RESUMEN
OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.
Asunto(s)
Neuropatías Amiloides Familiares , Benzoxazoles , Humanos , Masculino , Francia/epidemiología , Femenino , Persona de Mediana Edad , Anciano , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/epidemiología , Estudios Transversales , Adulto , Benzoxazoles/uso terapéutico , Benzoxazoles/efectos adversos , Anciano de 80 o más Años , Prealbúmina/genéticaRESUMEN
Preparticipation screening programmes for underlying cardiac pathologies are now commonplace for many international sporting organisations. However, providing medical clearance for an asymptomatic athlete without a family history of sudden cardiac death (SCD) is especially challenging when the athlete demonstrates particularly abnormal repolarisation patterns, highly suggestive of an inherited cardiomyopathy or channelopathy. Deep T-wave inversions of ≥ 2 contiguous anterior or lateral leads (but not aVR, and III) are of major concern for sports cardiologists who advise referring team physicians, as these ECG alterations are a recognised manifestation of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Subsequently, inverted T-waves may represent the first and only sign of an inherited heart muscle disease, in the absence of any other features and before structural changes in the heart can be detected. However, to date, there remains little evidence that deep T-wave inversions are always pathognomonic of either a cardiomyopathy or an ion channel disorder in an asymptomatic athlete following long-term follow-up. This paper aims to provide a systematic review of the prevalence of T-wave inversion in athletes and examine T-wave inversion and its relationship to structural heart disease, notably HCM and ARVC with a view to identify young athletes at risk of SCD during sport. Finally, the review proposes clinical management pathways (including genetic testing) for asymptomatic athletes demonstrating significant T-wave inversion with structurally normal hearts.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/diagnóstico , Atletas , Cardiomiopatía Hipertrófica/diagnóstico , Electrocardiografía , Deportes/fisiología , Displasia Ventricular Derecha Arritmogénica/terapia , Cardiomiopatía Hipertrófica/terapia , Vías Clínicas , Muerte Súbita Cardíaca/prevención & control , Diagnóstico Precoz , Pruebas Genéticas/métodos , Humanos , Examen Físico/métodos , Pronóstico , Medición de Riesgo/métodosRESUMEN
Hereditary cardiomyopathy is a primitive disorder in which the heart muscle is structurally and functionally abnormal in the absence of any other cause of cardiomyopathy. They are separated into four phenotypic groups, hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy and arrhythmogenic cardiomyopathy of the right ventricle. Hypertrophic cardiomyopathy was the first identified at the molecular level and then the first to benefit of molecular testing. The molecular analyses were then extended the following years to the dilated cardiomyopathy and restrictive cardiomyopathy. The arrhythmogenic right ventricular cardiomyopathy was the latest to be analyzed at the molecular level because the identification of genes involved in that phenotype was published only in 2002 to 2006. The genetics analysis of these diseases has developed over the past decade and, although still complex, is now available in current hospital practice. The objectives of these tests are to confirm a diagnosis difficult to achieve by classic clinical approach and to perform predictive and presymptomatic diagnosis in families when the mutation was identified. This allows for appropriate care of patients at risk, and may respond to a request for prenatal diagnosis in particularly serious forms. These tests are framed in the context of genetic counselling consultation and patients are the subjects of a multidisciplinary care in reference centres.
