Sarcomeric versus Non-Sarcomeric HCM

A previously healthy 32-year-old female undergoes evaluation after a syncopal episode. Physical examination reveals a systolic ejection murmur. Echocardiography demonstrates a vigorous LV with marked asymmetric septal hypertrophy, systolic anterior motion of the mitral valve, and a 50–mm Hg outflow tract gradient. Family history is notable for unexpected death in 4 paternal family members. She has 2 children (Figure 1A). Figure 1. A, HCM is a genetic cardiovascular disease. This family shows autosomal dominant inheritance with &50% of the family affected and equal numbers of affected male (▪) and female (•) family members. The case patient is indicated by an arrow. Deceased individuals are indicated by a diagonal slash (all died suddenly). B, DNA sequence analysis can identify sarcomere mutations that cause HCM. Top, The normal sequence of a portion of the cardiac troponin T gene is displayed with a triplet codon, TCC, encoding serine present. Bottom, DNA sequence obtained from a patient with HCM. The normal sequence is present on the allele inherited from the unaffected parent; the other allele shows a single base-pair substitution of a thymidine residue for the normal cytosine residue. This triplet codon, TTC, encodes phenylalanine and results in the substitution of a phenylalanine residue for the normal serine residue at amino acid position 179. The prevalence of unexplained left ventricular hypertrophy (LVH) in the general population is estimated to be 1 in 500.1,2 Hypertrophic cardiomyopathy (HCM) caused by sarcomere mutations may account for up to 60% of unexplained LVH, making HCM the most common genetic cardiovascular disorder.3–5 Accurate diagnosis of HCM is important for appropriate management of major HCM comorbidities, including atrial fibrillation, stroke, heart failure, and sudden cardiac death (SCD).6,7 HCM typically is diagnosed by unexplained LVH on echocardiography. Age of onset of LVH ranges from early childhood to …

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiac disorder and is the leading cause of sudden cardiac death in young individuals and athletes. It is caused by mutations in genes that encode for sarcomere proteins and is characterized by unexplained left ventricular (LV) hypertrophy (LVH). However, the penetrance of LVH is incomplete, highly variable, and age dependent. Recent reports have suggested that HCM mutation carriers without overt LVH frequently have risk factors for sudden cardiac death. Genetic testing provides a certain diagnosis for HCM mutation carriers before development of LVH, though it is hampered by being complex and unfeasible in up to 50% of HCM family members as genetic mutations are only identified in 40–60% of HCM patients. Therefore, an alternative family screening approach for early diagnosis of HCM patients is required. LV diastolic dysfunction as the first marker of disease in preclinical HCM mutation carriers has been previously detected by tissue Doppler imaging (TDI). However, the reported sensitivity and specificity were highly variable. Other imaging tools for the early identification of myocardial systolic dysfunction and myocardial structural alteration such as two–dimensional speckle tracking echocardiography (2DSTE) and integrated backscatter echocardiography, respectively were also investigated albeit with mixed results. Recently, cardiac magnetic resonance (CMR) imaging with its high spatial resolution has displayed subtle myocardial structural changes but also intramyocardial crypts in these mainly asymptomatic patients. However the availability of CMR is limited and the analysis is time consuming. Quantification of LA size and function is a good diagnostic tool for LV diastolic function as well as a predictor of therapy response and major cardiovascular outcomes in various cardiac patients including HCM patients. The assessment of left atrial (LA) longitudinal strain using 2DSTE has recently been shown as a feasible and reproducible marker of LA function. Three–dimensional speckle tracking echocardiography (3DSTE) is an emerging tool building on the strengths of 2DSTE for better quantification of myocardial volumes and mechanics including assessment of dyssynchrony in one fast analysis. In this study, we tested the ability of 3DSTE to distinguish HCM mutation carriers from normal subjects primarily by detecting subtle abnormalities in LA size and longitudinal strain as surrogate markers of early LV dysfunction. Likewise, we evaluated the magnitude and timing of systolic myocardial deformation to detect any abnormalities that can define early systolic dysfunction in these subjects.\nMethods and results: A total of 80 subjects with normal LV ejection fraction (EF) were divided into 3 groups: HCM mutation carriers (n = 23), manifest HCM patients (n = 28), and normal controls (n = 29). They prospectively underwent 3DSTE for left atrial (LA) and LV strain analysis. HCM mutation carriers showed significantly higher LA minimum volume (ml/m2) (17 ± 6 vs. 14 ± 4, respectively, P = 0.03) and a significantly lower peak atrial longitudinal strain (PALS) (%), (27 ± 5 vs. 31 ± 7, respectively, P = 0.02) when compared to controls. However, no differences were found in global or regional LV systolic myocardial deformation between carriers and normal controls. Manifest HCM patients, compared to carriers showed significantly higher LA minimum (27 ± 10 vs. 17 ± 6, respectively, P< 0.001) and maximum volume (42 ± 14 vs. 32 ± 8, respectively, P = 0.007) as well as lower LA EF (%) (35 ± 8 vs. 47 ± 9, respectively, P< 0.001) and PALS (17 ± 5 vs. 27 ± 5, respectively, P< 0.001). Comparing LV strain, HCM patients showed reduced global longitudinal (−11 ± 4 vs. −16 ± 3, respectively, P < 0.001) and area strain (−35 ± 6 vs. −40 ± 5, respectively, P = 0.005). In addition, there was higher mechanical dyssynchrony (SDI) in the long-axis motion (13.6 ± 10 vs. 8.3 ± 4, respectively, P = 0.007).\nConclusion: HCM mutation carriers could be distinguished from healthy subjects using 3DSTE through detection of LA dysfunction that might indicate subtle LV dysfunction. No differences were found in LV systolic myocardial deformation between both groups. The exact clinical value of 3DSTE in family screening for HCM needs to be further evaluated.

