Biochemical and structural insights into a 5' to 3' RNA ligase reveal a potential role in tRNA ligation.

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5'-phosphate and a 3'-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology.

CD73 contributes to the pathogenesis of fusion-negative rhabdomyosarcoma through the purinergic signaling pathway.

Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and adolescents. Fusion-negative RMS (FN-RMS) accounts for more than 80% of all RMS cases. The long-term event-free survival rate for patients with high-grade FN-RMS is below 30%, highlighting the need for improved therapeutic strategies. CD73 is a 5' ectonucleotidase that hydrolyzes AMP to adenosine and regulates the purinergic signaling pathway. We found that CD73 is elevated in FN-RMS tumors that express high levels of TWIST2. While high expression of CD73 contributes to the pathogenesis of multiple cancers, its role in FN-RMS has not been investigated. We found that CD73 knockdown decreased FN-RMS cell growth while up-regulating the myogenic differentiation program. Moreover, mutation of the catalytic residues of CD73 rendered the protein enzymatically inactive and abolished its ability to stimulate FN-RMS growth. Overexpression of wildtype CD73, but not the catalytically inactive mutant, in CD73 knockdown FN-RMS cells restored their growth capacity. Likewise, treatment with an adenosine receptor A2A-B agonist partially rescued FN-RMS cell proliferation and bypassed the CD73 knockdown defective growth phenotype. These results demonstrate that the catalytic activity of CD73 contributes to the pathogenic growth of FN-RMS through the activation of the purinergic signaling pathway. Therefore, targeting CD73 and the purinergic signaling pathway represents a potential therapeutic approach for FN-RMS patients.

Safety, Tolerability, and Pharmacokinetics of Same-Knee Intra-Articular Injection of Corticosteroid and Lorecivivint Within 7 Days: An Open-Label, Randomized, Parallel-Arm Study.

INTRODUCTION: Knee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart. METHODS: Healthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by "epoch", with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction. RESULTS: A total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences. CONCLUSION: No safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04598542.

Knee osteoarthritis (OA) is a common disorder characterized by pain and loss of function. This clinical trial tested if two different treatments for OA injected into the same knee 1 week apart would impact the safety or exposure of either treatment. The treatments evaluated were an injection of a corticosteroid, triamcinolone acetonide, and a potential OA treatment in development, lorecivivint, a novel small molecule thought to inhibit inflammation and a biological pathway called the Wnt pathway. The amount of either treatment found in circulation was not different when injected before or after the other treatment. The order of injection did not change the safety profile for either agent, suggesting injection of the two agents 1 week apart is unlikely to pose a safety concern.

Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma Model.

Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.

The effect of exercise training on blood pressure in menopause and postmenopausal women: A systematic review of randomized controlled trials.

The prevalence of hypertension is higher in postmenopausal than in premenopausal women. Regular exercise training has been shown to be effective in addressing hypertension. The aim of this systematic review was to synthesize the effect of exercise training on systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) in menopausal and postmenopausal women. This review was reported according to the PRISMA statement and registered in PROSPERO. The literature search was done in MEDLINE, Embase, Cochrane CENTRAL and ClinicalTrials. Randomized controlled trials involving menopausal and postmenopausal women undergoing exercise training were included. Two blinded reviewers assessed risk of bias in the included studies by using the Cochrane Risk of Bias tool. A random-effects model was used for all analyses. Significance was set at P < 0.05. Compared with the control group, exercise training resulted in clinically significant reductions on SBP (MD -3.43 mmHg; 95% CI, -5.16, -1.71; P < 0.0001), DBP (MD, -2.25 mmHg; 95% CI, -3.40, -1.11; P = 0.0001) and MAP (MD, -3.48 mmHg; 95% CI, -5.84, -1.11; P = 0.004). Aerobic training (AT) did not produce a significant reduction in SBP, DBP and MAP (P >0.05). Combined training (CT) generated larger reductions. Exercise training generated small but clinically relevant reductions in SBP, DBP and MAP in menopausal and postmenopausal women, younger or older than 65 years, with prehypertension or hypertension. AT did not lead to a clinically relevant improvement in blood pressure (BP) in this population. In addition, CT showed the largest reductions in SBP, DBP and MAP.

