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2.
Eur J Heart Fail ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32353199

RESUMO

AIMS: Laboratory measures of haemoconcentration correlate with invasive haemodynamics and clinical outcomes in hospitalized heart failure (HF) patients. We aimed to determine the association between haemoconcentration and haemodynamic measures in ambulatory HF patients with implantable pulmonary arterial pressure (PAP) sensors. METHODS AND RESULTS: We reviewed ambulatory HF patients (n = 23) managed at the Brigham and Women's Hospital with implantable PAP sensors (CardioMEMS™, Abbott, Atlanta, GA, USA) who had sufficient data for serial haemodynamic-haemoconcentration correlation. The primary measures of interest were the absolute changes in haemoglobin and diastolic PAP at follow-up compared to baseline values (obtained at implantation). In 23 patients (median age 64 years, 57% with HF with preserved ejection fraction), 518 paired laboratory-haemodynamic measurements were evaluated. At a median follow-up of 27 (interquartile range 13-42) months, 17 (74%) patients had at least one hospitalization (59 total hospitalizations including 30 HF hospitalizations). For the population as a whole, diastolic PAP was negatively correlated with haemoglobin level (r = -0.09, P = 0.053). This negative correlation was more apparent when changes in haemoglobin and diastolic PAP were evaluated at the time of HF hospitalization compared to baseline values (r = -0.40, P = 0.029). The mean rise in diastolic PAP of 3.6 mmHg at HF hospitalization corresponded to a numerical decline of 0.6 g/dL in haemoglobin (P = 0.20). CONCLUSION: Change in haemoglobin was correlated with change in diastolic PAP in ambulatory HF patients, especially at the time of HF hospitalization. These findings support the potential for investigation into the role of ambulatory monitoring of haemoglobin as an inexpensive, non-invasive tool to guide de-congestion strategies and potentially prevent HF hospitalizations.

3.
Eur J Heart Fail ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32353205

RESUMO

AIMS: Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of 'health deficits' across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Using a cumulative deficits approach, we constructed a 42-item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM-HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non-frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all-cause death or all-cause hospitalization: 40.7 (39.1-42.4) vs. 22.1 (21.2-23.0) per 100 person-years in the non-frail; adjusted hazard ratio 1.63 (1.53-1.75) (P < 0.001). The rate of all-cause hospitalizations, taking account of recurrences, was 61.5 (59.8-63.1) vs. 31.2 (30.3-32.2) per 100 person-years (incidence rate ratio 1.76; 1.62-1.90; P < 0.001). CONCLUSION: Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF.

4.
Circ Heart Fail ; 13(5): e006597, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32354280

RESUMO

BACKGROUND: Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status. METHODS: Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients. RESULTS: A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92]; P for interaction, 0.54). CONCLUSIONS: Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.

5.
Am J Hypertens ; 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32369546

RESUMO

BACKGROUND: Type 2 diabetes (T2D) and resistant hypertension (rHT) often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676). METHODS: Overall, 7020 patients received empagliflozin 10mg, 25mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ≥3 classes of antihypertensive drugs including a diuretic and uncontrolled BP (SBP≥140 and/or diastolic BP [DBP]≥90 mmHg), or ≥4 classes of antihypertensive, including a diuretic, and controlled BP. We explored the effect of empagliflozin on CV death, heart failure hospitalization (HHF), 3-point major adverse cardiac events (3P-MACE), all-cause death, and incident/worsening nephropathy by Cox regression and BP over time by a mixed-repeated-measures-model analysis. RESULTS: 1579 (22.5%) patients had prHT. The mean difference in change in SBP from baseline to week 12 versus placebo was -4.5 (95% CI, -5.9 to -3.1) mmHg (p<0.001) in prHT and -3.7 (-4.5, -2.9) mmHg (p<0.001) in patients without prHT. SBP was more frequently controlled (<130/80 mmHg) with empagliflozin than with placebo. Patients with prHT had 1.5 to 2-fold greater risk of HHF, incident/worsening nephropathy and CV death compared to those without prHT. Empagliflozin improved all outcomes in patients with and without prHT (interaction P>0.1 for all outcomes). CONCLUSIONS: Empagliflozin induced a clinically relevant reduction in SBP and consistently improved all outcomes regardless of prHT status. Due to these dual effects, empagliflozin should be considered for patients with hypertension and T2D.

