Late-onset Hypertrophic Cardiomyopathy Research Articles

Hypertrophic cardiomyopathy in MYBPC3 carriers in aging.

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the myocardium, leading to arrhythmias, heart failure, and elevated risk of sudden cardiac death, particularly among the young. This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3) gene are major contributors. HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms, affecting numerous cardiac functions and presenting significant health risks with a spectrum of clinical manifestations. Regulation of MYBPC3 expression involves various transcriptional and translational mechanisms, yet the destiny of mutant MYBPC3 mRNA and protein in late-onset HCM remains unclear. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency. Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. Advancements in high-throughput omics techniques have identified crucial molecular events and regulatory disruptions in cardiomyocytes expressing MYBPC3 variants. This review assesses the pathogenic mechanisms that promote late-onset HCM through the lens of transcriptional, post-transcriptional, and post-translational modulation of MYBPC3, underscoring its significance in HCM across carriers. The review also evaluates the influence of aging on these processes and MYBPC3 levels during HCM pathogenesis in the elderly. While pinpointing targets for novel medical interventions to conserve cardiac function remains challenging, the emergence of personalized omics offers promising avenues for future HCM treatments, particularly for late-onset cases.

Compound Heterozygosity for Late-Onset Cardiomyopathy-Causative ALPK3 Coding Variant and Novel Intronic Variant Cause Infantile Hypertrophic Cardiomyopathy.

Hypertrophic and dilated cardiomyopathy (HCM, DCM) are leading causes of cardiovascular morbidity and mortality in children. The pseudokinase alpha-protein kinase 3 (ALPK3) plays an essential role in sarcomere organization and cardiomyocyte differentiation. ALPK3 coding mutations are causative of recessively inherited pediatric-onset DCM and HCM with variable expression of facial dysmorphism and skeletal abnormalities and implicated in dominantly inherited adult-onset cardiomyopathy. We now report two variants in ALPK3-a coding variant and a novel intronic variant affecting splicing. We demonstrate that compound heterozygosity for both variants is highly suggestive to be causative of infantile-onset HCM with webbed neck, and heterozygosity for the coding variant presents with adult-onset HCM. Our data validate partial penetrance of heterozygous loss-of-function ALPK3 mutations in late-onset hypertrophic cardiomyopathy and expand the genotypic spectrum of autosomal recessive ALPK3-related cardiac disease with Noonan-like features.

172 Two mutations, one patient: which phenotype?

Abstract Methods and results Woman, 55 years old, she has as comorbidity high blood pressure and mild obesity. She came at our attention to perform screening cardiological exams after her brother, who was affected by amyloidotic TTR-related cardiomyopathy with Val30Met mutation, died for sudden cardiac death. At the first evaluation the patient is completely asymptomatic, she has not angor, dyspnoea and heartbeat. The ECG and echocardiography were negative for amyloidotic signs of heart involvement. The Tc-99-DPD scintigraphy showed no cardiac uptake (visual score = 0). To complete the diagnostic path the patient had been evaluated by a neurologist with electromyography, which was negative, and genetic test, which confirmed the presence of Val30Met mutation of TTR-gene. For this last outcome we decided to follow the patient at our clinics. In the following years the patient developed a progressive reduction of exercise tolerance and symmetric negative T waves in anterolateral and inferior lead at ECG. The echocardiogram showed a progressive medio-apical septal hypertrophy. To exclude an ischaemic cause the patient made a stress myocardial scintigraphy, which was negative for ischaemic signs, and she underwent to cardiac MRI which showed a septal thickness of 16 mm without amyloidotic radiological signs in T1-weighted and LGE sequences. For this reason, we suspected that the patient had a hypertrophic cardiomyopathy and she had been undergone another time to genetic test which confirmed the Val30Met TTR-mutation and MYBPC3 mutation. Usually, this last gene mutation for myosin binding protein C is associated with late-onset hypertrophic cardiomyopathy. Into account the new diagnosis and her sudden cardiac death family history we calculated the patient’s HCM-risk score which was under 4%, so that we did not undergo the patient to ICD implantation. Conclusions The case report is a rare example of coexistence of the transthyretin gene mutation and myosin binding protein C in the same patient. In this case to perform a correct diagnosis, it is crucial use an integrated multimodal approach including ECG, echocardiography and cardiac MRI.

