Case Of Hypertrophic Cardiomyopathy Research Articles

Cardiac myosin binding protein-C: a novel sarcomeric target for gene therapy

Through its ability to interact with both the thick and thin filament proteins within the sarcomere, cardiac myosin binding protein-C (cMyBP-C) regulates the contractile properties of the myocardium. The central regulatory role of cMyBP-C in heart function is emphasized by the fact that a large proportion of inherited hypertrophic cardiomyopathy cases in humans are caused by mutations in cMyBP-C. The primary dysfunction in cMyBP-C-related cardiomyopathies is likely to be abnormal myofilament contractile function; however, currently, there are no effective therapies for ameliorating these contractile defects. Thus, there is a compelling need to design novel therapies to restore normal contractile function in cMyBP-C-related cardiomyopathies. To this end, concepts gleaned from various structural, functional, and biochemical studies can now be utilized to engineer cMyBP-C proteins that, when incorporated into the sarcomere, can significantly improve contractile function. In this review, we discuss the rationale for cMyBP-C-based gene therapies that can be utilized to treat contractile dysfunction in inherited and acquired cardiomyopathies.

Hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary fistulae – A case report. One genotype, three phenotypes?

The authors present a rare case of hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary artery-left ventricular fistulae in a 42-year-old woman presenting with non-ST-elevation myocardial infarction. Coronary angiography, transthoracic echocardiography and cardiac magnetic resonance revealed the structural abnormalities of the left ventricle and the coronary tree.

Miocardiopatia hipertrófica associada a ventrículo esquerdo não compactado e fístulas coronárias – a propósito de um caso clínico. Um genótipo, três fenótipos?

The authors present a rare case of hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary artery-left ventricular fistulae in a 42-year-old woman presenting with non-ST-elevation myocardial infarction. Coronary angiography, transthoracic echocardiography and cardiac magnetic resonance revealed the structural abnormalities of the left ventricle and the coronary tree.

Primary prevention of sudden cardiac death in a low-risk child with familial hypertrophic cardiomyopathy: the role of cardiac magnetic resonance imaging

Sirs: The incidence of hypertrophic cardiomyopathy (HCM) is 0.2 %, and this condition is considered the most common genetic cardiovascular disease. In addition, HCM is one of the most common causes of sudden cardiac death (SCD) in young people [1]. An implantable cardioverter defibrillator (ICD) is a highly effective device for inhibiting ventricular tachyarrhythmias. It is generally agreed that the indications for an ICD strongly support the secondary prevention of SCD [2]. However, the indications for primary preventive ICD placement for SCD remain controversial. Recently, it has been shown that late gadolinium enhancement magnetic resonance imaging (LGE-MRI) can be used to evaluate myocardial fibrosis as an arrhythmic substrate [3, 4]. Here, we report a familial case of HCM in which we decided to place an ICD as primary prevention for SCD based on the LGE-MRI findings. The cases described are two brothers whose father and grandmother were diagnosed with HCM, and the elder brother of the father had a sudden death. Gene analysis was carried out in the father and the two brothers described here. An Ala63Val mutation in exon 2 of TPM1 gene, which encodes alpha tropomyosin, was found (Fig. 1a). The eldest brother in our two cases was 18 years old. He was diagnosed with HCM following medical screening at age 13. The interventricular septum diameter (IVSd) on echocardiography was 18.2 mm (Z-score was 8.5), which is far from the SCD risk criteria (over 30 mm) at age 18. LGE-MRI demonstrated diffuse contrast enhancement in the left ventricular myocardium. The extent of LGE was 8 % of the LV mass using previously reported methods [1] (Fig. 1b). The patient had been managed with mild limitation of physical activity. At the age of 18, he had syncope due to ventricular tachycardia (Fig. 1c) and was successfully resuscitated without any complications. Then, an ICD was implanted for secondary prevention of SCD. The youngest brother of the above-mentioned case was also diagnosed with HCM following medical screening at age 6. He has been managed by mild mobility limitation and treated by beta-blockers because a left ventricular outflow tract obstruction was detected by echocardiography. Though the extent of myocardial fibrosis using LGE-MRI was only 1 % of the LV mass at age 10, it markedly progressed to 16 % in 2 years (Fig. 1d). In addition, LGEMRI demonstrated a diffuse pattern of enhancement, similar to that observed in the elder brother. Because the presence of LGE was seen more strongly in the younger brother than in the elder brother, the younger brother was scheduled for the placement of a prophylactic ICD. The selection of patients for the primary prevention of SCD with an ICD has been predicated on the assessment of well-known five key risk factors, which were reported previously [2]. Recently, ACCF/AHA guidelines indicated primary prevention with the ICD a class IIa indication, based on the presence of one or more conventional key risk factors [5]. However, it is difficult to determine whether our case represents a form of primary prevention of SCD with an ICD because it was unclear whether the cause of sudden death in a family member was related to hypertrophic cardiomyopathy. In addition, there was no case of sudden death in a first-degree relative [2]. Recently, myocardial fibrosis detected by LGE-MRI was reported as a candidate for a new risk factor that may be able to predict SCD. Green et al. [6] mentioned that H. Yamazawa (&) A. Takeda K. Takei T. Furukawa Department of Pediatrics, Hokkaido University School of Medicine, North 15 West 7, Kitaku, Sapporo, Hokkaido 060-8638, Japan e-mail: h-yamazawa@umin.org

