Mutations In Sarcomere Protein Genes Research Articles

Sarcomere Protein Gene Mutations in Patients With Apical Hypertrophic Cardiomyopathy

Apical hypertrophic cardiomyopathy (HCM) is a unique form of HCM with left ventricular hypertrophy confined to the cardiac apex. The purpose of our study was to report genetic findings in a large series of unrelated patients with apical HCM and compare them with a nonapical HCM cohort. Overall, 429 patients with HCM underwent genetic testing. The panel included 8 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2). Sixty-one patients were diagnosed with apical HCM. A positive genotype was found in 8 patients with apical HCM. The genotype-positive and genotype-negative patients had similar maximal wall thicknesses (17.5 ± 3.5 mm versus 17.6 ± 3.3 mm, P = 0.71) and similar frequency of HCM-related events (2/8; 25% versus 13/53; 25%; P = 0.98). Thirteen percent with apical HCM and 40% with nonapical HCM had a positive genotype (P<0.001) most often involving the MYBPC3 and MYH7 genes. In apical HCM, a positive genotype was found less frequently than in nonapical HCM, and it was most often involving MYBPC3 and MYH7 genes. Only 13% of patients with apical HCM were found to be genotype positive, indicating that genome-wide association studies and gene expression profiling are needed for better understanding of the genetic background of the disease. There was no significant genotype-phenotype correlation in our cohort with apical HCM.

Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history.

This review provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights by physicians who initially detailed remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees solved the etiologic riddle of HCM and unexpectedly demonstrated mutations in sarcomere protein genes as the cause of disease. In addition to celebrating 20 years of genetic research in HCM, this article serves as an introductory overview to a thematic review series that will present contemporary advances in the field of hypertrophic heart disease. Through the continued application of advances in genetic methodologies, combined with biochemical and biophysical analyses of the consequences of human mutations, fundamental knowledge about HCM and sarcomere biology has emerged. Expanding research to elucidate the mechanisms by which subtle genetic variation in contractile proteins remodel the human heart remains an exciting opportunity, one with considerable promise to provide new strategies to limit or even prevent HCM pathogenesis.

Imaging Phenotype Versus Genotype in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common monogenetic cardiac disease with a prevalence of 0.2%1 that usually is inherited as an autosomal dominant trait with variable penetrance and expression. Clinically, HCM is defined by the presence of left ventricular (LV) hypertrophy (LVH) unexplained by abnormal loading conditions.1 The natural history varies from an asymptomatic course to drug-refractory angina/dyspnea, sudden cardiac death (SCD), and end-stage heart failure. The incidence of HCM-related SCD is approximately 1% to 2% in children and adolescents and 0.5% to 1% in adults.2,3 In this review, we examine the impact of advanced diagnostic imaging technologies on HCM, with particular emphasis on the detection of particular genetic subtypes. In ≈60% of cases, HCM is inherited as an autosomal dominant trait caused by mutations in genes coding for cardiac sarcomere proteins (Figure 1).4–7 Mutations in genes encoding Z-disc proteins and proteins involved in calcium regulation account for <5% of cases. The absence of sarcomeric gene mutations can be explained by limitations of current mutation detection techniques or mutations in as yet unidentified genes, but in some cases, hypertrophy is caused by other diseases that mimic the phenotype of sarcomeric protein disease. Table 1 lists genetic disorders associated with HCM. Figure 1. A schematic illustration of a cardiac sarcomere. View this table: Table 1. Currently Known Genes Implicated in HCM More than 600 different sarcomeric gene mutations are reported in patients with HCM.8–16 The majority are missense mutations, but nonsense, frameshift, and in-frame insertion/deletion mutations also occur. Most mutations are characterized by incomplete penetrance and variable clinical expression likely due to locus heterogeneity and the effect of mutations at different locations within the same gene. Most mutations probably have a dominant negative effect on sarcomere function, but in some cases, haploinsufficiency (ie, only a single functional …

Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity?

