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Many antihypertensive medications and lifestyle changes are proven to reduce blood pressure. Over the past few decades, numerous additional modalities have been evaluated in regard to their potential blood pressure-lowering abilities. However, these nondietary, nondrug treatments, collectively called alternative approaches, have generally undergone fewer and less rigorous trials. This American Heart Association scientific statement aims to summarize the blood pressure-lowering efficacy of several alternative approaches and to provide a class of recommendation for their implementation in clinical practice based on the available level of evidence from the published literature. Among behavioral therapies, Transcendental Meditation (Class IIB, Level of Evidence B), other meditation techniques (Class III, Level of Evidence C), yoga (Class III, Level of Evidence C), other relaxation therapies (Class III, Level of Evidence B), and biofeedback approaches (Class IIB, Level of Evidence B) generally had modest, mixed, or no consistent evidence demonstrating their efficacy. Between the noninvasive procedures and devices evaluated, device-guided breathing (Class IIA, Level of Evidence B) had greater support than acupuncture (Class III, Level of Evidence B). Exercise-based regimens, including aerobic (Class I, Level of Evidence A), dynamic resistance (Class IIA, Level of Evidence B), and isometric handgrip (Class IIB, Level of Evidence C) modalities, had relatively stronger supporting evidence. It is the consensus of the writing group that it is reasonable for all individuals with blood pressure levels >120/80 mm Hg to consider trials of alternative approaches as adjuvant methods to help lower blood pressure when clinically appropriate. A suggested management algorithm is provided, along with recommendations for prioritizing the use of the individual approaches in clinical practice based on their level of evidence for blood pressure lowering, risk-to-benefit ratio, potential ancillary health benefits, and practicality in a real-world setting. Finally, recommendations for future research priorities are outlined.

Chronic obstructive pulmonary disease (COPD) often coexists with other chronic diseases and comorbidities that can markedly influence patients' health status and prognosis. This is particularly true for cardiovascular disease (CVD). However, there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases. The "Study to Understand Mortality and Morbidity in COPD" (SUMMIT) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD. SUMMIT is a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial of 16 000 patients with moderate COPD randomly assigned to once daily treatment with fluticasone furoate/vilanterol (100/25 μg), fluticasone furoate (100 μg), vilanterol (25 μg) or matched placebo; mortality is the primary end-point. The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo. Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point. This article describes the design of the SUMMIT study.

The relationship between low concentrations of high density lipoprotein cholesterol (HDL-C) and heightened risk for cardiovascular (CV) disease has been known for decades. Despite the consistent inverse relationship among epidemiological studies, the linkage between a residual low HDL-C among patients treated with statins and excess cardiovascular risk is less clearly established. Encouraging results from trials using niacin over the past 40 years have not been validated among more recent trials in patients taking contemporary anti-atherosclerotic therapy. Emerging evidence suggests that certain subsets of HDL particles may be more protective and/or more closely associated with CV disease than others, which may impact therapeutic benefits. Ongoing clinical trials will clarify whether raising HDL-C per se directly translates into a reduction in hard CV events. Until those results are available, the clinician is left with only weak evidence to support whether or not to target treatment of HDL-C with pharmacological therapy.

Epidemiological studies suggest that fine particulate matter (PM2.5) may increase the risk for developing diabetes mellitus (DM). To evaluate possible mechanisms explaining these associations, we investigated if sub-acute ambient-level exposures can impair insulin sensitivity. Twenty-five healthy adults living in rural Michigan were transported to an urban location for 5 consecutive days (exposure-block) of daily 4- to 5-hour-long ambient air pollution exposures. Health outcomes, including the homeostasis model assessment of insulin resistance (HOMA-IR) the primary outcome of insulin sensitivity, were measured at 3 time points in relation to exposure-blocks: 7days prior to start; on the last exposure-day; and 7days after completion. PM2.5 was monitored at the urban exposure site and at community monitors near subjects' residences. We calculated 3 "sub-acute" exposure periods (approximately 5-days-long) starting retrospective from the time of health outcome measurements (PM2.5 ranges: 9.7±3.9 to 11.2±3.9μg·m(-3)). A 10μg·m(-3) increase in sub-acute PM2.5 exposures was associated with increased HOMA-IR (+0.7, 95% confidence interval (CI) 0.1 to 1.3; p=0.023) and reduced heart rate variability (standard deviation of normal-to-normal intervals [-13.1ms, 95%CI -25.3 to -0.9; p=0.035]). No alterations in other outcomes (inflammatory markers, vascular function) occurred in relation to PM2.5 exposures. Our findings suggest that ambient PM2.5, even at low levels, may reduce metabolic insulin sensitivity supporting the plausibility that air pollution could potentiate the development of DM., (Copyright © 2012 Elsevier B.V. All rights reserved.)

There is a paucity of prospective cohort studies investigating the impact of environmental factors on the development of cardiometabolic (CM) disorders like type II diabetes (T2DM). The objective of the Air-Pollution and Cardiometabolic Diseases (AIRCMD) study is to investigate the impact of personal level air pollution measures [personal black carbon (BC)/sulfate measures] and ambient fine particulate matter [(PM2.5)/NO2] levels on propensity to type II diabetes in Beijing, China. Subjects with metabolic syndrome will undergo four repeated study visits within each season over a one year period following an initial screening visit. At each study visit, subjects will be monitored for sub-acute exposure to personal and ambient measures of air-pollution exposure and will undergo a series of functional CM outcomes. The primary endpoints include independent associations between integrated 5-day mean exposure to PM2.5 and BC and homeostasis model assessment of insulin resistance (HOMA-IR) measures, 24-hour mean diastolic and mean arterial pressure and endothelial-dependent vasodilatation. The secondary endpoints will explore the mechanistic explanation for a causal relationship between exposures and propensity for type II diabetes and will include additional functional outcomes such as arterial compliance, heart rate variability and plasma adipokines. The novel aspects of the study include the launch of infrastructure for future translational investigations in highly polluted urbanized environments and the creation of novel methodologies for linking personalized exposure measurements with functional CM outcomes. We believe that AIRCMD will allow for unprecedented new investigations into the association between environmental risk factors and CM disorders., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In salt-sensitive HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155-138 mm Hg; P=0.02) and diastolic blood pressure (79-72 mm Hg; P=0.04), 24-hour ambulatory systolic (130-123 mm Hg; P=0.02) and diastolic blood pressure (67-62 mm Hg; P=0.02), and carotid-femoral pulse wave velocity (12.4-11.0 m/s; P=0.03). Urinary F2-isoprostanes decreased by 31% (209-144 pmol/mmol Cr; P=0.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of salt-sensitive hypertension, a phenotype present in many HFPEF animal models and suggest shared pathophysiological mechanisms linking these 2 conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF.

Current understanding of the association between household air-pollution (HAP) and cardiovascular disease is primarily derived from outdoor air-pollution studies. The lack of accurate information on the contribution of HAP to cardiovascular events has prevented inclusion of such data in global burden of disease estimates with consequences in terms of health care allocation and national/international priorities. Understanding the health risks, exposure characterization, epidemiology and economics of the association between HAP and cardiovascular disease represents a pivotal unmet public health need. Interventions to reduce exposure to air-pollution in general, and HAP in particular are likely to yield large benefits and may represent a cost-effective and economically sustainable solution for many parts of the world. A multi-disciplinary effort that provides economically feasible technologic solutions in conjunction with experts that can assess the health, economic impact and sustainability are urgently required to tackle this problem.

