Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.

Blood-based microRNA signatures differentiate various forms of cardiac hypertrophy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by mutations in different structural genes and induces pathological hypertrophy with sudden cardiac death as a possible consequence. HCM can be separated into hypertrophic non-obstructive and obstructive cardiomyopathy (HNCM/HOCM) with different clinical treatment approaches. We here distinguished between HNCM, HOCM, cardiac amyloidosis and aortic stenosis by using microRNA profiling and investigated potential interactions between circulating miRNA levels and the most common mutations in MYH7and MYBPC3 genes. METHODS: Our study included 4 different groups: 23 patients with HNCM, 28 patients with HOCM, 47 patients with aortic stenosis and 22 healthy controls. Based on previous findings, 8 different cardiovascular known microRNAs (miR-1, miR-21, miR-29a, miR-29b, miR-29c, miR-133a, miR-155 and miR-499) were studied in serum of all patients and compared with clinically available patient data. RESULTS: We found miR-29a levels to be increased in patients with HOCM and correlating markers of cardiac hypertrophy. This was not the case in HNCM patients. In contrast, we identified miR-29c to be upregulated in aortic stenosis but not the other patient groups. ROC curve analysis of miR-29a/c distinguished between HOCM patients and aortic stenosis patients. MiR-29a and miR-155 levels discriminated HNCM patients from patients with senile cardiac amyloidosis. MiR-29a increased mainly in HOCM patients with a mutation in MYH7, whereas miR-155 was decreased in hypertrophic cardiomyopathy patients with a mutation in MYBPC3. CONCLUSION: We demonstrated that miR-29a and miR-29c show a specific signature to distinguish between aortic stenosis, hypertrophic non-obstructive and obstructive cardiomyopathies and thus could be developed into clinically useful biomarkers.

Cardiac arrest and ventricular tachycardia in Japanese-type apical hypertrophic cardiomyopathy.

Apical hypertrophic cardiomyopathy (HCM) is a specific variant of HCM. This disease has been first described in Japan where the prevalence is much higher than in the western world. The prognosis of apical HCM with regard to sudden cardiac death is believed to be better than that of common HCM. We present, however, two male caucasian patients with apical HCM and malignant arrhythmias. Both patients had marked apical hypertrophy on echocardiography, 'giant' negative T-waves on the ECG and spade-like configuration of the left ventricle on angiography. The first patient had been successfully recussitated from cardiac arrest at the age of 52 years. The second patient had a syncope at the age of 42 years and had non-sustained ventricular tachycardia. In both cases, a cardioverter-defibrillator was implanted and treatment with verapamil was initiated. These observations suggest that the risk of sudden cardiac death might be increased not only in common HCM, but also in Japanese-type apical HCM.

Resting "Solar Polar" map pattern and reduced apical flow reserve: characteristics of apical hypertrophic cardiomyopathy on SPECT myocardial perfusion imaging.

BACKGROUND: Patients with apical hypertrophic cardiomyopathy (ACM) are often referred for myocardial perfusion single photon emission computed tomography (SPECT) as a result of marked T-wave inversion and chest pain syndromes. Stress perfusion defects have been reported in ACM, but the characteristic SPECT pattern as well as the typical findings on volume-weighted polar maps has not been described. METHODS AND RESULTS: Dual-isotope rest (thallium 201) and exercise or adenosine stress (technetium 99m tetrofosmin) myocardial perfusion SPECT was performed in 11 patients with ACM, including 8 with either normal coronary arteriography (n = 5) or a low pretest probability of coronary artery disease (CAD) (n = 3), and 14 control patients with concentric left ventricular hypertrophy. An 8-pixel-diameter circular region of interest was used to quantitatively compare apical and septal counts on CEqual volume-weighted polar maps. A characteristic "Solar Polar" map pattern resulting from the increased apical counts was present in each ACM patient at rest, with a mean apical-septal ratio of 1.39 +/- 0.17 (range, 1.23-1.62, P <.01 vs concentric left ventricular hypertrophy group). With stress, there was a significant decrease in the apical-septal ratio (0.96 +/- 0.18, P <.001 vs rest) in the ACM subgroup without CAD. CONCLUSION: Patients with ACM demonstrate a newly described "Solar Polar" map pattern at rest, as well as relative apical ischemia on the stress images even in the absence of CAD.

[Therapy and risk-stratification in hypertrophic cardiomyopathy--a current survey]. / Therapie und Risikostratifizierung der Hypertrophen Kardiomyopathie. Ein aktueller Uberblick.

