Anterior myocardial infarction in a patient with isolated left ventricular non-compaction.

We presented a 55-year-old male patient with isolated left ventricular non-compaction who was admitted to our emergency department for chest pain and exertional dyspnoea. He was hospitalised due to anterior myocardial infarction, and during his assessment, isolated left ventricular non-compaction was diagnosed.

CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy.

AIMS: Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). METHODS AND RESULTS: In TG cardiomyocytes, the Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10 nM). This increase in SpF was largely reversed by a CaMKII inhibitor (KN-93), but not by a protein kinase A inhibitor (H89). CaMKII phosphorylation at Ser2814 in RyR2 was increased significantly in TG. Spontaneous Ca2+ transients (sCaTs) after cessation of a 1-5 Hz pacing, frequently observed in ISO-treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca2+ sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca2+ release is mediated by destabilized RyR2. CONCLUSIONS: In FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII-mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca2+]i, causing aberrant Ca2+ release leading to lethal arrhythmia.

Sudden Collapse of a Preschool-Aged Child on the Playground.

PURPOSE: Primary cardiac events are rare in children. There is little information in the literature regarding the most appropriate emergency department (ED) management of this type of pediatric patient, especially with regard to medication use. SUMMARY: This case highlights the pediatric ED evaluation and treatment of sudden collapse in a child with an ultimate diagnosis of hypertrophic cardiomyopathy. Cardiac disorders represent 2% to 6% of cases of pediatric syncope presenting to EDs, particularly if there are previous prodromal symptoms and/or a history of exertion. Evaluation should include electrocardiogram, chest radiograph, and echocardiogram if available. Management should focus on decreasing the potential for a recurring arrhythmia while maintaining cardiac preload, which can be worsened with certain medication use. CONCLUSIONS: Although primary cardiac events in children are rare, a high index of suspicion should be maintained especially with a history of prodromal symptoms or collapse during exertion. If cardiac etiology is suspected, deliberate management should be used to exclude a treatment that could be detrimental. This case report provides an initial assessment and recommendations for management of these patients.

Myostatin regulates energy homeostasis in the heart and prevents heart failure.

RATIONALE: Myostatin is a major negative regulator of skeletal muscle mass and initiates multiple metabolic changes, including enhanced insulin sensitivity. However, the function of myostatin in the heart is barely understood, although it is upregulated in the myocardium under several pathological conditions. OBJECTIVE: Here, we aimed to decipher the role of myostatin and myostatin-dependent signaling pathways for cardiac function and cardiac metabolism in adult mice. To avoid potential counterregulatory mechanisms occurring in constitutive and germ-line-based myostatin mutants, we generated a mouse model that allows myostatin inactivation in adult cardiomyocytes. METHODS AND RESULTS: Cardiac MRI revealed that genetic inactivation of myostatin signaling in the adult murine heart caused cardiac hypertrophy and heart failure, partially recapitulating effects of the age-dependent decline of the myostatin paralog growth and differentiation factor 11. We found that myostatin represses AMP-activated kinase activation in the heart via transforming growth factor-ß-activated kinase 1, thereby preventing a metabolic switch toward glycolysis and glycogen accumulation. Furthermore, myostatin stimulated expression of regulator of G-protein signaling 2, a GTPase-activating protein that restricts Gaq and Gas signaling and thereby protects against cardiac failure. Inhibition of AMP-activated kinase in vivo rescued cardiac hypertrophy and prevented enhanced glycolytic flow and glycogen accumulation after inactivation of myostatin in cardiomyocytes. CONCLUSIONS: Our results uncover an important role of myostatin in the heart for maintaining cardiac energy homeostasis and preventing cardiac hypertrophy.

Fragmented QRS predicts heart failure progression in patients with hypertrophic cardiomyopathy.