Background: Epidemiological studies have assessed T-wave alternans (TWA) as a possible mechanism of cardiac arrhythmias related to air pollution in high-risk subjects and have reported associations with increased TWA magnitude., Objective: In this controlled human exposure study, we assessed the impact of exposure to concentrated ambient particulate matter (CAP) and ozone (O3) on T-wave alternans in resting volunteers without preexisting cardiovascular disease., Methods: Seventeen participants without preexisting cardiovascular disease were randomized to filtered air (FA), CAP (150 μg/m3), O3 (120 ppb), or combined CAP + O3 exposures for 2 hr. Continuous electrocardiograms (ECGs) were recorded at rest and T-wave alternans (TWA) was computed by modified moving average analysis with QRS alignment for the artifact-free intervals of 20 beats along the V2 and V5 leads. Exposure-induced changes in the highest TWA magnitude (TWAMax) were estimated for the first and last 5 min of each exposure (TWAMax_Early and TWAMax_Late respectively). ΔTWAMax (Late-Early) were compared among exposure groups using analysis of variance., Results: Mean ± SD values for ΔTWAMax were -2.1 ± 0.4, -2.7 ± 1.1, -1.9 ± 1.5, and -1.2 ± 1.5 in FA, CAP, O3, and CAP + O3 exposure groups, respectively. No significant differences were observed between pollutant exposures and FA., Conclusion: In our study of 17 volunteers who had no preexisting cardiovascular disease, we did not observe significant changes in T-wave alternans after 2-hr exposures to CAP, O3, or combined CAP + O3. This finding, however, does not preclude the possibility of pollution-related effects on TWA at elevated heart rates, such as during exercise, or the possibility of delayed responses.

Background: Numerous studies have reported associations between air pollution and cardiovascular diseases. While several studies illustrate that exposures to air pollutants can elevate blood pressure, few have evaluated the clinical relevance of this relationship. Hence, we aimed to explore the associations between daily concentrations of several air pollutants and emergency department visits for hypertension., Methods: Odds ratios (ORs) for emergency department visits for hypertension in Edmonton, Canada, from April 1992 to March 2002 were associated with pollutant levels (CO, NO(2), SO(2), O(3), and particulate matter [PM] < 10 microns [PM(10)] and < 2.5 microns [PM(2.5)] in aerodynamic diameter, respectively) by means of a case-crossover technique with time-stratified strategy to define controls. The analysis was performed for all (N = 5365), male (N = 2069), and female (N = 3296) patients and for six air pollutants lagged by 0 to 9 days. ORs and their 95% confidence intervals (CIs) were reported for an increase in an interquartile range (IQR) for each pollutant., Results: We observed associations for all patients and levels of NO(2) (IQR = 12.8 parts per billion; OR, 1.06; 95% CI, 1.00-1.12), SO(2) (IQR = 2.3 parts per billion; OR, 1.04; 95% CI, 1.00-1.08), and PM(10) (IQR = 15.0 μg/m(3); OR, 1.06; 95% CI, 1.01-1.11) for lag day 3, as well as for PM(10) (IQR = 15.0 μg/m(3); OR, 1.06; 95% CI, 1.01-1.11) and PM(2.5) (IQR = 6.2 μg/m(3); OR, 1.07; 95% CI, 1.01-1.11) for lag day 6., Conclusions: These findings support the contention that ambient pollution can produce clinically meaningful increases in blood pressure., (Copyright © 2012 Canadian Cardiovascular Society. All rights reserved.)

Folate has been implicated in cardiovascular disease with atypical antipsychotic (AAPs) use, and individuals with methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) variants are at greater risk. This study examined the relationship between the MTHFR 677C/T, MTHFR 1298A/C, and COMT Val158Met variants; metabolic syndrome; and lifestyle measures in schizophrenia and bipolar subjects. A total of 237 subjects with bipolar or schizophrenia receiving an antipsychotic for at least 6 months were included in this cross-sectional analysis. Subjects were screened for the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and MTHFR 677C/T, MTHFR 1298A/C, and Val158Met genotypes. In addition, serum folate and homocysteine were measured along with lifestyle factors. The subject's mean age was 44.7 (SD, 11.7) years; 72% were white, and 51% male; 61% were receiving an AAP; the mean body mass index was 32.6 (SD, 8.2) kg/m, and 48% were current smokers. Overall, 41% met metabolic syndrome criteria (n = 98). There were no differences in age, sex, AAP exposure, or body mass index between genotype groups. Metabolic syndrome was related to age, smoking, and the MTHFR 677T and COMT 158Val alleles (χ = 34.4, P < 0.0001). In addition, AAP use showed a trend association with metabolic syndrome (χ = 3.21, P = 0.07). These data support our previous reports and add more data pointing to folate's role in mediating a link between mental illness and cardiovascular disease. Use of this information clinically may help to reduce the risk for AAP metabolic complications in those whose clinical care necessitates the use of AAPs.

Background: Lipoprotein (a) [Lp(a)] has a strong association with coronary disease (CHD). We evaluated the implications of implementing a niacin strategy in persons above low risk by the Framingham risk score (FRS)., Methods: Patients referred to a university lipid management program from January 2004 to June 2010 had an Lp(a) level measured at initial evaluation. Factors associated with an increase in Lp(a) and predictors of a high risk Lp(a) (≥50 mg/dL) were assessed. FRS and Lp(a) levels were used to assess eligibility for niacin with an Lp(a) ≥50 mg/dL., Results: A total of 692 patients (57% male, mean age 52 ± 14 years) had a mean Lp(a) of 32 ± 40 mg/dL. In a multiple logistic regression model, African-American race, female gender, presence of CHD, and lower triglyceride levels were significant predictors of high risk Lp(a). Ten percent were determined to be intermediate and 44% high risk by FRS. A total of 9% of intermediate- and 26% of high-risk patients had an Lp(a) ≥50 mg/dL, and 84% were not taking niacin. A total of 19% of moderate- and high-risk patients were eligible for initiation of niacin based upon values ≥50 mg/dL. If niacin were also used for an high-density lipoprotein cholesterol levels ≤40 mg/dL, only 5.1% additional patients would require niacin., Conclusion: High-risk levels of Lp(a) are associated with female gender, African- American race, and CHD. 19% of moderate and high risk patients would be candidates for treatment with niacin if the indication is a cutpoint Lp(a) ≥50 mg/dL., (Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Environmental temperatures are inversely related to BP; however, the effects of short-term temperature changes within a 24-hour period and measured with high accuracy at the personal level have not been described. Fifty-one nonsmoking patients living in the Detroit area had up to 5 consecutive days of 24-hour personal-level environmental temperature (PET) monitoring along with daily cardiovascular measurements, including BP, performed mostly between 5 pm and 7 pm during summer and/or winter periods. The associations between hour-long mean PET levels during the previous 24 hours with the outcomes were assessed by linear mixed models. Accounting for demographics, environmental factors, and monitoring compliance, systolic and diastolic BP were positively associated with several hour-long PET measurements ending from 10 to 15 hours beforehand. During this time, corresponding mostly to a period starting from between 1 am and 3 am to ending between 7 am and 9 am, an increase of 1°C was associated with a 0.81 mm Hg to 1.44 mm Hg and 0.59 mm Hg to 0.83 mm Hg elevation in systolic and diastolic BP, respectively. Modestly warmer, commonly encountered PET levels posed a clinically meaningful effect (eg, a 6.95 mm Hg systolic pressure increase per interquartile range (4.8°C) elevation at lag hour 10). Community-level outdoor ambient temperatures were not related to BP. The authors provide the first evidence that personal exposure to warmer nighttime and early-morning environmental temperatures might lead to an increase in BP during the ensuing day., (© 2011 Wiley Periodicals, Inc.)

