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1.
Eur Heart J ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33825853

RESUMO

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

2.
Eur J Heart Fail ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33826207

RESUMO

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

4.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33642254

RESUMO

INTRODUCTION AND OBJECTIVES: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33538296

RESUMO

OBJECTIVES: Our goal was to define characteristic patterns of 18F-fluorodeoxyglucose in non-infected patients with ascending aortic prosthetic grafts during the first year after surgery. METHODS: 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed at 3, 6 and 12 months postoperatively in 26 uninfected patients. Clinical, analytical and microbiological (blood culture) assessments were performed to confirm the absence of infection. FDG uptake intensity [measured through maximum standardized uptake values (SUVmax) and the target-to-background ratio] and distribution patterns were obtained. Models of generalized estimating equations were used to assess the evolution of the SUVmax over time. The results were compared to those in our endocarditis-over-ascending-aortic-graft series database. The receiver operating characteristic curves of the control group and the 12-month group were assessed. RESULTS: All patients showed increased uptake in all areas. The uptake pattern was heterogeneous in 47.4%, 43.5% and 42.3% at 3, 6 and 12 months. The means and standard deviations of the SUVmax in the graft were 4.80 (±0.99), 4.28 (±0.88) and 4.14 (±0.87) at 3, 6 and 12 months after surgery. A comparison of all values obtained in the 6th and 12th months compared to those from the 3rd month revealed a slow decrease that may persist after the first year. The cut-off value of SUVmax of 4.24 had an overall sensitivity of 84.6% and specificity of 57.7% for patients seen at 12 months. CONCLUSIONS: Non-infected ascending aortic grafts showed no predominant uptake pattern; they also showed increased 18F-fluorodeoxyglucose activity that could persist beyond the first year. Caution is therefore recommended when interpreting PET/CT images obtained during the first year after surgery.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33594661

RESUMO

PURPOSE: Implantable cardiac defibrillator (ICD) is the only definitive therapy for prevention of sudden cardiac death in hypertrophic cardiomyopathy (HCM). Conventional transvenous ICDs can provide cardiac pacing unlike new subcutaneous ICD, but the usefulness of cardiac pacing in HCM patients is not well defined. We sought to assess the usefulness of ICD pacing in HCM. METHODS: We retrospectively analyzed 93 HCM patients who had undergone ICD implantation at our center. Usefulness of pacing was defined as follows: 1) need of pacing due to bradycardia or AV conduction disturbances, 2) improvement of LV outflow tract obstruction by sequential AV pacing, 3) need for CRT pacing, or 4) successful antitachycardia pacing without a subsequent shock. Independent predictors of useful pacing were investigated by multivariable analysis. RESULTS: During a mean follow-up of 91.3 ± 5.5 months, 43 patients (46.2%) reached the composite endpoint. Independent predictors of pacing usefulness were older age (HR 1.36; 95%CI: 1.088-1.709; p=0.007) and NYHA functional class ≥ II (HR 2.15; 95%CI: 1.083-4.301; p=0.029). Twenty-eight (30.1%) patients had appropriate ICD interventions, triggered by a monomorphic ventricular tachycardia (MVT) in 22 of them (78.5%). In 17 individuals with MVT (77%), antitachycardia pacing successfully treated MVT. CONCLUSIONS: In our HCM series of patients with ICD, 46% of individuals benefitted from cardiac pacing. MVT were documented in nearly 80% of the patients with ventricular arrhythmias and antitachycardia pacing successfully treated them in 77% of cases.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33474682

RESUMO

Identification of Anderson-Fabry disease (AFD) in cardiac patients has been restricted so far to patients with left ventricular hypertrophy. Coronary microvascular dysfunction has been described in AFD with and without cardiac hypertrophy and may represent the only manifestation in AFD patients, offering a possible earlier diagnosis. We studied the prevalence of AFD in 663 patients with chest pain with normal or non-obstructive coronary arteries. The overall prevalence of AFD in this cohort was only 0.15% (1/663). AFD is not a frequent cause of chest pain without obstructive coronary artery disease and screening efforts should not be conducted in this patient population.

8.
Eur Heart J ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33156912

RESUMO

AIMS: The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups. METHODS AND RESULTS: We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping. CONCLUSION: The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.

