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1.
Circulation ; 144(20): 1600-1611, 2021 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-34587765

RESUMEN

BACKGROUND: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. METHODS: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP-related arrhythmogenic cardiomyopathies were used for prognostic comparison. RESULTS: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD. CONCLUSIONS: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.


Asunto(s)
Cardiomiopatías/etiología , Filaminas/genética , Predisposición Genética a la Enfermedad , Variación Genética , Fenotipo , Adulto , Alelos , Cardiomiopatías/diagnóstico , Cardiomiopatías/epidemiología , Cardiomiopatías/terapia , Terapia Combinada , Manejo de la Enfermedad , Ecocardiografía , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pronóstico , Sistema de Registros
2.
Ethn Health ; 26(3): 460-469, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-30303400

RESUMEN

Aims: There are very few studies comparing epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) in different ethnic groups. Previous ethnicity studies have mostly determined OHCA differences between African American and Caucasian populations. The aim of this study was to compare epidemiology, clinical presentation, and outcomes of OHCA between the local Middle Eastern Gulf Cooperation Council (GCC) Arab and the migrant North African populations living in Qatar.Methods: This was a retrospective cohort study of Middle Eastern GCC Arabs and migrant North African patients with presumed cardiac origin OHCA resuscitated by Emergency Medical Services (EMS) in Qatar, between June 2012 and May 2015.Results: There were 285 Middle Eastern GCC Arabs and 112 North African OHCA patients enrolled during the study period. Compared with the local GCC Arabs, univariate analysis showed that the migrant North African OHCA patients were younger and had higher odds of initial shockable rhythm, pre-hospital interventions (defibrillation and amioderone), pre-hospital scene time, and decreased odds of risk factors (hypertension, respiratory disease, and diabetes) and pre-hospital response time. The survival to hospital discharge had greater odds for North African OHCA patients which did not persist after adjustment. Multivariable logistic regression showed that North Africans were associated with lower odds of diabetes (OR 0.48, 95% CI 0.25-0.91, p = 0.03), and higher odds of initial shockable rhythm (OR 2.86, 95% CI 1.30-6.33, p = 0.01) and greater scene time (OR 1.02 95% CI 1.0-1.04, p = 0.02).Conclusions: North African migrant OHCA patients were younger, had decreased risk factors and favourable OHCA rhythm and received greater ACLS interventions with shorter pre-hospital response times and longer scene times leading to better survival.


Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco Extrahospitalario , Árabes , Humanos , Paro Cardíaco Extrahospitalario/epidemiología , Paro Cardíaco Extrahospitalario/terapia , Qatar/epidemiología , Sistema de Registros , Estudios Retrospectivos
3.
Genome Res ; 26(8): 1013-22, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27325115

RESUMEN

Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in Tbr1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of Tbr1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.


Asunto(s)
Trastorno del Espectro Autista/genética , Proteínas de Unión al ADN/genética , Neocórtex/fisiopatología , Neurogénesis/genética , Animales , Trastorno del Espectro Autista/fisiopatología , Modelos Animales de Enfermedad , Exoma/genética , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Ratones , Mutación , Neocórtex/crecimiento & desarrollo , Neuronas/metabolismo , Neuronas/patología , Factores de Riesgo , Proteínas de Dominio T Box
4.
J Anat ; 235(5): 962-976, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31347708