IntroductionDiagnostic genetic testing is an integral part of patient management in hypertrophic cardiomyopathy (HCM). Over time, the number of genes included in diagnostic genetic panels increased. The aim of the...

The latest response to consumers’ increased demand for accessible genetic health information is the US Food and Drug Administration (FDA)’s recent approval of 23andMe’s direct-to-consumer (DTC) genetic test for the three common BRCA1 and BRCA2 pathogenic variants found in the Ashkenazi Jewish population.1 23andMe and other DTC genetic testing companies officially report out ancestry, trait, and some health information, while also providing consumers with files of their raw genetic data. Up to 62% of consumers use third-party applications to interpret the raw data and health information not included in companies’ reports.2 Little data exists on the nature and prevalence of clinical follow up of third-party raw genetic data interpretation, nor on the psychosocial impact on the consumer and their families.3 This information is of timely importance as a recent study suggests that 40% of genetic variations within DTC raw data sent for clinical confirmation are false positives.4 This raises many questions about the impact of DTC genetic testing and third-party interpretation tools, including the appropriate use of healthcare resources, clinical utility, provider and patient understanding of limitations, and psychological impact on consumers. In this commentary, we present four case vignettes from cardiovascular genetics clinics to bring awareness to possible harms of DTC raw data interpretation. Future studies investigating the breadth and frequency of cases such as these are required to understand the scope of this harm.

Characterization of atrial histology in a patient with hypertrophic cardiomyopathy: Possible evidence of a primary atrial myopathy