Non-compaction of the left ventricular myocardium (LVNC) has gained increasing recognition during the last 25 years. There is a morphological trait of the myocardial structure with a spectrum from normal variants to the pathological phenotype of LVNC, which reflects the embryogenic structure of the human heart due to an arrest in the compaction process during the first trimester. It must be cautioned not to overdiagnose LVNC: the morphological spectrum of trabeculations, from normal variants to pathological trabeculations with the morphological feature of LVNC must be carefully considered. The classical triad of complications are heart failure, arrhythmias, including sudden cardiac death, and systemic embolic events. Non-compaction of the left ventricular myocardium can occur in isolation or in association with congenital heart defects (CHDs), genetic syndromes, and neuromuscular disorders among others. The clinical spectrum is wide and the outcome is more favourable than in previously described populations with a negative selection bias. Familial occurrence is frequent with autosomal dominant and X-linked transmissions. Different mutations in sarcomere protein genes were identified and there seems to be a shared molecular aetiology of different cardiomyopathic phenotypes, including LVNC, hypertrophic and dilated cardiomyopathies. Thus, genetic heterogeneity, with an overlap of different phenotypes, and the variability of hereditary patterns, raise the questions whether there is a morphological trait from dilated/hypertrophic cardiomyopathy to LVNC and what are the triggers and modifiers to develop either dilated, hypertrophic cardiomyopathy, or LVNC in patients with the same mutation. The variety in clinical presentation, the genetic heterogeneity, and the phenotype of the first transgenetic animal model of an LVNC-associated mutation question the hypothesis that LVNC be a distinct cardiomyopathy: it seems to be rather a distinct phenotype or phenotypic, morphological expression of different underlying diseases than a distinct cardiomyopathy.

Phenotypic Variability of Myosin Binding Protein C Gene Mutation Associated Cardiomyopathy: A Role for Cardiac Magnetic Resonance Imaging in Clinical Screening

Left ventricular non compaction (LVNC) and hypertrophic cardiomyopathy (HCM) are genetically mediated primary cardiomyopathies that have both been associated with mutations in sarcomere protein genes. We describe the first case of the MYBPC3 p.Arg502Trp mutation manifesting as an LVNC phenotype. In addition, we describe this occurring within a family where the phenotype had been expressed as HCM in other kindred. Clinical screening including repeated electrocardiograms and echocardiograms of the 27 year old son of a woman with previously diagnosed HCM revealed only borderline findings. Cardiac magnetic resonance (CMR) i g m

Heterogeneous myocyte enhancer factor-2 (Mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy

Unknown molecular responses to sarcomere protein gene mutations account for pathologic remodeling in hypertrophic cardiomyopathy (HCM), producing myocyte growth and increased cardiac fibrosis. To determine if hypertrophic signals activated myocyte enhancer factor-2 (Mef2), we studied mice carrying the HCM mutation, myosin heavy-chain Arg403Gln, (MHC(403/+)) and an Mef2-dependent β-galactosidase reporter transgene. In young, prehypertrophic MHC(403/+) mice the reporter was not activated. In hypertrophic hearts, activation of the Mef2-dependent reporter was remarkably heterogeneous and was observed consistently in myocytes that bordered fibrotic foci with necrotic cells, MHC(403/+) myocytes with Mef2-dependent reporter activation reexpressed the fetal myosin isoform (βMHC), a molecular marker of hypertrophy, although MHC(403/+) myocytes with or without βMHC expression were comparably enlarged over WT myocytes. To consider Mef2 roles in severe HCM, we studied homozygous MHC(403/403) mice, which have accelerated remodeling, widespread myocyte necrosis, and neonatal lethality. Levels of phosphorylated class II histone deacetylases that activate Mef2 were substantially increased in MHC(403/403) hearts, but Mef2-dependent reporter activation was patchy. Sequential analyses showed myocytes increased Mef2-dependent reporter activity before death. Our data dissociate myocyte hypertrophy, a consistent response in HCM, from heterogeneous Mef2 activation and reexpression of a fetal gene program. The temporal and spatial relationship of Mef2-dependent gene activation with myocyte necrosis and fibrosis in MHC(403/+) and MHC(403/403) hearts defines Mef2 activation as a molecular signature of stressed HCM myocytes that are poised to die.

Analysis of the sarcomere protein gene mutation on cardiomyopathy – Mutations in the cardiac troponin I gene

Developments in the molecular genetic studies of cardiomyopathy (CM) have led to discovery of a large number of mutations in the genes encoding the sarcomeric proteins. In this study, comprehensive screening of TNNI3 was performed in 36 consented autopsy cases diagnosed as CM, in order to evaluate the prevalence of gene mutations in sudden death caused by CM. In DCM cases, a new missense mutation Pro16Thr was detected. A single nucleotide polymorphism at −8 position of intron 3 (IVS 3 −8 T>A) was identified, which had a significant difference in allele frequency between DCM and control cases. From these results, it was indicated that this study contribute to genetic based diagnosis, risk stratification and prevention of sudden death caused by CM.

