N-terminal pro-brain natriuretic peptide and adverse outcomes in Chinese patients with hypertrophic cardiomyopathy.

BACKGROUND: Although numerous studies have suggested that elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) is positively correlated with cardiovascular events, especially the heart failure and heart failure-related death (HFRD), evidence of the association between NT-proBNP and the adverse outcomes of hypertrophic cardiomyopathy (HCM) is still relatively limited. The present study was performed to evaluate the relationship between NT-proBNP and outcomes in patients with HCM. METHODS: Observational cohort methodology was used in the present study, and a total of 227 patients were included. And the patients were followed for 44.97 ± 16.37 months. Patients were categorized into three groups according to these NT-proBNP tertiles: first tertile (≤910 pg/ml, n=68), second tertile (913-2141 pg/ml, n=68), and third tertile (≥2151 pg/ml, n=69). The adverse outcomes of the present study were all-cause death (ACD) and cardiac death (CD). RESULTS: According to the risk category of NT-proBNP, the incidence of ACD (P=0.005) and CD (P=0.032) among the three groups showed significant differences. Multivariate Cox regression analysis suggested that the ACD and CD in the third tertile have 7.022 folds (hazard risk [HR] = 7.022 [95% confidence interval [CI]: 1.397-35.282], P=0.018) and 7.129 folds (HR = 7.129 [95% CI: 1.329-38.237], P=0.022) increased risks as compared with those in the first tertile. Kaplan-Meier survival analyses showed that the cumulative risks of ACD and CD in patients with HCM tended to increase. CONCLUSION: The present study indicated NT-proBNP was a novel biomarker suitable for predicting adverse prognosis in patients with HCM, which may be used for early recognition and risk stratification.

Associations of Race and Ethnicity With Presentation and Outcomes of Hypertrophic Cardiomyopathy: JACC Focus Seminar 6/9.

Significant racial and ethnicity-based disparities in clinical presentation, management, and outcome of hypertrophic cardiomyopathy (HCM) are reported. Black patients with HCM are more likely to present with heart failure but are less commonly referred for symptom management, sudden cardiac death stratification, surgical septal myectomy, or for implantable cardioverter-defibrillators, all interventions that increase survival. Prevalence of bystander cardiopulmonary resuscitation is lower for Black patients than for White patients. Black patients with HCM have decreased survival after hospital discharge following out-of-hospital cardiac arrest. Biomedical and social interventions are urgently needed to reduce ethnicity-based disparities, which have an impact on outcomes in HCM and other cardiovascular diseases. There is also a need to focus on implementation science to support durable adoption of evidence-based therapies in Black patients and communities.

Effect of rs4646994 polymorphism of angiotensin-converting enzyme on the risk of nonischemic cardiomyopathy.

BACKGROUND: Angiotensin-converting enzyme (ACE) gene polymorphisms have recently been shown to be associated with risk of developing left ventricular hypertrophy (LVH). However, the results were controversial. We aimed to conduct this meta-analysis to further confirm the association between ACE rs4646994 polymorphism and hypertrophic cardiomyopathy (HCM)/dilated cardiomyopathy (DCM). METHODS: PubMed, Embase, the Chinese National Knowledge Information, and Wanfang databases were searched for eligible studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies. Then we evaluated the association between ACE gene mutation and HCM/DCM by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs). Subgroup analysis was further performed to explore situations in specialized subjects. Sensitivity analysis and publication bias was assessed to confirm the study reliability. RESULTS: There were 13 studies on DCM (2004 cases and 1376 controls) and 16 studies on HCM (2161 controls and 1192 patients). ACE rs4646994 polymorphism was significantly associated with DCM in all genetic models. However, in HCM, four genetic models (allele model, homozygous model, heterozygous model, and dominant model) showed significant association between ACE rs4646994 polymorphism and DCM. In subgroup analysis, we found that ACE rs4646994 polymorphism was significantly associated with DCM/HCM in Asian population. Finally, we also conducted a cumulative meta-analysis, which indicates that the results of our meta-analysis are highly reliable. CONCLUSION: ACE rs4646994 polymorphism increases the risk of DCM/HCM in Asians, but not in Caucasians. More case-control studies are needed to strengthen our conclusions and to assess the gene-gene and gene-environment interactions between ACE rs4646994 polymorphism and DCM/HCM.

