Secondary Cardiovascular Disease Events Research Articles

The Great Controversy of Obstructive Sleep Apnea Treatment for Cardiovascular Risk Benefit: Advancing the Science Through Expert Consensus. An Official American Thoracic Society Workshop Report.

The prevalence of obstructive sleep apnea (OSA) is on the rise, driven by various factors including more sensitive diagnostic criteria, increased awareness, enhanced technology through at-home testing enabling easy and cost-effective diagnosis, and a growing incidence of comorbid conditions such as obesity. Treating symptomatic patients with OSA syndrome to enhance quality of life remains a cornerstone approach. However, there is a lack of consensus regarding treatment to improve cardiovascular disease (CVD) outcomes, particularly in light of overall negative results from several randomized controlled trials (RCT) indicating no benefit of positive airway pressure (PAP) therapy on primary and secondary CVD events. These RCTs were limited by suboptimal PAP adherence, use of composite CVD outcomes, and limited diversity and generalizability to Sleep Clinic patients. As such, this workshop assembled clinical experts, as well as researchers in basic and translational science, epidemiology, clinical trials, and population health to discuss the current state, and future research directions to guide personalized therapeutic strategies and future research directions in OSA. There was overall consensus among workshop participants that OSA represents a heterogeneous disease with variable endotypes and phenotypes, and heterogeneous responses to treatment. Future research should prioritize employing multi-modal therapeutic approaches within innovative and adaptive trial designs, focusing on specific subgroups of OSA patients hypothesized to benefit from a CVD perspective. Future work should also be inclusive of diverse populations and consider the life-course of OSA to better comprehend treatment strategies that can address the disproportionate impact of OSA on racially minoritized groups. Further, a more holistic approach to sleep must be adopted to include broader assessments of symptoms, sleep duration, and comorbid sleep and circadian disorders. Finally, it is imperative to establish a sleep research consortium dedicated to collecting raw data and biospecimens categorized by OSA subtypes. This will facilitate mechanistic determinations, foster collaborative research, and help bolster the pipeline of early-career researchers.

Endometriosis and cardiovascular disease: a population-based cohort study.

Endometriosis, a prevalent condition among females of reproductive age, may be associated with increased risk of cardiovascular disease (CVD) through chronic inflammation and early menopause. The objective of this study was to estimate the association between endometriosis and subsequent risk of CVD. We conducted a population-based cohort study using administrative health data from Ontario residents from 1993 to 2015. We compared the incidence of CVD and cardiovascular health outcomes between females with endometriosis and 2 age-matched females without endometriosis. The primary outcome was hospital admission for CVD. Secondary outcomes included in-hospital CVD events of interest and emergency department visits for CVD. We used Cox proportional hazards models to estimate adjusted hazard ratios (HRs) between endometriosis and CVD events. We identified 166 835 eligible patients with endometriosis and matched 333 706 patients without endometriosis. The mean age of those with endometriosis was 36.4 years. Patients with endometriosis had a higher incidence of hospital admission for CVD (195 admissions/100 000 person-years) compared with those without endometriosis (163 admissions/100 000 person-years). Similarly, the incidence of secondary CVD events was slightly higher among patients with endometriosis (292 cases/100 000 person-years) than among those without endometriosis (224 cases/100 000 person-years). Females with endometriosis had an increased risk of hospital admission (adjusted HR 1.14, 95% confidence interval [CI] 1.10-1.19) and secondary CVD events (adjusted HR 1.26, 95% CI 1.23-1.30). In this large, population-based study, endometriosis was associated with a small increased risk of CVD events. Future studies need to investigate potential etiological mechanisms and strategies to decrease long-term CVD risk in patients with endometriosis.

Cardiorespiratory Fitness in the Prevention and Management of Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of death among adults in the U.S. and elsewhere. Variation in the presence, severity, and control of major modifiable risk factors accounts for much of the variation in CVD rates worldwide. Cardiorespiratory fitness (CRF) reflects the integration of ventilation, circulation, and metabolism for the delivery and utilization of oxygen in support of dynamic aerobic physical activity. The gold standard measure of CRF is maximal oxygen uptake. Because the primary factor underlying differences in this measure between individuals is maximal cardiac output, it can serve as a clinical indicator of cardiac function. Higher CRF is associated with favorable levels of major CVD risk factors, lower prevalence and severity of subclinical atherosclerosis, and lower risks of developing both primary and secondary clinical CVD events. The beneficial associations between CRF and CVD are seen in women and men, older and younger adults, in those with multiple coexisting risk factors or prior diagnosis of CVD. Exercise training and regular physical activity of at least moderate intensities and volumes improves CRF in adults, and improvements in CRF are associated with lower risks of subsequent CVD and mortality. Routine assessment of CRF in primary care settings could enhance individual-level CVD risk assessment and thereby guide implementation of appropriate measures to prevent future clinical events.