Intermittent claudication (IC) due to peripheral arterial disease (PAD) causes substantial impairment in quality of life, and is strongly associated with increased cardiovascular morbidity and mortality. The overall medical approach to management focuses on reducing cardiovascular events, preventing progression of underlying PAD (eg, limb loss), and improving symptoms. Aggressive secondary prevention strategies (eg, statins and smoking cessation) are of critical importance. Cilostazol treatment should be considered for those with persistent IC symptoms despite exercise and risk factor control. Management of IC requires a comprehensive approach toward symptomatic relief of pain with strategies that prolong life and prevent limb loss., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Within schizophrenia cardiovascular disease (CVD) is highly prevalent secondary to atypical antipsychotic (AAP) use. Thorough assessments of diet, lifestyle, and endothelial functioning have not been done in this population. Omega 3 Fatty Acids (N-3 FAs) have garnered attention in relation to psychopathology as well as cardioprotection. This study examined the status of endothelial function within the schizophrenia population and determined pharmacogenetic, medication, dietary, and lifestyle factors associated with this functioning., Methods: Schizophrenia subjects were screened for the metabolic syndrome along with physical activity, smoking, and variants related to folate pharmacogenetics in this cross-sectional analysis. Arteriole endothelial-dependent vasodilatation was measured using non-invasive peripheral arterial tonometry (RH-PAT, EndoPAT2000). A 24h dietary food recall was used to construct intake profiles using the Nutrition Data Systems for Research software (NDSR). We examined associations between AAP use and RH-PAT values, and the influence of N-3 FA dietary intake on this measure. Preliminary data are reported in 83 subjects with a mean age (±s.d.) of 45.89 (±11.49), 64% were Caucasian (n=53), 64% were male (n=53), and 77% were receiving AAP treatment (n=63)., Results: A significant positive relationship was found between RH-PAT values and N-3 FA intake (F=17.7(1,16), p=0.0007) in subjects not receiving AAPs. This relationship was lost in those treated with AAPs (F=0.25(1,43), p>0.6). Regression analysis confirmed the interaction effect of AAP treatment on the relationship between RH-PAT and N-3 FAs (p=0.0105). Endothelial dysfunction was also related to folate pharmacogenetic variants., Conclusions: AAPs may counteract some vascular health benefits of a diet high in N-3 FAs. AAP use may necessitate a higher N-3 FA dose to regain these effects, but additional research is necessary to strengthen the preliminary findings. Pharmacogenetic variants related to folate and homocysteine metabolism may also increase endothelial dysfunction risk., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Apolipoprotein-B/A-1 (apoB/A-R) and total/high-density lipoprotein-cholesterol ratios (TC/HDL-R) outperform non-high-density lipoprotein-cholesterol (non-HDL-C) suggested by Adult Treatment Panel (ATP) III guidelines for predicting cardiovascular (CV) outcomes., Objective: To evaluate the potential effects that implementing our proposed apoB/A-R and TC/HDL-R treatment algorithms would have on clinical management., Methods: We performed a chart review of all patients referred to the University of Michigan Lipid Clinic from January 2004 to June 2010. ATP III guidelines, including Framingham Risk Scores, were used to determine whether patients met non-HDL-C goals upon referral. Next, we evaluated whether subsequent management would differ if algorithms based upon potential apoB/A-R or TC/HDL-R targets derived from the literature were followed., Results: Among patients (n = 692), mean non-HDL-C, apoB/A-R, and TC/HDL-R were 192.2 ± 85.8 mg/dL, 0.92 ± 0.64, and 6.7 ± 8.0, respectively. Although moderately well correlated with apoB (r = 0.56, P < .01), non-HDL-C was less related to apoB/A-R (r = 0.20, P < .01) and TC/HDL-R (r = 0.39, P < .01). Most low-risk patients (<2 risk factors; n = 207) at non-HDL-C goal (<190 mg/dL) also met apoB/A-R <0.9 (79%) and TC/HDL-R <6.0 (92%) targets. However, a minority of high-risk patients (Framingham Risk Score >20%, cardiovascular disease or risk equivalent; n = 307) meeting non-HDL-C goal (<130 mg/dL) achieved targets for apoB/A-R <0.5 (21%) or TC/HDL-C <3.5 (42%). The percentages of intermediate-risk patients meeting both non-HDL-C and ratio goals varied; nonetheless, few met an aggressive apoB/A-R <0.6 (36%-50%) target., Conclusions: Most high- and many intermediate-risk patients at non-HDL-C goals would require more aggressive treatment to reach the suggested apoB/A-R or TC/HDL-R targets. Whether this strategy yields superior outcomes merits future investigation., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Levels of fine particulate matter [≤ 2.5 μm in aerodynamic diameter (PM(2.5))] are associated with alterations in arterial hemodynamics and vascular function. However, the characteristics of the same-day exposure-response relationships remain unclear., Objectives: We aimed to explore the effects of personal PM(2.5) exposures within the preceding 24 hr on blood pressure (BP), heart rate (HR), brachial artery diameter (BAD), endothelial function [flow-mediated dilatation (FMD)], and nitroglycerin-mediated dilatation (NMD)., Methods: Fifty-one nonsmoking subjects had up to 5 consecutive days of 24-hr personal PM(2.5) monitoring and daily cardiovascular (CV) measurements during summer and/or winter periods. The associations between integrated hour-long total personal PM(2.5) exposure (TPE) levels (continuous nephelometry among compliant subjects with low secondhand tobacco smoke exposures; n = 30) with the CV outcomes were assessed over a 24-hr period by linear mixed models., Results: We observed the strongest associations (and smallest estimation errors) between HR and TPE recorded 1-10 hr before CV measurements. The associations were not pronounced for the other time lags (11-24 hr). The associations between TPE and FMD or BAD did not show as clear a temporal pattern. However, we found some suggestion of a negative association with FMD and a positive association with BAD related to TPE just before measurement (0-2 hr)., Conclusions: Brief elevations in ambient TPE levels encountered during routine daily activity were associated with small increases in HR and trends toward conduit arterial vasodilatation and endothelial dysfunction within a few hours of exposure. These responses could reflect acute PM(2.5)-induced autonomic imbalance and may factor in the associated rapid increase in CV risk among susceptible individuals.

