Limited data are available on the long-term effects of contemporary drug-eluting stents versus contemporary bare-metal stents on rates of death, myocardial infarction, repeat revascularization, and ...stent thrombosis and on quality of life.
We randomly assigned 9013 patients who had stable or unstable coronary artery disease to undergo percutaneous coronary intervention (PCI) with the implantation of either contemporary drug-eluting stents or bare-metal stents. In the group receiving drug-eluting stents, 96% of the patients received either everolimus- or zotarolimus-eluting stents. The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularization, stent thrombosis, and quality of life.
At 6 years, the rates of the primary outcome were 16.6% in the group receiving drug-eluting stents and 17.1% in the group receiving bare-metal stents (hazard ratio, 0.98; 95% confidence interval CI, 0.88 to 1.09; P=0.66). There were no significant between-group differences in the components of the primary outcome. The 6-year rates of any repeat revascularization were 16.5% in the group receiving drug-eluting stents and 19.8% in the group receiving bare-metal stents (hazard ratio, 0.76; 95% CI, 0.69 to 0.85; P<0.001); the rates of definite stent thrombosis were 0.8% and 1.2%, respectively (P=0.0498). Quality-of-life measures did not differ significantly between the two groups.
In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents. (Funded by the Norwegian Research Council and others; NORSTENT ClinicalTrials.gov number, NCT00811772 .).
We previously showed that treatment with folic acid (FA)/B12 was associated with more rapid progression of coronary artery disease (CAD). High doses of FA may induce methylation by increasing the ...availability of S-adenosyl-methionine (SAM). Asymmetric dimethylarginine (ADMA) and trimethyllysine (TML) are both produced through proteolytic release following post-translational SAM-dependent methylation of precursor amino acid. ADMA has previously been associated with CAD. We investigated if plasma levels of ADMA and TML were associated with progression of CAD as measured by quantitative coronary angiography (QCA).
183 patients from the Western Norway B Vitamin Intervention Trial (WENBIT) undergoing percutaneous coronary intervention (PCI) were randomized to daily treatment with 0.8 mg FA/0.4 mg B12 with and without 40 mg B6, B6 alone or placebo. Coronary angiograms and plasma samples of ADMA and TML were obtained at both baseline and follow-up (median 10.5 months). The primary end-point was progression of CAD as measured by diameter stenosis (DS) evaluated by linear quantile mixed models.
A total of 309 coronary lesions not treated with PCI were identified. At follow-up median (95% CI) DS increased by 18.35 (5.22-31.49) percentage points per µmol/L ADMA increase (p-value 0.006) and 2.47 (0.37-4.58) percentage points per µmol/L TML increase (p-value 0.021) in multivariate modeling. Treatment with FA/B12 (±B6) was not associated with ADMA or TML levels.
In patients with established CAD, baseline ADMA and TML was associated with angiographic progression of CAD. However, neither ADMA nor TML levels were altered by treatment with FA/B12 (±B6).
Controlled-Trials.com NCT00354081.
Fish consumption is considered health beneficial as it decreases cardiovascular disease (CVD)-risk through effects on plasma lipids and inflammation. We investigated a salmon protein hydrolysate ...(SPH) that is hypothesized to influence lipid metabolism and to have anti-atherosclerotic and anti-inflammatory properties. 24 female apolipoprotein (apo) E(-/-) mice were divided into two groups and fed a high-fat diet with or without 5% (w/w) SPH for 12 weeks. The atherosclerotic plaque area in aortic sinus and arch, plasma lipid profile, fatty acid composition, hepatic enzyme activities and gene expression were determined. A significantly reduced atherosclerotic plaque area in the aortic arch and aortic sinus was found in the 12 apoE(-/)- mice fed 5% SPH for 12 weeks compared to the 12 casein-fed control mice. Immunohistochemical characterization of atherosclerotic lesions in aortic sinus displayed no differences in plaque composition between mice fed SPH compared to controls. However, reduced mRNA level of Icam1 in the aortic arch was found. The plasma content of arachidonic acid (C20:4n-6) and oleic acid (C18:1n-9) were increased and decreased, respectively. SPH-feeding decreased the plasma concentration of IL-1β, IL-6, TNF-α and GM-CSF, whereas plasma cholesterol and triacylglycerols (TAG) were unchanged, accompanied by unchanged mitochondrial fatty acid oxidation and acyl-CoA:cholesterol acyltransferase (ACAT)-activity. These data show that a 5% (w/w) SPH diet reduces atherosclerosis in apoE(-/-) mice and attenuate risk factors related to atherosclerotic disorders by acting both at vascular and systemic levels, and not directly related to changes in plasma lipids or fatty acids.