Dynamic remodeling of host membranes by self-organizing bacterial effectors.

During infection, intracellular bacterial pathogens translocate a variety of effectors into host cells that modify host membrane trafficking for their benefit. We found a self-organizing system consisting of a bacterial phosphoinositide kinase and its opposing phosphatase that formed spatiotemporal patterns, including traveling waves, to remodel host cellular membranes. The Legionella effector MavQ, a phosphatidylinositol (PI) 3-kinase, was targeted to the endoplasmic reticulum (ER). MavQ and the Legionella PI 3-phosphatase SidP, even in the absence of other bacterial components, drove rapid PI 3-phosphate turnover on the ER and spontaneously formed traveling waves that spread along ER subdomains inducing vesicle and tubule budding. Thus, bacteria can exploit a self-organizing membrane-targeting mechanism to hijack host cellular structures for survival.

A Bacterial Effector Mimics a Host HSP90 Client to Undermine Immunity.

The molecular chaperone HSP90 facilitates the folding of several client proteins, including innate immune receptors and protein kinases. HSP90 is an essential component of plant and animal immunity, yet pathogenic strategies that directly target the chaperone have not been described. Here, we identify the HopBF1 family of bacterial effectors as eukaryotic-specific HSP90 protein kinases. HopBF1 adopts a minimal protein kinase fold that is recognized by HSP90 as a host client. As a result, HopBF1 phosphorylates HSP90 to completely inhibit the chaperone's ATPase activity. We demonstrate that phosphorylation of HSP90 prevents activation of immune receptors that trigger the hypersensitive response in plants. Consequently, HopBF1-dependent phosphorylation of HSP90 is sufficient to induce severe disease symptoms in plants infected with the bacterial pathogen, Pseudomonas syringae. Collectively, our results uncover a family of bacterial effector kinases with toxin-like properties and reveal a previously unrecognized betrayal mechanism by which bacterial pathogens modulate host immunity.

Protein AMPylation by an Evolutionarily Conserved Pseudokinase.

Approximately 10% of human protein kinases are believed to be inactive and named pseudokinases because they lack residues required for catalysis. Here, we show that the highly conserved pseudokinase selenoprotein-O (SelO) transfers AMP from ATP to Ser, Thr, and Tyr residues on protein substrates (AMPylation), uncovering a previously unrecognized activity for a member of the protein kinase superfamily. The crystal structure of a SelO homolog reveals a protein kinase-like fold with ATP flipped in the active site, thus providing a structural basis for catalysis. SelO pseudokinases localize to the mitochondria and AMPylate proteins involved in redox homeostasis. Consequently, SelO activity is necessary for the proper cellular response to oxidative stress. Our results suggest that AMPylation may be a more widespread post-translational modification than previously appreciated and that pseudokinases should be analyzed for alternative transferase activities.

Progression of coronary calcium and incident coronary heart disease events: MESA (Multi-Ethnic Study of Atherosclerosis).

OBJECTIVES: The study examined whether progression of coronary artery calcium (CAC) is a predictor of future coronary heart disease (CHD) events. BACKGROUND: CAC predicts CHD events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. METHODS: We studied 6,778 persons (52.8% female) aged 45 to 84 years from the MESA (Multi-Ethnic Study of Atherosclerosis) study. A total of 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n = 1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max = 9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HRs) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. RESULTS: A total of 343 and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 Agatston units. Among persons without CAC at baseline (n = 3,396), a 5-unit annual change in CAC was associated with an adjusted HR (95% Confidence Interval) of 1.4 (1.0 to 1.9) for total and 1.5 (1.1 to 2.1) for hard CHD. Among those with CAC >0 at baseline, HRs (per 100 unit annual change) were 1.2 (1.1 to 1.4) and 1.3 (1.1 to 1.5), respectively. Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HRs of 3.8 (1.5 to 9.6) for total and 6.3 (1.9 to 21.5) for hard CHD compared to those without progression. CONCLUSIONS: Progression of CAC is associated with an increased risk for future hard and total CHD events.