Aspirin for Primary and Secondary Prevention of Mortality, Cardiovascular Disease, and Kidney Failure in the Chronic Renal Insufficiency Cohort (CRIC) Study

Chronic kidney disease is a risk enhancing factor for cardiovascular disease (CVD) and mortality, and the role of aspirin use is unclear in this population. We investigated the risk and benefits of aspirin use in primary and secondary prevention of CVD in the Chronic Renal Insufficiency Cohort Study. Prospective observational cohort. 3,664 Chronic Renal Insufficiency Cohort participants. Aspirin use in patients with and without preexisting CVD. Mortality, composite and individual CVD events (myocardial infarction, stroke, and peripheral arterial disease), kidney failure (dialysis and transplant), and major bleeding. Intention-to-treat analysis and multivariable Cox proportional hazards modelto examine associations of time varying aspirin use. The primary prevention group was composed of 2,578 (70.3%) individuals. Mean age was 57±11 years, 46% women, 42% Black, and 47% had diabetes. The mean estimated glomerular filtration rate was 45mL/min/1.73m2. Median follow-up was 11.5 (IQR, 7.4-13) years. Aspirin was not associated with all-cause mortality in those without preexisting cardiovascular disease (CVD) (HR, 0.84; 95% CI, 0.7-1.01; P=0.06) or those with CVD (HR, 0.88; 95% CI, 0.77-1.02, P=0.08). Aspirin was not associated with a reduction of the CVD composite in primary prevention (HR, 0.97; 95% CI, 0.77-1.23; P=0.79) and in secondary prevention because the original study design was not meant to study the effects of aspirin. This is not a randomized controlled trial, and therefore, causality cannot be determined. Aspirin use in chronic kidney disease patients was not associated with reduction in primary or secondary CVD events, progression to kidney failure, or major bleeding.

Smoking cessation for secondary prevention of cardiovascular disease.

Smoking is a leading cause of cardiovascular disease (CVD), particularly coronary heart disease (CHD). However, quitting smoking may prevent secondary CVD events in people already diagnosed with CHD. OBJECTIVES: To examine the impact of smoking cessation on death from CVD and major adverse cardiovascular events (MACE), in people with incident CHD. We searched the Cochrane Tobacco Addiction Group's Specialised Register, CENTRAL, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and the trials registries clinicaltrials.gov and the International Clinical Trials Registry Platform. We ran all searches from database inception to 15 April 2021. SELECTION CRITERIA: We included cohort studies, and both cluster- and individually randomised controlled trials of at least six months' duration. We treated all included studies as cohort studies and analysed them by smoking status at follow-up. Eligible studies had to recruit adults (> 18 years) with diagnosed CHD and who smoked tobacco at diagnosis, and assess whether they quit or continued smoking during the study. Studies had to measure at least one of our included outcomes with at least six months' follow-up. Our primary outcomes were death from CVD and MACE. Secondary outcomes included all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, new-onset angina and change in quality of life. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. We assessed the risk of bias for the primary outcomes using the ROBINS-I tool. We compared the incidence of death from CVD and of MACE (primary outcomes) between participants who quit smoking versus those who continued to smoke for each included study that reported these outcomes. We also assessed differences in all-cause mortality, incidence of non-fatal myocardial infarction, incidence of non-fatal stroke and new onset angina. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI). For our outcome, change in quality of life, we calculated the pooled standardised mean difference (SMD) and 95% CI for the difference in change in quality of life from baseline to follow-up between those who had quit smoking and those who had continued to smoke. For all meta-analyses we used a generic inverse variance random-effects model and quantified statistical heterogeneity using the I²statistic. We assessed the certainty of evidence for our primary outcomes using the eight GRADE considerations relevant to non-randomised studies. We included 68 studies, consisting of 80,702 participants. For both primary outcomes, smoking cessation was associated with a decreased risk compared with continuous smoking: CVD death (HR 0.61, 95% CI 0.49 to 0.75; I² = 62%; 18 studies, 17,982 participants; moderate-certainty evidence) and MACE (HR 0.57, 95% CI 0.45 to 0.71; I² = 84%; 15 studies, 20,290 participants; low-certainty evidence). These findings were robust to our planned sensitivity analyses. Through subgroup analysis, for example comparing adjusted versus non-adjusted estimates, we found no evidence of differences in the effect size. While there was substantial heterogeneity, this was primarily in magnitude rather than the direction of the effect estimates. Overall, we judged 11 (16%) studies to be at moderate risk of bias and 18 (26%) at serious risk, primarily due to possible confounding. There was also some evidence of funnel plot asymmetry for MACE outcomes. For these reasons, we rated our certainty in the estimates for CVD death as moderate and MACE as low. For our secondary outcomes, smoking cessation was associated with a decreased risk in all-cause mortality (HR 0.60, 95% CI 0.55 to 0.66; I² = 58%; 48 studies, 59,354 participants), non-fatal myocardial infarction (HR 0.64, 95% CI 0.58 to 0.72; I² = 2%; 24 studies, 23,264 participants) and non-fatal stroke (HR 0.70, 95% CI 0.53 to 0.90; I² = 0%; 9 studies, 11,352 participants). As only one study reported new onset of angina, we did not conduct meta-analysis, but this study reported a lower risk in people who stopped smoking. Quitting smoking was not associated with a worsening of quality of life and suggested improvement in quality of life, with the lower bound of the CI also consistent with no difference (SMD 0.12, 95% CI 0.01 to 0.24; I² = 48%; 8 studies, 3182 participants). AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that smoking cessation is associated with a reduction of approximately one-third in the risk of recurrent cardiovascular disease in people who stop smoking at diagnosis. This association may be causal, based on the link between smoking cessation and restoration of endothelial and platelet function, where dysfunction of both can result in increased likelihood of CVD events. Our results provide evidence that there is a decreased risk of secondary CVD events in those who quit smoking compared with those who continue, and that there is a suggested improvement in quality of life as a result of quitting smoking. Additional studies that account for confounding, such as use of secondary CVD prevention medication, would strengthen the evidence in this area.

