RESUMO
Autonomic regulation plays a role in the progression of heart failure with reduced ejection fraction (HrEF).Twenty-one HFrEF patients, 60.8⯱â¯13.1â¯years, receiving angiotensin inhibition, were replaced by angiotensin receptor-neprilysin inhibitor (ARNI). A 24-hour Holter recording was performed before and after 3â¯months of the maximum tolerated dose of ARNi. We evaluated changes in autonomic tone using heart rate variability (SDNN, rMSSD, pNN50, LF, HF, LF/HF, α1, α2), and heart rate turbulence (TO and TS). ARNI was up-titrated to a maximum daily dose of 190⯱â¯102â¯mg, 47.5% of the target dose. ARNI therapy was not associated with any improvement in any of the parameters related with heart rate variability or heart rate turbulence (pâ¯>â¯0.05 for all). ARNI use at lower than target doses did not improve autonomic cardiac tone as evaluated by 24-hour Holter monitoring.
Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Sistema Nervoso Autônomo/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/administração & dosagem , Compostos de Bifenilo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Eletrocardiografia Ambulatorial , Feminino , Determinação da Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , ValsartanaRESUMO
BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.
Assuntos
Cardiomiopatia Dilatada , Genótipo , Penetrância , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Conectina/genética , Eletrocardiografia , Seguimentos , Espanha/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Beta-trace protein (BTP) and cystatin C (CysC) are novel biomarkers of renal function. We assessed the ability of both to predict major bleeding (MB) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), compared to other renal function parameters and clinical risk scores. METHODS AND RESULTS: We included 273 patients. Blood samples were obtained within 24h of admission. The endpoint was MB. During a follow-up of 760 days (411-1,098 days), 25 patients (9.2%) had MB. Patients with MB had higher concentrations of BTP (0.98 mg/L; 0.71-1.16 mg/L vs. 0.72 mg/L, 0.60-0.91 mg/L, P=0.002), CysC (1.05 mg/L; 0.91-1.30 mg/L vs. 0.90 mg/L, 0.75-1.08 mg/L, P=0.003), higher CRUSADE score (39 ± 16 points vs. 29 ± 15 points, P=0.002) and lower estimated glomerular filtration rate (eGFR; 66 ± 27 vs. 80 ± 30 ml·min(-1)·1.73 m(-2), P=0.02) than patients without MB; there was no difference in creatinine level between the groups (P=0.14). After multivariable adjustment, both were predictors of MB, while eGFR and creatinine did not achieve statistical significance. Among subjects with eGFR >60 ml·min(-1)·1.73 m(-2), those with elevated concentrations of both biomarkers had a significantly higher risk for MB. Net reclassification indexes from the addition of BTP and CysC to CRUSADE risk score were 38% and 21% respectively, while the relative integrated discrimination indexes were 12.5% and 3.8%. CONCLUSIONS: Among NSTE-ACS patients, BTP and CysC were superior to conventional renal parameters for predicting MB, and improved clinical stratification for hemorrhagic risk.
Assuntos
Síndrome Coronariana Aguda/sangue , Cistatina C/sangue , Hemorragia/sangue , Oxirredutases Intramoleculares/sangue , Lipocalinas/sangue , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Creatinina/sangue , Feminino , Seguimentos , Hemorragia/etiologia , Hemorragia/fisiopatologia , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
AIMS: Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. METHODS AND RESULTS: Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. CONCLUSION: LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.
Assuntos
Cardiomiopatia Dilatada , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/complicações , Meios de Contraste , Gadolínio , Volume Sistólico , Função Ventricular Esquerda , Arritmias Cardíacas , Estudos de Associação Genética , Valor Preditivo dos Testes , Imagem Cinética por Ressonância Magnética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genéticaRESUMO
BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.
Assuntos
Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Adulto , Feminino , Humanos , Masculino , Arritmias Cardíacas , Insuficiência Cardíaca/genética , Estudos Retrospectivos , Volume Sistólico , Disfunção Ventricular Esquerda/genética , Função Ventricular EsquerdaRESUMO
BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare.
