Clinical Manifestations Of Hypertrophic Cardiomyopathy Research Articles

Neonatal hypertrophic cardiomyopathy with dyspnoea as the first symptom: a case report

Neonatal hypertrophic cardiomyopathy (HCM) is an idiopathic disease characterised by myocardial hypertrophy with normal or small ventricular chambers, a systolic hyperdynamic state and diastolic dysfunction. The etiology, pathogenesis and clinical manifestations of HCM are diverse, and it is likely to progress to sudden cardiac death. The highly heterogeneous nature of this disease determines the difficulty of its diagnosis, and it is especially rare to report that can be diagnosed conclusively in the neonatal period. However, when it does occur, the younger the age of onset is, the higher the mortality rate and the worse the prognosis. The genetic variants and diagnostic timing can affect the life course of the patient. This case report describes a neonate with a family history of HCM who was diagnosed with hypertrophic non-obstructive cardiomyopathy by echocardiography shortly after birth. At 4 years of age, the patient presented with slow weight gain, feeding difficulties, tachypnoea and diaphoresis, and cardiac ultrasound findings suggesting progression to severe hypertrophic obstructive cardiomyopathy, with a high likelihood of arrhythmias, heart failure, pulmonary hypertension, syncope and even sudden death. Neonatal congenital hypertrophic cardiomyopathy is extremely rare and difficult to diagnose before the onset of symptoms. Echocardiography has a definite diagnostic value in hypertrophic cardiomyopathy and helps in early detection and treatment. At the time of clinical diagnosis, children with hypertrophic cardiomyopathy should be asked about their family history and, if necessary, a survey of family members should be conducted for the early detection of mildly ill patients and gene carriers to enable timely intervention and treatment, which remains the focus of our research and efforts.

Predictive genotype-phenotype correlation of four tropomyosin-1 variants of unknown significance.

Cardiomyopathies affect nearly 20% of humanity worldwide and are often caused by mutations in heart muscle genes that encode cardiac thin filament (TF) proteins. The on-off switching of cardiac muscle contraction is controlled by the TF proteins troponin and tropomyosin responding to alterations in sarcoplasmic calcium levels. In the absence of calcium, troponin-tropomyosin inhibits actomyosin interactions and induces muscle relaxation, whereas the addition of calcium relieves this constraint leading to contraction. Many mutations in TF proteins that are linked to cardiomyopathy appear to disrupt this regulatory switching. Here, we applied an interdisciplinary approach to correlate atomic-level alterations in tropomyosin structure to myofilament and tissue-level function to better understand mechanisms of disease. Twenty variants of unknown significance (VUS) in TPM1 from ClinVar were screened computationally using molecular dynamics to predict effects on tropomyosin structure and dynamics. Four candidate variants (A102D, D258E, K233N, and A239T) were identified and selected for further functional studies using in vitro motility assays and human engineered heart tissue (EHT) mechanics. The variants associated with hypertrophic cardiomyopathy, D258E and A102D, increased calcium sensitivity, while K233N, a VUS associated with dilated cardiomyopathy, lead to a decrease in calcium sensitivity. EHTs expressing A102D displayed a nearly 50% increase in peak isometric twitch force and delayed relaxation and D258E-EHTs also slowed relaxation. These phenotypes are consistent with the increased calcium sensitivity observed in the in vitro motility assay and with clinical manifestations of hypertrophic cardiomyopathy. Meanwhile, DCM-associated variants K233N and A239T caused dramatic and significant reductions in isometric twitch force when expressed in EHTs. Our approach reveals an important step toward predictive genotype-phenotype correlation and has the potential to benefit patients by accelerating the characterization and classification of tropomyosin variants.

