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1.
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.

2.
Clin Res Cardiol ; 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253507

RESUMO

BACKGROUND: Plasma volume (PV) estimated from Duarte's formula (based on hemoglobin/hematocrit) has been associated with poor prognosis in patients with heart failure (HF). There are, however, limited data regarding the association of estimated PV status (ePVS) derived from hemoglobin/hematocrit with clinical profiles and study outcomes in patients with HF and preserved ejection fraction (HFpEF). METHODS AND RESULTS: Patients from North and South America enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) with available hemoglobin/hematocrit data were studied. The association between ePVS (Duarte formula and Hakim formula) and the composite of cardiovascular mortality, HF hospitalization, or aborted cardiac arrest was assessed. Among 1747 patients (age 71.6 years; males 50.1%), mean ePVS derived from Duarte formula was 4.9 ± 1.0 mL/g. Higher Duarte-derived ePVS was associated with prior HF admission, diabetes, more severe congestion, poor renal function, higher natriuretic peptide level, and E/e'. After adjustment for potential covariates including natriuretic peptide, higher Duarte-derived ePVS was associated with an increased rate of the primary outcome [highest vs. lowest ePVS quartile: adjusted-HR (95%CI) = 1.79 (1.28-2.50), p < 0.001]. Duarte-derived ePVS improved prognostic performance on top of clinical and routine variables (including natriuretic peptides) (NRI = 11, p < 0.001), whereas Hakim-derived ePVS did not (p = 0.59). The prognostic value of Duarte-derived ePVS was not modified by renal function (P interaction > 0.10 for all outcomes). CONCLUSION: ePVS from Duarte's formula was associated with congestion status and improved risk stratification regardless of renal function. Our findings suggest that Duarte-derived ePVS is a useful congestion variable in patients with HFpEF.

3.
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.

4.
ESC Heart Fail ; 2020 Mar 13.
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.

5.
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.

6.
J Am Heart Assoc ; 9(7): e013836, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32200718

RESUMO

Background The diet impact on cardiovascular diseases has been investigated widely, but the association between dietary patterns (DPs) and subclinical cardiovascular damage remains unclear. More informative DPs could be provided by considering metabolic syndrome components as intermediate markers. This study aimed to identify DPs according to generation and sex using reduced-rank regression (RRR) with metabolic syndrome components as intermediate markers and assess their associations with intima-media thickness, left ventricular mass, and carotid-femoral pulse-wave velocity in an initially healthy population-based family study. Methods and Results This study included 1527 participants from the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort fourth examination. DPs were derived using reduced-rank regression according to generation (G1: age ≥50 years; G2: age <50 years) and sex. Associations between DPs and cardiovascular damage were analyzed using multivariable linear regression models. Although identified DPs were correlated between generations and sex, qualitative differences were observed: whereas only unhealthy DPs were found for both men generations, healthy DPs were identified in G2 ("fruity desserts") and G1 ("fiber and w3 oil") women. The "alcohol," "fast food and alcohol," "fried, processed, and dairy products," and "meat, starch, sodas, and fat" DPs in G1 and G2 men and in G1 and G2 women, respectively, were associated with high left ventricular mass (ß [95% CI], 0.23 [0.10-0.36], 0.76 [0.00-1.52], 1.71 [0.16-3.26], and 1.80 [0.45-3.14]). The "alcohol" DP in G1 men was positively associated with carotid-femoral pulse-wave velocity (0.22 [0.09-0.34]). Conclusions The DPs that explain the maximum variation in metabolic syndrome components had different associations with subclinical cardiovascular damage across generation and sex. Our results indicate that dietary recommendations should be tailored according to age and sex. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01391442.

7.
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.

8.
Clin Res Cardiol ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32006155

RESUMO

BACKGROUND: Estimated plasma volume status (ePVS) has diagnostic and prognostic value in patients with heart failure (HF). However, it remains unclear which congestion markers (i.e., biological, imaging, and hemodynamic markers) are preferentially associated with ePVS. In addition, there is evidence of sex differences in both the hematopoietic process and myocardial structure/function. METHOD AND RESULTS: Patients with significant dyspnea (NYHA ≥ 2) underwent echocardiography and lung ultrasound within 4 h prior to cardiac catheterization. Patients were divided according to tertiles based on sex-specific ePVS thresholds calculated from hemoglobin and hematocrit measurements using Duarte's formula. Among the 78 included patients (median age 74.5 years; males 69.2%; HF 48.7%), median ePVS was 4.1 (percentile25-75 = 3.7-4.9) mL/g in males (N = 54) and 4.8 (4.4-5.3) mL/g in females (N = 24). Patients with the highest ePVS had more frequently HF, higher NT-proBNP, larger left atrial volume, and higher E/e' (all p values < 0.05), but no difference in inferior vena cava diameter or pulmonary congestion assessed by lung ultrasound (all p values > 0.10). In multivariable analysis, higher E/e' and lower diastolic blood pressure were significantly associated with increased ePVS. The association between ePVS and congestion variables was not sex-dependent except for left-ventricular end-diastolic pressure, which was only correlated with ePVS in females (Spearman Rho = 0.53, p < 0.01 in females and Spearman Rho = - 0.04, p = 0.76 in males; pinteraction = 0.08). CONCLUSION: ePVS is associated with E/e' regardless of sex, while only associated with invasively measured left-ventricular end-diastolic pressure in females. These results suggest that ePVS is preferably associated with left-sided hemodynamic markers of congestion.