BACKGROUND: Although fragmented QRS complex (frag-QRS) reflecting intra-ventricular conduction delay has been shown to be a prognostic marker for cardiac events, few data exist regarding the impact of frag-QRS on cardiac events in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Ninety-four HCM patients (56 male; mean age, 58 ± 17 years) were retrospectively investigated. Frag-QRS was defined as the presence of various RsR' patterns in at least 2 contiguous ECG leads. Major arrhythmic events (MAE) were defined as sudden cardiac death, and combined sustained ventricular tachycardia/ventricular fibrillation. New-onset atrial fibrillation (AF) was diagnosed based on ECG during provisional or routine medical examination. Heart failure (HF) with hospitalization was defined as hospital admission due to subjective or objective symptoms. Frag-QRS was detected in 31 patients (33%).TNNI3 was the most frequent disease-causing gene. Median follow-up was 4.6 years. The 4-year cumulative survival rates of cardiac death, MAE, new-onset AF and HF with hospitalization were 97.6%, 94.6%, 87.5% and 89.3%, respectively. On multivariate analysis, frag-QRS was significantly associated with HF with hospitalization (adjusted hazard ratios [95% confidence intervals]: 5.4 [1.2-36], P=0.03). Moreover, HF-free survival was significantly lower in the frag-QRS (+) group compared to the frag-QRS (-) group (79.0% vs. 95.1%, P=0.03). CONCLUSIONS: Frag-QRS is associated with HF with hospitalization in HCM patients who had a unique distribution of gene mutations.

Hypertrophic or non-compaction cardiomyopathy: a challenging diagnosis.

We present a rare case of mutation in the cardiac alfa actine (ACTC) gene. This patient showed phenotypic features of both hypertrophic and non-compaction cardiomyopathy. These cases may represent a diagnostic challenge in daily clinical practice.

[Renin-angiotensin-aldosterone system in hypertrophic cardiomyopathy].

Keeping in mind an important role of renin-angiotensin aldosterone system (RAS) in developing of cardiac remodeling and fibrosis, genetic polymorphisms coding its components could have influence with clinical variants of the course. Biomarkers could appear predictors of adverse. To examine the contribution of the RAS to developing of different hypertrophic cardiomyopathy (HCM) clinical variants of the course we studied 58 patients with HCM and controls comparable by age and gender. All patients were genotyped of gene polymorphisms CMA1 A(-1903)G rs1800875, AGTM235T rs699, AGTR1 A1166C rs5186, CYP11B2-344 T/C rs1799998. Angiotensin-converting enzyme (ACE) and angiotensin II (AII) levels were measured in 40 patients with HCM and 39 controls. We found out that AII were significantly decreased in patients with HCM than in healthy controls. The positive correlation between AII and left ventricle posterior wall (LVPW) were detected. Severity of heart hypertrophy were associated with pejorative genotype of AGT M235T polymorphism and CMA1 A(-1903) polymorphism. Significant association between the AG genotype of CMA1 A(-1903) polymorphism and angina class II-III and ventricular extrasystole of high gradation was observed. Our data not only support the hypothesis that RAAS polymorphisms may influence phenotype, but also allow for create new approaches to possible predicting adverse outcomes.

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

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

Fast diastolic swinging motion of the mitral valve as a clinical marker of familial hypertrophic cardiomyopathy in genetically affected young children without left ventricular hypertrophy: a new role for noninvasive imaging?

Structural mitral valve (MV) abnormalities are common in patients with hypertrophic cardiomyopathy (HCM). This is the first report demonstrating MV abnormalities in very young children as the sole overt clinical feature of a known HCM-causing sarcomere protein gene mutation. Due to MV leaflet elongation, we also noticed a typical fast diastolic swinging motion of the MV in our patients. This novel echocardiographic feature may be used as a clinical marker of HCM disease in the absence of left ventricular hypertrophy.

Genetic etiology and evaluation of sudden cardiac death.

