Severe Form Of Hypertrophic Cardiomyopathy Research Articles

Rare Mutations V453X and Y847X in the MYBPC3 Gene Do Not Lead to a Severe Form of Hypertrophic Cardiomyopathy in the Russian Population

Rare Mutations V453X and Y847X in the MYBPC3 Gene Do Not Lead to a Severe Form of Hypertrophic Cardiomyopathy in the Russian Population

Aborted sudden cardiac death and a severe form of hypertrophic cardiomyopathy in a 2-year-old

Although hypertrophic cardiomyopathy has a reported prevalence of 1/500, compound, double, and triple mutations are infrequent. There is phenotypic variation between individuals with HCM, making disease course difficult to predict. There is some debate as to whether multiple mutations confer a worse prognosis and the extent to which the mutations affect an individual's prognosis. We report a case of homozygous MYBPC3 mutations in a 2-year-old presenting with aborted sudden cardiac death and a severe form of hypertrophic cardiomyopathy.

Novel filamin C (FLNC) variant causes a severe form of familial mixed hypertrophic-restrictive cardiomyopathy.

Variants of filamin C (FLNC) have been identified as rare genetic substrate for hypertrophic cardiomyopathy (HCM). Data on the clinical course of FLNC-related HCM are conflicting with some studies suggesting mild phenotypes whereas other studies have reported more severe outcomes. In this study, we present a novel FLNC variant (Ile1937Asn) that was identified in a large family of French-Canadian descent with excellent segregation data. FLNC-Ile1937Asn is a novel missense variant characterized by full penetrance and poor clinical outcomes. End stage heart failure requiring transplantation occurred in 43% and sudden cardiac death in 29% of affected family members. Other particular features of FLNC-Ile1937Asn include an early disease onset (mean age of 19 years) and the development of a marked atrial myopathy (severe biatrial dilatation with remodeling and multiple complex atrial arrhythmias) that was present in all gene carriers. The FLNC-Ile1937Asn variant is a novel, pathogenic mutation resulting in a severe form of HCM with full disease penetrance. The variant is associated with a high proportion of end-stage heart failure, heart transplantation, and disease-related mortality. Close follow-up and appropriate risk stratification of affected individuals at specialized heart centers is recommended.

Rare mutations V453X and Y847X in MYBPC3 gene do not lead to severe form of hypertrophic cardiomyopathy in Russian population

Rare mutations V453X and Y847X in MYBPC3 gene do not lead to severe form of hypertrophic cardiomyopathy in Russian population

Severe early-onset cardiomyopathy and poor prognosis observed in 73 patients with pathogenic KLHL24 variants

Abstract Background/Introduction Pathogenic variants in KLHL24 might cause skin fragility or cardiomyopathy. KLHL24 controls desmin turnover and patients with heterozygous gain-of-function variants (HET-GOF; i.e. overactivity), typically born with epidermolysis bullosa simplex (EBS), can develop dilated cardiomyopathy (DCM), whereas patients with homozygous loss-of-function variants (HOM-LOF) can develop hypertrophic cardiomyopathy (HCM). Purpose This study aims to characterize the cardiac phenotype and prognosis of patients with pathogenic KLHL24 variants. Methods Observational studies on KLHL24 found in PUBMED were included in this analysis. Patients were stratified according to their genotype and the study outcomes were cardiomyopathy diagnosis and cardiovascular (CV) events. CV events were defined as sudden cardiac death (SCD), death from heart failure (HF) or heart transplantation (HTx). Kaplan-Meier (KM) curves were constructed to visualize the age at diagnosis and CV event free-survival. For the HET-GOF group, this analysis was stratified by sex and log-rank testing was used to test for significant differences in the distribution. To achieve between group balance, the sex-stratified KM curves were weighted for age and cohort. Results In total, 73 patients from 14 studies were included in this analysis and Figure 1A shows their geographic distribution. In general, patients have a median age [IQR] of 18 [7–33]), 53% were men, 38% were diagnosed with cardiomyopathy, and 84% were patients with HET-GOF variants. Patients with HOM-LOF variants have a median age of 27 [26–31] and 55% is male (Figure 1B). HOM-LOF variants c.917G>A [p.(Arg306His)] and c.1048G>T [p.(Glu350*)] segregated in 2 Middle Eastern families, reporting 11 patients born from seemingly unaffected consanguineous heterozygous parents. All HOM-LOF patients were diagnosed with HCM before the age of 32 (27, [26–31]; Figure 1C), resulting in 4 CV events (SCD n=3; HTx n=1; Figure 1D). Patients with HET-GOF variants have a median age of 14 [6–33] and 53% were men (Figure 1B). HET-GOF variants c.1A>G, c.1A>T, c.2T>C, c.3G>T, c.3G>A and c.22A>T [p.(Val2_Met29)] segregated with disease in 34 families, reporting 62 patients in 14 countries. All patients with HET-GOF had EBS at birth and 27% was diagnosed with DCM. The probability of diagnosis during lifetime was significantly different (p<0.001, weighted p<0.001) between men (25 [16–34], n=9) and women (45 [31–47], n=8; Figure 1E). In total, 7 CV events (SCD n=1; HF n=4; HTx n=2) were reported for patients with HET-GOF variants. Figure 1F shows the general differences in CV events between sexes (p=0.026, weighted p=0.073). The median age of CV events for men was 20 (n=4) and 54 for women (n=3). Conclusions Patients with HOM-LOF variants were diagnosed at an early age with a severe form of HCM. Men with HET-GOF variants were diagnosed with DCM earlier than women. Men also have a higher probability for CV events at a younger age than women. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Counsel (ERC-2016-STG)