Asunto(s)
Cardiomiopatías/genética , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/patología , Cardiomiopatías/clasificación , Cardiomiopatías/diagnóstico , Cardiomiopatías/patología , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Cardiomiopatía Hipertrófica Familiar/diagnóstico , Cardiomiopatía Hipertrófica Familiar/genética , Cardiomiopatía Hipertrófica Familiar/patología , Cardiomiopatía Restrictiva/diagnóstico , Cardiomiopatía Restrictiva/genética , Cardiomiopatía Restrictiva/patología , Análisis Citogenético , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/patología , Diagnóstico Diferencial , Asesoramiento Genético , Humanos , Técnicas de Diagnóstico Molecular , Proteínas Musculares/deficiencia , Proteínas Musculares/genética , FenotipoRESUMEN
Access to active search for actionable secondary findings (SF) in diagnostic practice is a major psychological and ethical issue for genomic medicine. In this study, we analyzed the preferences of patients and their families regarding SF and identified the reporting procedures necessary for informed consent. We interviewed parents of patients with undiagnosed rare diseases potentially eligible for exome sequencing and patients affected by the diseases listed in the ACMG recommendations. Four focus groups (FG) were formed: parents of patients with undiagnosed rare diseases (FG1, nâ¯=â¯5); patients with hereditary cancers (FG2, nâ¯=â¯10); patients with hereditary cardiac conditions (FG3, nâ¯=â¯3); and patients with metabolic diseases (FG4, nâ¯=â¯3). Psychologists presented three broad topics for discussion: 1. Favorable or not to SF access, 2. Reporting procedures, 3. Equity of access. Discussions were recorded and analyzed using simplified Grounded Theory. Overall, 8 participants declared being favorable to SF because of the medical benefit (mainly FG1); 11 were unfavorable because of the psychological consequences (mainly FG2, FG3, FG4); 2 were ambivalent. The possibility of looking for SF in minors was debated. The 4 key information-based issues for participants ranked as follows: explanation of SF issues, autonomy of choice, importance of a reflection period, and quality of interactions between patients and professionals. Examining equity of access to SF led to philosophical discussions on quality of life. In conclusion, individual experience and life context (circumstances) were decisive in participants' expectations and fears regarding access to SF. Additional longitudinal studies based on actual SF disclosure announcements are needed to establish future guidelines.
Asunto(s)
Ética Médica , Genómica/ética , Secuenciación de Nucleótidos de Alto Rendimiento/ética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/psicología , Pruebas Genéticas , Genoma Humano , Humanos , Hallazgos Incidentales , Persona de Mediana Edad , Secuenciación del ExomaRESUMEN
INTRODUCTION: The prognosis of pregnancy in patients with Arrhythmogenic Right Ventricular Cardiomyopathy/dysplasia (ARVC/D) is poorly documented. The aim of this study is to assess the cardiac risks during pregnancy and the impact of ARVC/D on fetuses/neonates/children. METHODS: We included all ARVC/D women with a history of pregnancy from the ARVC/D Pitié-Salpêtrière registry. Cardiac and obstetrical events having occurred during pregnancy/delivery/post-partum periods and neonatal data/follow-up were collected. RESULTS: Sixty pregnancies in twenty-three patients were identified between 1968 and 2016. Only two major non-fatal cardiac events (one sustained non-documented tachycardia and one ventricular tachycardia) were recorded during pregnancy in two different mothers (3% of pregnancies, 9% of mothers). None occurred during delivery or in the postpartum period. No mother developed heart failure. Beta-blocker therapy during pregnancy (n=15) was associated with lower birthweight (2730 vs 3400g, p=0.004). Only two preterm deliveries occurred, unrelated to cardiac condition. Caesarean section was performed in 13% of cases. Premature sudden-death occurred in 10% (n=5) of children before 25years-old including two in the first year of life. CONCLUSION: ARVC/D is associated with a low rate of major cardiac events during pregnancy and vaginal delivery appears safe. The risk of sustained ventricular arrhythmia seems poorly predictable and supports the continuation of beta-blockers during pregnancy. Major cardiac events were frequent in childhood, justifying close cardiac monitoring.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/diagnóstico por imagen , Displasia Ventricular Derecha Arritmogénica/epidemiología , Complicaciones Cardiovasculares del Embarazo/diagnóstico por imagen , Complicaciones Cardiovasculares del Embarazo/epidemiología , Resultado del Embarazo/epidemiología , Aborto Espontáneo/diagnóstico por imagen , Aborto Espontáneo/epidemiología , Aborto Espontáneo/prevención & control , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Displasia Ventricular Derecha Arritmogénica/tratamiento farmacológico , Femenino , Humanos , Recién Nacido , Persona de Mediana Edad , Embarazo , Complicaciones Cardiovasculares del Embarazo/tratamiento farmacológico , Nacimiento Prematuro/diagnóstico por imagen , Nacimiento Prematuro/epidemiología , Nacimiento Prematuro/prevención & control , Estudios Retrospectivos , Adulto JovenRESUMEN
Conduction defects are usually secondary to elective aging of the conduction pathways. However, some familial and genetic forms are now being described. Here we report a particular electrocardiographic pattern in four members of the same family over three generations, naturally leading to the suspicion of a hereditary origin. The ECG appearance is very specific and includes conduction defects (RBBB and occasionally left anterior hemiblock), short PR interval, pseudo appearance of atrial hypertrophy, and occasionally sinus dysfunction or supraventricular extrasystole. Gene analysis identified a R302Q mutation of the gamma2 subunit producing AMP protein kinase, coded by the gene PRKAG2. This is a wrong sense mutation present in the heterozygous state in each of those displaying the ECG anomalies, and is transmitted in an autosomal dominant fashion. The clinical picture here appears to constitute a clinical entity distinct from those previously described as being associated with mutations of the PRKAG2 gene, without any left ventricular hypertrophy or Wolff-Parkinson-White syndrome.