Plasma trimethylamine-N-oxide (TMAO) is associated with cardiovascular disease; however specific relationships with cardiac arrhythmias are unknown. We evaluated the association between plasma TMAO ...and incident atrial fibrillation (AF).
Risk associations were explored among 3797 patients with suspected stable angina in the Western Norway Coronary Angiography Cohort (WECAC) and verified in 3143 elderly participants in the community-based Hordaland Health Study (HUSK). Information on endpoints was obtained from nationwide registries.
Median follow-up was 7.3 and 10.8 years in the WECAC and HUSK cohorts, respectively, and 412 (10.9%) and 484 (15.4%) subjects were registered with incident AF. The age and gender adjusted HRs were 1.16, 95% CI 1.05–1.28 and 1.10, 95% CI 1.004–1.19 per 1 SD increase in log-transformed plasma TMAO. Adjusting for hypertension, BMI, smoking, diabetes, or intake of total choline, a TMAO precursor, did not materially influence the risk associations. Among patients in WECAC, further extensive adjustment for other AF risk factors yielded similar results. Adding TMAO to traditional AF risk factors (age, gender, hypertension, BMI, smoking and diabetes) yielded a continuous net reclassification improvement of 0.108, 95% CI 0.015–0.202 and 0.139, 95% CI 0.042–0.235.
Plasma TMAO was associated with and improved reclassification of incident AF in two independent Norwegian cohorts with long-term follow-up. The relationship was independent of traditional AF risk factors, as well as of dietary choline intake. Our findings motivate further studies to explore endogenous metabolic factors influencing the relationship between TMAO and cardiovascular disease.
•Plasma trimethylamine-N-oxide (TMAO) is associated with cardiovascular disease.•We investigated the association between TMAO and incident atrial fibrillation.•Two large, Norwegian cohorts were used.•TMAO was positively associated with incident atrial fibrillation.•TMAO improved risk prediction of atrial fibrillation.
Background
Although choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite ...betaine with cardiac arrhythmias.
Methods and Results
We evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long‐term atrial fibrillation (AF) risk in a community‐based cohort, HUSK (the Hordaland Health Study n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B‐Vitamin) Trial (n=3733). Information on AF was obtained from the CVDNOR (Cardiovascular Disease in Norway) project. In HUSK, WECAC (Western Norway Coronary Angiography Cohort), and NORVIT, 552, 411, and 663 AF cases were identified during a median follow‐up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later AF risk after multivariable adjustments in HUSK. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08‐1.19, P<0.001) and 1.16 (95% confidence interval 1.10‐1.22, P<0.001) per SD increment for log‐transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with AF risk (pooled hazard ratio 1.29, 95% confidence interval 1.01‐1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and AF risk.
Conclusions
Our findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of AF, suggesting a potential role of choline metabolism in the pathogenesis of AF.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov.Unique identifier: NCT00671346.
Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk ...factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks. Rats fed PPC had reduced total homocysteine plasma level and increased levels of choline, dimethylglycine and cysteine, whereas the plasma level of methionine was unchanged compared to control. PPC feeding increased the plasma level of TMAO, carnitine, its precursors trimethyllysine and γ-butyrobetaine. There was a close correlation between plasma TMAO and carnitine, trimethyllysine, and γ-butyrobetaine, but not between TMAO and choline. The present data suggest that PPC has a homocysteine lowering effect and is associated with altered plasma concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. Moreover, the present study reveals a non-obligatory role of gut microbiota in the increased plasma TMAO level as it can be explained by the PPC's content of TMAO. The increased level of carnitine and carnitine precursors is interpreted to reflect increased carnitine biosynthesis.