A wide range of inherited syndromes can result in ventricular arrhythmias and sudden cardiac death (SCD). The natural histories of inherited arrhythmia syndromes are highly variable and current risk stratification techniques are limited. Thus, the management of these conditions can be difficult and often involves a combination of risk assessment, lifestyle modification, cardiac interventions, counselling, and family screening. Recent advances in high throughput sequencing have enabled routine testing in patients with a high clinical index of suspicion for an inherited arrhythmia condition, and cascade screening in relatives of mutation carriers. Given the complexity in screening and data interpretation that has been introduced by recent genomic advances, individuals with inherited arrhythmia syndromes are encouraged to seek care at specialized centers with cardiovascular genetics expertise. In this review, we discuss the etiologies of SCD syndromes and discuss strategies for the evaluation of patients at risk for SCD with a focus on the role of genetic testing and family screening.

Hypertrophic Cardiomyopathy in Saudi Arabia: A Systematic Review of the Epidemiological, Clinical, and Imaging Features.

BACKGROUND: A systematic review was performed to deliver a critical view of clinical and research practice on hypertrophic cardiomyopathy (HCM) in Saudi Arabia. Scopus, PubMed, and Google Scholar databases were searched for original articles reporting clinical and/or imaging findings among HCM patients in Saudi Arabia. Of 559 records identified, 3 studies and 1 abstract were included, involving 169 patients. METHODS: The mean age ranged between 40and 56 years, up to 93.3% were males. A family history of HCM was reported in one study (5%), and sudden cardiac death was investigated in two studies (9% and 13%). Dyspnea was the most frequent symptom (60-68.7%) reported, followed by chest pain (12.5%-73.3%). RESULTS: Regarding complications, atrial fibrillation was reported among 0-25% of the patients, mitral regurgitations among 13.3-50%, and ventricular tachycardia among 5-12.5%. Imaging parameters were inadequately documented and suggested a high prevalence of left atrial enlargement, SVI + RV5 > 35 mm, blocks, and asymmetric septal hypertrophy. CONCLUSION: The ejection fraction was reported by two studies with a mean±SD of 68±13% and 77.2±8.07%. The researchers stress the paucity, low quality, and disparity in time of original studies about HCM in Saudi Arabia and recommend conducting national multicenter studies, with appropriate design, notably using screening-based recruitment methods.

Clinical utility of cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by substantial genetic and phenotypic heterogeneity, leading to considerable diversity in clinical course including the most common cause of sudden death in young people and a determinant of heart failure symptoms in patients of any age. Traditionally, two-dimensional echocardiography has been the most reliable method for establishing a clinical diagnosis of HCM. However, cardiovascular magnetic resonance (CMR), with its high spatial resolution and tomographic imaging capability, has emerged as a technique particularly well suited to characterize the diverse phenotypic expression of this complex disease. For example, CMR is often superior to echocardiography for HCM diagnosis, by identifying areas of segmental hypertrophy (ie., anterolateral wall or apex) not reliably visualized by echocardiography (or underestimated in terms of extent). High-risk HCM patient subgroups identified with CMR include those with thin-walled scarred LV apical aneurysms (which prior to CMR imaging in HCM remained largely undetected), end-stage systolic dysfunction, and massive LV hypertrophy. CMR observations also suggest that the cardiomyopathic process in HCM is more diffuse than previously regarded, extending beyond the LV myocardium to include thickening of the right ventricular wall as well as substantial morphologic diversity with regard to papillary muscles and mitral valve. These findings have implications for management strategies in patients undergoing invasive septal reduction therapy. Among HCM family members, CMR has identified unique phenotypic markers of affected genetic status in the absence of LV hypertrophy including: myocardial crypts, elongated mitral valve leaflets and late gadolinium enhancement. The unique capability of contrast-enhanced CMR with late gadolinium enhancement to identify myocardial fibrosis has raised the expectation that this may represent a novel marker, which may enhance risk stratification. At this time, late gadolinium enhancement appears to be an important determinant of adverse LV remodeling associated with systolic dysfunction. However, the predictive significance of LGE for sudden death is incompletely resolved and ultimately future large prospective studies may provide greater insights into this issue. These observations underscore an important role for CMR in the contemporary assessment of patients with HCM, providing important information impacting diagnosis and clinical management strategies.

