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1.
PLoS One ; 15(4): e0232280, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32349122

RESUMO

INTRODUCTION: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls. MATERIALS AND METHODS: Prospective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization. RESULTS: Compared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); p<0.0001. Compared to controls, HFpEF was characterized by (mild) reductions in LVEF, more myocardial fibrosis, LA remodeling/dysfunction and RV dysfunction. HFrEF patients had lower LVEF, increased LV volumes, greater burden of focal and diffuse fibrosis, more RV remodeling, lower LAEF and higher LA volumes compared to HFpEF. Inflammatory/fibrotic/renal dysfunction plasma markers were similarly elevated in both HF groups but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, N-terminal pro-atrial natriuretic peptide and troponin-I) were higher in HFrEF compared to HFpEF; p<0.0001. Focal fibrosis was associated with galectin3, GDF-15, MMP-3, MMP-7, MMP-8, BNP, pro-BNP and NTproANP; p<0.05. Diffuse fibrosis was associated with GDF-15, Tenascin-C, MMP-2, MMP-3, MMP-7, BNP, proBNP and NTproANP; p<0.05. Composite event rates (median 1446 days follow-up) did not differ between HFpEF and HFrEF (Log-Rank p = 0.784). CONCLUSIONS: HFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.

2.
Int J Cardiovasc Imaging ; 36(6): 1133-1146, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32152811

RESUMO

Strain assessment allows accurate evaluation of myocardial function and mechanics in ST-segment elevation myocardial infarction (STEMI). Strain using cardiovascular magnetic resonance (CMR) has traditionally been assessed with tagging but limitations of this technique have led to more widespread use of alternative methods, which may be more robust. We compared the inter-study repeatability of circumferential global peak-systolic strain (Ecc) and peak-early diastolic strain rate (PEDSR) derived by tagging with values obtained using novel cine-based software: Feature Tracking (FT) (TomTec, Germany) and Tissue Tracking (TT) (Circle cvi42, Canada) in patients following STEMI. Twenty male patients (mean age 56 ± 10 years, mean infarct size 13.7 ± 7.1% of left ventricular mass) were randomised to undergo CMR 1-5 days post-STEMI at 1.5 T or 3.0 T, repeated after ten minutes at the same field strength. Ecc and PEDSR were assessed using tagging, FT and TT. Inter-study repeatability was evaluated using Bland-Altman analyses, coefficients of variation (CoV) and intra-class correlation coefficient (ICC). Ecc (%) was significantly lower with tagging than with FT or TT at 1.5 T (- 9.5 ± 3.3 vs. - 17.5 ± 3.8 vs. -15.5 ± 5.2, respectively, p < 0.001) and 3.0 T (- 13.1 ± 1.8 vs. - 19.4 ± 2.9 vs. - 17.3 ± 2.1, respectively, p = 0.001). This was similar for PEDSR (.s-1): 1.5 T (0.6 ± 0.2 vs. 1.5 ± 0.4 vs. 1.0 ± 0.4, for tagging, FT and TT respectively, p < 0.001) and 3.0 T (0.6 ± 0.2 vs. 1.5 ± 0.3 vs. 0.9 ± 0.3, respectively, p < 0.001). Inter-study repeatability for Ecc at 1.5 T was good for tagging and excellent for FT and TT: CoV 16.7%, 6.38%, and 8.65%, respectively. Repeatability for Ecc at 3.0 T was good for all three techniques: CoV 14.4%, 11.2%, and 13.0%, respectively. However, repeatability of PEDSR was generally lower than that for Ecc at 1.5 T (CoV 15.1%, 13.1%, and 34.0% for tagging, FT and TT, respectively) and 3.0 T (CoV 23.0%, 18.6%, and 26.2%, respectively). Following STEMI, Ecc and PEDSR are higher when measured with FT and TT than with tagging. Inter-study repeatability of Ecc is good for tagging, excellent for FT and TT at 1.5 T, and good for all three methods at 3.0 T. The repeatability of PEDSR is good to moderate at 1.5 T and moderate at 3.0 T. Cine-based methods to assess Ecc following STEMI may be preferable to tagging.