Demonstrating the Utility of New Linked National Health Survey and Administrative Data: Secondary CVD Prevention in The Community

IntroductionCardiovascular events are largely preventable though access to timely quality primary health care and use of guideline-recommended medication. However, around half of Australians with cardiovascular disease (CVD) are not receiving best practice treatment. This study aims to identify factors associated with under treatment, using National Health Survey (NHS) linked for the first time to administrative health data.
 Objectives and ApproachParticipants with self-reported CVD in the NHS 2014-15 were included in the study, with data linked to Medicare (MBS) and pharmaceutical (PBS) data by the Australian Bureau of Statistics through the Multi-Agency Data Integration Project (MADIP). Use of primary and specialist ambulatory care and blood pressure- and lipid-lowering medications and their relation to sociodemographic and health characteristics were quantified using logistic and Poisson regression analyses.
 Results1100 participants with self-reported CVD were available for analysis, with linkage rates for NHS data to a Person Linkage Spine of 95%. We will present our findings from adjusted regression models (incomplete at time of abstract submission).
 Conclusion / ImplicationsThe nationally representative linked data developed under this project provides a unique opportunity to quantify and identify points to improve access to best practice CVD care, with the ultimate aim of preventing secondary CVD events in the population. Findings will also inform optimal use of MADIP data by the research community in order to answer questions of national importance and provide robust evidence to drive improvement in health and health care.

Association between fetuin-A and prognosis of CAD: A systematic review and meta-analysis.

Fetuin-A is an anti-inflammation and anti-calcification factor involved in the course of coronary artery disease (CAD). But the association between serum fetuin-A level and the prognosis of CAD patients was still controversial. To clarify the association between serum fetuin-A level and the prognosis of CAD patients, we conducted the present meta-analysis. The included studies should be potentially relevant prospective studies published in English language before January 2019. The target population of the present meta-analysis was restricted to patients with CAD. The results of studies must report hazard ratio (HR) or Kaplan-Meier survival curve for all-cause mortality or incidence of secondary cardiovascular disease (CVD) events. The pooled HRs were analysed by the method of meta-analysis. A total of four prospective studies, including 4256 participants with CAD disease, were chosen to be included. The pooled HR for all-cause mortality was 0.57 (95% CI: 0.37-0.87), showing a statistically significant association between high serum fetuin-A level and low all-cause mortality in CAD patients. For the incidence of secondary CVD events, the pooled HR was 0.86 (95% CI: 0.60-1.23), indicating no statistically significant association between serum fetuin-A level and incidence of secondary CVD events in CAD patients. High serum fetuin-A level associated with lower all-cause mortality in patients with CAD. No association between serum fetuin-A level and incidence of secondary CVD events was found in patients with CAD.

