ABSTRACT
Takotsubo cardiomyopathy (TCM) is characterized by transient left ventricular dysfunction, diagnosed via echocardiography or left ventriculography. In most cases, TCM involves an emotional, physical, or combined trigger. Acute coronary syndrome is one of the most frequent misdiagnoses in TCM patients due to electrocardiogram (ECG) abnormalities and elevated cardiac biomarkers. Typically, coronary angiography reveals no stenosis or occlusion of the coronary arteries. Hypertrophic cardiomyopathy (HCM) is a distinct pathology characterized by a hypertrophied left ventricle with various phenotypes. However, some reports have described TCM cases mimicking obstructive-type HCM in some patients. We present a case of a female patient diagnosed with TCM based on clinical, laboratory, and imaging tests. Differentiating TCM from HCM was challenging due to ventriculography and echocardiography findings, as hyperdynamic contraction of the basal segments of the left ventricle caused an increased left ventricular outflow tract (LVOT) gradient and severe mitral valve regurgitation. Detailed evaluation and close echocardiographic follow-up are essential in such rare cases.
Subject(s)
Cardiomyopathy, Hypertrophic , Electrocardiography , Takotsubo Cardiomyopathy , Humans , Takotsubo Cardiomyopathy/diagnosis , Takotsubo Cardiomyopathy/diagnostic imaging , Takotsubo Cardiomyopathy/physiopathology , Female , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/physiopathology , Diagnosis, Differential , Echocardiography , Middle AgedSubject(s)
Cardiomyopathy, Hypertrophic , Heart Neoplasms , Humans , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/complications , Heart Neoplasms/diagnostic imaging , Heart Neoplasms/complications , Male , Echocardiography , Female , Middle Aged , Diagnosis, Differential , Apical Hypertrophic CardiomyopathyABSTRACT
Despite substantial advances in the management of hypertrophic cardiomyopathy, advanced heart failure remains a major cause of morbidity in this patient population. This narrative review presents the case of a patient with hypertrophic obstructive cardiomyopathy who underwent alcohol septal ablation to frame a discussion of modern therapies for hypertrophic cardiomyopathy. The current treatment landscape includes medications, both old and new, and surgical and procedural interventions to relieve mechanical obstruction. Several promising new modalities for relieving obstruction are in the nascent stages of development.
Subject(s)
Ablation Techniques , Cardiomyopathy, Hypertrophic , Humans , Cardiomyopathy, Hypertrophic/therapy , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/surgery , Ablation Techniques/methods , Male , Treatment Outcome , Ethanol/therapeutic use , Middle AgedABSTRACT
Hypertrophic cardiomyopathy (HCM) is a hereditary cardiac disorder marked by anomalous thickening of the myocardium, representing a significant contributor to mortality. While the involvement of immune inflammation in the development of cardiac ailments is well-documented, its specific impact on HCM pathogenesis remains uncertain. Five distinct machine learning algorithms, namely LASSO, SVM, RF, Boruta and XGBoost, were utilized to discover new biomarkers associated with HCM. A unique nomogram was developed using two newly identified biomarkers and subsequently validated. Furthermore, samples of HCM and normal heart tissues were gathered from our institution to confirm the variance in expression levels and prognostic significance of GATM and MGST1. Five novel biomarkers (DARS2, GATM, MGST1, SDSL and ARG2) associated with HCM were identified. Subsequent validation revealed that GATM and MGST1 exhibited significant diagnostic utility for HCM in both the training and test cohorts, with all AUC values exceeding 0.8. Furthermore, a novel risk assessment model for HCM patients based on the expression levels of GATM and MGST1 demonstrated favourable performance in both the training (AUC = 0.88) and test cohorts (AUC = 0.9). Furthermore, our study revealed that GATM and MGST1 exhibited elevated expression levels in HCM tissues, demonstrating strong discriminatory ability between HCM and normal cardiac tissues (AUC of GATM = 0.79; MGST1 = 0.86). Our findings suggest that two specific cell types, monocytes and multipotent progenitors (MPP), may play crucial roles in the pathogenesis of HCM. Notably, GATM and MGST1 were found to be highly expressed in various tumours and showed significant prognostic implications. Functionally, GATM and MGST1 are likely involved in xenobiotic metabolism and epithelial mesenchymal transition in a wide range of cancer types. GATM and MGST1 have been identified as novel biomarkers implicated in the progression of both HCM and cancer. Additionally, monocytes and MPP may also play a role in facilitating the progression of HCM.
