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Inflammation has a direct role in the development of atherosclerotic vascular disease, and oral colchicine displays broad anti-inflammatory properties. Several large, randomised controlled trials (RCTs) have evaluated colchicine's impact on cardiovascular outcomes. Results from a meta-analysis of these trials demonstrate that colchicine reduces the risk of recurrent major adverse cardiovascular events (MACEs) by 25%, leading to its recent approval by the Food and Drug Administration for the treatment and prevention of cardiovascular disease. Despite this, colchicine has not been shown to confer any survival benefit in these trials. The non-significant reduction in cardiovascular death of 18% (95% CI: 45% decrease to 23% increase) is outweighed by a more prominent, borderline non-significant increase in the risk of non-cardiovascular death by 38% (95% CI: 1% decrease to 92% increase). Key populations including those with heart failure, those undergoing surgical revascularisation, women, elderly individuals and non-Caucasians are under-represented in completed trials, which limits generalisability. C reactive protein has been proposed as a biomarker for colchicine response and shows promise for identifying a high-risk population where the benefit on MACE reduction and specifically reduced cardiovascular death might outweigh any real increased risk of non-cardiovascular death; however, this approach is still to be validated in ongoing RCTs. In conclusion, while colchicine shows promise in reducing MACE, its net risk-benefit profile requires further elucidation before its widespread adoption into clinical practice for the secondary prevention of atherosclerotic cardiovascular disease. Much more large-scale, long-term trial data are still needed in this space., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

TNF-related apoptosis-inducing ligand (TRAIL) was originally discovered, almost 20 years ago, for its ability to kill cancer cells. More recent evidence has described pleiotropic functions, particularly in the cardiovascular system. There is potential for TRAIL concentrations in the circulation to act as prognostic and/or diagnostic factors for cardiovascular diseases (CVD). Pre-clinical studies also describe the therapeutic capacity for TRAIL signals, particularly in the context of atherosclerotic disease and diseases of the myocardium. Because diabetes mellitus significantly contributes to the progression and pathogenesis of CVDs, in this review we highlight recent evidence for the prognostic, diagnostic, and therapeutic potential of TRAIL signals in CVDs, and where relevant, the impact of diabetes mellitus. A greater understanding of how TRAIL signals regulate cardiovascular protection and pathology may offer new diagnostic and therapeutic avenues for patients suffering from CVDs.

Objectives: Examine the associations of sleep measures with kidney function changes over time among individuals from a community-based study., Methods: The sample includes 1657 participants (287 with chronic kidney disease [CKD]) in the Multi-Ethnic Study of Atherosclerosis Sleep Cohort (mean age: 57.7 years, male: 46.0%). We examined associations between a large set of sleep variables (polysomnography, actigraphy, and questionnaires) and cardiovascular disease risk factors and changes in estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio over approximately 5 years using high-dimensional regression. We investigated the modifying effect of sleep on the associations between cardiovascular disease risk factors and kidney function., Results: Sleep metrics predicted kidney function decline only among individuals with baseline CKD. Among this group, eGFR decline was associated with decreased stage N3 sleep (0.32 mL/min/1.73 m 2 /y per 10% decrease in N3, p < .001); increased actigraphy napping frequency (beta: -0.20 [-0.30, -0.07]); and actigraphy sleep midpoint trajectory in early morning (ref: midnight, beta: -0.84 [-1.19, -0.50]). Urinary albumin-to-creatinine ratio increase was associated with high wake bouts trajectory (ref: low, beta: 0.97 [0.28, 1.67]) and increased sleep-related hypoxemia (oxygen saturation %time<90 [≥5%], beta: 2.17 [1.26, 3.08]). Sleep metrics--N3 sleep, naps, and midpoint trajectory--significantly modified associations between hemoglobin A1C and eGFR decline., Conclusions: Reduced deep sleep, daytime napping, increased wake bouts, delayed sleep rhythms, and overnight hypoxemia are associated with longitudinal kidney function decline, with effects most apparent in individuals with CKD. Deep sleep, napping, and sleep timing modified the association between hemoglobin A1C and kidney function., (Copyright © 2022 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular outcomes. For years, colchicine has been used as a safe and well-tolerated agent in diseases such as gout and familial Mediterranean fever. The widely available therapeutic has several anti-inflammatory effects, however, that have proven effective in a broad spectrum of cardiovascular diseases as well. It is considered standard-of-care therapy for pericarditis, and several clinical trials have evaluated its role in postoperative and postablation atrial fibrillation, postpericardiotomy syndrome, coronary artery disease, percutaneous coronary interventions, and cerebrovascular disease. We aim to summarize colchicine's pharmacodynamics and the mechanism behind its anti-inflammatory effect, outline thus far accumulated evidence on treatment with colchicine in cardiovascular disease, and present ongoing randomized clinical trials. We also emphasize real-world clinical implications that should be considered on the basis of the merits and limitations of completed trials. Altogether, colchicine's simplicity, low cost, and effectiveness may provide an important addition to other standard cardiovascular therapies. Ongoing studies will address complementary questions pertaining to the use of low-dose colchicine for the treatment of cardiovascular disease.

