Summary Background Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is ...frequently assumed but has rarely been reported. Our aim was to test this association. Methods We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis. Findings Of 22 eligible studies, 16 with 36 984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2–7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94–1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95–1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10–1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r =−0·06 and r =−0·02). Interpretation The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials. Funding Deutsche Forschungsgemeinschaft.
Recent discoveries have revealed that microRNAs (miRNAs) play a key role in the regulation of gene expression. In this review, we summarize the rapidly evolving knowledge about liver miRNAs ...(including miR-33, -33*, miR-223, -30c, -144, -148a, -24, -29, and -122) and their link to hepatic lipid metabolism, atherosclerosis and cardiovascular disease, non-alcoholic fatty liver disease, metabolic syndrome, and type-2 diabetes. With regards to its biomarker potential, the main focus is on miR-122 as the most abundant liver miRNA with exquisite tissue specificity. MiR-122 has been proposed to play a central role in the maintenance of lipid and glucose homeostasis and is consistently detectable in serum and plasma. This miRNA may therefore constitute a novel biomarker for cardiovascular and metabolic diseases.
Abstract Background Routine apolipoprotein (apo) measurements for cardiovascular disease (CVD) are restricted to apoA-I and apoB. Here, the authors measured an unprecedented range of apolipoproteins ...in a prospective, population-based study and relate their plasma levels to risk of CVD. Objectives This study sought to measure apolipoproteins directly by mass spectrometry and compare their associations with incident CVD and to obtain a system-level understanding of the correlations of apolipoproteins with the plasma lipidome and proteome. Methods Associations of 13 apolipoproteins, 135 lipid species, and 211 other plasma proteins with incident CVD (91 events), defined as stroke, myocardial infarction, or sudden cardiac death, were assessed prospectively over a 10-year period in the Bruneck Study (N = 688) using multiple-reaction monitoring mass spectrometry. Changes in apolipoprotein and lipid levels following treatment with volanesorsen, a second-generation antisense drug targeting apoC-III, were determined in 2 human intervention trials, one of which was randomized. Results The apolipoproteins most significantly associated with incident CVD were apoC-II (hazard ratio per 1 SD HR/SD: 1.40; 95% confidence interval CI: 1.17 to 1.67), apoC-III (HR/SD: 1.38; 95% CI: 1.17 to 1.63), and apoE (HR/SD: 1.31; 95% CI: 1.13 to 1.52). Associations were independent of high-density lipoprotein (HDL) and non-HDL cholesterol, and extended to stroke and myocardial infarction. Lipidomic and proteomic profiles implicated these 3 very-low-density lipoprotein (VLDL)-associated apolipoproteins in de novo lipogenesis, glucose metabolism, complement activation, blood coagulation, and inflammation. Notably, apoC-II/apoC-III/apoE correlated with a pattern of lipid species previously linked to CVD risk. ApoC-III inhibition by volanesorsen reduced plasma levels of apoC-II, apoC-III, triacylglycerols, and diacylglycerols, and increased apoA-I, apoA-II, and apoM (all p < 0.05 vs. placebo) without affecting apoB-100 (p = 0.73). Conclusions The strong associations of VLDL-associated apolipoproteins with incident CVD in the general community support the concept of targeting triacylglycerol-rich lipoproteins to reduce risk of CVD.
Objectives This study sought to explore the association between baseline levels of microRNAs (miRNAs) (1995) and incident myocardial infarction (1995 to 2005) in the Bruneck cohort and determine ...their cellular origin. Background Circulating miRNAs are emerging as potential biomarkers. We previously identified an miRNA signature for type 2 diabetes in the general population. Methods A total of 19 candidate miRNAs were quantified by real-time polymerase chain reactions in 820 participants. Results In multivariable Cox regression analysis, 3 miRNAs were consistently and significantly related to incident myocardial infarction: miR-126 showed a positive association (multivariable hazard ratio: 2.69 95% confidence interval: 1.45 to 5.01, p = 0.002), whereas miR-223 and miR-197 were inversely associated with disease risk (multivariable hazard ratio: 0.47 95% confidence interval: 0.29 to 0.75, p = 0.002, and 0.56 95% confidence interval: 0.32 to 0.96, p = 0.036). To determine their cellular origin, healthy volunteers underwent limb ischemia-reperfusion generated by thigh cuff inflation, and plasma miRNA changes were analyzed at baseline, 10 min, 1 h, 5 h, 2 days, and 7 days. Computational analysis using the temporal clustering by affinity propagation algorithm identified 6 distinct miRNA clusters. One cluster included all miRNAs associated with the risk of future myocardial infarction. It was characterized by early (1 h) and sustained activation (7 days) post–ischemia-reperfusion injury and consisted of miRNAs predominantly expressed in platelets. Conclusions In subjects with subsequent myocardial infarction, differential co-expression patterns of circulating miRNAs occur around endothelium-enriched miR-126, with platelets being a major contributor to this miRNA signature.
Spermidine administration is linked to increased survival in several animal models.
The aim of this study was to test the potential association between spermidine content in diet and mortality in ...humans.