Risk of injury after alcohol consumption from case-crossover studies in five countries from the Americas.

AIMS: This study aimed to: (i) provide relative risk (RR) estimates between acute alcohol use and injuries from emergency departments (EDs) in the Dominican Republic, Guatemala, Guyana, Nicaragua and Panama, and (ii) test whether the RR differs if two control periods for the estimates were used. DESIGN: Case-crossover methodology was used to obtain estimates of the RR of having an injury within 6 hours after drinking alcohol, using a pair-matching design with control periods of the same time of day on the day prior to injury, and the same time of day and day of week during the week prior to injury. SETTING: EDs. PARTICIPANTS: A total of 2503 injured patients from EDs were interviewed between 2010 and 2011, with a response rate of 92.6%. MEASUREMENTS: Number of drinks consumed within 6 hours prior to the injury and in the two control periods. FINDINGS: The RR of injury after drinking alcohol was 4.38 [95% confidence interval (CI): 3.29-5.84] using the prior week as the control period, and 5.35 (CI: 3.50-8.17) using the prior day as a control period. The RR was 5.08 (CI: 4.15-6.23) in multiple matching. Those drinking one to two drinks had a RR of 4.85 (CI: 3.12-7.54); those drinking three to five drinks an RR of 5.00 (CI: 3.47-7.18); those drinking six to 15 drinks an RR of 4.54 (CI: 3.36-6.14); and those drinking 16 or more drinks an RR of 10.42 (CI: 4.38-24.79). CONCLUSIONS: As in other countries, drinking alcohol is an important trigger for an injury in the Dominican Republic, Guatemala, Guyana, Nicaragua and Panama.

Abdominal aortic calcium and multi-site atherosclerosis: the Multiethnic Study of Atherosclerosis.

BACKGROUND: Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis. METHODS: Among 1812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD. RESULTS: AAC prevalence ranged from 34% in those aged 45-54 to 94% in those aged 75-84 (p < 0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p < 0.0001). CAC prevalence, mean maximum CIMT ≥ 1mm, and ABI < 0.9 was greater in those with vs. without AAC: CAC 60% vs. 16%, CIMT 38% vs. 7%, and ABI 5% vs. 1% for women and CAC 80% vs. 37%, CIMT 43% vs. 16%, and ABI 4% vs. 2% for men (p < 0.01 for all except p < 0.05 for ABI in men). The substantially greater prevalence for CAC in men compared to women all ages is not seen for AAC. By age 65, 97% of men and 91% of women have AAC, CAC, increased CIMT, and/or low ABI. The presence of multi-site atherosclerosis (≥ 3 of the above) ranged from 20% in women to 30% in men (p < 0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45-54 to 53% in those aged 75-84 (p < 0.01 to p < 0.001). Finally, increased AAC was associated with 2-3-old relative risks for the presence of increased CIMT, low ABI, or CAC. CONCLUSIONS: AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.

Use of the UKPDS Outcomes Model to predict all-cause mortality in U.S. adults with type 2 diabetes mellitus: comparison of predicted versus observed mortality.

AIMS: The applicability of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model is unknown in populations with type 2 diabetes mellitus (T2DM) outside the United Kingdom. We compared all-cause mortality predicted from the UKPDS model with observed mortality among T2DM subjects in the U.S. METHODS: we studied participants with T2DM from the National Health and Nutrition Examination Survey 1988-1994 with characteristics comparable to the UKPDS cohort. The 10-year observed all-cause mortality was compared to the UKPDS model-predicted mortality. The Lifetable method was used to estimate the probability of mortality for 10 years following diagnosis. RESULTS: among 156 subjects with characteristics comparable to the UKPDS cohort, mean age was 49.6 years, age at T2DM diagnosis was 47.1 years, and T2DM duration averaged 2.6 years, with follow-up for 10.4 years. The UKPDS model-predicted 10-year mortality was 15.7%, similar to the observed mortality of 14.2%. Corresponding 10-year predicted versus observed mortality was 32.7% versus 32.4% including subjects >age 65, 17.0% versus 19.3% including individuals with pre-existing CVD, and 31.1% versus 20.9% including individuals with diabetes duration ≥ 6 years. CONCLUSION: all-cause mortality predicted by the UKPDS model was comparable to observed mortality in U.S. NHANES participants with characteristics similar to the UKPDS.

Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study.

OBJECTIVES: The ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study prospectively evaluated iodine-123 meta-iodobenzylguanidine ((123)I-mIBG) imaging for identifying symptomatic heart failure (HF) patients most likely to experience cardiac events. BACKGROUND: Single-center studies have demonstrated the poorer prognosis of HF patients with reduced (123)I-mIBG myocardial uptake, but these observations have not been validated in large multicenter trials. METHODS: A total of 961 subjects with New York Heart Association (NYHA) functional class II/III HF and left ventricular ejection fraction (LVEF) < or =35% were studied. Subjects underwent (123)I-mIBG myocardial imaging (sympathetic neuronal integrity quantified as the heart/mediastinum uptake ratio [H/M] on 4-h delayed planar images) and myocardial perfusion imaging and were then followed up for up to 2 years. Time to first occurrence of NYHA functional class progression, potentially life-threatening arrhythmic event, or cardiac death was compared with H/M (either in relation to estimated lower limit of normal [1.60] or as a continuous variable) using Cox proportional hazards regression. Multivariable analyses using clinical, laboratory, and imaging data were also performed. RESULTS: A total of 237 subjects (25%) experienced events (median follow-up 17 months). The hazard ratio for H/M > or =1.60 was 0.40 (p < 0.001); the hazard ratio for continuous H/M was 0.22 (p < 0.001). Two-year event rate was 15% for H/M > or =1.60 and 37% for H/M <1.60; hazard ratios for individual event categories were as follows: HF progression, 0.49 (p = 0.002); arrhythmic events, 0.37 (p = 0.02); and cardiac death, 0.14 (p = 0.006). Significant contributors to the multivariable model were H/M, LVEF, B-type natriuretic peptide, and NYHA functional class. (123)I-mIBG imaging also provided additional discrimination in analyses of interactions between B-type natriuretic peptide, LVEF, and H/M. CONCLUSIONS: ADMIRE-HF provides prospective validation of the independent prognostic value of (123)I-mIBG scintigraphy in assessment of patients with HF. (Meta-Iodobenzylguanidine Scintigraphy Imaging in Patients With Heart Failure and Control Subjects Without Cardiovascular Disease, NCT00126425; Meta-Iodobenzylguanidine [123I-mIBG] Scintigraphy Imaging in Patients With Heart Failure and Control Subjects Without Cardiovascular Disease, NCT00126438).

Extent of control of cardiovascular risk factors and adherence to recommended therapies in US multiethnic adults with coronary heart disease: from a 2005-2006 national survey.

