Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and ß-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations. METHODS: As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography. RESULTS: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p = 0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p = 0.085). Laboratory analyses revealed normal levels of creatinine (85.5 ± 18.3 vs. 81.3 ± 16.4 µmol/l; p = 0.487) and blood urea nitrogen (10.2 ± 15.6 vs. 6.9 ± 3.9 mmol/l; p = 0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p = 0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p = 0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p = 0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8 ± 3.3, MYH7 13.9 ± 6.9, p = 0.079). CONCLUSIONS: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

[Management of hypertrophic cardiomyopathy - the most common inherited heart disease]. / Hypertrofisk kardiomyopati vanligaste ärftliga hjärtsjukdomen - Sjukdomsförloppet är ofta godartat ­ men risken för plötslig död i arytmi är välkänd.

Hypertrophic cardiomyopathy is the most common cardiogenetic disease affecting 1/500-1/1 000 individuals. Dyspnea is common but chest pain, dizziness or fainting may also cause considerable limitation for the patient. The diagnosis can be suspected from ECG. Echocardiography confirms hypertrophy of at least 15 mm, usually in the septum. If the obstruction of the outflow tract is severe, myectomy or alcohol ablation can relieve symptoms. Genetic evaluation of family members is advisable. To reduce symptoms, betablockers are used; verapamil or disopyramide are alternatives. Atrial fibrillation is often prevalent and requires special attention concerning anticoagulation and rhythm or rate control. An end-stage heart failure warrants advanced treatment options such as cardiac resynchronization therapy, ventricular assist devices or heart transplant. Sudden cardiac death is unpredictable and evaluation of risk markers is important to identify potential candidates for an implantable defibrillator.

Surgical pathology of subaortic septal myectomy: histology skips over clinical diagnosis.

BACKGROUND: Subaortic septal myectomy is usually performed to mitigate obstruction in patients with the obstructive form of hypertrophic cardiomyopathy (HCM) or in those with congenital subaortic stenosis. Moreover, it is combined with aortic valve replacement in patients with severe aortic valve stenosis (SAS) and asymmetrical septal hypertrophy causing concomitant left ventricular outflow tract obstruction. When both conditions coexist, it is conceptually difficult to identify a cardiomyopathy beyond an adaptive myocardial hypertrophy, strictly related to pressure overload. Myectomy histopathology might be useful to enlighten the cause of the obstruction and establish the diagnosis. AIM: The aim was to describe the pathological findings of surgical septal myectomy specimens obtained from a group of patients with diverse clinical diagnosis, including HCM, severe aortic stenosis, and asymmetrical septal hypertrophy. METHODS: This was a retrospective study of 56 patients undergoing septal myectomy along a 10-year period at a tertiary cardiac surgical center. Clinical, interventional, and anatomopathological findings between patients with and without a preoperative diagnosis of HCM were analyzed and compared. RESULTS: Mean age at intervention was 67.5±20.5 years; 37 (66.1%) were female Preoperative diagnosis of sarcomeric obstructive HCM was assumed in 23 (41.1%) patients. All the other patients (58.9%) were referred for surgery with preoperative diagnosis of asymmetric septal hypertrophy, mainly in the context of severe aortic stenosis (24 patients). Twenty-seven (48.2%) patients had a greater than 30 mmHg intraventricular gradient at rest. Patients with presumed HCM were significantly younger (56.5±15.8 vs. 70.2±13.3 years, P<.001), had higher prevalence of significant intraventricular obstruction at rest [20 (87.0%) vs. 8 (34.8%), P<.001], and more frequently had moderate or severe mitral regurgitation [9 (39.1%) vs. 5(15.1%), P=.043]. All patients with aortic valve stenosis underwent both aortic valve replacement and septal myectomy. Twelve (52.1%) of the patients with obstructive HCM had isolated septal myectomy, while in the remaining 11, the procedure was combined with intervention on the mitral valve. Histopathological final diagnosis was of nonspecific reactive myocardial hypertrophy in all but 4 (92.2%) patients. In those, 2 (3.6%) had the final diagnosis of HCM and 2 (3.6%) the diagnosis of congenital subaortic membranous stenosis with reactive myocardial hypertrophy. Different grades of subendocardial fibroelastosis and myocardial fibrosis, mainly interstitial, were present [27 (48.2%) and 18 (32%) patients, respectively]. When microscopic data were compared between patients with or without a preoperative clinical diagnosis of HCM, no significant differences were found. CONCLUSION: In patients submitted to surgical septal myectomy, histology was mostly indistinctive among different clinical entities. Since different myocardial hypertrophy etiologies may share similar pathological expression, there is a need for detailed clinical assessment when trying to define the best strategy for clinical management.

