Family History Of Hypertrophic Cardiomyopathy Research Articles

Prevalence and clinical correlates of QT prolongation in patients with hypertrophic cardiomyopathy

Congenital or acquired QT prolongation is a risk factor for life-threatening arrhythmias. In patients with hypertrophic cardiomyopathy (HCM), the QT interval may be intrinsically prolonged. However, the prevalence, cause, and significance of QT prolongation among patients with HCM are unknown. After exclusion of patients on QT-prolonging drugs, a blinded, retrospective analysis of electrocardiograms, echocardiograms, and genotype status in 479 unrelated patients with HCM [201 females, age at diagnosis 41 ± 18 years, maximal left ventricular wall thickness (MLVWT) 22 ± 6 mm] from two independent centres was performed. The mean QTc was 440 ± 28 ms. The QTc exceeded 480 ms in 13% of patients. Age, gender, family history of HCM or sudden cardiac arrest, and genotype status had no association with QTc. Patients with a QTc over 480 ms were more symptomatic at diagnosis (P < 0.001), had a higher MLVWT (P = 0.03), were more obstructive (P < 0.001), and were more likely to have undergone septal reduction therapy (P = 0.02). There was a weak but significant direct linear relationship between QTc and peak outflow gradient (r(2) = 0.05, P < 0.0001). Compared with <1 in 200 otherwise healthy adults, QT prolongation (QTc > 480 ms) was present in 1 out of 8 patients with HCM. The QTc was partly reflective of the degree of cardiac hypertrophy and left ventricular outflow tract obstruction. Because of its pro-arrhythmic potential and its potential relevance to management and risk stratification, routine QTc assessment should be performed in patients with HCM, particularly when concomitant use of QT-prolonging medications is considered.

Multiple left ventricular inferoseptal clefts

Left ventricular inferoseptal clefts are a localized variant of myocardial structure, easily overlooked but potentially raising concern when identified through imaging. Here we illustrate and describe inferoseptal clefts by means of multimodality imaging and consider them in relation to possible differential diagnoses. A 49-year-old male patient was investigated for chest pain and found to have multiple inferoseptal clefts. The pain subsequently resolved and was thought to have been pleuritic. There was no evidence or family history of hypertrophic cardiomyopathy. The diagnosis of clefts was arrived at after consultation with several cardiac imaging specialists and the few available relevant published reports. Echocardiography, cardiovascular magnetic resonance, invasive ventriculography and computed tomography each showed the clefts in relation to surrounding compact and contractile myocardium of the inferoseptal region, which occluded the clefts in systole. In terms of location, orientation and systolic occlusion the inferoseptal clefts resembled the isolated clefts reported in healthy volunteers, and have features in common with crypts reported in carriers of a genetic mutation associated with hypertrophic cardiomyopathy (HCM). The incidence and implications of multiple inferoseptal clefts have yet to be determined. Multimodality imaging permits clear depiction of left ventricular inferoseptal clefts, which should be distinguished from different entities such as left ventricular noncompaction cardiomyopathy (LVNC), cardiac diverticula and cardiac aneurysms. Inferoseptal clefts have yet to be widely recognized as a distinct variant of regional left ventricular structure.

PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: Summary of the literature and implications for genetic testing

hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young athletes and one of the most common inherited cardiovascular diseases, affecting 1 in 500 individuals. Often viewed as a disease of the cardiac sarcomere, mutations in genes encoding myofilament proteins are associated with disease pathogenesis. Despite a clinically available genetic test, a significant portion of HCM patients remain genetically unexplained. We sought to determine the spectrum and prevalence of mutations in PLN-encoded phospholamban in a large cohort of HCM cases as a potential cause of mutation-negative HCM. comprehensive genetic interrogation of the promoter and coding region of PLN was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing. one L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family. Compared with similar studies, we identified an overall yield of PLN-HCM mutations of 0.65%, similar to 3 genes that are part of current HCM genetic test panels. We did not observe any PLN coding sequence genetic variation in 600 reference alleles. overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible. The exact role of mutations in PLN and other calcium-handling proteins in the development of HCM warrants further investigation.