Asunto(s)
Arritmias Cardíacas/genética , Complejos Multienzimáticos/genética , Mutación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Quinasas Activadas por AMP , Adulto , Anciano , Arritmias Cardíacas/fisiopatología , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
The aim of this study was to validate a two-dimensional echocardiographic score for left ventricular hypertrophy in familial hypertrophic cardiomyopathy (HCM) by fast CT scan and to study the diagnostic value by an indexed threshold value in affected and genotyped families in comparison with the classical diagnostic method of maximal wall thickness (E max). The study was performed successively in two patient groups with HCM. The echo/CT scan population comprised 26 patients. They underwent echocardiography and Imatron CT scanning. The E max and 2D echo score (sum of the thickness of 4 segments) were measured by echocardiography and compared to the left ventricular mass obtained by the CT method. The 2D echo score was closely correlated to the CT left ventricular mass (r = 0.85) with a higher correlation coefficient than the E max (r = 0.78). The echo/generic population comprised 109 genotyped adults with an identified mutation. The E max and 2D echo score were measured. The genotype was the reference for diagnosis. A theoretical value of the 2D echo score was determined in healthy individuals by a multiple linear regression model of ages, sex and body surface area. A threshold value for abnormality was established after analysis of the ROC. The sensitivity and specificity were 63% and 100% respectively for E max and 73% and 96% respectively for the indexed 2D echo score. The improvement in sensitivity was marked in young adults (< 50 years) with 69% for the indexed 2D echo score versus 54% for E max, p < 0.04. The authors conclude that the indexed 2D score has been validated as an index of hypertrophy by the Imatron CT and has a better diagnostic value than E max, especially in young adults. This echocardiographic criterion could be proposed as an alternative diagnostic sign for screening families.
Asunto(s)
Cardiomiopatía Hipertrófica Familiar/complicaciones , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Femenino , Humanos , Hipertrofia Ventricular Izquierda/complicaciones , Masculino , Persona de Mediana Edad , UltrasonografíaRESUMEN
Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.
Asunto(s)
Miosinas Cardíacas , Cardiomiopatía Hipertrófica/genética , Genes/genética , Cadenas Ligeras de Miosina/genética , Mutación Puntual/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cardiomiopatía Hipertrófica/fisiopatología , Niño , Mapeo Cromosómico , Cromosomas Humanos Par 12/genética , ADN/sangre , Análisis Mutacional de ADN , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple , Alineación de SecuenciaRESUMEN
AIMS: A major breakthrough in the molecular genetics of hypertrophic cardiomyopathy (HCM) has made genetic testing now available in clinical practice, raising new questions about its implications, potential benefits, and the organisation of the procedure. The aim of this work was (1) to discuss the different questions related to genetic testing in HCM, and propose guidelines for the different situations, (2) to report our preliminary experience with a specific procedure. METHODS AND RESULTS: The main questions asked by patients and relatives concern presymptomatic diagnosis and prenatal counselling/diagnosis, while clinicians sometimes discuss diagnostic and prognostic testing. To take into account the complex medical and psychological implications of this new approach, we developed a specific, multidisciplinary, and multiple step procedure, including a cardiologist, a geneticist, and a psychologist. Seventy subjects were examined, including (1) 29 adults for presymptomatic diagnosis (of whom 10 left the procedure after the first visit and 19 continued, among whom six had a mutation and two experienced negative psychological impact, observed during follow up), (2) nine couples of parents for presymptomatic diagnosis in their children (the procedure was stopped after the first visit in eight and continued in one), (3) 22 couples for prenatal counselling (no prenatal genetic testing was asked for after the first visit), and (4) 10 subjects for diagnostic testing. We decided to perform no prognostic testing. CONCLUSION: Our preliminary experience confirms the complexity of the situation and suggests the necessity for a specific procedure to ensure good practice in genetic testing of HCM.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Asesoramiento Genético/métodos , Pruebas Genéticas/métodos , Adolescente , Adulto , Anciano , Femenino , Francia , Asesoramiento Genético/ética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/ética , Humanos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Diagnóstico Prenatal/ética , Diagnóstico Prenatal/métodos , PronósticoRESUMEN
