Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 63
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
J Cell Sci ; 136(4)2023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36695453

RESUMEN

The heat shock (HS) response is crucial for cell survival in harmful environments. Nuclear lamin A/C, encoded by the LMNA gene, contributes towards altered gene expression during HS, but the underlying mechanisms are poorly understood. Here, we show that upon HS, lamin A/C was reversibly phosphorylated at serine 22 in concert with HSF1 activation in human cells, mouse cells and Drosophila melanogaster in vivo. Consequently, the phosphorylation facilitated nucleoplasmic localization of lamin A/C and nuclear sphericity in response to HS. Interestingly, lamin A/C knock-out cells showed deformed nuclei after HS and were rescued by ectopic expression of wild-type lamin A, but not by a phosphomimetic (S22D) lamin A mutant. Furthermore, HS triggered concurrent downregulation of lamina-associated protein 2α (Lap2α, encoded by TMPO) in wild-type lamin A/C-expressing cells, but a similar response was perturbed in lamin A/C knock-out cells and in LMNA mutant patient fibroblasts, which showed impaired cell cycle arrest under HS and compromised survival at recovery. Taken together, our results suggest that the altered phosphorylation stoichiometry of lamin A/C provides an evolutionarily conserved mechanism to regulate lamina structure and serve nuclear adaptation and cell survival during HS.


Asunto(s)
Lamina Tipo A , Serina , Humanos , Ratones , Animales , Lamina Tipo A/genética , Fosforilación , Serina/metabolismo , Drosophila melanogaster/metabolismo , Núcleo Celular/metabolismo
2.
Eur Heart J ; 45(28): 2548-2569, 2024 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-38594778

RESUMEN

BACKGROUND AND AIMS: Contemporary multicentre data on clinical and diagnostic spectrum and outcome in myocarditis are limited. Study aims were to describe baseline features, 1-year follow-up, and baseline predictors of outcome in clinically suspected or biopsy-proven myocarditis (2013 European Society of Cardiology criteria) in adult and paediatric patients from the EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry. METHODS: Five hundred eighty-one (68.0% male) patients, 493 adults, median age 38 (27-52) years, and 88 children, aged 8 (3-13) years, were divided into 3 groups: Group 1 (n = 233), clinically suspected myocarditis with abnormal cardiac magnetic resonance; Group 2 (n = 222), biopsy-proven myocarditis; and Group 3 (n = 126) clinically suspected myocarditis with normal or inconclusive or no cardiac magnetic resonance. Baseline features were analysed overall, in adults vs. children, and among groups. One-year outcome events included death/heart transplantation, ventricular assist device (VAD) or implantable cardioverter defibrillator (ICD) implantation, and hospitalization for cardiac causes. RESULTS: Endomyocardial biopsy, mainly right ventricular, had a similarly low complication rate in children and adults (4.7% vs. 4.9%, P = NS), with no procedure-related death. A classical myocarditis pattern on cardiac magnetic resonance was found in 31.3% of children and in 57.9% of adults with biopsy-proven myocarditis (P < .001). At 1-year follow-up, 11/410 patients (2.7%) died, 7 (1.7%) received a heart transplant, 3 underwent VAD (0.7%), and 16 (3.9%) underwent ICD implantation. Independent predictors at diagnosis of death or heart transplantation or hospitalization or VAD implantation or ICD implantation at 1-year follow-up were lower left ventricular ejection fraction and the need for immunosuppressants for new myocarditis diagnosis refractory to non-aetiology-driven therapy. CONCLUSIONS: Endomyocardial biopsy was safe, and cardiac magnetic resonance using Lake Louise criteria was less sensitive, particularly in children. Virus-negative lymphocytic myocarditis was predominant both in children and adults, and use of immunosuppressive treatments was low. Lower left ventricular ejection fraction and the need for immunosuppressants at diagnosis were independent predictors of unfavourable outcome events at 1 year.