Introduction Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease, typically transmitted in an autosomal dominant manner. Although pathogenic variants in sarcomere-encoding genes are key determinants of disease onset and progression, genetic testing has faced hurdles in terms of human and financial resources, necessitating efficient prioritization. The Mayo HCM Genotype Predictor Score (Mayo score) and the Toronto HCM Genotype Score (Toronto score), both derived from clinical and echocardiographic variables, have showed acceptable performance estimating the pre-test probability of genotype positivity. While electrocardiogram (ECG) is a low-cost and minimally invasive modality and pathogenic variants are associated with electrophysiological abnormalities, ECG parameters were not incorporated into these models. Purpose This study aimed to develop an improved predictive model for genotype positivity in HCM by integrating ECG parameters. Methods We retrospectively analysed 507 unrelated HCM patients from a Japanese multicentre cohort. Genotype positivity was defined as the presence of pathogenic or likely pathogenic (P/LP) variants in definitive sarcomeric genes. Candidate ECG variables were selected via univariate analysis and stepwise selection based on Akaike’s information criterion in a multivariable logistic regression model. A novel point-based Mayo-ECG score was developed and internally validated using bootstrap resampling. Predictive performance was assessed by the area under the receiver operating characteristic curve (AUROC) and net reclassification improvement (NRI). Results Overall, 162 (32.0%) were genotype positive. P/LP variants were most frequently identified in MYBPC3 (n = 74), followed by MYH7 (n = 62), and the other genes. Genotype-positive patients had a higher prevalence of atrial fibrillation, intraventricular conduction disturbance (QRS duration ≥ 120 msec or bundle branch block), prolonged QT interval, left axis deviation, lower Sokolow-Lyon index and less frequent T-wave inversion in the precordial leads compared to genotype-negative patients. The Mayo-ECG score (Figure 1) stratified genotype positivity from 7.6% (score ≤ -1) to 90.9% (score ≥ 4) (Figure 2A). Bootstrap resampling demonstrated the Mayo-ECG score (AUROC, 0.81 [95% CI, 0.77-0.85]) outperformed the Mayo score (AUROC, 0.76 [95% CI, 0.72-0.81]; p < 0.001, NRI: 0.21 [95% CI, 0.13-0.29]; p = 0.007) and the Toronto score (AUROC, 0.75 [95% CI, 0.70-0.79]; p = 0.009, NRI: 0.17 [95% CI, 0.06-0.27]; p < 0.001) (Figure 2B), with good calibration (Brier score: 0.156, max calibration error: 0.024). Conclusions Genotype-positive and genotype-negative HCM patients exhibited distinct ECG characteristics. The Mayo-ECG score significantly enhances genotype prediction in HCM by incorporating ECG parameters, outperforming conventional models. Its simplicity and improved accuracy support its use for optimizing genetic screening in HCM.Novel Mayo-ECG score Performance of Mayo-ECG score

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and fibrosis. HCM is an autosomal-dominant disease caused by more than 400 mutations in sarcomeric genes. Changes in nonsarcomeric genes contribute to its phenotypic heterogeneity. Cardiac fibrosis can be studied using late gadolinium enhancement (LGE) cardiac magnetic resonance imaging. We evaluated the potential role of two polymorphisms in nonsarcomeric genes on interstitial fibrosis in HCM. Two polymorphisms in nonsarcomeric genes [ACE (deletion of 287 bp in the 16th intron) and RETN (-420C>G)] were analysed in 146 HCM patients. Cardiac fibrosis was assessed using LGE to determine the number of affected segments. Allelic frequencies in ACE and RETN polymorphisms were consistent with the Hardy-Weinberg equilibrium (both P > 0.05). We found that the presence of the polymorphic allele in the -420C>G RETN polymorphism was independently associated with the number of affected segments of LGE (P = 0.038). Increased circulating resistin concentration, measured by enzyme-linked immunosorbent assay, was associated with a higher degree of cardiac fibrosis. Myocardial fibrosis, assessed by Masson's trichrome staining, was associated with the -420C>G RETN polymorphism in 46 tissue samples obtained by septal myectomy (P = 0.044). The -420C>G RETN polymorphism was independently associated with the degree of cardiac fibrosis, assessed by LGE, in patients with HCM. In addition, there was an association between the polymorphism and the circulating resistin levels as well as with myocardial fibrosis in tissues obtained by myectomy. Investigating the physiological implication of the RETN polymorphism in HCM in combination with the use of imaging technologies might help to establish the severity of disease in patients with HCM.

Genetic Testing in Cardiovascular Medicine.

Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data. Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM. This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

ObjectivesTo describe the population of patients diagnosed with hypertrophic cardiomyopathy (HCM) in Denmark and determine temporal trends in incidence and patient characteristics over time.DesignNationwide retrospective cohort study.SettingDanish nationwide administrative and...