The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals

Introduction and objectivesUp to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. Mutations in CSRP3 have been associated with HCM, but evidence supporting pathogenicity is inconclusive. In this study, we describe an HCM cohort with a missense variant in CSRP3 (p.Cys150Tyr) with supporting evidence for pathogenicity and a description of the associated phenotype. MethodsCSRP3 was sequenced in 6456 index cases with a diagnosis of HCM and in 5012 probands with other cardiomyopathies. In addition, 3372 index cases with hereditary cardiovascular disorders other than cardiomyopathies (mainly channelopathies and aortopathies) were used as controls. ResultsThe p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6456 HCM probands, and it was not identified in patients with other cardiomyopathies (p < 0.0001) or in our control population (p < 0.0001). Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype. Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease. The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm. The variant showed highly age-dependent penetrance. After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients. ConclusionsThe p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers.

CRISPR-Cas9 generated Pompe knock-in murine model exhibits early-onset hypertrophic cardiomyopathy and skeletal muscle weakness

Infantile-onset Pompe Disease (IOPD), caused by mutations in lysosomal acid alpha-glucosidase (Gaa), manifests rapidly progressive fatal cardiac and skeletal myopathy incompletely attenuated by synthetic GAA intravenous infusions. The currently available murine model does not fully simulate human IOPD, displaying skeletal myopathy with late-onset hypertrophic cardiomyopathy. Bearing a Cre-LoxP induced exonic disruption of the murine Gaa gene, this model is also not amenable to genome-editing based therapeutic approaches. We report the early onset of severe hypertrophic cardiomyopathy in a novel murine IOPD model generated utilizing CRISPR-Cas9 homology-directed recombination to harbor the orthologous Gaa mutation c.1826dupA (p.Y609*), which causes human IOPD. We demonstrate the dual sgRNA approach with a single-stranded oligonucleotide donor is highly specific for the Gaac.1826 locus without genomic off-target effects or rearrangements. Cardiac and skeletal muscle were deficient in Gaa mRNA and enzymatic activity and accumulated high levels of glycogen. The mice demonstrated skeletal muscle weakness but did not experience early mortality. Altogether, these results demonstrate that the CRISPR-Cas9 generated Gaac.1826dupA murine model recapitulates hypertrophic cardiomyopathy and skeletal muscle weakness of human IOPD, indicating its utility for evaluation of novel therapeutics.

Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder characterized by left ventricular hypertrophy and cardiac hyper-contractility. Mutations in the β-cardiac myosin heavy chain gene (β-MyHC) are a major cause of HCM, but the specific mechanistic changes to myosin function that lead to this disease remain incompletely understood. Predicting the severity of any β-MyHC mutation is hindered by a lack of detailed examinations at the molecular level. Moreover, because HCM can take ≥20 years to develop, the severity of the mutations must be somewhat subtle. We hypothesized that mutations that result in early onset disease would have more severe changes in function than do later onset mutations. Here, we performed steady-state and transient kinetic analyses of myosins carrying one of seven missense mutations in the motor domain. Of these seven, four were previously identified in early onset cardiomyopathy screens. We used the parameters derived from these analyses to model the ATP-driven cross-bridge cycle. Contrary to our hypothesis, the results indicated no clear differences between early and late onset HCM mutations. Despite the lack of distinction between early and late onset HCM, the predicted occupancy of the force-holding actin·myosin·ADP complex at [Actin] = 3 Kapp along with the closely related duty ratio (the fraction of myosin in strongly attached force-holding states), and the measured ATPases all changed in parallel (in both sign and degree of change) compared with wildtype (WT) values. Six of the seven HCM mutations were clearly distinct from a set of previously characterized DCM mutations.

LATE-ONSET HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM) is often considered a disease of the youth; however, it is also diagnosed in the elderly. The presentation of late-onset hypertrophic cardiomyopathy is not ubiquitous and precise diagnosis requires a multimodality approach. A 71-year-old man presented without

AB171. RNA alternative splicing modulator can effectively increase lymphoblast enzyme activity in patients with cardiac fabry disease caused by IVS4+919G >A mutation

Background In Taiwan, DNA-based newborn screening showed a surprisingly high incidence (1/875 in males and 1/399 in females) of a cardiac fabry mutation (IVS4 + 919G >A). The common cardiac variant fabry mutation, IVS4+919G >A, affects the splicing of GLA RNA by introducing a 57-nucleotide insertion between exons 4 and 5 that contains a stop codon and leads to a truncated protein and inactive enzyme. And this mutation affected males have up to 10% residual enzyme activity and present clinically with late-onset hypertrophic cardiomyopathy. Due to the high cost of enzyme replacement therapy and the large number of patients with this mutation, the development of alternative therapies is essential. Several low-molecular-mass compounds, such as histone deacetylase inhibitors or kinase/phosphatase inhibitors, have been identified as modulators of alternative splicing. It may offer a potential alternative to enzyme replacement therapy. We expect to find out a more economic and effective drug by the detailed study of the mechanism of the small molecule modulators on the IVS4+919G >A mutation for the greater benefits of patients with this mutation.