Colchicine, an inexpensive immunomodulatory drug used traditionally to treat gout and familial Mediterranean fever, is rapidly accumulating basic and clinical evidence for a therapeutic role in atherosclerotic cardiovascular disease. Its athero-protective properties are thought to be mainly related to its effect on tubulin polymerisation, enabling a broad range of effect on multiple atherosclerotic plaque cell types and cellular processes, including cell division, cell migration as well as pro-inflammatory cytokine and chemokine secretion. These properties indicate the potential to favourably affect all stages of atherosclerotic plaque development including formation, progression, destabilisation, and plaque rupture. This review focusses on the pharmacology of colchicine, the mechanisms by which it modulates atherosclerosis pathobiology, and summarises the current clinical evidence for its use along with the upcoming clinical trial landscape. Given the current lack of primary immunomodulatory drugs in the treatment of atherosclerosis, colchicine is a promising candidate to fill this therapeutic gap., (Copyright © 2020. Published by Elsevier B.V.)

Cardiovascular disease is the leading cause of death in Australian women, as well as men, with clear disparities in treatment and outcomes between the sexes. Moreover, disease pathophysiology differs between the sexes, with women more likely to suffer from microvascular coronary disease, endothelial dysfunction and heart failure with preserved ejection fraction, as compared to men, who are more likely to experience macrovascular disease or heart failure with reduced ejection fraction. Evidence suggests that both traditional and novel cardiovascular risk factors are often under-recognised and under-treated in women. Certain 'traditional' risk factors, including diabetes mellitus and smoking, may also portend a greater risk of cardiovascular disease in women than men. Furthermore, a number of female-specific risk factors have been identified as increasing the risk of cardiovascular disease in women, including pre-term delivery, pre-eclampsia, gestational diabetes, and polycystic ovary syndrome. Currently, these factors are not included in primary prevention risk stratification tools, nor are they routinely considered in a cardiovascular assessment at a clinical level. This represents a missed opportunity, as early identification may allow for risk factor modification and possible amelioration of the disease burden. This review explores the role of traditional, sex-specific and novel risk factors for cardiovascular disease in women, in addition to pathophysiological differences between the sexes, and contributing societal and behavioural factors. These differences argue strongly for a 'precision medicine' approach to cardiovascular disease that includes sex as a key component., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