Asunto(s)
Miocarditis , Miocardio , Sistema de Registros , Humanos , Miocarditis/patología , Miocarditis/diagnóstico , Miocarditis/mortalidad , Masculino , Niño , Femenino , Adolescente , Adulto , Biopsia/métodos , Preescolar , Pronóstico , Persona de Mediana Edad , Miocardio/patología , Trasplante de Corazón/estadística & datos numéricos , Europa (Continente)/epidemiología , Desfibriladores Implantables , Corazón Auxiliar
3.
BMC Cardiovasc Disord ; 23(1): 414, 2023 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-37612617

RESUMEN

BACKGROUND: Primary tumors of the heart are a rare phenomenon. Lymphatic malformations are congenital anomalies of the lymphatic system that tend to grow progressively. Lymphatic malformations are typically found in the cervical and axillary regions and found on pediatric patients. We report a 40-year-old woman with giant epimyocardial lymphatic malformation. CASE PRESENTATION: A 40-year-old woman was assessed due to suspected traumatic cardiac tamponade. Computed tomography of the heart and cardiac magnetic resonance imaging were compatible with either a large pericardial hemangioma or angiosarcoma. The tumor infiltrated deeply into the myocardium and could only be partially resected. Histopathological diagnosis was a cardiac lymphatic malformation with micro- and macrocystic components. The patient has remained asymptomatic for fourteen years after the surgery. In the latest follow-up, her left ventricular function had remained normal and the maximum thickness of the residual tumor had regressed. CONCLUSIONS: Even when a complete removal of a cardiac lymphatic malformation is not possible, a debulking procedure can yield a good long-term result.


Asunto(s)
Taponamiento Cardíaco , Hemangioma , Humanos , Niño , Femenino , Adulto , Miocardio , Pericardio , Cuello
4.
J Med Genet ; 59(9): 858-864, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34400560

RESUMEN

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course. METHODS: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed. RESULTS: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among PKP2 than DSC2/DSG2/DSP carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01). CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica , Insuficiencia Cardíaca , Arritmias Cardíacas/genética , Displasia Ventricular Derecha Arritmogénica/complicaciones , Displasia Ventricular Derecha Arritmogénica/genética , Desmosomas , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Placofilinas/genética , Volumen Sistólico/genética , Función Ventricular Izquierda
5.
J Nucl Cardiol ; 29(3): 1021-1029, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-33094472

RESUMEN

BACKGROUND: Transthyretin amyloidosis (ATTR) is an occasional incidental finding on bone scintigraphy. We studied its prognostic impact in elderly patients. METHODS: The study population consisted of 2000 patients aged over 70 years who underwent bone scintigraphies with clinical indications in three nuclear medicine departments (Kymenlaakso, Jorvi and Meilahti hospitals) in Finland. All studies were performed using 99mTechnetium labeled hydroxymethylene diphosphonate (HMDP). ATTR was suspected in patients with ≥grade 2 Perugini grade uptake (grade 0-3). Heart-to-contralateral ratio (H/CL) of ≥ 1.30 was considered positive for ATTR. The overall and cardiovascular mortality were obtained from the Finnish National Statistical Service. RESULTS: There were a total of 1014 deaths (51%) and 177 cardiovascular deaths (9%) during median follow-up of 4 ± 2 years. ATTR was suspected in 69 patients (3.6%) of which 54 (2.7%) had grade 2 and 15 (.8%) had grade 3 uptake and in 47 patients (2.4%) by H/CL ratio. In multivariate analyses age, bone metastasis, H/CL ratio and grade 3 uptake were independent predictors of overall and cardiovascular mortality. Grade 2 uptake was a predictor of cardiovascular mortality. CONCLUSIONS: A suspected ATTR as an incidental finding on bone scintigraphy predicts elevated overall and cardiovascular mortality in elderly patients.