RESUMEN

Myoarchitectural disarray - the multiscalar disorganisation of myocytes, is a recognised histopathological hallmark of adult human hypertrophic cardiomyopathy (HCM). It occurs before the establishment of left ventricular hypertrophy (LVH) but its early origins and evolution around the time of birth are unknown. Our aim is to investigate whether myoarchitectural abnormalities in HCM are present in the fetal heart. We used wild-type, heterozygous and homozygous hearts (n = 56) from a Mybpc3-targeted knock-out HCM mouse model and imaged the 3D micro-structure by high-resolution episcopic microscopy. We developed a novel structure tensor approach to extract, display and quantify myocyte orientation and its local angular uniformity by helical angle, angle of intrusion and myoarchitectural disarray index, respectively, immediately before and after birth. In wild-type, we demonstrate uniformity of orientation of cardiomyocytes with smooth transitions of helical angle transmurally both before and after birth but with traces of disarray at the septal insertion points of the right ventricle. In comparison, heterozygous mice free of LVH, and homozygous mice showed not only loss of the normal linear helical angulation transmural profiles observed in wild-type but also fewer circumferentially arranged myocytes at birth. Heterozygous and homozygous showed more disarray with a wider distribution than in wild-type before birth. In heterozygous mice, disarray was seen in the anterior, septal and inferior walls irrespective of stage, whereas in homozygous mice it extended to the whole LV circumference including the lateral wall. In conclusion, myoarchitectural disarray is detectable in the fetal heart of an HCM mouse model before the development of LVH.


Asunto(s)
Cardiomiopatía Hipertrófica/patología , Corazón Fetal/patología , Corazón/embriología , Miocardio/patología , Animales , Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Ratones , Ratones Noqueados , Miocitos Cardíacos/patología
5.
Circ Res ; 121(7): 722-730, 2017 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-28912179

RESUMEN

In the past 25 years, major advances were achieved in the nosography of cardiomyopathies, influencing the definition and taxonomy of this important chapter of cardiovascular disease. Nearly, 50% of patients dying suddenly in childhood or adolescence or undergoing cardiac transplantation are affected by cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic, restrictive, and noncompacted) and added to update the World Health Organization classification. Myocarditis has also been named inflammatory cardiomyopathy. Extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed establishment of dilated cardiomyopathy as mostly cytoskeleton, force transmission disease; hypertrophic-restrictive cardiomyopathies as sarcomeric, force generation disease; and arrhythmogenic cardiomyopathy as desmosome, cell junction disease. Channelopathies (short and long QT, Brugada, and catecholaminergic polymorphic ventricular tachycardia syndromes) should also be considered cardiomyopathies because of electric myocyte dysfunction. Cardiomyopathies are easily diagnosed but treated only with palliative pharmacological or invasive therapy. Curative therapy, thanks to insights into the molecular pathogenesis, has to target the fundamental mechanisms involved in the onset and progression of these conditions.


Asunto(s)
Cardiomiopatías/clasificación , Cardiomiopatías/epidemiología , Terminología como Asunto , Cardiomiopatías/genética , Cardiomiopatías/terapia , Predisposición Genética a la Enfermedad , Humanos , Miocardio/patología , Fenotipo , Pronóstico , Factores de Riesgo , Disfunción Ventricular
6.
Proc Natl Acad Sci U S A ; 112(37): 11702-7, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26324926

RESUMEN

Generation of distinct cortical projection neuron subtypes during development relies in part on repression of alternative neuron identities. It was reported that the special AT-rich sequence-binding protein 2 (Satb2) is required for proper development of callosal neuron identity and represses expression of genes that are essential for subcerebral axon development. Surprisingly, Satb2 has recently been shown to be necessary for subcerebral axon development. Here, we unravel a previously unidentified mechanism underlying this paradox. We show that SATB2 directly activates transcription of forebrain embryonic zinc finger 2 (Fezf2) and SRY-box 5 (Sox5), genes essential for subcerebral neuron development. We find that the mutual regulation between Satb2 and Fezf2 enables Satb2 to promote subcerebral neuron identity in layer 5 neurons, and to repress subcerebral characters in callosal neurons. Thus, Satb2 promotes the development of callosal and subcerebral neurons in a cell context-dependent manner.