3.
Int J Cardiovasc Imaging ; 36(5): 921-928, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32030576

RESUMO

The aim of this study was to assess the agreements of both biplane and short-axis Simpson's (SAX) methods for left atrial ejection fraction (LAEF) calculation utilising cardiovascular magnetic resonance imaging (CMR) in heart failure with preserved ejection fraction (HFpEF) and evaluate their relation to clinical outcomes. One hundred and thirty six subjects (HFpEF n = 97, controls n = 39) underwent CMR, six-minute walk tests and blood sampling in our prospective, observational, single-centre study. Overall, LAEF (%) was lower in HFpEF patients compared to controls (SAX 34 ± 13 vs 47 ± 8, biplane 34 ± 16 vs 51 ± 11; p < 0.0001 for both). Atrial fibrillation (AF) was present in 24% of HFpEF and was associated with higher LA volumes and lower LAEF compared to sinus rhythm (p < 0.0001) with both methods. Biplane LAEF correlated strongly with SAX measurements (overall Pearson's r = 0.851, sinus rhythm r = 0.651, AF r = 0.882; p < 0.0001). Biplane LAEF did not differ significantly compared to SAX LAEF (overall 34 ± 16 vs 34 ± 13%; p = 0.307) except in AF subjects in whom biplane LAEF was lower (mean difference 2 ± 4%, p = 0.013). There were 44 composite events (25 deaths, 19 HF hospitalizations) in HFpEF during median follow-up of 1429 days. LAEF below the median was associated with increased risk of composite endpoints (Log-Rank biplane p < 0.0001; SAX p = 0.009). In multivariable Cox proportional hazards regression analysis, both biplane LAEF (hazard ratio [HR] 0.604; 95% confidence interval [CI] (0.406-0.900); p = 0.013) and SAX LAEF (HR 0.636; CI 0.441-0.918; p = 0.016) remained independent predictors along with indexed extracellular volume. CMR LAEF, derived from either the short-axis or biplane method is lower in HFpEF compared to healthy controls and remains a strong marker of prognosis.

4.
Cardiovasc Res ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32065620

RESUMO

AIMS: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. CONCLUSION: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

5.
Circ Heart Fail ; 13(2): e006472, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32059630

RESUMO

BACKGROUND: There are multiple risk factors for heart failure, but contemporary temporal trends according to sex, socioeconomic status, and ethnicity are unknown. METHODS: Using a national UK general practice database linked to hospitalizations (1998-2017), 108 638 incident heart failure patients were identified. Differences in risk factors among patient groups adjusted for sociodemographic factors and age-adjusted temporal trends were investigated using logistic and linear regression. RESULTS: Over time, a 5.3 year (95% CI, 5.2-5.5) age difference between men and women remained. Women had higher blood pressure, body mass index, and cholesterol than men (P<0.0001). Ischemic heart disease prevalence increased for all to 2006 before reducing in women by 0.5% per annum, reaching 42.7% (95% CI, 41.7-43.6), but not in men, remaining at 57.7% (95% CI, 56.9-58.6; interaction P=0.002). Diabetes mellitus prevalence increased more in men than in women (interaction P<0.0001). Age between the most deprived (74.6 years [95% CI, 74.1-75.1]) and most affluent (79.9 [95% CI, 79.6-80.2]) diverged (interaction P<0.0001), generating a 5-year gap. The most deprived had significantly higher annual increases in comorbidity numbers (+0.14 versus +0.11), body mass index (+0.14 versus +0.11 kg/m2), and lower smoking reductions (-1.2% versus -1.7%) than the most affluent. Ethnicity trend differences were insignificant, but South Asians were overall 6 years and the black group 9 years younger than whites. South Asians had more ischemic heart disease (+16.5% [95% CI, 14.3-18.6]), hypertension (+12.5% [95% CI, 10.5-14.3]), and diabetes mellitus (+24.3% [95% CI, 22.0-26.6]), and the black group had more hypertension (+12.3% [95% CI, 9.7-14.8]) and diabetes mellitus (+13.1% [95% CI, 10.1-16.0]) but lower ischemic heart disease (-10.6% [95% CI, -13.6 to -7.6]) than the white group. CONCLUSIONS: Population groups show distinct risk factor trend differences, indicating the need for contemporary tailored prevention programs.

6.
Eur Heart J ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31898721

RESUMO

AIMS: To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury. METHODS AND RESULTS: One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case-control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P <0.01) compared to healthy controls. Infarcts were small with few large infarcts (median 4.06%; range 0-30.9%) and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass]. CONCLUSION: The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

7.
Circulation ; 141(4): 313-328, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31986093

RESUMO

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.