Socioeconomic variation in incidence of primary and secondary major cardiovascular disease events: an Australian population-based prospective cohort study.

BackgroundCardiovascular disease (CVD) disproportionately affects disadvantaged people, but reliable quantitative evidence on socioeconomic variation in CVD incidence in Australia is lacking. This study aimed to quantify socioeconomic variation in rates of primary and secondary CVD events in mid-age and older Australians.MethodsBaseline data (2006–2009) from the 45 and Up Study, an Australian cohort involving 267,153 men and women aged ≥ 45, were linked to hospital and death data (to December 2013). Outcomes comprised first event – death or hospital admission – for major CVD combined, as well as myocardial infarction and stroke, in those with and without prior CVD (secondary and primary events, respectively). Cox regression estimated hazard ratios (HRs) for each outcome in relation to education (and income and area-level disadvantage), separately by age group (45–64, 65–79, and ≥ 80 years), adjusting for age and sex, and additional sociodemographic factors.ResultsThere were 18,207 primary major CVD events over 1,144,845 years of follow-up (15.9/1000 person-years), and 20,048 secondary events over 260,357 years (77.0/1000 person-years). For both primary and secondary events, incidence increased with decreasing education, with the absolute difference between education groups largest for secondary events. Age-sex adjusted hazard ratios were highest in the 45-64 years group: for major CVDs, HR (no qualifications vs university degree) = 1.62 (95% CI: 1.49–1.77) for primary events, and HR = 1.49 (1.34–1.65) for secondary events; myocardial infarction HR = 2.31 (1.87–2.85) and HR = 2.57 (1.90–3.47) respectively; stroke HR = 1.48 (1.16–1.87) and HR = 1.97 (1.42–2.74) respectively. Similar but attenuated results were seen in older age groups, and with income. For area-level disadvantage, CVD gradients were weak and non-significant in older people (> 64 years).ConclusionsIndividual-level data are important for quantifying socioeconomic variation in CVD incidence, which is shown to be substantial among both those with and without prior CVD. Findings reinforce the opportunity for, and importance of, primary and secondary prevention and treatment in reducing socioeconomic variation in CVD and consequently the overall burden of CVD morbidity and mortality in Australia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12939-016-0471-0) contains supplementary material, which is available to authorized users.

Long-term prognostic value of IgM antibodies against phosphorylcholine for adverse cardiovascular events in patients with stable coronary heart disease

BackgroundLow concentrations of IgM-phosphorylcholine autoantibodies (IgM-anti-PC) have been shown to be associated with increased risk of incident cardiovascular disease (CVD) events and total mortality in patients suffering from an acute coronary syndrome. We assessed whether IgM-anti-PC concentrations add prognostic information for cardiovascular risk in patients with known stable coronary artery disease (CAD). MethodsIgM-anti-PC concentrations were measured in serum obtained from 1062 patients with clinically manifest stable CAD at baseline. The relation of IgM-anti PC concentrations with CVD events during long-term follow-up was assessed by the Kaplan–Meier and life table method and quantified by means of the log-rank test. Then, Cox proportional hazards regression analysis was performed to assess the independent association of IgM anti-PC concentration with risk of secondary CVD events after adjustment for established and emerging risk factors. ResultsIn n = 1062 patients with stable CAD only very low IgM anti-PC serum concentrations were associated with increased risk for future fatal and non-fatal coronary events (n = 201 during median of 10 years of follow-up). Among patients with IgM anti-PC concentrations in the lowest decile, the partly adjusted hazard ratio for fatal and non-fatal coronary events was 1.60 (95% confidence interval (CI) 1.01–2.55) compared to the top quartile and 1.94 (95%-CI 1.18–3.18) after adjustment for multiple covariates. ConclusionIn patients with stable CAD, very low concentrations of IgM anti-PC are associated with increased risk for fatal and non-fatal future coronary events and thus may add prognostic information to traditional cardiovascular risk factors among these patients.

Prognostic value of midregional pro-A-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide in patients with stable coronary heart disease followed over 8 years.