Thin Filament Cardiomyopathy: Natural History, Clinical Features, And Outcomes

Introduction Hypertrophic cardiomyopathy due to thin filament mutations (HCM-Thin) has classically been characterized as more malignant with a higher burden of lethal arrhythmias and higher risk for sudden cardiac death compared to HCM from thick filament mutations (HCM-Thick). However, due to paucity of data and conflicting reports from small retrospective studies, the treatment of patients with HCM from thin and thick filament mutations have largely been the same. Objectives This systemic review includes all published case reports and series on HCM-Thin to understand the natural history and clinical outcomes in those with this condition. Methods A PubMed query regarding HCM-TF cases published until April 22, 2020 yielded twenty manuscripts that met inclusion criteria. Patients were included if a pathogenic mutation was identified or if the patient had clinical manifestations of hypertrophic cardiomyopathy and a first degree relative with positive genetic testing. Demographic, clinical characteristics, imaging data and outcomes were collected. Results A total of 211 HCM-Thin patients were identified with the most common mutations being TNNT2 (50.0%), TNNI3 (23.7%), and TPM1 (22.2%). The most common symptom reported was dyspnea (62.4%) with 22.4% classified as NYHA III and IV. Left ventricular outflow obstruction was present in 9.6% patients with the median left ventricular maximal thickness of 16.5 mm. Cardiac conduction abnormalities were frequent (56.9%) with the most common being ST-T abnormalities; Notably 26% were found to have atrial fibrillation and 18.3% had ventricular arrhythmias. The composite outcome of death, heart transplant, or ventricular assist device occurred in 18.5% of the cohort. Sudden cardiac death (55.6%) was the most common cause of mortality, but only 15.9% of patients received an ICD. Conclusion In this systematic analysis, HCM-Thin patients had a high risk of all-cause mortality or heart transplant, arrhythmia and advanced heart failure despite low rates of obstruction and hypertrophy. HCM-Thin may be a unique endotype that deserves distinct therapeutic approaches. Hypertrophic cardiomyopathy due to thin filament mutations (HCM-Thin) has classically been characterized as more malignant with a higher burden of lethal arrhythmias and higher risk for sudden cardiac death compared to HCM from thick filament mutations (HCM-Thick). However, due to paucity of data and conflicting reports from small retrospective studies, the treatment of patients with HCM from thin and thick filament mutations have largely been the same. This systemic review includes all published case reports and series on HCM-Thin to understand the natural history and clinical outcomes in those with this condition. A PubMed query regarding HCM-TF cases published until April 22, 2020 yielded twenty manuscripts that met inclusion criteria. Patients were included if a pathogenic mutation was identified or if the patient had clinical manifestations of hypertrophic cardiomyopathy and a first degree relative with positive genetic testing. Demographic, clinical characteristics, imaging data and outcomes were collected. A total of 211 HCM-Thin patients were identified with the most common mutations being TNNT2 (50.0%), TNNI3 (23.7%), and TPM1 (22.2%). The most common symptom reported was dyspnea (62.4%) with 22.4% classified as NYHA III and IV. Left ventricular outflow obstruction was present in 9.6% patients with the median left ventricular maximal thickness of 16.5 mm. Cardiac conduction abnormalities were frequent (56.9%) with the most common being ST-T abnormalities; Notably 26% were found to have atrial fibrillation and 18.3% had ventricular arrhythmias. The composite outcome of death, heart transplant, or ventricular assist device occurred in 18.5% of the cohort. Sudden cardiac death (55.6%) was the most common cause of mortality, but only 15.9% of patients received an ICD. In this systematic analysis, HCM-Thin patients had a high risk of all-cause mortality or heart transplant, arrhythmia and advanced heart failure despite low rates of obstruction and hypertrophy. HCM-Thin may be a unique endotype that deserves distinct therapeutic approaches.

The relationship between β1 -adrenergic and M2 -muscarinic receptor autoantibodies and hypertrophic cardiomyopathy.