Rationale: Chronic exposure to ambient air-borne particulate matter of < 2.5 μm (PM₂.₅) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive., Objective: To investigate the molecular mechanisms by which PM₂.₅ mediates inflammatory responses in a mouse model of chronic exposure., Methods and Results: Here, we show that chronic exposure to ambient PM₂.₅ promotes Ly6C(high) inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor (TLR)4 and Nox2 (gp91(phox)) deficiency prevented monocyte NADPH oxidase activation in response to PM₂.₅ and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47(phox) phosphorylation in TLR4 deficient animals. PM₂.₅ exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow-derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM₂.₅ exposure, whereas TLR4 deficiency attenuated this response., Conclusions: Taken together, our findings suggest that PM₂.₅ triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase-dependent mechanisms.

Epidemiologic studies have proposed a relationship between hyperuricemia and cardiovascular (CV) risk. However, it is unclear whether uric acid (UA) is an independent risk factor for CV disease (CVD) after controlling for other predisposing conditions. Gout patients might have persistent systemic inflammation, which, in addition to hyperuricemia, may potentiate CVD. This study examined vascular function and markers of CV damage in gout patients when compared with healthy controls. Brachial artery flow-mediated dilatation, arterial compliance, and microvascular function were measured. Circulating apoptotic endothelial cells and endothelial progenitor cells were quantified by FACS and circulating biomarkers of CVD by enzyme-linked immunosorbent assay. Gout patients displayed significant increases in body mass index, C-reactive protein, UA, and triglycerides and decreases in high-density lipoprotein. There were no significant differences in other CV traditional risk factors, adhesion molecules, or chemokines. Gout patients did not differ from controls in vascular function. In univariate and multivariate analysis, UA was not associated with the quantified CV risk parameters. Despite an increase in several CV risk factors, inflammation, and UA, gout patients display normal endothelial function and no increases in biomarkers of CVD. These results do not support the notion that gout is an independent risk factor for premature CVD., (© 2010 Wiley Periodicals, Inc.)

Background: The purpose of this study was to assess patient awareness of the coronary heart disease (CHD) risks posed by air pollution., Methods: We distributed a questionnaire to 500 patients at a University of Michigan cardiology clinic., Results: More than half of patients (n = 264, 53%) did not believe that air pollution was "proven" or "likely" to cause CHD, whereas a similar percentage (n = 284, 57%) were not previously aware of its association with CHD. Most patients (n = 459, 92%) reported that a health care provider had not informed them of the potential CHD risks posed by air pollution nor discussed ways to lower their exposure (n = 471, 94%)., Conclusion: Patients were mostly unaware of the CHD risks posed by air pollution. These findings suggest that a serious knowledge gap exists among at-risk patients regarding this important CHD risk factor and support the need for educational efforts targeting patients and health care providers alike., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Higher ambient fine particulate matter (PM₂.₅) levels can be associated with increased blood pressure and vascular dysfunction., Objectives: To determine the differential effects on blood pressure and vascular function of daily changes in community ambient- versus personal-level PM₂.₅ measurements., Methods: Cardiovascular outcomes included vascular tone and function and blood pressure measured in 65 non-smoking subjects. PM₂.₅ exposure metrics included 24 h integrated personal- (by vest monitors) and community-based ambient levels measured for up to 5 consecutive days (357 observations). Associations between community- and personal-level PM₂.₅ exposures with alterations in cardiovascular outcomes were assessed by linear mixed models., Results: Mean daily personal and community measures of PM₂.₅ were 21.9±24.8 and 15.4±7.5 μg/m³, respectively. Community PM₂.₅ levels were not associated with cardiovascular outcomes. However, a 10 μg/m³ increase in total personal-level PM₂.₅ exposure (TPE) was associated with systolic blood pressure elevation (+1.41 mm Hg; lag day 1, p<0.001) and trends towards vasoconstriction in subsets of individuals (0.08 mm; lag day 2 among subjects with low secondhand smoke exposure, p=0.07). TPE and secondhand smoke were associated with elevated systolic blood pressure on lag day 1. Flow-mediated dilatation was not associated with any exposure., Conclusions: Exposure to higher personal-level PM₂.₅ during routine daily activity measured with low-bias and minimally-confounded personal monitors was associated with modest increases in systolic blood pressure and trends towards arterial vasoconstriction. Comparable elevations in community PM₂.₅ levels were not related to these outcomes, suggesting that specific components within personal and background ambient PM₂.₅ may elicit differing cardiovascular responses.

Objectives: We tested the hypothesis that exposure to concentrated ambient particles (CAP) and/or ozone (O(3)) would increase dispersion of ventricular repolarization., Background: Elevated levels of air pollution are associated with cardiac arrhythmias through mechanisms yet to be elucidated., Methods: Each of 25 volunteers (18 to 50 years of age) had four 2-h exposures to 150 μg/m(3) CAP; 120 parts per billion O(3); CAP + O(3); and filtered air (FA). Exposure-induced changes (Δ = 5-min epochs at end-start) in spatial dispersion of repolarization were determined from continuous 12-lead electrocardiographic recording., Results: Spatial dispersion of repolarization assessed by corrected ΔT-wave peak to T-wave end interval increased significantly for CAP + O(3) (0.17 ± 0.03, p < 0.0001) exposure only, remaining significant when factoring FA (CAP + O(3) - FA) as control (0.11 ± 0.04, p = 0.013). The influence on repolarization was further verified by a significant increase in ΔQT dispersion (for CAP + O(3) compared with FA (5.7 ± 1.4, p = 0.0002). When the low-frequency to high-frequency ratio of heart rate variability (a conventional representation of sympathetic-parasympathetic balances) was included as a covariate, the effect estimate was positive for both corrected ΔT-wave peak to T-wave end interval (p = 0.002) and ΔQT dispersion (p = 0.038). When the high-frequency component (parasympathetic heart rate modulation) was included as a covariate with corrected ΔT-wave peak to T-wave end interval, the effect estimate for high frequency was inverse (p = 0.02)., Conclusions: CAP + O(3) exposure alters dispersion of ventricular repolarization in part by increasing sympathetic and decreasing parasympathetic heart rate modulation. Detection of changes in repolarization parameters, even in this small cohort of healthy individuals, suggests an underappreciated role for air pollutants in urban arrhythmogenesis., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Statins reduce cardiovascular events and cardiovascular and total mortality in persons at risk for and with coronary disease, but there remains a significant residual event rate, particularly in those with the atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol. Large outcome trials designed to assess the value of combining statins with other agents to target HDL cholesterol and non-HDL cholesterol will not be completed for a few years, but there is ample evidence for the clinician to consider combination therapy. The choices for therapies to supplement statins include niacin, fibrates, and omega-3 fatty acids. We present the argument that after therapeutic lifestyle changes, the first priority should be the maximally tolerated effective dose of a potent statin. Evidence supports the addition of niacin as the second agent. In some situations, high-dose omega-3 fatty acid therapy could be the first agent added to statins. Although fibrate monotherapy alone or in combination with non-statin low-density lipoprotein cholesterol-lowering agents can be effective in mixed hyperlipidemia when statins are not tolerated, the combination of statin+fibrate should be considered second-line therapy until the efficacy and safety are established., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Prev Cardiol. Long-term exposure to secondhand smoke (SHS) is associated with impaired vascular function. The authors investigated the vascular and blood pressure (BP) reactions to acute SHS exposure. Twenty-five healthy nonsmoking adults underwent a 1-hour exposure to SHS (mean fine particulate matter < 2.5 μm level = 315 ± 116 μg/m(3) ). Microvascular endothelial-dependent vasodilatation (EDV) (EndoPAT, Itamar Medical, Caesarea, Israel) and aortic hemodynamics/compliance (SphygmoCor, AtCor Medical, West Ryde, Australia) were measured before and after the SHS exposure with BP measured every 15 minutes during and for a 24-hour period before and after the exposure. SHS exposure did not change EDV, aortic hemodynamics, arterial compliance, or 24-hour BP. However, diastolic BP significantly increased during the SHS exposure period by 3.4 ± 5.6 mm Hg. Our brief SHS exposure did not impair microvascular endothelial function or arterial compliance in healthy nonsmoking adults, but brachial diastolic BP increased., (© 2010 Wiley Periodicals, Inc.)

