RESUMO
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP). OBJECTIVES: In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC. METHODS: Six AC pedigrees with 38 carriers of a dominant loss-of-function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping. RESULTS: All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin. CONCLUSIONS: This study identifies a highly recognizable cutaneous phenotype associated with dominant loss-of-function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.
Assuntos
Cardiomiopatias/genética , Desmoplaquinas/genética , Doenças do Cabelo/genética , Ceratodermia Palmar e Plantar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/diagnóstico , Cardiomiopatias/patologia , Cardiomiopatia Dilatada , Análise Mutacional de DNA , Feminino , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/patologia , Coração/diagnóstico por imagem , Heterozigoto , Humanos , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/patologia , Mutação com Perda de Função , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Isoformas de Proteínas/genética , Pele/patologia , Adulto JovemRESUMO
Myocarditis, simply defined as inflammation of the heart muscle, is a commonly encountered cardiac disease in primary and secondary care, both in the UK and on Operational deployments. In the UK Armed Forces, myocarditis results in deaths as well as the premature termination of military careers on medical grounds. The aetiology is usually the result of a number of infectious aetiologies with viruses being the most common pathogens in the vast majority of cases. However, it may also be the result of autoimmune activation, chemical or pharmacological toxins, environmental insult or hypersensitivity reactions. Particular aetiologies that are more likely to be seen in a military population are discussed and include certain infections, smallpox vaccine, and hyperthermia and hypothermia. The clinical features can be highly variable ranging from an asymptomatic infection to fulminant heart failure. Features pertinent to the military doctor, including the natural history, investigative modalities and management strategies, with a particular emphasis on the occupational impact of myocarditis in the UK Armed Forces are reviewed.
Assuntos
Militares , Miocardite , Adulto , Diagnóstico Diferencial , Eletrocardiografia , Humanos , Masculino , Miocardite/diagnóstico , Miocardite/etiologia , Miocardite/fisiopatologiaRESUMO
To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Proteínas de Membrana/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/patologia , Eletrocardiografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder manifesting as cardiac hypertrophy with myocyte disarray and an increased risk of sudden death. Mutations in five different loci cause FHC and 3 disease genes have been identified: beta cardiac myosin heavy chain, alpha tropomyosin and cardiac troponin T. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sarcomere components. Two further FHC loci have been mapped to chromosomes 11p13-q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11p11.2 and proposed as a candidate FHC gene. Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments. Phosphorylation of MyBP-C appears to modulate contraction. We report that cardiac MyBP-C is genetically linked to CMH4 and demonstrate a splice donor mutation in one family with FHC and a duplication mutation in a second. Both mutations are predicted to disrupt the high affinity, C-terminal, myosin-binding domain of cardiac MyBP-C. These findings define cardiac MyBP-C mutations as the cause of FHC on chromosome 11p and reaffirm that FHC is a disease of the sarcomere.
Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Cromossomos Humanos Par 11 , Mutação , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Splicing de RNARESUMO
BACKGROUND: Two principal mechanisms are thought to be responsible for Brugada syndrome (BS): (1) right ventricular (RV) conduction delay and (2) RV subepicardial action potential shortening. This in vivo high-density mapping study evaluated the conduction and repolarization properties of the RV in BS subjects. METHODS AND RESULTS: A noncontact mapping array was positioned in the RV of 18 BS patients and 20 controls. Using a standard S(1)-S(2) protocol, restitution curves of local activation time and activation recovery interval were constructed to determine local maximal restitution slopes. Significant regional conduction delays in the anterolateral free wall of the RV outflow tract of BS patients were identified. The mean increase in delay was 3-fold greater in this region than in control (P=0<0.001). Local activation gradient was also maximally reduced in this area: 0.33+/-0.1 (mean+/-SD) mm/ms in BS patients versus 0.51+/-0.15 mm/ms in controls (P<0.0005). The uniformity of wavefront propagation as measured by the square of the correlation coefficient, r(2), was greater in BS patients versus controls (0.94+/-0.04 versus 0.89+/-0.09 [mean+/-SD]; P<0.05). The odds ratio of BS hearts having any RV segment with maximal restitution slope >1 was 3.86 versus controls. Five episodes of provoked ventricular tachycardia arose from wave breaks originating from RV outflow tract slow-conduction zones in 5 BS patients. CONCLUSIONS: Marked regional endocardial conduction delay and heterogeneities in repolarization exist in BS. Wave break in areas of maximal conduction delay appears to be critical in the initiation and maintenance of ventricular tachycardia. These data indicate that further studies of mapping BS to identify slow-conduction zones should be considered to determine their role in spontaneous ventricular arrhythmias.
