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1.
ESC Heart Fail ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32045114

RESUMO

AIM: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor developed for the treatment of heart failure with reduced ejection fraction. Its benefits are achieved through the inhibition of neprilysin (NEP) and the specific blockade of the angiotensin receptor AT1. The many peptides metabolized by NEP suggest multifaceted potential consequences of its inhibition. We sought to evaluate the short-term changes in serum endorphin (EP) values and their relation with patients' physical functioning after initiation of sacubitril/valsartan treatment. METHODS AND RESULTS: A total of 105 patients with heart failure with reduced ejection fraction, who were candidates for sacubitril/valsartan treatment, were included in this prospective, observational, multicentre, and international study. In a first visit, and in agreement with current guidelines, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker was replaced by sacubitril/valsartan because of clinical indication by the responsible physician. By protocol, patients were reevaluated at 30 days after the start of sacubitril/valsartan. Serum levels of α- (α-EP), γ-Endorphin (γ-EP), and soluble NEP (sNEP) were measured using enzyme-linked immunoassays. New York Heart Association (NYHA) functional class was used as an indicator of patient's functional status. Baseline median levels of circulating α-EP, γ-EP, and sNEP were 582 (160-772), 101 (37-287), and 222 pg/mL (124-820), respectively. There was not a significant increase in α-EP nor γ-EP serum values after sacubitril/valsartan treatment (P value = 0.194 and 0.102, respectively). There were no significant differences in sNEP values between 30 days and baseline (P value = 0.103). Medians (IQR) of Δα-EP, Δγ-EP, and ΔsNEP between 30 days and baseline were 9.3 (-34 - 44), -3.0 (-46.0 - 18.9), and 0 units (-16.4 - 157.0), respectively. In a pre-post sacubitril/valsartan treatment comparison, there was a significant improvement in NYHA class, with 36 (34.3%) patients experiencing improvement by at least one NYHA class category. Δα-EP and ΔsNEP showed to be significantly associated with NYHA class after 30 days of treatment (P = 0.014 and P < 0.001, respectively). Δα-EP was linear and significantly associated with NYHA class improvement after 30 days of sacubitril/valsartan treatment. CONCLUSIONS: These preliminary data suggest that beyond the haemodynamic benefits achieved with sacubitril/valsartan, the altered cleavage of endorphin peptides by NEP inhibition may participate in patients' symptoms improvement.

2.
Eur J Heart Fail ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919929

RESUMO

AIMS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. METHODS AND RESULTS: Individual data from 5301 patients with chronic HF and NT-proBNP, hs-TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60-69 years (n = 1628, 31%), 70-79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT-proBNP 1564 ng/L, hs-TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT-proBNP and hs-TnT, but not sST2. The best NT-proBNP and hs-TnT cut-offs for 1-year and 5-year all-cause and cardiovascular mortality and 1- to 12-month HF hospitalization increased with age, while the best sST2 cut-offs did not. When stratifying patients according to age- and outcome-specific cut-offs, this stratification yielded independent prognostic significance over NT-proBNP levels only, or the composite of NT-proBNP and hs-TnT, and improved risk prediction for most endpoints. Finally, absolute NT-proBNP, hs-TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables. CONCLUSIONS: Soluble ST2 is less influenced by age than NT-proBNP or hs-TnT; all these biomarkers predict outcome regardless of age. The use of age- and outcome-specific cut-offs of NT-proBNP, hs-TnT and sST2 allows more accurate risk stratification than NT-proBNP alone or the combination of NT-proBNP and hs-TnT.

