Abstract Background Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of ...mortality and CV morbidity in 12,944 patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS). Methods Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (≥30 but <300 mg/dL), or macroalbuminuria (≥300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury (AKI), identified by adverse event reporting and creatinine increase (absolute ≥0.3 mg/dL or relative ≥50%), was descriptively reported. Results Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs. 27%) or hypertension (86% vs. 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria), at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed AKI rates were 0.6%, 1.2%, and 2.9% (n=79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15–2.37); and after adjustment with eGFR, 1.37 (95% CI 0.93–2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37–2.42) and 1.47 (95% CI 1.08–1.98). Conclusions High-risk patients with NSTE ACS and albuminuria have increased morbidity and increased overall mortality independent of eGFR.
Objectives This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non–ST-segment elevation acute coronary ...syndromes (NSTE-ACS). Background Little is known about HF-complicating NSTE-ACS. Methods Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality. Results Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio OR: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization. Conclusions In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed.
Recent observations of changes in some tundra ecosystems appear to be responses to a warming climate. Several experimental studies have shown that tundra plants and ecosystems can respond strongly to ...environmental change, including warming; however, most studies were limited to a single location and were of short duration and based on a variety of experimental designs. In addition, comparisons among studies are difficult because a variety of techniques have been used to achieve experimental warming and different measurements have been used to assess responses. We used metaanalysis on plant community measurements from standardized warming experiments at 11 locations across the tundra biome involved in the International Tundra Experiment. The passive warming treatment increased plant-level air temperature by 1-3°C, which is in the range of predicted and observed warming for tundra regions. Responses were rapid and detected in whole plant communities after only two growing seasons. Overall, warming increased height and cover of deciduous shrubs and graminoids, decreased cover of mosses and lichens, and decreased species diversity and evenness. These results predict that warming will cause a decline in biodiversity across a wide variety of tundra, at least in the short term. They also provide rigorous experimental evidence that recently observed increases in shrub cover in many tundra regions are in response to climate warming. These changes have important implications for processes and interactions within tundra ecosystems and between tundra and the atmosphere.
Patients with peripheral arterial disease (PAD) have lower functional capacity and worse clinical outcomes than age- and gender-matched patients. Few data exist on the relation of PAD to functional ...and clinical outcomes in patients with heart failure (HF). We sought to compare patients with HF with and without PAD for baseline functional capacity, response to exercise training, and clinical outcomes. HF-ACTION was a randomized controlled trial comparing usual care to structured exercise training plus usual care in patients with HF and an ejection fraction ≤35% and New York Heart Association class II to IV HF symptoms. Cardiopulmonary exercise testing occurred at enrollment, 3 months, and 1 year. Clinical follow-up occurred up to 4 years. Of the 2,331 HF-ACTION patients, 157 (6.8%) had PAD. At baseline, patients with HF and PAD had a shorter exercise duration (8.0 vs 9.8 minutes, p <0.001), lower peak oxygen consumption (12.5 vs 14.6 ml/kg/min, p <0.001), and shorter 6-minute walking distance (306 vs 371 m, p <0.001) compared to patients with HF without PAD. At 3 months patients with HF and PAD had less improvement on cardiopulmonary exercise testing (exercise duration 0.5 vs 1.1 minutes, p = 0.002; mean change in peak oxygen consumption 0.1 vs 0.6 ml/kg/min, p = 0.04) compared to patients with HF without PAD. PAD was an independent predictor of all-cause death or hospitalization (hazard ratio 1.31, 95% confidence interval 1.06 to 1.62, p = 0.011). Patients with PAD and HF had deceased baseline exercise capacity and decreased response to exercise training. In conclusion, PAD is an independent predictor of all-cause death or hospitalization in patients with HF.