Subject(s)
Biomarkers , Cardiomyopathy, Hypertrophic , Machine Learning , Neoplasms , Humans , Cardiomyopathy, Hypertrophic/metabolism , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/genetics , Neoplasms/metabolism , Neoplasms/diagnosis , Neoplasms/genetics , Neoplasms/pathology , Biomarkers/metabolism , Male , Female , Prognosis , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Middle Aged , NomogramsABSTRACT
BACKGROUND: Patients with obstructive hypertrophic cardiomyopathy (oHCM) have a substantial humanistic, clinical, and economic burden due to the array of symptoms and complications associated with the disease. The objective of this review was to identify key evidence gaps related to oHCM, specifically in Europe, North America, and Japan. METHODS: A targeted literature review was conducted using PubMed to identify English-language studies published between 2012 and 2022 assessing patients with HCM/oHCM in France, Germany, Italy, Spain, the United Kingdom (UK), the United States (US), Canada, and Japan. Outcomes of interest were epidemiology, natural history, pathophysiology, management, and clinical, economic, and humanistic burden. Identified studies were assessed qualitatively to characterize evidence gaps. RESULTS: Among 2,262 abstracts and 531 full-text articles screened, 178 articles were included from PubMed searches. An additional 16 unique studies were identified via a supplemental Google Scholar search initially conducted in January 2023 and updated in July 2024. Disease natural history, pathophysiology, and management were well documented globally. Significant evidence gaps were noted for the epidemiology, treatment, and burden of oHCM. Although multiple US studies were identified on the clinical, economic, and humanistic burden of oHCM, and one clinical burden study was found for Japan, there was a lack of evidence for France, Germany, Italy, Spain, the UK, and Canada. CONCLUSIONS: Major evidentiary gaps exist for the epidemiology, treatment, and burden of oHCM. Future research should address these gaps, with a specific focus on generating real-world evidence for Canada and European countries that will support the evaluation of emerging therapies in these regions.
Subject(s)
Cardiomyopathy, Hypertrophic , Humans , Cardiomyopathy, Hypertrophic/epidemiology , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/therapy , Cardiomyopathy, Hypertrophic/diagnosis , Health Care Costs , Cost of Illness , Europe/epidemiology , MaleABSTRACT
Objective To analyze the research progress and hot topics in hypertrophic cardiomyopathy from 2018 to 2022.Methods The publications in the field of hypertrophic cardiomyopathy from January 1,2018 to December 31,2022 were retrieved from Web of Science core collection database and included for a bibliometric analysis.Results A total of 6355 publications were included,with an average citation frequency of 7 times.The year 2021 witnessed the most publications (1406).The analysis with VOSviewer showed that the research on sudden death related to hypertrophic cardiomyopathy,especially the predictive value of late gadolinium-enhanced cardiac MRI in sudden death,was a hot topic.In addition,gene detection and the new drug mavacamten became hot research topics.The United States was the country with the largest number of publications and the highest citation frequency in this field.Chinese scholars produced the second largest number of publications,which,however,included few high-quality research results.Conclusions Risk stratification and prevention of sudden death is still an important and hot research content in the field of hypertrophic cardiomyopathy.Chinese scholars should carry out multi-center cooperation in the future to improve the research results.
Subject(s)
Bibliometrics , Cardiomyopathy, Hypertrophic , Cardiomyopathy, Hypertrophic/epidemiology , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/diagnosis , Humans , Death, Sudden, Cardiac/epidemiology , Publications/statistics & numerical data , China/epidemiologyABSTRACT
Hypertrophic cardiomyopathy (HCM) is a well-known manifestation of inherited mitochondrial disease. Still, currently available gene panels do not include mitochondrial genome sequencing. Mitochondrial dysfunction plays a very important role in the pathogenesis of HCM, whether tested positive or negative by the currently available gene panels for HCM. Mitochondrial DNA variations may act as modifiers of disease manifestation in genotype-positive individuals. In genotype-negative individuals, it may be the primary driver of pathogenesis. A recent study has demonstrated that mitochondrial dysfunction is correlated with septal hypertrophy in genotype-negative HCM, which can be amenable to mitochondria-targeted therapy. It is important to consider mitochondrial genome sequencing as part of the genetic evaluation of HCM.