Asunto(s)
Neuropatías Amiloides Familiares , Enfermedades Cardiovasculares , Anciano , Neuropatías Amiloides Familiares/diagnóstico por imagen , Enfermedades Cardiovasculares/diagnóstico por imagen , Humanos , Pronóstico , Cintigrafía , Tomografía Computarizada por Rayos X
6.
Europace ; 24(2): 306-312, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-34279601

RESUMEN

AIMS: Treatment with implantable cardioverter-defibrillators (ICD) is a cornerstone for prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at describing the complications associated with ICD treatment in a multinational cohort with long-term follow-up. METHODS AND RESULTS: The Nordic ARVC registry was established in 2010 and encompasses a large multinational cohort of ARVC patients, including their clinical characteristics, treatment, and events during follow-up. We included 299 patients (66% males, median age 41 years). During a median follow-up of 10.6 years, 124 (41%) patients experienced appropriate ICD shock therapy, 28 (9%) experienced inappropriate shocks, 82 (27%) had a complication requiring surgery (mainly lead-related, n = 75), and 99 (33%) patients experienced the combined endpoint of either an inappropriate shock or a surgical complication. The crude rate of first inappropriate shock was 3.4% during the first year after implantation but decreased after the first year and plateaued over time. Contrary, the risk of a complication requiring surgery was 5.5% the first year and remained high throughout the study period. The combined risk of any complication was 7.9% the first year. In multivariate cox regression, presence of atrial fibrillation/flutter was a risk factor for inappropriate shock (P < 0.05), whereas sex, age at implant, and device type were not (all P > 0.05). CONCLUSION: Forty-one percent of ARVC patients treated with ICD experienced potentially life-saving ICD therapy during long-term follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica , Desfibriladores Implantables , Adulto , Displasia Ventricular Derecha Arritmogénica/complicaciones , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/terapia , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Desfibriladores Implantables/efectos adversos , Cardioversión Eléctrica/efectos adversos , Femenino , Humanos , Masculino , Sistema de Registros , Factores de Riesgo , Resultado del Tratamiento
7.
Heart Lung Circ ; 31(5): 629-637, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35063379

RESUMEN

BACKGROUND: This study evaluated the prevalence and prognostic significance of cardiac transthyretin amyloidosis (ATTR) diagnosed using 99mTc- hydroxymethylene-diphosphonate (99mTc-HMDP) scintigraphy in an elderly heart failure population. METHODS: This retrospective study included 335 patients aged >70 years with heart failure and who underwent 99mTc-HMDP scintigraphy due to non-cardiac reasons in three imaging centres in Finland (Kymenlaakso Central Hospital, Jorvi Central Hospital, and Meilahti University Hospital). A Perugini grade >2 and heart-to-contralateral ratio (H/CL) of ≥1.30 were considered positive for cardiac ATTR. The overall and cardiovascular mortality were obtained from the national statistical service (Statistics Finland). RESULTS: There were 234 deaths, of which 70 were classified as being due to cardiovascular causes during a median follow-up of 1 (1-3) year. Transthyretin amyloidosis was diagnosed in 22 patients (6.6%) using visual analysis and 17 patients using the H/CL ratio (5.1%). Patients with ATTR were older (85±5 vs 80±5 yrs; p=0.002) and had higher N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels (1,451 [813-3,799] vs 6,192 [2,030-8,833] ng/L; p=0.02). Age, bone metastases, and glomerular filtration rate were independent predictors of overall mortality in multivariable analysis. Age, glomerular filtration rate, ≥grade 2 visual cardiac uptake, and H/CL ratio were independent predictors of cardiovascular mortality. CONCLUSIONS: Cardiac uptake suggestive of ATTR was found in 5% of elderly patients with chronic heart failure. The presence of cardiac uptake on bone scintigraphy did not convey independent prognostic value on overall mortality but was independently associated with cardiovascular mortality.