We assessed the association of BMI with all-cause and cardiovascular (CV) mortality in a contemporary acute coronary syndrome cohort. Patients from the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events and Global Registry of Acute Coronary Events between 2009 and 2019, were divided into BMI subgroups (underweight: <18.5, healthy: 18.5 to 24.9, overweight: 25 to 29.9, obese: 30 to 39.9, extremely obese: >40). Logistic regression was used to determine the association between BMI group and outcomes of all cause and CV death in hospital, and at 6 months. 8,503 patients were identified, mean age 64 ± 13, 72% male. The BMI breakdown was: underweight- 95, healthy- 2,140, overweight- 3,258, obese- 2,653, extremely obese- 357. Obese patients were younger (66 ± 12 vs 67 ± 13), with more hypertension, diabetes, and dyslipidemia vs healthy (all p < 0.05). Obese had lower hospital mortality than healthy: all-cause: 1% versus 4%, aOR (95% CI): 0.49(0.27, 0.87); CV: 1% versus 3%, 0.51(0.27, 0.96). At 6-month underweight had higher mortality than healthy: all-cause: 11% versus 4%, 2.69(1.26, 5.76); CV: 7% versus 1%, 3.54(1.19, 10.54); whereas obese had lower mortality: all-cause: 1% versus 4%, 0.48(0.29, 0.77); CV: 0.4% versus 1%, 0.42(0.19, 0.93). When BMI was plotted as a continuous variable against outcome a U-shaped relationship was demonstrated, with highest event rates in the most obese (>60). In conclusion, BMI is associated with mortality following an acute coronary syndrome. Obese patients had the best outcomes, suggesting persistence of the obesity paradox. However, there was a threshold effect, and favorable outcomes did not extend to the most obese., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) is the leading cause of death and disability in women globally, accounting for 32% of deaths in females. There are several female-specific risk factors for CVD that are under appreciated clinically, insufficiently researched and not given adequate attention in CVD risk prediction. Hypertensive and metabolic disorders of pregnancy are independent risk factors for the development of premature CVD. They confer more than double the risk of CVD in exposed women, but are not included in any current, multivariable CVD risk prediction models. Failure to recognise this risk leads to a lost opportunity to identify at risk women, institute primary preventive strategies, and potentially improve their health trajectory. This also translates into a missed opportunity to educate women and their families about their CVD risks, and to a lack of awareness and prioritisation of CVD within the broader community. Improving CVD outcomes for women globally also requires attention to research methodology and analysis. Researchers should be encouraged to include a thorough pregnancy history in prospective CVD datasets and to power their studies to report on gender disaggregated CVD outcomes. Particular attention should be given to the inclusion of young women of child-bearing age in CVD intervention trials. Ultimately, women should be offered CVD assessment using gender specific risk prediction models that are validated across broad ethic and socioeconomic groups. These prediction models should account for female specific risk factors and their complex interactions with traditional risk factors. This will pave the way for a gender-specific approach to CVD diagnosis, investigation and management., (Copyright © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Ideal cardiovascular health (CVH) was proposed by the American Heart Association to promote population health. We aimed to characterize the association between ideal CVH and markers of subclinical cardiovascular disease (CVD)., Hypothesis: We hypothesized that ideal CVH is associated with several markers of subclinical CVD., Methods: We used data from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. We assigned 1 for each of the ideal CVH factors met. Endothelial function, expressed as Framingham reactive hyperemia index (fRHI), was measured using the EndoPAT device. Coronary artery calcium (CAC) and carotid intima-media thickness (CIMT) were quantified using electron beam computed tomography and carotid ultrasonography, respectively., Results: A total of 1933 participants (mean [SD] age: 59 [7.5] years, 34% male, 44% black) were included. The mean number of ideal CVH factors met was 2.3 ± 1.3, with blacks having significantly lower score compared to whites (2.0 ± 1.2 vs 2.5 ± 1.4, respectively; P < 0.001). Seven hundred and eighty-nine participants (41%) achieved ≥3 ideal CVH factors. Participants with ≥3 ideal CVH factors (compared to those with <3 factors) had an average of 107 (95% confidence interval [CI]: 50-165) Agatston units lower CAC, 0.04 (0.01-0.06) mm lower CIMT, and 0.07 (0.02-0.12) units higher fRHI, after adjusting for age, sex, race, income, education, and marital status. Participants with ≥3 ideal CVH factors had 50% lower odds (95% CI: 28%-66%) of having CAC >100 Agatston units., Conclusion: In a community-based study with low prevalence of ideal CVH, even achieving three or more ideal CVH factors were associated with lower burden of subclinical CVD, indicating the utility of this construct for disease prevention., (© 2018 Wiley Periodicals, Inc.)

Obstructive sleep apnoea (OSA) is a common condition characterized by repetitive upper airway obstruction during sleep. OSA promotes wide intrathoracic pressure swings, intermittent hypoxia and sleep fragmentation. Growing evidence derived from animal models mimicking the oxygen profile observed in patients with OSA as well as clinical studies support that this important sleep-disordered breathing is associated with increased cardiovascular risk. Although the precise mechanisms are not fully established, it is conceivable that the metabolic deregulation promoted by the components of OSA may have an important causal role in the poor cardiovascular prognosis. In this review, we summarize the potential role of OSA and its components on cardiometabolic disease. We also summarize evidence evaluating the impact of OSA treatment (notably continuous positive airway pressure) on reversing the metabolic deregulation promoted by OSA. Finally, we discuss the research agenda and perspectives for this important research area., (© 2017 Asian Pacific Society of Respirology.)