Asunto(s)
Corteza Cerebral/embriología , Proteínas de Unión al ADN/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Factores de Transcripción/metabolismo , Alelos , Animales , Axones/metabolismo , Sitios de Unión , Mapeo Encefálico , Linaje de la Célula , Perfilación de la Expresión Génica , Ratones , Ratones Transgénicos , Prosencéfalo/embriología , ARN Mensajero/metabolismo
7.
Br J Cancer ; 117(4): 503-512, 2017 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-28677687

RESUMEN

BACKGROUND: Tumour-specific radiosensitising treatments may enhance the efficacy of radiotherapy without exacerbating side effects. In this study we determined the radiation response following depletion or inhibition of TOPK, a mitogen-activated protein kinase kinase family Ser/Thr protein kinase that is upregulated in many cancers. METHODS: Radiation response was studied in a wide range of cancer cell lines and normal cells using colony formation assays. The effect on cell cycle progression was assessed and the relationship between TOPK expression and therapeutic efficacy was studied in a cohort of 128 prostate cancer patients treated with radical radiotherapy. RESULTS: TOPK knockdown did not alter radiation response in normal tissues, but significantly enhanced radiosensitivity in cancer cells. This result was recapitulated in TOPK knockout cells and with the TOPK inhibitor, OTS964. TOPK depletion altered the G1/S transition and G2/M arrest in response to radiation. Furthermore, TOPK depletion increased chromosomal aberrations, multinucleation and apoptotic cell death after irradiation. These results suggest a possible role for TOPK in the radiation-induced DNA damage checkpoints. These findings have clinical relevance, as elevated TOPK protein expression was associated with poorer clinical outcomes in prostate cancer patients treated with radical radiotherapy. CONCLUSIONS: This study demonstrates that TOPK disruption may cause tumour-specific radiosensitisation in multiple different tumour types.


Asunto(s)
Puntos de Control del Ciclo Celular , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Neoplasias de la Próstata/radioterapia , Tolerancia a Radiación , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/efectos de la radiación , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/efectos de la radiación , Aberraciones Cromosómicas/efectos de los fármacos , Aberraciones Cromosómicas/efectos de la radiación , Técnicas de Silenciamiento del Gen , Células HCT116 , Células HeLa , Humanos , Masculino , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Neoplasias de la Próstata/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Quinolonas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Tolerancia a Radiación/genética , Tasa de Supervivencia
8.
J Card Fail ; 23(2): 107-112, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27154489

RESUMEN

BACKGROUND: Outcomes of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients after heart transplantation have not been well studied. Diagnostic criteria were established in 1994 and subsequently revised in 2010. We sought to better characterize this population in a national cohort. METHODS: A total of 35,138 heart transplant-only recipients were identified from the United Network for Organ Sharing (UNOS) Thoracic Registry (1994-2011); 73 had ARVC. The non-ARVC group included ischemic cardiomyopathy, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and other. Survival was censored at 12 years. Multivariate Cox proportional hazard regression analysis was adjusted for age, sex, DM, race, ischemia time, dialysis, life support, wait time, and HLA mismatch. RESULTS: There were 73 ARVC and 35,065 non-ARVC patients. The ARVC cohort was associated with less ventricular assist device use (P = .001) and significantly decreased pulmonary arterial and capillary wedge pressures (P < .001). Survivals at 1, 5, and 10 years were, respectively, ARVC 87%, 81%, and 77%, and non-ARVC 87%, 72%, and 53% (log rank P = .07). The ARVC unadjusted hazard ratio for all-cause mortality was 0.59 (95% confidence interval [CI] 0.34-1.04; P = .073). Multivariate analysis yielded a hazard ratio of 0.68 (95% CI 0.35-1.30; P = .25). ARVC survival was similar to restrictive, hypertrophic, and dilated cardiomyopathies and significantly better than ischemic cardiomyopathy. CONCLUSIONS: This is the largest reported series of ARVC after heart transplantation, of which 11% were pediatric. Survival was similar to the non-ARVC cohort, with improved survival over ischemic and restrictive etiologies.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica/mortalidad , Displasia Ventricular Derecha Arritmogénica/cirugía , Causas de Muerte , Trasplante de Corazón/mortalidad , Trasplante de Corazón/métodos , Sistema de Registros , Adulto , Factores de Edad , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Modelos de Riesgos Proporcionales , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Análisis de Supervivencia , Factores de Tiempo , Estados Unidos
9.
Europace ; 19(4): 622-628, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28431055