8.
Int J Cardiovasc Imaging ; 36(1): 101-110, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31401742

RESUMO

The aim of this study was to determine whether left atrial ejection fraction (LAEF) quantified with cardiovascular magnetic resonance (CMR) was different between heart failure with preserved ejection fraction (HFpEF) and controls, and its relation to prognosis. As part of our single-centre, prospective, observational study, 188 subjects (HFpEF n = 140, controls n = 48) underwent phenotyping with contrast-enhanced CMR, transthoracic echocardiography, blood sampling and six-minute walk testing. LAEF was calculated using the biplane method. Atrial fibrillation (AF) was present in 43 (31%) of HFpEF subjects. Overall, LAEF (%) was lower in HFpEF patients inclusive of AF (32 ± 16) or those in sinus rhythm alone (41 ± 12) compared to controls (51 ± 11), p < 0.0001. LAEF correlated inversely with maximal and minimal left atrial volumes indexed (r = - 0.602, r = - 0.762), and plasma N-terminal pro-atrial natriuretic peptide (r = - 0.367); p < 0.0001. During median follow-up (1429 days), there were 67 composite events of all-cause death or hospitalization for heart failure (22 deaths, 45 HF hospitalizations) in HFpEF. Lower LAEF (below median) was associated with an increased risk of composite endpoints (Log-Rank: all p = 0.028; sinus p = 0.036). In multivariable Cox regression analysis, LAEF (adjusted hazard ratio [HR] 0.767, 95% confidence interval [CI] 0.591-0.996; p = 0.047) and indexed extracellular volume (HR 1.422, CI 1.015-1.992; p = 0.041) were the only parameters that remained significant when added to a base prognostic model comprising age, prior HF hospitalization, diastolic blood pressure, lung disease, NYHA, six-minute-walk-test-distance, haemoglobin, creatinine and B-type natriuretic peptide. CMR-derived LAEF is lower in HFpEF compared to healthy controls and is a strong prognostic biomarker.


Assuntos
Função do Átrio Esquerdo , Insuficiência Cardíaca/fisiopatologia , Volume Sistólico , Função Ventricular Esquerda , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Progressão da Doença , Ecocardiografia , Tolerância ao Exercício , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/mortalidade , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos
9.
Perit Dial Int ; 39(5): 486-489, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31501293

RESUMO

Peritoneal ultrafiltration (PuF) has been employed for severe heart failure (HF), but evidence for its benefit is lacking. The Peritoneal Dialysis for Heart Failure (PDHF) study was a multicenter prospective randomized controlled trial which aimed to investigate this issue. The trial stopped early due to inadequate recruitment. We describe methods, trial activity, and lessons learned.The trial aimed to recruit 130 participants with severe diuretic-resistant HF (New York Heart Association [NYHA] 3/4) and chronic kidney disease (CKD) stage 3/4 on optimal medical treatment for ≥ 4 weeks from 6 UK centers. Participants were randomized to either continuation of conventional HF treatment or to additionally receiving PuF (1 overnight exchange using Icodextrin dialysate). Primary outcome was change in 6-minute walk test (6MWT) between baseline and 28 weeks (end of trial). Secondary outcomes were changes in patient reported quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire, short form 36 (SF 36) health survey results, hospitalization, and mortality.Over a 2-year period, 290 patients were screened from which only 20 met inclusion criteria and 10 were recruited. Reasons for ineligibility were fluctuating estimated glomerular filtration rate (eGFR), suboptimal HF treatment, frailty, and patients being too unwell for randomization. Barriers to recruitment included patient frailty, with some participants considered only when they were at end of life, unwillingness to engage in an invasive therapy, and suboptimal coordination between cardiology and renal services. This is a challenging patient group in which to perform research, and lessons learned from the peritoneal dialysis (PD)-HF trial will be helpful in the planning of future studies in this area.