AIMS: Mutations in the lamin A/C gene (LMNA) have been reported to be involved in dilated cardiomyopathy (DCM) associated with conduction system disease and/or skeletal myopathy. The aim of this study was to perform a mutational analysis of LMNA in a large white population of patients affected by dilated cardiomyopathy with or without associated symptoms. METHODS: We performed screening of the coding sequence of LMNA on DNA samples from 66 index cases, and carried out cell transfection experiments to examine the functional consequences of the mutations identified. RESULTS: A new missense (E161K) mutation was identified in a family with early atrial fibrillation and a previously described (R377H) mutation in another family with a quadriceps myopathy associated with DCM. A new mutation (28insA) leading to a premature stop codon was identified in a family affected by DCM with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy. Functional analyses have identified potential physiopathological mechanisms involving identified mutations, such as haploinsufficiency (28insA) or intermediate filament disorganisation (E161K, R377H). CONCLUSION: For the first time, a specific phenotype characterised by early atrial fibrillation is associated with LMNA mutation. Conversely, mutations in LMNA appear as a rare cause of isolated dilated cardiomyopathy. The variable phenotypes observed in LMNA-DCM might be explained by the variability of functional consequences of LMNA mutations.
Asunto(s)
Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/fisiopatología , Lamina Tipo A/genética , Mutación , Adolescente , Adulto , Anciano , Animales , Células COS , Cardiomiopatía Dilatada/mortalidad , Línea Celular , Niño , Chlorocebus aethiops , Análisis Mutacional de ADN , Femenino , Humanos , Lamina Tipo A/fisiología , Masculino , Ratones , Persona de Mediana Edad , Mioblastos/química , Mioblastos/metabolismo , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , TransfecciónRESUMEN
Heart failure is a major health problem and is associated with a high mortality and morbidity. Recently, the role of the genetic background in the onset and the development of the disease has been evidenced in both heart failure with and without systolic dysfunction and in familial and non-familial forms of this condition. Preliminary studies suggest that the I/D polymorphism of the Angiotensin Converting Enzyme gene influence the development of left ventricular hypertrophy, a major determinant of heart failure. Familial hypertrophic cardiomyopathy (FHC) is a highly heterogenous autosomal dominant disease. Seven genes have been identified which all encode proteins of the sarcomere or proteins involved in the regulation of contraction. More than one hundred mutations have been evidenced. Modifier genes such as the I/D polymorphism seem to play a role in the expression of the disease. Susceptibility genes have been searched for in sporadic forms of dilated cardiomyopathy and conflicting results have been published with regard to the I/D polymorphism. Finally, familial forms of dilated cardiomyopathy (FDC) are frequent. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. It has been postulated that the molecular defect involved in FDC is an abnormality in the transmission of contractile force. The analysis of genetic factors that predispose to heart failure looks promising: it should allow better understanding of the underlying mechanisms that promote the progression of the disease, to identify subjects at risk of the disease who would benefit from early medical management and promote the development of pharmacogenetics.
Asunto(s)
Insuficiencia Cardíaca/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/genética , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/etiología , Humanos , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/genética , Mutación , FenotipoRESUMEN
UNLABELLED: The aims of the study were to analyze the clinical features, the penetrance and the mode of inheritance of 13 French families with dilated cardiomyopathy using diagnostic criteria recently established by a European collaboration. METHODS: Screening consisted of physical examination, ECG and Echo of all the probands first degree relatives (n = 118). Using major Echo criteria [ejection fraction (EF) < 45% or FS < 25% and left ventricular diameter (LVD) > 117% of the predictive value], or combined minor Echo/ECG criteria, relatives were classified as affected, unknown or healthy. RESULTS: (1) Adult affected relatives (n = 31) were identified with major Echo criteria in 74% of cases, and with combined minor Echo/ECG criteria in 26% of cases. (2) In the unknown relatives (n = 21), the most common abnormality was an isolated left ventricular dilation (67%). (3) Mode of inheritance was autosomal dominant (AD) in 11 families and possibly autosomal recessive in two. (4) In AD families, the penetrance was incomplete in adults (72%), age-related (O.R.: 1.3 per 10 years; 95% CI 1.03-1.56) and sex-related [greater in men (87%) than in women (61%), actuarial survival curve: P<0.002]. (5) Mortality related to end stage heart failure was 2.2 times as high as mortality related to sudden death (11% vs. 5%). CONCLUSIONS: (1) In the absence of a specific phenotype of FDC, the characterization of relatives appears more accurate when minor criteria were added. (2) Since high mortality (16%) and incomplete penetrance frequently give rise to small nuclei of clinically affected and alive relatives per family, the accurate model of penetrance that we proposed might be helpful in the future to enhance the statistical power of linkage analysis in this disease.
