Clinical Phenotype Of Hypertrophic Cardiomyopathy Research Articles

Association between traditional cardiovascular risk factors and clinical phenotype of hypertrophic cardiomyopathy

Despite the fact that the principles of diagnosing hypertrophic cardiomyopathy (HCM) are clearly defined in current guidelines, in real clinical practice one has to deal with a large number of comorbid patients where the diagnosis of HCM is not so obvious. Objective. To analyze the clinical and demographic characteristics of patients referred to the Almazov National Medical Research Center with the diagnosis of HCM. Design and methods. The registry included 1168 patients who were provisionally or definitively diagnosed with HCM in the period from 2010–2021. Out of them, 280 patients were excluded from the study. The patients included in the registry were divided into two groups: 1) patients meeting the criteria for HCM — 578 people (57,0 %); 2) patients of the so-called “gray zone” with the left ventricular wall thickness of 15-19 mm and concomitant arterial hypertension (HTN) — 310 (30,0 %) people. Results. In the first group of patients with HCM criteria, 326 (56,4 %) patients were aged 31–59 years and 35,5 % in the group older than 60 years. In the 2nd group there were 52,9 % (n = 164) patients older than 60 years, p < 0,001. 69,2 % of patients in the first group and 96,1 % of the 2nd group had a previous history of HTN. In relatives of patients of the first group, sudden cardiac death was more common — 3,5 versus 0,6 % in group 2, p < 0,05. Family history of HCM was observed in 6,2 % in group 1 versus 0,3 % in group 2, p < 0,001. In the first group, the obstructive form of HCM was more common — 54,5 versus 37,7 % in the second group, p < 0,001. Using logistic regression, the correctness of the classification of patients with HCM was assessed. The percentage of correct diagnoses was 94,1 % (Wald test = 78,317, p < 0,0001). Conclusions. Traditional risk factors, such as HTN and diabetes mellitus, not only make it difficult to diagnose HCM, but also aggravate its clinical presentation: myocardial hypertrophy, ventricular arrhythmias, and atrial fibrillation. The most important indicators in the classification of patients with suspected HCM were the thickness of the left ventricular wall according to echocardiographic data and the presence of HTN disproportionate to the degree of structural changes in the myocardium.

Association between clinical phenotypes of hypertrophic cardiomyopathy and Ca2+ gene variation gene variation

Objective: To observe the association between clinical phenotypes of hypertrophic cardiomyopathy (HCM) patients and a rare calcium channel and regulatory gene variation (Ca2+ gene variation) and to compare clinical phenotypes of HCM patients with Ca2+ gene variation, a single sarcomere gene variation and without gene variation and to explore the influence of rare Ca2+ gene variation on the clinical phenotypes of HCM. Methods: Eight hundred forty-two non-related adult HCM patients diagnosed for the first time in Xijing Hospital from 2013 to 2019 were enrolled in this study. All patients underwent exon analyses of 96 hereditary cardiac disease-related genes. Patients with diabetes mellitus, coronary artery disease, post alcohol septal ablation or septal myectomy, and patients who carried sarcomere gene variation of uncertain significance or carried>1 sarcomere gene variation or carried>1 Ca2+ gene variation, with HCM pseudophenotype or carrier of ion channel gene variations other than Ca2+ based on the genetic test results were excluded. Patients were divided into gene negative group (no sarcomere or Ca2+ gene variants), sarcomere gene variation group (only 1 sarcomere gene variant) and Ca2+ gene variant group (only 1 Ca2+ gene variant). Baseline data, echocardiography and electrocardiogram data were collected for analysis. Results: A total of 346 patients were enrolled, including 170 patients without gene variation (gene negative group), 154 patients with a single sarcomere gene variation (sarcomere gene variation group) and 22 patients with a single rare Ca2+ gene variation (Ca2+ gene variation group). Compared with gene negative group, patients in Ca2+ gene variation group had higher blood pressure and higher percentage of family history of HCM and sudden cardiac death (P<0.05); echocardiographic results showed that patients in Ca2+ gene variation group had thicker ventricular septum ((23.5±5.8) mm vs. (22.3±5.7) mm, P<0.05); electrocardiographic results showed that patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (400.6±47.2) ms, P<0.05) and higher RV5+SV1 ((4.51±2.26) mv vs. (3.50±1.65) mv, P<0.05). Compared with sarcomere gene variation group, patients in Ca2+ gene variation group had later onset age and higher blood pressure (P<0.05); echocardiographic results showed that there was no significant difference in ventricular septal thickness between two groups; patients in Ca2+ gene variation group had lower percentage of left ventricular outflow tract pressure gradient>30 mmHg (1 mmHg=0.133 kPa, 22.8% vs. 48.1%, P<0.05) and the lower early diastolic peak velocity of the mitral valve inflow/early diastolic peak velocity of the mitral valve annulus (E/e') ratio ((13.0±2.5) vs. (15.9±4.2), P<0.05); patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (399.0±43.0) ms, P<0.05) and lower percentage of ST segment depression (9.1% vs. 40.3%, P<0.05). Conclusion: Compared with gene negative group, the clinical phenotype of HCM is more severe in patients with rare Ca2+ gene variation; compared with patients with sarcomere gene variation, the clinical phenotype of HCM is milder in patients with rare Ca2+ gene variation.