Particulate matter (PM) air pollution less than 2.5 microm in diameter (PM(2.5)), which is now an all-pervading element of modern-day society, is associated with heightened cardiovascular morbidity and mortality. Not only can short-term PM(2.5) exposure trigger acute cardiovascular events, but longer-term exposure over years augments cardiovascular risk to an even greater extent. One biological mechanism capable of explaining this observation is that chronic exposure may promote the progression and vulnerability of atherosclerotic plaques. Indeed, recent epidemiologic studies have demonstrated an association between ambient PM(2.5) exposure and the presence or extent of atherosclerosis in humans. Several animal experiments have provided corroborating evidence that chronic exposures in fact do enhance the progression and perhaps vulnerability of atherosclerotic lesions. Due to the billions of people continually exposed to PM(2.5), the long-term pro-atherosclerotic effects of this ubiquitous air pollutant are likely to be of enormous and growing global public health importance.

A short-term increase in fine particulate matter air pollution (PM(2.5)) concentration increases the risk for myocardial infarctions, strokes, and heart failure exacerbations. An important mechanism likely contributing to these associations is an elevation in arterial blood pressure (BP). Exposure to ambient PM(2.5) even at present-day concentrations can increase BP within a period of a few days while long-term exposure might also promote the development of chronic hypertension. Controlled human and animal experiments have corroborated the veracity of these findings and elucidated plausible biological mechanisms. PM(2.5) deposition within the pulmonary tree is capable of rapidly triggering autonomic nervous system imbalance, thereby increasing BP within minutes of inhalation. In addition, fine particles can instigate a systemic pro-inflammatory response over a more prolonged period of exposure. Higher circulating levels of activated immune cells and inflammatory cytokines could consequently cause vascular endothelial dysfunction leading to an imbalance in vascular homeostatic responses. Indeed, chronic PM(2.5) exposure augments pro-vasoconstrictive pathways while blunting vasodilator capacity. Finally, certain particle constituents (e.g., metals, organic compounds, and ultra-fine particles) might also be capable of reaching the systemic circulation upon inhalation and thereafter directly impair vascular function. At the molecular level, the generation of oxidative stress with the consequent up-regulation of redox sensitive pathways appears to be a common and fundamental mechanism involved in the instigation of these pro-hypertensive responses. Due to the ubiquitous, continuous and often involuntary nature of exposure, PM(2.5) may be an important and under-appreciated worldwide environmental risk factor for increased arterial BP.

Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 microg/m(3)) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor alpha. In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.

Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of < 2.5 microm (PM(2.5)) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM(2.5) or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM(2.5) exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM(2.5) exposure along with increased expression of the guanine exchange factors (GEFs) PDZ-RhoGEF and p115 RhoGEF in PM(2.5)-exposed mice. Parallel with increased RhoA activation, PM(2.5) exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM(2.5) potentiates cardiac remodeling in response to ANG II through RhoA/Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution.

Background: In patients with hypertriglyceridemia, non-high density lipoprotein cholesterol (nonHDL-C) is a targeted goal. However, apoprotein B100 (apoB) may be superior in predicting cardiovascular risk so we assessed the utility of an apoB-based., Methods: New patients (n = 125) who had both apoB and standard lipids measured on the same day were included and we determined the concordances of having achieved goal lipid levels based upon proposed apoB versus nonHDL-C (ATP III) targets in patients with elevated TG (>or=150 mg*dl(-1)) levels., Results: Although apoB was correlated with nonHDL-C (r = 0.47, p or= 150 mg*dl(-1), as specifically outlined in ATP III guidelines. In total, > 50% of all subjects would have been treated either more or less aggressively following an apoB-based therapeutic algorithm., Conclusions: Our findings confirm that the majority of patients referred with hypertriglyceridemia would be managed differently by following an apoB-based treatment algorithm compared to ATP III guidelines. Although many patients would be candidates for more intense therapy, many would be treated less aggressively., ((c) 2009 Wiley Periodicals, Inc.)

Recent studies have suggested a link between exposure to ambient particulate matter <2.5 microm in diameter (PM(2.5)) and adverse cardiovascular outcomes. The objective of this study was to examine the effects of differing community-level exposure to PM(2.5) on daily measures of blood pressure (BP) among an adult population. During the period May 2002 through April 2003, BP was examined at 2 time points for 347 adults residing in 3 distinct communities of Detroit, Michigan. Exposure to PM(2.5) was assessed in each community during this period, along with multivariate associations between PM(2.5) and BP. In models combining all 3 of the communities, PM(2.5) was significantly associated with systolic blood pressure; a 10-microg/m(3) increase in daily PM(2.5) was associated with a 3.2-mm Hg increase in systolic blood pressure (P=0.05). However, in models that added a location interaction, larger effects were observed for systolic blood pressure within the community with highest PM(2.5) levels; a 10-microg/m(3) increase in daily PM(2.5) was associated with a 8.6-mm Hg increase in systolic blood pressure (P=0.01). We also found young age (<55 years) and not taking BP medications to be significant predictors of increased BP effects. Among those taking BP medications, the PM(2.5) effect on BP appeared to be mitigated, partially explaining the age effect, because those participants <55 years of age were less likely to take BP medications. Short-term increases in exposure to ambient PM(2.5) are associated with acute increases in BP in adults, especially within communities with elevated levels of exposure.