Assuntos
Cardiomiopatia Dilatada , Insuficiência Cardíaca , Cadeias Pesadas de Miosina , Adolescente , Adulto , Arritmias Cardíacas/complicações , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Miosinas Cardíacas/genética , Cardiomiopatia Dilatada/genética , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/genética , Humanos , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Fenótipo , Remodelação Ventricular/genética , Adulto JovemRESUMO
INTRODUCTION AND OBJECTIVES: Study of inherited heart diseases (IHD) involves performing diagnostic tests, which are sometimes inconvenient or stressful, in asymptomatic relatives. The aim of this study was to analyze refusal to undergo various diagnostic tests and follow therapeutic recommendations. METHODS: We assessed 1992 consecutive families with IHD to analyze refusal to undergo family screening. The study included 1539 individuals who were recommended to undergo cardiac magnetic resonance, and 837 who were recommended a drug challenge test. To study treatment refusal, we assessed 395 patients with an indication for an implantable cardioverter-defibrillator (ICD) and 402 patients with an indication for anticoagulation. RESULTS: A total of 28% of families who were recommended to undergo screening for suspected IHD did not attend, but refusal was lower if there was a family history of sudden cardiac death. In all, 23% did not undergo magnetic resonance, and the 2 main reasons were administrative problems (53%) and claustrophobia (18%). Refusal was more common in older people, women, symptomatic persons, individuals with arrhythmias, and relatives. Nearly one fifth (19%) did not take the drug challenge test, due to fear (46%) or administrative issues (25%). Refusal was more frequent in older individuals, asymptomatic persons, those with a history of arrhythmias, relatives, and those with a positive genetic study. Only a minority of patients rejected the treatments (5.1% ICD, 2.5% anticoagulation). The percentage of sudden cardiac death in persons rejecting ICD implantation was high (4.5% per year). CONCLUSIONS: One fifth of people attending screening for IHD refused to undergo more sophisticated and stressful tests. This study identified several independent predictors associated with refusal. Only a minority of high-risk patients refused treatments such as ICD implantation and anticoagulation.
Assuntos
Desfibriladores Implantáveis , Testes Diagnósticos de Rotina , Idoso , Arritmias Cardíacas , Morte Súbita Cardíaca , Feminino , HumanosRESUMO
Introduction: Inherited cardiovascular diseases are an important cause of sudden cardiac death (SD). The use of risk scores identify high risk patients who would benefit from an implantable cardioverter-defibrillators (ICDs). The development of automated devices for out-of-hospital cardiac arrest improves early resuscitation. The objective of the study is to quantify prevented SD and the neurological recovery of patients with inherited cardiovascular diseases. Methods: Two hundred fifty-seven cases of SD (age 42 ± 18 years, 79.4% men) of non-ischemic cardiac cause were prospectively collected during the study period (2009-17). Fifty three (20.6%) had a resuscitated cardiac arrest (RCA) (age 40 ± 18 years, 64.2% male). Epidemiological, clinical and autopsy aspects were analyzed. Prevented SD was defined as a combination of RCA and appropriate ICD therapy cases. Results: An autopsy was performed in 157/204 (77.0%) cases who died. There were 19 (12.1%) cases with a negative autopsy. The diagnosis of cardiomyopathy and channelopathy was 58.0 and 18.7%, respectively. Female sex and confirmed or suspected channelopathy were associated with successful resuscitation. The percentage of prevented SD remained low during the study period (mean 35.6%). 60.4% of RCA cases presented good neurological outcome. There was no association between neurological recovery and therapeutic hypothermia, but there was association with time of resuscitation (min). Conclusion: A fifth part of non-ischemic cardiac arrests were resuscitated. Female sex and channelopathies were more prevalent among RCA. Two thirds of RCA had a good neurological recovery.
