Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy).

BACKGROUND: While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes. METHODS: This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment. RESULTS: The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0-1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2-1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering. CONCLUSIONS: This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg. GOV IDENTIFIER: NCT03472508 (Registration Date: March 21, 2018).

Relationship of serum copper and zinc with kidney function and urinary albumin to creatinine ratio: Cross-sectional data from the NHANES 2011-2016.

BACKGROUND & OBJECTIVE: Chronic kidney disease (CKD) is a common condition in worldwide with underlying causes. The role of trace elements such as copper and zinc in CKD is uncertain. We aimed to examine the relationship of serum copper and zinc with kidney function status and explore its possible effect modifiers in the general population. METHODS: Data from 5353 National Health and Nutrition Examination Survey (NHANES) participants from 2011 to 2016 were analyzed for the role of trace elements in the age range 18 to 80 years. The kidney outcomes were reduced estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and increased urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g. RESULTS: Findings showed a significant positive association between serum copper and urinary ACR (OR = 1.04, 95% CI = 1.00-1.07). Serum copper levels of 18.0 µmol/L (median) or higher (reference level <18.0 µmol/L) were significantly associated with increased urinary ACR (OR = 1.67, 95% CI = 1.21-2.31) after adjusting for confounding factors. In contrast, there was a significant inverse association between serum zinc and reduced eGFR (OR = 0.89,95% CI = 0.81-0.99). Where serum zinc level was greater than 12.3 µmol/L (median), the prevalence of reduced eGFR was lower (OR = 0.65, 95% CI = 0.16-0.60). In addition, a stratified analysis based on various risk factors found that in those individuals with serum albumin greater than 43 g/L or systolic blood pressure greater than 120 mmHg, positive correlations between serum copper and risk of increased urinary ACR was more significant. CONCLUSIONS: Our findings suggest that the reference levels of serum copper and zinc levels in healthy individuals may be different from current understanding. If further studies substantiate the same, the results will be a useful guide for designing future clinical trials and nutritional guidelines.

Association Between White Blood Cell Counts and Brachial-Ankle Pulse Wave Velocity in Chinese Hypertensive Adults: A Cross-Sectional Study.

Increased arterial stiffness is highly prevalent in patients with hypertension and is associated with cardiovascular (CV) risk. Increased white blood cell (WBC) counts may also be an independent risk factor for arterial stiffness and CV events. The aim of the study was to investigate the relationship between differential WBC counts and brachial-ankle pulse wave velocity (baPWV) in hypertensive adults. A total of 14 390 participants were included in the final analysis. A multivariate linear regression model was applied for the correlation analysis of WBC count and baPWV. Higher WBC counts were associated with a greater baPWV: adjusted ß = 10 (95% CI, 8-13, P < .001). The same significant association was also found when WBC count was assessed as categories or quartiles. In addition, the effect of differential WBC subtypes, including neutrophil count and lymphocyte count on baPWV, showed the similar results. These findings showed that baPWV has positive associations with differential WBC counts in hypertensive adults.

Positive relationship of hypertensive retinopathy with carotid intima--media thickness in hypertensive patients.

OBJECTIVES: We aimed to explore the relationship of hypertensive retinopathy with carotid intima--media thickness (CIMT), and to examine the possible effect modifiers in Chinese adults with hypertension. METHODS: We conducted a cross-sectional study of 12 342 hypertensive patients with complete exit site visit data from the China Stroke Primary Prevention Trial. CIMT was measured by carotid ultrasonography. Hypertensive retinopathy was diagnosed according to the Keith--Wagener--Barker classification. RESULTS: The mean (SD) CIMT among study participants was 739.9 (111.4) µm. Compared with patients with grade 1 hypertensive retinopathy or without hypertensive retinopathy, a significantly higher CIMT level (ß, 7.63, 95% CI: 2.54--12.73) was observed in patients with grade 2-4 hypertensive retinopathy. Moreover, the association between hypertensive retinopathy (grade 2-4 versus grade 1 or normal) and CIMT was stronger in participants of younger age (<60 years; ß, 13.70, 95% CI: 5.65--21.75; versus ≥60 years; ß, 1.03, 95% CI: -5.58 to 7.63; P interaction = 0.006); or with lower total homocysteine levels [<12.1 µmol/l (median); ß, 12.70, 95% CI: 5.98--19.42; versus ≥12.1 µmol/l; ß, 2.07, 95% CI: -5.63 to 9.78; P interaction = 0.030). None of the other variables, including sex, BMI, study centers, treatment group, SBP, triglycerides, total cholesterol, fasting blood glucose, folate, serum creatinine, current smoking and alcohol drinking, significantly modified the relation of hypertensive retinopathy with CIMT levels. CONCLUSION: Hypertensive retinopathy (grade 2 and higher) was significantly associated with increased CIMT in hypertensive patients. The association was stronger in those of younger age or with lower total homocysteine levels.