Asunto(s)
Neuropatías Amiloides Familiares , Cardiomiopatías , Cardiopatías , Insuficiencia Cardíaca , Anciano , Neuropatías Amiloides Familiares/diagnóstico por imagen , Cardiomiopatías/diagnóstico por imagen , Cardiopatías/diagnóstico por imagen , Insuficiencia Cardíaca/diagnóstico por imagen , Humanos , Pronóstico , Cintigrafía , Estudios Retrospectivos , Tomografía Computarizada por Rayos X
8.
BMC Cardiovasc Disord ; 21(1): 126, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33673806

RESUMEN

BACKGROUND: Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world. METHODS: A retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic. RESULTS: A total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p < 0.0001), a higher maximum wall thickness (MWT) (p < 0.0001), a positive family history (p < 0.0001), the absence of hypertension (p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004). CONCLUSION: The diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population.


Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Pruebas Genéticas , Variación Genética , Adolescente , Adulto , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Niño , Preescolar , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Fenotipo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto Joven
9.
BMC Med Genet ; 21(1): 19, 2020 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-32005173

RESUMEN

BACKGROUND: Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. METHODS: We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed. RESULTS: We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. CONCLUSIONS: The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica/genética , Cardiomiopatía Dilatada/genética , Desmoplaquinas/genética , Predisposición Genética a la Enfermedad , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Displasia Ventricular Derecha Arritmogénica/diagnóstico por imagen , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/fisiopatología , Medios de Contraste/administración & dosificación , Femenino , Gadolinio/administración & dosificación , Ventrículos Cardíacos/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Linaje , Penetrancia , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/fisiopatología
10.
Europace ; 22(12): 1873-1879, 2020 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-32681178

RESUMEN

AIMS: Women with arrhythmogenic right ventricular cardiomyopathy (ARVC) are at relatively lower risk of ventricular arrhythmias (VAs) than men, but the physical burden associated with pregnancy on VA risk remains insufficiently studied. We aimed to assess the risk of VA in relation to pregnancies in women with ARVC. METHODS AND RESULTS: We included 199 females with definite ARVC (n = 121) and mutation-positive family members without ascertained ARVC diagnosis (n = 78), of whom 120 had at least one childbirth. Ventricular arrhythmia-free survival after the latest childbirth was compared between women with one (n = 20), two (n = 67), and three or more (n = 37) childbirths. Cumulative probability of VA for each pregnancy (n = 261) was assessed from conception through 2 years after childbirth and compared between those pregnancies that occurred before (n = 191) or after (n = 19) ARVC diagnosis and in mutation-positive family members (n = 51). The nulliparous women had lower median age at ARVC diagnosis (38 vs. 42 years, P < 0.001) and first VA (22 vs. 41 years, P < 0.001). Ventricular arrhythmia-free survival after the latest childbirth was not related to the number of pregnancies. No pregnancy-related VA was reported among the family members. Women who gave birth after ARVC diagnosis had elevated risk of VA postpartum (hazard ratio 13.74, 95% confidence interval 2.9-63, P = 0.001), though only two events occurred during pregnancies. CONCLUSION: In women with ARVC, pregnancy was uneventful for the overwhelming majority and the number of prior completed pregnancies was not associated with VA risk. Pregnancy-related VA was primarily related to the phenotypical severity rather than pregnancy itself.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiología , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/epidemiología , Displasia Ventricular Derecha Arritmogénica/genética , Femenino , Humanos , Masculino , Mutación , Embarazo , Modelos de Riesgos Proporcionales , Sistema de Registros
11.
Eur Heart J ; 39(20): 1784-1793, 2018 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-29378019

RESUMEN

Aims: The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. Methods and results: A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). Conclusion: By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.