Dilated Cardiomyopathy With Conduction Disease and Arrhythmia

case presentation: A 48-year-old woman presents with exertional dyspnea and recurrent syncope. One year earlier, a permanent pacemaker was placed after she complained of fatigue and was found to have high-grade atrioventricular block. Now, she has echocardiographic evidence of moderate to severe left ventricular (LV) systolic dysfunction with regional wall-motion abnormalities. Nuclear imaging is notable for heterogeneous myocardial uptake of technetium Tc99m sestamibi, and coronary angiography reveals widely patent epicardial vessels. Multiple episodes of nonsustained ventricular tachycardia (VT) are documented on continuous ECG monitoring. What are the diagnostic considerations for this patient, and what further evaluations are indicated? This patient presents with dilated cardiomyopathy (DCM) with electric instability (DCM+E), which we define as conduction disease and arrhythmia out of proportion to the severity of LV systolic dysfunction. Diverse causes can result in DCM+E and fall into general categories of inflammatory, infectious, hereditary, and infiltrative processes. Cardiac presentation associated with these conditions is distinct from more common causes of DCM such as ischemic heart disease, viral myocarditis, valvular dysfunction, pregnancy, or substance abuse. Clinical features that are suggestive of DCM+E include supraventricular arrhythmias or conduction disease that precedes cardiomyopathy, multiple VT morphologies, and features suggestive of ischemic heart disease (Q waves, regional wall-motion abnormalities, perfusion defects, ventricular aneurysm) in the absence of epicardial stenoses. In this Clinician Update, we focus on the diagnostic approach to patients with DCM+E. Emphasis is placed on diagnoses that are relatively common or for which the clinical management would be impacted significantly by recognition of the underlying cause. Ischemic heart disease may present with conduction disease and a high burden of arrhythmia, especially in the setting of acute myocardial ischemia/infarction. The exclusion of obstructive coronary artery disease is strongly recommended in patients with DCM+E because atherosclerosis is so prevalent, evidence-based treatment is readily available, and the …

Prevalence and Clinical Outcomes of Incidentally Diagnosed Hypertrophic Cardiomyopathy

The purpose of the present study was to evaluate the prevalence and prognosis of patients incidentally diagnosed with hypertrophic cardiomyopathy (HC). We studied 380 consecutive patients with HC (49.3 +/- 17.2 years; 65% men) for a median of 58 months (range 6 to 454). The patients were divided into 2 groups: those incidentally diagnosed from routine examination findings (precordial murmur and/or abnormal electrocardiographic findings) and those diagnosed either because of symptomatic status or by screening because of a family history of HC. Those patients who had been incidentally diagnosed constituted 29.2% of our study cohort. Although overall mortality did not differ between the 2 groups (p = 0.12), the patients diagnosed either because of symptoms or a family history tended to have at least a 4.5-fold greater risk of cardiovascular death (relative risk 4.5, 95% confidence interval 1.04 to 19.6, p = 0.04) and a 4.22 greater risk of sudden death (relative risk 4.22, 95% confidence interval 1.0 to 18.22, p = 0.04). Despite the greater sudden death mortality among the nonincidentally diagnosed patients, no statistically significant difference was found concerning the sudden death risk factor frequency (p = 0.96) between the 2 groups. In conclusion, the discrepancy between the low numbers of patients reported by published registries and the relatively high prevalence of the disease in the general population can be attributed to the large number of patients who remain asymptomatic, even throughout their life, awaiting an accidental diagnosis. Those patients with an incidental diagnosis have a more benign course, as shown by the total cardiovascular and composite sudden death mortality. A high level of awareness and suspicion for HC among physicians is essential for clinical recognition of such patients.