Disease Expression and Outcomes in Black and White Adults With Hypertrophic Cardiomyopathy.

Background There is limited research on hypertrophic cardiomyopathy (HCM), which is the most common inherited cardiac disorder, in diverse populations, including Black individuals. Current literature lacks comprehensive data on HCM disease expression, comorbidities, and outcomes in this historically disadvantaged group. The purpose of this study was to examine structural HCM characteristics, comorbidities, and outcomes in a Black and White cohort with HCM. Methods and Results The study was a subgroup analysis from a longitudinal, prospective study on HCM, with supplemental chart review. The sample included adults (≥18 years) with a clinical diagnosis of HCM, who self-identified as Black/African American or White. The study sample comprised 434 individuals; 57 (13.1%) were Black, and 180 (41.5%) were women. Black patients were younger than White patients, 54.6 (13.4) versus 62.5 (14.8) years, P=0.001. Black patients were more likely to have sub-basal and diffuse hypertrophy, 22 (38.6%) versus 56 (14.9%), P<0.001, 6 (10.5%) versus 15 (4%), P=0.017, mid-LV obstruction, 7 (12.3%) versus 21 (5.5%), P=0.025, and cardiac fibrosis ≥15%, 10 (22.2%) versus 19 (8.8%), P=0.009, than White patients. Black patients were more likely to experience appropriate implantable cardioverter defibrillator interventions, 5 (38.5) versus 5 (6.8), P<0.001 and were more likely to have ≥2 sudden death risk factors. Comorbidities were largely similar between groups, though more Black participants had Class II obesity, 12 (21.8) versus 30 (8.1), P<0.001. Both groups had similar rates of genetic testing usage. Conclusions This study underscores the need for continued research of HCM in Black populations, including tailored approaches to diagnosis and precise evaluation of cardiac anatomy.

Clinical Profile and Health Disparities in a Multiethnic Cohort of Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population. METHODS: We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed. RESULTS: Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m2, P<0.0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%, P=0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%, P<0.0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%, P=0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%, P<0.0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%, P=0.037). East Asians were more likely to have a causative variant in a gene other than MYBPC3 or MYH7, whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%, P<0.0001). CONCLUSIONS: There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine-based care of individuals with hypertrophic cardiomyopathy.

Aortic dilatation: Value of echocardiography in the systematic assessment of elite rugby players in the French National Rugby League (LNR).

The value of echocardiography in the screening of athletes in addition to the electrocardiogram is debated and still unclear. 336 rugby players in French professional divisions (Top 14, Pro D2) were prospectively assessed with electrocardiogram and echocardiography. 75% were Caucasian, 16.4% Pacific Islanders, and 8.6% Afro-Caribbean. Six (1.8%) players had electrocardiogram abnormalities, exclusively negative T waves. Twenty-one (6.25%) of them had abnormal echocardiography findings: one possible early hypertrophic cardiomyopathy, one anomalous origin of coronary artery, two left ventricular dilatations, one isolated bicuspid aortic valve, two aortic regurgitations, and 14 ascending aortic dilatations. The median aortic diameter was modestly correlated with age: 32 mm [23-48] in players aged ≤25 years vs 33.5 mm [24-50] in those aged >25 years (P = 0.02, correlation coefficient -.01). This tendency increased with cumulative hours of weight training: 34 mm [24-50] in forwards vs 32 mm [25-44] in backs (P = 0.01); and ethnicity, with Pacific Islanders having higher values in both raw data and body surface area or height-indexed data than Afro-Caribbeans and Caucasians: 34 [25-50] vs 32 [27-48] and 33 [23-49] mm (P = 0.017); 15 [12.2-21] vs 14.8 [11-19.9] and 14.8 [10-20.9] mm/m2 (P < 0.0001); 18.5 [14-25] mm/m vs 17.4 [14.8-25] mm/m and 17.6 [12.2-25.3] mm/m (P = 0.0125). In a population of professional rugby players, echocardiography was contributive. The main anomaly was aortic dilatation (14/336, 4.2%). While this is proportionally much higher than in other sports, the cutoffs need to be defined more precisely by including the criterion of ethnicity, as is already the case for electrocardiography.