Assuntos
Arritmias Cardíacas/fisiopatologia , Síndrome de Brugada/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/fisiopatologia , Potenciais de Ação/fisiologia , Adulto , Idoso , Síndrome de Brugada/genética , Estudos de Casos e Controles , Eletrocardiografia , Endocárdio/fisiopatologia , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.5 , Canais de Sódio/genética , Taquicardia Ventricular/fisiopatologiaRESUMO
The ability of myosin to generate motile forces is based on elastic distortion of a structural element of the actomyosin complex (cross-bridge) that allows strain to develop before filament sliding. Addressing the question, which part of the actomyosin complex experiences main elastic distortion, we suggested previously that the converter domain might be the most compliant region of the myosin head domain. Here we test this proposal by studying functional effects of naturally occurring missense mutations in the beta-myosin heavy chain, 723Arg --> Gly (R723G) and 736Ile --> Thr (I736T), in comparison to 719Arg --> Trp (R719W). All three mutations are associated with hypertrophic cardiomyopathy and are located in the converter region of the myosin head domain. We determined several mechanical parameters of single skinned slow fibers isolated from Musculus soleus biopsies of hypertrophic cardiomyopathy patients and healthy controls. Major findings of this study for mutation R723G were i), a >40% increase in fiber stiffness in rigor with a 2.9-fold increase in stiffness per myosin head (S( *)(rigor R723G) = 0.84 pN/nm S( *)(rigor WT) = 0.29 pN/nm); and ii), a significant increase in force per head (F( *)(10 degrees C), 1.99 pN vs. 1.49 pN = 1.3-fold increase; F( *)(20 degrees C), 2.56 pN vs. 1.92 pN = 1.3-fold increase) as well as stiffness per head during isometric steady-state contraction (S( *)(active10 degrees C), 0.52 pN/nm vs. 0.28 pN/nm = 1.9-fold increase). Similar changes were found for mutation R719W (2.6-fold increase in S( *)(rigor); 1.8-fold increase in F( *)(10 degrees C), 1.6-fold in F( *)(20 degrees C); twofold increase in S( *)(active10 degrees C)). Changes in active cross-bridge cycling kinetics could not account for the increase in force and active stiffness. For the above estimates the previously determined fraction of mutated myosin in the biopsies was taken into account. Data for wild-type myosin of slow soleus muscle fibers support previous findings that for the slow myosin isoform S( *) and F( *) are significantly lower than for fast myosin e.g., of rabbit psoas muscle. The data indicate that two mutations, R723G and R719W, are associated with an increase in resistance to elastic distortion of the individual mutated myosin heads whereas mutation I736T has essentially no effect. The data strongly support the notion that major elastic distortion occurs within the converter itself. Apparently, the compliance depends on specific residues, e.g., R719 and R723, presumably located at strategic positions near the long alpha-helix of the light chain binding domain. Because amino acids 719 and 723 are nonconserved residues, cross-bridge stiffness may well be specifically tuned for different myosins.