Asunto(s)
Cardiomiopatías/epidemiología , Cardiomiopatías/terapia , Sistema de Registros , Adulto , Factores de Edad , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/epidemiología , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/terapia , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/terapia , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/epidemiología , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/terapia , Cardiomiopatía Restrictiva/diagnóstico , Cardiomiopatía Restrictiva/epidemiología , Cardiomiopatía Restrictiva/genética , Cardiomiopatía Restrictiva/terapia , Desfibriladores , Manejo de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos
12.
J Cell Sci ; 129(14): 2732-43, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27235420

RESUMEN

Mutation of the LMNA gene, encoding nuclear lamin A and lamin C (hereafter lamin A/C), is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here, we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild-type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A was significantly more dynamic. In in vitro association studies, p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole-genome expression analysis revealed an elevated unfolded protein response (UPR) in cells expressing p.S143P lamin A/C. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of cells expressing mutant lamin further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability.


Asunto(s)
Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Estrés del Retículo Endoplásmico , Lamina Tipo A/metabolismo , Mutación/genética , Biomarcadores/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/ultraestructura , Proteínas Fluorescentes Verdes/metabolismo , Células HeLa , Humanos , Proteínas Mutantes/metabolismo , Agregado de Proteínas , Transfección , Regulación hacia Arriba
13.
Ann Noninvasive Electrocardiol ; 23(6): e12582, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29974557

RESUMEN

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by ventricular repolarization abnormalities and risk of ventricular arrhythmias. Our aim was to study the association between the phenotype and ventricular repolarization dynamics in HCM patients. METHODS: HCM patients with either the MYBPC3-Q1061X or TPM1-D175N mutation (n = 46) and control subjects without mutation and hypertrophy (n = 35) were studied with 24-hr ambulatory ECG recordings by measuring time intervals of rate-adapted QT (QTe), maximal QT, and T-wave apex to wave end (TPE) intervals and the QTe/RR slope. Findings were correlated to specified echocardiographic and cardiac magnetic resonance imaging (CMRI) findings. RESULTS: Rate-adapted QTe interval was progressively longer in HCM patients with decreasing heart rates compared to control subjects (p = 0.020). The degree of hypertrophy correlated with measured QTe values. HCM patients with maximal wall thickness higher than the mean (20.6 mm) had longer maximum QTe and median TPE intervals compared to control subjects and HCM patients with milder hypertrophy (p < 0.001 and p = 0.014, respectively). HCM patients with late gadolinium enhancement (LGE) on CMRI had steeper QTe/RR slopes compared to HCM patients without LGE and control subjects (p = 0.044 and p = 0.001, respectively). LGE was an independent predictor of QTe/RR slope (p = 0.023, B = 0.043). CONCLUSION: Dynamics of ventricular repolarization in HCM are affected by hypertrophy and fibrosis. LGE may confer an independent effect on QT dynamics which may increase the arrhythmogenic potential in HCM.


Asunto(s)
Electrofisiología Cardíaca , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/patología , Electrocardiografía Ambulatoria/métodos , Gadolinio , Imagen por Resonancia Cinemagnética/métodos , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Ecocardiografía Doppler/métodos , Femenino , Fibrosis/diagnóstico por imagen , Fibrosis/patología , Finlandia , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Valores de Referencia , Medición de Riesgo , Índice de Severidad de la Enfermedad
14.
J Electrocardiol ; 51(6): 983-989, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30497761