Objective: Fine particulate matter <2.5 microm (PM(2.5)) has been implicated in vasoconstriction and potentiation of hypertension in humans. We investigated the effects of short-term exposure to PM(2.5) in the angiotensin II (AII) infusion model., Methods and Results: Sprague-Dawley rats were exposed to PM(2.5) or filtered air (FA) for 10 weeks. At week 9, minipumps containing AII were implanted and the responses studied over a week. Mean concentration of PM(2.5) inside the chamber was 79.1+/-7.4 microg/m(3). After AII infusion, mean arterial pressure was significantly higher in PM(2.5)-AII versus FA-AII group. Aortic vasoconstriction to phenylephrine was potentiated with exaggerated relaxation to the Rho-kinase (ROCK) inhibitor Y-27632 and increase in ROCK-1 mRNA levels in the PM(2.5)-AII group. Superoxide (O(2).(-)) production in aorta was increased in the PM(2.5)-AII compared to the FA group, inhibitable by apocynin and L-NAME with coordinate upregulation of NAD(P)H oxidase subunits p22(phox) and p47(phox) and depletion of tetrahydrobiopterin. In vitro exposure to ultrafine particles (UFP) and PM(2.5) was associated with an increase in ROCK activity, phosphorylation of myosin light chain, and myosin phosphatase target subunit (MYPT1). Pretreatment with the nonspecific antioxidant N-acetylcysteine and the Rho kinase inhibitors (Fasudil and Y-27632) prevented MLC and MYPT-1 phosphorylation by UFP suggesting a O(2)(.-)-mediated mechanism for PM(2.5) and UFP effects., Conclusions: Short-term air pollution exaggerates hypertension through O(2)(.-)-mediated upregulation of the Rho/ROCK pathway.

Air pollution is a heterogeneous mixture of gases, liquids and PM (particulate matter). In the modern urban world, PM is principally derived from fossil fuel combustion with individual constituents varying in size from a few nanometres to 10 microm in diameter. In addition to the ambient concentration, the pollution source and chemical composition may play roles in determining the biological toxicity and subsequent health effects. Nevertheless, studies from across the world have consistently shown that both short- and long-term exposures to PM are associated with a host of cardiovascular diseases, including myocardial ischaemia and infarctions, heart failure, arrhythmias, strokes and increased cardiovascular mortality. Evidence from cellular/toxicological experiments, controlled animal and human exposures and human panel studies have demonstrated several mechanisms by which particle exposure may both trigger acute events as well as prompt the chronic development of cardiovascular diseases. PM inhaled into the pulmonary tree may instigate remote cardiovascular health effects via three general pathways: instigation of systemic inflammation and/or oxidative stress, alterations in autonomic balance, and potentially by direct actions upon the vasculature of particle constituents capable of reaching the systemic circulation. In turn, these responses have been shown to trigger acute arterial vasoconstriction, endothelial dysfunction, arrhythmias and pro-coagulant/thrombotic actions. Finally, long-term exposure has been shown to enhance the chronic genesis of atherosclerosis. Although the risk to one individual at any single time point is small, given the prodigious number of people continuously exposed, PM air pollution imparts a tremendous burden to the global public health, ranking it as the 13th leading cause of morality (approx. 800,000 annual deaths).

Background: This study was designed to determine whether overweight or obese status is independently associated with myocardial flow reserve (MFR), an established predictor of cardiovascular mortality, in a group of postmenopausal women with no previous cardiovascular disease. Postmenopausal women are the largest group of overweight and physically inactive individuals in the United States. Increased body mass index (BMI) is consistently associated with increased cardiovascular mortality in this population. Whether this is because of obesity itself or the accompanying increase in cardiovascular risk factors (CRFs) remains controversial., Methods: We examined the relationship of myocardial blood flow (MBF), coronary vascular resistance, and MFR to BMI in 60 postmenopausal women with no coronary heart disease. Subjects underwent dynamic N-13 ammonia positron emission tomography for the measurement of MBF and MFR. Baseline demographics, CRF, and hemodynamic parameters were recorded for each subject. Datasets were divided into 3 groups according to BMI: normal (18 to 24), overweight (25 to 29), and obese (>or=30)., Results: The overweight and obese groups showed significantly higher resting MBF and lower MFR than the normal-weight group (both P < .001), even after adjusting for CRF. A further analysis of subjects without any CRF (n = 35) showed that the MFR remained significantly lower in the obese compared with normal-weight subjects (P = .05). Levels of known markers of vascular inflammation (high-sensitivity C-reactive protein and homocysteine) and high-density lipoprotein cholesterol levels correlated with declining MFR., Conclusions: These findings provide a mechanistic link between obesity and coronary heart disease in this population.

Objective: We report results from a pilot study aimed at optimizing the use of CT bidimensional measurements and 18F-FDG PET maximum standardized uptake values (SUVs-(max)) for determining response to prolonged imatinib mesylate treatment in patients with advanced gastrointestinal stromal tumors (GISTs)., Subjects and Methods: Sixty-three patients enrolled in a multicenter trial evaluating imatinib mesylate therapy for advanced GIST underwent FDG PET at baseline and 1 month after initiation of treatment. Of these 63 patients, 58 underwent concomitant CT. Time-to-treatment failure (TTF) was used as the outcome measure. Patients were followed up over a range of 23.7 to 37 months (median, 31.7 months). The predictive power of change in CT bidimensional measurements, change in PET SUVmax, and PET SUVmax at 1 month after initiation of treatment were determined, optimized, and compared. The effectiveness of combining metrics was also evaluated., Results: Both a threshold PET SUVmax value of 2.5 at 1 month (p = 0.04) and the European Organization for Research and Treatment of Cancer (EORTC) criteria for partial response on FDG PET (25% reduction in PET SUVmax) at 1 month (p = 0.004) were predictive of prolonged treatment success. The Southwest Oncology Group (SWOG) criteria for partial response ((3) 50% reduction in CT bidimensional measurements) at 1 month were not predictive (p = 0.55) of TTF. Optimizing metrics improved results performance. An optimized PET SUVmax threshold of 3.4 (p = 0.00002), a reduction in the SUVmax of 40% (p = 0.002), and an optimized CT bidimensional measurement threshold--that is, no growth from baseline to 1 month (p = 0.00005)--outperformed the existing standards (i.e., EORTC and SWOG criteria). Combinations of metrics did not improve performance., Conclusion: The two best metrics were the optimized PET SUVmax threshold of 3.4 at 1 month (p = 0.00002) and the optimized CT bidimensional measurement threshold (no growth from baseline to 1 month, p = 0.00005) in this patient group.

Background: Leptin may play a role in mediating obesity-related hypertension. However, its effects on the vasculature and blood pressure (BP) remain poorly defined in humans., Methods: In the first study, we performed a short-term, placebo-controlled, randomized, double-blind, cross-over experiment investigating the actions of recombinant human leptin (r-metHuLeptin) in 15 nonobese adults. To compliment the acute study, we retrospectively analyzed available BP results from a previously performed 85-day, placebo-controlled, randomized, double-blind, parallel weight-loss study using r-metHuLeptin in 284 obese adults., Results: In the acute study, conduit artery endothelial function determined by brachial flow-mediated dilatation (FMD) increased 2 hours following 0.2 mg . Kg(1) subcutaneously (SC) of r-metHuLeptin versus placebo (+3.3% versus -2.8%, P = .02). BP remained unchanged 4 hours after injections. In the retrospective analysis of the weight loss study data, 10 mg every day before noon (QAM), 10 mg every day after noon (QPM), or 10 mg twice a day (BID) SC of r-metHuLeptin was found to not alter the degree of weight loss (-3.2 +/- 3.7 versus -2.9 +/- 3.2 Kg, P = .54), change in systolic (-1.6 + 12.9 versus -2.0 +/- 13.9 mmHg, P = .85) and diastolic BP (-0.2 +/- 8.7 versus -1.5 +/- 8.6, P = .30), as well as heart rate (-1.4 +/- 10.7 versus -1.4 +/- 10.4 beats/min, P = .98) compared to placebo., Conclusions: In our acute study, marked hyperleptinemia rapidly enhanced endothelial function and did not alter BP. The available data from a longer-term study in healthy obese adults did not demonstrate a significant effect of hyperleptinemia upon BP. These combined findings do not support a direct role for leptin in linking obesity to hypertension, however more studies are required to corroborate these observations.