Plasma magnesium and the risk of new-onset hyperuricaemia in hypertensive patients.

We aimed to evaluate the relationship of plasma Mg with the risk of new-onset hyperuricaemia and examine any possible effect modifiers in hypertensive patients. This is a post hoc analysis of the Uric acid (UA) Sub-study of the China Stroke Primary Prevention Trial (CSPPT). A total of 1685 participants were included in the present study. The main outcome was new-onset hyperuricaemia defined as a UA concentration ≥417 µmol/l in men or ≥357 µmol/l in women. The secondary outcome was a change in UA concentration defined as UA at the exit visit minus that at baseline. During a median follow-up duration of 4·3 years, new-onset hyperuricaemia occurred in 290 (17·2 %) participants. There was a significantly inverse relation of plasma Mg with the risk of new-onset hyperuricaemia (per sd increment; OR 0·85; 95 % CI 0·74, 0·99) and change in UA levels (per sd increment; ß -3·96 µmol/l; 95 % CI -7·14, -0·79). Consistently, when plasma Mg was analysed as tertiles, a significantly lower risk of new-onset hyperuricaemia (OR 0·67; 95 % CI 0·48, 0·95) and less increase in UA levels (ß -8·35 µmol/l; 95 % CI -16·12, -0·58) were found among participants in tertile 3 (≥885·5 µmol/l) compared with those in tertile 1 (<818·9 µmol/l). Similar trends were found in males and females. Higher plasma Mg levels were associated with a decreased risk of new-onset hyperuricaemia in hypertensive adults.

U-shaped association between serum albumin and development of chronic kidney disease in general hypertensive patients.

BACKGROUND & AIMS: We aimed to examine the association between serum albumin (SAlb) and the development of chronic kidney disease (CKD), and examine any possible effect modifiers in general hypertensive patients with normal renal function and with no previous cardiovascular diseases (CVD). METHODS: This is a post-hoc analysis (performed at May, 2018) of 12,621 hypertensive adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and SAlb ≥35.0 g/L from the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT), conducted from May 2008 to August 2013. The primary outcome was development of CKD, defined as a decrease in eGFR of ≥30% and to a level of <60 mL/min/1.73 m2; or end stage renal disease. RESULTS: The median follow-up duration was 4.4 years. Overall, the association between SAlb levels and risk of the primary outcome followed a U-shape. The risk of CKD development significantly decreased with the increment of SAlb (per g/L: OR = 0.92; 95% CI: 0.88-0.96) in participants with SAlb <51.4 g/L, and increased with the increment of SAlb (per g/L: OR = 1.06; 95%CI: 1.01-1.11) in participants with SAlb ≥51.4 g/L. Moreover, in participants with SAlb <51.4 g/L, the association between SAlb and CKD development remained significant in participants without proteinuria (per g/L: OR = 0.93; 95% CI: 0.88-0.99). The association between SAlb and CKD development was not significantly modified by age, sex, folic acid treatment, proteinuria, systolic blood pressure (SBP) at baseline and time-averaged SBP during the treatment period (all P-interactions>0.05). CONCLUSIONS: There was a U-shaped association between SAlb levels and risk of CKD development among general hypertensive patients with normal renal function and without CVD, with a turning point at about 51.4 g/L.