Asunto(s)
Cardiomiopatía Dilatada/genética , Adulto , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/mortalidad , Ecocardiografía , Electrocardiografía , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Volumen Sistólico , Tasa de SupervivenciaRESUMEN
Endogenous epinephrine has been found to increase alveolar liquid clearance (ALC) in several pulmonary edema models. In this study, we infused epinephrine intravenously for 1 h in anesthetized rats to produce plasma epinephrine concentrations commonly observed in this species under stressful conditions and measured ALC by mass balance. Epinephrine increased ALC from 31.5 +/- 3.2 to 48.9 +/- 1.1 (SE)% of the instilled volume (P < 0.05). The increased ALC was prevented by either propranolol or amiloride. To determine whether ALC returns to normal after plasma epinephrine concentration normalizes, we measured ALC 2 h after stopping an initial 1-h epinephrine infusion and found ALC to be at baseline values. Finally, to determine whether desensitization of the liquid clearance response occurs, we evaluated the effects of both repeated 1-h infusions and a continuous 4-h infusion of epinephrine on ALC and found no reduction in ALC under either condition. We conclude that epinephrine increases ALC by stimulating beta-adrenoceptors and sodium transport, that the increase is reversible once plasma epinephrine concentration normalizes, and that desensitization of the ALC response does not appear to occur after 4 h of continuous epinephrine exposure.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Epinefrina/farmacología , Alveolos Pulmonares/efectos de los fármacos , Amilorida/farmacología , Animales , Líquido del Lavado Bronquioalveolar/química , Epinefrina/sangre , Masculino , Norepinefrina/sangre , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Albúmina Sérica/metabolismo , Factores de TiempoRESUMEN
Heart failure is a major health problem and is associated with a high mortality and morbidity. Recently, the role of the genetic background in the onset and development of the disease has been evidenced in both heart failure with and without systolic dysfunction, and in familial and non-familial forms of this condition. Familial forms of dilated cardiomyopathy are more frequent than previously thought. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. Five genes (dystrophin, cardiac actin, desmin, lamin A/C and delta-sarcoglycan), and additional loci, have been identified in families in which dilated cardiomyopathy is isolated or associated with other cardiac or non-cardiac symptoms. It has been postulated that the molecular defect involved could lead to abnormal interactions between cytoskeletal proteins, responsible either for defect in force transmission or for membrane disruption. More recently, the identification of mutations in genes encoding sarcomeric proteins has led to a second hypothesis in which the disease might also result from a force generation defect. In non-monogenic dilated cardiomyopathy, susceptibility genes (role in the development of the disease) and modifier genes (role in the evolution/prognosis of the disease) have so far been identified. Some data suggest that the efficacy of angiotensin converting enzyme inhibitors, and side-effects, might be related to some genetic polymorphisms, such as the I/D polymorphism of the angiotensin converting enzyme gene. Although preliminary, these data are promising and might be the first step towards application of phamacogenetics in heart failure. This is of paramount importance as the medical treatment of heart failure is characterized by the need for polypharmacy. One of the major challenges of the next millenium, therefore, will be to identify genetic factors which might help define responders to major treatment classes, including angiotensin converting enzyme inhibitors, beta-adrenoreceptor antagonists, angiotensin AT1 receptor antagonists, spironolactone, vasopeptidase inhibitors and endothelin receptor antagonists.