RESUMEN

OBJECTIVES: The sensitivity and specificity of the conventional 12-lead ECG to identify carriers of hypertrophic cardiomyopathy (HCM) - causing mutations without left ventricular hypertrophy (LVH) has been limited. We assessed the ability of novel electrocardiographic parameters to improve the detection of HCM mutation carriers. METHODS: We studied 140 carriers (G+) of the TPM1-Asp175Asn or MYBPC3-Gln1061X pathogenic variants for HCM: The G+/LVH+ group (n = 98) consisted of mutation carriers with LVH and the G+/LVH- group (n = 42) without LVH. The control group consisted of 30 subjects. The standard 12-lead ECG was comprehensively analyzed and two novel ECG variables were introduced: RV1RV3 and septal remodeling. A subset of 65 individuals underwent cardiac magnetic resonance imaging and 2D strain echocardiography. RESULTS: Conventional major ECG criteria were sensitive (90%) and specific (97%) in identifying G+/LVH+ subjects. RV1RV3 and septal remodeling were more prevalent in the G+/LVH- subjects compared to the control group (33% vs 3%, p = 0.005 and 45% vs 3%, p < 0.001, respectively). The combination of RV1RV3 and Q waves and repolarization abnormalities (QR) differentiated between the G+/LVH- subjects and the control group with a sensitivity of 52% and specificity of 97%. The combination of septal remodeling and QR differentiated between G+/LVH- subjects and the control group with a sensitivity of 64% and specificity of 97%. CONCLUSIONS: The novel ECG-parameters RV1RV3 and septal remodeling were effective in identifying G+/LVH- subjects and could be useful in the diagnostics of new suspected HCM patients and in the screening and follow-up of HCM families.


Asunto(s)
Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Electrocardiografía/métodos , Mutación/genética , Adulto , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Proteínas Portadoras , Medios de Contraste , Ecocardiografía , Femenino , Finlandia , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Tropomiosina
15.
BMC Med Genet ; 18(1): 86, 2017 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-28818065

RESUMEN

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. CASE PRESENTATION: We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands' siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies. CONCLUSIONS: The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica/genética , Desmogleína 2/genética , Anciano , Anciano de 80 o más Años , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Femenino , Corazón/diagnóstico por imagen , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Adulto Joven
16.
J Cardiovasc Magn Reson ; 18(1): 33, 2016 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-27259862

RESUMEN

BACKGROUND: Previous data suggest that mitral valve leaflets are elongated in hypertrophic cardiomyopathy (HCM), and mitral valve leaflet elongation may constitute a primary phenotypic expression of HCM. Our objective was to measure the length of mitral valve leaflets by cardiovascular magnetic resonance (CMR) in subjects with HCM caused by a Finnish founder mutation in the myosin-binding protein C gene (MYBPC3-Q1061X), carriers of the same mutation without left ventricular hypertrophy, as well as in unselected consecutive patients with HCM, and respective controls. METHODS: Anterior mitral valve leaflet (AML) and posterior mitral valve leaflet (PML) lengths were measured by CMR in 47 subjects with the Q1061X mutation in the gene encoding MYBPC3 and in 20 healthy relatives without the mutation. In addition, mitral valve leaflet lengths were measured by CMR in 80 consecutive non-genotyped patients with HCM in CMR and 71 age- and gender-matched healthy subjects. RESULTS: Of the subjects with the MYBPC-Q1016X mutation, 32 had left ventricular hypertrophy (LVH, LV maximal wall thickness ≥ 13 mm in CMR) and 15 had no hypertrophy. PML was longer in patients with the MYBPC3-Q1061X mutation and LVH than in controls of the MYBPC group (12.8 ± 2.8 vs 10.6 ± 1.9 mm, P = 0.013), but the difference between the groups was not statistically significant when PML was indexed for BSA (P = 0.066), or when PML length was adjusted for BSA, age, gender, LV mass and ejection fraction (P = 0.195). There was no significant difference in the PML length in mutation carriers without LVH and controls (11.1 ± 3.4 vs 10.6 ± 1.9, P = 0.52). We found no difference in AML lengths between the MYBPC mutation carriers with or without hypertrophy and controls. In 80 consecutive non-genotyped patients with HCM, there was no difference either in AML or PML lengths in subjects with HCM compared to respective control subjects. CONCLUSIONS: In subjects with HCM caused by the Q1061X mutation in the MYBPC3 gene, the posterior mitral valve leaflets may be elongated, but mitral valve elongation does not constitute primary phenotypic expression of the disease. Instead, elongated mitral valve leaflets seem to be associated with body size and left ventricular remodeling.


Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Imagen por Resonancia Magnética , Válvula Mitral/diagnóstico por imagen , Adolescente , Adulto , Tamaño Corporal , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Proteínas Portadoras/genética , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Finlandia , Predisposición Genética a la Enfermedad , Humanos , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Persona de Mediana Edad , Válvula Mitral/fisiopatología , Mutación , Fenotipo , Valor Predictivo de las Pruebas , Estudios Prospectivos , Volumen Sistólico , Función Ventricular Izquierda , Remodelación Ventricular , Adulto Joven
17.
Eur Heart J ; 36(34): 2327-37, 2015 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-26084686

RESUMEN

AIMS: Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool. METHODS AND RESULTS: Using OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype-phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410× and 99.42% of the nucleotides were sequenced at least 15× read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively. CONCLUSION: Panel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.


Asunto(s)
Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/epidemiología , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Mutación del Sistema de Lectura/genética , Genotipo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Fenotipo , Recurrencia
18.
J Cardiovasc Magn Reson ; 17: 89, 2015 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-26496977

RESUMEN

BACKGROUND: Autosomal dominantly inherited PRKAG2 cardiac syndrome is due to a unique defect of the cardiac cell metabolism and has a distinctive histopathology with excess intracellular glycogen, and prognosis different from sarcomeric hypertrophic cardiomyopathy. We aimed to define the distinct characteristics of PRKAG2 using cardiovascular magnetic resonance (CMR). METHODS: CMR (1.5 T) and genetic testing were performed in two families harboring PRKAG2 mutations. On CMR, segmental analysis of left ventricular (LV) hypertrophy (LVH), function, native T1 mapping, and late gadolinium enhancement (LGE) were performed. RESULTS: Six individuals (median age 23 years, range 16-48; two females) had a PRKAG2 mutation: five with an R302Q mutation (family 1), and one with a novel H344P mutation (family 2). Three of six mutation carriers had LV mass above age and gender limits (203 g/m2, 157 g/m2 and 68 g/m2) and others (with R302Q mutation) normal LV masses. All mutation carriers had LVH in at least one segment, with the median maximal wall thickness of 13 mm (range 11-37 mm). Two R302Q mutation carriers with markedly increased LV mass (203 g/m2 and 157 g/m2) showed a diffuse pattern of hypertrophy but predominantly in the interventricular septum, while other mutation carriers exhibited a non-symmetric mid-infero-lateral pattern of hypertrophy. In family 1, the mutation negative male had a mean T1 value of 963 ms, three males with the R302Q mutation, LVH and no LGE a mean value of 918 ± 11 ms, and the oldest male with the R302Q mutation, extensive hypertrophy and LGE a mean value of 973 ms. Of six mutations carriers, two with advanced disease had LGE with 11 and 22 % enhancement of total LV volume. CONCLUSIONS: PRKAG2 cardiac syndrome may present with eccentric distribution of LVH, involving focal mid-infero-lateral pattern in the early disease stage, and more diffuse pattern but focusing on interventricular septum in advanced cases. In patients at earlier stages of disease, without LGE, T1 values may be reduced, while in the advanced disease stage T1 mapping may result in higher values caused by fibrosis. CMR is a valuable tool in detecting diffuse and focal myocardial abnormalities in PRKAG2 cardiomyopathy.


Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/patología , Imagen por Resonancia Cinemagnética , Mutación , Miocardio/patología , Adolescente , Adulto , Cardiomiopatía Hipertrófica/enzimología , Cardiomiopatía Hipertrófica/fisiopatología , Medios de Contraste , Análisis Mutacional de ADN , Electrocardiografía , Femenino , Fibrosis , Predisposición Genética a la Enfermedad , Humanos , Hipertrofia Ventricular Izquierda/enzimología , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Meglumina , Persona de Mediana Edad , Compuestos Organometálicos , Fenotipo , Valor Predictivo de las Pruebas , Función Ventricular Izquierda , Remodelación Ventricular , Adulto Joven
19.
J Med Internet Res ; 16(12): e282, 2014 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-25498992