What is the central question of this study? The concentrations of β1 -adrenergic receptor and M2 -muscarinic receptor autoantibodies in hypertrophic cardiomyopathy (HCM) patients and the relationship between the cardiac autoantibodies and clinical manifestations of HCM have rarely been reported. What is the main finding and its importance? We found that the concentrations of the two autoantibodies in HCM patients were significantly higher than those in control subjects. Furthermore, we found that the concentrations of the two autoantibodies could reflect myocardial injury and diastolic dysfunction in HCM patients to some extent and might be involved in the occurrence of arrhythmia. These findings might be valuable in exploration of the mechanisms of occurrence and progression of HCM. Increasing attention is being given to the role of immunological mechanisms in the development of heart failure. The purpose of this study was to investigate the concentration of serum β1 -adrenergic receptor autoantibody (β1 -AAb) and M2 -muscarinic receptor autoantibody (M2 -AAb) in patients with hypertrophic cardiomyopathy (HCM), and the relationship between β1 -AAb, M2 -AAb and clinical indices. One hundred and thirty-four patients with HCM were recruited consecutively into the HCM group. Forty healthy subjects were assigned as the normal controls (NCs). Serum samples were collected to measure the concentrations of β1 -AAb and M2 -AAb by enzyme-linked immunosorbent assay. The clinical data of HCM patients were collected. The serum concentrations of β1 -AAb and M2 -AAb of HCM patients were significantly higher than those of NCs. In HCM patients, those with a left atrial diameter ≥50mm or moderate-to-severe mitral regurgitation had significantly higher concentrations of the two autoantibodies. Patients with a history of syncope had higher concentrations of β1 -AAb. Female patients and patients with a family history of sudden cardiac death or atrial fibrillation had higher concentrations of M2 -AAb. Maximal wall thickness, interventricular septum thickness and resting left ventricular outflow tract gradient were positively correlated with logβ1 -AAb or logM2 -AAb in HCM patients. In conclusion, the serum concentrations of β1 -AAb and M2 -AAb of HCM patients were significantly higher than those of NCs. Being female, syncope, a family history of sudden death, atrial fibrillation, left atrial diameter ≥50mm, moderate-to-severe mitral regurgitation, maximal wall thickness, interventricular septum thickness and resting left ventricular outflow tract gradient may affect the concentrations of the two autoantibodies.

Miocardiopatía hipertrófica. Reporte de caso

Hypertrophic cardiomyopathy is a common inherited disease, which occurs in 1 in 500 individuals and affects both sexes.It presents with left ventricular hypertrophy in the absence of another cardiac or systemic disease capable of producing an increase in the thickness of the left ventricle wall. The clinical manifestations of hypertrophic cardiomyopathy are varied, from asymptomatic left ventricular hypertrophy or progressive heart failure to sudden cardiac death. Common symptoms include dyspnea, chest pain, palpitations, pre-syncope and syncope. Most of the time, left ventricular hypertrophy is evident during adolescence or youth. We describe the case of a male patient of 43 years, who presented a hypertensive emergency without previous history of systemic arterial hypertension. Through complementary exams, hypertrophic middle-apical myocardiopathy was diagnosed without obstruction of the left ventricular outflow tract.

Elevated high-sensitivity troponin T levels are associated with adverse cardiac remodelling and myocardial fibrosis in hypertrophic cardiomyopathy

Clinical manifestations of hypertrophic cardiomyopathy (HCM) range from asymptomatic disease to early-onset heart failure and sudden cardiac death (SCD). Risk stratification for SCD remains imperfect and novel risk markers are needed. The aim of our study was to evaluate the association of elevated high-sensitivity cardiac troponin T levels (hs-cTnT) with the severity of disease expression and adverse events in patients with HCM. All patients followed-up at a dedicated HCM clinic at a tertiary care centre between April 2012 and March 2014 were analysed. The clinical care track for these patients includes 12-lead ECG, blood work-up, echocardiography, Holter ECG, exercise stress testing and cardiovascular magnetic resonance imaging (CMR). Clinical data were obtained from medical records. Of 91 HCM patients (77% males, mean age at follow up 51 ± 16 years), 46 (51%) had elevated hs-cTnT levels (>0.014 ng/ml). Patients with elevated hs-cTnT levels had greater maximum wall thickness (23 ± 7 mm vs 19 ± 3 mm, p = 0.001), more often had myocardial fibrosis (96% vs 54%, p <0.001), and lower exercise capacity (90% predicted vs 76% predicted, p = 0.002). There was a trend towards lower event-free survival estimates (Kaplan-Meier method, 15% vs 7%, p = 0.16). Elevated hs-cTnT levels in HCM patients are associated with disease severity and, potentially, with more adverse cardiac events. Future studies should test whether integration of hs-cTnT in clinical decision algorithms will improve risk stratification.