Hypertrophic cardiomyopathy caused by mutations in the <I>PRKAG2</I> gene

Clinical observations of three cases of hypertrophic cardiomyopathy caused by mutations in the PRKAG2 gene with a debut in early childhood are presented. The  sisters whose father suffered from a severe form of  hypertrophic cardiomyopathy in  combination with Wolf—Parkinson—White syndrome and died at a young age from progressive heart failure are described. Early manifestation of  the disease is characteristic, while there was a combination of  ventricular preexitation syndrome and myocardial hypertrophy with rapid progression to extreme values. Hypertrophy was concentric symmetrical and biventricular. The main clinical symptom in  the first observation was frequent paroxysms of supraventricular tachycardia. New atrioventricular fenestrations were detected during dynamic observation, insufficient effectiveness of radiofrequency ablation, recurrence of supraventricular tachycardia, and a good response to propafenone were noted. The third clinical case is sporadic, a long-term follow-up for 15 years is presented and clearly reflects the progression of  the increase in myocardial hypertrophy and cardiac arrhythmias. The disease debuted from an early age in the form of hypertrophy in combination with severe bradycardia, which made drug therapy difficult. Due to the high risk of sudden cardiac death against the background of extreme myocardial hypertrophy, a cardioverter defibrillator was implanted. Signs of mitochondrial insufficiency according to skeletal muscle biopsy are described. 

Prevalence and Prognostic Implications of Right Ventricular Dysfunction in Patients With Hypertrophic Cardiomyopathy

Right ventricular (RV) dysfunction is a well-known prognostic factor in several cardiac diseases. However, the prevalence of RV dysfunction in hypertrophic cardiomyopathy (HC) is unclear and its prognostic value is unknown. This study aims at addressing these issues assessing RV function with speckle tracking echocardiography. In 267 HC patients (52 ± 15 years, 68% male), standard and advanced echocardiographic measurements of RV function were performed including RV 4-chamber longitudinal strain (RV4CLS) and RV free wall longitudinal strain (RVFWLS). The primary end point was all-cause mortality and heart failure development. RV dysfunction was observed in 9% of patients based on tricuspid annular plane systolic excursion (≤17 mm), 5% based on fractional area change (<35%), 23% based on RVFWLS ≥-19%, 39% based on RVFWLS ≥-23%, and 55% based on RV4CLS ≥-20%. In total 59 (22%) patients reached the primary end point during a median follow-up of 6.7 (interquartile range 4.2 to 9.8) years. Kaplan-Meier survival curve showed a significant worse survival free of the end point for patients with impaired RV4CLS ≥-20% versus patients with preserved RV4CLS <-20% (log-rank 7.0, p = 0.008) and for patients with impaired RVFWLS ≥-19% versus patients with preserved RVFWLS <-19% (log-rank 4.4, p = 0.037). Multivariable Cox regression analysis showed that E/E' (hazards ratio [HR] 2.26 [1.30 to 3.92], p = 0.004), left ventricular global longitudinal strain LV GLS (HR 1.08 (1.01 to 1.17), p = 0.034) and RV4CLS (HR 1.08 (1.02 to 1.15), p = 0.007) were independently associated with the primary end point. In conclusion, RV dysfunction as measured by longitudinal strain is relatively frequent in HC patients. Impaired RV4CLS is - together with LV GLS and E/E' - associated with adverse outcome, which may indicate a more severe form of HC.