Assuntos
Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismo , Cardiomiopatias/genética , Fibras Musculares de Contração Lenta/fisiologia , Músculo Esquelético/fisiopatologia , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Adenosina Trifosfatases/metabolismo , Miosinas Cardíacas/química , Cardiomiopatias/fisiopatologia , Elasticidade , Humanos , Contração Isométrica/fisiologia , Cinética , Modelos Lineares , Força Muscular/fisiologia , Cadeias Pesadas de Miosina/químicaRESUMO
OBJECTIVES: The phenotypic triad of arrhythmogenic right ventricular cardiomyopathy (ARVC) associated with palmoplantar keratoderma and woolly hair has been previously associated with homozygous mutations in both plakoglobin and desmoplakin, which are both critical components of the desmosome. We present here a clinical and genetic study of a consanguineous pedigree in which 2 siblings present with ARVC with left ventricular involvement and associated mild palmoplantar keratoderma and woolly hair. METHODS: Clinical evaluation of the 2 patients and their family members was undertaken along with a homozygosity-mapping approach to identify the relevant gene and sequencing analysis to identify the causative mutation. RESULTS: The homozygosity-mapping approach excluded the involvement of both plakoglobin and desmoplakin in this pedigree. However, an extended region of homozygosity in both affected cases was revealed at the chromosome 18 desmocollin/desmoglein cluster, genes which encode components of the desmosome. Sequence analysis of the democollin-2 gene, located within this cluster, revealed a homozygous single-base deletion in exon 12 (1841delG). This mutation is predicted to lead to a frame shift and a premature termination codon at position 625 (S614fsX625). CONCLUSIONS: This is the first reported case of a mutation in desmocollin-2 associated with autosomal recessive ARVC.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Desmocolinas/genética , Desmossomos/metabolismo , Ceratodermia Palmar e Plantar/genética , Adulto , Idoso , Displasia Arritmogênica Ventricular Direita/metabolismo , Feminino , Genes Recessivos , Cabelo , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/metabolismo , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Three novel beta cardiac myosin heavy chain (MHC) gene missense mutations, Phe513Cys, Gly716Arg, and Arg719Trp, which cause familial hypertrophic cardiomyopathy (FHC) are described. One mutation in exon 15 (Phe513Cys) does not alter the charge of the encoded amino acid, and affected family members have a near normal life expectancy. The Gly716Arg mutation (exon 19; charge change of +1) causes FHC in three family members, one of whom underwent transplantation for heart failure. The Arg719Trp mutation (exon 19; charge change of -1) was found in four unrelated FHC families with a high incidence of premature death and an average life expectancy in affected individuals of 38 yr. A comparable high frequency of disease-related deaths in four families with the Arg719Trp mutation suggests that this specific gene defect directly accounts for the observed malignant phenotype. Further, the significantly different life expectancies associated with the Arg719Trp vs. Phe513Cys mutation (P < 0.001) support the hypothesis that mutations which alter the charge of the encoded amino acid affect survival more significantly than those that produce a conservative amino acid change.
Assuntos
Cardiomiopatia Hipertrófica/genética , Miocárdio/metabolismo , Miosinas/genética , Mutação Puntual , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Cardiomiopatia Hipertrófica/mortalidade , Cardiomiopatia Hipertrófica/fisiopatologia , Criança , Cromossomos Humanos Par 14 , Primers do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Prognóstico , Deleção de Sequência , Análise de Sobrevida , Taxa de SobrevidaRESUMO
Criteria of organ-specific autoimmunity are fulfilled in a subset of patients with myocarditis/dilated cardiomyopathy (DCM). In particular, circulating heart-reactive autoantibodies are found in such patients and symptom-free relatives. These autoantibodies are directed against multiple antigens, some of which are expressed in the heart (organ-specific), others in heart and some skeletal muscle fibres (partially heart-specific) or in heart and skeletal muscle (muscle-specific). Distinct autoantibodies have different frequency in disease and normal controls. Different techniques detect one or more antibodies, thus they cannot be used interchangeably for screening. It is unknown whether the same patients produce more antibodies or different patient groups develop autoimmunity to distinct antigens. IgG antibodies, shown to be cardiac- and disease-specific for myocarditis/DCM, can be used as autoimmune markers for relatives at risk as well as for identifying patients in whom immunosuppression may be beneficial. Some autoantibodies may also have a functional role, but further work is needed.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/fisiologia , Miocardite/imunologia , Miocárdio/imunologia , Autoanticorpos , Autoantígenos/imunologia , Doenças Autoimunes/fisiopatologia , Miosinas Cardíacas/imunologia , Cardiomiopatia Dilatada/classificação , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/fisiopatologia , Proteínas da Matriz Extracelular/imunologia , Humanos , Proteínas Mitocondriais/imunologia , Miocardite/classificação , Miocardite/fisiopatologia , Especificidade de Órgãos , Receptores Adrenérgicos/imunologia , Sarcolema/enzimologia , ATPase Trocadora de Sódio-Potássio/imunologiaRESUMO
BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of premature death; this is particularly apparent for patients with mutations of the troponin T gene. Myocyte disarray and interstitial fibrosis, pathological features of HCM, may be determinants in these deaths. The relation between genotype, pathological phenotype, and mode of death has not been explored. METHODS AND RESULTS: Seventy-five hearts with HCM were examined. DNA was available in 50 for screening of the troponin T gene. The macroscopic findings, percentage of disarray, percentage of fibrosis, and percentage of small-vessel disease were correlated with the genotype. A troponin T mutation was identified in 9 of the 50 patients, 8 of whom died suddenly. Patients with a troponin T mutation were younger (mean age, 21.0 years [range, 6 to 37] versus 39.1 years [range, 14 to 72]; P<0.0001), had more sudden death (P=0.02), and had lower heart weights, less fibrosis, and greater disarray than other HCM patients (mean heart weight, 380.3+/-105.4 versus 585.0+/-245.7 g, P=0.002; mean fibrosis, 0.7+/-0.4% versus 2.6+/-2.8%, P=0.001; mean disarray, 46.2+/-7.2% versus 24.1+/-15.9%, P<0.0001; and mean small-vessel disease, 11.7+/-14.6 versus 14.1+/-8.7, P=0.6, respectively). Similarly, patients with troponin T mutations who died suddenly had lower heart weights and greater disarray than patients who died suddenly with unknown genotype (ie, troponin T mutation excluded) (mean heart weight, 429.8+/-75.4 versus 559.6+/-204.43 g, P=0.04, and mean disarray, 40.1+/-9.4% versus 20.2+/-12.6%, P=0.002, respectively). CONCLUSIONS: Patients with troponin T mutations had severe disarray, with only mild hypertrophy and fibrosis. These patients died suddenly and at an especially early age. We propose that extensive myocyte disarray in the absence of marked hypertrophy is the pathological substrate for sudden death in these patients.
Assuntos
Morte Súbita Cardíaca/patologia , Cardiopatias/genética , Cardiopatias/patologia , Miocárdio/patologia , Troponina T/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Criança , Análise Mutacional de DNA , Morte Súbita Cardíaca/etiologia , Feminino , Testes Genéticos , Genótipo , Cardiopatias/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Miocárdio/metabolismo , Tamanho do Órgão , Fenótipo , Troponina T/metabolismoRESUMO
Arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disease characterized by peculiar RV involvement and electrical instability that precipitates ventricular arrhythmias and sudden death. The purpose of the present consensus report of the Study Group on ARVD/C of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation is to review the considerable progress in our understanding of the etiopathogenesis, morbid anatomy, and clinical presentation of ARVD/C since it first was described in 1977. The present article focuses on important but still unanswered issues, mostly regarding risk stratification, clinical outcome, and management of affected patients. Because ARVD/C is relatively uncommon and any one center may have experience with only a few patients, an international registry is being established to accumulate information and enhance the numbers of patients that can be analyzed and thus answer pending questions. The registry also will facilitate pathological, molecular, and genetics research on the causes and pathogenesis of the ARVD/C. Furthermore, availability of an international database will enhance awareness of this largely unrecognized condition among the medical community. Physicians are encouraged to enroll patients in the International Registry of ARVD/C.
Assuntos
Displasia Arritmogênica Ventricular Direita , Sistema de Registros , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/etiologia , Displasia Arritmogênica Ventricular Direita/patologia , Displasia Arritmogênica Ventricular Direita/terapia , Progressão da Doença , HumanosRESUMO
BACKGROUND: Although studies have suggested that "late-onset" hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population. METHODS AND RESULTS: Plasma alpha-galactosidase A (alpha-Gal) was measured in 79 men with HCM who were diagnosed at > or =40 years of age (52.9+/-7.7 years; range, 40-71 years) and in 74 men who were diagnosed at <40 years (25.9+/-9.2 years; range, 8-39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low alpha-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low alpha-Gal activity had alpha-Gal gene mutations. CONCLUSION: Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.