Hypertrophic cardiomyopathy or 'thick heart' is a common heart problem that can lead to abnormal heart rhythm and even heart failure. In older adults, it is often due to high blood pressure that causes the heart to pump against high resistance and hence becoming thick. However, it can occur without high blood pressure, often in young individuals with underlying heart muscle disease. Sometimes, there are many individuals in a family with thick hearts. In these instances, it is likely genetic. The individual may have a faulty gene related to heart muscle function causing the heart to become thick as an adaptation to inefficient heart muscle function. Mitochondria are tiny organelles inside our cells that make energy. When there is mitochondrial damage, heart muscles cannot generate energy efficiently. This can lead to a thick heart as well. Hence, it is important to test mitochondrial genes along with the heart muscle genes to find the cause of thick heart when it is unexplained, or a genetic cause is suspected.
Subject(s)
Cardiomyopathy, Hypertrophic , DNA, Mitochondrial , Humans , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/diagnosis , DNA, Mitochondrial/genetics , Mitochondria , Mitochondrial Diseases/genetics , Mitochondrial Diseases/diagnosis , MutationABSTRACT
Three cats were presented for unusual collapsing episodes. Echocardiography revealed a hypertrophic cardiomyopathy (HCM) phenotype in each cat. Continuous electrocardiographic monitoring showed that the clinical signs coincided with periods of severe ST-segment elevation in each cat. The first cat was treated with amlodipine and diltiazem but did not improve and was euthanized due to poor quality of life. Postmortem examination revealed cardiac lymphoma without obstructive coronary disease. The second cat was thought to have cardiac lymphoma, based on pericardial effusion cytology, and was euthanized before starting therapy. The third cat was diagnosed with HCM and left ventricular outflow tract obstruction and was treated with atenolol and diltiazem. This treatment reduced the frequency of episodic clinical signs, but the cat subsequently developed congestive heart failure and was euthanized. This case series describes clinical signs associated with severe ST elevation in cats with an HCM phenotype, and their outcomes. Continuous electrocardiographic monitoring was necessary to detect transient ST elevation in each case.
Subject(s)
Cardiomyopathy, Hypertrophic , Cat Diseases , Electrocardiography , Animals , Cats , Cardiomyopathy, Hypertrophic/veterinary , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/diagnosis , Cat Diseases/diagnosis , Cat Diseases/drug therapy , Cat Diseases/pathology , Electrocardiography/veterinary , Male , Female , Echocardiography/veterinary , Diltiazem/therapeutic useABSTRACT
BACKGROUND: Patients with refractory, symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy have few therapeutic options. Right ventricular pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized that site-specific pacing would reduce LVMCO gradients and improve symptoms. METHODS: Patients with symptomatic-drug-refractory LVMCO were recruited for a randomized, blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical right ventricular pacing sites were assessed during an invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular delays, defining PPoP, were selected on the basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6 months of active PPoP or backup pacing in a crossover design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP. RESULTS: A total of 17 patients were recruited; 16 of whom met primary end points. Baseline New York Heart Association was 3±0.6, despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the right ventricular apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and right ventricular apex in 2. The mean baseline gradient of 80±29 mmâ Hg fell to 31±21 mmâ Hg with best-site pacing, a 60% reduction (P<0.0001). One cardiac vein perforation occurred in 1 case, and 15 subjects entered crossover; 2 withdrawals occurred during crossover. Of the 13 completing crossover, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 versus 285.8±105.5 m; P=0.018); other outcome measures also indicated benefit with PPoP. CONCLUSIONS: In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic patients with LVMCO. REGISTRATION: URL: https://clinicaltrials.gov/study; Unique Identifier: NCT03450252.