Background. We investigated hyperactivity of the renin-angiotensin system (RAS) as a cause of endothelial dysfunction in obese humans. Methods. Thirty five healthy overweight (BMI = 33.6 +/- 6.6 kg m (2)) adults (33 +/- 10 years old) without cardiovascular risk factors received valsartan (160 mg) orally daily or a matching placebo for 6 weeks each. Results. Baseline flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) were not altered by placebo or valsartan. However, fasting plasma insulin was significantly decreased by valsartan compared to placebo (-4.6 +/- 16.0 muUmL(1) versus -0.4 +/- 11.6 muUmL(1), P = 0.032) with no changes in glucose. A secondary analysis in patients with elevated waist to hip ratios (ÿ0.85, n = 18) showed an increase in FMD with valsartan. Conclusions. Our findings suggest that angiotensin 2 receptor blockade may aid in the prevention of diabetes even at the earliest stages of risk due solely to uncomplicated obesity. The lack of an improvement in FMD does not support a central role of RAS-hyperactivity in the etiology of the vascular dysfunction due solely to obesity. However, it is possible that obese patients with central adiposity may improve FMD with RAS blockade, and future investigation is warranted in this subgroup.

Exposure to ambient levels of particulate matter (PM) air pollution increases the risk of a host of cardiovascular diseases and events. One potential mechanism explaining this association is that acute exposure to PM at high concentrations is capable of raising blood pressure within hours to days. Epidemiologic studies confirm that even commonly encountered levels of airborne pollutants can result in a prohypertensive response in humans. Several biologic pathways may be involved, including autonomic nervous system imbalance and arterial vascular dysfunction/vasoconstriction due to systemic oxidative stress/inflammation triggered by PM inhalation. The clinical importance of this vasopressor response and its relative role in promoting cardiovascular events associated with PM remain unclear. Because air pollution exposure is ubiquitous throughout the world, however, all health care providers and especially those who treat hypertension should be aware of this emerging and important biologic relationship.

Particulate matter (PM) air pollution is associated with an increased risk of cardiovascular morbidity and mortality. The focus of this review will be on the role that both acute and chronic exposure to PM plays in causing cardiovascular disease and on the latest major new findings and controversies in this field of research. Even short-term exposure to PM2.5 over a few hours can trigger myocardial infarctions, cardiac ischemia, arrhythmias, heart failure, stroke, exacerbation of peripheral arterial disease, and sudden death. Chronic exposure to moderately elevated levels also enhances the risk for developing a variety of cardiovascular diseases, possibly including hypertension and systemic atherosclerosis. Recent epidemiologic studies have furthered our understanding of the linkage between air pollutants and human health, with a multitude of plausible mechanistic explanations having been demonstrated experimentally during the past few years. Although a number of finer details relating to both the epidemiology and the mechanisms involved require more investigation, the overall weight of evidence is now sufficient to implicate PM exposure as a cause of cardiovascular disease. Without doubt, exposure to particulate matter can play a causal role in triggering a host of acute cardiovascular events via many mechanisms. Although long-term air pollution exposure has been shown to promote the development of atherosclerosis, the clinical significance of this relation requires more investigation.

Objective: Coronary calcium score (CCS), carotid plaque area (CPA), intima-media thickness (IMT), and C-reactive protein (CRP) are independent predictors of cardiovascular prognosis. Although each test may enhance risk stratification, their comparative abilities to screen for underlying coronary stenoses in individual patients is less established., Methods and Results: Forty-two patients who had a 16-slice coronary computed tomography angiogram (CTA) performed were invited to have CPA, IMT, and CRP measured. CPA was defined as the sum of all the cross-sectional areas of each plaque >1 mm in diameter found in all carotid vessels bilaterally. CCS and the number plus degree of stenotic coronary arteries were determined by CTA. The presence of clinically significant coronary artery disease (CAD) was defined as the existence of any stenosis > or =50%. CTA identified clinically significant CAD in 43% of the patients. CPA >0 was more sensitive (72%) and specific (58%) than a CCS >0 (58% and 55%) for identifying CAD. A "clean" carotid artery (CPA=0) provides a superior negative predictive value (74%) and likelihood ratio of a negative test (0.48) than all other studies, in particular versus a CCS=0 (65% and 0.72). The areas under the receiver-operator curves for CPA and CCS in relation to any CAD were similar (0.640 versus 0.675). Carotid IMT and CRP performed poorly compared with CPA and CCS. For detecting CAD in only the left main or left anterior descending artery, the negative predictive value and likelihood ratio of a negative test remained superior for CPA (87% and 0.33) compared with CCS (80% and 0.56). In our population with a prevalence of these coronary lesions of 30%, the post-test probability in any patient with a negative CPA result is reduced to 10%., Conclusions: CPA determination is superior to CCS, IMT, and CRP in its ability to reduce the likelihood of clinically significant underlying CAD in patients of varying cardiac risk.

Obesity promotes the development of several major cardiovascular risk factors. Moreover, excess adiposity may play a direct role in initiating atherosclerosis as fat cells are capable of affecting the systemic vasculature through a variety of mechanisms. Recent studies demonstrate that obesity per se may impair vascular endothelial function. This is important as endothelial dysfunction is a key factor in the pathogenesis of atherosclerosis and in triggering acute ischemic events. At present, few studies have determined the beneficial impact of weight loss on cardiovascular outcomes and mortality. However, several experiments have demonstrated that weight loss can lead to improvements in endothelial function, a validated surrogate marker of cardiovascular risk. The mechanisms whereby weight loss restores vascular health are likely multifactorial. However, the relative importance of reduced adiposity versus the specific dietary regimens prescribed, the role of concomitant exercise, and the direct effect of medications remain unclear. Several other unresolved issues such as the longevity of improvement, the amount of weight loss required, and whether the improvement in endothelial function actually translates into a reduction in cardiovascular events also remain to be determined. Nevertheless, lifestyle changes that lead to weight reduction are able to improve vascular function in overweight adults.