9.
Med Clin (Barc) ; 2020 Oct 30.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33138983

RESUMO

Transthyretin (TTR) cardiac amyloidosis is a severe, progressive, infiltrative disease caused by the deposition of TTR at cardiac level. It may be due to a genetic alteration in its hereditary form (ATTRv) or as a consequence of an age-related degenerative process (ATTRwt). Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that ATTR is more frequent than traditionally considered and that it is particularly relevant in patients over 65 years with heart failure or with aortic stenosis. With the appearance of several treatment options capable of modifying the natural history of ATTR, it is necessary for clinicians to be familiar with the diagnostic process and treatment of this disease. This review will cover the clinical spectrum of presentation of ATTR, its diagnosis and treatment.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33151750

RESUMO

Background - The X-linked Danon disease (DD) manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease (DD) in cardiomyopathy centers throughout Europe. Methods - Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results - The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 yr. in males and 2-65 in females. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in males but not in females. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of males (who had LVEF 34±11%) and 59% of females (LVEF 28±13%). The risk of arrhythmia and heart failure (HF) were comparable among genders. The age of first HF hospitalization was lower in males (18 ± 6 vs. 28 ±17 yr., p<0.003). HF was the leading cause of death (10/17, 59%), and LV systolic dysfunction predicted an adverse outcome. Eight males and 8 females (28%) underwent heart transplantation or received a left ventricular assist device (LVAD). Our cohort suggests better prognosis of female compared to male heart transplant recipients. Conclusions - DD presents earlier in males than females and runs a malignant course in both genders, due to cardiac complications. Cardiomyopathy features: heart failure and arrhythmia, are similar among the genders. Clinical diagnosis and management is extremely challenging in females due to phenotypic diversity and absence of extracardiac manifestations.

11.
Am J Cardiovasc Dis ; 10(4): 350-355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224582

RESUMO

BACKGROUND: Urinary sodium excretion predicts long-term adverse events after discharge in patients with acute heart failure (AHF). The role of natriuresis as an early marker of poor diuretic response during an AHF episode has been scarcely investigated. We sought to evaluate whether early natriuresis or its change during heart failure hospitalization is associated with the development of in-hospital diuretic resistance (DR). METHODS: This was a prospective, observational single center study of consecutive patients with AHF. Urine electrolytes were estimated from a spot urine sample within the first 6 hours following the first diuretic dose and 48 hours after admission. In-hospital DR was defined as poor diuretic response based on diuretic efficiency metrics and persistent congestion despite an intensive diuretic protocol. RESULTS: Between January and December 2018, 143 patients were admitted for AHF. Of these, 102 fulfilled the inclusion criteria (60% males, median age 77 years [interquartile range [IQR]: 69-83), and 20 patients (19.6%) met the definition of DR. Early natriuresis was lower in patients with DR than in non-resistant patients (46 mEq/L [IQR: 38.5-80.0] vs 97.5 mEq/L [IQR: 70.5-113.5], P<0.001). Urinary sodium <50 mEq/L increased the risk of developing in-hospital DR (risk ratio: 5.011 [95% confidence interval 2.408-10.429], P<0.001). The area under the receiver operating characteristic curve for early natriuresis to predict DR was 0.791 (95% confidence interval 0.681-0.902, P<0.001). CONCLUSIONS: Initial natriuresis can predict in-hospital DR. Patients with urinary sodium <50 mEq/L have an increased risk of early resistance to diuretic treatment.

12.
Rev. esp. cardiol. (Ed. impr.) ; 73(11): 902-909, nov. 2020. tab, graf
Artigo em Espanhol | IBECS-Express | IBECS | ID: ibc-ET1-6955

RESUMO

INTRODUCCIÓN Y OBJETIVOS: La endocarditis infecciosa (EI) es una enfermedad compleja con elevada mortalidad. La evaluación pronóstica es esencial en el tratamiento de la enfermedad; sin embargo, las guías internacionales no aportan una evaluación objetiva del riesgo individual. Se desarrolló un modelo predictivo de mortalidad hospitalaria en EI izquierda combinando las variables pronósticas propuestas por la guía europea. MÉTODOS: Se utilizaron 2 cohortes prospectivas de pacientes con EI izquierda. La cohorte 1 (n=1.002) se aleatorizó 2:1 para obtener 2 muestras: muestra de derivación (n=688) y muestra de validación interna (n=314). La cohorte 2 (n=133) se utilizó para la validación externa. RESULTADOS: El modelo incluyó edad, endocarditis protésica, comorbilidades, insuficiencia cardiaca, insuficiencia renal, shock séptico, Estafilococo aureus, hongos, complicaciones perianulares, disfunción ventricular y vegetaciones como predictores independientes de mortalidad hospitalaria. El modelo mostró buena capacidad discriminativa (área bajo la curva ROC=0,855; IC95%, 0,825-0,885) y calibración (p valor test Hosmer-Lemeshow=0,409) que se ratificaron en la validación interna (área bajo curva ROC=0,823; IC95%, 0,774-0,873) y externa (área bajo curva ROC=0,753; IC95%, 0,659-0,847). Para la muestra de validación interna (mortalidad 29,9%) el modelo predijo una mortalidad de 30,7% (IC95%, 27,7-33,7) y para la muestra de validación externa (mortalidad 27,1%) 26,4% (IC95%, 22,2-30,5). CONCLUSIONES: Se presenta un modelo predictivo de mortalidad hospitalaria en EII basado en las variables pronósticas propuestas por la guía europea de EI y con alta capacidad discriminativa