Serial Observations and Mutational Analysis of an Adoptee with Family History of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an autosomal dominant mode of transmission. Comprehensive genetic screening of several genes frequently found mutated in HCM is recommended for first-degree relatives of HCM patients. Genetic testing provides the means to identify those at risk of developing HCM and to institute measures to prevent sudden cardiac death (SCD). Here, we present an adoptee whose natural mother and maternal relatives were known be afflicted with HCM and SCD. The proband was followed closely from age 6 to 17 years, revealing a natural history of the progression of clinical findings associated with HCM. Genetic testing of the proband and her natural mother, who is affected by HCM, revealed that they were heterozygous for both the R719Q and T1513S variants in the cardiac beta-myosin heavy chain (MYH7) gene. The proband's ominous family history indicates that the combination of the R719Q and T1513S variants in cis may be a “malignant” variant that imparts a poor prognosis in terms of the disease progression and SCD risk.

Prevalence of Sarcomere Protein Gene Mutations in Preadolescent Children With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM. Seventy-nine consecutive patients diagnosed with HCM aged 13 years or younger underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, and TNNC1), the genes encoding desmin (DES), and the gamma-2 subunit of AMP kinase (PRKAG2) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had 2 mutations). The genes most commonly implicated were MYH7 (48.9%) and MYBPC3 (36.2%); mutations in TNNT2, ACTC, MYL3, and TNNI3 accounted for <5% of cases each. A total of 16.7% patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without or between patients with 2 mutations and those with 1 or no mutations. This study shows that familial disease is common among infants and children with HCM and that, in most cases, disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, the finding that one sixth of patients with sarcomeric disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of familial HCM may have to be revised.

Prevalence of Hypertrophic Cardiomyopathy in Highly Trained Athletes: Relevance to Pre-Participation Screening

This study sought to determine the prevalence of hypertrophic cardiomyopathy (HCM) in elite athletes. Hypertrophic cardiomyopathy is considered to be the most common cause of exercise-related sudden death in young athletes. The prevalence of HCM in elite athletes has never been reported but has important implications with regard to pre-participation screening for the disorder. Between 1996 and 2006, 3,500 asymptomatic elite athletes (75% male) with a mean age of 20.5 +/- 5.8 years (range 14 to 35 years) underwent 12-lead electrocardiography and 2-dimensional echocardiography. None had a known family history of HCM. Of the 3,500 athletes, 53 (1.5%) had left ventricular hypertrophy (mean 13.6 +/- 0.9, range 13 to 16), and of these 50 had a dilated left ventricular cavity with normal diastolic function to indicate physiological left ventricular hypertrophy. Three (0.08%) athletes with left ventricular hypertrophy had a nondilated left ventricular cavity and associated deep T-wave inversion that could have been consistent with HCM. However, none of the 3 athletes had any other phenotypic features of HCM on further noninvasive testing and none had first-degree relatives with features of HCM. One of the 3 athletes agreed to detrain for 12 weeks, which showed resolution of electrocardiography and echocardiographic changes confirming physiologic left ventricular hypertrophy. The prevalence of HCM in highly trained athletes is extremely rare. Structural and functional changes associated with HCM naturally select out most individuals from competitive sports. Screening athletes with echocardiography is not cost effective. However, electrocardiography is useful in selecting out those individuals who may have pathological left ventricular hypertrophy for subsequent echocardiography.

