle biopsy, or both, and DNA analysis. Results . Electrocardiographic and echocardiographic findings were abnormal in 68% and 62% of the patients, respectively. Right ventricular involvement was detected in 52%. Left ventricular impairment was observed either as an isolated phenomenon (10%) or in association with right ventricular dysfunction (29%). Right ventricular disease was manifested in the teenagers, and an impairment of the left ventricle was observed in older patients. Right ventricular end-diastolic volumes were significantly increased compared with those in a control group. The left ventricular ejection fraction was significantly lower in older patients than in control subjects or younger patients. Life-threatening ventricular arrhythmias were detected in four patients. No correlations were found between skeletal muscle disease, cardiac involvement and dystrophin abnormalities. In our patients, exon 49 deletion was invariably associated with cardiac involvement. Exon 48 deletion was associated with cardiac disease in all but two patients. Conclusions . The cardiac manifestation of Becker muscular dystrophy is characterized by early right ventricular involvement associated or not with left ventricular impairment. Exon 49 deletion is associated with cardiac disease.

Echocardiographic and Doppler studies were performed in 134 patients with a Hancock bioprosthesis in the mitral valve position during a followup period of 1 to 216 months. Among the xenografts, 57% were clinically normal and 43% had severe dysfunction. Among the normal bioprostheses, 35% had echocardiographically thickened mitral cusps (≥3 mm) with normal hemodynamic function; by setting the tower 95% confidence limit of valve area at 1.7 cm2 these patients had a significantly (p < 0.01) smaller valve area than that of normal control subjects. Evaluation of all thickened normal mitral valves showed the highest incidence of thickening at 9 years after implantation. Valve replacement surgery was subsequently performed in 33 patients with dysfunctioning bioprostheses, and echocardiographic diagnosis was confirmed in 91% of explanted valves (bioprosthetic stenosis 21%, incompetence 46%, and combined stenosis and regurgitation 33%). In 2 valves that were found to be stenotic on echocardiographic examination, a calcium-related commissural tear was also observed at reoperation, and in another, a paravalvular leak was found. Dystrophic calcification, isolated (64%) or occasionally associated with fibrous tissue overgrowth (21%), was the main cause of failure. Pannus was present in prostheses with longer satisfactory function (168 ± 31 vs 124 ± 21 months; p < 0.001). Long-term performance was evaluated by the Kaplan-Meier method for up to 18 years of follow-up. Freedom from structural valvular disfunction after mitral replacement was 89% at 6 years, 77% at 8 years, 56% at 10 years, 31% at 12 years, 16% at 15 years, and 15% at 18 years.

From 1968 to 1989, 280 patients with post-rheumatic pure mitral stenosis underwent surgical commissurotomy; 134 a closed and 146 an open technique. Follow-up exceeded 15 years in 56.7% of the patients. Echocardiographic analysis was performed in 120 patients and disclosed a larger mitral valve area in patients who underwent open valvulotomy (1.9 +/- 0.5 cm2 vs. 1.5 +/- 0.4 cm2 for the closed technique, P0.0002). On the other hand, considering the occurrence of post-surgical mitral regurgitation at a level greater than, or equal to moderate, open valvulotomy produced less favorable results (18.5% vs. 5% for the closed technique, P0.01).

The influence of practolol on the activity of digoxin in atrial fibrillation has been studied in seven hospitalized patients by determining plasma levels of the cardiac glycoside and its effects on the ventricular rate, before and during the association with the beta blocker. Digoxin alone (0.25 mg/day p.o.) demonstrated a rather feeble activity, by giving a satisfactory control of ventricular rate only in two patients. Furthermore, a poor correlation has been observed between plasma levels and ventricular rate in the different patients. The association with low doses of practolol (50 or 100 mg twice a day p.o.) results in a significant increase of activity) tachycardic patients being the most responsive to the combined therapy.

The severity and site of hypertrophy is important in determining the clinical picture and the natural history of hypertrophic cardiomyopathy (HCM). We evaluated left ventricular hypertrophy by means of two-dimensional echocardiographic score and score index, and correlated these findings with symptoms, electrovector-cardiographic data, and ventricular arrhythmias. A total of 42 patients with HCM were studied by clinical examination, ECG, VCG, M-mode and 2D echocardiography, and 24-h Holter monitoring. The extent and severity of the hypertrophic process were calculated by a score system. The left ventricle was divided into 11 segments and a hypertrophic score (HS) was given to each segment. A hypertrophy score index (HSI) was also calculated by dividing the number of hypertrophied segments by 13. No correlation was found between symptoms and HS and HSI, nor ECG-VCG abnormalities and HS and HSI. A statistically significant relationship between the severity of ventricular arrhythmias and HS and HSI was found (p less than 0.01). The mechanism responsible for ventricular tachyarrhythmias in severe and diffuse hypertrophy might reside in the high intraventricular pressures which produce or worsen areas of myocardial ischemia.

Arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. Here we describe for the first time co-inheritance of mutations in genes associated with ACM or HCM in two families with recurrence of both cardiomyopathies. Among the double heterozygotes for mutations in desmoplakin (DSP) and myosin binding protein C (MYBPC3) genes identified in Family A, two were diagnosed with ACM and two with HCM. In Family B, one patient was identified to carry mutations in α-T-catenin (CTTNA3) and β-myosin (MYH7) genes, but he does not fulfill the current diagnostic criteria neither for ACM nor for HCM. Interestingly, the double heterozygotes showed a variable clinical expression of both cardiomyopathies and they do not exhibit a more severe phenotype than family members carrying only one of the two mutations.

Objectives. Because sudden death due to complete atrioventricular (AV) block or ventricular arrhythmias is the most dramatic event in myotonic dystrophy, we assessed the relation of cardiac disease to cytosine—thymine—guanine (CTG) triplet mutation in adults affected with myotonic dystrophy. Background. The myotonic dystrophy mutation, identified as an unstable deoxyribonucleic acid (DNA) sequence (CTG) prone to increase the number of trinucleotide repeats, produces clinical manifestations of the disease in skeletal muscle, the heart and many organ systems. Methods. Forty-two adult patients underwent electrocardiography and echocardiography; in addition, signal-averaging electrocardiography was performed in 22, and 24-h Holter monitoring was recorded in 32. The diagnosis was established by neurologic examination, electromyography, muscle biopsy and DNA analysis. The patients were then classified into three subgroups on the basis of the number of CTG trinucleotide repeat expansions: E1= 18 patients with 0 to 500 CTG repeats; E2= 12 patients with up to 1,000 repeats; E3+ E4= 10 patients with up to 1,500 repeats and 2 patients with >1,500 repeats. Results. The incidence of normal electrocardiographic (ECG) results was found to be significantly different in the three subgroups (55%, 50%, 17% in E1, E2, E3+ E4, respectively, p = 0.04), with the highest values in the group with fewer repeat expansions. The incidence of complete left bundle branch block was also significantly different among the groups (5% in E1, 0% in E2, 42% in E3+ E4, p = 0.01) and was directly correlated with the size of the expansion. A time-domain analysis of the signal-averaged ECG obtained in 12 patients in E1, 4 in E2, 5 in E3and 1 in E4showed that abnormal ventricular late potentials were directly correlated with CTG expansion (33% in E1, 75% in E2, 83% in E3+ E4, p = 0.05). Moreover, the incidence of ventricular couplets or triplets showed a positive correlation with size of CTG expansion (0 in E1, 0 in E2, 29% in E3+ E4, chi square 0.02). Conclusions. Our findings suggest that the involvement of specialized cardiac tissue, accounting for severe AV and intraventricular conduction defects, is related to CTG repeat length. In addition, the presence of abnormal late potentials directly correlates to CTG expansion. Abnormal late potentials, caused by slowed and fragmented conduction through damaged areas of myocardium, represent a substrate for malignant reentrant ventricular arrhythmias. In the future, therefore, molecular analysis of DNA should identify patients with cardiac disease at high risk for development of AV block or lethal ventricular arrhythmias.

Summary: We evaluated the progression of conduction system and myocardial disease in 17 asymptomatic myotonic dystrophy patients by clinical evaluation, electrocardiography, vector cardiogmphy , and echocardiography. An exercise test was done in 10 patients. After 8 years, a follow-up study of 12 of the 17 original patients was done with a similar protocol. During this period, 2 patients died: one of sudden death while the other had acute left ventricular failure. In our first control study, we found EKG abnormalities in 15 of our patients, consisting mostly of conduction defects or pseudonecrotic patterns. In our second control, all patients had conduction system disease and, in addition, 3 of them had premature ventricular beats. One patient developed dilated cardiomyopathy. In 6 patients, structural involvement of the right ventricle was found. We conclude that even in asymptomatic myotonic dystrophy patients a conduction system deficit is present and progresses, and cardiac death may occur in about 12% of these patients.