INTRODUCTION AND OBJECTIVES: Infective endocarditis (IE) is a complex disease with high in-hospital mortality. Prognostic assessment is essential to select the most appropriate therapeutic approach; however, international IE guidelines do not provide objective assessment of the individual risk in each patient. We aimed to design a predictive model of in-hospital mortality in left-sided IE combining the prognostic variables proposed by the European guidelines. METHODS: Two prospective cohorts of consecutive patients with left-sided IE were used. Cohort 1 (n=1002) was randomized in a 2:1 ratio to obtain 2 samples: an adjustment sample to derive the model (n=688), and a validation sample for internal validation (n=314). Cohort 2 (n=133) was used for external validation. RESULTS: The model included age, prosthetic valve IE, comorbidities, heart failure, renal failure, septic shock, Staphylococcus aureus, fungi, periannular complications, ventricular dysfunction, and vegetations as independent predictors of in-hospital mortality. The model showed good discrimination (area under the ROC curve=0.855; 95%CI, 0.825-0.885) and calibration (P value in Hosmer-Lemeshow test=0.409), which were ratified in the internal (area under the ROC curve=0.823; 95%CI, 0.774-0.873) and external validations (area under the ROC curve=0.753; 95%CI, 0.659-0.847). For the internal validation sample (observed mortality: 29.9%) the model predicted an in-hospital mortality of 30.7% (95%CI, 27.7-33.7), and for the external validation cohort (observed mortality: 27.1%) the value was 26.4% (95%CI, 22.2-30.5). CONCLUSIONS: A predictive model of in-hospital mortality in left-sided IE based on the prognostic variables proposed by the European Society of Cardiology IE guidelines has high discriminatory ability

13.
Physiol Genomics ; 52(12): 563-574, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33044885

RESUMO

Calcific aortic valve disease (CAVD) is a significant cause of illness and death worldwide. Identification of early predictive markers could help optimize patient management. RNA-sequencing was carried out on human fetal aortic valves at gestational weeks 9, 13, and 22 and on a case-control study with adult noncalcified and calcified bicuspid and tricuspid aortic valves. In dimension reduction and clustering analyses, diseased valves tended to cluster with fetal valves at week 9 rather than normal adult valves, suggesting that part of the disease program might be due to reiterated developmental processes. The analysis of groups of coregulated genes revealed predominant immune-metabolic signatures, including innate and adaptive immune responses involving lymphocyte T-cell metabolic adaptation. Cytokine and chemokine signaling, cell migration, and proliferation were all increased in CAVD, whereas oxidative phosphorylation and protein translation were decreased. Discrete immune-metabolic gene signatures were present at fetal stages and increased in adult controls, suggesting that these processes intensify throughout life and heighten in disease. Cellular stress response and neurodegeneration gene signatures were aberrantly expressed in CAVD, pointing to a mechanistic link between chronic inflammation and biological aging. Comparison of the valve RNA-sequencing data set with a case-control study of whole blood transcriptomes from asymptomatic individuals with early aortic valve calcification identified a highly predictive gene signature of CAVD and of moderate aortic valve calcification in overtly healthy individuals. These data deepen and broaden our understanding of the molecular basis of CAVD and identify a peripheral blood gene signature for the early detection of aortic valve calcification.

14.
Eur J Heart Fail ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33070419

RESUMO

AIMS: Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose. METHODS AND RESULTS: In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval (CI): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo. CONCLUSION: Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80 mg as the optimal dose. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01994889; NCT02791230.

15.
Circ Heart Fail ; 13(10): e006832, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32964742

RESUMO

BACKGROUND: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. METHODS: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). RESULTS: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). CONCLUSIONS: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.

16.
Lancet ; 396(10253): 759-769, 2020 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-32871100

RESUMO

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.


Assuntos
Benzilaminas/uso terapêutico , Miosinas Cardíacas/antagonistas & inibidores , Cardiomiopatia Hipertrófica/tratamento farmacológico , Uracila/análogos & derivados , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Benzilaminas/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiomiopatia Hipertrófica/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Método Duplo-Cego , Tolerância ao Exercício/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Avaliação de Resultados da Assistência ao Paciente , Uracila/efeitos adversos , Uracila/uso terapêutico
17.
J Am Coll Cardiol ; 76(2): 186-197, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32646569

RESUMO

BACKGROUND: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

18.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32616434

RESUMO

INTRODUCTION AND OBJECTIVES: According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) <45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria. METHODS: The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure. RESULTS: We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF <45% (P=.001) and NSVT (P <.001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF <45% (P <.001). CONCLUSIONS: In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF <45%. Therefore, female carriers of missense variants with either NSVT or LVEF <45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis.