The influence of shunts between the coronary artery (CA) and the left ventricle (LV), on chest pain (CP) in patients with hypertrophic cardiomyopathy (HCM) is unknown. We examined the incidence of CA-LV shunts and their influence on CP in HCM patients. Twenty normal control subjects (NCS), 3 with CP due to CA-LV shunts (CP patients), and 60 with HCM participated. Interventricular septal wall thickness (IVST), LV posterior wall thickness (LVPWT), cardiac and stroke indexes (CI and SI), LV end-diastolic pressure (LVEDP), and proximal diameters of the CA were measured. Twenty-five HCM patients had a CA-LV shunt (41.7%). Both IVST and LVPWT were greater in the HCM patients than in NCS and CP patients. These values showed no significant differences between the HCM with shunt and HCM without shunt groups. CI and SI were lower in the HCM patients than in NCS and CP patients. LVEDP was higher in the HCM and CP patients than in NCS. CA diameters were larger in the HCM and CP patients than in NCS. CP was found in 32 HCM patients (53%). The incidence of CP was greater in the HCM with shunt group than in HCM without shunt group (80 vs. 34%, p < 0.0005). There was no significant difference in CA diameters between the HCM patients with CP and those without CP. CA-LV shunts are often found in HCM patients and are closely related to CP. Thus, CA-LV shunts are an important factor behind CP in HCM patients.

Background Septal left ventricular hypertrophy (LVH) can represent a diagnostic challenge, with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) being the most common differential diagnoses. Purpose To assess the ability of a multi-parametric cardiac magnetic resonance (CMR) evaluation, combined with electrocardiographic findings, to inform the differential diagnosis between HCM and HHD in patients presenting with septal LVH phenotype. Methods This two-center study enrolled consecutive patients with HCM (diagnosed as currently defined by guidelines) and HHD with septal LVH who underwent a clinically indicated CMR examination and ECG within 6 months. Patients with increased LV wall thickness in areas other than the basal and/or mid interventricular septum were excluded. A multi-parametric CMR protocol with cine, native T1 mapping, late gadolinium enhancement (LGE) imaging and feature-tracking strain analysis was performed. Results A total of 150 patients (86 HCM, 64 HHD) were included. HCM patients showed significantly greater septal maximal wall thickness (MWT) compared to HHD [median (IQR); HCM: 16 (15, 19); HHD: 14 (13, 15); p&amp;lt;0.001] and higher LGE volume percentage (p&amp;lt;0.001). Conversely, the evidence of non-specific LGE limited to the LV/right ventricle insertion points was significantly more frequent in the HHD cohort (p&amp;lt;0.001). Global [HCM: -16.5 (-18.4, -4.1); HHD: -17.9 (-19.2, -15.7); p=0.009] and septal longitudinal strain [HCM: -15.1 (-17.8, -12.0); HHD: -17.4 (-20.1, -15.4); p&amp;lt;0.001] were more impaired in HCM vs HHD. Torsion was enhanced in HCM patients compared to HHD [HCM: 1.8 (1.4-2.4); HHD: 1.5 (1.1-1.8); p=0.028]. At the ECG, repolarization abnormalities were significantly more prevalent among HCM patients (62% vs 40%; p=0.011). Multivariable analysis identified LGE volume percentage (OR 0.63, 95% CI 0.42-0.85; p=0.009), septal LGE location (OR 0.17, 95% CI 0.04-0.73; p=0.019), enhanced torsion (OR 0.46, 95% CI 0.21-0.97, p=0.047), septal MWT (OR 0.42, 95% CI 0.20-0.69, p=0.005) and ECG repolarization abnormalities (OR 0.02, 95% CI 0.00-0.20, p=0.005) as independent predictors of HCM diagnosis. LGE volume&amp;gt;4% discriminated HCM from HHD with 74.1% sensitivity and 84.5% specificity (AUC 0.81). In both groups, a mild but significant correlation was observed between septal MWT and septal longitudinal strain (HCM: R= 0.29, p=0.009; HHD: R= 0.37, p=0.002) while no correlation was observed between septal MWT and torsion (HCM: R= -0.13, p=0.23; HHD: R= -0.02, p=0.89). Conclusions In the challenging diagnostic scenario of septal LVH, multiparametric CMR and ECG aid to differentiate HCM versus HHD. Septal MWT, the percentage of LGE and its septal location, together with enhanced torsion and ECG repolarization abnormalities, are independent predictors of HCM. While strain impairment worsens with increasing LVH in both diseases, torsion is enhanced in HCM independently from LVH severity.