Abstract 3391: Prevalence Of Hypertrophic Cardiomyopathy In Elite Athletes

Objectives: The prevalence of HCM in the general population is estimated to be around 1 in 500. The exact prevalence of HCM in athletes has never been reported and has important implications with regards to potential future national pre-participation screening programme in countries such as United Kingdom, where currently there is no such programme for junior athletes. Methods: Between 1996 and 2006, 3500 asymptomatic and normotensive elite athletes (70% males) aged between 14–35 years (mean: 20.5±5.80) and a mean body surface area of 1.86±0.16 m 2 (range1.36–2.29) underwent 12-lead EKG and 2D-echocardiography. Cardiac dimensions and function were measured using conventional methods. Results: Of the 3500 athletes, 53 (2%) had maximal left ventricular wall thickness (LVWTd) &gt; 12 mm (mean: 13.6 ± 0.9, range: 13–16). All 53 were male athletes and all except 3 of them had associated dilated LV cavity (58.5 ± 5.14 mm, range 52– 65) implying physiological left ventricular hypertrophy (LVH). This was also supported by normal indices of diastolic function and absence of family history of HCM or sudden cardiac death (SCD). However, there were 3 athletes with LVWT &gt; 12mm who had a relatively non-dilated LV cavity (range:45– 46) and bizarre EKG changes (deep T-wave inversion) that that raised the suspicion of HCM. But none of them exhibited any other phenotypic feature of HCM on further testing with 48-hour EKG recording, cardiopulmonary exercise testing and assessment of their first-degree family members. Only one of the 3 athletes agreed to detrain for 12-weeks, which resulted in regression of LVH and complete resolution of EKG changes. Conclusion: In our study, only 3 athletes had echocardiographic findings that could have been consisted with the diagnosis of HCM but further investigations failed to support the diagnosis. These results indicate that the prevalence of HCM in highly trained athletes is extremely rare. The structural and functional changes associated with HCM precludes generation of large amounts of cardiac output that are required during exercise selecting out most of these individuals from competitive sports. Our findings also questions the validity of previous data which proposes that HCM is the commonest cause of exercise related SCD in young athletes.

Influência da gestação na evolução clínica materno-fetal de portadoras de cardiomiopatia hipertrófica

To study clinical evolution of women with HCM during pregnancy; the influencing factors of gestation on natural course of HCM and the frequency of HCM in their children in early childhood. A prospective study was conducted in 35 women with HCM; there were 23 pregnant women (PG group) and 12 nonpregnant control patients (NP group), matched for age and functional class (FC). Clinical monthly evaluations were carried out and electrocardiogram and transthoracic echocardiography tests were performed. The offspring endpoints included stillbirth and prematurity rates and investigation of HCM during childhood. No deaths occurred in either group. Cardiac arrhythmias were significantly (p< 0.05) more frequent in the NP group (33.3% vs. 13.4%), and no differences were observed between the groups (p>0.05) in heart failure (30.3% vs. 16.6%) or ischemic stroke (4.3% vs. 8.3%) rates. In the PG group, required hospitalization for treatment of cardiac complication was more frequent (p=0.05) in patients with family history of HCM (71.4% vs. 25.0%). Cesarean section was performed in 12 (52%) patients, for obstetrical reasons; there were 7 (30.4%) premature babies and 1 (4.3%) neonatal death. One child was clinically diagnosed as having HCM, and his genetic study identified a mutation in the beta myosin heavy chain gene, located on chromosome 14. Heart failure is a frequent cardiac complication in women with HCM during pregnancy, particularly in patients with family history of the disease, but this did not influence the natural course of HCM. In one child, clinical examination allowed HCM identification during early childhood.

Subaortic and midventricular obstructive hypertrophic cardiomyopathy with extreme segmental hypertrophy

BackgroundSubaortic and midventricular hypertrophic cardiomyopathy in a patient with extreme segmental hypertrophy exceeding the usual maximum wall thickness reported in the literature is a rare phenomenon.Case PresentationA 19-year-old man with recently diagnosed hypertrophic cardiomyopathy (HCM) was referred for sudden death risk assessment. The patient had mild exertional dyspnea (New York Heart Association functional class II), but without syncope or chest pain. There was no family history of HCM or sudden death. A two dimensional echocardiogram revealed an asymmetric type of LV hypertrophy; anterior ventricular septum = 49 mm; posterior ventricular septum = 20 mm; anterolateral free wall = 12 mm; and posterior free wall = 6 mm. The patient had 2 types of obstruction; a LV outflow obstruction due to systolic anterior motion of both mitral leaflets (Doppler-estimated 38 mm Hg gradient at rest); and a midventricular obstruction (Doppler-estimated 43 mm Hg gradient), but without apical aneurysm or dyskinesia. The patient had a normal blood pressure response on exercise test and no episodes of non-sustained ventricular tachycardia in 24-h ECG recording. Cardiac MRI showed a gross late enhancement at the hypertrophied septum. Based on the extreme degree of LV hypertrophy and the myocardial hyperenhancement, an implantation of a cardioverter-defibrillator was recommended prophylactically for primary prevention of sudden death.ConclusionMidventricular HCM is an infrequent phenotype, but may be associated with an apical aneurysm and progression to systolic dysfunction (end-stage HCM).

