In older persons without known cardiovascular disease, the use of low-dose aspirin resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of ...cardiovascular disease than placebo.
Testosterone is the main male sex hormone and is essential for the maintenance of male secondary sexual characteristics and fertility. Androgen deficiency in young men owing to organic disease of the ...hypothalamus, pituitary gland or testes has been treated with testosterone replacement for decades without reports of increased cardiovascular events. In the past decade, the number of testosterone prescriptions issued for middle-aged or older men with either age-related or obesity-related decline in serum testosterone levels has increased exponentially even though these conditions are not approved indications for testosterone therapy. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. However, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess cardiovascular events; therefore, the cardiovascular safety of this therapy remains unclear. In this Review, we provide an overview of epidemiological data on the association between serum levels of endogenous testosterone and cardiovascular disease, prescription database studies on the risk of cardiovascular disease in men receiving testosterone therapy, randomized trials and meta-analyses evaluating testosterone replacement therapy and its association with cardiovascular events and mechanistic studies on the effects of testosterone on the cardiovascular system. Our aim is to help clinicians to make informed decisions when considering testosterone replacement therapy in their patients.
Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established ...cardiovascular disease or on statin therapy is uncertain.
Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis.
Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years SD 8; 8064 28% women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change −39% 95% CI −43 to −35) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91–1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00–1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08–1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81–1·10), 1·06 (0·94–1·21), and 1·43 (1·15–1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics.
In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials.
Novartis Pharma AG.
Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to ...be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
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•Gut microbe formed phenylacetyl glutamine (PAGln) contributes to cardiac disease•Microbial porA and fldH impact host PAGln levels, platelet function, and thrombosis•PAGln transmits cellular responses via the α2A, α2B, and β2 adrenergic receptors•β blocker therapy attenuates PAGln-induced heightened thrombosis risk
A microbially generated metabolite, PAGIn, is associated with cardiovascular disease and death in humans. Studies in animal models provide insights into PAGIn metabolism as well as its effects in driving platelet responsiveness and thrombosis through adrenergic receptors.
In a randomized trial of patients with type 2 diabetes, treatment with dapagliflozin, an SGLT2 inhibitor that promotes glucosuria, did not result in a higher or lower rate of cardiovascular death, ...myocardial infarction, or stroke than placebo but did result in a lower rate of hospitalization for heart failure.
It is unclear what level of moderate to vigorous intensity physical activity (MVPA) offsets the health risks of sitting.
The purpose of this study was to examine the joint and stratified associations ...of sitting and MVPA with all-cause and cardiovascular disease (CVD) mortality, and to estimate the theoretical effect of replacing sitting time with physical activity, standing, and sleep.
A longitudinal analysis of the 45 and Up Study calculated the multivariable-adjusted hazard ratios (HRs) of sitting for each sitting-MVPA combination group and within MVPA strata. Isotemporal substitution modeling estimated the per-hour HR effects of replacing sitting.
A total of 8,689 deaths (1,644 due to CVD) occurred among 149,077 participants over an 8.9-year (median) follow-up. There was a statistically significant interaction between sitting and MVPA only for all-cause mortality. Sitting time was associated with both mortality outcomes in a nearly dose-response manner in the least active groups reporting <150 MVPA min/week. For example, among those reporting no MVPA, the all-cause mortality HR comparing the most sedentary (>8 h/day) to the least sedentary (<4 h/day) groups was 1.52 (95% confidence interval: 1.13 to 2.03). There was inconsistent and weak evidence for elevated CVD and all-cause mortality risks with more sitting among those meeting the lower (150 to 299 MVPA min/week) or upper (≥300 MVPA min/week) limits of the MVPA recommendation. Replacing sitting with walking and MVPA showed stronger associations among high sitters (>6 sitting h/day) where, for example, the per-hour CVD mortality HR for sitting replaced with vigorous activity was 0.36 (95% confidence interval: 0.17 to 0.74).
Sitting is associated with all-cause and CVD mortality risk among the least physically active adults; moderate-to-vigorous physical activity doses equivalent to meeting the current recommendations attenuate or effectively eliminate such associations.
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The relation between sodium intake and cardiovascular disease is controversial. This study used individual-participant data from six prospective cohorts of healthy adults. Higher sodium and lower ...potassium intakes, estimated from multiple 24-hour urine samples, were associated in a dose-dependent manner with a higher cardiovascular risk.
The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II - initially thought to be ...biologically inactive - have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7, angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT
R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical renin-angiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review, we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.