Vagal Enhancement Linking Abnormal Blood Pressure Response and Subendocardial Ischemia in Hypertrophic Cardiomyopathy

An abnormal blood pressure response to exercise has been reported to be associated with left ventricular subendocardial ischemia in patients with hypertrophic cardiomyopathy (HCM), but the underlying mechanism remains unclear. We report a case of HCM with an abnormal blood pressure response and subendocardial ischemia, in which the analysis of heart rate variability revealed exercise-induced vagal enhancement. The present case highlights the possible mechanism linking abnormal blood pressure response and left ventricular subendocardial ischemia in patients with HCM.

An In Silico Analysis of Troponin I Mutations in Hypertrophic Cardiomyopathy of Indian Origin

Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases.

The ECG after out-of-hospital cardiac arrest is a reliable tool to guide immediate triage? Analysis of 88 patients matched with acute coronary angiography

Background: In comatose patients resuscitated (ROSC) after out-of-hospital cardiac arrest (OHCA) the ECG is not considered a reliable tool to predict acute coronary-artery occlusion. Thus, immediate coronary angiography (CA) has been suggested for diagnostic and therapeutic purposes. However, CA could delay therapeutic hypothermia (TH), when indicated, and has other logistics drawbacks. Therefore, aim of the study was to evaluate in survivors of OHCA the reliability of ECG to triage to immediate or delayed CA and interventions. Methods: Observational prospective analysis of patients (pts) with ROSC after OHCA admitted alive to the Emergency Room (ER) of a tertiary center from March 27, 2004 to December 31, 2012 treated with TH and undergoing early CA and PCI. Results: We analysed 142 pts patients with ROSC after OHCA, admitted alive to our hospital, that underwent early CA (median age: 66.5 (IQR 55-74) yrs, males: 70%, shockable rhythm: 71%, interval OHCA-resuscitation ≤20 min: 69%) with at least 2 consecutive ECGs post ROSC available. 88 pts fulfilled the study criteria and ECG were analyzed from two different operators. The mean time between ROSC and the first ECG was 5±4 min. 36 pts (41%) meet the ECG criteria for ST elevated myocardial infarction (STEMI, Group A), 28 pts (32%) for subendocardial ischemia (Group B), and in 24 (27%) pts there were no ECG signs of ischemia (Group C). In the Group A at early CA 23 pts (64%) had acute coronary occlusion, 7 pts (19%) subocclusion of at least one vessel, and 6 (17%) 3 vessels disease or no lesions. 30 (83%) pts underwent successful PCI. In the Group B 7 pts (25%) underwent to PCI (1 case 100% acute occlusion of distal right coronary artery and 6 cases of stenosis 70-90%). As opposed in the Group C, no one patient had acute coronary occlusion at CA. Notably, only 1 case in the Group B and 1 case in the Group C developed elevated Troponin I (one case of myocarditis and one case ofhypertrophic cardiomyopathy, respectively). The in-hospital crude mortality of patients was 20% in Group A, 15% in Group B and 22% in Group C; 60% of survivors were discharged with a good neurological outcome. Conclusions: Our preliminary data suggest that a simple ECG after ROSC in OHCA survivors could be a good predictor for acute coronary occlusion. Therefore, ST elevation cases could be triage to immediate CA (Group A), in the presence of ECG ischemia the CA can be considered (Group B), while in the absence of ECG ischemia CA could be delayed (Group C). These findings, if confirmed by adequately sized studies, could simplify the triage of ROSC pts after OHCA to CA.