Exercise training during childhood and adolescence is associated with favorable diastolic function in hypertrophic cardiomyopathy

BackgroundDiastolic dysfunction is an important part of the clinical phenotype in hypertrophic cardiomyopathy (HCM). While exercise training is known to improve left ventricular (LV) diastolic function in normal hearts, the effects of exercise training during childhood and adolescence in carriers of HCM-associated genetic variants are unknown. MethodsIn a cross-sectional and retrospective study, we combined clinical and echocardiographic data with history of exercise training from childhood to time of examination in 187 participants with HCM or an HCM-causative genotype. Multiple linear regression was used to identify correlations between exercise training performed prior to 20 years of age and LV diastolic parameters from echocardiography. ResultsExercise training during childhood and adolescence was correlated with a favorable e’, E/e’, E deceleration time, and end-diastolic volume (EDV), when adjusting for the effects of age at examination, and presence of left ventricular hypertrophy (LVH). This correlation was evident both in patients with a HCM phenotype (HCM LVH+), and in individuals with an HCM-causative genotype without LV hypertrophy (G+ LVH-). None of the diastolic parameters correlated unfavorably with increasing exercise exposure. ConclusionMore exercise training during childhood and adolescence was associated with favorable LV diastolic function in both HCM LVH+ and G+ LVH- groups, regardless of presence of hypertrophy at the time of examination. These results indicate that exercise training initiated during childhood and adolescence has positive effects on cardiac function later in life for individuals with HCM or an HCM-causative genotype.

Variation p.R1045H in MYH7 correlated with hypertrophic cardiomyopathy in a Chinese pedigree

BackgroundInherited hypertrophic cardiomyopathy (HCM) is a common heart muscle disease that damages heart function and may cause the heart to suddenly stop beating. Genetic factors play an important role in HCM. Pedigree analysis is a good way to identify the genetic defects that cause disease.MethodsAn HCM pedigree was determined in Yunnan, China. Whole-exome sequencing was performed to identify the genetic variants of HCM. Another 30 HCM patients and 200 healthy controls were also used to investigate the frequency of the variants by customized TaqMan genotyping assay.ResultsThe variant NM_000257.4:c.3134G > A (NP_000248.2:p.Arg1045His, rs397516178, c.3134G > A in short) was found to cosegregate with the clinical phenotype of HCM. Moreover, the variant was not found in the 200 control subjects. After genotyping the variant in 30 HCM patients, there was one patient who carried the variant and had a family history.ConclusionsOur findings suggest that this variant may be closely related to the occurrence of the disease. According the ACMG guidelines, the c.3134G > A variant should be classified as "Likely pathogenic".

Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.MethodsAs a part of the international multidisciplinary SILICOFCM project (www.silicofcm.eu) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.ResultsThe most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p = 0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p = 0.085). Laboratory analyses revealed normal levels of creatinine (85.5 ± 18.3 vs. 81.3 ± 16.4 µmol/l; p = 0.487) and blood urea nitrogen (10.2 ± 15.6 vs. 6.9 ± 3.9 mmol/l; p = 0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p = 0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p = 0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p = 0.001). The difference in diastolic function, i.e. E/e′ ratio between the two groups was also noted (MYBPC3 8.8 ± 3.3, MYH7 13.9 ± 6.9, p = 0.079).ConclusionsMajor findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

Gender variability in the clinical phenotype of hypertrophic cardiomyopathy

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a structural heart disease defined by an increase in left-ventricular (LV) wall thickness, that may be complicated with a clinical syndrome of heart failure, arrhythmia and death. Purpose To characterize the clinically significant factors for female HCM patients and bring forward the awareness to gender-based differences in HCM. Methods We reviewed the patient records of 1297 patients age ≥18 years, diagnosed with HCM, from two tertiary medical centers in Spain and Israel, and analyzed 748 male and female patients matched for age ≥60 years at admission, BMI, hypertension, diabetes and obstructive HCM. Results Female patients were older at original diagnosis [median 54 years (38–66) vs. 50 years (35–60), p=0.007], and had higher rates of family history of both HCM (46% vs. 37%, p=0.01) and sudden cardiac death (23% vs. 15%, p=0.02). Female patients had lower rates of active smoking (11% vs. 25%, p&amp;lt;0.001) and coronary disease (3% vs. 8%, p=0.007). In echocardiographic studies, females had a smaller LV cavity both during diastole [median 42mm (39–46) vs. 46 (42–50), p&amp;lt;0.001] and during systole [median 24 (21–29) vs. 27 (23–31), p&amp;lt;0.001]. Female patients had higher rates of significant mitral insufficiency (37% vs. 19%, p&amp;lt;0.001), and despite no significant differences in the rates of obstructive HCM, diastolic dysfunction, left-atrial enlargement, atrial fibrillation, ventricular tachyarrhythmia or pulmonary disease, they also had more significant pulmonary hypertension (≥45mmHg, 29% vs. 14%, p&amp;lt;0.001). Women had a lower functional capacity (p&amp;lt;0.001 for differences in NYHA, see fig.), and lower exercise capacity [median 7.0 METs (5–10) vs. 10.0 (7–12), p&amp;lt;0.001) and more abnormal blood pressure response to exercise (35% vs. 26%, p=0.03). Electrocardiographic features were similar across genders, except for a non-clinically significant shorter QRS duration in females. No significant differences were seen in 5-year mortality follow-up, which was ∼3% in the entire cohort. Conclusions Female patients suffering from HCM have a clinical phenotype defined by slightly later presentation (and shorter time until admission to a tertiary-center cardiomyopathy clinic), smaller LV cavity size, higher severity of mitral insufficiency and pulmonary hypertension and worse functional and exercise capacities. Genders did not differ in 5-year mortality, which was relatively low. Functional and exercise capacity Funding Acknowledgement Type of funding source: None

Deletion of the N-Terminus of Myosin Essential Light Chain (N-ELC) in the Background of HCM-A57G Mutation in Double Mutant Mice Rescues Hypercontractile Myosin Phenotype