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

Mutations in sarcomere protein genes can cause hypertrophic cardiomyopathy (HCM), a disorder characterized by myocyte enlargement, fibrosis, and impaired ventricular relaxation. Here, we demonstrate that sarcomere protein gene mutations activate proliferative and profibrotic signals in non-myocyte cells to produce pathologic remodeling in HCM. Gene expression analyses of non-myocyte cells isolated from HCM mouse hearts showed increased levels of RNAs encoding cell-cycle proteins, Tgf-β, periostin, and other profibrotic proteins. Markedly increased BrdU labeling, Ki67 antigen expression, and periostin immunohistochemistry in the fibrotic regions of HCM hearts confirmed the transcriptional profiling data. Genetic ablation of periostin in HCM mice reduced but did not extinguish non-myocyte proliferation and fibrosis. In contrast, administration of Tgf-β-neutralizing antibodies abrogated non-myocyte proliferation and fibrosis. Chronic administration of the angiotensin II type 1 receptor antagonist losartan to mutation-positive, hypertrophy-negative (prehypertrophic) mice prevented the emergence of hypertrophy, non-myocyte proliferation, and fibrosis. Losartan treatment did not reverse pathologic remodeling of established HCM but did reduce non-myocyte proliferation. These data define non-myocyte activation of Tgf-β signaling as a pivotal mechanism for increased fibrosis in HCM and a potentially important factor contributing to diastolic dysfunction and heart failure. Preemptive pharmacologic inhibition of Tgf-β signals warrants study in human patients with sarcomere gene mutations.

Short Communication: The Cardiac Myosin Binding Protein C Arg502Trp Mutation

Rationale : The myosin-binding protein C isoform 3 ( MYBPC3 ) variant Arg502Trp has been identified in multiple hypertrophic cardiomyopathy (HCM) cases, but compelling evidence to support or refute the pathogenicity of this variant is lacking. Objective : To determine the prevalence, origin and clinical significance of the MYBPC3 Arg502Trp variant. Methods and Results : The prevalence of MYBPC3 Arg502Trp was ascertained in 1414 sequential HCM patients of primarily European descent. MYBPC3 Arg502Trp was identified in 34 of these 1414 unrelated HCM patients. Segregation of MYBPC3 Arg502Trp with clinical status was assessed in family members. Disease haplotypes were examined in 17 families using two loci flanking MYBPC3 . Family studies identified an additional 43 variant carriers, many with manifest disease, yielding a calculated odds ratio of 11 000:1 for segregation of MYBPC3 Arg502Trp with HCM. Analyses in 17 families showed at least 4 independent haplotypes flanked MYBPC3 Arg502Trp. Eight individuals (4 probands and 4 family members) also had another sarcomere protein gene mutation. Major adverse clinical events occurred in approximately 30% of MYBPC3 Arg502Trp carriers by age 50; these were significantly more likely ( P &lt;0.0001) when another sarcomere mutation was present. Conclusions : MYBPC3 Arg502Trp is the most common and recurrent pathogenic mutation in a diverse primarily European descent HCM cohort, occurring in 2.4% of patients. MYBPC3 Arg502Trp conveys a 340-fold increased risk for HCM by 45 years of age, when more than 50% of carriers have overt disease. HCM prognosis worsens when MYBPC3 Arg502Trp occurs in the setting of another sarcomere protein gene mutation.

Clinical Features and Outcome of Hypertrophic Cardiomyopathy Associated With Triple Sarcomere Protein Gene Mutations

The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or biventricular pacing (n=2). The fourth patient, however, had clinically mild disease. Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.

Prevalence of Sarcomere Protein Gene Mutations in Preadolescent Children With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM. Seventy-nine consecutive patients diagnosed with HCM aged 13 years or younger underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, and TNNC1), the genes encoding desmin (DES), and the gamma-2 subunit of AMP kinase (PRKAG2) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had 2 mutations). The genes most commonly implicated were MYH7 (48.9%) and MYBPC3 (36.2%); mutations in TNNT2, ACTC, MYL3, and TNNI3 accounted for <5% of cases each. A total of 16.7% patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without or between patients with 2 mutations and those with 1 or no mutations. This study shows that familial disease is common among infants and children with HCM and that, in most cases, disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, the finding that one sixth of patients with sarcomeric disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of familial HCM may have to be revised.