Heterozygous deletion of AKT1 rescues cardiac contractility, but not hypertrophy, in a mouse model of Noonan Syndrome with Multiple Lentigines

Noonan Syndrome with Multiple Lentigines (NSML) is associated with congenital heart disease in form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Genetically, NSML is primarily caused by mutations in the non-receptor protein tyrosine phosphatase SHP2. Importantly, certain SHP2 mutations such as Q510E can cause a particularly severe form of HCM with heart failure in infancy. Due to lack of insight into the underlying pathomechanisms, an effective custom-tailored therapy to prevent heart failure in these patients has not yet been found.SHP2 regulates numerous signaling cascades governing cell growth, differentiation, and survival. Experimental models have shown that NSML mutations in SHP2 cause dysregulation of downstream signaling, in particular involving the protein kinase AKT. AKT, and especially the isoform AKT1, has been shown to be a major regulator of cardiac hypertrophy. We therefore hypothesized that hyperactivation of AKT1 is required for the development of Q510E-SHP2-induced HCM. We previously generated a transgenic mouse model of NSML-associated HCM induced by Q510E-SHP2 expression in cardiomyocytes starting before birth. Mice display neonatal-onset HCM with initially preserved contractile function followed by functional decline around 2months of age. As a proof-of-principle study, our current goal was to establish to which extent a genetic reduction in AKT1 rescues the Q510E-SHP2-induced cardiac phenotype in vivo. AKT1 deletion mice were crossed with Q510E-SHP2 transgenic mice and the resulting compound mutant offspring analyzed. Homozygous deletion of AKT1 greatly reduced viability in our NSML mouse model, whereas heterozygous deletion of AKT1 in combination with Q510E-SHP2 expression was well tolerated. Despite normalization of pro-hypertrophic signaling downstream of AKT, heterozygous deletion of AKT1 did not ameliorate cardiac hypertrophy induced by Q510E-SHP2. However, the functional decline caused by Q510E-SHP2 expression was effectively prevented by reducing AKT1 protein. This demonstrates that AKT1 plays an important role in the underlying pathomechanism. Furthermore, the functional rescue was associated with an increase in the capillary-to-cardiomyocyte ratio and normalization of capillary density per tissue area in the compound mutant offspring. We therefore speculate that limited oxygen supply to the hypertrophied cardiomyocytes may contribute to the functional decline observed in our mouse model of NSML-associated HCM.

Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines.

Noonan syndrome with multiple lentigines (NSML) is primarily caused by mutations in the nonreceptor protein tyrosine phosphatase SHP2 and associated with congenital heart disease in the form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Our goal was to elucidate the cellular mechanisms underlying the development of HCM caused by the Q510E mutation in SHP2. NSML patients carrying this mutation suffer from a particularly severe form of HCM. Drawing parallels to other, more common forms of HCM, we hypothesized that altered Ca(2+) homeostasis and/or sarcomeric mechanical properties play key roles in the pathomechanism. We used transgenic mice with cardiomyocyte-specific expression of Q510E-SHP2 starting before birth. Mice develop neonatal onset HCM with increased ejection fraction and fractional shortening at 4-6 wk of age. To assess Ca(2+) handling, isolated cardiomyocytes were loaded with fluo-4. Q510E-SHP2 expression increased Ca(2+) transient amplitudes during excitation-contraction coupling and increased sarcoplasmic reticulum Ca(2+) content concurrent with increased expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase. In skinned cardiomyocyte preparations from Q510E-SHP2 mice, force-velocity relationships and power-load curves were shifted upward. The peak power-generating capacity was increased approximately twofold. Transmission electron microscopy revealed that the relative intracellular area occupied by sarcomeres was increased in Q510E-SHP2 cardiomyocytes. Triton X-100-based myofiber purification showed that Q510E-SHP2 increased the amount of sarcomeric proteins assembled into myofibers. In summary, Q510E-SHP2 expression leads to enhanced contractile performance early in disease progression by augmenting intracellular Ca(2+) cycling and increasing the number of power-generating sarcomeres. This gives important new insights into the cellular pathomechanisms of Q510E-SHP2-associated HCM.

Surgery for biventricular obstruction in hypertrophic cardiomyopathy in children and young adults: technique and outcomes†.