Pathophysiological studies suggest that A-type natriuretic peptides (ANPs) might provide valuable information beyond B-type natriuretic peptides (BNPs) about cardiac dysfunction in patients with coronary heart disease (CHD). We aimed to assess the predictive value of midregional pro-A-type natriuretic peptide (MR-proANP) for recurrent cardiovascular disease (CVD) events in stable CHD patients for whom information on N-terminal proBNP (NT-proBNP) was already available. Plasma concentrations of MR-proANP and NT-proBNP were measured at baseline in a cohort of 1048 patients aged 30-70 years with CHD who were participating in an in-hospital rehabilitation program. Main outcome measures were cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. During a median follow-up of 8.1 years, 150 patients (incidence 21.1 per 1000 patient-years) experienced a secondary CVD event. MR-proANP was associated with a hazard ratio (HR) of 1.89 (95% CI, 1.01-3.57) when the top quartile was compared to the bottom quartile in the fully adjusted model (P for trend = 0.011). For NT-proBNP the respective HR was 2.22 (95% CI, 1.19-4.14) with a P for trend = 0.001. Finally, MR-proANP improved various model performance measures, including c-statistics and reclassification metrics, but without being superior to NT-proBNP. Although we found an independent association of MR-proANP as well as NT-proBNP when used as single markers with recurrent CVD events after adjustment for established risk factors, the results of a simultaneous assessment of both markers indicated that MR-proANP fails to provide additional prognostic information to NT-proBNP in the population studied.

Invited Commentary: The Association of Low Vitamin D With Cardiovascular Disease--Getting at the "Heart and Soul" of the Relationship

Low concentrations of 25-hydroxyvitamin D have been consistently associated with cardiovascular disease (CVD) in many observational studies. In an analysis published in this issue of the American Journal of Epidemiology, Welles et al. (Am J Epidemiol. 2014;179(11):1279-1287) used data from 946 participants with stable CVD who were enrolled in the Heart and Soul Study (San Francisco Bay Area, 2000-2012) and found that the association of low 25-hydroxyvitamin D with increased secondary CVD event risk was attenuated after adjustment for parathyroid hormone level, suggesting that parathyroid hormone may mediate this association. They used observational data to gain insight into potential mechanisms underlying the association between vitamin D and CVD risk. Their study focused on secondary CVD events, whereas many previous observational studies have focused on incident CVD events among persons without a history of CVD. In this commentary, we place the study by Welles et al. in context with the existing literature and propose future directions for vitamin D research. We highlight a number of methodological concepts that are important in analyzing vitamin D data, including racial differences in vitamin D concentrations and adjustment for seasonal variation in vitamin D concentrations. We agree that randomized controlled trials should be conducted before making guidelines for screening and treating vitamin D deficiency for the prevention of CVD events.

Cytochrome P450 2C19*2 polymorphism in patients with stable coronary heart disease and risk for secondary cardiovascular disease events: results of a long-term follow-up study in routine clinical care

BackgroundCYP2C19*2 polymorphism is related to metabolizer phenotypes resulting in reduced effectiveness in converting the antiplatelet drug clopidogrel to active drug. An association of the genotype itself with adverse outcomes is discussed. We investigated the prognostic value of carriage of the CYP2C19*2 allele in a high risk group of patients with prevalent coronary heart disease (CHD) at baseline during long-term follow-up under conditions of routine clinical care.MethodsIn n=1050 patients with stable CHD at baseline genotyping of CYP2C19 allele *2 (rs4244285; 681G>A) was performed. The Cox-proportional hazards model was employed to investigate the association of CYPC19*2 allele status with cardiovascular disease (CVD) events during eight year follow-up. The analysis was also performed in patients who did not take clopidogrel or ticlopidin.ResultsOnly the very few patients homozygous for a loss-of-function variant of CYP2C19, allele *2 (2.6%), had a statistically significantly higher incidence rate for secondary CVD events during long-term follow-up than wild-type carriers (50.8 versus 21.5 per 1000 patients years; rate for heterozygous carries 17.2 per 1000 patient years). The hazard ratio after adjustment for covariates compared to the wild-type carriers was 2.59 (95% confidence interval (CI) 1.27-5.28) and 0.80 (95% CI 0.52-1.23) for homozygous and heterozygous allele carriers, respectively.ConclusionsIn this medium-size group of patients with stable CHD homozygous carriers of the loss-of-function allele CYP2C19*2 were at increased risk for subsequent CVD events during 8 year follow-up independent of other risk factors. As only few patients carried the homozygous loss-of-function variant and we found overall no evidence for improved clinical utility, a benefit of genotyping in this patient population seems unlikely.

Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor, which has been associated with total and cardiovascular mortality in various clinical settings. Studies on its structural isomer, symmetric dimethylarginine (SDMA), are scarce. This study aimed to determine the associations of both ADMA and SDMA levels with secondary cardiovascular disease events and all-cause mortality in patients with stable coronary heart disease (CHD). In the observational prospective cohort study KAROLA, 1,148 CHD patients were followed for a median of 8.1years. ADMA and SDMA were determined by liquid chromatography-tandem mass spectrometry. Baseline ADMA and SDMA levels were categorized in quartiles or standardized by their respective standard deviation, and appropriate hazard ratios and 95% confidence intervals (HR [95% CI]) were estimated in Cox proportional hazards models. 150 patients experienced secondary cardiovascular disease events (CVD) and 121 patients died. After adjustment for confounders, ADMA was not associated with the risk of secondary CVD events (HR per standard deviation increase: 1.02 [95%CI: 0.86-1.21]), whereas an association was suggested for SDMA (HR 1.17 [1.00-1.37]). Higher hazard ratios were observed in all-cause mortality models (ADMA: HR 1.15 [0.95-1.37]; SDMA: HR 1.29 [1.09-1.52]). Our results suggest that especially SDMA might possibly have potential as a risk marker for all-cause mortality and to a lesser extent for secondary cardiovascular events. Future studies are needed to quantify these associations more precisely and should, in particular, further address the possibility of residual confounding by impaired kidney function.

Abstract 319: Potential Lifetime Cost-Effectiveness of Catheter-Based Renal Sympathetic Denervation in Patients with Resistant Hypertension

Aims - Recent studies have demonstrated the safety and efficacy of catheter-based renal sympathetic denervation (RD) for the treatment of resistant hypertension. We aimed to determine the cost-effectiveness of this approach separately for men and women of different ages. Methods and results - A Markov state-transition model accounting for costs, survival, quality of life, and incremental cost-effectiveness was developed to compare RD with best medical therapy (BMT). The model ran from age 30 to 100 years or death, with a Markov cycle length of 1 year. All patients entered the model with elevated systolic blood pressure (SBP, 180 mmHg), but free from prior cardiovascular disease (CVD) events. Patients could remain in this disease-free state or could have one of the following primary CVD events: myocardial infarction, angina, stroke or heart failure. After an event, patients transitioned into chronic disease states and/or could suffer from secondary CVD events. In the base case scenario, RD resulted in a sustained SBP reduction of 20 mmHg and in a corresponding relative risk reduction of adverse CVD events and death. The cost analysis was conducted from a health care payer perspective. Effectiveness was expressed as quality-adjusted life-years (QALY) gained. Costs and effects were discounted at 3% per annum, respectively. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the results. As compared with BMT, RD gained 0.99 QALYs in men and 0.91 QALYs in women 60 years of age at an additional cost of $3,265 and $2,594, respectively. As the incremental cost-effectiveness ratio increased with patient age, RD consistently yielded more QALYs at lower costs in lower age groups. Considering a willingness to pay threshold of $50,000/QALY, there was a 95% probability that RD would remain cost-effective up to an age of 82 and 80 years in men and women, respectively. Cost-effectiveness was influenced most by the extent of SBP lowering by RD, the rate of RD non-responders, and the costs associated with the RD procedure. Conclusion - RD offers a cost-effective treatment option for the prevention of CVD events in patients with resistant hypertension. An earlier intervention produces better cost-effectiveness ratios.

Circulating Adipocyte Fatty Acid-Binding Protein Levels and Cardiovascular Morbidity and Mortality in Patients With Coronary Heart Disease

Adipocyte fatty acid-binding protein (A-FABP) abundantly expressed in mature adipocytes and activated macrophages has dramatic effects on atherosclerosis in mice. Whether this pathophysiological role of A-FABP may also apply to atherosclerotic disease in humans is still unknown. This study investigated associations among serum A-FABP levels, cardiovascular risk factors, and long-term secondary cardiovascular disease (CVD) outcome in patients with coronary heart disease. Serum A-FABP levels were measured in 1069 patients with prevalent coronary heart disease and a 10-year prospective follow-up was conducted (median, 119.5 [interquartile range, 74.1-120.6] months). During this period 204 patients (incidence, 24.0/1000 patient-years) experienced a secondary cardiovascular disease event (defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal cerebrovascular stroke). At baseline, circulating A-FABP was positively associated with a cluster of metabolic and inflammatory risk factors and independently predicted the presence of the metabolic syndrome (odds ratio per unit increase of natural log-transformed A-FABP, 2.95; 95% CI, 2.22-3.92, P<0.001). On long-term follow-up, subjects with high baseline A-FABP showed an increased risk for secondary cardiovascular disease events (hazard ratio per unit increase, 1.52; 95% CI, 1.18-1.95; P=0.001), which was attenuated after multivariable adjustment (hazard ratio 1.30; 95% CI, 0.98-1.73). In contrast, A-FABP remained significantly associated with cardiovascular death even after multivariable adjustment (hazard ratio, 1.75; 95% CI, 1.17-2.62, P=0.007). Circulating A-FABP levels are associated with long-term prognosis in patients with coronary heart disease and may represent an important pathophysiological mediator of atherosclerosis, which may point to a new target of treatment options.