11.
Lancet Public Health ; 4(8): e406-e420, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31376859

RESUMO

BACKGROUND: Heart failure is an important public health issue affecting about 1 million people in the UK, but contemporary trends in cause-specific outcomes among different population groups are unknown. METHODS: In this retrospective, population-based study, we used the UK Clinical Practice Research Datalink and Hospital Episodes Statistics databases to identify a cohort of patients who had a diagnosis of incident heart failure between Jan 1, 1998, and July 31, 2017. Patients were eligible for inclusion if they were aged 30 years or older with a first code for heart failure in their primary care or hospital record during the study period. We assessed cause-specific admission to hospital (ie, hospitalisation) and mortality, by age, sex, socioeconomic status, and place of diagnosis (ie, hospital vs community diagnosis). We calculated outcome rates separately for the first year (first-year rates) and for the second-year onwards (subsequent-year rates). Patients were followed up until death or study end. This study is registered with Clinical Practice Research Datalink Independent Scientific Advisory Committee, protocol number 18_037R. FINDINGS: We identified 88 416 individuals with incident heart failure over the study period, of whom 43 461 (49%) were female. The mean age was 77·8 years (SD 11·3) and median follow-up was 2·4 years (IQR 0·5 to 5·7). Age-adjusted first-year rates of hospitalisation increased by 28% for all-cause admissions, from 97·1 (95% CI 94·3 to 99·9) to 124·2 (120·9 to 127·5) per 100 person-years; by 28% for heart failure-specific admissions, from 17·2 (16·2 to 18·2) to 22·1 (20·9 to 23·2) per 100 person-years; and by 42% for non-cardiovascular admissions, from 59·2 (57·2 to 61·2) to 83·9 (81·3 to 86·5) per 100 person-years. 167 641 (73%) of 228 113 hospitalisations were for non-cardiovascular causes and annual rate increases were higher for women (3·9%, 95% CI 2·8 to 4·9) than for men (1·4%, 0·6 to 2·1; p<0·0001); and for patients diagnosed with heart failure in hospital (2·4%, 1·4 to 3·3) than those diagnosed in the community (1·2%, 0·3 to 2·2). Annual increases in hospitalisation due to heart failure were 2·6% (1·9 to 3·4) for women compared with stable rates in men (0·6%, -0·9 to 2·1), and 1·6% (0·6 to 2·6) for the most deprived group compared with stable rates for the most affluent group (1·2%, -0·3 to 2·8). A significantly higher risk of all-cause hospitalisation was found for the most deprived than for the most affluent (incident rate ratio 1·34, 95% CI 1·32 to 1·35) and for the hospital-diagnosed group than for the community-diagnosed group (1·76, 1·73 to 1·80). Age-adjusted first-year rates of all-cause mortality decreased by 6% from 24·5 (95% CI 23·4 to 39·2) to 23·0 (22·0 to 24·1) per 100 person-years. Annual change in mortality was -1·4% (95% CI -2·3 to -0·5) in men but was stable for women (0·3%, -0·5 to 1·1), and -2·7% (-3·2 to -2·2) for the community-diagnosed group compared with -1·1% (-1·8 to -0·4) in the hospital-diagnosed group (p<0·0001). A significantly higher risk of all-cause mortality was seen in the most deprived group than in the most affluent group (hazard ratio 1·08, 95% CI 1·05 to 1·11) and in the hospital-diagnosed group than in the community-diagnosed group (1·55, 1·53 to 1·58). INTERPRETATION: Tailored management strategies and specialist care for patients with heart failure are needed to address persisting and increasing inequalities for men, the most deprived, and for those who are diagnosed with heart failure in hospital, and to address the worrying trends in women. FUNDING: Wellcome Trust.

12.
N Engl J Med ; 381(8): 716-726, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31433919

RESUMO

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).


Assuntos
Doenças Cardiovasculares/mortalidade , Insuficiência Cardíaca/tratamento farmacológico , Relaxina/uso terapêutico , Vasodilatadores/uso terapêutico , Doença Aguda , Idoso , Pressão Sanguínea/efeitos dos fármacos , Progressão da Doença , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Incidência , Infusões Intravenosas , Masculino , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Relaxina/efeitos adversos , Relaxina/farmacologia , Falha de Tratamento , Vasodilatadores/efeitos adversos
13.
Ther Adv Endocrinol Metab ; 10: 2042018819861593, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308926