Subject(s)
Cardiac Pacing, Artificial , Cardiomyopathy, Hypertrophic , Cross-Over Studies , Ventricular Function, Left , Humans , Male , Female , Cardiac Pacing, Artificial/methods , Middle Aged , Cardiomyopathy, Hypertrophic/therapy , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/diagnosis , Treatment Outcome , Aged , Quality of Life , Time Factors , Hemodynamics , Ventricular Outflow Obstruction/physiopathology , Ventricular Outflow Obstruction/therapy , Ventricular Outflow Obstruction/diagnosis , Exercise Tolerance , Ventricular Function, Right , Recovery of FunctionABSTRACT
Rest imaging in hypertrophic cardiomyopathy may underestimate or miss left ventricular outflow tract obstruction, leading to suboptimal management decisions that negatively affect symptomatic patients. The 2024 hypertrophic cardiomyopathy guidelines describe exercise stress testing as an important tool to determine overall exercise tolerance and latent, exercise-provoked left ventricular outflow tract obstruction.
Subject(s)
Cardiomyopathy, Hypertrophic , Exercise Test , Ventricular Outflow Obstruction , Humans , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnosis , Exercise Test/methods , Ventricular Outflow Obstruction/physiopathology , Ventricular Outflow Obstruction/diagnostic imaging , Ventricular Outflow Obstruction/etiology , Male , Middle Aged , Ventricular Outflow Obstruction, LeftABSTRACT
A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband's eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband's sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype-phenotype correlations in cardiomyopathy.
Subject(s)
Pedigree , Humans , Female , Male , Adult , Cardiomyopathies/genetics , Cardiomyopathies/diagnosis , Exome Sequencing , Abnormalities, Multiple/genetics , Hearing Loss, Sensorineural/genetics , Phenotype , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/diagnosisABSTRACT
BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.
Subject(s)
Cardiomyopathy, Hypertrophic , Stroke Volume , Ventricular Function, Left , Humans , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/diagnosis , Male , Female , Middle Aged , Aged , Ventricular Function, Left/drug effects , Stroke Volume/drug effects , Treatment Outcome , Double-Blind Method , Dose-Response Relationship, Drug , Adult , Atrial Fibrillation/drug therapy , Atrial Fibrillation/diagnosis , Atrial Fibrillation/physiopathology , Benzylamines , Uracil/analogs & derivativesABSTRACT
Pathogenic variation in genes encoding proteins of the cardiac sarcomere is responsible for 30%-40% of cases of hypertrophic cardiomyopathy. The main clinical utility of genetic testing is to provide diagnostic confirmation and facilitation of family screening. It also assists in the detection of aetiologies, which require distinct monitoring and treatment approaches. Other clinical applications, including the use of genetic information to inform risk prediction models, have been limited by the challenge of establishing robust genotype-phenotype correlations with actionable consequences, but new data on the interaction between rare and common genetic variation, as well as the emergence of therapies targeting disease-specific pathogenic mechanisms, herald a new era for genetic testing in routine practice.
Subject(s)
Cardiomyopathy, Hypertrophic , Genetic Testing , Sarcomeres , Humans , Genetic Testing/methods , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/diagnosis , Sarcomeres/genetics , Mutation , Genetic Predisposition to Disease/genetics , Genetic Variation/geneticsABSTRACT
Symptoms of apical hypertrophic cardiomyopathy (ApHCM) can mimic acute myocardial infarction (AMI). Following COVID-19 infection, the elevation of troponin in ApHCM might be confusing, due to its similarity with AMI. We report the case of a 64-year-old male patient presenting with exertional dyspnoea and chest discomfort. He had no history of coronary artery disease (CAD), but his swab test was positive for COVID-19. The physical examination was normal. The 12-lead electrocardiogram showed a sinus rhythm of 78 bpm, with deep inverted T waves in leads V2 to V6, I, and aVL, and left ventricular hypertrophy. An Echocardiographic examination showed an 18 mm apical wall thickness of the left ventricle. Laboratory tests revealed elevated hs- Troponin level, but diagnostic coronary angiography was normal. The diagnostic criteria fulfilled apical cardiac hypertrophic cardiomyopathy. Coronavirus can induce atypical cardiovascular symptoms in pre-existing ApHCM. Misdiagnosis and failure to recognize may result in inappropriate therapy and delay in definitive treatment.