Cardiac pathologic remodeling including fibrosis, diastolic dysfunction and increased Ca2+ sensitivity of force has been observed in mice expressing the A57G mutation in myosin ventricular ELC (MYL3 gene) with clinical phenotype of hypertrophic cardiomyopathy (HCM). Our previous investigation showed that the lack of the unique 43 amino acid-long N-terminus ELC (N-ELC) in >7-month-old Δ43 mice results in non-pathological cardiac hypertrophy. Papillary muscles (PM) from ∼8 mo-old Δ43 hearts were subjected to mantATP-chase assay and compared to those from age-matched WT-ELC and A57G mice. The data showed that Δ43 fibers favor the super-relaxed (SRX) state of myosin with increased population of slowly cycling heads compared to PM from age-matched WT-ELC mice. The opposite was true for A57G mice whose PM demonstrated a pathologic hypercontractile behavior with significantly inhibited SRX. We then tested the effect of N-ELC deletion in A57G mice on the SRX in offspring resulting from breeding Δ43 with A57G mice (Δ43xA57G) and expressing 0-22% of Δ43 and 0-84% of A57G. Single nucleotide turnover assays on PM from all Δ43xA57G animals showed stabilization of the SRX state that was reminiscent of Δ43 alone, and different from all other groups of mice. Interestingly, echocardiographic evaluation of ∼8-month-old Δ43xA57G mice revealed a decrease in cardiac hypertrophy (decrease in LV mass) compared to A57G and Δ43 animals. Myocardial performance index was also improved in Δ43xA57G crosses compared to HCM-A57G mice, and not different compared to WT or Δ43 mice. Our studies suggest that the deletion of N-ELC in the background of HCM-ELC mutation may be beneficial in reversing some of the pathological myosin motor phenotypes associated with HCM. Supported by NIH R01HL123255 and R56HL146133 (DSC).

The impact of diabetes mellitus on the clinical phenotype of hypertrophic cardiomyopathy.

Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM. We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation. Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction.

Novel genotype–phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy

ObjectiveA predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this study were...

High-throughput genotyping and phenotyping reveals new genetic determinants of clinical phenotype in hypertrophic cardiomyopathy

High-throughput genotyping and phenotyping reveals new genetic determinants of clinical phenotype in hypertrophic cardiomyopathy

HYPERTROPHIC CARDIOMYOPATHY: FIBROSIS OR HYPERTROPHY

Objective.Despite the high frequency — 0,2 % (1:500) population, hypertrophic cardiomyopathy (HCM) is still considered one of the most mysterious and misunderstood diseases of myocardium. Insidious pathology has neither specific anatomical and morphological, nor clinical features which makes it a delayed-action bomb: nobody is capable to predict when and what clinical symptoms develop. The clinical phenotype of HCM varies from latent course when the symptoms are absent till rapid progress of heart failure syndrome and sudden cardiac death due to severe arrhythmia. The review covers modern view on genetics, morphology and pathogenesis of HCM.

Diagnostic contribution of left ventricular endomyocardial biopsy in patients with clinical phenotype of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy phenotype is shared by heterogeneous entities. The purpose of the study was to evaluate the diagnostic role of left ventricular endomyocardial biopsy. One hundred fifty-one consecutive patients with unexplained left ventricular hypertrophy and normal/elevated QRS voltages or left bundle-branch block underwent left ventricular endomyocardial biopsy because of associated left ventricular dysfunction (37%), presence of sporadic form of left ventricular hypertrophy (32%), or patient desire for a definite diagnosis (31%). Biopsy samples were processed for histology and electron microscopy. Blood samples were collected for histologically oriented gene analysis of major sarcomeric (MYH7, MYBPC3, TNNT2, TPM1) and lysosomal (LAMP2, PRKAG2, α-galactosidase A) proteins. Histology showed changes consistent/compatible with hypertrophic cardiomyopathy in 124 patients: myocardial storage disease in 18 due to Fabry disease in 12 and glycogen-storage disease in 6 and myocardial infiltrative disease in 9 because of amyloidosis in 7 and sarcoidosis in 2. Gene analysis was positive in 67% of patients with hypertrophic cardiomyopathy (MYH7 mutation in 36, MYBP in 29, TNNT2 in 14, and TPM1 in 5) and in 83% of patients with lysosomal storage disease (α-galactosidase A mutation in 12, PRKAG2 in 2, and LAMP2 in 1). In patients with hypertrophic cardiomyopathy phenotype, left ventricular endomyocardial biopsy is safe and may recognize infiltrative/storage diseases in up to 18% of evolving and sporadic cases.