Background
Omega‐3 polyunsaturated fatty acids from oily fish (long‐chain omega‐3 (LCn3)), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants ...(alpha‐linolenic acid (ALA)) may benefit cardiovascular health. Guidelines recommend increasing omega‐3‐rich foods, and sometimes supplementation, but recent trials have not confirmed this.
Objectives
To assess the effects of increased intake of fish‐ and plant‐based omega‐3 fats for all‐cause mortality, cardiovascular events, adiposity and lipids.
Search methods
We searched CENTRAL, MEDLINE and Embase to February 2019, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to August 2019, with no language restrictions. We handsearched systematic review references and bibliographies and contacted trial authors.
Selection criteria
We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation or advice to increase LCn3 or ALA intake, or both, versus usual or lower intake.
Data collection and analysis
Two review authors independently assessed trials for inclusion, extracted data and assessed validity. We performed separate random‐effects meta‐analysis for ALA and LCn3 interventions, and assessed dose‐response relationships through meta‐regression.
Main results
We included 86 RCTs (162,796 participants) in this review update and found that 28 were at low summary risk of bias. Trials were of 12 to 88 months' duration and included adults at varying cardiovascular risk, mainly in high‐income countries. Most trials assessed LCn3 supplementation with capsules, but some used LCn3‐ or ALA‐rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5 g a day to more than 5 g a day (19 RCTs gave at least 3 g LCn3 daily).
Meta‐analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all‐cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.93 to 1.01; 143,693 participants; 11,297 deaths in 45 RCTs; high‐certainty evidence), cardiovascular mortality (RR 0.92, 95% CI 0.86 to 0.99; 117,837 participants; 5658 deaths in 29 RCTs; moderate‐certainty evidence), cardiovascular events (RR 0.96, 95% CI 0.92 to 1.01; 140,482 participants; 17,619 people experienced events in 43 RCTs; high‐certainty evidence), stroke (RR 1.02, 95% CI 0.94 to 1.12; 138,888 participants; 2850 strokes in 31 RCTs; moderate‐certainty evidence) or arrhythmia (RR 0.99, 95% CI 0.92 to 1.06; 77,990 participants; 4586 people experienced arrhythmia in 30 RCTs; low‐certainty evidence). Increasing LCn3 may slightly reduce coronary heart disease mortality (number needed to treat for an additional beneficial outcome (NNTB) 334, RR 0.90, 95% CI 0.81 to 1.00; 127,378 participants; 3598 coronary heart disease deaths in 24 RCTs, low‐certainty evidence) and coronary heart disease events (NNTB 167, RR 0.91, 95% CI 0.85 to 0.97; 134,116 participants; 8791 people experienced coronary heart disease events in 32 RCTs, low‐certainty evidence). Overall, effects did not differ by trial duration or LCn3 dose in pre‐planned subgrouping or meta‐regression. There is little evidence of effects of eating fish.
Increasing ALA intake probably makes little or no difference to all‐cause mortality (RR 1.01, 95% CI 0.84 to 1.20; 19,327 participants; 459 deaths in 5 RCTs, moderate‐certainty evidence),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25; 18,619 participants; 219 cardiovascular deaths in 4 RCTs; moderate‐certainty evidence), coronary heart disease mortality (RR 0.95, 95% CI 0.72 to 1.26; 18,353 participants; 193 coronary heart disease deaths in 3 RCTs; moderate‐certainty evidence) and coronary heart disease events (RR 1.00, 95% CI 0.82 to 1.22; 19,061 participants; 397 coronary heart disease events in 4 RCTs; low‐certainty evidence). However, increased ALA may slightly reduce risk of cardiovascular disease events (NNTB 500, RR 0.95, 95% CI 0.83 to 1.07; but RR 0.91, 95% CI 0.79 to 1.04 in RCTs at low summary risk of bias; 19,327 participants; 884 cardiovascular disease events in 5 RCTs; low‐certainty evidence), and probably slightly reduces risk of arrhythmia (NNTB 91, RR 0.73, 95% CI 0.55 to 0.97; 4912 participants; 173 events in 2 RCTs; moderate‐certainty evidence). Effects on stroke are unclear.
Increasing LCn3 and ALA had little or no effect on serious adverse events, adiposity, lipids and blood pressure, except increasing LCn3 reduced triglycerides by ˜15% in a dose‐dependent way (high‐certainty evidence).
Authors' conclusions
This is the most extensive systematic assessment of effects of omega‐3 fats on cardiovascular health to date. Moderate‐ and low‐certainty evidence suggests that increasing LCn3 slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia.
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