Subject(s)
COVID-19 , Cardiomyopathy, Hypertrophic , Electrocardiography , Myocardial Infarction , Humans , Male , COVID-19/complications , COVID-19/diagnosis , Middle Aged , Myocardial Infarction/diagnosis , Diagnosis, Differential , Cardiomyopathy, Hypertrophic/diagnosis , Echocardiography , SARS-CoV-2 , Apical Hypertrophic CardiomyopathyABSTRACT
BACKGROUND: Previous studies have shown the importance of energy deficiency and malfunctioning mitochondria in the pathophysiology of hypertrophic cardiomyopathy (HCM). There has been a little research into the relationship between plasma free fatty acids (FFA), one of the heart's main energy sources, and HCM. We evaluated its clinical importance in HCM to see if there was a link between plasma FFA metabolism and HCM. METHODS: In a single-center retrospective observational study, we investigated 420 HCM patients diagnosed at Beijing Anzhen Hospital between January 1, 2018, and December 31, 2022. Meanwhile, 1372 individuals without HCM (non-HCM) were recruited. 391 non-HCM patients were chosen as controls via a propensity score matching (PSM) study with a 1:1 ratio. RESULTS: FFA in HCM patients showed statistically significant correlations with creatinine (r = 0.115, p = 0.023), estimated GFR (r=-0.130, p = 0.010), BNP (r = 0.152, p = 0.007), LVEF (r=-0.227, p < 0.001), LVFS (r=-0.160, p = 0.002), and LAD (r = 0.112, p = 0.028). Higher FFA levels were found in HCM patients who had atrial fibrillation and NYHY functional classes III or IV (p = 0.015 and p = 0.022, respectively). In HCM patients, multiple linear regression analysis revealed that BNP and LVEF had independent relationships with increasing FFA (Standardized = 0.139, p = 0.013 and =-0.196, p < 0.001, respectively). CONCLUSIONS: Among HCM patients, the plasma FFA concentration was lower, and those with AF and NYHY functional class III or IV had higher FFA levels, and LVEF and BNP were independently associated with increasing FFA. The findings of the study should help inspire future efforts to better understand how energy deficiency contributes to hypertrophic cardiomyopathy (HCM) development.
Subject(s)
Biomarkers , Cardiomyopathy, Hypertrophic , Fatty Acids, Nonesterified , Humans , Cardiomyopathy, Hypertrophic/physiopathology , Cardiomyopathy, Hypertrophic/blood , Cardiomyopathy, Hypertrophic/diagnosis , Retrospective Studies , Male , Female , Fatty Acids, Nonesterified/blood , Middle Aged , Biomarkers/blood , Adult , Energy Metabolism , Aged , Ventricular Function, Left , Beijing/epidemiologyABSTRACT
BACKGROUND: Catalogues of pathogenic genetic mutations in hypertrophic cardiomyopathy (HCM) are disproportionately small when compared to that of the size of the population with South Asian ancestry and their collective increased risk of heart disease. METHODS: We conducted clinical exome sequencing of 200 HCM patients to identified cardiomyopathy-associated genetic mutations. The clinical and echocardiographic characteristics of genotype-positive and genotype-negative patients were compared, and the likelihood of detecting a positive genetic test result was evaluated. Allelic burden analysis was done to compare the minor allele frequencies (MAF) of the pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) identified in the cohort against various population genomics databases. RESULTS: The genetic yield was 40% for P/LP variants, with MYBPC3 and MYH7 as the predominant sarcomere genes. Younger age-at-diagnosis, family history of HCM, asymmetric hypertrophic (ASH) pattern, the ratio of the interventricular septum to posterior wall thickness (IVS/PW ratio), left atrial (LA) dimensions, severe mitral regurgitation grade (MR grade), late gadolinium enhancement (LGE) detected fibrosis and absence of hypertension were associated with an increased likelihood of HCM-associated variants. Patients who experienced ventricular tachycardia and premature cardiovascular death were significantly likely to carry MYBPC3 or loss-of-function variants. LA and interventricular septal (IVS) dimensions were associated with MYH7 variants. The rare variant burden for P/LP variants and VUSs was significantly enriched in HCM cases compared to population controls. CONCLUSION: Our study provides a comprehensive evaluation of HCM-associated genetic mutations from an Indian population. The identified genotype-phenotype associations could improve the yield of targeted genetic testing in HCM.