Hypertrophic cardiomyopathy (HCM) is a common monogenetic cardiac disease with a prevalence of 0.2%1 that usually is inherited as an autosomal dominant trait with variable penetrance and expression. Clinically, HCM is defined by the presence of left ventricular (LV) hypertrophy (LVH) unexplained by abnormal loading conditions.1 The natural history varies from an asymptomatic course to drug-refractory angina/dyspnea, sudden cardiac death (SCD), and end-stage heart failure. The incidence of HCM-related SCD is approximately 1% to 2% in children and adolescents and 0.5% to 1% in adults.2,3 In this review, we examine the impact of advanced diagnostic imaging technologies on HCM, with particular emphasis on the detection of particular genetic subtypes. In ≈60% of cases, HCM is inherited as an autosomal dominant trait caused by mutations in genes coding for cardiac sarcomere proteins (Figure 1).4–7 Mutations in genes encoding Z-disc proteins and proteins involved in calcium regulation account for <5% of cases. The absence of sarcomeric gene mutations can be explained by limitations of current mutation detection techniques or mutations in as yet unidentified genes, but in some cases, hypertrophy is caused by other diseases that mimic the phenotype of sarcomeric protein disease. Table 1 lists genetic disorders associated with HCM. Figure 1. A schematic illustration of a cardiac sarcomere. View this table: Table 1. Currently Known Genes Implicated in HCM More than 600 different sarcomeric gene mutations are reported in patients with HCM.8–16 The majority are missense mutations, but nonsense, frameshift, and in-frame insertion/deletion mutations also occur. Most mutations are characterized by incomplete penetrance and variable clinical expression likely due to locus heterogeneity and the effect of mutations at different locations within the same gene. Most mutations probably have a dominant negative effect on sarcomere function, but in some cases, haploinsufficiency (ie, only a single functional …

Background Sarcoidosis, a systemic inflammatory disorder, can manifest as progressive inflammatory heart disease, termed cardiac sarcoidosis (CS). Despite advances in treatment, the impact of CS on health-related quality of life (HRQoL) remains incompletely understood. This study aimed to compare HRQoL between patients with CS and those with non-inflammatory cardiomyopathies, namely dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Purpose To assess and compare HRQoL across patients with cardiac sarcoidosis and non-inflammatory cardiomyopathies. Methods A total of 240 CS patients (86% response rate), 96 DCM patients (55% response rate), and 81 HCM patients (65% response rate) completed the RAND-36 general health-related questionnaire, comprising eight dimensions. Patients listed for transplantation were excluded. Clinical data were obtained from the Finnish myocardial inflammatory diseases registry for CS patients and from medical records in hospitals for HCM and DCM patients. Results Median age ranged from 56 to 59 years across the groups. Unlike DCM, which typically presents with heart failure symptoms, a substantial proportion (82%) of CS patients presented with advanced atrioventricular block or ventricular arrhythmias, while HCM cases were often incidentally detected or identified through family screening. Most CS patients (94%) had implanted pacemakers or ICDs, compared to a lower proportion in HCM (26%) and DCM (63%). DCM patients exhibited a higher prevalence of impaired LVEF (&amp;lt;50%) compared to CS and HCM patients. Functional impairment, as measured by NYHA class, was most pronounced in DCM patients. CS patients experienced more adverse events between diagnosis and the study entry, particularly sustained ventricular tachycardia/ventricular fibrillation. However, heart failure hospitalizations did not significantly differ between groups. Table 1 presents a comparative analysis of patient-reported outcomes across four functional and mental dimensions to assess the relative burden of disease among patients with CS, HCM, and DCM. While the functional dimensions in CS exhibited disparities from both HCM and DCM, no significant differences were observed in the mental dimensions between CS and HCM. CS patients reported lower scores in the domains of role physical, and general health compared to either HCM or DCM counterparts. Conclusion Patients with CS demonstrated significantly poorer HRQoL compared to those with non-inflammatory cardiomyopathies. This underscores the substantial burden of disease associated with CS and highlights the importance of comprehensive management strategies to address both clinical and quality of life aspects in affected individuals.