Autosomal Recessive Transmission of MYBPC3 Mutation Results in Malignant Phenotype of Hypertrophic Cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.MethodsA pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.ResultsA novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.ConclusionsOur data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

HEART's Original [症例] 院外心肺停止後脳低体温療法が奏効し社会復帰に成功した肥大型心筋症の1例

HEART's Original [症例] 院外心肺停止後脳低体温療法が奏効し社会復帰に成功した肥大型心筋症の1例

症例 経過中心電図で異常Q波が出現した肥大型心筋症の4症例 異常Q波出現の臨床的意義について

症例 経過中心電図で異常Q波が出現した肥大型心筋症の4症例 異常Q波出現の臨床的意義について

症例 運動負荷によりST-Tの著明な変化を示した肥大型心筋症の母子例

症例 運動負荷によりST-Tの著明な変化を示した肥大型心筋症の母子例

The Clinical Case of Hypertrophic Cardiomyopathy in a Patient With Systemic Lupus Erythematous

The Clinical Case of Hypertrophic Cardiomyopathy in a Patient With Systemic Lupus Erythematous

ASSA13-06-5 Autosomal Recessive Tansmission of MYBPC3 Mutation Resulted in Malignant Phenotpye of Hypertrophic Cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) secondary to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved. Methods A pedigree was identified with suspected autosomal recessive transmission of HCM. The proband and his younger brother were diagnosed with HCM, and his older brother incurred sudden cardiac death at 23 years of age. However, other family members were all clinically normal. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members. Results A novel missense mutation (c.1469G > T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM. Conclusions These data suggest that the inheritance pattern of HCM may be more complex than previously thought. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counselling.

Loss of the AE3 Cl−/HCO−3 exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart

Cl−/HCO−3 exchangers are expressed abundantly in cardiac muscle, suggesting that HCO−3 extrusion serves an important function in heart. Mice lacking Anion Exchanger Isoform 3 (AE3), a major cardiac Cl−/HCO−3 exchanger, appear healthy, but loss of AE3 causes decompensation in a hypertrophic cardiomyopathy (HCM) model. Using intra-ventricular pressure analysis, in vivo pacing, and molecular studies we identified physiological and biochemical changes caused by loss of AE3 that may contribute to decompensation in HCM. AE3-null mice had normal cardiac contractility under basal conditions and after β-adrenergic stimulation, but pacing of hearts revealed that frequency-dependent inotropy was blunted, suggesting that AE3-mediated HCO−3 extrusion is required for a robust force-frequency response (FFR) during acute biomechanical stress in vivo. Modest changes in expression of proteins that affect Ca2+-handling were observed, but Ca2+-transient analysis of AE3-null myocytes showed normal twitch-amplitude and Ca2+-clearance. Phosphorylation and expression of several proteins implicated in HCM and FFR, including phospholamban (PLN), myosin binding protein C, and troponin I were not altered in hearts of paced AE3-null mice; however, phosphorylation of Akt, which plays a central role in mechanosensory signaling, was significantly higher in paced AE3-null hearts than in wild-type controls and phosphorylation of AMPK, which is affected by Akt and is involved in energy metabolism and some cases of HCM, was reduced. These data show loss of AE3 leads to impaired rate-dependent inotropy, appears to affect mechanical stress-responsive signaling, and reduces activation of AMPK, which may contribute to decompensation in heart failure.