A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain.

INTRODUCTION AND OBJECTIVES: Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A). METHODS: We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed. RESULTS: A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308+1 G>A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308+1G>A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis. CONCLUSIONS: The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age.

Congenital heart disease in monochorionic twins with and without twin-to-twin transfusion syndrome.

OBJECTIVE: This study aims to evaluate the prevalence of congenital heart disease (CHD) in monochorionic (MC) twin pregnancies with and without twin-to-twin transfusion syndrome (TTTS) in an unselected cohort, which underwent prenatal and postnatal echocardiography. METHOD: This was a retrospective cohort study including 451 MC twin pregnancies between 2002 and 2012. Complete outcome data were available for 381 pregnancies. All patients had prenatal echocardiography, and postnatal echocardiography was performed in all newborns with symptoms or to follow-up on prenatal findings. Data from prenatal and postnatal echocardiography and autopsy were analyzed. The classification of Houyel et al. was used for structural CHD. RESULTS: Structural CHD was diagnosed in 5.5% of all MC twins (42/762). Twins with TTTS showed a significant higher rate of CHD than unaffected twins (9.3% vs 4.7%; p = 0.03). Prenatal detection rate of CHD was 48%. Most common abnormalities were ventricular septal defects (VSD) (2.1%) followed by anomalies of the ventricular outflow tracts (1.3%) in the overall population and VSD (2.9%) and anomalies of the great arteries (2.9%) in the group with TTTS. CONCLUSION: MC twin pregnancies show a high prevalence of structural CHD (5.5%), especially those affected by TTTS. A detailed prenatal and postnatal echocardiography could be considered in these pregnancies.

Penetrance of hypertrophic cardiomyopathy in children and adolescents: a 12-year follow-up study of clinical screening and predictive genetic testing.

BACKGROUND: The penetrance of hypertrophic cardiomyopathy (HCM) during childhood and adolescence has been only sparsely described. We studied the penetrance of HCM and the short- and long-term outcomes of clinical screening and predictive genetic testing of child relatives of patients with HCM. METHODS AND RESULTS: Ninety probands and 361 relatives were included in a family screening program for HCM (1994-2001). Eleven sarcomere genes, CRYAB, α-GAL, and titin were screened. Sixty-six relatives and 4 probands were <18 years of age at inclusion. Twelve child relatives were mutation carriers (age, 12 ± 5 years), and 26 had unknown genetic status, ie, relatives from families without identified mutations (n = 21) or not tested (n = 5) (age, 11 ± 5 years). Twenty-eight noncarriers (42%; age, 10 ± 4 years) served as control subjects. Two of 38 child relatives (5%) at risk of developing HCM fulfilled diagnostic criteria for HCM at inclusion. After 12 ± 1 years of follow-up, 2 of the 36 (6%; 95% confidence interval, 2-18) at-risk child relatives who were phenotype negative at inclusion had developed the HCM phenotype at 26 and 28 years of age. During follow-up, none of the child relatives experienced serious cardiac events. Participation in the screening program had no long-term negative psychological impact. CONCLUSIONS: The penetrance of HCM in phenotype-negative child relatives at risk of developing HCM was 6% after 12 years of follow-up. The finding of phenotype conversion in the mid-20s warrants continued screening into adulthood. Forty-two percent of the child relatives were noncarriers, and repeat clinical follow-up could be safely limited to the remaining children.

[Disease progression and systolic dysfunction in patients with hypertrophic cardiomyopathy: genetic basis, pathophysiology and clinical presentation]. / Progressione di malattia e disfunzione sistolica nei pazienti con cardiomiopatia ipertrofica: basi genetiche, fisiopatologia e presentazione clinica.

