Blood pressure variability and cardiovascular risk in the PROspective study of pravastatin in the elderly at risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects

Adiposity and Age Explain Most of the Association between Physical Activity and Fitness in Physically Active Men

BACKGROUND: To determine if there is an association between physical activity assessed by the short version of the International Physical Activity Questionnaire (IPAQ) and cardiorespiratory and muscular fitness. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and eighty-two young males (age range: 20-55 years) completed the short form of the IPAQ to assess physical activity. Body composition (dual-energy X-Ray absorptiometry), muscular fitness (static and dynamic muscle force and power, vertical jump height, running speed [30 m sprint], anaerobic capacity [300 m running test]) and cardiorespiratory fitness (estimated VO(2)max: 20 m shuttle run test) were also determined in all subjects. Activity-related energy expenditure of moderate and vigorous intensity (EEPA(moderate) and EEPA(vigorous), respectively) was inversely associated with indices of adiposity (r = -0.21 to -0.37, P<0.05). Cardiorespiratory fitness (VO(2)max) was positively associated with LogEEPA(moderate) (r = 0.26, P<0.05) and LogEEPA(vigorous) (r = 0.27). However, no association between VO(2)max with LogEEPA(moderate), LogEPPA(vigorous) and LogEEPA(total) was observed after adjusting for the percentage of body fat. Multiple stepwise regression analysis to predict VO(2)max from LogEEPA(walking), LogEEPA(moderate), LogEEPA(vigorous), LogEEPA(total), age and percentage of body fat (%fat) showed that the %fat alone explained 62% of the variance in VO(2)max and that the age added another 10%, while the other variables did not add predictive value to the model [VO(2)max  = 129.6-(25.1× Log %fat) - (34.0× Log age); SEE: 4.3 ml.kg(-1). min(-1); R(2) = 0.72 (P<0.05)]. No positive association between muscular fitness-related variables and physical activity was observed, even after adjusting for body fat or body fat and age. CONCLUSIONS/SIGNIFICANCE: Adiposity and age are the strongest predictors of VO(2)max in healthy men. The energy expended in moderate and vigorous physical activities is inversely associated with adiposity. Muscular fitness does not appear to be associated with physical activity as assessed by the IPAQ

First line chemotherapy with planned sequential administration of gemcitabine followed by docetaxel in elderly advanced non-small-cell lung cancer patients: a multicenter phase II study

This multicenter phase II study evaluated, in chemonaive patients with stage IIIB–IV NSCLC, age ⩾70 and with a performance status 0–2, the activity, efficacy and tolerability of planned sequential administration of gemcitabine 1200 mg m−2 on days 1 and 8 every 3 weeks for three courses followed by three cycles of docetaxel 37.5 mg m−2 on days 1 and 8 every 3 weeks, provided there was no evidence of disease progression. A total of 56 patients entered the study. According to intention-to-treat analysis, the objective response rate was 16.0% (95% CI 7.6–28.3%); 23 patients (41.0%) had stable disease and 24 patients (43%) had progressive disease. Five patients who had a stable disease after three courses of gemcitabine obtained a conversion to partial response by docetaxel. Median time to progression was 4.8 months (95% CI 3.6–6.0 months) and median duration of survival was 8.0 months (95% CI 5.6–10.5 months). The 1-year survival rate was 34%. No grade 4 haematological toxicity was observed and grade 3 neutropenia and thrombocytopenia were reported in 5.4 and 3.6% of the patients, respectively. Grade 3/4 mucositis and grade 3 diarrhoea, both occurred in 3.6% of the patients and grade 3 asthenia was observed in 9% of patients. One patient reported a grade 4 skin toxicity. No treatment-related deaths occurred. Sequential gemcitabine and docetaxel is a well-tolerated and effective regimen in elderly advanced NSCLC patients

The influence of persistent pathogens on circulating levels of inflammatory markers: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis

Background: Systemic inflammation is linked to cardiovascular risk, but the influence of persistent pathogens, which are conventionally dichotomously categorized, on circulating levels of inflammatory markers is not clear. Antibody levels of pathogens have not been examined in relation to inflammation. Methods: Using data from a subsample of the Multi-Ethnic Study of Atherosclerosis, we examined circulating levels of interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen in relation to five common persistent pathogens: cytomegalovirus, herpes simplex virus-1, Hepatitis A virus, Helicobacter pylori and Chlamydia pneumoniae. We tested the hypothesis that the number of seropositive pathogens (based on conventional cut-off points) would not be as sensitive a marker of inflammation as immune response measured by antibody levels to pathogens. Results: High antibody response to multiple pathogens showed graded and significant associations with IL-6 (p \u3c 0.001), CRP (p = 0.04) and fibrinogen (p = 0.001), whereas seropositive pathogen burden did not. In multiple linear regression models, high antibody response to multiple pathogens maintained a positive association only with IL-6 (4.4% per pathogen exhibiting high antibody response, 95% CI 0.0-8.9). Conclusions: High antibody response to pathogens was a more consistent marker of inflammatory outcomes compared to seropositivity alone and high antibody response to multiple pathogens was a stronger marker compared to any single pathogen