Hypertrophic Cardiomyopathy from A to Z: Genetics, Pathophysiology, Imaging, and Management.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous group of diseases related to sarcomere gene mutations exhibiting heterogeneous phenotypes with an autosomal dominant mendelian pattern of inheritance. The disorder is characterized by diverse phenotypic expressions and variable natural progression, which may range from dyspnea and/or syncope to sudden cardiac death. It is found across all racial groups and is associated with left ventricular hypertrophy in the absence of another systemic or cardiac disease. The management of HCM is based on a thorough understanding of the underlying morphology, pathophysiology, and clinical course. Imaging findings of HCM mirror the variable expressivity and penetrance heterogeneity, with the added advantage of diagnosis even in cases where a specific mutation may not yet be found. The diagnostic information obtained from imaging varies depending on the specific stage of HCM-phenotype manifestation, including the prehypertrophic, hypertrophic, and later stages of adverse remodeling into the burned-out phase of overt heart failure. However, subtle or obvious, these imaging findings become critical components in diagnosis, management, and follow-up of HCM patients. Although diagnosis of HCM traditionally relies on clinical assessment and transthoracic echocardiography, recent studies have demonstrated increased utility of multidetector computed tomography (CT) and particularly cardiac magnetic resonance (MR) imaging in diagnosis, phenotype differentiation, therapeutic planning, and prognostication. In this article, we provide an overview of the genetics, pathophysiology, and clinical manifestations of HCM, with the spectrum of imaging findings at MR imaging and CT and their contribution in diagnosis, risk stratification, and therapy.

The role of magnetic resonance imaging in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiac disorder, with an estimated prevalence of 1:500 in the general population. Most cases of HCM are phenotypically expressed in adolescence or early adulthood but age-related penetrance with certain phenotypes is increasingly recognized. Clinical manifestations of HCM are usually the result of systolic and/or diastolic dysfunction, left ventricular outflow tract (LVOT) obstruction, arrhythmias and sudden cardiac death (SCD). In recent years magnetic resonance imaging (MRI) has become established as an important tool for the evaluation of suspected HCM as it can reliably establish the diagnosis, help distinguish HCM from other causes of left ventricular hypertrophy (LVH) and identify those patients at greatest risk of SCD. This article reviews the current status of MRI in the evaluation of the HCM patient including imaging protocols, disease characterization and the emerging role of MRI for risk stratification and proband screening.

Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy.

Modifier genes contribute to the diverse clinical manifestations of hypertrophic cardiomyopathy (HCM), but are still largely unknown. Muscle ring finger (MuRF) proteins are a class of muscle-specific ubiquitin E3-ligases that appear to modulate cardiac mass and function by regulating the ubiquitin-proteasome system. In this study we screened all the three members of the MuRF family, MuRF1, MuRF2 and MuRF3, in 594 unrelated HCM patients and 307 healthy controls by targeted resequencing. Identified rare variants were confirmed by capillary Sanger sequencing. The prevalence of rare variants in both MuRF1 and MuRF2 in HCM patients was higher than that in control subjects (MuRF1 13/594 (2.2%) vs. 1/307 (0.3%), p = 0.04; MuRF2 22/594 (3.7%) vs. 2/307 (0.7%); p = 0.007). Patients with rare variants in MuRF1 or MuRF2 were younger (p = 0.04) and had greater maximum left ventricular wall thickness (p = 0.006) than those without such variants. Mutations in genes encoding sarcomere proteins were present in 19 (55.9%) of the 34 HCM patients with rare variants in MuRF1 and MuRF2. These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of HCM. The findings suggest that dysregulation of the ubiquitin-proteasome system contributes to the pathogenesis of HCM.

HYPERTROPHIC CARDIOMYOPATHY IN ELDERLY PEOPLE

Hypertrophic cardiomyopathy (HCM) is a leader in genetic structure of cardiovascular system. According to modern concepts, hypertrophic cardiomyopathy associated with mutations of sarcomere proteins is just one of the reasons leading to the left ventricular hypertrophy (LVH). Hypertrophic phenotype is also observed in a number of genetically and non-genetically related diseases. According to population-based studies conducted in the USA, Europe and Japan, the prevalence of HCM is 1:500. Apparently, the data obtained in these studies and based primarily on the phenotypic screening cannot be extrapolated to the full cohort of patients with HCM and reflect the general incidence of hypertrophic phenotype in different populations. There are some publications on the prevalence of HCM in the structure of LVH of unknown cause in children and adolescents. The features of the clinical course of HCM, risk stratification of sudden cardiac death (SCD), medical management in young and middle age are studied. At the same time elderly patients with unexplained LVH are the least studied cohort. Study of the natural history of the disease, risk factors for adverse events, including the SCD, the impact of comorbidity on the clinical manifestations of HCM in the elderly will contribute better understanding of this pathology, as well as a number of other diseases occurring under the guise of HCM. This can help to develop the algorithms for diagnosis, prediction criteria and management of LVH of unknown cause.