Dilated-Hypokinetic Evolution of Hypertrophic Cardiomyopathy: Prevalence, Incidence, Risk Factors, and Prognostic Implications in Pediatric and Adult Patients

This study sought to investigate the incidence, risk factors, and prognosis of dilated-hypokinetic evolution in a large cohort of patients with hypertrophic cardiomyopathy (HCM) followed up at a cardiology center serving both the pediatric and the adult population. The available data on this evolution of HCM mainly regards prevalence (rather than incidence) in adults, with very little being known about the pediatric population. A total of 222 consecutive HCM patients (65% men, 19% < or =18 years old) were prospectively evaluated for a mean follow-up of 11 +/- 9 years. A diagnosis of dilated-hypokinetic HCM was made in 12 patients at first evaluation (11 without previous septal myectomy surgery; prevalence, 4.9%). Twelve of the 210 patients with classic HCM at first evaluation underwent dilated-hypokinetic evolution (incidence, 5.3/1,000 patient-years). Patients with prevalent/incident dilated-hypokinetic evolution were younger at first evaluation (32 +/- 14 years vs. 41 +/- 21 years, p = 0.04) and more often had a family history of HCM (61% vs. 26%, p = 0.002) or sudden death (43% vs. 19%, p = 0.01) with respect to patients who maintained classic HCM. Moreover, they showed greater interventricular septum (23 +/- 3 mm vs. 19 +/- 6 mm, p = 0.004) and posterior wall (15 +/- 3 mm vs. 13 +/- 4 mm, p = 0.006) thickness. Cardiovascular death-free survival was lower among patients with dilated-hypokinetic HCM (p < 0.04). Cox proportional hazards regression analysis identified left ventricular wall thickness (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 1.01 to 1.14; p = 0.03) and end-diastolic diameter (HR = 1.08; 95% CI 1.04 to 1.11; p = 0.0001) as independent predictors of cardiovascular death. Dilated-hypokinetic evolution is rare but not exceptional in HCM. Young age at diagnosis, family history of HCM, and greater wall thickness are incremental risk factors for dilated-hypokinetic HCM, which carries an ominous prognosis.

Amyloid heart disease mimicking hypertrophic cardiomyopathy*

To investigate the importance of transthyretin (TTR) gene mutations in explaining the phenotypic expression in patients diagnosed with hypertrophic cardiomyopathy (HCM) in northern Sweden. Hypertrophic cardiomyopathy is relatively common and often caused by mutations in sarcomeric protein genes. Mutations in the TTR gene are also common, one of which causes familial amyloid polyneuropathy (FAP), with peripheral polyneuropathy and frequently, cardiac hypertrophy. These circumstances were highlighted by the finding of an index case with amyloidosis, presenting itself as HCM. Initial rectal and fat biopsies did not show amyloid deposits. Later on, the patient was shown to carry a TTR gene mutation, and cardiac amyloidosis was confirmed by myocardial biopsy. Only then was a repeated fat biopsy positive for amyloid deposits. Cross-sectional study. Cardiology tertiary referral centre. Forty-six unrelated individuals with HCM and the index case were included. Common diagnostic criteria for HCM were used. The 46 patients with HCM were previously analysed for mutations in eight sarcomeric protein genes and the TTR gene was now analysed by denaturing high-performance liquid chromatography and direct sequencing. One mutation in the TTR gene (Val30Met) was found in three individuals and the index case. Three of the 46 cases with HCM carried the Val30Met mutation, and were considered likely to have cardiac amyloidosis, like the index case. As a correct diagnosis of cardiac amyloidosis is mandatory for a potentially life-saving treatment, TTR mutation analysis should be considered in cases of HCM not explained by mutations in sarcomeric protein genes.