Gender Disparities in Clinical Outcome After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy in the Chinese Han Population: A Cohort Study.

BACKGROUND: Sex differences in the long-term prognosis of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients undergoing alcohol septal ablation (ASA) remain unclear, especially in the Chinese Han population. METHOD: This cohort study included 320 HOCM Chinese Han patients who underwent ASA because of symptomatic left ventricular outflow tract (LVOT) obstruction. Patients were grouped according to sex: females (mean±standard deviation age [SD] 50.7±6.8 years) and males (mean±SD age 52.6±7.3 years). Individuals were followed over the long term. RESULTS: Pre-procedure, women had more symptoms (New York Heart Association [NYHA] class III-IV 67.3% vs 56.3%, p=0.03), more atrial fibrillation (23.5% vs 14.6%, p=0.047) than men. Transient complete atrioventricular block after ASA was more common in woman than in men (34.0 vs 23.4%; p=0.048). Residual LVOT gradient, post-procedural residual left ventricular wall thickness, NYHA functional class, and adverse arrhythmic events were comparable between the two groups. The 10-year survival rate (77% vs 89%, p=0.037) and the annual adverse arrhythmic event rate (1.3% vs 0.4%, p<0.01) following ASA were significantly worse in women compared with men. Kaplan-Meier analysis showed a significantly lower survival in women compared with men (p=0.023). In multivariable modelling, female sex remained independently associated with higher all-cause mortality (hazard ratio, 1.12; 95% confidence interval, 1.08-1.27; p=0.03) when adjusted for age, NYHA class III-IV symptoms, and other cardiovascular comorbidities. CONCLUSIONS: Female patients with HOCM undergoing ASA tended to have more severe symptoms and adverse arrhythmic events. The 10-year survival rate after ASA was significantly worse in women compared with men with HOCM. Sex may need to be considered as an important factor in the clinical management of patients with symptomatic HOCM.

Family screening in black patients with isolated left ventricular non-compaction: the Chris Hani Baragwanath experience.

BACKGROUND: Isolated left ventricular non-compaction (ILVNC), dilated cardiomyopathy (DCMO) and hypertrophic cardiomyopathy (HCM) are diseases that may be present in family members of patients with ILVNC. The primary aim of this study was to identify the prevalence and spectrum of cardiomyopathy in first-degree relatives of patients with ILVNC. A secondary aim was to compare a strategy of clinical screening, utilising only a clinical assessment and electrocardiogram (ECG), compared to one that included echocardiography for screening of family members of patients with ILVNC. METHODS: Eighty-three close relatives of 38 unrelated patients from the ILVNC clinic at the Chris Hani Baragwanath Hospital underwent a detailed clinical history, physical examination, ECG and echocardiogram. RESULTS: Echocardiographic screening revealed unexplained left ventricular (LV) dysfunction in 10 (12.05%) relatives. Nine out of the 10 individuals satisfied the criteria for diagnosis of DCMO. No cases of HCM or LVNC were identified. A strategy of clinical assessment and ECG had a sensitivity of 76% and a specificity of 42% versus the gold standard of echocardiographic screening. CONCLUSIONS: Echocardiographic screening detected DCMO in 10.8% of subjects. A strategy of clinical screening that included electrocardiography was sub-optimal as a screening strategy compared to echocardiographic screening.

Reevaluation of the South Asian MYBPC3Δ25bp Intronic Deletion in Hypertrophic Cardiomyopathy.

BACKGROUND: The common intronic deletion, MYBPC3Δ25, detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort. METHODS: Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3Δ25 frequency and co-occurrence of pathogenic variants in HCM genes. Case-control and haplotype analyses were performed to compare variant frequencies and assess disease association. Analyses were also undertaken to investigate the pathogenicity of a candidate variant MYBPC3 c.1224-52G>A. RESULTS: Our data suggest that the risk of HCM, previously attributed to MYBPC3Δ25, can be explained by enrichment of a derived haplotype, MYBPC3Δ25/-52, whereby a small subset of individuals bear both MYBPC3Δ25 and a rare pathogenic variant, MYBPC3 c.1224-52G>A. The intronic MYBPC3 c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in ≈1% of our HCM cohort. CONCLUSIONS: The MYBPC3 c.1224-52G>A variant explains the disease risk previously associated with MYBPC3Δ25 in the South Asian population and is one of the most frequent pathogenic variants in HCM in all populations; genotyping services should ensure coverage of this deep intronic mutation. Individuals carrying MYBPC3Δ25 alone are not at increased risk of HCM, and this variant should not be tested in isolation; this is important for the large majority of the 100 million individuals of South Asian ancestry who carry MYBPC3Δ25 and would previously have been declared at increased risk of HCM.