The nurse's role in diagnosing hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder and the most common cause of sudden cardiac death (SCD) in people under 30 years. Although the causes are generally well known, SCD is often the first clinical manifestation of HCM. If those at risk of SCD and other complications are identified and treated appropriately, HCM is relatively benign. Priority should lie with identifying family and first-degree relatives of SCD victims, as HCM is predominantly a familial disorder. Patients with symptoms of HCM should be thoroughly assessed by health-care professionals. Knowledge of symptoms of HCM can lead to further investigations that can aid diagnosis. Symptoms include angina, dyspnoea, syncope/presyncope, palpitations and dizziness. The nurse plays an important role in assessing the patient for signs and symptoms of HCM through competent knowledge and skills in history taking, physical examination and electrocardiogram interpretation, which may provide the basis for a referral for an echocardiogram that can lead to the diagnosis of HCM. Treatment can then be commenced, thus reducing the risk of SCD. Implantable cardiac defibrillators are a common surgical intervention in HCM that have proven to be life saving.

Burden of Rare Sarcomere Gene Variants in the Framingham and Jackson Heart Study Cohorts

Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis.

Heterogeneity of Clinical Manifestation of Hypertrophic Cardiomyopathy Caused by Deletion of Lysine 183 in Cardiac Troponin I Gene Insight From Two Autopsy Cases With an Identical Sarcomeric Gene Mutation

Hypertrophic cardiomyopathy (HCM) is associated with gene mutations that encode sarcomeric proteins. However, the relationship between genotype and histopathologic findings is unclear. We report on two autopsy cases with advanced HCM associated with deletion of lysine 183 mutation in the cardiac troponin I gene. One case, a 74-year-old female exhibited dilated cardiomyopathy-like features. Transmural scarring was diffuse and circumferential, involving the whole left ventricle, especially the ventricular septum which was replaced with extensive fibrosis and showed marked wall thinning. The other case, a 92-year-old male revealed typical HCM findings. Patchy scars which corresponded to replacement fibrosis were found extending from the septum to the anterior wall. These two autopsy cases indicate the clinical heterogeneity of HCM even within the same disease-causing mutation and suggest that the degree and extent of fibrosis determine differences in the clinical manifestations of HCM. This is the first autopsy report that demonstrates identical sarcomeric gene mutations causing different clinical manifestations and histologic findings. The findings suggest that additional genetic or environmental factors influence the phenotypic expressions and clinical courses of HCM caused by genetic mutation of sarcomeric proteins.

Gene Mutations in Apical Hypertrophic Cardiomyopathy

Nonobstructive hypertrophy localized to the cardiac apex is an uncommon morphological variant of hypertrophic cardiomyopathy (HCM) that often is further distinguished by distinct giant negative T waves and a benign clinical course. The genetic relationship between HCM with typical hypertrophic morphology versus isolated apical hypertrophy is incompletely understood. Genetic cause was investigated in 15 probands with apical hypertrophy by DNA sequence analyses of 9 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2) implicated in idiopathic cardiac hypertrophy. Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in GLA, PRKAG2, or LAMP2. Clinical evaluations demonstrated familial apical HCM in 4 probands, and in 3 probands disease-causing mutations were identified. Two families shared a cardiac actin Glu101Lys missense mutation; all members of both families with clinical manifestations of HCM (n=16) had apical hypertrophy. An essential light chain missense mutation Met149Val caused apical or midventricular segment HCM in another proband and 5 family members, but 6 other affected relatives had typical HCM morphologies. No other sarcomere gene mutations identified in the remaining probands caused apical HCM in other family members. Sarcomere protein gene mutations that cause apical hypertrophy rather than more common HCM morphologies reflect interactions among genetic etiology, background modifier genes, and/or hemodynamic factors. Only a limited number of sarcomere gene defects (eg, cardiac actin Glu101Lys) consistently produce apical HCM.