Background: Although existing research highlights the relationship of OSA and cardiovascular disease, the effect of OSA treatment on cardiovascular biomarkers remains unclear. We evaluated the effect of OSA treatment on oxidative stress/inflammation measures., Methods: We conducted a parallel, randomized controlled trial in moderate to severe OSA (apnea-hypopnea index ≥ 15) patients to examine effects of 2-month CPAP vs sham-CPAP on the primary outcome of oxidative stress/inflammation (F2-isoprostanes: ng/mg) and myeloperoxidase: pmol/L) and secondary oxidative stress measures. Exploratory secondary analyses included vascular and systemic inflammation markers. Linear models adjusted for baseline values examined effect of CPAP on biomarker change (least squares means, 95% CI) including secondary stratified analyses examining CPAP adherence and degree of hypoxia., Results: Of 153 participants, 76 were randomized to CPAP and 77 to sham-CPAP. In an intent-to-treat analyses, no significant change was observed in the sham and CPAP groups respectively: F2-isoprostanes (-0.02 [-0.12 to 0.10] vs -0.08 [-0.18 to 0.03]) or myeloperoxidase (-3.33 [-17.02 to 10.37] vs -5.15 [-18.65 to 8.35]), nor other oxidative markers; findings that persisted in analyses stratified by adherence and hypoxia. Exploratory analyses revealed percentage reduction of soluble IL-6 receptor (ng/mL) levels (-0.04 [-0.08 to -0.01] vs 0.02 [-0.02 to 0.06], P = .019) and augmentation index (%) (-6.49 [-9.32 to -3.65] vs 0.44 [-2.22 to 3.10], P < .001) with CPAP compared with sham, respectively., Conclusions: In moderate to severe OSA, 2-month CPAP vs sham did not reduce oxidative stress despite consideration of a broad range of measures, positive airway pressure adherence, and hypoxia burden. These findings suggest that nonoxidative stress pathways primarily modulate OSA-related cardiovascular consequences., Trial Registration: ClinicalTrials.govNCT00607893., (Copyright © 2016 American College of Chest Physicians. All rights reserved.)

Background: Mild obstructive sleep apnea (OSA) is a highly prevalent disorder in adults; however, whether mild OSA has significant neurocognitive and cardiovascular complications is uncertain., Objectives: The specific goals of this Research Statement are to appraise the evidence regarding whether long-term adverse neurocognitive and cardiovascular outcomes are attributable to mild OSA in adults, evaluate whether or not treatment of mild OSA is effective at preventing or reducing these adverse neurocognitive and cardiovascular outcomes, delineate the key research gaps, and provide direction for future research agendas., Methods: Literature searches from multiple reference databases were performed using medical subject headings and text words for OSA in adults as well as by hand searches. Pragmatic systematic reviews of the relevant body of evidence were performed., Results: Studies were incongruent in their definitions of "mild" OSA. Data were inconsistent regarding the relationship between mild OSA and daytime sleepiness. However, treatment of mild OSA may improve sleepiness in patients who are sleepy at baseline and improve quality of life. There is limited or inconsistent evidence pertaining to the impact of therapy of mild OSA on neurocognition, mood, vehicle accidents, cardiovascular events, stroke, and arrhythmias., Conclusions: There is evidence that treatment of mild OSA in individuals who demonstrate subjective sleepiness may be beneficial. Treatment may also improve quality of life. Future research agendas should focus on clarifying the effect of mild OSA and impact of effective treatment on other neurocognitive and cardiovascular endpoints as detailed in the document.

Objective: With the expanding armamentarium of noninsulin therapies for type 2 diabetes mellitus, the use of insulin with various oral agents is becoming more common. In this study, we assessed the efficacy and cardiovascular (CV) safety of the dipeptidyl peptidase-4 inhibitor linagliptin as add-on to insulin in patients with type 2 diabetes., Methods: In this post hoc analysis, data for patients receiving basal or basal-bolus insulin were pooled from 4 randomized, double-blind, phase 3 clinical trials of linagliptin 5 mg once daily or placebo given as add-on to background glucose-lowering treatment. Changes in glycated hemoglobin (A1C) and CV risk factors were assessed from baseline to end of trial. The primary CV endpoint was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to unstable angina., Results: The number of patients receiving basal or basal-bolus insulin as background therapy was 1613 (linagliptin: n=811; placebo: n=802). The placebo-adjusted mean (SE) change from baseline in A1C was -0.41 (0.05)% (95% CI -0.50, -0.32; p<0.0001). Treatment with linagliptin provided a relative weight benefit and reduced insulin requirements without affecting blood pressure, heart rate or lipids. The incidence of hypoglycemia with linagliptin was similar to that for placebo (38.7% vs. 39.4%, respectively). The hazard ratio (HR) for the primary endpoint showed that treatment with linagliptin was not associated with an increased CV risk (HR 1.07 [95% CI 0.62, 1.85])., Conclusions: Linagliptin, when added to ongoing insulin treatment in patients with type 2 diabetes, improves glycemic control and has a neutral impact on major adverse CV events., (Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Background: The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM)., Methods: Pre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥ 12 weeks' duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks' duration, 8778 subjects) were also analyzed., Results: 5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55-1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43-2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68-1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients., Conclusions: Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (NCT01243424) is an ongoing, randomized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride. Eligible patients were sulphonylurea-naïve with HbA1c 6.5%-8.5% or previously exposed to sulphonylurea (in monotherapy or in a combination regimen <5 years) with HbA1c 6.5%-7.5%. Primary outcome is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. A total of 631 patients with primary outcome events will be required to provide 91% power to demonstrate non-inferiority in cardiovascular safety by comparing the upper limit of the two-sided 95% confidence interval as being below 1.3 for a given hazard ratio. Hierarchical testing for superiority will follow, and the trial has 80% power to demonstrate a 20% relative cardiovascular risk reduction. A total of 6041 patients were treated with median type 2 diabetes duration 6.2 years, 40.0% female, mean HbA1c 7.2%, 66% on 1 and 24% on 2 glucose-lowering agents and 34.5% had previous cardiovascular complications. The results of CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes may influence the decision-making process for selecting a second glucose-lowering agent after metformin in type 2 diabetes., (© The Author(s) 2015.)