Association of Race With Disease Expression and Clinical Outcomes Among Patients With Hypertrophic Cardiomyopathy.

Importance: Racial differences are recognized in multiple cardiovascular parameters, including left ventricular hypertrophy and heart failure, which are 2 major manifestations of hypertrophic cardiomyopathy. The association of race with disease expression and outcomes among patients with hypertrophic cardiomyopathy is not well characterized. Objective: To assess the association between race, disease expression, care provision, and clinical outcomes among patients with hypertrophic cardiomyopathy. Design, Setting, and Participants: This retrospective cohort study included data on black and white patients with hypertrophic cardiomyopathy from the US-based sites of the Sarcomeric Human Cardiomyopathy Registry from 1989 through 2018. Exposures: Self-identified race. Main Outcomes and Measures: Baseline characteristics; genetic architecture; adverse outcomes, including cardiac arrest, cardiac transplantation or left ventricular assist device implantation, implantable cardioverter-defibrillator therapy, all-cause mortality, atrial fibrillation, stroke, and New York Heart Association (NYHA) functional class III or IV heart failure; and septal reduction therapies. The overall composite outcome consists of the first occurrence of any component of the ventricular arrhythmic composite end point, cardiac transplantation, left ventricular assist device implantation, NYHA class III or IV heart failure, atrial fibrillation, stroke, or all-cause mortality. Results: Of 2467 patients with hypertrophic cardiomyopathy at the time of analysis, 205 (8.3%) were black (130 male [63.4%]; mean [SD] age, 40.0 [18.6] years) and 2262 (91.7%) were white (1351 male [59.7%]; mean [SD] age, 45.5 [20.5] years). Compared with white patients, black patients were younger at the time of diagnosis (mean [SD], 36.5 [18.2] vs 41.9 [20.2] years; P < .001), had higher prevalence of NYHA class III or IV heart failure at presentation (36 of 205 [22.6%] vs 174 of 2262 [15.8%]; P = .001), had lower rates of genetic testing (111 [54.1%] vs 1404 [62.1%]; P = .03), and were less likely to have sarcomeric mutations identified by genetic testing (29 [26.1%] vs 569 [40.5%]; P = .006). Implantation of implantable cardioverter-defibrillators did not vary by race; however, invasive septal reduction was less common among black patients (30 [14.6%] vs 521 [23.0%]; P = .007). Black patients had less incident atrial fibrillation (35 [17.1%] vs 608 [26.9%]; P < .001). Black race was associated with increased development of NYHA class III or IV heart failure (hazard ratio, 1.45; 95% CI, 1.08-1.94) which persisted on multivariable Cox proportional hazards regression (hazard ratio, 1.97; 95% CI, 1.34-2.88). There were no differences in the associations of race with stroke, ventricular arrhythmias, all-cause mortality, or the overall composite outcome. Conclusions and Relevance: The findings suggest that black patients with hypertrophic cardiomyopathy are diagnosed at a younger age, are less likely to carry a sarcomere mutation, have a higher burden of functionally limited heart failure, and experience inequities in care with lower use of invasive septal reduction therapy and genetic testing compared with white patients. Further study is needed to assess whether higher rates of heart failure may be associated with underlying ancestry-based disease pathways, clinical management, or structural inequities.

[Analysis of genotype-phenotype correlation for a novel MYH7-D554Y mutation identified in an ethnic Han Chinese pedigree affected with hypertrophic cardiomyopathy].