Echocardiographic Findings and Clinical Manifestations of Hypertrophic Cardiomyopathy: Including 3 Cases of Anomalous Insertion of Papillary Muscle

Echocardiographic Findings and Clinical Manifestations of Hypertrophic Cardiomyopathy: Including 3 Cases of Anomalous Insertion of Papillary Muscle

The Frequency of Occurrence of Anti-cardiac Receptor Autoantibodies and their Correlation with Clinical Manifestation in Patients with Hypertrophic Cardiomyopathy

The purpose of this study was to investigate the frequency of occurrence of autoantibodies against G-protein coupled cardiovascular receptors and their relation to the clinical manifestation of hypertrophic cardiomyopathy (HCM). Autoantibodies against β1-receptors, Muscarin-2-receptors, Angiotensin-II-receptor subtype 1 and α1-receptors were determined with ELISA in 52 patients with HCM (37 male, 15 female, mean age 55 ± 15 years) and 40 healthy, age and sex matched controls. The clinical characterization of the HCM-patients included ECG, 24-h Holter, and echocardiography.The results showed that there is no significant difference in the frequency of a single autoantibody between HCM-patients and controls. However, if the number of patients who have autoantibodies against β1-receptors and/or Muscarin-2-receptors were counted together, there are significantly more autoantibodies in HCM compared to controls (11 vs. 2, p = 0.035). Analysis of clinical data from this pooled group of patients showed that in patients with autoantibodies, heart rate variability (HRV), ultra low frequency (ULF) and very low frequency (VLF) were decreased (HRV by 20%, ULF by 50%, and VLF by 46%, p < 0.008) whereas the QTc-interval was increased by 8% (p < 0.02 each). The ratio of septal to posterior wall thickness was increased by 23% (p = 0.05), and the preejection period was prolonged by 46% in patients with autoantibodies (p < 0.001).These results suggest that the existence of these autoantibodies could be associated with an advanced stage or a severe manifestation of HCM.

Clinical manifestations of hypertrophiccardiomyopathy with mutations in the cardiac beta-myosin heavy chain gene or cardiac troponin T gene

Introduction of molecular genetics has improved our understanding of HCM substantially, but has simultaneously raised further important questions. Studies on HCM are revealing a more complex picture than might have been expected on clinical grounds. Further extensive studies are warranted to elucidate the pathogenesis and pathophysiology of HCM, and to establish therapeutic strategies to cure or prevent the development of the disease.

Relation between extent of left ventricular hypertrophy and occurrence of sudden cardiac death in hypertrophic cardiomyopathy

Sudden unexpected death can be the first clinical manifestation of hypertrophic cardiomyopathy and is the most devastating feature of the natural history of the disease. Left ventricular hypertrophy appears to be an important determinant of many clinical features of hypertrophic cardiomyopathy, but the relation between its magnitude and the occurrence of sudden cardiac death has not been clearly defined. In this study, the magnitude of hypertrophy was assessed with two-dimensional echocardiography in 29 asymptomatic or mildly sym ptomadc patients with hypertrophic cardiomyopathy who subsequently died suddenly or experienced cardiac arrest with documentw ventricular fibrillation. Findings were compared with those obtained in a control group of 95 patients of similar age and symptomatic state.Maximal left ventricular wall thickness was significantly greater in patients with sudden death (26±7 mm) than in control patients (21 ± 5 mm, p < 0.001). Left ventricular wall thickness index, a quantitative expression of the overall extent of hypertrophy, was also greater in patients with sudden death (76 ± 20 mm) than in surviving control patients (62 ± 13 mm, p < 0.001). Particularly marked and diffuse hypertrophy, with maximal wall thickness ≥30 mm or wall thickness ≥25 mm in two or more of the four segments into which the left ventricle had been divided, was eight times more common in patients with sudden death (11 [38%] of 29) than in control patients (5 [5%] of 95, p < 0.001). The prevalence of mild and localized hypertrophy, with maximal wall thickness ≤517 mm involving only one segment, was similar in patients with sudden death (4 [14%] of 29) and in control patients (23 [24%) of 95, p > 0.05); however, of the four patients with sudden death and mild hypertrophy, only one was an adult; three were preadolescent children whose hypertrophy would have been considered to be more substantial if corrected for body surface area.It is concluded that most asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy who die suddenly have marked and diffuse left ventricular hypertrophy, and that a relation exists between the extent of hypertrophy and the occurrence of sudden and unexpected death in this disease. Sudden cardiac death is uncommon in asymptomatic or mildly symptomatic adult patients with hypertrophic cardiomyopathy and relatively mild left ventricular hypertrophy.