Methylmalonic acid, vitamin B12, and mortality risk in patients with preexisting coronary heart disease: a prospective cohort study.

BACKGROUND: The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD. METHODS: The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk. RESULTS: Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31-2.20) for all-cause mortality, and 2.00 (1.39-2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001). CONCLUSION: MMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.

Cardiac-targeted delivery of nuclear receptor RORα via ultrasound targeted microbubble destruction optimizes the benefits of regular dose of melatonin on sepsis-induced cardiomyopathy.

BACKGROUND: Large-dose melatonin treatment in animal experiments was hardly translated into humans, which may explain the dilemma that the protective effects against myocardial injury in animal have been challenged by clinical trials. Ultrasound-targeted microbubble destruction (UTMD) has been considered a promising drug and gene delivery system to the target tissue. We aim to investigate whether cardiac gene delivery of melatonin receptor mediated by UTMD technology optimizes the efficacy of clinically equivalent dose of melatonin in sepsis-induced cardiomyopathy. METHODS: Melatonin and cardiac melatonin receptors in patients and rat models with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis were assessed. Rats received UTMD-mediated cardiac delivery of RORα/cationic microbubbles (CMBs) at 1, 3 and 5 days before CLP surgery. Echocardiography, histopathology and oxylipin metabolomics were assessed at 16-20 h after inducing fatal sepsis. RESULTS: We observed that patients with sepsis have lower serum melatonin than healthy controls, which was observed in the blood and hearts of Sprague-Dawley rat models with LPS- or CLP-induced sepsis. Notably, a mild dose (2.5 mg/kg) of intravenous melatonin did not substantially improve septic cardiomyopathy. We found decreased nuclear receptors RORα, not melatonin receptors MT1/2, under lethal sepsis that may weaken the potential benefits of a mild dose of melatonin treatment. In vivo, repeated UTMD-mediated cardiac delivery of RORα/CMBs exhibited favorable biosafety, efficiency and specificity, significantly strengthening the effects of a safe dose of melatonin on heart dysfunction and myocardial injury in septic rats. The cardiac delivery of RORα by UTMD technology and melatonin treatment improved mitochondrial dysfunction and oxylipin profiles, although there was no significant influence on systemic inflammation. CONCLUSIONS: These findings provide new insights to explain the suboptimal effect of melatonin use in clinic and potential solutions to overcome the challenges. UTMD technology may be a promisingly interdisciplinary pattern against sepsis-induced cardiomyopathy.

Effects of omega-3 fatty acid on major cardiovascular outcomes: A systematic review and meta-analysis.

BACKGROUND: The effects of omega-3 fatty acid on cardiovascular health obtained inconsistent results. A systematic review and meta-analysis were therefore conducted to assess the effects of omega-3 fatty acid supplementation for primary and secondary prevention strategies of major cardiovascular outcomes. METHODS: The databases of PubMed, Embase, and the Cochrane library were systematically searched from their inception until September 2020. Relative risks (RRs) with 95% confidence intervals were used to assess effect estimates by using the random-effects model. RESULTS: Twenty-eight randomized controlled trials involving 136,965 individuals were selected for the final meta-analysis. Omega-3 fatty acid was noted to be associated with a lower risk of major cardiovascular events (RR, 0.94; 95% CI, 0.89-1.00; P = .049) and cardiac death (RR, 0.92; 95% CI, 0.85-0.99; P = .022). However, no significant differences was noted between omega-3 fatty acid and the control for the risks of all-cause mortality (RR, 0.97; 95% CI, 0.92-1.03; P = .301), myocardial infarction (RR, 0.90; 95% CI, 0.80-1.01; P = .077), and stroke (RR, 1.02; 95% CI, 0.94-1.11; P = .694). CONCLUSIONS: Major cardiovascular events and cardiac death risks could be avoided with the use of omega-3 fatty acid. However, it has no significant effects on the risk of all-cause mortality, myocardial infarction, and stroke.

Cobalamin Intake and Related Biomarkers: Examining Associations With Mortality Risk Among Adults With Type 2 Diabetes in NHANES.

OBJECTIVE: Despite that periodical monitoring of cobalamin (vitamin B12) in metformin-treated patients with diabetes is recommended, cobalamin-associated mortality benefits or risks remain unclear. We investigated the association between cobalamin intake and related biomarkers and mortality risk in adults with diabetes using metformin or not. RESEARCH DESIGN AND METHODS: This study included 3,277 adults with type 2 diabetes from the National Health and Nutrition Examination Survey (NHANES) and followed up until 31 December 2015. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mortality risk. RESULTS: Among 3,277 participants, 865 all-cause deaths occurred during a median follow-up of 7.02 years. There was no robust relationship between all-cause mortality and serum cobalamin or intake of foods or cobalamin supplements, regardless of metformin treatment (each P ≥ 0.120). The doubling of methylmalonic acid (MMA), a cobalamin-deficiency marker, was significantly associated with higher all-cause (HR 1.31 [95% CI 1.18-1.45], P < 0.001) and cardiac (HR 1.38 [95% CI 1.14-1.67], P = 0.001) mortality. Cobalamin sensitivity was assessed by the combination of binary B12low/high and MMAlow/high (cutoff values: cobalamin 400 pg/mL, MMA 250 nmol/L). Patients with decreased cobalamin sensitivity (MMAhighB12high) had the highest mortality risk. The multivariable-adjusted HRs (95% CIs) of all-cause mortality in MMAlowB12low, MMAlowB12high, MMAhighB12low, and MMAhighB12high groups were 1.00 (reference), 0.98 (0.75-1.28), 1.49 (1.16-1.92), and 1.96 (1.38-2.78), respectively. That association was especially significant in metformin nonusers. CONCLUSIONS: Serum and dietary cobalamin were not associated with reduced mortality. Decreased cobalamin sensitivity was significantly associated with all-cause and cardiac mortality, particularly among metformin nonusers.