Biventricular obstruction in hypertrophic cardiomyopathy (HCM) is uncommon, and some clinicians believe that, when symptoms are refractory to medical treatment, this severe form of HCM is best treated by transplantation. We describe our conventional surgical approach and outcomes to treat biventricular obstruction in HCM. From 1993 to 2013, we treated 11 symptomatic patients with biventricular outflow obstruction. Relief of left ventricular (LV) obstruction was obtained by performing a transaortic extended septal myectomy and/or a left apical ventriculotomy. Right ventricular outflow tract (RVOT) obstruction was relieved with patch enlargement in all patients and selective resection of muscle bundles. The mean age at surgery was 13 years (2 months-28 years); of the total, 7 (63%) were males. All were symptomatic with shortness of breath, reduced exercise tolerance or failure to thrive. All patients had preserved biventricular systolic function and systolic anterior motion (SAM) of the mitral valve (9 patients had ≥ moderate mitral regurgitation). Preoperative RVOT and LV outflow tract gradients were 60 ± 18 and 78 ± 24 mmHg, respectively. There were no early deaths. Mitral regurgitation secondary to SAM resolved following LV myectomy. The median follow-up time was 4.6 years (maximum 16.3 years). Eight patients (72%) were in NYHA class I. There have been no late ventricular arrhythmias, sudden deaths, reoperations or heart transplantations at follow-up. Biventricular obstruction is rare in HCM. Surgical relief of left- and right-sided obstruction can be achieved with good early outcomes. Symptoms are improved at intermediate-term follow-up and sudden death is rare.

Double chamber left ventricle associated with severe form of hypertrophic cardiomyopathy

In a 28-month-old girl, from a normal pregnancy and absolutely healthy parents, weighing 16.3 kg, a systolic murmur was noted during a routine pediatric examination and she was referred for cardiological examination at tertiary level. The child’s growth and development were completely normal. Her arterial blood gas level was within normal limits. The clinical examination demonstrated: a quiet precordium, normal first heart sound, short midsystolic murmur 2-3/6 degree on the apex and left sternal border, and a single second heart sound. The electrocardiogram showed: left axis deviation, and biventricular hypertrophy. A chest radiogram revealed an enlarged cardiac silhouette with a narrow mediastinum. Echocardiography demonstrated: normal systemic and pulmonary vein connections, with reduced interatrial communication. There were normal atrio-ventricular and ventriculo-arterial connections. From an apical four-chamber view, symmetric hypertrophy of the left ventricle was demonstrated during diastole, and a subaortic obstruction, together with interventricular septal hypertrophy and thickening. In addition, the echocardiographic examination revealed 2 DOUBLE CHAMBER LEFT VENTRICLE ASSOCIATED WITH SEVERE FORM OF HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein

AimTo analyze the genesis of hypertrophic cardiomyopathy on a large cohort of patients from molecular genetics point of view and perform the functional analysis of the 3D molecular model of defective myosin-7 protein in silico.MethodsThe study enrolled 153 patients with diagnosed hypertrophic cardiomyopathy from different parts of the Czech Republic. DNA samples were analyzed for mutations in exons 21 and 22 of the MYH7 gene, which have been associated with high mutation clustering. The 3D model of human myosin-7 was built using the x-ray structure of nucleotide-free scallop myosin S1 as the structural template. We performed de novo structure prediction of mutant and wild type peptides spanning the 769-788 amino acids region of the myosin-7 protein.ResultsThe Arg870His and Asp778Val amino acid alterations were found in 2 unrelated patients with a severe form of hypertrophic cardiomyopathy. The Asp778Val variation was chosen for subsequent 3D molecular modeling in silico. The mutation of the Asp by Val not only changes the character of the interaction pattern with other amino acids or ions but Val, being a small hydrophobic amino acid, can also completely change the stability of the region.ConclusionMutation location in the MYH7 gene and changes in amino acid composition may have a crucial negative impact on the outcome of the disease in patients with hypertrophic cardiomyopathy. In addition, a mutation that changes the charge of the amino acid is more likely to affect protein function than a conservative mutation.

Hypertrophic Cardiomyopathy in a Young Adult with RV Aneurysm: Report of a Rare Finding and Review of the Literature

We report a case of a 22-year-old patient with a severe form of hypertrophic cardiomyopathy involving both ventricles, for which he underwent surgical treatment. Echocardiogram and magnetic resonance imaging confirmed the presence of an aneurysm in the inferior-anterior portion of the right ventricle.