Yield of Genetic Testing in Hypertrophic Cardiomyopathy

To determine the clinical parameters of hypertrophic cardiomyopathy (HCM) that correlated significantly with the presence of an identifiable sarcomeric mutation. Previous comprehensive mutational analyses of all protein-coding exons of 8 sarcomeric genes revealed pathogenic mutations in 147 (38%) of 389 unrelated patients seen at the HCM outpatient clinic at the Mayo Clinic in Rochester, Minn, between April 1997 and December 2001. Clinical data, extracted from patient records and blinded to patient genotype, were maintained in a custom database. In 389 unrelated patients, younger age at diagnosis, family history of HCM, and Increasing left ventricular wall thickness were all associated with Increased likelihood of identifying an HCM-associated sarcomeric mutation. In contrast, family history of sudden cardiac death, myectomy status, and anatomical subtype did not correlate significantly with genotype-positive status. With use of a simple scoring system based on age at diagnosis, left ventricular wall thickness, and family history of HCM, the likelihood of a sarcomeric mutation could be estimated. Clinical predictors of positive genotype, such as the presence of an implantable cardioverter-defibrillator, age at diagnosis, degree of left ventricular wall hypertrophy, and family history of HCM, may aid in patient selection for genetic testing and increase the yield of cardiac sarcomere gene screening.

Left Ventricular Doppler Characteristics in First-Degree Relatives of Patients with Hypertrophic Cardiomyopathy

Left ventricular (LV) diastolic function may be affected early in patients with hypertrophic cardiomyopathy (HCM), regardless of the phenotypic expression of the disease. The aim of the present study was to detect whether LV diastolic performance, evaluated by conventional Doppler echocardiography, is impaired in first-degree relatives of patients with phenotypically expressed HCM, who had no clinical, electrocardiographic, or echocardiographic signs of the disease. Twenty-two young adults having the previously described characteristics comprised the study population and 22 sex- and age-matched healthy individuals served as controls. The 2 groups were compared according to several echocardiographic parameters and the following diastolic function indices: peak velocity of E wave, representing early filling; peak velocity of A wave, representing late filling; ratio of peak early to peak late velocity (E/A); deceleration time of E wave; and LV isovolumic relaxation time. Slower deceleration time of transmitral early filling in first-degree relatives of patients with HCM (192 +/- 31 vs 149 +/- 31 msec, p < 0.001) was the only variable that significantly differentiated the 2 groups. This study shows that in healthy persons with a family history of HCM, Doppler-derived mitral filling pattern shifted toward that observed in HCM and the slower deceleration time may serve as an early sign of disease development.

Sarcomeric Genotyping in Hypertrophic Cardiomyopathy

To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness).The French study population harbored the highest frequency of mutations (61%), followed by the Mayo Clinic (38%), Harvard Medical School (36%), and Swedish (30%) study populations. For every study population, mutations in myosin binding protein C (MYBPC3) were the most common cause of HCM. Patients with a family history of HCM had mutations more frequently than those without. This pooled analysis revealed no statistically significant differences in left ventricular wall thickness or in mean age at diagnosis across all genotypes.Differentiation of sarcomeric genotypes, such as MYBPC3-HCM and MYH7-HCM, is not possible on the basis of currently reported phenotypic data. A myriad of genetic and/or environmental modifiers in addition to the primary disease-causing genetic substrate must play an important role in determining a patient's particular phenotype.

Comparison of the Clinical Features of Apical Hypertrophic Cardiomyopathy Versus Asymmetric Septal Hypertrophy in Korea

BackgroundWe sought to test whether patients with apical hypertrophic cardiomyopathy (APH) have different clinical features compared to those with typical asymmetric septal hypertrophy (ASH).MethodsAmong 32,534 patients who underwent routine echocardiography at Asan Medical Center from January 2000 to December 2001, 305 patients (0.9%), who were finally diagnosed with hypertrophic cardiomyopathy (HCMP), were evaluated. The type of HCMP was classified according to the echocardiographic findings.ResultsASH was the most frequent type (n=160, 53%, group I), and APH was the second most frequent (n=91, 30%, group II). Mean age (60.8±10 vs. 48.2±14 years, p<0.001) and prevalence of hypertension (32% vs. 19%, p=0.022) were significantly higher in group II than in group I. Family history of HCMP (4.4% vs. 0% p=0.043) and sudden cardiac death (8.8% vs. 1.1% p=0.014) was more prevalent in group I. During the follow-up period of 32.0± 37.2 months, cardiac events occurred at a significantly higher rate in group I (25.5% vs. 8.8%, p=0.003).ConclusionAPH comprises a significant proportion of HCMP in Korea and patients with APH show different clinical features compared to those with ASH.

Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy

We sought to determine the frequency and phenotype of mutations in myosin binding protein C (MYBPC3) in a large outpatient cohort of patients with hypertrophic cardiomyopathy (HCM) seen at our tertiary referral center. Mutations in MYBPC3 are one of the most frequent genetic causes of HCM and have been associated with variable onset of disease and prognosis. However, the frequency of mutations and associated clinical presentation have not been established in a large, unrelated cohort of patients. Using deoxyribonucleic acid from 389 unrelated patients with HCM, each protein coding exon of MYBPC3 was analyzed for mutations by polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. Clinical data were extracted from patient records blinded to patient genotype. Of 389 patients with HCM, 71 (18%) had mutations in MYBPC3. In all, 46 mutations were identified, 33 of which were novel (72%). Patients with MYBPC3 mutations did not differ significantly from patients with thick filament-HCM, thin filament-HCM, or genotype-negative HCM with respect to age at diagnosis, degree of hypertrophy, incidence of myectomy, or family history of HCM or sudden death. Patients with multiple mutations (n = 10, 2.6%) had the most severe disease presentation. This study defines the frequency and associated phenotype for MYBPC3 and/or multiple mutations in HCM in the largest cohort to date. In this cohort, unrelated patients with MYBPC3-HCM virtually mimicked the phenotype of those with mutations in the beta-myosin heavy chain. Patients with multiple mutations had the most severe phenotype.

Comprehensive Analysis of the Beta-Myosin Heavy Chain Gene in 389 Unrelated Patients With Hypertrophic Cardiomyopathy

We sought to determine the prevalence and phenotype of beta-myosin heavy chain gene MYH7 mutations in a large cohort of unrelated patients with hypertrophic cardiomyopathy (HCM). Hypertrophic cardiomyopathy is a heterogeneous cardiac disease. MYH7 mutations are one of the most common genetic causes of HCM and have been associated with severe hypertrophy, young age of diagnosis, and high risk of sudden cardiac death. However, these clinical findings from large, family studies have not been confirmed in a large unrelated cohort. Deoxyribonucleic (DNA) samples obtained from 389 HCM outpatients seen at this tertiary referral center were analyzed for mutations, using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing for all 38 protein-coding exons of MYH7. Clinical data were extracted from patient records blinded to patient genotype. Fifty-eight patients (15%) harbored 40 different mutations in MYH7. Compared with HCM patients without MYH7 mutations, HCM patients with MYH7 were younger at diagnosis (32.9 vs. 42.7 years, p = 0.0002), had more hypertrophy (left ventricular wall thickness of 24.2 vs. 21.1 mm, p = 0.0009), and more frequently underwent myectomy (60% vs. 38%, p = 0.002). The HCM patients with MYH7 mutations more often had a family history of HCM (43% vs. 29%, p = 0.006), but there was no difference in family history of sudden death (16% vs. 14%, p = NS). In this setting, HCM patients with MYH7 were diagnosed at a younger age and had more hypertrophy, but they had no greater frequency of sudden death among first-degree relatives. Although these associations may prove useful for targeted gene screening, caution should be exercised in terms of using pathogenic status in risk stratification.

Clinical practice. Hypertrophic obstructive cardiomyopathy.

A 28-year-old man presents with a two-year history of increasing dyspnea on strenuous exertion and is found to have hypertrophic cardiomyopathy, with a septal thickness of 23 mm and a left ventricular outflow gradient of 80 mm Hg. There is no family history of hypertrophic cardiomyopathy or sudden death. Forty-eight-hour Holter monitoring shows infrequent premature ventricular contractions. How should this patient be treated?