Hypertrophic cardiomyopathy (HCM) is a relatively common disease of the cardiac sarcomere with broad heterogeneity in terms of the disease-causing gene mutation, phenotypic expression, therapy and prognosis. Besides the standard drug treatment, there are several therapeutic options available for severe refractory symptomatic HCM with obstruction. Dual-chamber pacing and transcoronary ablation of septal hypertrophy (TASH) have recently emerged as alternatives to myectomy. However, myectomy remains the current gold standard of therapy for HCM until the promising initial follow-up data for TASH can be transferred into a long-term follow-up period, or prospective randomized comparative trials between these therapies are available. However, even now, TASH represents an important therapeutic alternative in patients with relevant co-morbidities and a high operative risk. Despite significant gradient reduction and amelioration of clinical symptoms, none of these treatment strategies has a proven influence on the natural history of HCM. Hence, regarding the long-term prognosis of the disease, risk stratification of sudden cardiac death using non-invasive risk assessment has become of paramount importance, while genotyping might become the determinant and stratifying marker in the near future. At present, according to secondary prevention, treatment with an implanted cardioverter-defibrillator +/- amiodarone therapy is mandatory, while according to primary prevention treatment should particularly depend on the individual risk profile.

Wavelet decomposition analysis of the signal averaged electrocardiogram used for risk stratification of patients with hypertrophic cardiomyopathy.

AIMS: To study the predictive value of wavelet decomposition, as demonstrated by the signal-averaged ECG, in order to identify patients with hypertrophic cardiomyopathy at increased risk for malignant ventricular arrhythmias or sudden death. METHODS AND RESULTS: Two hundred and forty-six patients with hypertrophic cardiomyopathy were studied. During a mean follow-up of 68 +/- 17 months 32 patients died, of whom 17 died suddenly. Patients with sudden death, together with eight patients with a history of ventricular fibrillation (sudden death/ventricular fibrillation group) were analysed and compared to the other 221 patients as well as to a subgroup of 82 patients without a history of syncope, ventricular arrhythmias on a long-term ECG recording or a family history of sudden death. There were no differences in mean values of the four wavelet decomposition parameters among patients in the sudden death/ ventricular fibrillation group, those without sudden death/ ventricular fibrillation or patients in the low risk group. There were, however, significant differences between patients dying non-suddenly and patients being alive at the end of follow-up. Eighty-seven patients (35%) demonstrated evidence of non-sustained ventricular tachycardia on a long-term ECG. Analysis of wavelet decomposition resulted in abnormal findings in these patients more often than in those without ventricular arrhythmias. CONCLUSION: The usefulness of wavelet decomposition analysis in predicting sudden death or ventricular fibrillation is limited in patients with hypertrophic cardiomyopathy. It may, however, play a role in identifying patients at risk of dying non-suddenly and of patients with non-sustained ventricular tachycardia.

[Clinical and molecular genetics of hypertrophic cardiomyopathy]. / A hypertrophiás cardiomyopathia klinikai és molekuláris genetikája.

Recent developments in molecular genetics have allowed to identify mutations in seven genes coding the beta myosin heavy chain, troponin T, alpha tropomyosin, myosin binding protein C, essential and regulatory myosin light chains and troponin I causing hypertrophic cardiomyopathy. These mutations affect critical, evolutionary conserved nucleotides of these genes and influence vital functions of the encoded proteins. As all seven genes encodes sarcomeric proteins in the heart muscle, hypertrophic cardiomyopathy is regarded these days as a disease of the sarcomer. Recent data indicate that some mutations are associated with "malignant" clinical picture, with rapidly developing, severe symptoms of the disease and increased risk of sudden cardiac death while other mutations bear a more favourable prognosis. Apart of the disease causing mutation other factors, including disease modifier genes, are likely to make an impact on the clinical appearance of hypertrophic cardiomyopathy. The knowledge provided by molecular genetics influences the clinical management of the disease even today and based on the investigation of mutation carrying patients new diagnostic criteria was proposed for hypertrophic cardiomyopathy. The challenge for the future is the establishment of routine genetic diagnostics and the development of possible gene therapy.

Prognostic determinants of hypertrophic cardiomyopathy--the results of the Shiga Cardiomyopathy Study.

Previous studies have reported that patients with hypertrophic cardiomyopathy (HCM) are prone to sudden death. In this study, we retrospectively assessed the prognosis and any influencing factors in 83 patients (66 male, 17 female) with HCM. Twenty-two patients were obstructive, 40 were non-obstructive, 18 were apical HCM and 3 were unclassified. Four of the 83 cases progressed to left ventricular dilatation and dysfunction during the follow-up period. The mean age was 51.2 years (range 16 to 73) and the mean duration of follow-up was 6.7 years (range 0.3 to 15.1). The 5- and 10-year survival rates were 98% and 89%, respectively. Five patients dies; 3 from cardiac events (two sudden deaths and one due to congestive heart failure) and 2 from malignant diseases. The lack of a family history of sudden death and the amplitude of the S wave in lead V1 (less than 2.0 mV) were associated with a favorable prognosis. None of the patients who were diagnosed before age 50 died, but this observation was not statistically significant. None of the patients with apical HCM died, but the classification of HCM was not significantly associated with the prognosis. None of the patients without medication died and medical treatment did not influence the prognosis. Sex, family history of HCM, the patient's symptoms and physical signs, NYHA classification of cardiovascular disability, thickness of the septum and the posterior wall of the left ventricle, dimension of the left atrium, and the left and right ventricles in echocardiogram, amplitude of the R wave in lead V5, the depth of the negative T wave and atrial fibrillation did not influence the prognosis.