Background: Obstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk., Methods: We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea-hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure., Results: Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (-2.4 mm Hg; 95% confidence interval [CI], -4.7 to -0.1; P=0.04) or the group receiving supplemental oxygen (-2.8 mm Hg; 95% CI, -5.1 to -0.5; P=0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis., Conclusions: In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800 .).

Rationale: We hypothesized increasing obstructive sleep apnea (OSA) severity would be associated with nondipping blood pressure (BP) in increased cardiovascular disease (CVD) risk., Methods: Baseline data from 298 cardiology patients recruited for a multicenter randomized controlled trial were examined. Dipping was defined as a sleep-related BP or heart rate (HR) reduction of at least 10%. Logistic regression models were fit, adjusting for age, sex, race, BMI, CVD risk factors, CVD, and study site., Results: There was a statistically significant 4% increase in the odds of nondipping SBP per 1-unit increase in both apnea hypopnea index (AHI) and oxygen desaturation index (ODI). There was no significant relationship between AHI and nondipping mean arterial pressure (MAP); however, a 3% increase in the odds of nondipping MAP per 1-unit increase in ODI was observed [odds ratio (OR) = 1.03; 95% confidence interval (CI) 1.00-1.05]. At severe OSA levels, a 10 and 4% increase in odds of nondipping DBP per 1-unit increase in AHI and ODI were observed, respectively. A 6% [OR = 1.06; 95% CI (1.01-1.10)] increase in nondipping HR odds was observed with each increase in ODI until the upper quartile of ODI., Conclusion: In patients at cardiovascular risk and moderate-to-severe OSA, increasing AHI and/or ODI were associated with increased odds of nondipping SBP and nondipping MAP. More severe levels of AHI and ODI also were associated with nondipping DBP. These results support progressive BP burden associated with increased OSA severity even in patients managed by cardiology specialty care.

The objective of this study is to examine whether increasing obstructive sleep apnea (OSA) severity is associated with worsening endothelial function. The design is a cross-sectional examination of the baseline assessment of a multi-centre randomized controlled clinical trial examining the effects of oxygen, continuous positive airway pressure (CPAP) therapy or lifestyle modifications on cardiovascular biomarkers. Participants were recruited from cardiology clinics at four sites. Participants with an apnea-hypopnea index (AHI) of 15-50 and known cardio/cerebrovascular disease (CVD) or CVD risk factors were included. OSA severity indices [oxygen desaturation index (ODI), AHI and percentage of sleep time below 90% oxygen saturation (total sleep time <90)] and a measure of endothelium-mediated vasodilatation [Framingham reactive hyperaemia index (F-RHI) derived from peripheral arterial tonometry (PAT)] were assessed. The sample included 267 individuals with a mean AHI of 25.0 ± 8.5 SD and mean F-RHI 0.44 ± 0.38. In adjusted models, the slope of the relationship between ODI and F-RHI differed above and below an ODI of 24.6 (P = 0.04), such that above an ODI of 24.6 there was a marginally significant decline in the geometric mean of the PAT ratio by 3% [95% confidence interval (CI): 0%, 5%; P = 0.05], while below this point, there was a marginally significant incline in the geometric mean of the PAT ratio by 13% (95% CI: 0%, 27%; P = 0.05) per 5-unit increase in ODI. A similar pattern was observed between AHI and F-RHI. No relation was noted with total sleep time <90 and F-RHI. There was evidence of a graded decline in endothelial function in association with higher levels of intermittent hypoxaemia., (© 2013 European Sleep Research Society.)