OBJECTIVE: To explore the genotype-phenotype correlation of a MYH7-D554Y mutation identified in an ethnic Han Chinese pedigree affected with hypertrophic cardiomyopathy. METHODS: Ninety six cardiovascular disease-related genes were detected in the proband by exonic amplification and high-throughput sequencing. Suspected mutations were verified by Sanger sequencing among 300 healthy controls as well as family members of the proband. The pathogenicity and conservation of the detected mutations were analyzed with ClustalX, MutationTaster, PolyPhen-2, Provean and SIFT software. RESULTS: Four of the 5 first-degree relatives of the proband were diagnosed with hypertrophic cardiomyopathy. The proband has featured extremely hypertrophic left ventricular wall with a maximal thickness of 35 mm. Genetic testing showed that four of them have carried a heterozygous c.1660G>T (p.Asp554Tyr) mutation of the MYH7 gene, who the remaining one was phenotypically normal and did not carry the mutation. The mutation has not been recorded by the Human Gene Mutation Database (HGMD) and other databases. Bioinformatics analysis suggested that the mutation site is highly conserved and that the mutation is pathogenic. CONCLUSION: The p.Asp554Tyr mutation of the MYH7 gene probably underlies the hypertrophic cardiomyopathy in this pedigree.

Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes.

OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM). METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings. RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+S wave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69 mV vs 0.21±0.17 mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (ρ=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5 mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity. CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

Association of Cardiomyopathy With MYBPC3 D389V and MYBPC3Δ25bpIntronic Deletion in South Asian Descendants.

Importance: The genetic variant MYBPC3Δ25bp occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp. Objective: To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp. Design, Setting, andParticipants: South Asian individuals living in the United States were screened for MYBPC3Δ25bp, and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016. Main Outcomes and Measures: Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3Δ25bp. Results: In this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23% female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3Δ25bpcarrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3Δ25bp carrier group. Strikingly, 9.6% of MYBPC3Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3Δ25bp, and D389V was only seen in the presence of MYBPC3Δ25bp. In contrast to MYBPC3Δ25bp, MYBPC3Δ25bp/D389V was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P < .03) and stem cell-derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca2+ transients. Conclusions and Relevance: MYBPC3Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3Δ25bp.

Common miR-590 Variant rs6971711 Present Only in African Americans Reduces miR-590 Biogenesis.

MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and fibrosis. Recent studies have demonstrated that genetic variations which cause alterations in miRNA:target interactions can lead to disease. We hypothesized that genetic variations in miRNAs that regulate cardiac hypertrophy/fibrosis might be involved in generation of the cardiac phenotype in patients diagnosed with hypertrophic cardiomyopathy (HCM). To investigate this question, we Sanger sequenced 18 miRNA genes previously implicated in myocyte hypertrophy/fibrosis and apoptosis, using genomic DNA isolated from the leukocytes of 199 HCM patients. We identified a single nucleotide polymorphism (rs6971711, C57T SNP) at the 17th position of mature miR-590-3p (= 57th position of pre-miR-590) that is common in individuals of African ancestry. SNP frequency was higher in African American HCM patients (n = 55) than ethnically-matched controls (n = 100), but the difference was not statistically significant (8.2% vs. 6.5%; p = 0.5). Using a cell culture system, we discovered that presence of this SNP resulted in markedly lower levels of mature miR-590-5p (39 ± 16%, p<0.003) and miR-590-3p (20 ± 2%, p<0.003), when compared with wild-type (WT) miR-590, without affecting levels of pri-miR-590 and pre-miR-590. Consistent with this finding, the SNP resulted in reduced target suppression when compared to WT miR-590 (71% suppression by WT vs 60% suppression by SNP, p<0.03). Since miR-590 can regulate TGF-ß, Activin A and Akt signaling, SNP-induced reduction in miR-590 biogenesis could influence cardiac phenotype by de-repression of these signaling pathways. Since the SNP is only present in African Americans, population studies in this patient population would be valuable to investigate effects of this SNP on myocyte function and cardiac physiology.

Comparison of Clinical Features in Blacks Versus Whites With Hypertrophic Cardiomyopathy.