9.
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.

10.
ESC Heart Fail ; 7(2): 503-511, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31951323

RESUMO

AIMS: The Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure trial investigated the effects of adaptive servo-ventilation (ASV) (vs. control) on outcomes of 1325 patients with heart failure and reduced ejection fraction (HFrEF) and central sleep apnoea (CSA). The primary outcome (a composite of all-cause death or unplanned HF hospitalization) did not differ between the two groups. However, all-cause and cardiovascular (CV) mortality were higher in the ASV group. Circulating biomarkers may help in better ascertain patients' risk, and this is the first study applying a large set of circulating biomarkers in patients with both HFrEF and CSA. METHODS AND RESULTS: Circulating protein-biomarkers (n = 276) ontologically involved in CV pathways, were studied in 749 (57% of the trial population) patients (biomarker substudy), to investigate their association with the study outcomes (primary outcome, CV death and all-cause death). The mean age was 69 ± 10 years, and > 90% were male. The groups (ASV vs. control and biomarker substudy vs. no biomarker) were well balanced. The "best" clinical prognostic model included male sex, systolic blood pressure < 120 mmHg, diabetes, loop diuretic, cardiac device, 6-min walking test distance, and N-terminal pro BNP as the strongest prognosticators. On top of the "best" clinical prognostic model, the biomarkers that significantly improved both the discrimination (c-index) and the net reclassification index (NRI) of the model were soluble suppression of tumorigenicity 2 for the primary outcome; neurogenic locus notch homolog protein 3 (Notch-3) for CV-death and all-cause death; and growth differentiation factor 15 (GDF-15) for all-cause death only. CONCLUSIONS: We studied 276 circulating biomarkers in patients with HFrEF and central sleep apnoea; of these biomarkers, three added significant prognostic information on top of the best clinical model: soluble suppression of tumorigenicity 2 (primary outcome), Notch-3 (CV and all-cause death), and GDF-15 (all-cause death).

11.
Eur J Heart Fail ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944496

RESUMO

AIMS: To develop a risk model for sudden cardiac death (SCD) in high-risk acute myocardial infarction (AMI) survivors. METHODS AND RESULTS: Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non-SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0-3.5) per 100 person-years over a median follow-up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate < 60 mL/min/1.73 m2 ; and no coronary reperfusion or revascularisation therapy for index AMI. The model was well calibrated and showed good discrimination (C-statistic = 0.72), including in the early period after AMI. The observed 2-year event rates increased steeply with each quintile of risk score (1.9%, 3.6%, 6.2%, 9.0%, 13.4%, respectively). CONCLUSION: An easy to use SCD risk score developed from routinely collected clinical variables in patients with heart failure, left ventricular systolic dysfunction or both, early after AMI was superior to left ventricular ejection fraction. This score might be useful in identifying patients for future trials testing treatments to prevent SCD early after AMI.

12.
Eur J Heart Fail ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919958

RESUMO

BACKGROUND: To assess the prognostic value of mineralocorticoid receptor antagonist (MRA) initiation and change in serum potassium (K+ ) during follow-up in patients post-acute myocardial infarction with left ventricular dysfunction or chronic heart failure (HF) and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Risk scores for predicting cardiovascular death (primary outcome), hospitalization for HF and all-cause death were developed. K+ and other relevant time-updated clinical and biological variables were added to conventional prognostic factors when constructing these new models. EPHESUS (n = 6632) was the derivation cohort, while EMPHASIS-HF (chronic HF, n = 2737) was used as external validation cohort. The final cardiovascular death risk score included medical history, clinical and biological parameters (e.g. K+ , below or above the normal range of 4-5 mmol/L, estimated glomerular filtration rate, and anaemia), as well as aspects of treatment (any diuretic usage, MRA use or discontinuation, and beta-blocker use). The risk score performed well in both the derivation and validation cohorts and outperformed the MAGGIC score. A web-based calculator was created to allow easy determination of the risk score (http://cic-p-nancy.fr/CardiovascularriskscoreCalculator/). CONCLUSION: Adding time-updated variables, including K+ and MRA treatment, improved risk prediction of cardiovascular death (on top of the MAGGIC score) in patients with HF eligible for renin-angiotensin system inhibitors and MRA therapy. This new risk score including MRA usage and K+ may be of value in helping physicians to better use MRAs, avoid unnecessary and potentially detrimental permanent discontinuations, and therefore improving cardiovascular outcomes in patients with chronic HFrEF or HF after acute myocardial infarction with left ventricular dysfunction.