Objectives: This study sought to determine the effect of aggressive 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy on surrogate markers in non-ischemic cardiomyopathy (NICM) patients and average low-density lipoprotein (LDL) concentrations., Background: The effects of statins may well go beyond lipid lowering, and these pleiotropic effects may be of benefit in the treatment of heart failure., Methods: Fifteen patients with NICM on standard maximized heart failure medication were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial. Patients received 80 mg atorvastatin (ATV) or matching placebo for a 12-week treatment period with a minimum of an 8-week washout period. The following surrogate markers were evaluated: N-terminal-pro brain natriuretic peptide, high-sensitivity C-reactive protein, oxidized LDL antibody, soluble receptor tumor necrosis factor, tumor necrosis factor-alpha, circulating levels of vascular adhesion molecule-1, intercellular adhesion molecule-1, P-selectin, non-invasive endothelial function studies, and heart rate variability., Results: After ATV therapy, there was a significant decrease in LDL concentration from 110 +/- 27 mg/dl to 55 +/- 18 mg/dl (p < 0.05). There were no differences between ATV and placebo with regard to the surrogate markers measured., Conclusions: Based on these findings, it seems that the administration of high-dose statins to a heart failure population with modest LDL levels and no other indication for statin therapy was neither beneficial nor detrimental as determined by surrogate marker measures. Further studies are needed to determine whether there is an appropriate patient population and optimal dose (LDL concentration) for the treatment of systolic heart failure with statin therapy.

Context: Recent studies have suggested a link between inhaled particulate matter exposure in urban areas and susceptibility to cardiovascular events; however, the precise mechanisms remain to be determined., Objective: To test the hypothesis that subchronic exposure to environmentally relevant particulate matter, even at low concentrations, potentiates atherosclerosis and alters vasomotor tone in a susceptible disease model., Design, Setting, and Participants: Between July 21, 2004, and January 12, 2005, 28 apolipoprotein E-/- (apoE-/-) mice were, based on randomized assignments, fed with normal chow or high-fat chow and exposed to concentrated ambient particles of less than 2.5 microm (PM2.5) or filtered air (FA) in Tuxedo, NY, for 6 hours per day, 5 days per week for a total of 6 months., Main Outcome Measures: Composite atherosclerotic plaque in the thoracic and abdominal aorta and vasomotor tone changes., Results: In the high-fat chow group, the mean (SD) composite plaque area of PM2.5 vs FA was 41.5% (9.8%) vs 26.2% (8.6%), respectively (P<.001); and in the normal chow group, the composite plaque area was 19.2% (13.1%) vs 13.2% (8.1%), respectively (P = .15). Lipid content in the aortic arch measured by oil red-O staining revealed a 1.5-fold increase in mice fed the high-fat chow and exposed to PM2.5 vs FA (30.0 [8.2] vs 20.0 [7.0]; 95% confidence interval [CI], 1.21-1.83; P = .02). Vasoconstrictor responses to phenylephrine and serotonin challenge in the thoracic aorta of mice fed high-fat chow and exposed to PM2.5 were exaggerated compared with exposure to FA (mean [SE], 134.2% [5.2%] vs 100.9% [2.9%], for phenylephrine, and 156.0% [5.6%] vs 125.1% [7.5%], for serotonin; both P = .03); relaxation to the endothelium-dependent agonist acetylcholine was attenuated (mean [SE] of half-maximal dose for dilation, 8.9 [0.2] x 10(-8) vs 4.3 [0.1] x 10(-8), respectively; P = .04). Mice fed high-fat chow and exposed to PM2.5 demonstrated marked increases in macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine (all P<.001)., Conclusion: In an apoE-/- mouse model, long-term exposure to low concentration of PM2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.

Exposure to particulate matter (PM) air pollution increases the risk for myocardial infarctions, strokes, and cardiovascular mortality. A variety of responsible mechanisms have been described, including PM-induced elevations in blood pressure. Observational studies and controlled experiments have provided evidence that PM is capable of acutely increasing blood pressure in certain scenarios. Enhanced sympathetic tone and vascular dysfunction due to PM-induced systemic oxidative stress/inflammation are leading explanations. The hemodynamic responses to air pollution may be altered by underlying cardiovascular risk factors and the chemical composition of the PM. However, even the small elevations in blood pressure observed following certain exposures to PM have tremendous public health implications, due to the ubiquitous nature of air pollution.

Background: Cardiovascular disease is largely explained by the traditional risk factors, but there are several novel risk factors that have been shown to predict cardiovascular morbidity. The measurement of low-density lipoprotein particle size (LDLPS) is a novel cardiovascular risk factor, yet it is unknown whether this measurement provides additional information that may influence the subsequent medical treatment of patients., Hypothesis: The measurement of LDLPS provides additional information that may influence preventive treatment for cardiovascular disease., Methods: In an observational study of 82 patients referred to a tertiary care preventive cardiology clinic, LDLPS was dichotomized as either small or large and was determined by either the NMR LipoProfile test, the Vertical Auto Profile (VAP) cholesterol test, or gradient gel electrophoresis. Lipid profiles were obtained and Framingham risk scores were calculated. Patients were stratified by Adult Treatment Panel guidelines as being at low, intermediate, or high risk., Results: The study included 56 men and 26 women with a mean age of 54 +/- 11 years. In the entire cohort of 82 patients, only 31 (38%) were at non-high-density lipoprotein (HDL) goal, only 21 (26%) were at goals for both non-HDL and HDL, and only 18 (22%) were at goal for non-HDL, HDL, and triglycerides. When considering each of the risk factor strata, 19 of 43 (44%) low-risk patients were at non-HDL goal and 12 of these also had a small LDLPS. Only 8 of 18 (44%) intermediate-risk patients were at non-HDL goal and 7 of these (88%) had small LDLPS. Finally, only four high-risk patients were at non-HDL goal and three of these (75%) had small LDLPS., Conclusions: Knowing the LDLPS could alter subsequent therapeutic recommendations for most patients who have reached target lipid values.

Exposure to air pollution has been shown to cause arterial vasoconstriction and alter autonomic balance. Because these biologic responses may influence systemic hemodynamics, we investigated the effect of air pollution on blood pressure (BP). Responses during 2-hr exposures to concentrated ambient fine particles (particulate matter < 2.5 microm in aerodynamic diameter; PM2.5) plus ozone (CAP+O3) were compared with those of particle-free air (PFA) in 23 normotensive, nonsmoking healthy adults. Mean concentrations of PM2.5 were 147 +/- 27 versus 2 +/- 2 microg/m3, respectively, and those of O3 were 121 +/- 3 versus 8 +/- 5 ppb, respectively (p < 0.0001 for both). A significant increase in diastolic BP (DBP) was observed at 2 hr of CAP+O3 [median change, 6 mm Hg (9.3%); binomial 95% confidence interval (CI), 0 to 11; p = 0.013, Wilcoxon signed rank test] above the 0-hr value. This increase was significantly different (p = 0.017, unadjusted for basal BP) from the small 2-hr change during PFA (median change, 1 mm Hg; 95% CI, -2 to 4; p = 0.24). This prompted further investigation of the CAP+O3 response, which showed a strong association between the 2-hr change in DBP (and mean arterial pressure) and the concentration of the organic carbon fraction of PM2.5 (r = 0.53, p < 0.01; r = 0.56, p < 0.01, respectively) but not with total PM2.5 mass (r < or = 0.25, p > or = 0.27). These findings suggest that exposure to environmentally relevant concentrations of PM2.5 and O3 rapidly increases DBP. The magnitude of BP change is associated with the PM2.5 carbon content. Exposure to vehicular traffic may provide a common link between our observations and previous studies in which traffic exposure was identified as a potential risk factor for cardiovascular disease.