Overlapping Phenotypes

Patient KM is a 26-year-old male in whom a systolic ejection murmur was recently identified on a routine physical examination. As part of his evaluation, he underwent 2-dimensional echocardiography, which revealed asymmetrical left ventricular (LV) hypertrophy with a maximum LV wall thickness of 22 mm in the basal anterior septum and extension of hypertrophy into the posterior septum. His LV ejection fraction was 55%, with a normal cavity size and no evidence of resting LV outflow tract obstruction. In addition, the myocardium was noted to be highly trabeculated from the apex to the midportion of the LV (Figure 1; online-only Data Supplement Movie I). The right ventricle was normal in size and function. He has never developed heart failure …

Restrictive cardiomyopathy

Purpose of review Restrictive cardiomyopathy (RCM) is an uncommon myocardial disease characterized by impaired filling of the ventricles in the presence of normal wall thickness and systolic function. Most affected individuals have severe signs and symptoms of heart failure. A large number die shortly after diagnosis unless they receive a cardiac transplant. Controversy has existed about the exact definition of the condition and diagnostic criteria that will be discussed along with an update on recent findings. Recent findings Previously, RCM was believed to be of idiopathic origin unless otherwise associated with inflammatory, infiltrative or systemic disease. Recent investigations have shown that the condition may be caused by mutations in sarcomeric disease genes and even may coexist with hypertrophic cardiomyopathy in the same family. However, most sarcomeric RCM mutations appear to be de novo and associated with a severe disease expression and an early onset. Summary Recent reports suggest that mutations in sarcomeric contractile protein genes are not uncommon in RCM. These findings imply that RCM may be hereditary, and that clinical assessment of relatives should be considered in addition to genetic investigations when systemic disease has been excluded. Identification and risk stratification of affected relatives is important to avoid adverse disease complications and diminish the rate of sudden death.

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.

The Effects of Candesartan on Left Ventricular Hypertrophy and Function in Nonobstructive Hypertrophic Cardiomyopathy: A Pilot, Randomized Study

Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ss-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy.

Current management of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a heterogeneous clinical syndrome with a wide spectrum of pathophysiologic consequences. Most cases are inherited and caused by sarcomeric protein gene mutations, although phenocopies are often encountered. Genomic research and family studies have improved our recognition of the disease and understanding of its natural history; however, tenuous links exist between genotype and phenotype and thus far have done little to alter clinical management. Surgery and, more recently, implantable cardiac defibrillators have had an impact on sudden cardiac death rates, with improved short- and medium-term survival. Therefore, managing heart failure has become increasingly challenging. Although heart failure due to fibrosis and a progressive loss of contractile function is common, treatment remains largely empiric. Case series and animal studies suggest that biventricular pacing and renin-angiotensin-aldosterone system modifiers may be useful in some patients, but there is a need for large prospective randomized controlled trials to study these and other treatments. Risk stratification and eligibility for sports participation remain hot topics, but one of the greatest challenges is the management of a growing cohort of asymptomatic gene carriers identified during family screening. Ultimately, major advances in treatment and disease prevention will come from a better understanding of the genomic, proteomic, and metabolomic profiles of individual patients.

Abstract 810: Impact of Elevated Plasma Matrix Metalloproteinase-2 on Prognosis in Hypertrophic Cardiomyopathy: Evidence from Long-Term Follow-Up of Genotyped Patients