The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic resonance.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the heart. HCM is characterized by a wide range of clinical expression, ranging from asymptomatic mutation carriers to sudden cardiac death as the first manifestation of the disease. Over 1000 mutations have been identified, classically in genes encoding sarcomeric proteins. Noninvasive imaging is central to the diagnosis of HCM and cardiovascular magnetic resonance (CMR) is increasingly used to characterize morphologic, functional and tissue abnormalities associated with HCM. The purpose of this review is to provide an overview of the clinical, pathological and imaging features relevant to understanding the diagnosis of HCM. The early and overt phenotypic expression of disease that may be identified by CMR is reviewed. Diastolic dysfunction may be an early marker of the disease, present in mutation carriers prior to the development of left ventricular hypertrophy (LVH). Late gadolinium enhancement by CMR is present in approximately 60% of HCM patients with LVH and may provide novel information regarding risk stratification in HCM. It is likely that integrating genetic advances with enhanced phenotypic characterization of HCM with novel CMR techniques will importantly improve our understanding of this complex disease.

Can an athlete have too much ticker? Hypertrophic cardiomyopathy in young athletes.

Sudden cardiac death (SCD) is an uncommon but devastating potential consequence of participation in competitive sport. It is seen in adolescent and young adult athletes. The most common cause of this, hypertrophic cardiomyopathy (HCM), is a genetic disorder responsible for more than a third of cases and is manageable. Screening is undertaken for HCM, using differing strategies in Europe and North America. Screening and early diagnosis have reduced the mortality rate but has come at a significant economic cost. The evidence and relevant arguments for and against screening are presented together with management strategies as reflected by an illustrative case.

Hypertrophic cardiomyopathy in children.

Hypertrophic cardiomyopathy (HCM) characterized by asymmetric ventricular septal hypertrophy, is the commonest cause of sudden cardiac death (SCD) in the young. The underlying etiology of HCM in the childhood and adolescent patients is diverse. Moreover, the prognosis of pediatric HCM depends on the age of presentation and etiology. Despite the complexity of children with obstructive HCM, surgical treatment results in a favorable outcome for carefully selected patients in experienced tertiary referral center in contemporary era. Implantable cardioverter-defibrillator (ICD) remains the most effective and reliable treatment to prevent SCD. New pediatric SCD risk prediction model, which has good discrimination and calibration and can distinguish patients who are most benefit from an ICD implantation, is expected to be further refined in the future.

Significance of Pulmonary Hypertension in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent hereditary cardiac disease characterized by the presence of left ventricular and/or septal hypertrophy in the absence of other underlying cardiac disorders. Patients of HCM have a broad range of clinical presentation from being asymptomatic to severely ill condition requires hospitalization and urgent management. Broadly, HCM is classified in two variants: obstructive and nonobstructive. The mainstay of diagnosis is through echocardiography. As HCM chiefly affect the left heart, pulmonary hypertension (PH) is an expected complication of this disease. Though the existence of PH in HCM is known for a long time, its clinical significance, underlying mechanism, and prognostic impact in HCM have been revealed by few recent studies. Specifically, studies have shown increased events of thromboembolism, atrial fibrillation, and heart failure in patients with HCM and PH. These studies elucidated the underlying mechanism of PH in HCM--a rise of pressure in the precapillary and postcapillary pulmonary vasculature. In addition to left ventricular involvement, studies have shown right ventricular involvement and the association of left and right ventricular dysfunction in these patients. Further, it has been shown that surgical intervention to reduce septal thickness improves survival in pharmacotherapy nonresponders and the presence of PH does not increase mortality in these patients. We present a comprehensive review exploring the prevalence, underlying mechanisms, and impact of PH on HCM.