RESUMEN

AIMS: The differentiation between idiopathic right ventricular outflow tract (RVOT) arrhythmias and early arrhythmogenic right ventricular cardiomyopathy (ARVC) can be challenging. We aimed to assess whether QRS morphological features and coupling interval of ventricular ectopic beats (VEBs) can improve differentiation between the two conditions. METHODS AND RESULTS: Twenty desmosomal-gene mutation carriers (13 females, mean age 43 years) with no or mild ARVC phenotypic expression and 33 age- and sex-matched subjects with idiopathic RVOT arrhythmias were studied. All patients exhibited isolated monomorphic VEBs with left bundle branch block/inferior axis morphology. The predictive value of ectopic QRS morphology and coupling interval was evaluated. Five ectopic QRS features were significantly more common in desmosomal-gene mutation carriers than in idiopathic RVOT-ventricular arrhythmia patients: maximal QRS duration >160 ms (60 vs. 27%, P = 0.02), intrinsicoid deflection time >80 ms (65 vs. 24%, P = 0.01), initial QRS slurring (40 vs. 12%, P = 0.04), QS pattern in lead V1 (90 vs. 36%, P < 0.001), and QRS axis >90° in limb leads (60 vs. 24%, P = 0.01). In the multivariate analysis, intrinsicoid deflection time >80 ms [odds ratio (OR) = 9.9], QS pattern in lead V1 (OR = 28), and QRS axis >90° (OR = 5.7) remained independent predictors of early ARVC. The coupling interval did not differ between the two groups. CONCLUSIONS: In patients with RVOT VEBs and no major electrocardiographic or echocardiographic abnormalities, the ectopic QRS morphology aids in the differential diagnosis between idiopathic RVOT arrhythmias and early ARVC.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica/diagnóstico , Diagnóstico Precoz , Electrocardiografía/métodos , Taquicardia Ventricular/diagnóstico , Complejos Prematuros Ventriculares/diagnóstico , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Obstrucción del Flujo Ventricular Externo/diagnóstico
10.
Europace ; 18(4): 610-6, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25825460

RESUMEN

AIMS: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a genetically determined disorder, mostly caused by mutations in genes encoding desmosomal proteins. We evaluated phenotype/genotype characteristics to predict the risk for the first major arrhythmic event in desmosomal-mutation-associated ARVC families. METHODS AND RESULTS: A cohort of 105 desmosomal-mutation carriers belonging to 39 consecutive ARVC families was evaluated. Serial clinical work-up consisting of history, physical examination, 12-lead/signal-averaged/24 h ambulatory ECG, and two-dimensional echocardiography was performed every 6-12 months. The predictive value of gender and genotype for the first major arrhythmic event was investigated within the cohort using time-to-event analysis. ECG/echocardiographic features were evaluated at the time of event and associated with the outcome using an age-matched nested case-control study within the cohort. Forty-three (41%) participants experienced the primary arrhythmic outcome at median age of 29 (21-46) years. The first event was sustained ventricular tachycardia in 31 and sudden cardiac death in 12. Definite diagnosis according to the 2010 Task Force criteria, showed 57% positive and 100% negative predictive value for the occurrence of arrhythmic outcome. Male gender (hazard ratio = 3.26, 95%CI, 1.63-6.51), predicted the first major arrhythmic event, independently of genotype, on multivariable analysis. Repolarization abnormalities and left-ventricular dysfunction independently associated with clinical disease profile at the time of event. CONCLUSION: Male gender, independently of genotype is an arrhythmic risk predictor in ARVC-associated desmosomal-mutation carriers. Repolarization abnormalities and left-ventricular dysfunction are important components of the first event-associated clinical disease profile.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica/genética , Muerte Súbita Cardíaca/etiología , Mutación , Taquicardia Ventricular/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/mortalidad , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Ecocardiografía , Electrocardiografía Ambulatoria , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Grecia , Herencia , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Linaje , Fenotipo , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/mortalidad , Taquicardia Ventricular/fisiopatología , Factores de Tiempo , Función Ventricular Izquierda , Adulto Joven
11.
Europace ; 18(6): 888-96, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26498160

RESUMEN

AIMS: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. METHODS AND RESULTS: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. CONCLUSION: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.