Plasma selenium levels and risk of new-onset diabetes in hypertensive adults.

OBJECTIVE: The association between plasma selenium and new-onset diabetes in hypertensive adults is still unclear. We aimed to evaluate the relationship of baseline plasma selenium with new-onset diabetes and examine possible effect modifiers in a post-hoc analysis of the China Stroke Primary Prevention Trial (CSPPT). METHODS: A total of 2367 hypertensive, non-diabetic patients with plasma selenium measurements at baseline were included. The primary outcome was new-onset diabetes, defined as physician-diagnosed diabetes or use of glucose-lowering drugs during the follow-up period, or fasting glucose (FG) ≥126.0 mg/dL at the exit visit. RESULTS: At baseline, higher FG levels were found among participants with plasma selenium in quartile 4 (≥94.8 µg/L) (ß, 1.64 mg/dL; 95%CI: 0.54, 2.73) compared to those in quartiles 1-3. During a median follow-up duration of 4.5 years, new-onset diabetes occurred in 270 (11.4%) participants. Graphic plot showed a positive association between baseline selenium levels and risk of new-onset diabetes. This was further confirmed by adjusted regression analyses; the odds ratios (OR) for new-onset diabetes comparing quartile 4 (≥94.8 µg/L) to quartiles 1-3 was 1.36 (95%CI: 1.01, 1.83). No clear trend was evident across quartiles 1-3. CONCLUSIONS: Our data suggest that high plasma selenium (≥94.8 µg/L) was associated with increased risk of new-onset diabetes in hypertensive patients.

Plasma copper and the risk of first stroke in hypertensive patients: a nested case-control study.

BACKGROUND: Previous studies indicated that trace elements may play an important role in cardiovascular diseases. However, data concerning the association between blood copper and the risk of stroke are limited. OBJECTIVE: The aim of this study was to evaluate the association between plasma copper and the risk of first stroke, and examine any possible effect modifiers in hypertensive patients. METHODS: We conducted a nested case-control study, using data from the China Stroke Primary Prevention Trial. Hypertension is defined as systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg, or taking antihypertensive medication. A total of 618 first stroke cases and 618 controls matched for age, sex, treatment group, and study site were included in this study. The crude and adjusted risks of first stroke were estimated by ORs and 95% CIs using conditional logistic regression, without or with adjusting for pertinent covariates, respectively. RESULTS: There were significant positive associations of plasma copper with risk of first stroke (per SD increment-OR: 1.20; 95% CI: 1.03, 1.39) and first ischemic stroke (OR: 1.26; 95% CI: 1.07, 1.50). When plasma copper was categorized in quartiles, significantly higher risks of first stroke (OR: 1.72; 95% CI: 1.12, 2.65) and first ischemic stroke (OR: 1.91; 95% CI: 1.18, 3.11) were found in participants in quartile 4 (≥ 117.0 µg/dL) than in those in quartile 1 (< 91.2 µg/dL). Furthermore, the plasma copper-first stroke association was significantly stronger in participants with higher BMI (< 25.0 compared with ≥ 25.0 kg/m2, P-interaction = 0.024). However, there was no significant association between plasma copper and first hemorrhagic stroke. CONCLUSIONS: In Chinese hypertensive patients, there was a significant positive association between baseline plasma copper and the risk of first stroke, especially among those with higher BMI.This trial was registered at clinicaltrials.gov as NCT00794885.

Serum Phosphate and the Risk of New-Onset Hyperuricemia in Hypertensive Patients.