Background More than three fourths of patients with heart failure (HF) are 65 years and older, and older age is associated with worse symptoms and prognoses than is younger age. Reduced exercise ...capacity is a chief HF complaint and indicates poorer prognosis, especially among elderly persons, but the mechanisms underlying functional decline in older patients with HF are largely unknown. Methods Baseline cardiopulmonary exercise testing data from the HF-ACTION trial were assessed to clarify age effects on peak oxygen consumption (VO2 ) and ventilation–carbon dioxide production (VE/VCO2 ) slope. Results Among 2,331 New York Heart Association class II-IV patients with HF, increased age corresponded to decreased peak VO2 (−0.14 mL kg−1 min−1 per year >40 years; P < .0001) and increased VE/VCO2 slope (0.30 U/y >70 years; P < .0001). In a multivariable model with 34 other potential determinants, age was the strongest independent predictor of peak VO2 (partial R2 0.130, total R2 0.392; P < .001) and a significant but relatively weaker predictor of VE/VCO2 slope (partial R2 0.037, total R2 0.199; P < .001). Blunted peak heart rate was also a strong predictor of peak VO2 . Although peak heart rate and age were strongly correlated, both were significant independent predictors of peak VO2 when analyzed simultaneously in a model. Aggregate comorbidity increased significantly with age but did not account for age effects on peak VO2. Conclusions Age is the strongest predictor of peak VO2 and a significant predictor of VE/VCO2 slope in the HF-ACTION population. Age-dependent comorbidities do not explain changes in peak VO2 . Age-related changes in cardiovascular physiology, potentially magnified by the HF disease state, should be considered a contributor to the pathophysiology and a target for more effective therapy in older patients with HF.
Objectives To examine the relationship between N-terminal pro–brain natriuretic peptide (NT-proBNP) and exercise capacity in a large contemporary cohort of patients with chronic heart failure. ...Background Natriuretic peptides such as NT-proBNP are important biomarkers in heart failure. The relationship between NT-proBNP and exercise capacity has not been well studied. Methods We analyzed the relationship between baseline NT-proBNP and peak oxygen uptake (peak V o2 ) or distance in the 6-minute walk test in 1383 subjects enrolled in the HF-ACTION study. Linear regression models were used to analyze the relationship between NT-proBNP and peak V o2 or distance in the 6-minute walk test in the context of other clinical variables. Receiver operator curve analysis was used to evaluate the ability of NT-proBNP to accurately predict a peak V o2 <12 mL/kg per minute. Results NT-proBNP was the most powerful predictor of peak V o2 (partial R2 = 0.13, P < .0001) of 35 candidate variables. Although NT-proBNP was also a predictor of distance in the 6-minute walk test, this relationship was weaker than that for peak V o2 (partial R2 = 0.02, P < .0001). For both peak V o2 and distance in the 6-minute walk test, much of the variability in exercise capacity remained unexplained by the variables tested. Receiver operator curve analysis suggested NT-proBNP had moderate ability to identify patients with peak V o2 <12 mL/kg per minute (c-index, 0.69). Conclusions In this analysis of baseline data from HF-ACTION, NT-proBNP was the strongest predictor of peak V o2 and a significant predictor of distance in the 6-minute walk test. Despite these associations, NT-proBNP demonstrated only modest performance in identifying patients with a low peak V o2 who might be considered for cardiac transplantation. These data suggest that, although hemodynamic factors are important determinants of exercise capacity, much of the variability in exercise performance in heart failure remains unexplained by traditional clinical and demographic variables.
Objectives This study sought to determine if there is an association between bleed location and clinical outcomes in acute coronary syndromes (ACS) patients. Background The prognostic significance of ...bleeding location among ACS patients undergoing cardiac catheterization is not well known. Methods We analyzed in-hospital bleeding events among 9,978 patients randomized in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) study. Bleeding events were categorized by location as access site, systemic, surgical, or superficial, and severity was graded using the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definition. We assessed the association of each bleeding location and severity with 6-month risk of death or myocardial infarction using a multicovariate-adjusted Cox proportional hazard model. Results A total of 4,900 bleeding events were identified among 3,694 ACS patients with in-hospital bleeding. Among 4,679 GUSTO mild/moderate bleeding events, only surgical and systemic bleeds were associated with an increased risk of 6-month death or myocardial infarction (adjusted hazard ratio HR: 2.52 95% confidence interval (CI): 2.16 to 2.94, and 1.40 95% CI: 1.16 to 1.69, respectively). Mild/moderate superficial and access-site bleeds were not associated with downstream risk (adjusted HR: 1.17 95% CI: 0.97 to 1.40, and 0.96 95% CI: 0.82 to 1.12, respectively). Among 221 GUSTO severe bleeds, surgical bleeds were associated with the highest risk (HR: 5.27 95% CI: 3.80 to 7.29), followed by systemic (HR: 4.48 95% CI: 2.98 to 6.72), and finally access-site bleeds (HR: 3.57 95% CI: 2.35 to 5.40). Conclusions Among ACS patients who develop in-hospital bleeding, systemic and surgical bleeding are associated with the highest risks of adverse outcomes regardless of bleeding severity. Although the most frequent among bleeds, GUSTO mild/moderate access-site bleeding is not associated with increased risk. These data underscore the importance of strategies to minimize overall bleeding risk beyond vascular access site management.
Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large ...genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r² = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018).
This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.
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