[Atypical forms of hypertrophic cardiomyopathy]. / Nietypowe postaci kardiomiopatii przerostowej.

UNLABELLED: Hypertrophic cardiomyopathy is characterized by a diverse clinical and morphological spectrum. In this report we describe five patients with atypical hypertrophic cardiomyopathy and significantly dilated atria. Diagnostic difficulties are stressed. All patients underwent clinical examination, noninvasive studies including 2-D echocardiogram, cardiac catheterization. In three patients endomyocardial biopsy was taken and examined by light microscopy. All but one patient were men, ranging in age from 28 years to 40 years at initial examination. In all patients disproportion between mildly elevated or, in two cases normal filling pressures and degree of dilatation of both atria was found. Two patients C.G. and D.T. had auscultatory and roentgenographic findings of mitral stenosis. Following echocardiographic and angiocardiographic studies an increase in left and right ventricular thickness associated with dilatation of both atria was found. Endomyocardial biopsy in both cases did not show endocardial thickening or infiltrative changes. In family S, two patients W.S. and Je.S had marginal left ventricular hypertrophy. The presence of left ventricular hypertrophy in patient Ja. S and finding, after family studies, hypertrophic, obstructive cardiomyopathy in patient A.S. enabled establishing the correct diagnosis. Beside varying degree of hypertrophy in family S, mild dilation of the right ventricle and incomplete right bundle branch block were found. In two patients of family S. restrictive cardiomyopathy was found, in patient Ja. S. during cardiac catheterization at initial presentation, in patient W.S. on doppler transmitral flow velocity examination at late follow-up. Paroxysmal atrial fibrillation was the first symptom in four patients, thromboembolic event in one patient. In four patients pacemaker requirement was found. During long-term follow-up (mean 4.8 years) slowly progressive heart failure associated with further dilatation of atria is observed. Mild doses of diuretics are effective in controlling congestive symptoms. CONCLUSION: in hypertrophic cardiomyopathy significantly dilated atria and clinical signs of mitral stenosis can be present. The presence of myocardial hypertrophy is not necessary to diagnose hypertrophic cardiomyopathy. Familial studies can be helpful in establishing the correct diagnosis.

[Effect of hypertension on asymmetrical septal hypertrophy: an echocardiographic study].

The effect of hypertension on asymmetrical septal hypertrophy was studied by echocardiography to differentiate idiopathic asymmetrical septal hypertrophy (ASH) from ASH with hypertension. One hundred eight patients with ASH proven by echocardiography were categorized in two groups; 53 patients with hypertension (greater than 160 systolic, greater than 95 diastolic) (hypertensive group: HT) and 55 patients with normal blood pressure (normotensive group: NT). Septal hypertrophy was classified as mid-portion (M-type), diffuse (D-type), and basal (B-type) hypertrophy by the long-axis view, and also diffuse (I-type), anterolateral (II-type), anteroseptal (III-type), and anterior septal (IV-type) by the short-axis view, respectively. Endomyocardial biopsy and left ventriculography were performed in 50 patients (18 hypertensives and 32 normotensives). In the hypertensive group, 45%, 30%, and 25% of cases had diffuse, basal and mid-portion hypertrophy, respectively. There was no case in the basal hypertrophy whose biopsy findings were compatible with hypertrophic cardiomyopathy. In the normotensive group, 78% and 22% of patients had midportion and diffuse hypertrophy, respectively, but none of them had the basal hypertrophy. Type IV was seen in only six patients in the normotensive group.

The echocardiographic assessment of cardiomyopathy: diagnosis, classification and problems.

Two-hundred-and-sixty-three patients with cardiomyopathy were studied by M-mode echocardiography. Measurements of left ventricular cavity size, wall thickness and myocardial contraction were used to classify cardiomyopathy into "congestive" (212 patients) and "hypertrophic" (50 patients) groups; the "hypertrophic" group was further divided into asymmetric septal hypertrophy (37) and symmetric (concentric) mural thickening (13). Using clinical and electrocardiographic information as well as echocardiographic data, the latter group could then be further classified into "concentric infiltrative cardiomyopathy" (9) and "concentric hypertrophic cardiomyopathy" (4). The former either presented with signs of restriction or were known to have systemic amyloidosis; the electrocardiograph showed low voltage and myocardial contraction was impaired in advanced cases. The latter had evidence of severe left ventricular hypertrophy and resembled asymmetric septal hypertrophy clinically. Problems encountered with the echocardiographic diagnosis of congestive cardiography were mainly concerned with proper clinical interpretation of the echocardiographic data whilst technical difficulties in recording the echocardiogram and in interpretation of tracings were a common problem in hypertrophic cardiomyopathy.