Hypertrophic Cardiomyopathy

Our research is a pilot study that specializes in the molecular genetic investigation of the TNNT2 gene in Czech patients with HCM/FHC disease. This study was initiated with exons 9 and 11 of TNNT2 because of their crucial role in the binding ability of cardiac troponin T to alpha-tropomyosin, and continued with analyses in other regions of the gene. Hundred and eighty-one Czech probands with HCM/FHC were enrolled in this study. The study group consisted of 24 families with FHC and probands without FHC history but with HCM diagnosis. The clinical diagnosis was based on echocardiography. DNA was isolated from peripheral blood lymphocytes and subsequently analyzed by the polymerase chain reaction (PCR), followed by DNA sequencing analyses, which were cross-sequenced. The DeltaGlu160 mutation was observed in a sequence of the TNNT2 gene in a patient with the severe form of hypertrophic cardiomyopathy. No sequence alteration was found in exons 9 and 11 of the TNNT2 gene found in the rest of the DNA samples. The DeltaGlu160 mutation was observed in patients with severe forms of hypertrophic cardiomyopathy. This region is responsible for binding troponin T to alpha-tropomyosin. This mutation may lead to functional and structural effects on the troponin T protein. Mutations in this region are reported relatively rarely and therefore it was unique to observe the DeltaGlu160 mutation in our study.

Hypertrophic cardiomyopathy linked to homozygosity for a new mutation in the myosin-binding protein C gene (A627V) suggests a dosage effect

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are responsible for up to 50% of familial cases with hypertrophic cardiomyopathy (HC). Compared to patients with mutations in other sarcomeric genes, patients with MYBPC3 mutations would have a milder form of the disease, with a lower incidence of sudden cardiac death. Because most of the mutations have been found in only one family, it is currently difficult to establish a correlation between a particular mutation and the HC phenotype. The aim of our study was to contribute to understanding of the role of MYBPC3 mutations in HC. We analysed the MYBPC3 exons and intron flanking regions in 10 patients from 10 families with at least two HC cases. After direct sequencing of polymerase chain reaction (PCR) fragments, we found three new mutations in three families (V771M, V342D, and A627V). These changes affected evolutionary conserved amino acids and were not found in 100 healthy controls. The Ala 627>Val was found homozygous in a 47-year-old patient with a severe form of HC, while his mother and a nephew were heterozygous carriers and asymptomatic. This fact suggests a dosage effect for mutations at the MYPBC3 gene.

Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients.

Mutations in the cardiac beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes are reportedly responsible for up to 40% of familial cases with hypertrophic cardiomyopathy (HC). Although there are no mutational hotspots, most of the mutations are located in specific exons of the MYH7 and TNNT2 genes. Currently it is not possible to predict the phenotype in carriers of mutations in these genes, although it is widely accepted that mutations in the MYH7 gene predispose to severe HC, whereas TNNT2 mutations are frequently linked to sudden cardiac death (SCD) in spite of minimal hypertrophy. We sequenced exons 8, 9, 13-16, 19, 20, 22-24, and 30 of the MYH7 gene and exons 8, 9, 11, and 14-16 of the TNNT2 gene in 30 HC patients (18-60 years of age) from the region of Asturias (Northern Spain); 25 cases (80%) had a family history of the disease. Genomic DNA was amplified, and fragments were directly sequenced. Each DNA variant found in the patients was also analyzed in 200 healthy controls through single-strand conformation analysis. Four of the probands had nucleotide changes absent in the healthy controls. Two cases had mutations previously described in the MYH7 gene (exon 14, Arg453Cys) or the TNNT2 gene (exon 16, Arg278Cys). Two cases had new mutations (MYH7 exon 22, Met822Val; TNNT2 exon 14, Lys247Arg) not found among the healthy controls. We found MYH7 Met822Val in a woman with a severe form of HC; the mutation was absent in her parents, indicating a de novo mutation. MYH7 R453C was present in a woman with mild HC, mother of a son who died from SCD. TNNT2 R278C was present in a woman with severe HC, but a sister and a daughter were mutation carriers and did not have hypertrophy. A patient with severe HC was carrier of TNNT2 247Arg. Mutations in the MYH7 and TNNT2 genes can be found in patients without a family history of HC. However, compared with other populations MYH7 or TNNT2 mutations were rare among our HC patients. This study illustrates the extreme phenotypic heterogeneity in carriers of MYH7 or TNNT2 mutations.

Prognosis of nonobstructive hypertrophic cardiomyopathy

Among primary cardiac diseases, hypertrophic cardiomyopathy (HC) is known for its diverse clinical manifestations 1 and different morphologic aspects. 2 The clinical picture ranges from an asymptomatic form, corresponding with a mild, nonobstructive ventricular septal hypertrophy, to the disabled patient with impaired cardiac function or even sudden death, 3 when a massive myocardial thickening and a very small left ventricular cavity can be found. 5 Scarce data are available about the natural history of mild, nonobstructive HC. 5 The present study explores this abnormality to see if it progresses to a more severe form of HC and if it results in any complications.