Sulphonylureas (SUs) are widely used glucose-lowering agents in type 2 diabetes mellitus (T2DM) with apparent declining efficacy over time. Concerns have been raised from observational retrospective studies on the cardiovascular (CV) safety of SUs but there are few long-term data on CV outcomes from randomized controlled trials (RCTs) involving the use of this class of agents. Most of the observational studies and registry data are conflicting and vary with study population and methodology used for analyses. To address the SU controversy, we reviewed the recently published literature (until end of the year 2011) to evaluate the impact of SUs on CV outcomes in modern, longer-term (≥72 weeks) RCTs where they were compared in a head-to-head fashion versus an active comparator or were used as part of a treatment strategy. We identified 15 trials and found no report of an increase in the incidence of CV events with the use of SUs. However, the available data are limited, and, most importantly, there was no adequately powered formal head-to-head CV outcome trial designed to address CV safety. Since SUs are still being advocated as second-line therapy added-on to metformin, as one of several classes, and in certain circumstances first-line therapy in T2DM management, definitive data from a dedicated RCT addressing the CV safety question with SUs would be informative. Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) is such a trial, ongoing since November 2010, and is currently the largest head-to-head CV outcome trial that involves a comparison of a SU (glimepiride) with a dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin) and will provide a unique perspective with respect to CV outcomes with these two commonly used agents.

Background: This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments., Methods: This was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis., Results: Of 5239 treated patients (mean ± SD HbA1c 65 ± 10 mmol/mol [8.0 ± 0.9%], age 58 ± 10 years, BMI 29 ± 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0])., Conclusions: These results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM., (© 2012 Johansen et al; licensee BioMed Central Ltd.)

Objective: Sleep habits have been associated with risk of cardiovascular disease (CVD) and metabolic disturbances, but the mechanisms underlying these associations have yet to be fully elucidated. We aim to determine whether sleep duration and/or snoring are associated with biomarkers of CVD in women with type 2 diabetes., Research Design and Methods: We studied 935 women aged 43-69 years enrolled in the Nurses' Health Study cohort with type 2 diabetes who had no history of documented coronary heart disease or stroke in 1990. Information on sleep duration and snoring frequency was collected in 1986 from mailed questionnaires, and biomarkers of CVD were measured from blood samples taken in 1989-1990., Results: Longer sleep duration was associated with increased levels of C-reactive protein after adjusting for age, BMI, lifestyle factors, family history of diabetes, glycemic control, and medication use (P = 0.05). HDL was decreased with short and long sleep duration among normotensive (P = 0.02) but not hypertensive women. More frequent snoring was directly associated with triglycerides (P = 0.02) and inversely associated with HDL cholesterol (0.03) and adiponectin (P = 0.03) in multivariate-adjusted analyses., Conclusions: The associations of sleep duration and snoring with lipid profile, hormone measures, and/or inflammatory markers may partially explain the previously reported relationship between sleep habits and cardiovascular and metabolic disorders.

Current treatment of ischaemic vascular diseases such as coronary and peripheral artery disease includes angioplasty and bypass grafting, as well as lipid lowering therapies and control of other cardiovascular risk factors. Numerous members of the tumour necrosis factor superfamily (TNFSF) have recently shown emerging roles in both the protection and progression of such diseases. Understanding the role TNFSF members play in ischaemic vascular disease may provide insight into the development of novel therapeutics to prevent or treat diseases relating to atherosclerosis and ischaemia. This review summarizes the most recent findings relating to TNFSF members and the mechanisms that precede ischaemic vascular disease progression, particularly endothelial dysfunction, chronic inflammation, and atherosclerotic plaque development. This review also explores recent translational research on the role of TNFSF therapies in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Timing and stability of the sleep-wake cycle are potential modifiable risk factors for cardiometabolic disease. The aim of this study was to evaluate the relationship between objective measures of sleep-wake timing and stability with cardiometabolic disease risk.Methods: In this multicenter, cross-sectional, population-based study, actigraphy data were obtained from the 2,156 adults, aged 18 to 64 years, recruited from the Sueño ancillary study of the Hispanic Community Health Study/Study of Latinos (2010-2013). These data were correlated with measures of cardiometabolic disease risk, including systolic and diastolic BPs, homeostatic assessment of insulin resistance, glycosylated hemoglobin, BMI, and hypertension and diabetes status.Results: Each 10% decrease in interdaily stability was associated with a 3.0% absolute increase in the prevalence of hypertension (95% CI, 0.6-5.3; P < .05), an increase in systolic BP by 0.78 mm Hg (95% CI, 0.12-1.45; P < .05) and an increase in diastolic BP by 0.80 mm Hg (95% CI, 0.28-1.32; P < .05). In addition, delaying the midpoint of sleep by 1 h was associated with an increase in systolic BP by 0.73 mm Hg (95% CI, 0.30-1.16; P < .01) and diastolic BP by 0.53 mm Hg (95% CI, 0.17-0.90; P < .01). These associations were not significant after adjusting for shift work status. No association was found between interdaily stability or sleep timing and diabetes, BMI, or insulin resistance.Conclusions: These results suggest that beyond sleep duration, the timing and regularity of sleep-wake schedules are related to hypertension prevalence and BP. [ABSTRACT FROM AUTHOR]