3.
J Am Heart Assoc ; 9(2): e014708, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31959034

RESUMO

Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort of 323 patients treated with anthracyclines and/or trastuzumab followed over a maximum of 3.7 years with serial echocardiograms. CTRCD was defined as a ≥10% decline in left ventricular ejection fraction to a value <50%. Associations between changes in biomarkers and left ventricular ejection fraction were evaluated in repeated-measures linear regression models. Cox regression models assessed the associations between biomarkers and CTRCD. Early increases in all biomarkers occurred with anthracycline-based regimens. hs-cTnT levels >14 ng/L at anthracycline completion were associated with a 2-fold increased CTRCD risk (hazard ratio, 2.01; 95% CI, 1.00-4.06). There was a modest association between changes in NT-proBNP and left ventricular ejection fraction in the overall cohort; this was most pronounced with sequential anthracycline and trastuzumab (1.1% left ventricular ejection fraction decline [95% CI, -1.8 to -0.4] with each NT-proBNP doubling). Increases in NT-proBNP were also associated with CTRCD (hazard ratio per doubling, 1.56; 95% CI, 1.32-1.84). Increases in myeloperoxidase were associated with CTRCD in patients who received sequential anthracycline and trastuzumab (hazard ratio per doubling, 1.28; 95% CI, 1.04-1.58). Conclusions Cardiovascular biomarkers may play an important role in CTRCD risk prediction in patients with breast cancer who receive cardiotoxic cancer therapy, particularly in those treated with sequential anthracycline and trastuzumab therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01173341.

5.
N Engl J Med ; 382(5): 416-426, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31995687

RESUMO

BACKGROUND: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS: We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR. RESULTS: The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells. CONCLUSIONS: High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).


Assuntos
Lesão Renal Aguda/sangue , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Angiografia Coronária/efeitos adversos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Biomarcadores/sangue , Estado Terminal , Modelos Animais de Doenças , Feminino , Humanos , Unidades de Terapia Intensiva , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Razão de Chances , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Medição de Risco/métodos , Ativador de Plasminogênio Tipo Uroquinase/farmacologia
8.
Ann Intern Med ; 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31869834

RESUMO

Background: Preliminary data suggest that preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) may improve risk prediction in patients undergoing noncardiac surgery. Objective: To determine whether preoperative NT-proBNP has additional predictive value beyond a clinical risk score for the composite of vascular death and myocardial injury after noncardiac surgery (MINS) within 30 days after surgery. Design: Prospective cohort study. Setting: 16 hospitals in 9 countries. Patients: 10 402 patients aged 45 years or older having inpatient noncardiac surgery. Measurements: All patients had NT-proBNP levels measured before surgery and troponin T levels measured daily for up to 3 days after surgery. Results: In multivariable analyses, compared with preoperative NT-proBNP values less than 100 pg/mL (the reference group), those of 100 to less than 200 pg/mL, 200 to less than 1500 pg/mL, and 1500 pg/mL or greater were associated with adjusted hazard ratios of 2.27 (95% CI, 1.90 to 2.70), 3.63 (CI, 3.13 to 4.21), and 5.82 (CI, 4.81 to 7.05) and corresponding incidences of the primary outcome of 12.3% (226 of 1843), 20.8% (542 of 2608), and 37.5% (223 of 595), respectively. Adding NT-proBNP thresholds to clinical stratification (that is, the Revised Cardiac Risk Index [RCRI]) resulted in a net absolute reclassification improvement of 258 per 1000 patients. Preoperative NT-proBNP values were also statistically significantly associated with 30-day all-cause mortality (less than 100 pg/mL [incidence, 0.3%], 100 to less than 200 pg/mL [incidence, 0.7%], 200 to less than 1500 pg/mL [incidence, 1.4%], and 1500 pg/mL or greater [incidence, 4.0%]). Limitation: External validation of the identified NT-proBNP thresholds in other cohorts would reinforce our findings. Conclusion: Preoperative NT-proBNP is strongly associated with vascular death and MINS within 30 days after noncardiac surgery and improves cardiac risk prediction in addition to the RCRI. Primary Funding Source: Canadian Institutes of Health Research.