Asunto(s)
Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Exoma/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Adolescente , Adulto , Autopsia , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Muerte Súbita Cardíaca/prevención & control , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Canal de Sodio Activado por Voltaje NAV1.5/genética , Linaje , Análisis de Secuencia de ADN , Reino Unido , Adulto Joven
12.
Eur Heart J ; 36(44): 3061-9, 2015 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-26333366

RESUMEN

AIMS: The REGENERATE-DCM trial is the first phase II randomized, placebo-controlled trial aiming to assess if granulocyte colony-stimulating factor (G-CSF) administration with or without adjunctive intracoronary (IC) delivery of autologous bone marrow-derived cells (BMCs) improves global left ventricular (LV) function in patients with dilated cardiomyopathy (DCM) and significant cardiac dysfunction. METHODS AND RESULTS: Sixty patients with DCM and left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy were randomized equally into four groups: peripheral placebo (saline), peripheral G-CSF, peripheral G-CSF and IC serum, and peripheral G-CSF and IC BMC. All patients, except the peripheral placebo group, received 5 days of G-CSF. In the IC groups, this was followed by bone marrow harvest and IC infusion of cells or serum on Day 6. The primary endpoint was LVEF change from baseline to 3 months, determined by advanced cardiac imaging. At 3 months, peripheral G-CSF combined with IC BMC therapy was associated with a 5.37% point increase in LVEF (38.30% ± 12.97 from 32.93% ± 16.46 P = 0.0138), which was maintained to 1 year. This was associated with a decrease in NYHA classification, reduced NT-pro BNP, and improved exercise capacity and quality of life. No significant change in LVEF was seen in the remaining treatment groups. CONCLUSION: This is the first randomized, placebo-controlled trial with a novel combination of G-CSF and IC cell therapy that demonstrates an improvement in cardiac function, symptoms, and biochemical parameters in patients with DCM.


Asunto(s)
Células Madre Adultas/trasplante , Trasplante de Médula Ósea/métodos , Cardiomiopatía Dilatada/terapia , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Trasplante de Células Madre/métodos , Cardiomiopatía Dilatada/fisiopatología , Terapia Combinada/métodos , Tolerancia al Ejercicio/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/metabolismo , Fragmentos de Péptidos/metabolismo , Calidad de Vida , Volumen Sistólico/fisiología , Resultado del Tratamiento
14.
Circulation ; 129(16): 1637-49, 2014 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-24619464

RESUMEN

BACKGROUND: Recent efforts have focused on improving the specificity of the European Society of Cardiology (ESC) criteria for ECG interpretation in athletes. These criteria are derived predominantly from white athletes (WAs) and do not account for the effect of Afro-Caribbean ethnicity or novel research questioning the relevance of several isolated ECG patterns. We assessed the impact of the ESC criteria, the newly published Seattle criteria, and a group of proposed refined criteria in a large cohort of black athletes (BAs) and WAs. METHODS AND RESULTS: Between 2000 and 2012, 1208 BAs were evaluated with history, examination, 12-lead ECG, and further investigations as appropriate. ECGs were retrospectively analyzed according to the ESC recommendations, Seattle criteria, and proposed refined criteria which exclude several specific ECG patterns when present in isolation. All 3 criteria were also applied to 4297 WAs and 103 young athletes with hypertrophic cardiomyopathy. The ESC recommendations raised suspicion of a cardiac abnormality in 40.4% of BAs and 16.2% of WAs. The Seattle criteria reduced abnormal ECGs to 18.4% in BAs and 7.1% in WAs. The refined criteria further reduced abnormal ECGs to 11.5% in BAs and 5.3% in WAs. All 3 criteria identified 98.1% of athletes with hypertrophic cardiomyopathy. Compared with ESC recommendations, the refined criteria improved specificity from 40.3% to 84.2% in BAs and from 73.8% to 94.1% in WAs without compromising the sensitivity of the ECG in detecting pathology. CONCLUSION: Refinement of current ECG screening criteria has the potential to significantly reduce the burden of false-positive ECGs in athletes, particularly BAs.