Assuntos
Cardiomiopatia Hipertrófica/epidemiologia , Doença de Fabry/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/diagnóstico , Criança , Estudos de Coortes , Comorbidade , Análise Mutacional de DNA , Ecocardiografia , Eletrocardiografia , Doença de Fabry/sangue , Doença de Fabry/diagnóstico , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Conformacional de Fita Simples , Prevalência , Encaminhamento e Consulta , Reino Unido/epidemiologia , alfa-Galactosidase/sangue , alfa-Galactosidase/genéticaRESUMO
BACKGROUND: Dual-chamber pacing (DDD) has been proposed as a treatment alternative to surgery for severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies. METHODS AND RESULTS: This prospective, multicenter trial assessed pacing in 48 symptomatic HCM patients with >/=50 mm Hg basal gradient, refractory to drug therapy. Patients were randomized to 3 months each of DDD pacing and pacing backup (AAI-30) in a double-blind, crossover study design, followed by an uncontrolled and unblinded 6-month pacing trial. With randomization, no significant differences were evident between pacing and no pacing for subjective or objective measures of symptoms or exercise capacity, including NYHA functional class, quality of life score, treadmill exercise time or peak oxygen consumption. After 6 additional months of unblinded pacing, functional class and quality of life score were improved compared with baseline (P<0.01), but peak oxygen consumption was unchanged. Outflow gradient decreased 40%, 82+/-32 mm Hg to 48+/-32 mm Hg (P<0. 001), and was reduced in 57% of patients but showed no change or an increase in 43%. At 12 months, 6 individual patients (12%) showed improved functional capacity; each was 65 to 75 years of age. Left ventricular wall thicknesses in the overall study group showed no remodeling between baseline (22+/-5 mm) and 12 months (21+/-5 mm; P=NS). CONCLUSIONS: (1) Pacing cannot be regarded as a primary treatment for obstructive HCM; (2) with randomization, perceived symptomatic improvement was most consistent with a substantial placebo effect; (3) longer, uncontrolled pacing periods were associated with some subjective benefit but unaccompanied by objective improvement in cardiovascular performance and should be interpreted cautiously; (4) modest reduction in outflow gradient was achieved in most patients; and (5) a small subset (12%) >/= 65 years of age showed a clinical response, suggesting that DDD pacing could be a therapeutic option for some elderly patients.
Assuntos
Estimulação Cardíaca Artificial/métodos , Cardiomiopatia Hipertrófica/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Velocidade do Fluxo Sanguíneo/fisiologia , Estimulação Cardíaca Artificial/efeitos adversos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/fisiopatologia , Circulação Coronária/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Resistência a Medicamentos , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Função Ventricular Esquerda/fisiologiaRESUMO
BACKGROUND: Heart failure treatment depends partly on the underlying cause of the disease. We evaluated cardiovascular magnetic resonance (CMR) for the problem of differentiating dilated cardiomyopathy (DCM) from left ventricular (LV) dysfunction caused by coronary artery disease (CAD). METHODS AND RESULTS: Late gadolinium enhancement with CMR was performed in 90 patients with heart failure and LV systolic dysfunction (63 patients with DCM and unobstructed coronary arteries and 27 with significant CAD at angiography). We also studied 15 control subjects with no coronary risk factors and/or unobstructed coronary arteries. None (0%) of the control subjects had myocardial gadolinium enhancement; however, all patients (100%) with LV dysfunction and CAD had enhancement, which was subendocardial or transmural. In patients with DCM, there were 3 findings: no enhancement (59%); myocardial enhancement indistinguishable from the patients with CAD (13%); and patchy or longitudinal striae of midwall enhancement clearly different from the distribution in patients with CAD (28%). CONCLUSIONS: Gadolinium CMR is a powerful technique to distinguish DCM from LV dysfunction related to CAD and yields new insights in DCM. These data suggest that using the coronary angiogram as the arbiter for the presence of LV dysfunction caused by CAD could have lead to an incorrect assignment of DCM cause in 13% of patients, possibly because of coronary recanalization after infarction. The midwall myocardial enhancement in patients with DCM is similar to the fibrosis found at autopsy; it has not previously been visualized in vivo and warrants further investigation. CMR may become a useful alternative to routine coronary angiography in the diagnostic workup of DCM.