RESUMO

Background: Attempts to characterize cardiac structure in heart failure with preserved ejection fraction (HFpEF) in people with type 2 diabetes (T2D) have yielded inconsistent findings. We aimed to determine whether patients with HFpEF and T2D have a distinct pattern of cardiac remodelling compared with those without diabetes and whether remodelling was related to circulating markers of inflammation and fibrosis and clinical outcomes. Methods: We recruited 140 patients with HFpEF (75 with T2D and 65 without). Participants underwent comprehensive cardiovascular phenotyping, including echocardiography, cardiac magnetic resonance imaging and plasma biomarker profiling. Results: Patients with T2D were younger (age 70 ± 9 versus 75 ± 9y, p = 0.002), with evidence of more left ventricular (LV) concentric remodelling (LV mass/volume ratio 0.72 ± 0.15 versus 0.62 ± 0.16, p = 0.024) and smaller indexed left atrial (LA) volumes (maximal LA volume index 48 ± 20 versus 59 ± 29 ml/m2, p = 0.004) than those without diabetes. Plasma biomarkers of inflammation and extracellular matrix remodelling were elevated in those with T2D. Overall, there were 45 hospitalizations for HF and 22 deaths over a median follow-up period of 47 months [interquartile range (IQR) 38-54]. There was no difference in the primary composite endpoint of hospitalization for HF and mortality between groups. On multivariable Cox regression analysis, age, prior HF hospitalization, history of pulmonary disease and LV mass/volume were independent predictors of the primary endpoint. Conclusions: Patients with HFpEF and T2D have increased concentric LV remodelling, smaller LA volumes and evidence of increased systemic inflammation compared with those without diabetes. This suggests the underlying pathophysiology for the development of HFpEF is different in patients with and without T2D. ClinicalTrialsgov identifier: NCT03050593.

14.
J Physiol ; 597(17): 4481-4501, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31241168

RESUMO

KEY POINTS: Acute hyperglycaemia at the time of a heart attack worsens the outcome for the patient. Acute hyperglycaemia is not limited to diabetic patients and can be due to a stress response in non-diabetics. This study suggests that the damaging cardiac effects of hyperglycaemia can be reversed by selective PKC inhibition. If PKCα/ß isoforms are inhibited, then high glucose itself becomes protective against ischaemic damage. Selective PKC inhibition may therefore be a useful therapeutic tool to limit the damage that can occur during a heart attack by stress-induced hyperglycaemia. ABSTRACT: Hyperglycaemia has a powerful association with adverse prognosis for patients with acute coronary syndromes (ACS). Previous work shows that high glucose prevents ischaemic preconditioning and causes electrical and mechanical disruption via protein kinase C α/ß (PKCα/ß) activation. The present study aimed to: (i) determine whether the adverse clinical association of hyperglycaemia in ACS can be replicated in preclinical cellular models of ACS and (ii) determine the importance of PKCα/ß activation to the deleterious effect of glucose. Freshly isolated rat, guinea pig or rabbit cardiomyocytes were exposed to simulated ischaemia after incubation in the presence of normal (5 mm) or high (20 mm) glucose in the absence or presence of small molecule or tat-peptide-linked PKCαß inhibitors. In each of the four conditions, the following hallmarks of cardioprotection were recorded using electrophysiology or fluorescence imaging: cardiomyocyte contraction and survival, action potential stability and time to failure, intracellular calcium and ATP, mitochondrial depolarization, ischaemia-sensitive leak current, and time to Kir 6.2 opening. High glucose alone resulted in decreased cardiomyocyte contraction and survival; however, it also imparted cardioprotection in the presence of PKCα/ß inhibitors. This cardioprotective phenotype displayed improvements in all of the measured parameters and decreased myocardium damage during whole heart coronary ligation experiments. High glucose is deleterious to cellular and whole-heart models of simulated ischaemia, in keeping with the clinical association of hyperglycaemia with an adverse outcome in ACS. PKCαß inhibition revealed high glucose to show a cardioprotective phenotype in this setting. The results of the present study suggest the potential for the therapeutic application of PKCαß inhibition in ACS associated with hyperglycaemia.

16.
Heart ; 105(12): 902-903, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30826772
17.
Clin Res Cardiol ; 108(8): 940-949, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30767059