A novel nonsense mutation in TNNT2 in a Chinese pedigree with hypertrophic cardiomyopathy: A case report.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease and a common cause of sudden cardiac death, heart failure, atrial fibrillation and stroke. In families affected by HCM, genotyping is useful for identifying susceptible relatives. In the present study, we investigated the disease-causing mutations in a three-generation Chinese family with HCM using whole exome sequencing (WES). PATIENT CONCERNS: The proband, a 50-year-old man, was diagnosed with HCM at the age of 41 years. He presented with an asymmetric hypertrophic interventricular septum and a maximum interventricular septum thickness of 18.04 mm. His third elder sister, niece and daughter were also clinically affected by HCM. DIAGNOSIS: Autosomal dominant HCM. INTERVENTIONS: Seven family members, including 4 affected members, accepted WES. The genetic variants were subsequently called using Genome Analysis Toolkit and annotated using the InterVar program. Following frequency filtration by the Genome Aggregation Database, the variants were evaluated using an in-house bioinformatics analysis pipeline. OUTCOMES: HCM was transmitted as an autosomal dominant trait in the family. An extremely rare stop gained mutation, rs796925245 (g.1:201359630G>A, c.835C>T, p.Gln279Ter) in the troponin T2 (TNNT2) gene was identified as the disease-causing mutation. The stop gained mutation was predicted to result in a truncated troponin T protein in cardiac sarcomere. An adolescent family member who had normal echocardiographic measurements was found to carry the same disease-causing mutation. LESSONS: A novel nonsense TNNT2 mutation was identified as the HCM-causing mutation in this Chinese pedigree. Since HCM shows a low penetrance by clinical criteria in adolescents, the adolescent mutation carrier, who is still clinically unaffected, should be offered routine follow-ups and sport activity recommendations to prevent adverse events including sudden cardiac death in the future.

Clinical profiles of hypertrophic cardiomyopathy with apical phenotype--comparison of pure-apical form and distal-dominant form.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) with an apical phenotype, in which hypertrophy of the myocardium predominantly involves the apex of the left ventricle, is not uncommon in Japan, but its morphologic variations are not well recognized. The aim of this study was to investigate if these variations have different clinical characteristics although they are still confused to be the same. METHODS AND RESULTS: Patients with the apical phenotype were divided into 2 groups, the "pure-apical" form and the "distal-dominant" form, and their clinical profiles were compared. From the study cohort of 264 patients with HCM, 80 (30%) were classified as having the apical phenotype: 51 with the pure-apical form and 29 with the distal-dominant form. The age at diagnosis was approximately 60 years, and in both groups the majority were male. The distal-dominant group had a significantly larger left atrial diameter (43 vs 39 mm) and higher ratio of proven familial HCM (28 vs 6%), and were more symptomatic (New York Heart Association >or=3) at presentation (17 vs 0%). The event-free rate of cardiovascular events in patients with the distal-dominant form was significantly worse (log-rank P=0.012) than that in patients with the pure-apical form (follow-up period: asymptotically approximately 5 years). CONCLUSIONS: The 2 phenotypes of apical HCM should be recognized and distinguished clinically.

[Malignant form of familial hypertrophic cardiomyopathy complicated with ventricular fibrillation in siblings. Electrocardiogram in hypertrophic cardiomyopathy - a review]. / Zlosliwa postac rodzinnej kardiomiopatii przerostowej z migotaniem komór u rodzenstwa. Nowosci dotyczace zmian elektrokardiograficznych w kardiomiopatii przerostowej - przeglad pismiennictwa.

A family with hypertrophic cardiomyopathy (HCM) (15-year-old boy, his 17-year-old sister and 45-year-old father) is described. The first sign of HCM was cardiac arrest (CA) due to ventricular fibrillation (VF) in a boy. A few months later sister of proband had the episode of CA due to VF. Both had implanted cardioverter-defibrillator (ICD). Echocardiography revealed HCM in both cases and in a father, who also received prophylactic ICD. During 24-month follow-up fast VT was observed in sister of proband. We review electrocardiographic changes in HCM and their correlation with magnetic resonance.