Abstract P249: Cardiac Troponin I Pro82Ser Variant Impairs Myofilament Cooperativity, Induces Diastolic Dysfunction, and Blunts β-Adrenergic Response

Cardiac troponin I is a key regulatory protein for muscle contraction and necessary for an adequate β-adrenergic response. The Proline 82 Serine (P82S) sequence variant of troponin I gene ( TNNI3 ) is associated with late onset hypertrophic cardiomyopathy (HCM). Our preliminary data has shown that cTnIP82S is heterozygous in 3% of African Americans and is associated with increased LV mass in hypertensive black men. We hypothesize that cTnIP82S variant could influence the hypertrophic response to hypertension and/or the malignancy of the phenotypic expression when combined with known HCM disease causing myofilament mutations. We created a transgenic cTnIP82S mouse model. Echocardiography at baseline in older Tg and NTg mice (64-65 wks) showed impaired ejection time and relaxation, Tg display longer isovolumetric relaxation time (IVRT) (Tg 29.7±0.26 vs NTg 23± 0.23 msec, n=8 vs n=7 p&lt;0.05) and a significantly higher TEI index. In the young NTg and Tg (17 wks) there were no echocardiographic differences. However, preliminary data suggest that 1 wk after transverse aortic coarctation (TAC), diastolic dysfunction was evident in Tg, and 10 weeks after TAC LV mass was also increased compared to NTg. Skinned fibers studies showed in the Tg mice borderline lower maximal Force (F max ) and myofilament calcium sensitivity, whereas n Hill showed a marked depression (Tg 1.72±0.17 vs NTg 3.09±0.44, n=7 vs n=5, p&lt;0.05), this effect was not due to the global myofilament phosphorylation pattern. In addition, intact twitching cardiac muscle studies in Tg mice revealed an impaired dose-dependent β-adrenergic acceleration of relaxation, evidenced by a failure to increase relaxation ([-dF/dt min]/[+dF/dt max]) and accelerate calcium transients decay after isoproterenol. Pressure-volume (PV) loop studies confirm that Tg mice fail to increase: Δ change in dP/dt max (NTg 4,928.3±7.7 vs Tg 843.3±10.7, n=4 vs n=4 p&lt;0.05) in response to isoproterenol. TnIP82S variant is near a region of TnI-TnT interaction; this could explain its dramatic effects on myofilament cooperativity. Overall these studies suggest that the expression of cTnIP82S variant in the mice heart induces diastolic dysfunction, impairs relaxation at baseline and after β-adrenergic stimulation.

Long‐Term Outcome of 4 Korean Families With Hypertrophic Cardiomyopathy Caused by 4 Different Mutations

We sought to describe the long-term outcome of individuals in 4 Korean families with hypertrophic cardiomyopathy (HCM) with known mutations. Long-term clinical features of familial HCM might be characterized according to the mutation causing HCM. We performed long-term (mean, 13.1 y) clinical evaluations on 46 subjects from 4 Korean families with different mutations. Myosin light chain 3 gene (MYL3) mutation was associated with late-onset HCM with relatively poor prognosis; 1 sudden cardiac death and 2 cases of heart failure with atrial fibrillation occurred among 12 subjects with this mutation. Myosin binding protein C gene (MYBPC3) mutation was associated with 2 cases of sudden cardiac death and 3 cases of heart failure among 7 affected members. Cardiac troponin I type 3 gene (TNNI3) mutation was associated with 5 deaths related to atrial fibrillation and stroke among 12 mutation-positive members. Myosin heavy chain 7 gene (MYH7) mutation was associated with 11 deaths in 15 affected members. The clinical course was quite different for different HCM mutations. Even within the same family, individuals carrying the same mutation differed in disease expression and prognosis.