Genome-Wide Association Studies of the PR Interval in African Americans

The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5×10−8) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1–6.1, p = 3×10−23). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8–3.0, p = 3×10−16) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans

Dietary Protein and Blood Pressure: A Systematic Review

Background - Elevated blood pressure (BP), which is a major risk factor for cardiovascular disease, is highly prevalent worldwide. Recently, interest has grown in the role of dietary protein in human BP. We performed a systematic review of all published scientific literature on dietary protein, including protein from various sources, in relation to human BP. Methodology/Principal Findings - We performed a MEDLINE search and a manual search to identify English language studies on the association between protein and blood pressure, published before June 2010. A total of 46 papers met the inclusion criteria. Most observational studies showed no association or an inverse association between total dietary protein and BP or incident hypertension. Results of biomarker studies and randomized controlled trials indicated a beneficial effect of protein on BP. This beneficial effect may be mainly driven by plant protein, according to results in observational studies. Data on protein from specific sources (e.g. from fish, dairy, grain, soy, and nut) were scarce. There was some evidence that BP in people with elevated BP and/or older age could be more sensitive to dietary protein. Conclusions/Significance - In conclusion, evidence suggests a small beneficial effect of protein on BP, especially for plant protein. A blood pressure lowering effect of protein may have important public health implications. However, this warrants further investigation in randomized controlled trials. Furthermore, more data are needed on protein from specific sources in relation to BP, and on the protein-BP relation in population subgroup

Maternal Malaria Induces a Procoagulant and Antifibrinolytic State That Is Embryotoxic but Responsive to Anticoagulant Therapy

Low birth weight and fetal loss are commonly attributed to malaria in endemic areas, but the cellular and molecular mechanisms that underlie these poor birth outcomes are incompletely understood. Increasing evidence suggests that dysregulated hemostasis is important in malaria pathogenesis, but its role in placental malaria (PM), characterized by intervillous sequestration of Plasmodium falciparum, proinflammatory responses, and excessive fibrin deposition is not known. To address this question, markers of coagulation and fibrinolysis were assessed in placentae from malaria-exposed primigravid women. PM was associated with significantly elevated placental monocyte and proinflammatory marker levels, enhanced perivillous fibrin deposition, and increased markers of activated coagulation and suppressed fibrinolysis in placental plasma. Submicroscopic PM was not proinflammatory but tended to be procoagulant and antifibrinolytic. Birth weight trended downward in association with placental parasitemia and high fibrin score. To directly assess the importance of coagulation in malaria-induced compromise of pregnancy, Plasmodium chabaudi AS-infected pregnant C57BL/6 mice were treated with the anticoagulant, low molecular weight heparin. Treatment rescued pregnancy at midgestation, with substantially decreased rates of active abortion and reduced placental and embryonic hemorrhage and necrosis relative to untreated animals. Together, the results suggest that dysregulated hemostasis may represent a novel therapeutic target in malaria-compromised pregnancies

Mixed Cerebrovascular Disease and the Future of Stroke Prevention

Stroke prevention efforts typically focus on either ischemic or hemorrhagic stroke. This approach is overly simplistic due to the frequent coexistence of ischemic and hemorrhagic cerebrovascular disease. This coexistence, termed “mixed cerebrovascular disease”, offers a conceptual framework that appears useful for stroke prevention strategies. Mixed cerebrovascular disease incorporates clinical and subclinical syndromes, including ischemic stroke, subclinical infarct, white matter disease of aging (leukoaraiosis), intracerebral hemorrhage, and cerebral microbleeds. Reliance on mixed cerebrovascular disease as a diagnostic entity may assist in stratifying risk of hemorrhagic stroke associated with platelet therapy and anticoagulants. Animal models of hemorrhagic cerebrovascular disease, particularly models of cerebral amyloid angiopathy and hypertension, offer novel means for identifying underlying mechanisms and developing focused therapy. Phosphodiesterase (PDE) inhibitors represent a class of agents that, by targeting both platelets and vessel wall, provide the kind of dual actions necessary for stroke prevention, given the spectrum of disorders that characterizes mixed cerebrovascular disease