RESUMO

BACKGROUND: Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction. METHODS: In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.13 ± 10.73 years) and compared to 47 age and sex-matched controls. The primary endpoint was 2-years composite of all-cause mortality and/or heart failure rehospitalisation (HF). A subset (n = 163) received detailed imaging studies. RESULTS: PENK levels were raised in HFpEF (median [interquartile range] 88.9 [62.1-132.0]) compared to normal controls (56.3 [47.9-70.5]). PENK was correlated to urea, eGFR, Body Mass Index and E/e' (rs 0.635, - 0.741, - 0.275, 0.476, respectively, p < 0.0005). During 2 years follow-up 144 patients died and 220 had death/HF endpoints. Multivariable Cox regression models showed PENK independently predicted 2 year death/HF [hazard ratio (for 1 SD increment of log-transformed biomarker) HR 1.45 [95% CI 1.12-1.88, p = 0.005]], even after adjustment for troponin (HR 1.59 [1.14-2.20, p = 0.006]), and Body Mass Index (HR 1.63 [1.13-2.33, p = 0.009]). PENK showed no interaction with ejection fraction status for prediction of poor outcomes. Net reclassification analyses showed PENK significantly improved classification of death/HF outcomes for multivariable models containing natriuretic peptide, troponin and Body Mass Index (p < 0.05 for all). CONCLUSIONS: In HFpEF, PENK levels are related to BMI, and measures of diastolic dysfunction and are prognostic for all-cause mortality and heart failure rehospitalisation.


Assuntos
Encefalinas/sangue , Insuficiência Cardíaca/sangue , Ventrículos do Coração/diagnóstico por imagem , Precursores de Proteínas/sangue , Volume Sistólico/fisiologia , Idoso , Biomarcadores/sangue , Causas de Morte/tendências , Ecocardiografia Doppler , Feminino , Taxa de Filtração Glomerular/fisiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Prognóstico , Taxa de Sobrevida/tendências , Suíça/epidemiologia
18.
JACC Cardiovasc Imaging ; 12(11 Pt 2): 2291-2301, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30772227

RESUMO

OBJECTIVES: This study sought to assess the presence and extent of focal and diffuse fibrosis in heart failure in patients with preserved ejection fraction (HFpEF) compared to asymptomatic control subjects, and the relationship of fibrosis to clinical outcome. BACKGROUND: Myocardial fibrosis has been implicated in the pathophysiology of HFpEF. METHODS: In this prospective, observational study, 140 subjects of similar age and sex (HFpEF: n = 96; control subjects: n = 44; 73 ± 8 years of age; 49% males) underwent cardiac magnetic resonance imaging. Late gadolinium-enhanced (LGE) imaging and T1 mapping to calculate myocardial extracellular volume indexed to body surface area (iECV) were used to assess fibrosis. RESULTS: Patients with HFpEF had more concentric remodeling and worse diastolic function. Focal fibrosis was more frequent in HFpEF subjects (overall: n = 49; infarction: n = 17; nonischemic cases: n = 36; mixed patterns: n = 4) than in control subjects (overall: n = 3). Diffuse fibrosis was also greater in HFpEF subjects than control subjects (iECV: 13.7 ± 4.4 ml/m2 versus 10.9 ± 2.8 ml/m2; p < 0.0001). During median follow-up (1,429 days), there were 42 composite events (14 deaths; 28 heart failure hospitalizations) in cases of HFpEF. Myocardial infarction revealed on LGE imaging was a predictor of outcomes on univariate analysis only. With multivariate analysis, iECV (hazard ratio [HR]: 1.689; 95% confidence interval [CI]: 1.141 to 2.501; p = 0.009) was an independent predictor of outcome along with mitral peak velocity of early filling (E)-to-early diastolic mitral annular velocity (E') (E/E') ratio (HR: 1.716; 95% CI: 1.191 to 2.472; p = 0.004) and prior HF hospitalization (HR: 2.537; 95% CI: 1.090 to 5.902; p = 0.031). iECV was also significantly associated with ventricular/left atrial remodeling and renal dysfunction: right ventricular end-diastolic volume indexed (r = 0.456; p < 0.0001), left ventricular mass/volume (r = 0.348; p = 0.001), maximal left atrial volume indexed (r = 0. 269; p = 0.009), and creatinine (r = 0.271; p = 0.009). CONCLUSIONS: Both focal and diffuse myocardial fibrosis are more prevalent in HFpEF subjects than in control subjects of similar age and sex. iECV significantly correlates with indices of ventricular/left atrial remodeling and renal dysfunction and is an independent predictor of adverse outcome in HFpEF. (Developing Imaging And plasMa biOmarkers iN Describing Heart Failure With Preserved Ejection Fraction [DIAMONDHFpEF]; NCT03050593).

19.
BMC Cardiovasc Disord ; 19(1): 24, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30665364

RESUMO

Following publication of the original article [1], the author reported his name has erroneously spelled as Abishek Shetye. The correct name is Abhishek Shetye.

20.
Eur Heart J ; 39(30): 2773-2774, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30107425
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