It’s All in the Family: A Treatable Cause of Late-Onset Hypertrophic Cardiomyopathy

Abstract 1121 Ryan P Daly, E. Rene Rodriguez, Allan L Klein, Cleveland Clinic, Cleveland, OH Ryan Daly, 2008 Finalist and Presenting Author

Abstract 1121: It’s All in the Family: A Treatable Cause of Late-Onset Hypertrophic Cardiomyopathy

A 73-year-old woman with a history of hypertension (HTN) and mild aortic insufficiency (AI) presented to clinic with progressive dyspnea, fatigue and decreased functional capacity. Her family history was remarkable for a 45-year-old son with a “weak heart” and kidney dysfunction that was being evaluated. Her physical exam was unremarkable with the exception of bradycardia. ECG revealed sinus bradycardia of 46-bpm and a complete RBBB. Transthoracic echo revealed a small cavity with severely increased wall thickness, with obliteration in systole, with no obstruction and mild AI; notably without a history of poorly controlled HTN or significant valvular disease. A right heart catheterization revealed low output failure with a FICK cardiac index of 1.9 L/min-m2. Of note, her son’s work-up revealed Fabry’s disease, with cardiac and renal involvement. Her alpha-galactosidase enzyme levels were low-normal. A cardiac MRI with late gadolinium enhancement revealed a pattern of fibrosis suggestive infiltrative disease, and atypical for HOCM. Endocardial biopsy demonstrated myelin figures with curvilinear bodies in multiple myocytes on ultrastructural examination, diagnostic for cardiac Fabry’s disease. Enzymatic replacement therapy was initiated and a DDD pacemaker was placed with improvement of her NYHA class and BNP level. A treatable disease, representing up to 4% of late-onset hypertrophic cardiomyopathy (HCM), Fabry’s disease should be considered when evaluating patients with non-obstructive HCM. Keys to establishing this diagnosis lay in integrating clinical, genetic, and imaging data and recognizing Fabry’s disease as an X-linked dominant (not recessive) disease that may have isolated cardiac involvement, in heterozygous females, despite low-normal alpha-galactosidase activity.

Cardiovascular Manifestations in Fabry Disease: A Clinical and Echocardiographic Study

This study reviews the clinical and echocardiographic findings in a cohort of Fabry patients (n=12) and compares echocardiographic findings to normal controls. Almost all patients had extracardiac manifestations. Five out of 12 patients had cardiovascular symptoms. Nine out of 12 patients had left ventricular hypertrophy (LVH) on the electrocardiogram (ECG) and one patient had short PR interval. Three patients had epicardial coronary disease. Four patients had 'rat-tail' appearance on left ventriculogram. Six patients who had myocardial biopsy showed extensive vacuolation of the myocytes on light microscopy and concentric, myelinoid lamellar cytoplasmic inclusion bodies on electron microscopy. On echocardiography, LV mass was significantly increased in the Fabry group compared to normal controls. Traditional parameters of diastolic function including peak E velocity, peak A velocity and deceleration time were no different to normal controls. The IVRT was significantly prolonged in the Fabry subjects. The PV atrial reversal duration exceeded that of mitral A wave duration in the Fabry group. The septal E' velocity with Doppler tissue imaging (DTI) was significantly lower in the Fabry group than the normal controls. Fabry disease should be considered in the differential diagnosis in patients with unexplained LVH and late onset hypertrophic cardiomyopathy. Extracardiac manifestations are common.

Anesthesia for older patients with hypertrophic cardiomyopathy: is there cause for concern?

Hypertrophic cardiomyopathy (HCM) may remain clinically silent and undiagnosed until patients reach advanced age. We describe 2 older patients with previously undetected and probable late-onset HCM whose preoperative cardiac examination revealed only the presence of a systolic murmur. Both patients were diagnosed with HCM by perioperative echocardiography. We provide an algorithm for the evaluation of murmurs detected during the preoperative anesthesia evaluation, with emphasis on the clinical characteristics of HCM, and we discuss the perioperative management of these patients. In addition, recent findings concerning the natural progression of HCM are discussed, revealing differences between HCM in younger patient populations and that in older patient populations and its implications for anesthetic management.

Prevalence of Fabry Disease (FD) in female patients with late-onset hypertrophic cardiomyopathy (HCM)

Prevalence of Fabry Disease (FD) in female patients with late-onset hypertrophic cardiomyopathy (HCM)

Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy.

