Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study.

BACKGROUND: Betaine is a major osmolyte, also important in methyl group metabolism. Concentrations of betaine, its metabolite dimethylglycine and analog trimethylamine-N-oxide (TMAO) in blood are cardiovascular risk markers. Diabetes disturbs betaine: does diabetes alter associations between betaine-related measures and cardiovascular risk? METHODS: Plasma samples were collected from 475 subjects four months after discharge following an acute coronary admission. Death (n = 81), secondary acute MI (n = 87), admission for heart failure (n = 85), unstable angina (n = 72) and all cardiovascular events (n = 283) were recorded (median follow-up: 1804 days). RESULTS: High and low metabolite concentrations were defined as top or bottom quintile of the total cohort. In subjects with diabetes (n = 79), high plasma betaine was associated with increased frequencies of events; significantly for heart failure, hazard ratio 3.1 (1.2-8.2) and all cardiovascular events, HR 2.8 (1.4-5.5). In subjects without diabetes (n = 396), low plasma betaine was associated with events; significantly for secondary myocardial infarction, HR 2.1 (1.2-3.6), unstable angina, HR 2.3 (1.3-4.0), and all cardiovascular events, HR 1.4 (1.0-1.9). In diabetes, high TMAO was a marker of all outcomes, HR 2.7 (1.1-7.1) for death, 4.0 (1.6-9.8) for myocardial infarction, 4.6 (2.0-10.7) for heart failure, 9.1 (2.8-29.7) for unstable angina and 2.0 (1.1-3.6) for all cardiovascular events. In subjects without diabetes TMAO was only significant for death, HR 2.7 (1.6-4.8) and heart failure, HR 1.9 (1.1-3.4). Adding the estimated glomerular filtration rate to Cox regression models tended to increase the apparent risks associated with low betaine. CONCLUSIONS: Elevated plasma betaine concentration is a marker of cardiovascular risk in diabetes; conversely low plasma betaine concentrations indicate increased risk in the absence of diabetes. We speculate that the difference reflects control of osmolyte retention in tissues. Elevated plasma TMAO is a strong risk marker in diabetes.

Betaine and secondary events in an acute coronary syndrome cohort.

BACKGROUND: Betaine insufficiency is associated with unfavourable vascular risk profiles in metabolic syndrome patients. We investigated associations between betaine insufficiency and secondary events in acute coronary syndrome patients. METHODS: Plasma (531) and urine (415) samples were collected four months after discharge following an acute coronary event. Death (34), secondary acute myocardial infarction (MI) (70) and hospital admission for heart failure (45) events were recorded over a median follow-up of 832 days. PRINCIPAL FINDINGS: The highest and lowest quintiles of urinary betaine excretion associated with risk of heart failure (p = 0.0046, p = 0.013 compared with middle 60%) but not with subsequent acute MI. The lowest quintile of plasma betaine was associated with subsequent acute MI (p = 0.014), and the top quintile plasma betaine with heart failure (p = 0.043), especially in patients with diabetes (p<0.001). Top quintile plasma concentrations of dimethylglycine (betaine metabolite) and top quintile plasma homocysteine both associated with all three outcomes, acute MI (p = 0.004, <0.001), heart failure (p = 0.027, p<0.001) and survival (p<0.001, p<0.001). High homocysteine was associated with high or low betaine excretion in >60% of these subjects (p = 0.017). Median NT-proBNP concentrations were lowest in the middle quintile of plasma betaine concentration (p = 0.002). CONCLUSIONS: Betaine insufficiency indicates increased risk of secondary heart failure and acute MI. Its association with elevated homocysteine may partly explain the disappointing results of folate supplementation. In some patients, especially with diabetes, elevated plasma betaine also indicates increased risk.

The contrasting relationships between betaine and homocysteine in two clinical cohorts are associated with plasma lipids and drug treatments.

BACKGROUND: Urinary betaine excretion positively correlated with plasma homocysteine in outpatients attending a lipid disorders clinic (lipid clinic study). We aimed to confirm this in subjects with established vascular disease. METHODS: The correlation between betaine excretion and homocysteine was compared in samples collected from subjects 4 months after hospitalization for an acute coronary episode (ACS study, 415 urine samples) and from 158 sequential patients visiting a lipid disorders clinic. PRINCIPAL FINDINGS: In contrast to the lipid clinic study, betaine excretion and plasma homocysteine did not correlate in the total ACS cohort. Differences between the patient groups included age, non-HDL cholesterol and medication. In ACS subjects with below median betaine excretion, excretion correlated (using log transformed data) negatively with plasma homocysteine (r = -0.17, p = 0.019, n = 199), with no correlation in the corresponding subset of the lipid clinic subjects. In ACS subjects with above median betaine excretion a positive trend (r = +0.10) between betaine excretion and homocysteine was not significant; the corresponding correlation in lipid clinic subjects was r = +0.42 (p = 0.0001). In ACS subjects, correlations were stronger when plasma non-HDL cholesterol and betaine excretion were above the median, r = +0.20 (p = 0.045); in subjects above median non-HDL cholesterol and below median betaine excretion, r = -0.26 (p = 0.012). ACS subjects taking diuretics or proton pump inhibitors had stronger correlations, negative with lower betaine excretion and positive with higher betaine excretion. CONCLUSIONS: Betaine excretion correlates with homocysteine in subjects with elevated blood lipids.

Pharmacokinetic comparison of a generic coenzyme Q10 solubilizate and a formulation with soybean phytosterols.

Coenzyme Q10 (CoQ10) is essential for all cells, and deficiency has been implicated in cardiovascular disease. Plant phytosterols inhibit cholesterol absorption, and may thereby also reduce cardiovascular risk. This study compared the relative bioavailability of CoQ10 solubilized in low-dose soybean phytosterols (SterolQ10) with a generic CoQ10 solubilizate. In a randomized, cross-over design, 36 healthy males received a single 100 mg dose of CoQ10, as SterolQ10 or generic CoQ10, with a two-week washout between treatments. Plasma CoQ10 was analysed at baseline, and at 2, 4, 6, 8 and 10 h after supplement ingestion. Subjects were then administered either 100 mg/day of generic CoQ10 or SterolQ10 for 4 weeks. Fasting plasma CoQ10 levels were measured at baseline and following supplementation. The two preparations were bioequivalent in regard to the area under the curve (AUC(0-10h) ) and maximum increase in concentration (C(max) ), with geometric mean ratios of 0.89 (CI 0.81-0.98) and 0.88 (CI 0.80-0.96), respectively. Four-weeks of CoQ10 resulted in a comparable twofold increase in CoQ10 levels for both formulations (p < 0.001), which was similar between preparations (p = 0.74). The combined CoQ10 and phytosterol formulation, SterolQ10, showed bioequivalence to the generic CoQ10 following a single CoQ10 dose, and demonstrated comparable bioavailability following multiple dose administration.

A randomized, double-blind, placebo-controlled crossover study of coenzyme Q10 therapy in hypertensive patients with the metabolic syndrome.

BACKGROUND: Our aim was to examine the effects of adjunctive coenzyme Q(10) therapy on 24-h ambulatory blood pressure (BP) in subjects with the metabolic syndrome and inadequate BP control. METHODS: In a randomized, double-blind, placebo-controlled 12-week crossover trial, coenzyme Q(10) (100 mg twice daily) or placebo was administrated to 30 subjects with the metabolic syndrome, and inadequate BP control (an average clinic BP of ≥140 systolic mm Hg or ≥130 mm Hg for patients with type 2 diabetes) while taking an unchanged, conventional antihypertensive regimen. Clinic and 24-h ambulatory BP were assessed pre- and post-treatment phases. The primary outcomes were the changes in 24-h systolic and diastolic BP during adjunctive therapy with coenzyme Q(10) vs. placebo and prespecified secondary outcomes included changes in BP loads. RESULTS: Compared with placebo, treatment with coenzyme Q(10) was not associated with statistically significant reductions in systolic (P = 0.60) or diastolic 24-h ambulatory BP (P = 0.12) or heart rate (P = 0.10), although daytime diastolic BP loads, were significantly lower during coenzyme Q(10) administration with thresholds set at >90 mm Hg (P = 0.007) and ≥85 mm Hg (P = 0.03). Coenzyme Q(10) was well tolerated and was not associated with any clinically relevant changes in safety parameters. CONCLUSIONS: Although it is possible that coenzyme Q(10) may improve BP control under some circumstances, any effects are likely to be smaller than reported in previous meta-analyses. Furthermore, our data suggest that coenzyme Q(10) is not currently indicated as adjunctive antihypertensive treatment for patients with the metabolic syndrome whose BP control is inadequate, despite regular antihypertensive therapy.

Plasma lipids and betaine are related in an acute coronary syndrome cohort.

BACKGROUND: Low plasma betaine has been associated with unfavorable plasma lipid profiles and cardiovascular risk. In some studies raised plasma betaine after supplementation is associated with elevations in plasma lipids. We aimed to measure the relationships between plasma and urine betaine and plasma lipids, and the effects of lipid-lowering drugs on these. METHODOLOGY: Fasting plasma samples were collected from 531 subjects (and urine samples from 415) 4 months after hospitalization for an acute coronary syndrome episode. In this cross-sectional study, plasma betaine and dimethylglycine concentrations and urine excretions were compared with plasma lipid concentrations. Subgroup comparisons were made for gender, with and without diabetes mellitus, and for drug treatment. PRINCIPAL FINDINGS: Plasma betaine negatively correlated with triglyceride (Spearman's r(s) = -0.22, p<0.0001) and non-high-density lipoprotein cholesterol (r(s) = -0.27, p<0.0001). Plasma betaine was a predictor of BMI (p<0.05) and plasma non-high-density lipoprotein cholesterol and triglyceride (p<0.001) independently of gender, age and the presence of diabetes. Using data grouped by plasma betaine decile, increasing plasma betaine was linearly related to decreases in BMI (p = 0.008) and plasma non-HDL cholesterol (p = 0.002). In a non-linear relationship betaine was negatively associated with elevated plasma triglycerides (p = 0.004) only for plasma betaine >45 µmol/L. Subjects taking statins had higher plasma betaine concentrations (p<0.001). Subjects treated with a fibrate had lower plasma betaine (p = 0.003) possibly caused by elevated urine betaine loss (p<0.001). The ratio of coenzyme Q to non-high-density lipoprotein cholesterol was higher in subjects with higher plasma betaine, and in subjects taking a statin. CONCLUSION: Low plasma betaine concentrations correlated with an unfavourable lipid profile. Betaine deficiency may be common in the study population. Controlled clinical trials of betaine supplementation should be conducted in appropriate populations to determine whether correction affects cardiovascular risk.

Relationship between plasma coenzyme Q10, asymmetric dimethylarginine and arterial stiffness in patients with phenotypic or genotypic familial hypercholesterolemia on long-term statin therapy.

OBJECTIVE: We investigated whether statin-treated heterozygous familial hypercholesterolemic (FH) patients have lower plasma coenzyme Q(10) (CoQ(10)) levels than low-density lipoprotein receptor (LDLR) mutation negative FH patients on equivalent statin doses, and whether lower CoQ(10) concentrations are associated with increased arterial stiffness. METHODS: Thirty LDLR mutation negative patients with clinical FH and 30 mutation positive FH patients matched for gender, statin duration and dose, and a further 30 controls were studied. Plasma CoQ(10) and asymmetric dimethylarginine (ADMA) levels were measured by HPLC and the augmentation index by pulse wave analysis. RESULTS: Plasma CoQ(10) levels, and the ratios of CoQ(10) to total cholesterol and LDL-cholesterol were similar in treated FH patients with identified LDLR mutations to mutation negative patients on equivalent doses of statin therapy (p>0.05). CoQ(10) and lipid levels were also comparable to controls not using any lipid modifying treatment. Arterial stiffness was higher in mutation negative patients (p=0.04) and there was a trend for an increase in mutation positive patients (p=0.09). ADMA was higher in the mutation positive group (p<0.01). The augmentation index corrected for age, blood pressure, and heart rate, was negatively correlated with plasma CoQ(10) within FH patients (p<0.05). CONCLUSION: Long-term, high-dose statin therapy does not lead to subnormal CoQ(10) concentrations in patients with phenotypic or genotypic FH. Arterial stiffness is elevated in FH patients compared to untreated controls, and low CoQ(10) levels are associated with increased arterial stiffness. CoQ(10) supplementation trials are warranted in FH patients.

Coenzyme Q10; an adjunctive therapy for congestive heart failure?

Coenzyme Q10 (CoQ10) is essential for electron transport within the mitochondria and hence for ATP generation and cellular energy production. We recently demonstrated that plasma levels of CoQ10 are an independent predictor of survival in a cohort of 236 patients with chronic heart failure (CHF) followed for a median of 2.69 years. This is consistent with previous studies which have shown myocardial CoQ10 depletion in CHF, and correlated with the severity of the underlying disorder. Several intervention studies have been undertaken with CoQ10 in CHF, including randomized controlled trials with mostly positive outcomes in relation to improvement in plasma levels of CoQ10. A meta-analysis showed that CoQ10 resulted in an improvement in ejection fraction of 3.7% (95%CI 1.59-5.77) and the mean increase in cardiac output was 0.28 L/minute (95%CI 0.03-0.53). In a subgroup analysis, studies with patients not taking ACE inhibitors found a 6.7% increase in ejection fraction. The ongoing Q-SYMBIO trial will address whether CoQ10 supplementation improves survival in CHF patients. CoQ10 depletion may also be a contributory factor for why statin intervention has not improved outcomes in CHF. There is an emerging evidence base in support of CoQ10 as an adjunctive therapy in CHF.

Coenzyme Q10: an independent predictor of mortality in chronic heart failure.

OBJECTIVES: The aim of this study was to investigate the relationship between plasma coenzyme Q(10) (CoQ(10)) and survival in patients with chronic heart failure (CHF). BACKGROUND: Patients with CHF have low plasma concentrations of CoQ(10), an essential cofactor for mitochondrial electron transport and myocardial energy supply. Additionally, low plasma total cholesterol (TC) concentrations have been associated with higher mortality in heart failure. Plasma CoQ(10) is closely associated with low-density lipoprotein cholesterol (LDL-C), which might contribute to this association. Therefore we tested the hypothesis that plasma CoQ(10) is a predictor of total mortality in CHF and could explain this association. METHODS: Plasma samples from 236 patients admitted to the hospital with CHF, with a median (range) duration of follow-up of 2.69 (0.12 to 5.75) years, were assayed for LDL-C, TC, and total CoQ(10). RESULTS: Median age at admission was 77 years. Median (range) CoQ(10) concentration was 0.68 (0.18 to 1.75) micromol/l. The optimal CoQ(10) concentration for prediction of mortality (established with receiver-operator characteristic [ROC] curves) was 0.73 micromol/l. Multivariable analysis allowing for effects of standard predictors of survival--including age at admission, gender, previous myocardial infarction, N-terminal peptide of B-type natriuretic peptide, and estimated glomerular filtration rate (modification of diet in renal disease)--indicated CoQ(10) was an independent predictor of survival, whether dichotomized at the ROC curve cut-point (hazard ratio [HR]: 2.0; 95% confidence interval [CI]: 1.2 to 3.3) or the median (HR: 1.6; 95% CI: 1.0 to 2.6). CONCLUSIONS: Plasma CoQ(10) concentration was an independent predictor of mortality in this cohort. The CoQ(10) deficiency might be detrimental to the long-term prognosis of CHF, and there is a rationale for controlled intervention studies with CoQ(10).

Coenzyme Q10: is there a clinical role and a case for measurement?

Coenzyme Q(10) (CoQ(10)) is an essential cofactor in the mitochondrial electron transport pathway, and is also a lipid-soluble antioxidant. It is endogenously synthesised via the mevalonate pathway, and some is obtained from the diet. CoQ(10) supplements are available over the counter from health food shops and pharmacies. CoQ(10) deficiency has been implicated in several clinical disorders, including but not confined to heart failure, hypertension, Parkinson's disease and malignancy. Statin, 3-hydroxy-3- methyl-glutaryl (HMG)-CoA reductase inhibitor therapy inhibits conversion of HMG-CoA to mevalonate and lowers plasma CoQ(10) concentrations. The case for measurement of plasma CoQ(10) is based on the relationship between levels and outcomes, as in chronic heart failure, where it may identify individuals most likely to benefit from supplementation therapy. During CoQ(10) supplementation plasma CoQ(10) levels should be monitored to ensure efficacy, given that there is variable bioavailability between commercial formulations, and known inter-individual variation in CoQ(10) absorption. Knowledge of biological variation and reference change values is important to determine whether a significant change in plasma CoQ(10) has occurred, whether a reduction for example following statin therapy or an increase following supplementation. Emerging evidence will determine whether CoQ(10) does indeed have an important clinical role and in particular, whether there is a case for measurement.

Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia.

Myalgia is the most frequently reported adverse side effect associated with statin therapy and often necessitates reduction in dose, or the cessation of therapy, compromising cardiovascular risk management. One postulated mechanism for statin-related myalgia is mitochondrial dysfunction through the depletion of coenzyme Q(10), a key component of the mitochondrial electron transport chain. This pilot study evaluated the effect of coenzyme Q(10) supplementation on statin tolerance and myalgia in patients with previous statin-related myalgia. Forty-four patients were randomized to coenzyme Q(10) (200 mg/day) or placebo for 12 weeks in combination with upward dose titration of simvastatin from 10 mg/day, doubling every 4 weeks if tolerated to a maximum of 40 mg/day. Patients experiencing significant myalgia reduced their statin dose or discontinued treatment. Myalgia was assessed using a visual analogue scale. There was no difference between combined therapy and statin alone in the myalgia score change (median 6.0 [interquartile range 2.1 to 8.8] vs 2.3 [0 to 12.8], p = 0.63), in the number of patients tolerating simvastatin 40 mg/day (16 of 22 [73%] with coenzyme Q(10) vs 13 of 22 [59%] with placebo, p = 0.34), or in the number of patients remaining on therapy (16 of 22 [73%] with coenzyme Q(10) vs 18 of 22 [82%] with placebo, p = 0.47). In conclusion, coenzyme Q(10) supplementation did not improve statin tolerance or myalgia, although further studies are warranted.

Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure.

Although not currently indicated for chronic heart failure (CHF), statins have been associated with improved outcome in retrospective analysis. However, statin therapy reduces plasma levels of coenzyme Q(10) (ubiquinone), which may have adverse effects on heart failure states. We hypothesized that atorvastatin treatment improves endothelial function in patients with chronic heart failure independent of LDL-cholesterol alterations. Furthermore, we assessed how reductions in coenzyme Q(10) levels impact on potentially improved endothelial function. Twenty-four patients with stable, symptomatic heart failure (New York Heart Association Class II or III) and a left ventricular ejection fraction <40% were randomised to 40 mg atorvastatin or placebo for 6 weeks and crossed over to the other treatment arm for a further 6 weeks, after a 2-week wash out. Forearm resistance vessel function was assessed by venous occlusion plethysmography during infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and N(G)-monomethyl-L-arginine (L-NMMA) into the brachial artery. Atorvastatin treatment lowered triglycerides, LDL-cholesterol and coenzyme Q(10) levels (all p<0.001) and improved endothelium-dependent vasodilatation during acetylcholine infusion (p=0.015). Endothelium-dependent forearm blood flow improvements correlated with reductions in coenzyme Q(10) levels (p=0.011), but not with LDL-cholesterol levels (p=0.084). Coenzyme Q(10) remained the significant variable predicting improvement in NO dependent endothelial function after adjusting for LDL-cholesterol levels (p=0.041). In conclusion, short-term atorvastatin therapy improved endothelial function in chronic heart failure patients. Further studies are required to determine whether coenzyme Q(10) reductions are limiting the maximum favourable effects of statin therapy on the microcirculation.

An investigation of the antioxidant properties and colour of glasshouse grown tomatoes.

The colour and the antioxidant content of five different cultivars of tomatoes (Lycopersicon esculentum L.), grown in glasshouses using commercial hydroponic techniques, were measured in freshly harvested tomatoes and after 2 and 5 days of storage in the dark at 15 degrees C. The two cocktail cultivars of tomatoes, Aranca and Flavourine, were the smallest tomatoes but they contained higher dry matter contents compared with the three standard salad cultivars, Excell, Celero and Dutch Chaser. There were significant differences (P < 0.001) in lycopene (the major carotenoid), ascorbic acid and total antioxidant activity in the whole fruit of the five different cultivars evaluated at harvest, while the total phenolic contents were very similar. The lycopene levels of all the cultivars increased significantly (P < 0.001) after storage for 2 and 5 days at 15 degrees C. Overall, the total phenolic content of all the cultivars did not change appreciably after storage at 15 degrees C while the levels of ascorbic acid fell by 12.6% when stored for 5 days in the dark. There was a significant difference (P < 0.001) in the total antioxidant activity between the five different cultivars when freshly harvested; the highest levels of total antioxidant activity were observed in the two cocktail cultivars, Aranca and Flavourine. Antioxidant activity showed different patterns of change depending on cultivar. An increase in the total antioxidant values could be seen in cultivars Dutch chaser and Excell, after storage for 5 days at 15 degrees C. The total antioxidant activity values of Flavourine and Celero fell on storage while the values for stored Aranca were very similar to the values when freshly harvested. The skin colour, as shown by Commission Internationale l'Eclairage (CIE) L*a*b* values of each cultivar were markedly different at harvest even though each cultivar was harvested at the same maturity. The a* value of each cultivar increased significantly (P < 0.001) when they were stored in the dark, for either 2 or 5 days, at 15 degrees C. Regression analysis showed that overall there was no significant relationship (R(2) = 0.14) between the lycopene content and the a* value of all the tomatoes; however, when examined individually, the two cocktail tomatoes Aranca and Flavourine showed strong correlation-R(2) = 0.96 and R(2) = 0.97, respectively. Overall, the (a*/b*)(2) was the most reliable indicator of lycopene concentration (R(2) = 0.96) in the tomatoes examined in this study.