A new diagnostic feasibility for cardiomyopathy utilizing acoustic microscopy

Aims: Dilated cardiomyopathy often shows left ventricular systolic dysfunction, although histologically it always exhibits non-specific abnormality. We hypothesized that myocyte sound speed might be altered due to incomplete protein accumulation in cells. Methods and Results: Ninety eight biopsied samples were obtained from 49 patients comprising 43 with clinical dilated cardiomyopathy and 6 with hypertrophic cardiomyopathy. Sound speed was evaluated in deparaffinized 10 μm thick sections using an acoustic microscope (frequency range: 50 - 105 MHz). Conventional histology revealed 7 cases of persistent myocarditis derived from clinical dilated cardio- myopathy samples. Histology of the remaining dilated cardiomyopathy patients indicated non-specific abnormality. All hypertrophic cardiomyopathy cases exhibited myocardial disarray. Ten normal autopsied hearts were compared as controls. The sound speed of controls was 1627 ± 30m/sec. The sound speed in dilated cardiomyopathy samples (1700 ±51m/sec) was 1.045-fold faster compared to controls. The sound speed in hypertrophic cardiomyopathy samples (1734 ±51m/sec, 1.066-fold compared to controls) was faster than that of the myocarditis group (1672 ±30m/sec, 1.028-fold) (P = 0.0218). Furtheremore, desmin expression was evaluated as extent of emergence (grading 0 - 4). The desmin expression score in hypertrophic cardiomyopathy samples (2.7 ± 0.8) was significantly higher than in other groups (dilated 2.0 ± 1.4, myocarditis 1.6 ± 1.5 vs., controls 0, P ≤ 0.0001, 0.0001, 0.0129, respectively). Conclusion: Cardio-myopathy enhanced the sound speed, which correlated with the elasticity of myocytes, following the impaired compliance of left ventricle, despite the absence of histological changes. The elevation of sound speed of myocytes may be linked to cytoskeletal changes. Myocyte sound speed may be a new diagnostic tool for diagnosis of idiopathic cardiomyopathy independently of conventional histological diagnosis.

Progressive breathlessness in an Afro Caribbean hypertensive subject

The sensitivity and specificity of structural assessment of the heart by echocardiography in black hypertensive patients presenting with symptoms of heart failure is often incomplete. Cardiovascular magnetic resonance, mainly by virtue of its ability to characterize myocardial tissue composition, may be of value in differentiating some of the common pathologies noninvasively. We present an illustrative case of hypertrophic cardiomyopathy in a British Afro Caribbean hypertensive patient where at least some features of familial amyloidosis were present on screening echocardiography. Cardiovascular magnetic resonance examination of this case established not only the usefulness of this technique, but also highlighted the importance of recognizing the variations and departure from the usual which one associates with hypertrophic cardiomyopathy, so as to arrive at the final diagnosis.