BACKGROUND: Guidelines for cardiovascular risk factor control in people with coronary heart disease (CHD) focus on compliance with beta-adrenoceptor antagonists (beta-blockers), angiotensin receptor blockade (ACE inhibitors/angiotensin II receptor antagonists [angiotensin receptor blockers; ARBs]) [ACE/ARBs], and lipid-lowering agents, with goals for BP of <140/90 mmHg and low-density lipoprotein cholesterol (LDL-C) levels of <2.6 mmol/L (100 mg/dL). Most data derive from registries of hospitalized patients or are from clinical trials. Little data exist on goal attainment and adherence with therapy among CHD survivors of major US ethnic groups in the real-world setting. OBJECTIVE: We assessed levels of cardiovascular risk factor control and adherence with recommended therapies among US CHD survivors. METHODS: We identified 364 US adults (representing 12.8 million in the US with CHD) aged 18 years and over in the National Health and Nutrition Examination Survey 2005-6 with known CHD. We calculated proportions of patients who were receiving recommended treatments, and who achieved goal targets for BP, LDL-C levels, glycosylated hemoglobin (HbA(1c)), and nonsmoking status, and differences between actual and goal levels ('distance to goal'), stratified by sex and ethnicity. RESULTS: Overall, 58%, 38%, and 60% of CHD survivors were receiving beta-adrenoceptor antagonists, ACE/ARBs, and lipid-lowering medications, respectively (22% received all three). However, treatment rates for beta-adrenoceptor antagonists and lipid-lowering agents were lower (p < 0.05 to p < 0.01) in Hispanics (36% and 27%, respectively) and non-Hispanic Blacks (47% and 42%, respectively) than in non-Hispanic Whites. Moreover, lipid-lowering treatment rates were lower in females (50%) than in males (67%) [p < 0.01]. Overall, 78% were nonsmokers while 68% achieved goal levels for BP, 57% for LDL-C levels, and, if diabetic, 67% for HbA(1c). Only 12% met all four goals. Non-Hispanic Whites had the lowest SBP and DBP as well as HbA(1c) (p < 0.05 to p < 0.01 across ethnicity). In those who did not achieve goal levels, distance to goal averaged 1.0 mmol/L (37.0 mg/dL) for LDL-C levels, 15.6 mmHg for SBP, and 1.3% for HbA(1c). CONCLUSION: Despite clear treatment guidelines, we show that many US adults with CHD, especially Hispanics and non-Hispanic Blacks, are neither receiving recommended treatments nor adequately treated in terms of BP, LDL-C levels, and HbA(1c). Greater efforts by healthcare systems to disseminate and implement guidelines are needed.

Risk factor control and adherence to treatment in patients with coronary heart disease in the Republic of Srpska, Bosnia and Herzegovina in 2005-2006.

INTRODUCTION: European treatment guidelines in persons with known coronary heart disease (CHD) focus on adherence to antiplatelet therapy, ß-blockers, ACE/ARBs, and lipid-lowering agents, with goals for blood pressure (BP) of < 140/90 mm Hg and LDL cholesterol of < 3.0 mmol/l. Data on adherence to these measures in Eastern Europe are limited. MATERIAL AND METHODS: The Third Republic of Srpska, Bosnia and Herzegovina, Coronary Prevention Study (ROSCOPS III) was conducted in 2005-2006 at 10 primary heath care centres in 601 patients (36% female, mean age 55 years) with CHD including acute myocardial infarction or ischaemia, coronary artery bypass graft, or angioplasty who were examined and interviewed at least 6 months after the event. We examined the proportion of subjects on recommended treatments and at goal for BP, LDL-C, and non-smoking. RESULTS: The proportion of subjects on recommended treatments included 61% for ß-blockers, 79% for ACE/ARBs, 63% for lipid-lowering agents and 74% for antiplatelet therapy. Only 30% of subjects were on all four of these treatments. 59% of subjects had BP at goal of < 140/90 mm Hg and 33% were controlled to < 130/80 mm Hg, 41% for LDL-C, and 88% were non-smokers. Improvements were seen in lipid-lowering and ACE/ARB drug use and non-smoking status from an earlier survey (ROSCOPS II) in 2002-2003. CONCLUSIONS: Our data show, despite improvement over recent years, that many persons with CHD in the Republic of Srpska, Bosnia and Herzegovina are neither on recommended treatments nor at target for BP and/or LDL-C. Improved efforts targeted at both physicians and patients to address these issues are needed.

Combined association of lipids and blood pressure in relation to incident cardiovascular disease in the elderly: the cardiovascular health study.