The relationship of serum phosphate and new-onset hyperuricemia remains uncertain. We aimed to evaluate the relationship of serum phosphate with the risk of new-onset hyperuricemia, and to examine any possible effect modifiers in hypertensive patients. This is a post hoc analysis of the Uric Acid substudy of the CSPPT (China Stroke Primary Prevention Trial). A total of 10 612 participants with normal uric acid levels (<357 µmol/L [6 mg/dL]) at baseline were included in the current study. The primary outcome was new-onset hyperuricemia, which was defined as a uric acid concentration ≥417 µmol/L (7 mg/dL) in men or ≥357 µmol/L (6 mg/dL) in women. During a median follow-up of 4.4 years, 1663 (15.7%) participants developed new-onset hyperuricemia. Overall, there was a significant inverse association between serum phosphate and the risk of new-onset hyperuricemia (per SD increment; odds ratio, 0.71; 95% CI, 0.66-0.76). When serum phosphate was assessed as quartiles, a significantly lower risk of new-onset hyperuricemia was found in participants in quartile 4 (≥1.4 mmol/L; odds ratio, 0.48; 95% CI, 0.40-0.57) compared with those in quartile 1 (<1.2 mmol/L). Similar results were found in males and females. In summary, there was an inverse association between serum phosphate and the risk of new-onset hyperuricemia in hypertensive adults.

Serum Lipids and Risk of Rapid Renal Function Decline in Treated Hypertensive Adults With Normal Renal Function.

BACKGROUND: We aim to evaluate the effect of different lipids parameters, including triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), the TG to HDL-C (TG:HDL-C) ratio, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), on the risk of rapid renal function decline and examine any possible effect modifiers in general hypertensive patients with normal renal function. METHODS: A total of 12,549 hypertensive patients with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 in the renal sub-study of the China Stroke Primary Prevention Trial were included in the analyses. The primary outcome was rapid renal function decline, defined as an average decline in eGFR ≥ 5 ml/min/1.73 m2 per year. RESULTS: The median treatment duration was 4.4 years. After the full adjustment for TC, TG, HDL-C, and other major covariates, a significantly higher risk of rapid renal function decline was found in participants with higher TG [≥150 vs. <150 mg/dl, 7.7% vs. 5.5%; odds ratios (OR): 1.27; 95% confidence interval (CI): 1.06-1.51], higher TG:HDL-C ratio [≥2.7 (median) vs. <2.7, 7.7% vs. 5.0%; OR: 1.39; 95% CI: 1.14-1.71), lower TC (≥200 vs. <200 mg/dl, 6.0% vs. 7.0%; OR: 0.79; 95% CI: 0.67-0.93), or lower LDL-C levels (≥130 vs. <130 mg/dl, 6.1% vs. 7.0%; OR: 0.79; 95% CI: 0.67-0.94). Moreover, the increased risk of the primary outcome associated with elevated TG was particularly evident among individuals with lower total homocysteine levels [<12.4 (median) vs. ≥ 12.4 µmol/l, P interaction = 0.036]. CONCLUSIONS: Higher TG and TG:HDL-C ratio were independent risk factors for rapid renal function decline in hypertensive adults with normal renal function.

BMI is associated with the development of chronic kidney diseases in hypertensive patients with normal renal function.

OBJECTIVE: We aimed to investigate the relationship of BMI and waist circumference with the development of chronic kidney disease (CKD). METHODS: A total of 12 672 hypertensive patients with estimated glomerular filtration rate (eGFR) at least 60 ml/min per 1.73 m from the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT) were included. The primary outcome was the development of CKD, defined as a decrease in eGFR of at least 30% and to a level of less than 60 ml/min per 1.73 m at the exit visit, or end-stage renal disease. A secondary outcome was rapid renal function decline, defined as an average decline in eGFR of at least 5 ml/min/1.73 m per year. RESULTS: Over a median follow-up of 4.4 years, the risk of the primary event (per 1 kg/m increment; OR = 1.07, 95% CI 1.02-1.14) or rapid renal function decline (per 1 kg/m increment; OR = 1.05, 95% CI 1.01-1.08) increased with each increment of BMI. Consistently, compared with those with normal weight (BMI <24.0 kg/m), participants with obesity (BMI ≥28.0 kg/m) had an increased risk of the primary event (OR = 1.82; 95% CI 1.15-2.90) and rapid renal function decline (OR = 1.26; 95% CI 0.95-1.67). However, waist circumference had no obvious effect on the risk of the primary event (per 5 cm increment: OR = 0.94, 95% CI 0.85-1.04) or rapid renal function decline (OR = 0.96, 95% CI 0.90-1.03). CONCLUSION: Higher BMI, but not waist circumference, was significantly associated with an increased risk of CKD development in hypertensive patients with normal kidney function.

MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment.

OBJECTIVE: This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS: This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 µmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 µmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 µmol/L, group difference: 1.61 µmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS: Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Impact of achieved blood pressure on renal function decline and first stroke in hypertensive patients with chronic kidney disease.

Background: The effect of achieved blood pressure (BP) on first stroke and renal function decline among hypertensive patients with mild to moderate chronic kidney disease (CKD) is still uncertain. Methods: In total, 3230 hypertensive patients with estimated glomerular filtration rate 30-60 mL/min/1.73 m2 and/or proteinuria were included in the present analyses. Eligible participants were randomly assigned to a daily treatment of a combined enalapril 10 mg and folic acid 0.8 mg tablet or an enalapril 10 mg tablet alone. Participants were followed up every 3 months. The study outcomes included first stroke and the progression of CKD. Results: The median antihypertensive treatment duration was 4.7 years. Compared with participants with a time-averaged on-treatment systolic blood pressure (SBP) of 135 to ≤140 mmHg, the incidence of total first stroke [1.7% versus 3.3%; hazard ratio (HR), 0.51; 95% confidence interval (CI): 0.26-0.99] and ischemic stroke (1.3% versus 2.8%; HR, 0.46; 95% CI: 0.22-0.98) decreased significantly in those with a time-averaged SBP of ≤135 mmHg. Furthermore, a time-averaged diastolic blood pressure (DBP) of ≤80 mmHg, compared with a time-averaged DBP level of 80 to ≤90 mmHg, was significantly related to a decreased risk of hemorrhagic stroke (0.2% versus 0.9%; HR, 0.18; 95% CI: 0.04-0.80). However, compared with participants with a time-averaged SBP of 135 to ≤140 mmHg, a lower but non-significant trend of CKD progression was found in those with a time-averaged SBP of ≤130 mmHg. Conclusions: A BP treatment level of ≤135/80 mmHg, compared with a BP treatment level of 135-140/80-90 mmHg, could lead to a decreased risk of first stroke in hypertensive patients with mild-to-moderate CKD.

Effect of MTHFR A1298C and MTRR A66G Genetic Mutations on Homocysteine Levels in the Chinese Population: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: The Chinese population typically has inadequate folate intake and no mandatory folic acid fortification. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are the two key regulatory enzymes in the folate/homocysteine (Hcy) metabolism. Hcy has been implicated in the pathogenesis of cardiovascular disease. We conducted a meta-analysis to assess whether the MTHFR gene A1298C and the MTRR gene A66G polymorphisms affect Hcy levels in the Chinese population. METHODS: This analysis included 13 studies with Hcy levels reported as one of the study measurements. Summary estimates of weighted mean differences and 95% confidence intervals (CIs) were obtained using random-effect models. RESULTS: Overall, there were no significant differences in Hcy concentrations between participants with the MTHFR 1298 CC (12 trials, n = 129), AA (n = 2166; ß, -0.51 µmol/L; 95%CI: -2.14, 1.11; P = 0.53), or AC genotype (n = 958; ß, 0.55 µmol/L; 95%CI: -0.72, 1.82; P = 0.40). Consistently, compared to those with the MTRR 66 GG genotype (6 trials, n = 156), similar Hcy concentrations were found in participants with the AA (n = 832; ß, -0.43 µmol/L; 95%CI: -1.04, 0.17; P = 0.16) or AG (n =743; ß, -0.57 µmol/L; 95%CI: -1.46, 0.31; P = 0.21) genotype. Similar results were observed for the dominant and recessive models. CONCLUSIONS: Neither the MTHFR A1298C polymorphism nor the MTRR A66G polymorphism affects Hcy levels in the Chinese population.