6.
Eur J Heart Fail ; 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32452128

RESUMO

BACKGROUND: Spironolactone up-titration may be limited by side effects that could be minimized at lower than target doses, whether lower than target doses remain efficacious is unknown. In TOPCAT, spironolactone (or placebo) were started at 15 mg/day, and increased up to a maximum of 45 mg/day. The prognostic implications related to spironolactone dose are is yet to be reported. AIMS: To assess the average spironolactone/placebo doses provided during the trial, overall and within "high-risk" subgroups (e.g. elderly, renal dysfunction, high potassium); discontinuation rates; and the efficacy of lower than target doses in HFpEF. METHODS: 1767 patients from "TOPCAT-Americas" were included. Linear, logistic and Cox regressions were applied. RESULTS: Patients randomized to spironolactone received lower doses than placebo: 22.5 (15.0-27.5)mg/day vs. 27.5 (17.5-27.5)mg/day; p < 0.001. Patients aged≥75 years, with an eGFR≤60 mL/min/1.73m2 , and with a K+ > 4.5 mmol/L, received lower spironolactone doses (median≈20 mg/day). This pattern of dose-differences was not observed in patients taking placebo, where the between-subgroup placebo doses were similar (spironolactone-placebo by subgroup interactionp < 0.05). Among patients taking spironolactone, 25.4% discontinued the drug during the first year, compared with 18.3% of the patients taking placebo; p < 0.001. The discontinuation rates in the aforementioned "high-risk" subgroups reached 30% during the first year. Spironolactone reduced the primary outcome of HFH/CVD without significant heterogeneity between the studied subgroups (interactionp > 0.1). Spironolactone discontinuation was associated with a 2 to 4-fold higher risk of subsequent events. CONCLUSION: Spironolactone (but not placebo) was used at lower doses among the elderly, those with renal dysfunction and with higher potassium levels. The effect of spironolactone was homogenous across these subgroups. In patients unable to tolerate "target" doses, a low-dose strategy should be preferred to stopping treatment. This article is protected by copyright. All rights reserved.

7.
JACC Heart Fail ; 8(6): 441-450, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32466836

RESUMO

OBJECTIVES: The purpose of this study was to compare the win ratio (WR) with the corresponding hazard ratios (HRs) and 1/HR. BACKGROUND: The primary outcome in many cardiovascular trials is a composite that includes nonfatal and fatal events. The time-to-first event analysis gives equal statistical weighting to each component event. The WR, which takes into account the clinical importance and timing of the outcomes, has been suggested as an alternative approach. METHODS: Cox proportional hazards models and WR. RESULTS: In the these trials (n = 16) the WR and HR differed only slightly. For example, in the PARADIGM-HF (sacubitril/valsartan vs. enalapril), the primary outcome of time to first heart failure hospitalization (HFH) or cardiovascular death (CVD) and use of the Cox model gave a 1/HR of 1.25 (95% confidence interval [CI]: 1.12 to 1. 41; z-score = 4.8). Using WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.27 (95% CI: 1.15 to 1.39; z-score = 4.7), reflecting an effect similar to that of sacubitril/valsartan therapy on CVD and HFH. In the DIG (digoxin vs. placebo) trial, the outcome of time-to-first HFH or CVD using Cox gave a 1/HR of 1.18 (95% CI: 1.10 to 1.27; z-score = 4.5). Using the WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.14 (95% CI: 1.05 to 1.20; z-score = 3.1), reflecting a larger effect of digoxin on HFH than on CVD. Several other trials and endpoints including patient-reported measurements were studied. CONCLUSIONS: In 16 large cardiovascular outcome trials, HR and WR provided similar estimates of treatment effects. The WR allows prioritization of fatal outcomes and the hierarchical testing of broader composite endpoints including patient-reported outcomes. In this way, the WR allows for the incorporation of patient-centered and other outcomes, while prioritizing the competing risk of death and hospital admission.

8.
Eur J Heart Fail ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32237012

RESUMO

AIMS: In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results. METHODS AND RESULTS: In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naïve, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady-state concentrations had not been reached by 48 h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints. CONCLUSIONS: Lower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial.