Asunto(s)
Atletas , Población Negra , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/fisiopatología , Electrocardiografía/normas , Población Blanca , Adolescente , Adulto , Población Negra/etnología , Cardiomiopatía Hipertrófica/etnología , Electrocardiografía/métodos , Femenino , Humanos , Masculino , Estudios Retrospectivos , Encuestas y Cuestionarios , Población Blanca/etnología , Adulto Joven
15.
Radiology ; 277(3): 707-15, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26069924

RESUMEN

PURPOSE: To quantitatively determine the population variation and relationship of left ventricular (LV) trabeculation to LV function, structure, and clinical variables. MATERIALS AND METHODS: This HIPAA-compliant multicenter study was approved by institutional review boards of participating centers. All participants provided written informed consent. Participants from the Multi-Ethnic Study of Atherosclerosis with cardiac magnetic resonance (MR) data were evaluated to quantify LV trabeculation as a fractal dimension (FD). Entire cohort participants free of cardiac disease, hypertrophy, hypertension, and diabetes were stratified by body mass index (BMI) into three reference groups (BMI <25 kg/m(2); BMI ≥25 kg/m(2) to <30 kg/m(2); and BMI ≥30 kg/m(2)) to explore maximal apical FD (FDMaxApical). Multivariable linear regression models determined the relationship between FD and other parameters. RESULTS: Included were 2547 participants (mean age, 68.7 years ± 9.1 [standard deviation]; 1211 men). FDMaxApical are in arbitrary units. FDMaxApical reference ranges for BMI 30 kg/m(2) or greater (n = 163), 25 kg/m(2) or greater to less than 30 kg/m(2) (n = 206), and less than 25 kg/m(2) (n = 235) were 1.203 ± 0.06 (95% confidence interval: 1.194, 1.212), 1.194 ± 0.06 (95% confidence interval: 1.186, 1.202), and 1.169 ± 0.05 (95% confidence interval: 1.162, 1.176), respectively. In the entire cohort, adjusted for anthropometrics, trabeculation was higher in African American participants (standardized ß [sß] = 0.09; P ≤ .001) and Hispanic participants (sß = 0.05; P = .013) compared with white participants and was also higher in African American participants compared with Chinese American participants (sß = 0.08; P = .01), and this persisted after adjustment for hypertension and LV size. Hypertension (sß = 0.07; P < .001), LV mass (sß = 0.22; P < .001), and wall thickness (sß = 0.27; P < .001) were positively associated with FDMaxApical even after adjustment. In the group with BMIs less than 25 kg/m(2), Chinese American participants had less trabeculation than white participants (sß = -0.15; P = .032). CONCLUSION: Fractal analysis of cardiac MR imaging data measures endocardial complexity, which helps to differentiate normal from abnormal trabecular patterns in healthy versus diseased hearts. Trabeculation is influenced by race and/or ethnicity and, more importantly, by cardiac loading conditions and comorbidities. Clinicians who interpret cine MR imaging data should expect slightly less endocardial complexity in Chinese American patients and more in African American patients, Hispanic patients, hypertensive patients, and those with hypertrophy.