Progressive heart failure associated with left ventricular remodeling and systo-diastolic dysfunction is one of the most severe complications of hypertrophic cardiomyopathy (HCM). Such condition, for the lack of a better term, is referred to as end-stage (ES) HCM. During the last decade, we have begun to understand the mechanisms underlying progression from a hyperdynamic left ventricle to the striking patterns of ES. To date, different aspects of HCM progression remain obscure, including potential strategies for management and prevention. On the basis of recent evidence, it is appropriate to emphasize these aspects, which may be difficult to identify, particularly in the early stages when systolic function appears relatively preserved. Nevertheless, it is at these early stages that treatment may potentially interfere with the clinical evolution of HCM toward ES and heart failure. The possibility of early identification of patients at risk of ES progression may ultimately impact on the natural history of the disease in this challenging patient subgroup.

[Profiles of genotypes of familial hypertrophic cardiomyopathy according to data of clinical studies].

With the aim of studying clinical profiles of hereditary cases of hypertrophic cardiomyopathy (HCMP) we examined 64 patients with HCMP of both sexes (mean age 43.8+/-11.7 years). Genealogy of 40 patients (62.5%) revealed no cases of the disease among first degree relatives. They were defined as sporadic forms of HCMP. Genealogical screening revealed 22 patients (37.5%) with familial forms of HCMP. In 8 cases study of genealogy of probands detected 16 more patients. Results of assessment of familial history, ECG and echocardiographic investigations reflected degree of thickening of interventricular septum, asymmetric character of distribution of hypertrophy in the myocardium, and cases of sudden deaths in first degree relatives as possible hereditary signs in familial HCMP determining variations of clinical phenotype of the disease through interrelated disturbances of contractile and electrical myocardial functions.

Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Miocardiopatía hipertrófica. Estudio del gen de la troponina T en 127 familias españolas / Hypertrophic cardiomyopathy. A study of the troponin-T gene in 127 spanish families

La información sobre las relaciones genotipo-fenotipo y el pronóstico de las diferentes mutaciones en el gen de la troponina T es escasa y en ocasiones contradictoria. Se realizó estudio del gen TNNT2 en 127 pacientes con miocardiopatía hipertrófica (MCH), identificándose 3 mutaciones en 4 familias (3,1%): Phe87Leu, no descrita, Arg 278Cys (2 familias) y Asp271Ile. Se identificaron 7 portadores de Phe87Leu (29 a 52 años) con hipertrofia leve (grosor < 16 mm). Hubo 11 muertes relacionadas con la enfermedad (7 de ellas súbitas), con 4 de los fallecidos entre 14 y 16 años de edad. No hubo muertes súbitas en las otras 3 familias. En conclusión, las mutaciones en el gen de la troponina T son responsables de un 3% de casos de MCH en nuestra población. La mutación Phe87-Leu se asocia a hipertrofia de grado leve y alto riesgo de muerte súbita (AU)

The information available on the correlation between genotype and phenotype and the prognostic implications of different troponin-T gene mutations is sparse and, at times, contradictory. We studied the TNNT2 gene in 127 patients with hypertrophic cardiomyopathy and identified three mutations in patients from four families (3.1%): the Phe87Leu mutation, which has not been previously reported, the Arg278Cys mutation (two families) and the Asp271Ile mutation. Seven carriers of the Phe87Leu mutation (aged 29 to 52 years) were found to have mild hypertrophy (i.e., a wall thickness <16 mm there were 11 deaths associated with the condition seven sudden and four of those who died aged between 14 16 years no occurred in other three families conclusion troponin-t mutations responsible for 3 hypertrophic cardiomyopathy cases our study population phe87leu mutation was only mild hypertrophy but a high risk death (AU)

The evaluation of cardiac complaints in marathon runners.