11.
Am J Hypertens ; 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32267470

RESUMO

BACKGROUND: Recent studies have shown that hyperuricemia may be associated with incident hypertension (HTN). We examined whether serum uric acid (SUA) is a predictor of HTN and target organ damage (TOD) 20 years later in initially healthy middle-aged individuals. METHODS: Participants from the Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) a single-center familial longitudinal cohort study (961 initially healthy adults and 570 children) underwent clinical and laboratory measurements at baseline and after approximately 20 years. Blood pressure (BP: using ambulatory BP measurements), urine albumin-to-creatinine ratio, estimated glomerular filtration rate (eGFR), left ventricular hypertrophy (LVH), diastolic dysfunction, and carotid-femoral pulse wave velocity (PWV) were measured at the end of follow-up. RESULTS: In the parent population, higher baseline or last SUA levels and higher change in SUA (ΔUA) were significantly associated with an increased risk of HTN development, even after adjusting for known HTN risk factors (all P < 0.01). Higher baseline SUA was marginally associated with an increased risk of having high carotid-femoral PWV (P = 0.05). The association of SUA with BP increase was body mass index dependent (the increase in BP being greater in leaner subjects; interactionp < 0.05), and the association of SUA with eGFR decline was age dependent (the decline in eGFR being greater in older subjects; interactionp < 0.05). There was no significant association between SUA and diastolic dysfunction or LVH. In the whole population (i.e. including children), a significant association between SUA at baseline and the risk of HTN and higher carotid-femoral PWV was also found (both P < 0.02). CONCLUSIONS: Increased SUA is associated with the development of HTN and vascular/renal TOD in initially healthy midlife subjects.

12.
Eur Heart J ; 41(17): 1673-1683, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32118256

RESUMO

AIMS: The described association of low diastolic blood pressure (DBP) with increased cardiovascular outcomes could be due to reduced coronary perfusion or is simply due to reverse causation. If DBP is physiologically relevant, coronary reperfusion after myocardial infarction (MI) might influence DBP-risk association. METHODS AND RESULTS: The relation of achieved DBP with cardiovascular death or cardiovascular hospitalization, cardiovascular death, and all-cause death was explored in 5929 patients after acute myocardial infarction (AMI) with impaired left ventricular function, signs and symptoms of heart failure, or diabetes in the EPHESUS trial according to their reperfusion status. Cox regression models were used to assess the impact of reperfusion status on the association of DBP and systolic blood pressure (SBP) with outcomes in an adjusted fashion. In patients without reperfusion, lower DBP <70 mmHg was associated with increased risk for all-cause death [adjusted hazard ratios (HRs) 1.80, 95% confidence interval (CI) 1.41-2.30; P < 0.001], cardiovascular death (HR 1.70, 95% CI 1.3-3.22; P < 0.001), cardiovascular death or cardiovascular hospitalization (HR 1.54, 95% CI 1.26-1.87; P < 0.001). In patients with reperfusion, the risk increase at low DBP was not observed. At low SBP, risk increased independently of reperfusion. A sensitivity analysis in the subgroup of patients with optimal SBP of 120-130 mmHg showed again risk reduction of reperfusion at low DBP. Adding the treatment allocation to eplerenone or placebo into the models had no effects on the results. CONCLUSION: Patients after AMIs with a low DBP had an increased risk, which was sensitive to reperfusion therapy. Low blood pressure after MI identifies in patients with particular higher risk. These data support the hypothesis that low DBP in patients with stenotic coronary lesions is associated with risk, potentially involving coronary perfusion pressure and the recommendations provided by guidelines suggesting lower DBP boundaries for these high-risk patients.

13.
JACC Heart Fail ; 8(5): 359-368, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171760

RESUMO

OBJECTIVES: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial. BACKGROUND: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide ≥200 ng/l or N-terminal pro-B-type natriuretic peptide ≥800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. METHODS: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. RESULTS: A total of 5,022 patients with left ventricular ejection fraction ≤40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. CONCLUSIONS: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915).