Studies have reported an association between obstructive sleep apnea (OSA) and cardiovascular disease (CVD) morbidity and mortality. Proposed mechanisms include endothelial dysfunction and atherosclerosis. We aimed to investigate the associations of OSA with endothelial dysfunction and subclinical atherosclerotic coronary artery disease (CAD), and assess the impact of race on these associations. We used data from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study, a community-based prospective cohort with approximately equal representation of black and white participants. OSA severity was measured in 765 individuals using the apnea-hypopnea index (AHI). Endothelial dysfunction was measured using the Endo-PAT device, expressed as Framingham reactive hyperemia index (F_RHI). Coronary artery calcium (CAC), a marker of subclinical CAD, was quantified by electron beam computed tomography. There were 498 (65%) female participants, 282 (37%) black individuals, and 204 (26%) participants with moderate/severe OSA (AHI ≥15). In univariate models, moderate/severe OSA was associated with lower F_RHI and higher CAC, as well as several traditional CVD risk factors including older age, male sex, hypertension, diabetes, higher body mass index, and lower high-density lipoprotein cholesterol levels. In a multivariable model, individuals with moderate/severe OSA had 10% lower F_RHI and 35% higher CAC, which did not reach statistical significance (p=0.08 for both comparisons). There was no significant interaction of race on the association of OSA with F_RHI or CAC (p-value >0.1 for all comparisons). In a community-based cohort comprised of black and white participants, moderate/severe OSA was modestly associated with endothelial dysfunction and subclinical atherosclerotic CAD. These associations did not vary by race. [ABSTRACT FROM AUTHOR]

BACKGROUND: Short duration and poor quality of sleep have been associated with increased risks of obesity, cardiovascular disease, diabetes mellitus, and total mortality. However, few studies have investigated their associations with risk of colorectal neoplasia. METHODS: In a screening colonoscopy-based case-control study, the Pittsburg Sleep Quality Index (PSQI) was administered to 1240 study participants before colonoscopy. RESULTS: Three hundred thirty-eight (27.3%) of the participants were diagnosed with incident colorectal adenomas. Although there was no appreciable difference in the overall PSQI score between cases and adenoma-free controls (5.32 vs 5.11; P = .37), the authors found a statistically significant association of colorectal adenoma with the PSQI component 3, which corresponds to sleep duration (P = .02). Cases were more likely to average less than 6 hours of sleep per night (28.9% vs 22.1% in controls, P = .01). In multivariate regression analysis adjusted for age, gender, race, smoking, family history of colorectal cancer, and waist-to-hip ratio, individuals averaging less than 6 hours per night had an almost 50% increase in risk of colorectal adenomas (OR = 1.47; CI = 1.05-2.06, P for trend = .02) as compared with individuals sleeping at least 7 hours per night. Cases were also more likely to report being diagnosed with sleep apnea (9.8% vs 6.5%, P = .05) and more likely to have worked alternate shifts (54.0% vs 46.1%, P = .01), although these differences were not significant in multivariate models. CONCLUSIONS: Shorter duration of sleep significantly increases risk of colorectal adenomas. The authors' results suggest sleep duration as a novel risk factor for colorectal neoplasia. Cancer 2011;117:841-7. [ABSTRACT FROM AUTHOR]

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of medication with broad cardiovascular benefits in those with type 2 diabetes, chronic kidney disease, and heart failure. These include reductions in major adverse cardiac events and cardiovascular death. The mechanisms that underlie their benefits in atherosclerotic cardiovascular disease (ASCVD) are not well understood, but they extend beyond glucose lowering. This narrative review summarises the ASCVD benefits of SGLT2 inhibitors seen in large human outcome trials, as well as the mechanisms of action explored in rodent and small human studies. Potential pathways include favourable alterations in lipid metabolism, inflammation, and endothelial function. These all require further investigation in large human clinical trials with mechanistic endpoints, to further elucidate the disease modifying benefits of this drug class and those who will benefit most from it. [ABSTRACT FROM AUTHOR]