Has the Genomic Revolution Failed?

Has the Genomic Revolution Failed?

Genetic basis of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) was the first cardiovascular disorder in which a genetic basis was identified. The disease is characterized by a marked thickening of the left ventricle and is the most common structural cause of sudden cardiac death in those aged under 35 years. HCM is primarily a disease of the sarcomere with over 250 mutations identified currently within 13 sarcomere-related genes. At present, genetic screening is available for the genes shown to cause HCM most frequently, with a mutation pick-up rate of up to 60%. Current research is focused on the identification of additional causative genes and elucidation into signaling mechanisms involved in HCM pathogenesis, as well as investigation of modifying factors that can alter the clinical phenotype in HCM. The unifying goal of these studies is to improve our understanding of disease pathogenesis in HCM, thereby facilitating the process of new diagnostic and therapeutic approaches in patients, ultimately leading to disease prevention and possible curative treatment.

Novel Locus for an Inherited Cardiomyopathy Maps to Chromosome 7

Genetic mutations are the most common cause of hypertrophic cardiomyopathy (HCM) and an increasingly recognized cause of dilated cardiomyopathy. Autosomal dominant HCM is caused by mutations in sarcomere proteins; such mutations are not universally present, however, and fail to account for &40% of cases of phenotypic HCM. To add further complexity, other genetic origins can mimic the gross clinical phenotype of HCM, and mutations in sarcomere genes have been demonstrated to cause dilated cardiomyopathy. To explore novel genetic causes of inherited cardiomyopathies, genome-wide linkage analysis was used to study one kindred (4 generations, 32 individuals) with predominant clinical features of left ventricular hypertrophy in addition to cardiac dilation, end-stage heart failure, and sudden death. Of note, histopathology from 2 family members did not demonstrate myocyte disarray and fibrosis, indicating that this phenotype is not typical sarcomere mutation HCM. Direct DNA sequencing was performed on sarcomere genes known to cause HCM and dilated cardiomyopathy, and no mutations were identified. Linkage was then established to a novel locus on chromosome 7 (7p12.1-7q21). A maximum 2-point logarithm of odds score of 4.11 was obtained. Recombination events refine the disease interval between D7S506 and D7S3314, corresponding to a distance of 27.2 megabases. The discovery of a novel genetic locus in this family provides more evidence that molecular pathways leading to inherited cardiac hypertrophy extend beyond the sarcomere. Identification of the causal gene mutation and additional genotype-phenotype correlation studies will provide fundamental insight into mechanisms of cardiac remodeling.

MYBPC3 polymorphism is a modifier for expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy

Clinical phenotype of hypertrophic cardiomyopathy exhibits significant inter- and intra-familial heterogeneities. To test if MYBPC3 polymorphism could modify the expression of cardiac hypertrophy, 226 patients with hypertrophic cardiomyopathy and 226 age- and sex-matched controls were recruited according to the diagnostic criteria of WHO. Genotyping was completed by using PCR, restrictive enzyme digestion, and sequencing. Three polymorphisms of MYBPC3 were studied, only the GG genotype at 18443 in exon 30 associated with thicker left ventricular wall (25.2 ± 5.9 mm) in patient group, not the AA and AG genotypes (19.0 ± 5.0 mm, P < 0.001). After multiple regression analysis for adjustment of age and sex, the association remained. No difference was found in the genotype distribution between control and patients. Our results point out that GG genotype of MYBPC3 might be a genetic risk factor for the expression of cardiac hypertrophic phenotype in the patients with hypertrophic cardiomyopathy.