Physical Activity and Cardiovascular Mortality Risk

The biological mechanisms through which increased physical activity or structured exercise training lowers the risk of recurrent cardiac events are incompletely understood. We examined the extent to which modification of primary risk markers explains the association between physical activity and cardiovascular death in participants with diagnosed cardiovascular disease (CVD). In a prospective study of 1429 participants with physician-diagnosed CVD living in England and Scotland (age = 66.5 ± 11.1 yr (mean ± SD), 54.2% men), we measured physical activity and several risk markers (body mass index, total-to-HDL cholesterol ratio, diagnosed diabetes, systolic blood pressure, resting heart rate, C-reactive protein) at baseline. The main outcome was CVD death. There were a total of 446 all-cause deaths during an average of 7.0 ± 3.1 yr of follow-up, of which 213 were attributed to cardiovascular causes. Participation in moderate to vigorous physical activity at least three sessions per week was associated with lower risk of CVD death (hazard ratio = 0.61, 95% confidence interval = 0.38-0.98). Physically active participants demonstrated significantly lower levels of body mass index, diabetes, and inflammatory risk (C-reactive protein). Metabolic (body mass index, total-to-HDL cholesterol ratio, and physician-diagnosed diabetes) and inflammatory risk factors explained an estimated 12.8% and 15.4%, respectively, of the association between physical activity and CVD death. Physical activity may reduce the risk of secondary CVD events, in part, by improving metabolic and inflammatory risk markers.

Abstract 17392: High-Sensitivity Troponin T Predicts Recurrent Cardiovascular Disease Events in Stable Coronary Heart Disease Patients: 8-Year Follow-Up of the KAROLA Study

Purpose: The clinical relevance of only slightly elevated circulating troponin levels in patients with stable coronary heart disease (CHD) several weeks after an acute event has not been fully evaluated. We aimed to assess the predictive value of a new high-sensitivity troponin T assay (hsTnT) for recurrent cardiovascular disease (CVD) events in stable CHD patients, simultaneously controlling for a large number of potential confounders. Methods: Plasma concentrations of hsTnT (Roche Elecsys 2010) were measured at baseline in a cohort of 1,050 patients aged 30-70 years with CHD. The Cox proportional hazards model was used to determine the prognostic value of hsTnT on a combined CVD endpoint after adjustment for covariates. Results: The median hsTnT level was 10.9 ng/L (IQR 5.1-18.9). Elevated hsTnT levels were associated with higher age, history of hypertension, history of diabetes, a higher number of affected vessels, initial management of CHD, and left-ventricular dysfunction. In addition as determined by 12-lead routine ECG, rhythm disorders, and anterior wall infarction were associated with higher hsTnT levels. Furthermore, hsTnT was highly correlated with NT-proBNP and cystatin C (R=0.61 and R=0.32, respectively, both p-values &lt;0.0001). During a median follow-up of 8.1 years, 150 patients (21.0%) experienced a fatal- or non-fatal secondary CVD event. In a multivariate model, hsTnT was associated with a hazard ratio (HR) for secondary CVD events of 2.83 (95% CI, 1.68-4.79) when extreme quartiles were compared. Further adjustment for cystatin C, NT-proBNP, and CRP attenuated the association only slightly (2.27; 95% CI, 1.31-3.95), p for trend &lt;0.002). ROC analysis of a clinical model which included hsTnT to a baseline model showed a modest improvement in the AUC (0.69 vs 0.67). Conclusions: Slightly elevated hsTnT levels in stable CHD patients are associated with a number of CVD disorders and predict long-term CVD events in these patients.