13.
Chest ; 157(1): 99-110, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31381880

RESUMO

BACKGROUND: Early appropriate diagnosis of acute heart failure (AHF) is recommended by international guidelines. This study assessed the value of several lung ultrasound (LUS) strategies for identifying AHF in the ED. METHODS: This prospective study, conducted in four EDs, included patients with diagnostic uncertainty based on initial clinical judgment. A clinical diagnosis score for AHF (Brest score) was quantified, followed by an extensive LUS examination performed according to the 4-point (BLUE protocol) and 6-, 8-, and 28-point methods. The primary outcome was AHF discharge diagnosis adjudicated by two senior physicians blinded to LUS measurements. The C-index was used to quantify discrimination. RESULTS: Among the 117 included patients, AHF (n = 69) was identified in 27.4%, 56.2%, 54.8%, and 76.7% of patients with the 4-point (two bilateral positive points), 6-point, 8-point (≥ 1 bilateral positive point), and 28-point (B-line count ≥ 30) methods, respectively. The C-index (95% CI) of the Brest score was 72.8 (65.3-80.3), whereas the C-index of the 4-, 6-, 8-, and 28-point methods were 63.7 (58.5-68.8), 72.4 (65.0-79.8), 74.0 (67.1-80.9), and 72.4 (63.9-80.9). The highest increase in the C-index on top of the BREST score was observed with the 8-point method in the whole population (6.9; 95% CI, 1.6-12.2; P = .010) and in the population with an intermediate Brest score, followed by the 6-point method. CONCLUSIONS: In patients with diagnostic uncertainty, the 6-point/8-point LUS method (using the 1 bilateral positive point threshold) improves AHF diagnosis accuracy on top of the BREST score. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03194243; URL: www.clinicaltrials.gov.

14.
Eur J Intern Med ; 71: 62-69, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31708361

RESUMO

BACKGROUND: Knowledge on the association between heart failure (HF) etiologies, precipitant causes and clinical outcomes may help in ascertaining patient's risk and in selecting tailored therapeutic strategies. METHODS: The prognostic value of both HF etiologies and precipitants for worsening HF were analyzed using the index cohort of BIOSTAT-CHF. The studied HF etiologies were: a) ischemic HF; b) dilated cardiomyopathy; c) hypertensive HF; d) valvular HF; and e) other/unknown. The precipitating factors for worsening HF were: a) atrial fibrillation; b) non-adherence; c) renal failure; d) acute coronary syndrome; e) hypertension; and f) Infection. The primary outcome was the composite of all-cause death or HF hospitalization. RESULTS: Among 2465 patients included in the study, 45% (N = =1102) had ischemic HF, 23% (N = =563) dilated cardiomyopathy, 15% (N = =379) other/unknown, 10% (N = =237) hypertensive and 7% (N = =184) valvular HF. Patients with ischemic HF had the worst prognosis, whereas patients with dilated cardiomyopathy had the best prognosis. From the precipitating factors for worsening HF, renal failure was the one independently associated with worse prognosis (adjusted HR (95%CI) = =1.48 (1.04-2.09), p < 0.001). We found no interaction between HF etiologies and precipitating factors for worsening HF with regard to the study outcomes (p interaction > 0.10 for all). Treatment up-titration benefited patients regardless of their underlying etiology or precipitating cause (p interaction > 0.10 for all). CONCLUSIONS: In BIOSTAT-CHF, patients with HF of an ischemic etiology, and those with worsening HF precipitated by renal failure (irrespective of the underlying HF etiology), had the highest rates of death and HF hospitalization, but still benefited equally from treatment up-titration.

15.
Neurobiol Dis ; 136: 104709, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31843706

RESUMO

Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "severe" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.