Assuntos
Cardiomiopatia Dilatada/diagnóstico , Doença da Artéria Coronariana/diagnóstico , Gadolínio , Insuficiência Cardíaca/diagnóstico , Imageamento por Ressonância Magnética , Idoso , Cardiomiopatia Dilatada/complicações , Doença Crônica , Doença da Artéria Coronariana/complicações , Diagnóstico Diferencial , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Aumento da Imagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Valores de Referência , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologiaRESUMO
BACKGROUND: Hypertrophic cardiomyopathy is a myocardial disorder resulting from inherited sarcomeric dysfunction. We report a mutation in the myosin-binding protein-C (MyBP-C) gene, its clinical consequences in a large family, and myocardial tissue findings that may provide insight into the mechanism of disease. METHODS AND RESULTS: History and clinical status (examination, ECG, and echocardiography) were assessed in 49 members of a multigeneration family. Linkage analysis implicated the MyBP-C gene on chromosome 11. Myocardial mRNA, genomic MyBP-C DNA, and the myocardial proteins of patients and healthy relatives were analyzed. A single guanine nucleotide insertion in exon 25 of the MyBP-C gene resulted in the loss of 40 bases in abnormally processed mRNA. A 30-kDa truncation at the C-terminus of the protein was predicted, but a polypeptide of the expected size ( approximately 95 kDa) was not detected by immunoblot testing. The disease phenotype in this family was characterized in detail: only 10 of 27 gene carriers fulfilled diagnostic criteria. Five carriers showed borderline hypertrophic cardiomyopathy, and 12 carriers were asymptomatic, with normal ECG and echocardiograms. The age of onset in symptomatic patients was late (29 to 68 years). In 2 patients, outflow obstruction required surgery. Two family members experienced premature sudden cardiac death, but survival at 50 years was 95%. CONCLUSIONS: Penetrance of this mutation was incomplete and age-dependent. The large number of asymptomatic carriers and the good prognosis support the interpretation of benign disease.
Assuntos
Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Penetrância , Adulto , Idade de Início , Idoso , Cardiomiopatia Hipertrófica/diagnóstico , Cromossomos Humanos Par 11 , Ecocardiografia , Eletrocardiografia , Éxons , Feminino , Ligação Genética , Genótipo , Heterozigoto , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Mutação , FenótipoRESUMO
BACKGROUND: Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. METHODS AND RESULTS: This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments. CONCLUSIONS: When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Mibefradil/uso terapêutico , Idoso , Bloqueadores dos Canais de Cálcio/efeitos adversos , Canais de Cálcio Tipo T/efeitos dos fármacos , Método Duplo-Cego , Teste de Esforço , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Mibefradil/efeitos adversos , Pessoa de Meia-Idade , Morbidade , Mortalidade , Resistência Física/efeitos dos fármacosRESUMO
The distribution of left ventricular hypertrophy was assessed by M-mode and two-dimensional echocardiography in 89 patients with hypertrophic cardiomyopathy. Myocardial thickness was measured in the septum and the free and posterior wall in both the proximal and distal left ventricle. All patients had at least one myocardial region that was hypertrophied. The predominant pattern of hypertrophy was defined as symmetric (31%), asymmetric septal (55%) and distal ventricular (14%). The spectrum of wall thickness measurements between patients with symmetric hypertrophy was wide (1.5 to 4.5 cm) and was not related to age. In patients with asymmetric septal hypertrophy, the distribution of hypertrophy conformed to previously described patterns; hypertrophy was localized to the anterior septum (14%) or the anterior and posterior septum (35%) or involved both the septum and the left ventricular free wall (51%). The patients with distal ventricular hypertrophy had marked papillary muscle thickening, and only 1 of 12 patients could be correctly diagnosed using M-mode echocardiography. The proportion of patients with symmetric and distal ventricular hypertrophy was greater than that reported when patients are selected on the basis of M-mode diagnostic criteria. This reflects the limitations of the M-mode technique in the assessment of left ventricular hypertrophy and suggests that the recognition and understanding of hypertrophic cardiomyopathy have been biased by patients with asymmetric septal hypertrophy who previously were most readily identified.