Asunto(s)
Cardiopatías/tratamiento farmacológico , Cardiopatías/genética , Farmacogenética , Animales , Predisposición Genética a la Enfermedad , Humanos , Mutación , Polimorfismo GenéticoRESUMEN
BACKGROUND: Since the sensitivity of conventional diagnostic criteria for familial hypertrophic cardiomyopathy (HCM) is low, new diagnostic criteria were proposed by a European collaboration. However, their diagnostic value remains unknown. The aim of the study was to evaluate the accuracy of these new criteria, using the genetic status as the criterion of reference. METHODS: We studied 109 genotyped adults (54 genetically affected, 55 unaffected) from 7 families (mutations in 3 genes). Major European echographic criteria were a maximal wall thickness >or=13 mm or >or=15 mm according to the segment involved, or the presence of SAM. Major European ECG criteria were abnormal Q waves, left ventricular hypertrophy, or marked ST-T changes. Combined major/minor European criteria were also evaluated. RESULTS: Sensitivity and specificity of major European criteria (72 and 92%, respectively) were similar to those of major conventional criteria (70 and 94%) and were not improved by combined major/minor European criteria (72 and 90%). When all the minor European criteria were considered, sensitivity increased to 87% but specificity dramatically decreased to 51%. However, one of these minor ECG criteria, deep S V2, was of interest and when added to major European criteria, sensitivity increased to 76% and specificity remained good (90%). CONCLUSIONS: The diagnostic value of new European criteria for HCM was evaluated for the first time. We found that it was not different from that of conventional criteria, with a good specificity but a low sensitivity. Additional criteria should be studied to improve the early identification of HCM.
Asunto(s)
Cardiomiopatía Hipertrófica Familiar/diagnóstico , Cardiomiopatía Hipertrófica Familiar/genética , Genotipo , Adulto , Cardiomiopatía Hipertrófica Familiar/fisiopatología , Conducta Cooperativa , Ecocardiografía Doppler , Electrocardiografía , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant cardiac disease for which the penetrance remains a much-debated issue. Since the recent identification of the genes involved in the disease, the penetrance of FHC has not been reassessed in a large genotyped population. The aim of our study was therefore to evaluate it, according to age and sex, in ten families with previously identified mutations. Among 178 individuals we studied, 90 were genetically affected (9 different mutations in 3 genes). We found that penetrance, assessed by classical echocardiographic and electrocardiographic criteria, was (1) incomplete: 69%; (2) age-related: 55% between 10 and 29 years old, 75% between 30 and 49 y. and 95% over 50 y.; (3) greater in males than in females: 77% vs 58%, age-adjusted odds ratio: 3.98, CI 95%: 1.34 to 11,48; (4) similar for the genes analyzed. The consequences of these results for genetic counseling and linkage analyses are discussed.
Asunto(s)
Cardiomiopatía Hipertrófica/genética , Aberraciones Cromosómicas/genética , Genes Dominantes/genética , Adolescente , Adulto , Anciano , Cardiomiopatía Hipertrófica/diagnóstico , Niño , Preescolar , Trastornos de los Cromosomas , Análisis Mutacional de ADN , Femenino , Asesoramiento Genético , Ligamiento Genético/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Progress in the recognition of genetic factors implicated in cardiovascular diseases is now such that it poses the question of how to integrate these data into a clinical perspective. To be able to give the most relevant information to the patient and his family, and to use this information to optimise the medical management have become new objectives. This can only be achieved with the close collaboration between cardiologist and the genticist, who knows the legislative framework which governs the performance of genetic tests. During the genetic counselling consultation, and after time for compiling information on the disease and the family, the geneticist gives the most suitable information on the genetic nature of the disease. Depending on the illness, cardiological investigation for the relatives could be advocated. The performance of a molecular test is then discussed, as a function of its feasibility, relevance and the wishes of the patient. The complexity of the medical and psychological stakes varies according to the situation (presymptomatic diagnosis, prenatal diagnosis, diagnostic test, prognostic test) and the condition. In all cases, strict rules perfectly laid down by legislation must be respected, in such a way as to protect the patient from possible unfavourable repercussions and to assure him of better medical management and a greater well-being.
Asunto(s)
Cardiología/tendencias , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/genética , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Derivación y Consulta , Humanos , Planificación de Atención al Paciente , LinajeRESUMEN
Our understanding of the genetics of hypertrophic cardiomyopathy has progressed significantly over the last few years. Seven genes have been identified as being responsible for familiar forms of the disease. This information has been useful, mainly in the elucidation of the physiopathology but clinical implications are also beginning to see the light of day. One example is the assessment of the pertinence of traditional diagnostic criteria. The originality of these studies lies in the analysis of familial hypertrophic cardiomyopathies in which the causal mutation has been identified, using the genetic status of the individual as the reference. The conventional diagnostic criteria then appear to be very specific but not very sensitive, inciting further analysis of additional criteria which might improve the diagnostic performance of routine investigations. This also opens the door to a comprehensive revision of the diagnostic criteria of this disease.