16.
Clin Res Cardiol ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784904

RESUMO

INTRODUCTION: The SERVE-HF trial included patients with heart failure and reduced ejection fraction (HFrEF) with sleep-disordered breathing, randomly assigned to treatment with Adaptive-Servo Ventilation (ASV) or control. The primary outcome was the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. A subgroup analysis of the SERVE-HF trial suggested that patients with Cheyne-Stokes respiration (CSR) < 20% (low CSR) experienced a beneficial effect from ASV, whereas in patients with CSR ≥ 20% ASV might have been harmful. Identifying the proteomic signatures and the underlying mechanistic pathways expressed in patients with CSR could help generating hypothesis for future research. METHODS: Using a large set of circulating protein-biomarkers (n = 276, available in 749 patients; 57% of the SERVE-HF population) we sought to investigate the proteins associated with CSR and to study the underlying mechanisms that these circulating proteins might represent. RESULTS: The mean age was 69 ± 10 years and > 90% were male. Patients with CSR < 20% (n = 139) had less apnoea-hypopnea index (AHI) events per hour and less oxygen desaturation. Patients with CSR < 20% might have experienced a beneficial effect of ASV treatment (primary outcome HR [95% CI] = 0.55 [0.34-0.88]; p = 0.012), whereas those with CSR ≥ 20% might have experienced a detrimental effect of ASV treatment (primary outcome HR [95% CI] = 1.39 [1.09-1.76]; p = 0.008); p for interaction = 0.001. Of the 276 studied biomarkers, 8 were associated with CSR (after adjustment and with a FDR1%-corrected p value). For example, higher PAR-1 and ITGB2 levels were associated with higher odds of having CSR < 20%, whereas higher LOX-1 levels were associated with higher odds of CSR ≥ 20%. Signalling, metabolic, haemostatic and immunologic pathways underlie the expression of these biomarkers. CONCLUSION: We identified proteomic signatures that may represent underlying mechanistic pathways associated with patterns of CSR in HFrEF. These hypothesis-generating findings require further investigation towards better understanding of CSR in HFrEF. SUMMARY OF THE FINDINGS: PAR-1 proteinase-activated receptor 1, ADM adrenomedullin, HSP-27 heat shock protein-27, ITGB2 integrin beta 2, GLO1 glyoxalase 1, ENRAGE/S100A12 S100 calcium-binding protein A12, LOX-1 lectin-like LDL receptor 1, ADAM-TS13 disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 also known as von Willebrand factor-cleaving protease.

17.
Am Heart J ; 215: 83-90, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31291604

RESUMO

BACKGROUND: Reduced left ventricular ejection fraction (LVEF) after acute myocardial infarction (MI) increases risk of cardiovascular (CV) hospitalizations, but evidence regarding its association with non-CV outcome is scarce. We investigated the association between LVEF and adjudicated cause-specific hospitalizations following MI complicated with low LVEF or overt heart failure (HF). METHODS: In an individual patient data meta-analysis of 19,740 patients from 3 large randomized trials, Fine and Gray competing risk modeling was performed to study the association between LVEF and hospitalization types. RESULTS: The most common cause of hospitalization was non-CV (n = 2,368 for HF, n = 1,554 for MI, and n = 3,703 for non-CV). All types of hospitalizations significantly increased with decreasing LVEF. The absolute risk increase associated with LVEF ≪25% (vs LVEF ≫35%) was 15.5% (95% CI 13.4-17.5) for HF, 4.7% (95% CI 3.0-6.4) for MI, and 10.4% (95% CI 8.0-12.8) for non-CV hospitalization. On a relative scale, after adjusting for confounders, each 5-point decrease in LVEF was associated with an increased risk of HF (hazard ratio [HR] 1.15, 95% CI 1.12-1.18), MI (HR 1.06, 95% CI 1.03-1.10), and non-CV hospitalization (HR 1.03, 95% CI 1.01-1.05). CONCLUSIONS: In a high-risk population with complicated acute MI, the absolute risk increase in non-CV hospitalizations associated with LVEF ≪25% was two thirds of the absolute risk increase in HF hospitalizations and twice the absolute risk increase in MI hospitalizations. LVEF was an independent predictor of all types of hospitalization and appears as an integrative marker of sicker patient status.