Abstract 16978: Midregional Pro-Atrial Natriuretic Peptide and Risk of Recurrent Cardiovascular Disease Events in Patients with Stable Coronary Heart Disease Followed Over 8 Years

Aim: Natriuretic peptides provide valuble information about cardiac dysfunction. The clinical relevance of elevated circulating midregional pro-atrial natriuretic peptide (MR-proANP) in patients with stable coronary heart disease (CHD) several weeks after an acute event has not been fully evaluated. We aimed to assess the predictive value of MR-proANP for recurrent cardiovascular disease (CVD) events in stable CHD patients, simultaneously controlling for a large number of potential confounders. Methods: Plasma concentrations of MR-proANP (BRAHMS) were measured at baseline in a cohort of 1,048 patients aged 30-70 years with CHD. The Cox proportional hazards model was used to determine the prognostic value of MR-proANP on a combined CVD endpoint after adjustment for covariates. Results: The median MR-proANP level was 135.2 pmol/L (interquartile range 95.2-185.8). Elevated MR-proANP levels were associated with higher age, obesity, history of hypertension, diabetes, and heart failure, higher number of affected vessels, initial management of CHD, and left-ventricular dysfunction in a statistically significant way. Furthermore, after adjustment for age and gender MR-proANP was correlated with CRP (correlation coefficient (R=0.21), NT-proBNP (R=0.72), creatinine clearance (R= -0.32), cystatin C (R=0.43), hsTnT (R= 0.51) respectively (all p-values &lt;0.0001). During a median follow-up of 8.1 years, 150 patients (21.1%) experienced a fatal- or non-fatal secondary CVD event. In a multivariate model MR-proANP was associated with a hazard ratio (HR) of secondary CVD events of 3.00 (95% confidence interval (CI), 1.70-5.28) when extreme quartiles were compared. Further adjustment for NT-proBNP attenuated the association only slightly (HR 2.67; 95% CI, 1.48-4.79). Conclusions: Elevated MR-proANP levels in stable CHD patients are associated with several CVD disorders and predict long-term CVD events in these patients.

Type II Secretory Phospholipase A2 and Prognosis in Patients with Stable Coronary Heart Disease: Mendelian Randomization Study

BackgroundSerum type II secretory phospholipase A2 (sPLA2-IIa) has been found to be predictive of adverse outcomes in patients with stable coronary heart disease. Compounds targeting sPLA2-IIa are already under development. This study investigated if an association of sPLA2-IIa with secondary cardiovascular disease (CVD) events may be of causal nature or mainly a matter of confounding by correlated cardiovascular risk markers.Methodology/Principal FindingsEight-year follow-up data of a prospective cohort study (KAROLA) of patients who underwent in-patient rehabilitation after an acute cardiovascular event were analysed. Associations of polymorphisms (SNP) in the sPLA2-IIa-coding gene PLA2G2A with serum sPLA2-IIa and secondary fatal or non-fatal CVD events were examined by multiple regression. Hazard ratios (HR) were compared with those expected if the association between sPLA2-IIa and CVD were causal. The strongest determinants of sPLA2-IIa (rs4744 and rs10732279) were associated with an increase of serum concentrations by 81% and 73% per variant allele. HRs (95% confidence intervals) estimating the associations of the SNPs with secondary CVD events were increased, but not statistically significant (1.16 [0.89–1.51] and 1.18 [0.91–1.52] per variant allele, respectively). However, these estimates were very similar to those expected when assuming causality (1.18 and 1.17), based on an association of natural log-transformed sPLA2-IIa concentration with secondary events with HR = 1.33 per unit.ConclusionThe present findings regarding genetic polymorphisms, determination of serum sPLA2-IIa, and prognosis in CVD patients are consistent with a genuine causal relationship and thus might point to a valid drug target for prevention of secondary CVD events.

The J-curve of cardiovascular disease risk and how it relates to isolated systolic hypertension

Controversy persists regarding the presence and significance of the “J-curves” of increased cardiovascular disease (CVD) risk as they relate to older people with isolated systolic hypertension (ISH). A recent Framingham primary outcome study showed that of the 4 blood pressure (BP) components [diastolic BP (DBP), systolic BP (SBP), pulse pressure (PP), and mean arterial pressure (MAP)] only DBP showed non-linear tendencies, which presented as a J-curve of increased CVD risk. The reduction in DBP was associated with an increase in PP, the latter of which serves as a marker of increased arterial stiffness. On the other hand, when primary CVD events result in poor cardiac function, the presence of combined SBP and DBP J-curves serve as predictors of secondary CVD events—so called “reverse causality”; thus, risk is associated with decreased rather than by increased SBP. Lastly, treatment-induced cardiac risk is a potential third explanation for J-curves that occur in the presence of hemodynamically significant coronary artery stenosis. This review is directed at a better understanding of causes and consequences of the J-curve phenomena.