Asunto(s)
Aterosclerosis/patología , Miocardio/patología , Negro o Afroamericano , Antropometría , Asiático , Etnicidad , Variación Genética , Ventrículos Cardíacos , Hispánicos o Latinos , Humanos , Imagen por Resonancia Magnética , Miocardio/citología , Población Blanca
16.
J Cardiovasc Electrophysiol ; 26(11): 1204-1210, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26183028

RESUMEN

INTRODUCTION: Epsilon waves are hallmark features of arrhythmogenic cardiomyopathy (ACM) but information about their clinical significance is variable. We evaluated epsilon wave prevalence, characteristics, and their clinical significance in an ACM population. METHODS AND RESULTS: Eighty-six unselected patients fulfilling the 2010 Task Force criteria were enrolled. Seventy-six of them were carriers of desmosomal mutations. All subjects were serially evaluated with standard 12-lead ECG and 2-dimensional echocardiography. Epsilon waves were evaluated in all precordial and inferior leads. Novel parameters assessed included their duration and precordial/inferior lead extension. Twenty-five subjects (29%) had epsilon waves that were present in lead V3 and beyond in 9, and in the inferior leads in 7. Epsilon waves were associated with right ventricular outflow tract (RVOT) (P = 0.001) but not RV posterior wall (P = 0.21), RV apex (P = 0.30), or left ventricular (P = 0.94) wall motion abnormalities. Patients with epsilon waves had increased RVOT diameter (P < 0.0001). Extension of epsilon waves in lead V3 and beyond was associated with increased epsilon wave duration (P = 0.002) and RVOT diameter (P = 0.04). The duration of epsilon waves was positively correlated with RVOT diameter (r = 0.70, P = 0.0001). Epsilon waves were also associated with episodes of sustained ventricular tachycardia (P = 0.004) but not with heart failure (P = 0.41) or sudden cardiac death (P = 0.31). CONCLUSION: Detection of epsilon waves on 12-lead ECG reflects significant RVOT involvement, which was associated with episodes of sustained ventricular tachycardia but not sudden cardiac death.

17.
J Cardiovasc Magn Reson ; 17: 64, 2015 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-26219660

RESUMEN

BACKGROUND: Sarcomeric gene mutations cause hypertrophic cardiomyopathy (HCM). In gene mutation carriers without left ventricular (LV) hypertrophy (G + LVH-), subclinical imaging biomarkers are recognized as predictors of overt HCM, consisting of anterior mitral valve leaflet elongation, myocardial crypts, hyperdynamic LV ejection fraction, and abnormal apical trabeculation. Reverse curvature of the interventricular septum (into the LV) is characteristic of overt HCM. We aimed to assess LV septal convexity in subclinical HCM. METHODS: Cardiovascular magnetic resonance was performed on 36 G + LVH- individuals (31 ± 14 years, 33 % males) with a pathogenic sarcomere mutation, and 36 sex and age-matched healthy controls (33 ± 12 years, 33 % males). Septal convexity (SCx) was measured in the apical four chamber view perpendicular to a reference line connecting the mid-septal wall at tricuspid valve insertion level and the apical right ventricular insertion point. RESULTS: Septal convexity was increased in G + LVH- compared to controls (maximal distance of endocardium to reference line: 5.0 ± 2.5 mm vs. 1.6 ± 2.4 mm, p ≤ 0.0001). Expected findings occurred in G + LVH- individuals: longer anterior mitral valve leaflet (23.5 ± 3.0 mm vs. 19.9 ± 3.1 mm, p ≤ 0.0001), higher relative wall thickness (0.31 ± 0.05 vs. 0.29 ± 0.04, p ≤ 0.05), higher LV ejection fraction (70.8 ± 4.3 % vs. 68.3 ± 4.4 %, p ≤ 0.05), and smaller LV end-systolic volume index (21.4 ± 4.4 ml/m(2) vs. 23.7 ± 5.8 ml/m(2), p ≤ 0.05). Other morphologic measurements (LV angles, sphericity index, and eccentricity index) were not different between G + LVH- and controls. CONCLUSIONS: Septal convexity is an additional previously undescribed feature of subclinical HCM.


Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Ventrículos Cardíacos/patología , Imagen por Resonancia Cinemagnética , Adolescente , Adulto , Enfermedades Asintomáticas , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Cardiomiopatía Hipertrófica/fisiopatología , Estudios de Casos y Controles , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Valor Predictivo de las Pruebas , Volumen Sistólico , Función Ventricular Izquierda , Adulto Joven
18.
Biochem J ; 462(1): 133-42, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-24912595

RESUMEN

The KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene encodes the Kv7.1 potassium channel which forms a complex with KCNE1 (potassium voltage-gated channel Isk-related family member 1) in the human heart to produce the repolarizing IKs (slow delayed rectifier potassium current). Mutations in KCNQ1 can perturb IKs function and cause LQT1 (long QT syndrome type 1). In LQT1, compound mutations are relatively common and are associated with increased disease severity. LQT1 compound mutations have been shown to increase channel dysfunction, but whether other disease mechanisms, such as defective channel trafficking, contribute to the increase in arrhythmic risk has not been determined. Using an imaging-based assay we investigated the effects of four compound heterozygous mutations (V310I/R594Q, A341V/P127T, T391I/Q530X and A525T/R518X), one homozygous mutation (W248F) and one novel compound heterozygous mutation (A178T/K422fs39X) (where fs denotes frameshift) on channel trafficking. By analysing the effects in the equivalent of a homozygous, heterozygous and compound heterozygous condition, we identify three different types of behaviour. A341V/P127T and W248F/W248F had no effect, whereas V310I/R594Q had a moderate, but not compound, effect on channel trafficking. In contrast, T391I/Q530X, A525T/R518X and A178T/K422fs39X severely disrupted channel trafficking when expressed in compound form. In conclusion, we have characterized the disease mechanisms for six LQT1 compound mutations and report that, for four of these, defective channel trafficking underlies the severe clinical phenotype.


Asunto(s)
Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/genética , Canales de Potasio con Entrada de Voltaje/genética , Animales , Arritmias Cardíacas/etiología , Células CHO , Cricetulus , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Canal de Potasio KCNQ1/fisiología , Síndrome de QT Prolongado/complicaciones , Síndrome de QT Prolongado/fisiopatología , Mutación , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/metabolismo
20.
Eur Heart J ; 35(30): 2010-20, 2014 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-24126876

RESUMEN

AIMS: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death (SCD) in young adults. Current risk algorithms provide only a crude estimate of risk and fail to account for the different effect size of individual risk factors. The aim of this study was to develop and validate a new SCD risk prediction model that provides individualized risk estimates. METHODS AND RESULTS: The prognostic model was derived from a retrospective, multi-centre longitudinal cohort study. The model was developed from the entire data set using the Cox proportional hazards model and internally validated using bootstrapping. The cohort consisted of 3675 consecutive patients from six centres. During a follow-up period of 24 313 patient-years (median 5.7 years), 198 patients (5%) died suddenly or had an appropriate implantable cardioverter defibrillator (ICD) shock. Of eight pre-specified predictors, age, maximal left ventricular wall thickness, left atrial diameter, left ventricular outflow tract gradient, family history of SCD, non-sustained ventricular tachycardia, and unexplained syncope were associated with SCD/appropriate ICD shock at the 15% significance level. These predictors were included in the final model to estimate individual probabilities of SCD at 5 years. The calibration slope was 0.91 (95% CI: 0.74, 1.08), C-index was 0.70 (95% CI: 0.68, 0.72), and D-statistic was 1.07 (95% CI: 0.81, 1.32). For every 16 ICDs implanted in patients with ≥4% 5-year SCD risk, potentially 1 patient will be saved from SCD at 5 years. A second model with the data set split into independent development and validation cohorts had very similar estimates of coefficients and performance when externally validated. CONCLUSION: This is the first validated SCD risk prediction model for patients with HCM and provides accurate individualized estimates for the probability of SCD using readily collected clinical parameters.


Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Muerte Súbita Cardíaca/prevención & control , Adulto , Cardiomiopatía Hipertrófica/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Tamaño de la Muestra
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