Patients with diabetes have increased rates of major adverse cardiac events (MACEs). We hypothesized that this is explained by diabetes-associated differences in coronary plaque morphology and lipid ...content.
In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), 898 patients with acute myocardial infarction with or without ST-segment elevation underwent 3-vessel quantitative coronary angiography and coregistered near-infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Subsequent MACEs were adjudicated to either treated culprit lesions or untreated nonculprit lesions. This substudy stratified patients by diabetes status and assessed baseline culprit and nonculprit prevalence of high-risk plaque characteristics defined as maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Separate covariate-adjusted multivariable models were performed to identify whether diabetes was associated with nonculprit lesion-related MACEs and high-risk plaque characteristics.
Diabetes was present in 109 of 898 patients (12.1%). During a median 3.7-year follow-up, MACEs occurred more frequently in patients with versus without diabetes (20.1% versus 13.5% odds ratio (OR), 1.94 (95% CI, 1.14-3.30)), primarily attributable to increased risk of myocardial infarction related to culprit lesion restenosis (4.3% versus 1.1% OR, 3.78 (95% CI, 1.12-12.77)) and nonculprit lesion-related spontaneous myocardial infarction (9.3% versus 3.8% OR, 2.74 (95% CI, 1.25-6.04)). However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes concerning culprit (maximum plaque burden ≥70%: 90% versus 93%,
=0.34; maximum lipid core burden index ≥324.7: 66% versus 70%,
=0.49) and nonculprit lesions (maximum plaque burden ≥70%: 23% versus 22%,
=0.37; maximum lipid core burden index ≥324.7: 26% versus 24%,
=0.47). In multivariable models, diabetes was associated with MACEs in nonculprit lesions (adjusted OR, 2.47 95% CI, 1.21-5.04) but not with prevalence of high-risk plaque characteristics (adjusted OR, 1.21 95% CI, 0.86-1.69).
Among patients with recent myocardial infarction, both treated and untreated lesions contributed to the diabetes-associated ≈2-fold increased MACE rate during the 3.7-year follow-up. Diabetes-related plaque characteristics that might underlie this increased risk were not identified by multimodality imaging.
URL: https://www.
gov; Unique identifier: NCT02171065.
Loop diuretics are widely used in patients with heart and renal failure, as well as to treat hypertension and peripheral edema. However, there are no randomized, controlled trials (RCT) evaluating ...their long term safety, and several observational reports have indicated adverse effects. We sought to evaluate the impact of loop diuretics on long term survival in patients with suspected coronary artery disease, but without clinical heart failure, reduced left ventricular ejection fraction or impaired renal function.
From 3101 patients undergoing coronary angiography for suspected stable angina pectoris, subjects taking loop diuretics (n=109) were matched with controls (n=198) in an attempted 1:2 ratio, using propensity scores based on 59 baseline variables. During median follow-up of 10.1 years, 37.6% in the loop diuretics group and 23.7% in the control group died (log-rank p-value 0.005). Treatment with loop diuretics was associated with a hazard ratio (95% confidence interval) of 1.82 (1.20, 2.76), and the number needed to harm was 7.2 (4.1, 30.3). Inclusion of all 3101 patients using propensity score weighting and adjustment for numerous covariates provided similar estimates. The main limitation is the potential of confounding from unmeasured patient characteristics.
The use of loop diuretics in patients with suspected coronary artery disease, but without systolic heart failure or renal impairment, is associated with increased risk of all-cause mortality. Considering the lack of randomized controlled trials to evaluate long term safety of loop diuretics, our data suggest caution when prescribing these drugs to patients without a clear indication.
The TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes ...(NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI).
A blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB CK-MB and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a percutaneous coronary intervention (PCI)-related MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79-0.98; P = 0.021 and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77-0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73-0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73-1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077).
The PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.
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