BACKGROUND: Hypertension and dyslipidemia are highly prevalent in the elderly. We studied the combined impact of both conditions on cardiovascular disease (CVD) events. METHODS: We studied 4,311 participants aged 65-98 (61.2% female) from the Cardiovascular Health Study (CHS), a longitudinal epidemiologic study, with no prior CVD. We evaluated the relation of low-density lipoprotein (LDL), high-density lipoprotein (HDL), or non-HDL-cholesterol combined with blood pressure (BP) categories to incident CVD-including coronary heart disease (CHD) (angina, myocardial infarction (MI), angioplasty, coronary bypass surgery, or CHD death), stroke, claudication, and CVD death over 15 years. RESULTS: CVD incidence (per 1,000 person years) ranged from 38.4 when BP <120/80 mm Hg and LDL-C <100 mg/dl to 94.8 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl, and from 28.9 when BP <120/80 mm Hg and HDL >60 mg/dl to 87.1 for a BP >or=160/100 and HDL-C <40 mg/dl. Compared with those with BP <120/80 mm Hg with either LDL-C <100 mg/dl or HDL-C >60 mg/dl, hazard ratios (HRs) for CVD events were 2.1 when BP >or=160/100 mm Hg and LDL-C >or=160 mg/dl and 2.1 when BP >or=160/100 and HDL-C <40 mg/dl (all P < 0.01), with similar results for non-HDL-C. Elevated BP was associated with increased risk across all lipid levels. Increased LDL-C added risk mainly when BP <140/90 mm Hg, but lower HDL-C also predicted CVD in those with higher BP. CONCLUSION: Increased BP confers increased risks for CVD in elderly persons across all lipid levels. Although increased LDL-C added risk mainly when BP <140/90 mm Hg, low HDL-C added risk also in those with hypertension. These results document the importance of combined hypertension and dyslipidemia.

Cardiovascular comorbidities and blood pressure control in stroke survivors.

OBJECTIVE: To examine the association of cardiovascular(CV) comorbidities with the likelihood of being a stroke survivor and to determine the prevalence, treatment, and control of hypertension in this population. METHODS: In the National Health and Nutrition Examination Survey from 1999 to 2004, 495 stroke survivors, aged 20 years or older, were characterized by CV risk factors and comorbidities. Hypertension prevalence, treatment,and control rates were determined and logistic regression was performed to examine the likelihood of stroke according to the presence of comorbidities. RESULTS: Of the stroke survivors, 59.4% were women, 57.1%were at least 65 years of age, 66.2% were overweight/obese, 25.1% were current smokers, 75.1% had hypertension, and 79.3% had additional comorbidities,including diabetes mellitus (24.7%), coronary artery disease(28.8%), chronic kidney disease (25.3%), heart failure(16.5%), and peripheral arterial disease (10.9%). The odds(and 95% confidence intervals) of prevalent stroke were 2.2(1.5-3.2), 5.0 (3.2-7.8), 4.1 (2.1-7.8), and 10.0 (4.8-20.9)with one, two, three, and four or more comorbidities,respectively. Of these high-risk stroke survivors with comorbidities and hypertension, 18% were not receiving antihypertensive therapy; of those receiving therapy, 55.3%did not meet a systolic blood pressure goal of less than 140 mmHg and, on average, were 20 mmHg above this target. CONCLUSION: A high percentage of stroke survivors,projected to 4.98 million adults in the USA have multiple CV risk factors, numerous comorbidities, and poor control of hypertension, placing them at increased risk for further complications. Therefore, increased efforts must be made to reduce overall global risk in these high-risk persons.

Association of FVC and total mortality in US adults with metabolic syndrome and diabetes.