Background: Previous studies suggest that production of matrix metalloproteinase-2 (MMP-2) which is responsible for cardiac remodeling could determine prognosis of hypertrophic cardiomyopahty (HCM). However, few data exist regarding the importance of MMP-2 production in clinical settings. Therefore, we determined MMP-2 levels correlated to prognosis in HCM with sarcomere gene mutations. Methods and Results: Echocardiography and determination of plasma MMP-2 levels by enzyme-linked immunoassay were simultaneously performed in 31 HCM patients (22 women, mean age 56±12 years) with sarcomere protein gene mutation including 22 for cardiac troponin I, 5 for cardiac myosin binding-protein C, 3 for cardiac troponin T and 1 for beta-myosin heavy chain. Major cardiac events such as hospitalization due to congestive heart failure or ventricular fibrillation and mortality were prospectively examined for follow-up period of 48.4±29.1 months. When patients were divided into two groups (Group A: MMP-2 ≥800 ng/ml n=16 and Group B: MMP-2&lt;800ng/ml n=15), there was no differences in mean age (59.4±11.7 year vs 53.1±11.3 year, p=0.13). On echocardiograms, interventricular septal thickness in group A (11.7±4.2 mm) was smaller than that in group B (15.9±4.8 mm, p&lt;0.05) and percent fractional shortening (FS) was significantly impaired in group A (24.8±12.5%) in comparison with that in group B (37.7±8.1%, p=0.002). There was negative correlation between the MMP-2 levels and FS (p&lt;0.001, r=0.76). The frequency of cardiac events was significantly higher in group A (10 patients of 16 patients) than in group B (1 patient of 15 patients, p=0.0012). Importantly, 5 patients of group A died, although none of groupB patients did (p=0.018). Conclusion: These results demonstrate that the high plasma concentration of MMP-2 (≥800 ng/ml) could be a predictor of prognosis in HCM with sarcomere mutations probably through reflecting impaired left ventricular function.

Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy

To determine the influence of a positive genetic test for hypertrophic cardiomyopathy (HCM) on clinical outcome. A cohort of 203 unrelated patients with HCM (mean +/- SD age, 50+/-18 years) was enrolled from January 1, 2002, through December 31, 2003. They were followed up for a mean +/- SD time of 4.0+/-1.7 years after genetic testing of the 8 HCM-susceptibility genes that encode key sarcomeric/myofilament proteins. The clinical phenotype of those with a positive genetic test (myofilament-positive HCM) was compared with those with a negative genetic test (myofilament-negative HCM). In this cohort of 203 patients, 87 mutations were identified in 126 patients (myofilament-positive HCM, 62%); the remaining 77 patients (38%) were myofilament-negative. Despite similar baseline features, patients with myofilament-positive HCM showed increased risk of the combined end points of cardiovascular death, nonfatal stroke, or progression to New York Heart Association class III or IV compared with the patients with myofilament-negative HCM (25% vs 7%, respectively; independent hazard ratio, 4.27; P=.008). These end points occurred at any age among patients with myofilament-positive HCM (range, 14-86 years), but only in those aged 65 years and older among patients with myofilament-negative HCM. Moreover, patients with myofilament-positive HCM showed greater probability of severe left ventricular systolic and diastolic dysfunction, defined as an ejection fraction of less than 50% and a restrictive filling pattern (P=.02 and P<.02, respectively, vs myofilament-negative HCM). Screening for sarcomere protein gene mutations in HCM identifies a broad subgroup of patients with increased propensity toward long-term impairment of left ventricular function and adverse outcome, irrespective of the myofilament (thick, intermediate, or thin) involved.

Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site. We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.

Sarcomere Mutations in Cardiomyopathy, Noncompaction, and the Developing Heart

In this issue of Circulation , Klaassen and colleagues1 describe mutations in the genes encoding myosin heavy chain (MHC), cardiac actin, and troponin T in patients with left ventricular noncompaction (LVNC). LVNC, defined as excessive and unusual trabeculation of the mature left ventricle, is thought to reflect a developmental failure of the heart to form fully the compact myocardium during the later stages of cardiac development. Previously, mutations in sarcomeric genes have been linked extensively to the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). The finding of similar, but not identical, mutations in patients with LVNC suggests a continuum of cardiomyopathy that includes LVNC and further supports the essential role for normal sarcomere function during cardiac development. Article p 2893 Noncompaction of the ventricular myocardium is characterized by a spongy morphological appearance of the myocardium occurring primarily in the left ventricle and most evident in the apical portion.2 Noncompaction often is visualized as deep recesses within the thickened apex, and these sinusoids communicate with the ventricular cavity. During heart development, the myocardium is initially trabeculated during a period before coronary artery development and is thought to be an adaptation to provide blood flow to the developing myocardium. The development of the coronary vasculature is associated temporally with the loss of trabeculae and the full maturation of the compact myocardium. Between embryonic weeks 5 and 8, the trabeculae regress as the compact myocardium develops from base to apex. Isolated LVNC is defined as occurring in the absence of other cardiac structural malformation. Nonsyndromic LVNC refers to the absence of other extracardiac developmental disorders. In 2006, the American Heart Association scientific statement on classification of cardiomyopathies reclassified LVNC as its own disease entity.3 Klaassen et al now link genetic sarcomere defects to both familial and sporadic isolated, …