RESUMEN

BACKGROUND: Heart failure (HF) patients suffer from frequent and repeated hospitalizations, causing a substantial economic burden on society. Hospitalizations can be reduced considerably by better compliance with self-care. Home telemonitoring has the potential to boost patients' compliance with self-care, although the results are still contradictory. OBJECTIVE: A randomized controlled trial was conducted in order to study whether the multidisciplinary care of heart failure patients promoted with telemonitoring leads to decreased HF-related hospitalization. METHODS: HF patients were eligible whose left ventricular ejection fraction was lower than 35%, NYHA functional class ≥2, and who needed regular follow-up. Patients in the telemonitoring group (n=47) measured their body weight, blood pressure, and pulse and answered symptom-related questions on a weekly basis, reporting their values to the heart failure nurse using a mobile phone app. The heart failure nurse followed the status of patients weekly and if necessary contacted the patient. The primary outcome was the number of HF-related hospital days. Control patients (n=47) received multidisciplinary treatment according to standard practices. Patients' clinical status, use of health care resources, adherence, and user experience from the patients' and the health care professionals' perspective were studied. RESULTS: Adherence, calculated as a proportion of weekly submitted self-measurements, was close to 90%. No difference was found in the number of HF-related hospital days (incidence rate ratio [IRR]=0.812, P=.351), which was the primary outcome. The intervention group used more health care resources: they paid an increased number of visits to the nurse (IRR=1.73, P<.001), spent more time at the nurse reception (mean difference of 48.7 minutes, P<.001), and there was a greater number of telephone contacts between the nurse and intervention patients (IRR=3.82, P<.001 for nurse-induced contacts and IRR=1.63, P=.049 for patient-induced contacts). There were no statistically significant differences in patients' clinical health status or in their self-care behavior. The technology received excellent feedback from the patient and professional side with a high adherence rate throughout the study. CONCLUSIONS: Home telemonitoring did not reduce the number of patients' HF-related hospital days and did not improve the patients' clinical condition. Patients in the telemonitoring group contacted the Cardiology Outpatient Clinic more frequently, and on this way increased the use of health care resources. TRIAL REGISTRATION: Clinicaltrials.gov NCT01759368; http://clinicaltrials.gov/show/NCT01759368 (Archived by WebCite at http://www.webcitation.org/6UFxiCk8Z).


Asunto(s)
Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/enfermería , Cuidados de Enfermería en el Hogar/métodos , Monitoreo Fisiológico/métodos , Teleenfermería/métodos , Femenino , Finlandia , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Autocuidado
20.
Eur Heart J ; 34(19): 1448-58, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23211230

RESUMEN

In 2008, The ESC Working Group on Myocardial and Pericardial Diseases proposed an updated classification of cardiomyopathies based on morphological and functional phenotypes and subcategories of familial/genetic and non-familial/non-genetic disease. In this position statement, we propose a framework for the clinical approach to diagnosis in cardiomyopathies based on the recognition of diagnostic 'red flags' that can be used to guide rational selection of specialized tests including genetic analysis. The basic premise is that the adoption of a cardiomyopathy-specific mindset which combines conventional cardiological assessment with non-cardiac and molecular parameters increases diagnostic accuracy and thus improves advice and treatment for patients and families.


Asunto(s)
Cardiomiopatías/diagnóstico , Edad de Inicio , Arritmias Cardíacas/diagnóstico , Bloqueo Atrioventricular/diagnóstico , Enfermedades Autoinmunes/genética , Cardiomegalia/diagnóstico , Cardiomiopatías/clasificación , Cardiomiopatías/genética , Técnicas de Laboratorio Clínico/métodos , Creatina Quinasa/metabolismo , Diagnóstico por Imagen/métodos , Electrocardiografía , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Infarto del Miocardio/diagnóstico , Paraproteinemias/diagnóstico , Linaje , Fenotipo , Examen Físico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA