Stroke is the leading cause of death in China and second leading cause of death in the world.¹ Primary prevention is particularly important because about 77% of strokes are first events.² Uncertainty remains regarding the efficacy of folic acid therapy for primary prevention of stroke because of limited and inconsistent data.³

Background and Purpose—: Trimethylamine N-oxide (TMAO)—a gut derived metabolite—has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods—: We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results—: After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02–1.46). Consistently, compared with participants in the lowest tertile (<1.79 μmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 μmol/L; odds ratio, 1.34; 95% CI, 1.00–1.81) or in TMAO tertile 3 (≥3.19 μmol/L; odds ratio, 1.43; 95% CI, 1.02–2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions—: Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration—: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.

Chronic kidney disease (CKD) is a worldwide public health problem leading to poor outcomes and high cost;¹ CKD substantially increases the risk of progression to end-stage renal disease (ESRD) and cardiovascular disease (CVD).^2,3 It is estimated that more than 119 million Chinese people have CKD and are at high risk of developing ESRD.⁴ Antihypertensive therapy, especially aimed at inhibiting the renin-angiotensin system, remains the mainstay of treatment for slowing down renal function decline.⁵ However, despite treatment, the number of patients with ESRD and treated with renal replacement therapy continues to increase.^6,7 New therapeutic interventions that slow down the decline in renal function in patients with CKD are critically needed.

Background: Studies on the prospective association of body composition with mortality in US general populations are limited. We aimed to examine this association by utilizing data from the National Health and Nutrition Examination Survey (NHANES), a representative sample of US adults, linked with data from the National Death Index.Methods: We analysed data of NHANES 1988–1994 and 1999–2014, with 55 818 participants [50.6% female, baseline mean age: 45.0 years (SE, 0.2)]. Predicted fat mass and lean mass were calculated using the validated sex‐specific anthropometric prediction equations developed by the NHANES based on individual age, race, height, weight, and waist circumference. Body composition and other covariates were measured at only one time point. Multivariable Cox regression was used to investigate the associations of predicted fat mass and lean mass with overall and cause‐specific mortality, adjusting for potential confounders. Interactions between age and body composition on mortality were examined with likelihood ratio testing.Results: Mean predicted fat mass was 24.1 kg [95% confidence interval (CI): 23.9–24.3) for male participants and 29.9 kg (95% CI: 29.6–30.1) for female participants, while mean predicted lean mass was 59.3 kg (95% CI: 59.1–59.5) for male participants and 41.7 kg (95% CI: 41.5–41.8) for female participants. During a median period of 9.7 years from the survey, 10 408 deaths occurred. When predicted fat and lean mass were both included in the model, predicted fat mass showed a U‐shaped association with all‐cause mortality, with significantly higher risk at two ends: Quintile 1 (HR, 1.17; 95% CI: 1.05–1.31), Quintile 2 (HR, 1.14; 95% CI: 1.04–1.26) and Quintile 5 (HR, 1.37; 95% CI: 1.12–1.68) compared with Quintile 3. In contrast, predicted lean mass showed a L‐shaped association with all‐cause mortality, with higher mortality in those with lower lean mass: Quintile 1 (HR, 1.64; 95% CI: 1.46–1.83) and Quintile 2 (HR, 1.29; 95% CI: 1.18–1.42) compared with Quintile 3. Similar results were found for cardiovascular, cancer, and respiratory cause‐specific mortality. Age was a significant modifier: There was a monotonic positive association of predicted fat mass with mortality in younger participants (<60 years), but an approximate J‐shaped association in older participants (≥60 years) (P interaction <0.001); there was a stronger inverse association between predicted lean mass and mortality in older participants (≥60) compared with those <60 years (P interaction <0.001).Conclusions: In this US general population, predicted fat mass and lean mass were independent predictors for overall and cause‐specific mortality. Age was a significant modifier on the associations.

Background and Purpose—: Elevated blood homocysteine concentration increases the risk of stroke, especially among hypertensive individuals. Homocysteine is largely affected by the methylenetetrahydrofolate reductase C677T polymorphism and folate status. Among hypertensive patients, we aimed to test the hypothesis that the association between homocysteine and stroke can be modified by the methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention. Methods—: We analyzed the data of 20 424 hypertensive adults enrolled in the China Stroke Primary Prevention Trial. The participants, first stratified by methylenetetrahydrofolate reductase genotype, were randomly assigned to receive double-blind treatments of 10-mg enalapril and 0.8-mg folic acid or 10-mg enalapril only. The participants were followed up for a median of 4.5 years. Results—: In the control group, baseline log-transformed homocysteine was associated with an increased risk of first stroke among participants with the CC/CT genotype (hazard ratio, 3.1; 1.1–9.2), but not among participants with the TT genotype (hazard ratio, 0.7; 0.2–2.1), indicating a significant gene–homocysteine interaction ( P =0.008). In the folic acid intervention group, homocysteine showed no significant effect on stroke regardless of genotype. Consistently, folic acid intervention significantly reduced stroke risk in participants with CC/CT genotypes and high homocysteine levels (tertile 3; hazard ratio, 0.73; 0.55–0.97). Conclusions—: In Chinese hypertensive patients, the effect of homocysteine on the first stroke was significantly modified by the methylenetetrahydrofolate reductase C677T genotype and folic acid supplementation. Such information may help to more precisely predict stroke risk and develop folic acid interventions tailored to individual genetic background and nutritional status. Clinical Trial Registration—: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00794885.