Impact of Systolic Dysfunction in Genotyped Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere, and approximately 5% of cases of HCM show systolic dysfunction with poor prognosis. Few data exist regarding the systolic dysfunction in a large population of genotyped HCM subjects. The aim of this study was to assess the systolic dysfunction and prognosis in sarcomere gene mutation carriers. The study included 157 sarcomere gene mutation carriers from 69 unrelated HCM families (87 males; mean age, 46.5 ± 20.5 years). After exclusions for systolic dysfunction at baseline, 107 subjects underwent serial echocardiograms. At a mean follow-up of 7.0 years, 12 subjects experienced systolic dysfunction. In multivariate Cox analysis, systolic dysfunction was related to age and ejection fraction at initial evaluation (P < 0.001 and P = 0.020, respectively), and was associated with the absence of mutations in the cardiac myosin-binding protein C gene (MYBPC3) (P = 0.042). When the subjects were divided into MYBPC3 and non-MYBPC3 mutation carriers, and time from birth to development of systolic dysfunction was compared, the rate of systolic dysfunction was higher in the non-MYBPC3 group than in MYBPC3 group (Kaplan-Meier, log-rank test, P = 0.010). After the onset of systolic dysfunction, 11 of 12 subjects died during a mean follow-up of 8.3 years. Non-MYBPC3 mutation carriers developed left ventricular systolic dysfunction more frequently than MYBPC3 mutation carriers, and the majority of sarcomere gene mutation carriers with systolic dysfunction had fatal outcomes during follow-up. This suggests that subjects with mutations in sarcomeric genes require careful management for systolic dysfunction.

Websites of note

Websites of note

Apico-Aortic Conduit for Severe Hypertrophic Cardiomyopathy: Sudden Death despite Conduit Patency 31 Years Postoperatively

Although small experiences have been described with the use of apico-aortic valved conduit in the treatment of hypertrophic cardiomyopathy (HCM), the long-term follow-up has never been previously reported. In a young female patient with symptomatic HCM and a prognostically unfavorable phenotype, apico-aortic conduit was chosen instead of conventional myectomy because severe ventricular hypertrophy involved the whole ventricle, making outflow tract cavity virtually absent in systole. Close clinical and imaging follow-up was postoperatively performed. The patient remained asymptomatic, without cardioactive drug therapy for 30 years, also experiencing 2 successful pregnancies. A striking finding was the perfect patency of the conduit at the last follow-up control (31 years), with computed tomography and echocardiography showing no calcification of the porcine Hancock bioprosthesis inside the graft. Nevertheless, the disease slowly evolved towards the dilative phase and the patient experienced sudden death while scheduled for implantation of defibrillator in waiting list for heart transplant.The present case could suggest that, in selected cases of HCM not treatable by myectomy, apico-aortic conduit may be an option. The relief of the obstruction can provide even long-term freedom from symptoms, however, late evolution to end-stage cannot be prevented.

Two founder mutations in the alpha-tropomyosin and the cardiac myosin-binding protein C genes are common causes of hypertrophic cardiomyopathy in the Finnish population

Background. Hypertrophic cardiomyopathy (HCM) is predominantly caused by a large number of various mutations in the genes encoding sarcomeric proteins. However, two prevalent founder mutations for HCM in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes have previously been identified in eastern Finland. Objective. To assess the prevalence of these founder mutations in a large population of patients with HCM from all over Finland. Patients and methods. We screened for two founder mutations (TPM1-D175N and MYBPC3-Q1061X) in 306 unrelated Finnish patients with HCM from the regions covering a population of ∼4,000,000. Results. The TPM1-D175N mutation was found in 20 patients (6.5%) and the MYBPC3-Q1061X in 35 patients (11.4%). Altogether, the two mutations accounted for 17.9% of the HCM cases. In addition, 61 and 59 relatives of the probands were found to be carriers of TPM1-D175N and MYBPC3-Q1061X, respectively. The mutations showed regional clustering. TPM1-D175N was prevalent in central and western Finland, and MYBPC3-Q1061X in central and eastern Finland. Conclusion. The TPM1-D175N and MYBPC3-Q1061X mutations account for a substantial part of all HCM cases in the Finnish population, indicating that routine genetic screening of these mutations is warranted in Finnish patients with HCM.