B-vitamin Treatment Modifies the Mortality Risk Associated with Calcium Channel Blockers in Patients with Suspected Stable Angina Pectoris: A Prospective Cohort Study

Background Calcium channel blockers (CCBs) are used for the treatment of cardiovascular disease (CVD), including angina pectoris, and hypertension; however, the effect on survival remains uncertain. CCBs impair fibrinolysis and have been linked to elevated plasma homocysteine (Hcy), a CVD risk marker. Objective We explored the association between CCB use and mortality in a large prospective cohort of patients with suspected stable angina pectoris (SAP), and potential effect modifications by Hcy-lowering B-vitamin treatment (folic acid, B12, and/or B6) as 61.8% of the patients participated in a randomized placebo-controlled B-vitamin intervention trial. Methods Patient baseline continuous characteristics according to CCB treatment were tested by linear regression. Hazard ratios (HRs) for mortality associated with CCB treatment, also according to B-vitamin intervention, were examined using Cox regression analysis. The multivariable model included CVD risk factors, medical histories, and the use of CVD medications. Results A total of 3991 patients (71.5 % men) were included, of whom 907 were prescribed CCBs at discharge. During 10.3 years of median follow-up, 20.6% died and 8.9% from cardiovascular- and 11.7% from non-cardiovascular causes. Patients treated with CCBs had higher plasma Hcy, fibrinogen levels, and erythrocyte sedimentation rate (all P<0.001). Furthermore, CCB use was positively associated with mortality, also after multivariable adjustments (HRs [95% CIs]: 1.34 [1.15,1.57], 1.35 [1.08,1.70], and 1.33 [1.09,1.64] for total, CVD, and non-CVD death, respectively). Numerically stronger associations were observed among patients not treated with B-vitamins (HR [95% CI]: 1.54 [1.25, 1.88], 1.69 [1.25, 2.30], and 1.41 [1.06, 1.86] for total, CVD deaths, and non-CVD deaths, respectively), whereas no association was seen in patients treated with B-vitamins (HR [95% CI]: 1.15 [0.91, 1.46], 1.09 [0.76, 1.57], and 1.20 [0.88, 1.65]). Conclusions In patients with suspected SAP, CCB treatment was associated with increased mortality risk primarily among patients not treated with B-vitamins.publishedVersio

Even chained acylcarnitines predict long-term cardiovascular prognosis in patients with chest pain and non-obstructive coronary artery disease

Background Acylcarnitines are essential for mitochondrial fatty acid oxidation. Earlier studies suggest that impaired energy metabolism may be implicated in the pathogenesis of microvascular angina. We explored metabolites from the carnitine pathway as predictors of cardiovascular disease (CVD) - and all-cause mortality among patients with non-obstructive coronary artery disease (NOCAD). Methods A total of 1046 patients with suspected stable coronary syndrome underwent coronary angiography during 2000–2004, with findings of NOCAD. Serum levels of 8 selected carnitine metabolites were analyzed through liquid chromatography tandem mass spectrometry. Associations with CVD- and all-cause mortality were assessed by multivariable Cox regression models. Results Median age at inclusion was 57 years. 51.5% were men. During median (25th- 75th percentiles), 14.1 (13.2–15.4) years of follow-up, 5.7% of the participants died from CVD and the incidence of all-cause mortality was 17.3%. Serum acetyl, octanoyl- and palmitoylcarnitine predicted CVD mortality with multivariable HR and 95% CI (per SD increment log transformed) of 1.36 (1.01–1.83), 1.49 (1.15–1.93) and 2.07 (1.49–2.85), p ≤ 0.04, respectively. Higher serum acetyl- and palmitoylcarnitines were also associated with increased risk of all-cause mortality (HR (95% CI): 1.27 (1.01–1.50), and 1.51 (1.26–1.81), p ≤ 0.007. Baseline levels of the precursors trimethyllysine and ƴ-butyrobetaine, carnitine or the odd chained propionylcarnitine and (iso)valerylcarnitine were not associated with adverse outcomes. Conclusion Elevated serum even-chained acylcarnitines predicted adverse long-term prognosis in NOCAD. The strongest risk estimates were observed for palmitoylcarnitine, which predicted both CVD- and all-cause mortality after extensive multivariable adjustments. Underlying pathomechanisms should be further elucidated.publishedVersio

Circulating trimethylamine N-oxide levels do not predict 10-year survival in patients with or without coronary heart disease

Background Trimethylamine N-oxide (TMAO) is an amine oxide generated by gut microbial metabolism. TMAO may contribute to atherothrombosis and systemic inflammation. However, the prognostic value of circulating TMAO for risk stratification is uncertain. Methods We assessed prospective relationships of plasma TMAO with long-term risk of all-cause, cardiovascular (CV), and non-CV mortality in the Western Norway Coronary Angiography Cohort (WECAC; 4132 patients with suspected coronary artery disease) and the Hordaland Health Study (HUSK; 6393 community-based subjects). Risk associations were examined using Cox regression analyses. Results Mean follow-up was 9.8 and 10.5 years in WECAC and HUSK, respectively. Following adjustments for established CV risk factors and indices of renal function in WECAC, the hazard ratios (HRs) (95% confidence intervals [CIs]) per one standard deviation increase in log-transformed plasma TMAO were 1.04 (0.97–1.12), 1.06 (0.95–1.18), and 1.03 (0.93–1.13) for all-cause, CV, and non-CV mortality, respectively. Essentially similar results were obtained in patients with angiographically significant coronary artery disease and patients with reduced left ventricular ejection fraction. Corresponding HRs (95% CIs) in the HUSK cohort were 1.03 (0.96–1.10), 1.01 (0.89–1.13), and 1.03 (0.95–1.12) for all-cause-, CV, and non-CV mortality, respectively. Conclusions Circulating TMAO did not predict long-term all-cause, CV, or non-CV mortality in patients with coronary heart disease or in community-based adults. This large study does not support a role of TMAO for patient risk stratification in primary or secondary prevention.publishedVersio

Trimethyllysine predicts all-cause and cardiovascular mortality in community-dwelling adults and patients with coronary heart disease

Aims Trimethyllysine (TML) is involved in carnitine synthesis, serves as a precursor of trimethylamine N-oxide (TMAO) and is associated with cardiovascular events in patients with established coronary heart disease (CHD). We prospectively examined circulating TML as a predictor of all-cause and cardiovascular mortality in community-dwelling adults and patients with CHD. Methods and results By Cox regression modelling, risk associations were examined in 6393 subjects in the community-based Hordaland Health Study (HUSK). A replication study was conducted among 4117 patients with suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). During a mean follow-up of 10.5 years in the HUSK-cohort, 884 (13.8%) subjects died, of whom 287 from cardiovascular causes. After multivariable adjustments for traditional cardiovascular risk factors, the hazard ratio (HR) [95% confidence interval (95% CI)] for all-cause mortality comparing the 4th vs. 1st TML-quartile was 1.66 (1.31–2.10, P < 0.001). Particularly strong associations were observed for cardiovascular mortality [HR (95% CI) 2.04 (1.32–3.15, P = 0.001)]. Corresponding risk-estimates in the WECAC (mean follow-up of 9.8 years) were 1.35 [1.10–1.66, P = 0.004] for all-cause and 1.45 [1.06–1.98, P = 0.02] for cardiovascular mortality. Significant correlations between plasma TML and TMAO were observed in both cohorts (rs ≥ 0.42, P < 0.001); however, additional adjustments for TMAO did not materially influence the risk associations, and no effect modification by TMAO was found. Conclusions Elevated TML-levels were associated with increased risk of all-cause and cardiovascular mortality both in subjects with and without established CHD.publishedVersio

Dietary intake of n-3 long-chain polyunsaturated fatty acids and risk of myocardial infarction in coronary artery disease patients with or without diabetes mellitus: a prospective cohort study

Background: A beneficial effect of a high n-3 long-chain polyunsaturated fatty acid (LCPUFA) intake has been observed in heart failure patients, who are frequently insulin resistant. We investigated the potential influence of impaired glucose metabolism on the relation between dietary intake of n-3 LCPUFAs and risk of acute myocardial infarction (AMI) in patients with coronary artery disease. Methods: This prospective cohort study was based on the Western Norway B-Vitamin Intervention Trial and included 2,378 patients with coronary artery disease with available baseline glycosylated hemoglobin (HbA1c) and dietary data. Patients were sub-grouped as having no diabetes (HbA1c <5.7%), pre-diabetes (HbA1c ≥5.7%), or diabetes (previous diabetes, fasting baseline serum glucose ≥7.0, or non-fasting glucose ≥11.1 mmol/L). AMI risk was evaluated by Cox regression (age and sex adjusted), comparing the upper versus lower tertile of daily dietary n-3 LCPUFA intake. Results: The participants (80% males) had a mean age of 62 and follow-up of 4.8 years. A high n-3 LCPUFA intake was associated with reduced risk of AMI (hazard ratio 0.38, 95%CI 0.18, 0.80) in diabetes patients (median HbA1c = 7.2%), whereas no association was observed in pre-diabetes patients. In patients without diabetes a high intake tended to be associated with an increased risk (hazard ratio1.45, 95%CI 0.84, 2.53), which was significant for fatal AMI (hazard ratio 4.79, 95%CI 1.05, 21.90) and associated with lower HbA1c (mean ± standard deviation 4.55 ±0.68 versus 4.92 ±0.60, P = 0.02). No such differences in HbA1c were observed in those with pre-diabetes or diabetes. Conclusions: A high intake of n-3 LCPUFAs was associated with a reduced risk of AMI, independent of HbA1c, in diabetic patients, but with an increased risk of fatal AMI and lower HbA1c among patients without impaired glucose metabolism. Further studies should investigate whether patients with diabetes may benefit from having a high intake of n-3 LCPUFAs and whether patients with normal glucose tolerance should be careful with a very high intake of these fatty acids.publishedVersio

Components of the choline oxidation pathway in relation to acute myocardial infarction, type 2 diabetes and mortality. Prospective observational studies among patients with suspected or verified coronary heart disease in Norway

BACKGROUND. The choline oxidation pathway comprises the sequential metabolism of choline into betaine, dimethylglycine (DMG), and sarcosine. In addition, dietary choline and betaine can be turned into trimethylamine N-amino oxide (TMAO). Alterations in choline metabolism may relate to cardiovascular disease (CVD) and type 2 diabetes (T2D). Several investigations have focused on systemic concentrations of choline and betaine; however large-scale prospective data are scarce. There is therefore a need for more comprehensive assessments of choline metabolites in relation to incident CVD, T2D and mortality, in addition to investigating any potential benefit in risk prediction from such biomarkers. AIM. We carried out observational cohort studies of the prospective relationships between plasma DMG and incident acute myocardial infarction (AMI) and mortality, as well as the association between systemic and urinary choline metabolites with the risk of incident T2D. The biomarkers’ impact on model discrimination and reclassification of patients at risk was also assessed, as were their test-retest reliabilities and temporal trends according to B-vitamin treatment. MATERIALS AND METHODS. Analyses on the association between plasma DMG and incident AMI, as well as the relationships between choline metabolites and incident T2D were performed among patients evaluated for suspected stable angina pectoris (SAP). The risk assessment between plasma DMG and mortality included SAP patients and patients with AMI from an independent cohort. Clinical endpoint data were obtained from regional and national health registries. Endpoint analyses on incident AMI and mortality were carried out by Cox regression, whereas analyses on incident T2D were performed by logistic regression. Model discrimination and reclassification were explored by calculating the C-statistics, the integrated discrimination index (IDI), and the continuous net reclassification improvement (NRI>0), respectively. Mixed linear modelling was used for assessing temporal trends in metabolite concentrations. RESULTS. Higher plasma DMG was associated with several traditional risk factors for coronary heart disease (CHD). After about four and a half years of follow-up, plasma DMG showed linear relationships with incident AMI among 4154 patients with suspected SAP (age, gender and fasting adjusted hazard ratio (HR) for the fourth vs. first quartile (95% confidence intervals (CI)) 1.95 (1.42-2.68); P<0.001). The relationship between plasma DMG and incident AMI was particularly strong among non-smokers and patients with lower serum apoB and triglyceride levels (P for interaction≤0.03). Among essentially the same patients, as well as among 3733 patients with AMI who were followed for 7 years, higher plasma DMG was also associated with increased risk of all-cause mortality (age and gender adjusted HRs (95% CIs) for the fourth vs. the first quartile 1.72 (1.21–2.46) and 1.76 (1.42–2.18) among SAP and AMI patients, respectively) and CVD mortality (HRs (95% CIs) 1.94 (1.21–3.11) and 1.97 (1.50–2.59) among SAP and AMI patients, respectively). The associations were only slightly attenuated when adjusting for established CHD risk factors, to which adding plasma DMG also improved risk prediction for both AMI and all-cause mortality. Moreover, plasma DMG showed good to excellent within-person reproducibility throughout repeated measurements among patients not receiving supplementation with folic acid + vitamin B12. In general, higher plasma choline and lower plasma betaine and serum sarcosine levels were associated with an adverse risk profile of T2D. In urine, most choline metabolites were positively related to an adverse diabetes risk profile. After an average follow-up of 7.5 years, 233 (6.4%) out of 3621 non-diabetic patients were registered with new-onset T2D. Incident T2D was strongly inversely associated with plasma betaine and positively related to urine betaine, DMG and sarcosine (age, gender and fasting adjusted odds ratios (95% CIs) per 1 SD increment 0.72 (0.62-0.83), 1.25 (1.09-1.43), 1.22 (1.06-1.40), and 1.30 (1.13-1.49), respectively). We did not find any relationship between choline or TMAO and incident T2D. The estimates were not materially altered when adjusting for a range of traditional T2D risk factors and potential confounders, and were similar in sensitivity analyses. Among the choline metabolites associated with new-onset T2D in univariate analyses, plasma betaine and urine sarcosine were most strongly related to incident T2D, and both indices also enhanced risk prediction when added to the multivariate model. After 1 year, as compared to placebo treatment, supplementation with folic acid + vitamin B12 lowered plasma DMG and sarcosine, but increased plasma betaine and choline. No alterations in plasma TMAO were observed. In urine, we observed similar responses to supplementation as to those seen in blood. CONCLUSION AND IMPLICATIONS. Among patients with suspected or verified SAP, high plasma DMG was related to increased risk of AMI, as well as all-cause and CVD mortality, the latter endoints being validated among patients with AMI. Moreover, plasma DMG improved risk prediction of both AMI and mortality. Lower plasma betaine and higher urine betaine, DMG and sarcosine concentrations were related to incident T2D. Plasma betaine and urine sarcosine also improved reclassification of patients at risk. Plasma DMG and betaine, as well as urine sarcosine showed good to excellent within-subject reproducibility among patients not supplemented with folic acid + vitamin B12, justifying one-time assessment of biomarker status. Our observational findings suggest novel pathophysiological pathways involved in conditions heavily impacting the global burden of disease, warranting more research into the field of one-carbon and choline metabolism in relation to life-style related diseases

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Elevated plasma cystathionine is associated with increased risk of mortality among patients with suspected or established coronary heart disease

Background Elevated circulating cystathionine levels are related to atherosclerotic cardiovascular disease, a leading cause of death globally. Objective We investigated whether plasma cystathionine was associated with mortality in patients with suspected or established coronary heart disease (CHD). Methods Data from 2 independent cohorts of patients with suspected stable angina pectoris (SAP) (3033 patients; median 10.7 y follow-up; 648 deaths) or acute myocardial infarction (AMI) (3670 patients; median 7.0 y follow-up; 758 deaths) were included. Hazard ratios with 95% CIs per SD increment of log-transformed cystathionine were calculated using Cox regression modeling. Endpoint data was obtained from a national health registry. Results Among patients with SAP, there was a positive association between plasma cystathionine and death (age- and sex-adjusted HRs [95% CI] per SD: 1.23 [1.14, 1.32], 1.29 [1.16, 1.44], and 1.17 [1.05, 1.29] for total, cardiovascular, and noncardiovascular mortality, respectively). Corresponding risk estimates were 1.28 (1.19, 1.37) for all-cause, 1.33 (1.22, 1.45) for cardiovascular, and 1.19 (1.06, 1.34) for noncardiovascular death among AMI patients. In both cohorts, estimates were slightly attenuated after multivariate adjustments for established CHD risk factors. Subgroup analyses showed that the relation between cystathionine and all-cause mortality in SAP patients was stronger among nonsmokers and those with lower plasma concentration of pyridoxal-5′-phosphate (P-interaction ≤ 0.01 for both). Conclusions Elevated plasma cystathionine is associated with both cardiovascular and noncardiovascular mortality among patients with suspected or established CHD. The joint risk associations of high plasma cystathionine with lifestyle factors and impaired vitamin B-6 status on mortality need further investigation. This trial was registered at clinicaltrials.gov as NCT00354081 and NCT00266487