In the United States there are now approximately 521 marathons, and in 2005 approximately 432,000 participants completed one. The number of frequent runners (more than 100 days a year) is estimated at over 11 million. When one of these patients presents to the emergency department with cardiac complaints, the risk profile and evaluation may be different than in sedentary subjects. The first and most important step to patient evaluation is the history. An electrocardiogram (ECG) should be obtained in all patients with suspected cardiac complaints. Depending on the study and what is defined as abnormal, 40-80% of athletes' ECGs will show some abnormality. A normal ECG has a 96% negative predictive value for ruling out structural cardiovascular abnormalities, but a positive predictive value for disease of only 7%. The electrocardiogram, cardiac enzymes, and stress testing are useful, but should be interpreted in the context of the sport and the athlete. Echocardiography and cardiac magnetic resonance imaging are indicated for the diagnosis of certain conditions. Cardiology consultation or inpatient evaluation may be indicated when a specific disease process is suspected based on history, physical examination, or ECG. Some patients may require follow-up for further diagnostic testing.

Looking for hypertrophic cardiomyopathy in the community: why is it important?

Hypertrophic cardiomyopathy (HCM) is an epidemiologically relevant, worldwide spread condition which is frequently perceived as a rare disease. This misconception might be supported by some characteristics of HCM such as its incomplete penetrance and variable age at onset and by the fact that many patients remain asymptomatic for a long course of the disease and are thus unlikely to seek for medical evaluation. Multiple evidences suggest that early diagnosis of HCM is important, not only because it allows the patients to be addressed to appropriate diagnostic work-out and to adequate therapeutical options but because it may trigger the screening of family members with the potential of further, new diagnosis of HCM in previously unsuspected individuals. Increased awareness of the disease among physicians working in community-based hospitals and in outpatients facilities, and a facilitated communication and access to tertiary referral centers, will result into a wider knowledge of the spectrum of the disease, a better access to the state-of-the-art management options for patients, and to a more diffuse practice of genetic evaluation of HCM families.

MYBPC3 polymorphism is a modifier for expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy.

Clinical phenotype of hypertrophic cardiomyopathy exhibits significant inter- and intra-familial heterogeneities. To test if MYBPC3 polymorphism could modify the expression of cardiac hypertrophy, 226 patients with hypertrophic cardiomyopathy and 226 age- and sex-matched controls were recruited according to the diagnostic criteria of WHO. Genotyping was completed by using PCR, restrictive enzyme digestion, and sequencing. Three polymorphisms of MYBPC3 were studied, only the GG genotype at 18443 in exon 30 associated with thicker left ventricular wall (25.2+/-5.9 mm) in patient group, not the AA and AG genotypes (19.0+/-5.0mm, P<0.001). After multiple regression analysis for adjustment of age and sex, the association remained. No difference was found in the genotype distribution between control and patients. Our results point out that GG genotype of MYBPC3 might be a genetic risk factor for the expression of cardiac hypertrophic phenotype in the patients with hypertrophic cardiomyopathy.

Uncommon cause of a common disease.

Myocardial infarction is a common life-threatening condition. Multiple agents can be used to treat acute coronary syndrome (ACS). These therapeutic agents pose potential life-threatening complications when used outside the realm of the acute coronary syndrome. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder, occurring in 1 in 500 individuals, which may mimic ACS. The hypertrophy most typically involves the septum in patients with HCM. As many as 25% of Japanese patients with HCM have predominately apical involvement. Apical hypertrophic cardiomyopathy (AHC) occurs in only 1 to 2% of the non-Japanese population. Despite its low incidence, physicians caring for patients with chest pain need to consider AHC in their differential diagnosis. We present the case of a patient with chest pain and electrocardiographic changes suggestive of ACS who was later found to have AHC.

Arritmias cardíacas e cardiomiopatias / Cardiac arrhythmias and cardiomyopathies

As arritmias cardíacas freqüentemente complicam a evolução clínica dos pacientes com cardiomiopatias. Manifestam-se das formas mais diversas, desde simples extra-sístoles a complexos distúrbios do ritmo. Os sintomas são variáveis, os pacientes podem estar completamente assintomáticos e a arritmia pode ser um achado da avaliação clínica ou se acompanhar de sintomas graves, como síncopes de repetição. Apesar dos avanços no tratamento dos pacientes com cardiomiopatias, o manuseio das arritmias cardíacas ainda é um desafio, em particular na tentativa de prevenir a morte súbita, causa mais freqüente de morte nesses pacientes. O objetivo deste artigo é revisar o estado atual do tratamento das arritmias cardíacas nos pacientes com cardiomiopatias.