Fabry disease (FD) has been recognized as the cause of left ventricular hypertrophy in 6% of men with late-onset hypertrophic cardiomyopathy (HCM). Although FD is considered a recessive X-linked disorder, affected women are increasingly reported. The aim of our study was to determine the prevalence of FD in female patients with HCM. Thirty-four consecutive women (mean age, 50+/-13.6 years) who received an ECG and echocardiographic diagnosis of HCM were submitted to an invasive cardiac study that included a biventricular endomyocardial biopsy. Tissue samples were analyzed for histology and electron microscopy. Peripheral blood activity of alpha-galactosidase (alpha-Gal) A was assessed in all patients. None of them had a family history of FD. Histology and electron microscopy showed in 4 patients (12%; mean age, 51.5+/-3.9 years) the presence of cell vacuoles characterized by the accumulation of glycolipid material organized in concentric lamellar structures, diagnostic for FD. In the remaining patients, histology was consistent with HCM. In all the female carriers, the heart was the only organ clinically involved in the disease, showing concentric hypertrophy in 2 patients, asymmetric hypertrophy in 1, and apical hypertrophy in 1. The alpha-Gal A enzymatic activity was 44+/-14% of control values. Genetic analysis showed the presence of alpha-Gal A gene mutation in all 4 cases. FD may account for up to 12% of females with late-onset HCM. Those heterozygous for FD with left ventricular hypertrophy are potential candidates for enzyme enhancement/replacement therapy.

Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.

Although studies have suggested that "late-onset" hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population. Plasma alpha-galactosidase A (alpha-Gal) was measured in 79 men with HCM who were diagnosed at > or =40 years of age (52.9+/-7.7 years; range, 40-71 years) and in 74 men who were diagnosed at <40 years (25.9+/-9.2 years; range, 8-39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low alpha-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low alpha-Gal activity had alpha-Gal gene mutations. Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.

Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.

Hypertrophic cardiomyopathy, a familial myocardial condition caused by sarcomere protein mutations, is usually recognized by early adulthood. Hypertrophic cardiomyopathy of the elderly has similar clinical features but, notably, a later age of onset and noncontributory family history. Causes of elderly-onset hypertrophic cardiomyopathy are unknown. Eighteen women and 13 men diagnosed with late-onset hypertrophic cardiomyopathy were studied. Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years. None had family histories of cardiomyopathy. Echocardiography demonstrated maximal left ventricular wall thickness of 19.9+/-3.8 mm, systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients (average, 63+/-42.8 mm). Sarcomere protein gene analyses revealed 8 sequence variants in cardiac myosin binding protein-C (1 nonsense, 1 splice acceptor site, and 3 missense), cardiac troponin I (2 missense), and alpha-cardiac myosin heavy chain (1 missense). Seven variants were not found in over 170 normal chromosomes; 1 variant (cardiac myosin binding protein-C Arg326Gln) also occurred in a healthy adult. Hypertrophic cardiomyopathy of the elderly can be a genetic disorder caused by dominant sarcomere protein mutations. The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy. Whereas defects in beta-cardiac myosin heavy chain, cardiac troponin T, and alpha-tropomyosin account for > 45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy.

Beta-myosin Heavy Chain Gene Mutations and Hypertrophic Cardiomyopathy in Austrian Children

Hypertrophic cardiomyopathy occurs in two variants, either as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. Different genes coding sarcomeric proteins of the heart have been identified as causing hypertrophic cardiomyopathy. Missense mutations in the cardiac beta-myosin heavy chain gene are found in 30% of all cases of familial hypertrophic cardiomyopathy. We screened the beta-myosin heavy chain gene of children of nine Austrian families with hypertrophic cardiomyopathy (referred to as group A) and of seven children with sporadic hypertrophic cardiomyopathy (referred to as group B). We were able to find two previously described (V606M, R453C) and two unknown missense mutations (V406M, R663H) in group A. Additionally, in two children of group B we could indentify one already known missense mutation, R249Q as well as one previously unknown missense mutation, M877K. The genetically affected children of group A developed no or only mild clinical symptoms, whereas the children of group B with genetically confirmed sporadic hypertrophic cardiomyopathy showed manifest left ventricular hypertrophy and clinical symptoms including chest pain and dyspnoe. Clinical symptoms among the adults of group A, suffering from familial hypertrophic cardiomyopathy, varied significantly. We therefore believe V406M to be a more malignant missense mutation, probably linked with sudden death in the affected family, than R663H, which seems to be more benign causing late-onset hypertrophic cardiomyopathy and mild clinical symptoms in the affected family members.