18.
Clin Res Cardiol ; 108(11): 1215-1225, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30953180

RESUMO

BACKGROUND: In patients with acute myocardial infarction (MI), BMI < 18.5 kg/m2 and a decrease in BMI during follow-up have been associated with poor prognosis. For BMI ≥ 25 kg/m2, an "obesity paradox" has been suggested. Recently, high visit-to-visit BMI variability has also been associated with poor prognosis in patients with coronary artery disease. AIMS: To simultaneously evaluate several BMI measurements and study their association with cardiovascular (CV) outcomes in a large cohort of patients with acute myocardial infarction (MI) and left ventricular (LV) systolic dysfunction, heart failure (HF) or both. METHODS: The high-risk MI dataset is pooled from four trials: CAPRICORN, EPHESUS, OPTIMAAL and VALIANT. Mean BMI, change from baseline, and variability were assessed during follow-up. The primary outcome was CV death. Cox-proportional hazard models were performed to study the association between the various BMI parameters and outcomes (median follow-up = 1.8 years). RESULTS: A total of 12,719 patients were included (72% male, mean age 65 ± 11 years). Mean, change and visit-to-visit variability in BMI had a non-linear association with CV death (P < 0.001). Mean BMI < 26 kg/m2 (vs. ≥ 26-35 kg/m2) and BMI decrease during follow-up were independently associated with CV death (adjusted HR 1.32, 95% CI 1.16-1.51, P < 0.001 and adjusted HR 1.57, 95% CI 1.40-1.76, P < 0.001, respectively). Low and high BMI variability (< 2% and > 4%) were associated with increased event-rates, but lost statistical significance in sensitivity analysis including patients with ≥ 5 measurements or excluding patients with HF hospitalization, suggesting that BMI variability may be particularly associated with HF hospitalizations. CONCLUSION: Mean BMI < 26 kg/m2 and a BMI decrease during follow-up were independently associated with CV death in patients with MI and LV systolic dysfunction, HF or both. These associations likely reflect poorer patient status and causality cannot be inferred.

19.
Clin Transplant ; 33(4): e13508, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30821002

RESUMO

BACKGROUND: Assessment of human leukocyte antigen (HLA) matching by using high-resolution allele typing and knowledge of HLA molecule structure may lead to better prediction of de novo donor-specific antibody (dnDSA) development. METHODS: We conducted a single-center cohort study among 150 non-sensitized first kidney transplant recipients to compare the association between antigenic (Ag), allelic (Al), eplet (Ep), amino acid (AAMS) HLA matching and electrostatic (EMS) and hydrophobic (HMS) mismatch scores, and the development of dnDSA. RESULTS: After a mean follow-up time of 49.3 ± 17.7 months, 18 patients (12%) developed dnDSA. The number of HLA mismatches (MM) was significantly associated with the development of dnDSA. The optimal threshold, determined by Harrell's C-index, varied according to the method (5 MM for Ag, P = 0.006; 6 for Al, P = 0.009; 22 for Ep, P = 0.005; 42 for AAMS, P = 0.0007; 45 for EMS, P = 0.009 and 44 for HMS, P = 0.026). C-indices were similar for all matching approaches, suggesting a similar prediction of dnDSA development. CONCLUSION: In this cohort of low immunological risk transplant patients, the use of Al or Ep matching did not improve the prediction of dnDSA development in comparison with the traditional approach.

20.
Int J Cardiol ; 289: 91-98, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770263

RESUMO

AIMS: Pulmonary congestion is associated with poor prognosis following hospitalization for worsening heart failure (HF), although its quantification and optimal timing during HF hospitalization remains challenging. The aim of this study was to assess the prognostic value of radiographic pulmonary congestion at admission and discharge in patients with worsening HF. METHODS AND RESULTS: Clinical, echocardiographic, laboratory and chest X-ray data of 292 acute decompensated HF patients were retrospectively studied (follow-up 1 year). Lung congestion was blindly scored on chest X-ray performed at admission and discharge using a systematic 6-zone approach. Primary clinical outcome was a composite outcome of re-hospitalization for worsening HF or all cause death. Patients were stratified according to the median of congestion score index (CSI) at both admission (median CSI(A) = 1.33) and discharge (median CSI(D) = 0.33). BNP levels, LVEF and eGFR did not differ between CSI categories. In multivariable Cox regression analysis, discharge CSI (HR for 1-point increase = 1.83 [1.02 to 3.27] p = 0.04) and discharge BNP were significantly associated with the composite outcome whereas NYHA class, physical signs, admission CSI and echocardiographic data were not. Furthermore, discharge CSI significantly increased reclassification on top of clinical covariates (continuous NRI = 19.6% [4.0 to 30.0] p = 0.03 and IDI = 2.2% [0.0 to 7.6] p = 0.046) while discharge BNP did not significantly improve risk reclassification. CONCLUSIONS: Residual pulmonary congestion assessed by radiographic scoring predicts poor prognosis beyond physical assessment, echocardiographic parameters and BNP. These findings further support the capital prognostic value of radiographic pulmonary congestion in patients hospitalized for worsening HF.

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