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Ecocardiografia , Adolescente , Adulto , Idoso , Cardiomiopatia Hipertrófica/patologia , Criança , Feminino , Septos Cardíacos , Ventrículos do Coração , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy. It is uncertain, however, to what extent the right ventricle is also thickened. Right ventricular hypertrophy is found at autopsy in patients who die suddenly but, until recently, systematic evaluation of right ventricular morphology has not been feasible. In this two-dimensional echocardiographic study, a total of 4 to 10 (median 7) right ventricular wall thickness measurements were made from six right ventricular views in 73 patients with hypertrophic cardiomyopathy. Forty-one normal subjects were also studied for comparison. Thirty-two (44%) of the 73 patients had right ventricular hypertrophy with at least two of the wall thickness measurements exceeding 2 standard deviations (SD) from the mean value in the normal subjects. Right ventricular hypertrophy was mild (less than or equal to 8 mm) in 24 patients, moderate (9 to 12 mm) in 7 and severe (greater than 12 mm) in 1. The coefficient of variation of right ventricular wall thickness measurements was similar in normal subjects and patients with and without right ventricular hypertrophy (17 +/- 7, 11 +/- 8 and 10 +/- 8, respectively). The hypertrophy was concentric, with a coefficient of variation of 25% in all but one patient. There was a strong correlation of maximal right and mean left ventricular wall thickness (r = 0.643, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cardiomegalia/patologia , Cardiomiopatia Hipertrófica/patologia , Ecocardiografia , Miocárdio/patologia , Adolescente , Adulto , Idoso , Cardiomegalia/fisiopatologia , Cardiomiopatia Hipertrófica/fisiopatologia , Eletrocardiografia , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , PrognósticoRESUMO
Doppler echocardiography was used to assess diastolic function in 40 patients with hypertrophic cardiomyopathy and to relate it to the patients' symptoms, anaerobic threshold and maximal oxygen consumption during cardiopulmonary exercise testing. The patients had a smaller early (E wave) (p less than 0.01), higher late (A wave) (p less than 0.05) mitral diastolic flow velocity, larger A/E ratio (p less than 0.01), longer isovolumetric relaxation time and E wave duration (p less than 0.001) and slower deceleration rate of the E wave (p less than 0.001) than 40 age- and gender-matched normal subjects. In the patients with hypertrophic cardiomyopathy, maximal oxygen consumption and anaerobic threshold were, respectively, 26.3 +/- 9.2 and 21.1 +/- 6.1 ml/kg per min compared with 47 (range 39 to 68) (p less than 0.01) and 41 (range 27 to 58) ml/kg per min (p less than 0.01) in normal subjects. There was no relation between Doppler indexes and symptoms but symptomatic patients had lower maximal oxygen consumption and anaerobic threshold compared with asymptomatic patients (21.4 +/- 7 vs. 30.7 +/- 10, p less than 0.001 and 18.6 +/- 4.7 vs. 23.1 +/- 5.7, respectively, p less than 0.001). In conclusion, Doppler echocardiography can identify abnormalities of left ventricular filling in patients with hypertrophic cardiomyopathy. However, these indexes measured at rest do not correspond to the patient's professed symptomatic status or exercise capacity measured objectively. Conversely, cardiopulmonary exercise testing reveals a depressed maximal oxygen consumption and anaerobic threshold even in the least symptomatic patients.
Assuntos
Cardiomiopatia Hipertrófica/fisiopatologia , Diástole/fisiologia , Exercício Físico/fisiologia , Adolescente , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Ecocardiografia Doppler , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , PressãoRESUMO
Two-dimensional echocardiography was performed in 16 patients with Ebstein's anomaly to assess right ventricular anatomy and function in relation to clinical features and prognosis. Measurements of right ventricular anatomy and function were established in 10 normal subjects for comparison. Ten patients were in New York Heart Association functional class I, four in class II and one each in classes III and IV. Right ventricular morphology and the three tricuspid valve leaflets were assessed from right ventricular inflow tract and apical four chamber views. The anterior tricuspid leaflet was abnormal but not displaced in all patients; the septal and posterior leaflets were displaced in 14 (88%) and 11 (69%) patients respectively. The posterior leaflet was best visualized from the right ventricular inflow tract, and in two patients this view was required for the echocardiographic diagnosis of Ebstein's anomaly, based on displacement of the septal tricuspid valve leaflet. An index of right ventricular function, the fractional area contraction, was defined as the difference between the end-diastolic and the end-systolic area, normalized to the end-diastolic area. This index was calculated for both the proximal (atrialized) right ventricle and the total right ventricle. Total right ventricular end-diastolic area and fractional area contraction exceeded 95% confidence limits when compared with values in the normal group. During a median follow-up period of 4 years three patients died. They had severe right heart morphologic or functional abnormalities; two were in functional class III or IV and one was asymptomatic. None of the survivors had severe symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)