14.
Clin Res Cardiol ; 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32215700

RESUMO

BACKGROUND: The CHARM-Preserved trial suggested that the renin-angiotensin system (RAS) inhibitor candesartan might have been beneficial in heart failure with preserved ejection fraction (HFpEF); however, this hypothesis was not supported by the findings of I-Preserve with irbesartan. AIMS: To re-analyse the results of I-Preserve, adjusting for imbalances in baseline variables that may have influenced the trial outcomes. METHODS: Cox proportional hazards models with covariate adjustment for baseline variables, including age, sex, medical history, physiological and laboratory variables. RESULTS: In I-Preserve, 763 (37.0%) participants in the placebo group and 742 (35.9%) in the irbesartan group experienced the primary composite outcome (death from any cause or hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). The prespecified analysis of this outcome, stratifying for the use of ACEi at baseline, gave a hazard ratio (HR) of 0.95 (95% confidence interval, 0.86-1.05); p = 0.35. Adjusting the effect of treatment for key prognostic baseline variables, gave a HR of 0.89 (0.80-0.99); p = 0.033. Similar findings were observed for the composite of cardiovascular death or HF hospitalization. CONCLUSION: Adjusting for imbalances in baseline variables that influence outcomes (or the response to therapy or both) can improve the power around the estimate of the effect of treatment and may alter its statistical significance. Along with the CHARM-Preserved results, these findings suggest that angiotensin-receptor blockers may have a modest effect in HFpEF.

15.
J Am Heart Assoc ; 9(7): e014758, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32208829

RESUMO

Background PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds low-density lipoprotein receptor, preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis. The PCSK9-rs562556 variant has been reported as a gain-of-function mutation. The aim of this study was to determine whether the PCSK9-low-density lipoprotein receptor-rs562556 axis is associated with carotid artery plaques between 2 visits separated by almost 20 years in a longitudinal population cohort. Methods and Results The STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort is a longitudinal familial cohort from the Lorraine region of France. Participants attending 2 visits (visit 1 and visit 4) separated by 18.5 years (mean) were included (n=997). Carotid artery plaques were determined with standardized vascular echography. The mean age of the adult population at visit 1 was 42±5 years. At visit 4, 203 (20.4%) participants had arterial plaques. Participants who developed arterial plaques were older (42.7±5.4 versus 41.7±4.7 years), more often male (60% versus 49%), smokers (29% versus 18%), with diabetes mellitus (6% versus 3%), and higher cholesterol levels (low-density lipoprotein cholesterol, 1.6±0.4 versus 1.5±0.3 g/L) (all P<0.05). The independent factors associated with arterial plaques were age, smoking, and low-density lipoprotein cholesterol. Higher PCSK9 levels were associated with arterial plaques on top of the clinical model (odds ratio, 2.14; 95% CI,= 1.28-3.58); the missense mutation coding the single-nucleotide polymorphism rs562556 was associated with both higher PCSK9 concentration and incident carotid arterial plaques. Conclusions Higher PCSK9 concentration was associated with the development of arterial plaques almost 20 years in advance in a healthy middle-aged population. Mutations of the single-nucleotide polymorphism rs562556 associated with both PCSK9 levels and arterial plaques reinforce the potential causality of our findings. PCSK9 inhibitors could be useful for primary cardiovascular prevention.

16.
ESC Heart Fail ; 7(3): 953-963, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32167681

RESUMO

AIMS: Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF. METHODS AND RESULTS: We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile25-75 = 28-247) µIU/mL and 9.4 (percentile25-75 = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies. CONCLUSIONS: Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility.

17.
J Alzheimers Dis ; 74(1): 227-235, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32039844

RESUMO

BACKGROUND: Hippocampal atrophy is associated with cognitive decline. Determining the clinical features associated with hippocampal volume (HV)/atrophy may help in tailoring preventive strategies. OBJECTIVE: This study was aimed to investigate the association between HV (at visit 2) and vascular status (both at visit 1 and visit 2) in a cohort of individuals aged 60+ with hypertension and without overt cognitive impairment at visit 1 (visit 1 and visit 2 were separated by approximately 8 years). METHODS: Hippocampal volume was estimated in brain MRIs as HV both clinically with the Scheltens' Medial Temporal Atrophy score, and automatically with the Free Surfer Software application. A detailed medical history, somatometric measurements, cognitive tests, leukoaraiosis severity (Fazekas score), vascular parameters including pulse wave velocity, central blood pressure, and carotid artery plaques, as well as several biochemical parameters were also measured. RESULTS: 113 hypertensive patients, 47% male, aged 75.1±5.6 years, participated in both visit 1 and visit 2 of the ADELAHYDE study. Age (ß= -0.30) and hypertension duration (ß= -0.20) at visit 1 were independently associated with smaller HV at visit 2 (p < 0.05 for all). In addition to these variables, low body mass index (ß= 0.18), high MRI Fazekas score (ß= -0.20), and low Gröber-Buschke total recall (ß= 0.27) were associated with smaller HV at visit 2 (p < 0.05 for all). CONCLUSION: In a cohort of older individuals without cognitive impairment at baseline, we described several factors associated with lower HV, of which hypertension duration can potentially be modified.