19.
Rev. esp. cardiol. (Ed. impr.) ; 73(7): 561-568, jul. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-197836

RESUMO

INTRODUCCIÓN Y OBJETIVOS: En pacientes con insuficiencia cardiaca y fracción de eyección reducida (IC-FEr), se ha demostrado en ensayos clínicos que diferentes terapias reducen la mortalidad, pero hay pocos datos de la práctica real acerca del efecto en los distintos tipos de muerte. MÉTODOS: Se estudió a 2.351 pacientes ambulatorios con IC-FEr (FE <40%) procedentes de los registros prospectivos multicéntricos MUSIC (n=641, años 2003-2004) y REDINSCOR I (n=1.710, años 2007-2011). Las variables se registraron a la inclusión, y el seguimiento fue de 4 años. Un comité independiente adjudicó la mortalidad y sus causas. RESULTADOS: Los pacientes en el registro más contemporáneo recibieron con mayor frecuencia bloqueadores beta (el 85 frente al 71%; p <0,001), antialdosterónicos (el 64 frente al 44%; p <0,001), desfibrilador automático implantable (el 19 frente al 2%; p <0,001) y resincronización (el 7,2 frente al 4,8%; p = 0,04). La población más contemporánea presentó menos muerte súbita (el 6,8 frente al 11,4%; p <0,001). Tras emparejar por puntuación de propensión, se obtuvieron 2 poblaciones comparables que solo diferían en los tratamientos (575 frente a 575 pacientes): la población más contemporánea presentó menor riesgo de muerte total (HR=0,70; IC95%, 0,57-0,87; p = 0,001) y de muerte súbita (sHR=0,46; IC95%, 0,30-0,70; p <0,001), con una tendencia de muerte por IC (sHR=0,73; IC95%, 0,53-1,01; p = 0,059) y sin diferencias por otras causas (sHR=1,17; IC95%, 0,78-1,75; p = 0,445), independientemente de la clase funcional. CONCLUSIONES: En pacientes ambulatorios con IC-FEr, la mejora terapéutica se asoció con un menor riesgo de muerte, principalmente debido a la significativa reducción de las muertes súbitas


INTRODUCTION AND OBJECTIVES: In patients with heart failure and reduced ejection fraction (HFrEF), several therapies have been proven to reduce mortality in clinical trials. However, there are few data on the effect of the use of evidence-based therapies on causes of death in clinical practice. METHODS: This study included 2351 outpatients with HFrEF (< 40%) from 2 multicenter prospective registries: MUSIC (n=641, period: 2003-2004) and REDINSCOR I (n=1710, period: 2007-2011). Variables were recorded at inclusion and all patients were followed-up for 4 years. Causes of death were validated by an independent committee. RESULTS: Patients in REDINSCOR I more frequently received beta-blockers (85% vs 71%; P <.001), mineralocorticoid antagonists (64% vs 44%; P <.001), implantable cardioverter-defibrillators (19% vs 2%; P <.001), and resynchronization therapy (7.2% vs 4.8%; P=.04). In these patients, sudden cardiac death was less frequent than in those in MUSIC (6.8% vs 11.4%; P <.001). After propensity score matching, we obtained 2 comparable populations differing only in treatments (575 vs 575 patients). In patients in REDINSCOR I, we found a lower risk of total mortality (HR, 0.70; 95%CI, 0.57-0.87; P=.001) and sudden cardiac death (sHR, 0.46; 95%CI, 0.30-0.70; P <.001), and a trend toward lower mortality due to end-stage HF (sHR, 0.73; 95%CI, 0.53-1.01; P=.059), without differences in other causes of death (sHR, 1.17; 95%CI, 0.78-1.75; P=.445), regardless of functional class. CONCLUSIONS: In ambulatory patients with HFrEF, implementation of evidence-based therapies was associated with a lower risk of death, mainly due to a significant reduction in sudden cardiac death


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Causas de Morte/tendências , Insuficiência Cardíaca/mortalidade , Volume Sistólico/fisiologia , Insuficiência Cardíaca/terapia , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Desfibriladores Implantáveis , Terapia de Ressincronização Cardíaca/métodos , Morte Súbita Cardíaca/epidemiologia
20.
Heart ; 106(17): 1342-1348, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32451364

RESUMO

OBJECTIVE: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. TRIM63 has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in TRIM63 and the development of HCM. METHODS: TRIM63 was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls. RESULTS: Sixteen index cases with rare homozygous or compound heterozygous variants in TRIM63 (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15-69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%). CONCLUSION: TRIM63 appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction.

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