RESUMO
Cancer therapy-induced cardiomyopathy (CCM) manifests as left ventricular (LV) dysfunction and heart failure (HF). It is associated withparticular pharmacological agents and it is typically dose dependent, but significant individual variability has been observed. History of prior cardiac disease, abuse of toxics, cardiac overload conditions, age, and genetic predisposing factors modulate the degree of the cardiac reserve and the response to the injury. Genetic/familial cardiomyopathies (CMY) are increasingly recognized in general populations with an estimated prevalence of 1:250. Association between cardiac and oncologic diseases regarding genetics involves not only the toxicity process, but pathogenicity. Genetic variants in germinal cells that cause CMY (LMNA, RAS/MAPK) can increase susceptibility for certain types of cancer. The study of mutations found in cancer cells (somatic) has revealed the implication of genes commonly associated with the development of CMY. In particular, desmosomal mutations have been related to increased undifferentiation and invasiveness of cancer. In this article, the authors review the knowledge on the relevance of environmental and genetic background in CCM and give insights into the shared genetic role in the pathogenicity of the cancer process and development of CMY.
RESUMO
BACKGROUND: Testosterone deficiency is associated with heart failure (HF) progression and poor prognosis. Testosterone therapy has been shown to improve exercise capacity in patients with chronic HF, but no trial has evaluated the impact of replacement in patients with demonstrated testosterone deficiency. METHODS: Prospective, randomized, double-blind, placebo-controlled, and parallel-group trial comparing testosterone replacement with placebo in males with chronic HF with reduced ejection fraction (HFrEF) and testosterone deficiency (NCT01813201). Long-acting undecanoate testosterone at a fixed dose of 1000 mg was supplied by intramuscular injection at inclusion and then every 3 months. The placebo group received isotonic saline serum. Patients were randomly allocated 1:1 to testosterone or placebo while receiving optimal medical therapy, and the study was conducted for 12 months. RESULTS: The final sample comprised 29 patients, 15 in the placebo group and 14 in the testosterone group (aged 65 ± 8, 62% with an ischemic etiology, left ventricular ejection fraction [LVEF] 30% ± 6%, 69% New York Heart Association functional [NYHA II]). After 12 months, testosterone replacement increased testosterone levels ( P = .002) but was not associated with benefit in terms of clinical symptoms and functional capacity including NYHA class, Framingham score, Minnesota Living Heart Failure Questionnaire, 6-minute walk test, or LVEF and N-terminal pro-B-type natriuretic peptide levels. No significant side effects associated with testosterone treatment were observed. No effects were found in other hormonal, metabolic, and bone turnover biomarkers. CONCLUSION: In patients with HFrEF and testosterone deficiency, replacement therapy was not associated with any significant improvement.
Assuntos
Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Volume Sistólico/efeitos dos fármacos , Testosterona/análogos & derivados , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Doença Crônica , Método Duplo-Cego , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Qualidade de Vida , Recuperação de Função Fisiológica , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Testosterona/sangue , Testosterona/deficiência , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION AND OBJECTIVES: The transcription factor TBX1 plays an important role in the embryonic development of the heart. Nothing is known about its involvement in myocardial remodeling after acute myocardial infarction (AMI) and whether its expression can be modulated by a treatment with proven benefit such as mineralocorticoid receptor blockade. METHODS: Acute myocardial infarction was induced in 60 rats via left coronary artery ligation: 50 animals were randomized to be euthanized after 1, 2, 4, 12, or 24 weeks; 10 animals were treated with eplerenone (100 mg/kg/days) 7 days before the AMI until their euthanasia (4 weeks later); 8 additional animals underwent surgery without ligation (control). We analyzed the cardiac expression of TBX1, fetal genes, and fibrosis markers. RESULTS: The gene and protein expression of TBX1 was increased in the infarcted myocardium, peaking 1 week after AMI (P < .01), without changes in the noninfarcted myocardium. Levels of the fetal genes and fibrosis markers also increased, peaking 4 weeks (P < .001) and 1 week (P < .01) after AMI, respectively. The TBX1 expression was correlated with that of the fibrosis markers (P < .01) but not the fetal genes. Eplerenone reduced the TBX1 increase and fibrosis induced by AMI, with an association improvement in ventricular function and remodeling in echocardiography. CONCLUSIONS: These results show the reactivated expression of TBX1 and indicate its involvement in cardiac fibrosis and remodeling after AMI and its participation in the benefit from mineralocorticoid receptor blockade.