BACKGROUND: Reduced pulmonary function is an independent predictor of metabolic syndrome (MetS) and diabetes mellitus (DM), conditions associated with increased mortality. We investigated whether reduced pulmonary function is associated with increased mortality in persons with these conditions. METHODS: We examined 5,633 (projected, 62.4 million) US adults (age range, 18 to 79 years) in the Third National Health and Nutrition Examination Survey, who were never-smokers and were without known cardiovascular or obstructive lung disease. Cox regression (adjusted for age, sex, and ethnicity) was used to examine all-cause mortality risk across FVC categories (FVC: low, or= 95% predicted) among those with MetS, DM, or neither disease. RESULTS: The prevalence of DM and MetS significantly increased as predicted FVC decreased (p < 0.01). Age- and sex-adjusted mortality rates (per 1,000 person-years) increased in a stepwise manner as predicted FVC decreased in those patients with neither MetS nor DM (3.5 to 8.0), MetS (4.1 to 8.1), and DM (9.9 to 13.3). Compared to those with high FVC, those with low FVC had more than a fourfold increase in mortality among those with MetS (hazard ratio [HR], 4.27; 95% confidence interval [CI], 1.59 to 11.45; p < 0.01) and more than a twofold increase among those with neither disease (HR, 2.40; 95% CI, 1.06 to 5.43; p < 0.05). Also, every 10% reduction in FVC was associated with a 77% higher mortality (HR, 1.77; 95% CI, 1.33 to 2.37; p < 0.05) among persons with MetS. However, in those with DM, FVC did not contribute further to mortality risk. CONCLUSION: In persons with MetS, a reduced FVC is associated with further increases in mortality, suggesting that the evaluation of lung function may be useful for risk stratification in those with MetS.

Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study.

BACKGROUND: The utility of single versus combined blood pressure (BP) components in predicting cardiovascular disease (CVD) events is not established. We compared systolic BP (SBP) and diastolic BP (DBP) versus pulse pressure (PP) and mean arterial pressure (MAP) combined and each of these 4 BP components alone in predicting CVD events. METHODS AND RESULTS: In participants in the original (n=4760) and offspring (n=4897) Framingham Heart Study who were free of CVD events and BP-lowering therapy, 1439 CVD events occurred over serial 4-year intervals from 1952 to 2001. In pooled logistic regression with the use of BP categories, combining SBP with DBP and PP with MAP improved model fit compared with individual BP components (P<0.05 to P<0.0001). Significant interactions were noted between SBP and DBP (P=0.02) and between PP and MAP (P=0.01) in their respective multivariable models. Models with continuous variables for SBP+DBP and PP+MAP proved identical in predicting CVD events (Akaike Information Criteria=10 625 for both). Addition of a quadratic DBP(2) term to DBP and SBP further improved fit (P=0.0016). CONCLUSIONS: Combining PP with MAP and SBP with DBP produced models that were superior to single BP components for predicting CVD, and the extent of CVD risk varied with the level of each BP component. The combination of PP+MAP (unlike SBP+DBP) has a monotonic relation with risk and may provide greater insight into hemodynamics of altered arterial stiffness versus impaired peripheral resistance but is not superior to SBP+DBP in predicting CVD events.

Association of C-reactive protein with reduced forced vital capacity in a nonsmoking U.S. population with metabolic syndrome and diabetes.

OBJECTIVE: A relationship between inflammation, measured by C-reactive protein (CRP), and forced vital capacity (FVC) in diabetes or metabolic syndrome (MetS) has not been established. We investigated whether high CRP is related to reduced FVC in MetS and diabetes. RESEARCH DESIGN AND METHODS: We examined the association of MetS/diabetes and CRP (normal 3 mg/l) with predicted FVC in 4,272 nonsmoking U.S. adults aged 18-79 years without lung disease in the Third National Health and Nutrition Examination Survey. Logistic regression examined odds of FVC <80% by CRP and MetS/diabetes. RESULTS: Mean FVC in individuals with MetS and high CRP (95.7%) and those with diabetes and high CRP (93.7%) was lower than in those with no MetS/diabetes and normal CRP (101.7%) (P < 0.01) and was lower in those with MetS and high CRP (95.7%) than in those with MetS and normal CRP (98.5%) (P < 0.01). The odds ratio (95% CI) of FVC <80% was highest in individuals with MetS and high CRP (odds ratio 4.26 [95% CI 2.08-8.73], P < 0.01) compared with those with no MetS/diabetes and normal CRP. CONCLUSIONS: Elevated CRP is associated with lower FVC in people with MetS.