9.
Circulation ; 140(25): 2108-2118, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31841369

RESUMO

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

10.
J Am Heart Assoc ; 8(23): e014240, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31771438

RESUMO

Background The New York Heart Association (NYHA) classification has served as a fundamental tool for risk stratification of heart failure (HF) and determines clinical trial eligibility and candidacy for drugs and devices. However, its ability to adequately stratify risk is unclear. Methods and Results To compare NYHA class with objective assessments and survival in patients with HF, we performed secondary analyses of 4 multicenter National Institutes of Health-funded HF clinical trials that included patients classified as NYHA class II or III: TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), DIG (The Effect of Digoxin on Mortality and Morbidity in Patients With Heart Failure), HF-ACTION (Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure), and GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure). Twenty-month cumulative survival was compared between classes using Kaplan-Meier curves and the log rank test. NT-proBNP (N-terminal pro-B-type natriuretic peptide), Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, 6-minute walk distances, left ventricular ejection fraction, and cardiopulmonary test parameters were compared using Wilcoxon rank sum tests and percentage overlap using kernel density estimations. Cumulative mortality varied significantly across NYHA classes and HF clinical trials (likelihood ratio, P<0.001). Mortality at 20 months for NYHA class II ranged from 7% for patients in HF-ACTION to 15% in GUIDE-IT, whereas mortality for NYHA class III ranged from 12% in TOPCAT to 26% in GUIDE-IT. There was substantial percentage overlap in values for NT-proBNP levels (79% and 69%), KCCQ scores (63% and 54%), 6-minute walk distances (63% and 54%), and left ventricular ejection fraction (88% and 83%). Similarly, there was substantial overall in values for minute ventilation-carbon dioxide production relationship (71%), maximal oxygen uptake (54%), and exercise duration (53%). Conclusions The NYHA system poorly discriminates HF patients across the spectrum of functional impairment. These findings raise important questions about the need for improved phenotyping of these patients to facilitate risk stratification and response to interventions.

11.
Am J Med ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31715169

RESUMO

BACKGROUND: Despite significant progress in primary prevention, the rate of myocardial infarction has not decreased in young adults. We sought to compare the risk factor profiles and outcomes between individuals who experienced a first myocardial infarction at a very young (≤40 years) and a young (age 41-50 years) age. METHODS: We evaluated all patients ≤50 years of age admitted with a Type 1 myocardial infarction to 2 large academic hospitals from 2000 to 2016. Risk factors were determined by review of electronic medical records. The primary outcomes of interest were all-cause and cardiovascular mortality. RESULTS: Among 2097 consecutive young patients with myocardial infarction, 431 (20.5%) were ≤40 years of age. When compared with their older counterparts, very young patients had similar risk profiles, with the exception of greater substance abuse (17.9% vs 9.3%, P < .001) and less hypertension (37.9% vs 50.9%, P < .001). Spontaneous coronary artery dissection was more prevalent in very young patients (3.1% vs 1.1%, P = .003). Over a median follow-up of 11.2 years, very young myocardial infarction patients had a similar risk of all-cause and cardiovascular mortality. CONCLUSIONS: Despite being, on average, 10 years younger and having a lower prevalence of hypertension, very young myocardial infarction patients had similar 1-year and long-term outcomes when compared with those aged 41 to 50 years at the time of their index infarction. Our findings suggest the need for aggressive secondary prevention measures in very young patients who experience a myocardial infarction.

12.
Clin Infect Dis ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31740919

RESUMO

BACKGROUND: Among persons living with human immunodeficiency virus (PHIV), incident heart failure (HF) rates are increased and outcomes are worse; however, the role of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations among PHIV with HF has not been characterized. METHODS: Patients were derived from a registry of those hospitalized with HF at an academic center in a calender year. We compared the NT-proBNP concentrations and the changes in NT-proBNP levels between PHIV with HF and uninfected controls with HF. RESULTS: Among 2578 patients with HF, there were 434 PHIV; 90% were prescribed antiretroviral therapy and 62% were virally suppressed. As compared to controls, PHIV had higher admission (3822 [IQR, 2413-7784] pg/ml vs 5546 [IQR, 3257-8792] pg/ml, respectively; P < .001), higher discharge (1922 [IQR, 1045-4652] pg/ml vs 3372 [IQR, 1553-5452] pg/ml, respectively; P < .001), and lower admission-to-discharge changes in NT-proBNP levels (32 vs 48%, respectively; P = .007). Similar findings were noted after stratifying based on left ventricular ejection fraction (LVEF). In a multivariate analysis, cocaine use, a lower LVEF, a higher NYHA class, a higher viral load (VL), and a lower CD4 count were associated with higher NT-proBNP concentrations. In follow-up, among PHIV, a higher admission NT-proBNP concentration was associated with increased cardiovascular mortality (first tertile, 11.5; second tertile, 20; third tertile, 44%; P < .001). Among PHIV, each doubling of NT-proBNP was associated with a 19% increased risk of death. However, among patients living without HIV, each doubling was associated with a 27% increased risk; this difference was attenuated among PHIV with lower VLs and higher CD4 counts. CONCLUSIONS: PHIV with HF had higher admission and discharge NT-proBNP levels, and less change in NT-proBNP concentrations. Among PHIV, VLs and CD4 counts were associated with NT-proBNP concentrations; in follow-up, higher NT-proBNP levels among PHIV were associated with cardiovascular mortality.