Association of body mass index with risk of acute myocardial infarction and mortality in Norwegian male and female patients with suspected stable angina pectoris: A prospective cohort study

Background A number of previous studies have suggested that overweight or obese patients with coronary artery disease (CAD) may have lower morbidity and mortality than their leaner counterparts. Few studies have addressed possible gender differences, and the results are conflicting. We examined the association between body mass index (BMI) and risk of acute myocardial infarction (AMI), cardiovascular (CV) death and all-cause mortality in men and women with suspected stable angina pectoris. Method The cohort included 4164 patients with suspected stable angina undergoing elective coronary angiography between 2000 and 2004. Events were registered until the end of 2006. Hazard ratios (HR) (95% confidence intervals) were estimated using Cox regression by comparing normal weight (18.5-24.9 kg/m2) with overweight (25–29.9 kg/m2) and obese (≥30 kg/m2) patients. Underweight (<18.5 kg/m2) patients were excluded from the study. Results Of 4131 patients with complete data, 72% were males and 75% were diagnosed with significant CAD. The mean (standard deviation (SD)) age in the total population was 62 (10) years. Mean (SD) BMI was 26.8 (3.9) kg/m2, 34% was normal weight, 48% overweight and 19% obese. During follow up, a total of 337 (8.2%) experienced an AMI and 302 (7.3%) patients died, of whom 165 (4.0%) died from cardiovascular causes. We observed a significant interaction between BMI groups and gender with regards to risk of AMI (p = 0.011) and CV death (p = 0.031), but not to risk of all-cause mortality; obese men had a multivariate adjusted increased risk of AMI (HR 1.80 (1.28, 2.52)) and CV death (HR 1.60 (1.00, 2.55)) compared to normal weight men. By contrast, overweight women had a decreased risk of AMI (HR 0.56 (0.33, 0.98)) compared to normal weight women. The risk of all-cause mortality did not differ between BMI categories. Conclusion Compared with normal weight subjects, obese men had an increased risk of AMI and CV death, while overweight women had a decreased risk of AMI. These findings may potentially explain some of the result variation in previous studies reporting on the obesity paradox

β-blocker use and risk of all-cause mortality in patients with coronary heart disease: effect modification by serum vitamin A

Abstract Aims  Blockade of β-adrenoceptors reduces sympathetic nervous system activity and improves survival in patients with heart failure with reduced left ventricular ejection fraction (HFrEF); however, any improvement in longevity among patients with coronary heart disease (CHD) but without HFrEF remains uncertain. Vitamin A has been linked to the activation of tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine synthesis pathway. We investigated if vitamin A status modified the association of β-blocker use with the risk of all-cause mortality. Methods and results  A total of 4118 patients undergoing elective coronary angiography for suspected stable angina pectoris, of whom the majority had normal left ventricular ejection fraction (LVEF) were studied. Hazard ratios (HRs) of all-cause mortality comparing treatment vs. non-treatment of β-blockers according to the tertiles of serum vitamin A were explored in Cox proportional hazards regression models. During a median follow-up of 10.3 years, 897 patients (21.8%) died. The overall LVEF was 65% and 283 (6.9%) had anamnestic HF. After multivariable adjustments for traditional risk factors, medical history, and drug therapies of cardiovascular disease, β-blocker treatment was inversely associated with the risk of all-cause mortality [HR : 0.84; 95% CI (confidence interval), 0.72–0.97]. However, the inverse association was generally stronger among patients in the upper serum vitamin A tertile (HR :0.66; 95% CI, 0.50–0.86; Pinteraction = 0.012), which remained present after excluding patients with LVEF &amp;lt; 40%. Conclusion  In patients with suspected CHD, β-blocker treatment was associated with improved survival primarily among patients with high serum vitamin A levels