To date, there has not been a large systematic examination of the hypertrophic cardiomyopathy (HC) phenotype in blacks versus whites. In this study, we investigate differences in presentation of HC between blacks and whites. We included 441 consecutive patients with HC seen at the Johns Hopkins HC clinic in the period from February 2005 to June 2012. We compared 76 blacks for clinical presentation, electrocardiogram, exercise capacity, left ventricular morphology, and hemodynamics by echocardiography to 365 whites. Black patients with HC more often presented with abnormal electrocardiogram (93% vs 80%, p = 0.009), driven by a significant difference in repolarization abnormalities (79% vs 56%, p <0.001). Apical hypertrophy was more common in blacks (26% vs 9%, p <0.001); however, blacks had less severe systolic anterior movement of the mitral valve and had significantly lower left ventricular outflow tract gradients at rest (9 mm Hg; interquartile range [IQR] 7 to 19 vs 16 mm Hg; IQR 8 to 40, p <0.001) and during provocation (36 mm Hg; IQR 16 to 77 vs 59 mm Hg; IQR 26 to 110, p = 0.002). Despite the nonobstructive pathophysiology, blacks had lower exercise capacity (adjusted difference 1.45 metabolic equivalents [0.45 to 2.45], p = 0.005). In conclusion, blacks have an HC phenotype characterized by lower prevalence of the well-recognized echocardiographic features of HC such as systolic anterior movement of the mitral valve and left ventricular outflow tract obstruction and display worse exercise capacity.

A hypertrophic cardiomyopathy-associated MYBPC3 mutation common in populations of South Asian descent causes contractile dysfunction.

Hypertrophic cardiomyopathy (HCM) results from mutations in genes encoding sarcomeric proteins, most often MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). A recently discovered HCM-associated 25-base pair deletion in MYBPC3 is inherited in millions worldwide. Although this mutation causes changes in the C10 domain of cMyBP-C (cMyBP-C(C10mut)), which binds to the light meromyosin (LMM) region of the myosin heavy chain, the underlying molecular mechanism causing HCM is unknown. In this study, adenoviral expression of cMyBP-C(C10mut) in cultured adult rat cardiomyocytes was used to investigate protein localization and evaluate contractile function and Ca(2+) transients, compared with wild-type cMyBP-C expression (cMyBP-C(WT)) and controls. Forty-eight hours after infection, 44% of cMyBP-C(WT) and 36% of cMyBP-C(C10mut) protein levels were determined in total lysates, confirming equal expression. Immunofluorescence experiments showed little or no localization of cMyBP-C(C10mut) to the C-zone, whereas cMyBP-C(WT) mostly showed C-zone staining, suggesting that cMyBP-C(C10mut) could not properly integrate in the C-zone of the sarcomere. Subcellular fractionation confirmed that most cMyBP-C(C10mut) resided in the soluble fraction, with reduced presence in the myofilament fraction. Also, cMyBP-C(C10mut) displayed significantly reduced fractional shortening, sarcomere shortening, and relaxation velocities, apparently caused by defects in sarcomere function, because Ca(2+) transients were unaffected. Co-sedimentation and protein cross-linking assays confirmed that C10(mut) causes the loss of C10 domain interaction with myosin LMM. Protein homology modeling studies showed significant structural perturbation in cMyBP-C(C10mut), providing a potential structural basis for the alteration in its mode of interaction with myosin LMM. Therefore, expression of cMyBP-C(C10mut) protein is sufficient to cause contractile dysfunction in vitro.

[Pro731Ser mutation in the ß-myosin heavy chain and hypertrophic cardiomyopathy in a Chinese pedigree].

OBJECTIVE: To identify the casual mutation of a Chinese pedigree with hypertrophic cardiomyopathy (HCM), and to analyze the genotype-phenotype relationship. METHODS: The coding exons of 26 reported disease genes were sequenced by targeted resequencing in the proband and the identified mutation were detected with bi-directional Sanger sequencing in all family members and 307 healthy controls. The genotype-phenotype correlation was analyzed in the family. RESULTS: A missense mutation (c.2191C > T, p. Pro731Ser) in the 20th exon of MYH7 gene was identified. This mutation was absent in 307 healthy controls and predicted to be pathogenic by PolyPhen-HCM. Totally 13 family members carried this mutation, including 10 patients with HCM and 3 asymptomatic mutation carriers. The proband manifested severe congestive heart failure and 8 patients expressed various clinical manifestations of heart failure, including dyspnea, palpitations, chest pain, amaurosis or syncope. Five patients were diagnosed as HCM at the age of 16 or younger. One family member suffered sudden cardiac death. CONCLUSIONS: The Pro731Ser of MYH7 gene mutation is a causal and malignant mutation linked with familiar HCM.