13.
Am J Cardiol ; 124 Suppl 1: S20-S27, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31741436

RESUMO

Heart failure is a common complication among patients with type 2 diabetes mellitus and is associated with significantly increased risks of subsequent morbidity and mortality. Until recently, therapies and strategies were lacking to attenuate this excess risk of heart failure in this population. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a unique class of glucose-lowering therapies that have multisystem health benefits. Three large cardiovascular outcomes trials have demonstrated consistent reductions in heart failure events among patients with type 2 diabetes mellitus with, or at risk for, atherosclerotic cardiovascular disease. Another trial recently showed that an SGLT2 inhibitor, canagliflozin, also significantly reduced heart failure events among patients with type 2 diabetes mellitus and albuminuric chronic kidney disease. The SGLT2 inhibitor class represents an important new therapeutic approach for the prevention of heart failure in at-risk patients with type 2 diabetes mellitus, and is actively being studied for use in treating patients with heart failure (with or without type 2 diabetes mellitus). (Supplementary video "Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors" is available online.).

14.
JAMA ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31738818

RESUMO

Importance: Recent guidelines endorse using history of menopause before age 40 years to refine atherosclerotic cardiovascular disease risk assessments among middle-aged women. Robust data on cardiovascular disease risk in this population are lacking. Objective: To examine the development of cardiovascular diseases and cardiovascular risk factors in women with natural and surgical menopause before age 40 years. Design, Setting, and Participants: Cohort study (UK Biobank), with adult residents of the United Kingdom recruited between 2006 and 2010. Of women who were 40 to 69 years old and postmenopausal at study enrollment, 144 260 were eligible for inclusion. Follow-up occurred through August 2016. Exposures: Natural premature menopause (menopause before age 40 without oophorectomy) and surgical premature menopause (bilateral oophorectomy before age 40). Postmenopausal women without premature menopause served as the reference group. Main Outcomes and Measures: The primary outcome was a composite of incident coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism. Secondary outcomes included individual components of the primary outcome, incident hypertension, hyperlipidemia, and type 2 diabetes. Results: Of 144 260 postmenopausal women included (mean [SD] age at enrollment, 59.9 [5.4] years), 4904 (3.4%) had natural premature menopause and 644 (0.4%) had surgical premature menopause. Participants were followed up for a median of 7 years (interquartile range, 6.3-7.7). The primary outcome occurred in 5415 women (3.9%) with no premature menopause (incidence, 5.70/1000 woman-years), 292 women (6.0%) with natural premature menopause (incidence, 8.78/1000 woman-years) (difference vs no premature menopause, +3.08/1000 woman-years [95% CI, 2.06-4.10]; P < .001), and 49 women (7.6%) with surgical premature menopause (incidence, 11.27/1000 woman-years) (difference vs no premature menopause, +5.57/1000 woman-years [95% CI, 2.41-8.73]; P < .001). For the primary outcome, natural and surgical premature menopause were associated with hazard ratios of 1.36 (95% CI, 1.19-1.56; P < .001) and 1.87 (95% CI, 1.36-2.58; P < .001), respectively, after adjustment for conventional cardiovascular disease risk factors and use of menopausal hormone therapy. Conclusions and Relevance: Natural and surgical premature menopause (before age 40 years) were associated with a small but statistically significant increased risk for a composite of cardiovascular diseases among postmenopausal women. Further research is needed to understand the mechanisms underlying these associations.

15.
J Am Coll Cardiol ; 74(17): 2193-2203, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31648713

RESUMO

Soluble suppression of tumorigenesis-2 (sST2) is released in response to vascular congestion and inflammatory and pro-fibrotic stimuli, and is a strong, independent predictor of mortality and heart failure (HF) hospitalization in patients with acute or chronic HF. sST2 meets 2 fundamental criteria for clinically useful biomarkers: accurate, repeated measurements are available at a reasonable cost, and the biomarker provides information not already available from a careful clinical assessment. In particular, the prognostic value of sST2 is additive to natriuretic peptides and (in the case of chronic HF) to high-sensitivity troponin T. Nevertheless, the need for a multibiomarker approach to risk stratification and the role of sST2 as a guide to therapy decision-making remain to be established. Four years after a consensus document on sST2, and following major advances in the comprehension of the clinical value of this biomarker, the authors felt it worthwhile to reappraise current knowledge on sST2 in HF.

16.
JACC Heart Fail ; 7(10): 899-901, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31521686
17.
Diabetes Care ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31548242

RESUMO

OBJECTIVE: We sought to determine the prevalence of diabetes and associated cardiovascular outcomes in a contemporary cohort of young individuals presenting with their first myocardial infarction (MI) at age ≤50 years. RESEARCH DESIGN AND METHODS: We retrospectively analyzed records of patients presenting with a first type 1 MI at age ≤50 years from 2000 to 2016. Diabetes was defined as a hemoglobin A1c ≥6.5% (48 mmol/mol) or a documented diagnosis of or treatment for diabetes. Vital status was ascertained for all patients, and cause of death was adjudicated. RESULTS: Among 2,097 young patients who had a type 1 MI (mean age 44.0 ± 5.1 years, 19.3% female, 73% white), diabetes was present in 416 (20%), of whom 172 (41%) were receiving insulin. Over a median follow-up of 11.2 years (interquartile range 7.3-14.2 years), diabetes was associated with a higher all-cause mortality (hazard ratio 2.30; P < 0.001) and cardiovascular mortality (2.68; P < 0.001). These associations persisted after adjusting for baseline covariates (all-cause mortality: 1.65; P = 0.008; cardiovascular mortality: 2.10; P = 0.004). CONCLUSIONS: Diabetes was present in 20% of patients who presented with their first MI at age ≤50 years and was associated with worse long-term all-cause and cardiovascular mortality. These findings highlight the need for implementing more-aggressive therapies aimed at preventing future adverse cardiovascular events in this population.

18.
JAMA ; : 1-11, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31475295

RESUMO

Importance: In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. Objective: To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. Design, Setting, and Participants: Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. Exposures: NT-proBNP concentrations among patients treated with sacubitril-valsartan. Main Outcomes and Measures: The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months. Results: Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%). Conclusions and Relevance: In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF. Trial Registration: ClinicalTrials.gov Identifier: NCT02887183.

19.
20.
JACC Heart Fail ; 7(9): 782-794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401101

RESUMO

In response to injury, hemodynamic changes, or neurohormonal activation, the heart undergoes a series of structural and functional changes that have been termed cardiac remodeling. Remodeling is defined as changes in cardiac geometry and/or function over time and can be measured in terms of changes in cardiac chamber dimensions, wall thickness, volumes, mass, and ejection fraction at serial imaging examinations. As to cardiac chambers, left ventricular (LV) remodeling has been best studied in patients with heart failure with reduced ejection fraction. Although LV remodeling may compensate for abnormal hemodynamic parameters and function in the short term, left unchecked, it is associated with worsening cardiac function and poor prognosis. On the other hand, reversing LV geometry and/or function closer to that of a normal heart (also known as reverse remodeling) is associated with improved cardiac function and better prognosis. Because of its close relationship with clinical outcomes, remodeling may potentially be targeted in clinical management and used in trials as a surrogate endpoint. Standardized definition of remodeling and reliable tools to predict and monitor the presence, direction, and magnitude of cardiac remodeling are needed. Together with clinical and imaging findings, circulating biomarkers (most notably N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin, and soluble suppression of tumorigenesis-2) may be helpful in this respect.

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