Mural cells collectively refer to the smooth muscle cells and pericytes of the vasculature. This heterogenous population of cells play a crucial role in the regulation of blood pressure, distribution, and the structural integrity of the vascular wall. As such, dysfunction of mural cells can lead to the pathogenesis and progression of a number of diseases pertaining to the vascular system. Cardiovascular diseases, particularly atherosclerosis, are perhaps the most well-described mural cell-centric case. For instance, atherosclerotic plaques are most often described as being composed of a proliferative smooth muscle cap accompanied by a necrotic core. More recently, the role of dysfunctional mural cells in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, is being recognized. In this review, we begin with an exploration of the mechanisms underlying atherosclerosis and neurodegenerative diseases, such as mural cell plasticity. Next, we highlight a selection of signaling pathways (PDGF, Notch and inflammatory signaling) that are conserved across both diseases. We propose that conserved mural cell signaling mechanisms can be exploited for the identification or development of dual-pronged therapeutics that impart both cardio- and neuroprotective qualities. [ABSTRACT FROM AUTHOR]

Computed tomography coronary angiography (CTCA) is a non-invasive diagnostic modality that provides a comprehensive anatomical assessment of the coronary arteries and coronary atherosclerosis, including plaque burden, composition and morphology. The past decade has witnessed an increase in the role of CTCA for evaluating patients with both stable and acute chest pain, and recent international guidelines have provided increasing support for a first line CTCA diagnostic strategy in select patients. CTCA offers some advantages over current functional tests in the detection of obstructive and non-obstructive coronary artery disease, as well as for ruling out obstructive coronary artery disease. Recent randomised trials have also shown that CTCA improves prognostication and guides the use of guideline-directed preventive therapies, leading to improved clinical outcomes. CTCA technology advances such as fractional flow reserve, plaque quantification and perivascular fat inflammation potentially allow for more personalised risk assessment and targeted therapies. Further studies evaluating demand, supply, and cost-effectiveness of CTCA for evaluating chest pain are required in Australia. This discussion paper revisits the evidence supporting the use of CTCA, provides an overview of its implications and limitations, and considers its potential role for chest pain evaluation pathways in Australia. [ABSTRACT FROM AUTHOR]

Abstract The vascular endothelium is critical for maintenance of cardiovascular homeostasis. Endothelial dysfunction is a key event of atherosclerosis, with oxidative stress mediated by reactive oxygen species (ROS) playing a major role. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is increasingly recognised to play a protective role in atherosclerosis, however the molecular mechanisms by which it exerts its beneficial effects are unclear. Here we examined if TRAIL could attenuate vascular oxidative stress and improve endothelial cell (EC) function. In coronary artery disease patients, plasma TRAIL levels were significantly reduced compared to healthy individuals, and negatively correlated with the levels of circulating 8- iso Prostaglandin F 2α , a marker of in vivo oxidative stress. In vivo , high-fat fed, atherosclerotic Trail -/- Apoe -/- mice exhibited a significant impairment in endothelial-dependent vasorelaxation, which correlated with increased vascular ROS and 4-hydroxynonenal compared to Apoe -/- mice. Endothelial permeability measured by Evan's blue dye extravasation was increased in several organs of Trail -/- mice compared to wild-type mice, which correlated with a decrease in VE-cadherin expression. In vitro in ECs, angiotensin II (AngII)-induced ROS generation involving the mitochondria, NADPH oxidase-4 (NOX-4) and eNOS, was inhibited by pre-treatment with TRAIL. Furthermore, AngII-augmented VCAM-1 expression and monocyte adhesion to ECs was inhibited by TRAIL. Finally, AngII reduced VE-cadherin expression and redistributed this protein, all of which was brought back to baseline by TRAIL pre-treatment. These findings demonstrate for the first time that TRAIL protects against several forms of endothelial dysfunction involving its ability to control EC ROS generation. Understanding the role TRAIL plays in normal physiology and disease, may lead to potential new therapies to improve endothelial function and atherosclerosis. Graphical abstract fx1 Highlights • Plasma TRAIL negatively associates with circulating 8- iso prostaglandin F 2α levels in CAD patients. • TRAILdeletion in mice promotes oxidative stress, impaired endothelial-dependent relaxation and elevates permeability. • TRAIL protects against AngII-induced oxidative stress in ECs by limiting ROS generation. • TRAIL limits AngII-induced VCAM-1 expression and monocyte adhesion to ECs. • TRAIL limits AngII-mediated disruption of VE-cadherin plasma membrane localisation, and downregulation of its expression. [ABSTRACT FROM AUTHOR]