This prospective community-based cohort study included 829 participants aged 45–84 y, 49.9% of whom were male. Diet was assessed by repeated dietitian-administered validated food-frequency questionnaires (2540 assessments) in 1995, 2000, 2005, and 2010. During follow-up between 1995 and 2015, 341 deaths occurred.
All-cause mortality (deaths per 1000 person-years) decreased across thirds of increasing spermidine intake from 40.5 (95% CI: 36.1, 44.7) to 23.7 (95% CI: 20.0, 27.0) and 15.1 (95% CI: 12.6, 17.8), corresponding to an age-, sex- and caloric intake–adjusted 20-y cumulative mortality incidence of 0.48 (95% CI: 0.45, 0.51), 0.41 (95% CI: 0.38, 0.45), and 0.38 (95% CI: 0.34, 0.41), respectively. The age-, sex- and caloric ratio–adjusted HR for all-cause death per 1-SD higher spermidine intake was 0.74 (95% CI: 0.66, 0.83; P < 0.001). Further adjustment for lifestyle factors, established predictors of mortality, and other dietary features yielded an HR of 0.76 (95% CI: 0.67, 0.86; P < 0.001). The association was consistent in subgroups, robust against unmeasured confounding, and independently validated in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) Study (age-, sex-, and caloric ratio–adjusted HR per 1-SD higher spermidine intake: 0.71; 95% CI: 0.53, 0.95; P = 0.019). The difference in mortality risk between the top and bottom third of spermidine intakes was similar to that associated with a 5.7-y (95% CI: 3.6, 8.1 y) younger age.
Our findings lend epidemiologic support to the concept that nutrition rich in spermidine is linked to increased survival in humans. This trial was registered at www.clinicaltrials.gov as NCT03378843.
BACKGROUND—The bulk of cardiovascular disease risk is not explained by traditional risk factors. Recent advances in mass spectrometry allow the identification and quantification of hundreds of lipid ...species. Molecular lipid profiling by mass spectrometry may improve cardiovascular risk prediction.
METHODS AND RESULTS—Lipids were extracted from 685 plasma samples of the prospective population-based Bruneck Study (baseline evaluation in 2000). One hundred thirty-five lipid species from 8 different lipid classes were profiled by shotgun lipidomics with the use of a triple-quadrupole mass spectrometer. Levels of individual species of cholesterol esters (CEs), lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines (PEs), sphingomyelins, and triacylglycerols (TAGs) were associated with cardiovascular disease over a 10-year observation period (2000–2010, 90 incident events). Among the lipid species with the strongest predictive value were TAGs and CEs with a low carbon number and double-bond content, including TAG(54:2) and CE(16:1), as well as PE(36:5) (P=5.1×10, 2.2×10, and 2.5×10, respectively). Consideration of these 3 lipid species on top of traditional risk factors resulted in improved risk discrimination and classification for cardiovascular disease (cross-validated ΔC index, 0.0210 95% confidence interval, 0.0010-0.0422; integrated discrimination improvement, 0.0212 95% confidence interval, 0.0031-0.0406; and continuous net reclassification index, 0.398 95% confidence interval, 0.175-0.619). A similar shift in the plasma fatty acid composition was associated with cardiovascular disease in the UK Twin Registry (n=1453, 45 cases).
CONCLUSIONS—This study applied mass spectrometry-based lipidomics profiling to population-based cohorts and identified molecular lipid signatures for cardiovascular disease. Molecular lipid species constitute promising new biomarkers that outperform the conventional biochemical measurements of lipid classes currently used in clinics.
Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of ...coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.
RATIONALE:MicroRNAs (miRNAs) have been implicated in the epigenetic regulation of key metabolic, inflammatory, and antiangiogenic pathways in type 2 diabetes (DM) and may contribute to common disease ...complications.
OBJECTIVE:In this study, we explore plasma miRNA profiles in patients with DM.
METHODS AND RESULTS:Total RNA was extracted from plasma samples of the prospective population-based Bruneck study. A total of 13 candidate miRNAs identified by microarray screening and miRNA network inference were quantified by quantitative PCR in all diabetic patients of the Bruneck study and age- and sex-matched controls (1995 evaluation, n=80 each). Quantitative PCR assessment revealed lower plasma levels of miR-20b, miR-21, miR-24, miR-15a, miR-126, miR-191, miR-197, miR-223, miR-320, and miR-486 in prevalent DM, but a modest increase of miR-28-3p. Findings emerged as robust in multivariable analysis and were independent of the standardization procedure applied. For endothelial miR-126, results were confirmed in the entire Bruneck cohort (n=822) in univariate (odds ratio 95% confidence interval, 0.38 0.26 to 0.55; P=2.72×10) and multivariate analyses (0.57 0.37 to 0.86; P=0.0082). Importantly, reduced miR-15a, miR-29b, miR-126, miR-223, and elevated miR-28-3p levels antedated the manifestation of disease. Most differences in miRNA levels were replicated in plasma obtained from hyperglycemic Lep mice. High glucose concentrations reduced the miR-126 content of endothelial apoptotic bodies. Similarly in patients with DM, the reduction of miR-126 was confined to circulating vesicles in plasma.
CONCLUSIONS:We reveal a plasma miRNA signature for DM that includes loss of endothelial miR-126. These findings might explain the impaired peripheral angiogenic signaling in patients with DM.
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