18.
Eur J Heart Fail ; 22(5): 834-844, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077220

RESUMO

AIMS: Women with heart failure (HF) are under-represented in individual randomized clinical trials (RCTs). Little is known about sex-specific treatment effects in HF medications. We evaluated sex differences in the response to mineralocorticoid receptor antagonists (MRAs) in major HF MRA trials, including a broad spectrum of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Individual patient data fixed-effect meta-analysis was performed using 6167 patients (31.4% were women) recruited in three placebo-controlled RCTs: Randomized Aldactone Evaluation Study (RALES), Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) and Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT)-Americas. Compared to men, women were older, had higher body mass index and lower glomerular filtration rate. They also had higher LVEF and poorer New York Heart Association functional class and were less likely to be taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. Placebo-arm event rates were lower for women compared with men (15.4 vs. 22.1 per 100 person-year; P = 0.002). MRAs reduced consistently, in men and women, the relative risk for cardiovascular death or HF hospitalization (P for interaction = 0.83), cardiovascular death (P for interaction = 0.44) and all-cause death (P for interaction = 0.19). These findings remained consistent after adjustment for potential confounders, regardless of LVEF. There was no sex-specific impact of MRA on the rate of hyperkalaemia and worsening renal function during the median 22 months of follow-up. CONCLUSION: In three large MRA RCTs, women were substantially different from men with regard to their clinical features and event rates. Nonetheless, this meta-analysis supports a consistent and beneficial MRA effect regardless of sex.

19.
Biomarkers ; 25(2): 201-211, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32063068

RESUMO

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes.Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression.Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism.Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.

20.
Eur J Heart Fail ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31950604

RESUMO

AIMS: Asymptomatic patients with coronary artery disease (CAD), hypertension and/or type 2 diabetes mellitus (T2DM) are at greater risk of developing heart failure (HF). Fibrosis, leading to myocardial and vascular dysfunction, might be an important pathway of progression. The Heart OMics in AGing (HOMAGE) trial aims to investigate the effects of spironolactone on serum markers of collagen metabolism and on cardiovascular structure and function in people at risk of developing HF and potential interactions with a marker of fibrogenic activity, galectin-3. METHODS AND RESULTS: The HOMAGE trial is a prospective, randomised, open-label, blinded endpoint (PROBE) study comparing spironolactone (up to 50 mg/day) and standard care over 9 months in people with clinical risk factors for developing HF, including hypertension, CAD and T2DM, and elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP, 125 to 1000 ng/L) or B-type natriuretic peptide (BNP, 35 to 280 ng/L). Exclusion criteria included left ventricular ejection fraction < 45%, atrial fibrillation, severe renal dysfunction, or treatment with loop diuretics. The primary endpoint was the interaction between change in serum concentrations of procollagen type III N-terminal propeptide (PIIINP) and treatment with spironolactone according to median plasma concentrations of galectin-3 at baseline. For the 527 participants enrolled, median (interquartile range) age was 73 (69-79) years, 135 (26%) were women, 412 (78%) had hypertension, 377 (72%) CAD, and 212 (40%) T2DM. At baseline, medians (interquartile ranges) were for left ventricular ejection fraction 63 (58-67) %, for left atrial volume index 31 (26-37) mL/m2 , for plasma NT-proBNP 214 (137-356) ng/L, for serum PIIINP 3.9 (3.1-5.0) ng/mL, and for galectin-3 16.1 (13.5-19.7) ng/mL. CONCLUSIONS: The HOMAGE trial will provide insights on the effect of spironolactone on pathways that might drive progression to HF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02556450.

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