Abstract
Objective: Hypertension is a major risk factor for cardiovascular disease, kidney disease, and premature death. Increased levels of creatine kinase are associated with development of hypertension. However, it is unknown if creatine, a substrate of CK, is associated with the development of hypertension. We therefore, aimed to investigate the association between plasma creatine concentration and incident hypertension.Methods:We measured fasting plasma creatine concentrations by nuclear magnetic resonance spectroscopy in participants of the population-based PREVEND study. The study outcome was incident hypertension, defined as either a SBP of at least 140 mmHg, a DBP of at least 90 mmHg, or the new usage of antihypertensive drugs. Participants with hypertension at baseline were excluded.Results:We included 3135 participants (46% men) aged 49 ± 10 years. Mean plasma creatine concentrations were 36.2 ± 17.5 μmol/l, with higher concentrations in women than in men (42.2 ± 17.6 versus 29.2 ± 17.6 μmol/l; P < 0.001). During a median of 7.1 [interquartile range: 3.6–7.6] years of follow-up, 927 participants developed incident hypertension. Higher plasma creatine concentrations were associated with an increased risk of incident hypertension [HR per doubling of plasma creatine: 1.21 (95% confidence interval: 1.10–1.34); P < 0.001], which remained significant after adjustment for potential confounders. Sex-stratified analyses demonstrated higher plasma creatine that was independently associated with an increased risk of incident hypertension in men [hazard ratio: 1.26 (95% CI 1.11–1.44); P < 0.001], but not in women (hazard ratio: 1.13 (95% CI 0.96–1.33); P = 0.14]. Causal pathway analyses demonstrate that the association was not explained by sodium or protein intake.Conclusion:Higher plasma creatine is associated with an increased risk of hypertension in men. Future studies are warranted to determine the underlying mechanisms.
Highlights
Hypertension is a major risk factor for cardiovascular disease, chronic kidney disease, and premature death worldwide [1]
Women had a higher prevalence of parental hypertension as well as higher NT-proBNP, and high-density lipoprotein (HDL) cholesterol compared with men
The association between plasma creatine and incident hypertension was subject to substantial effect-modification by sex, as evidenced by a significant interaction term (P 1⁄4 0.04)
Summary
Hypertension is a major risk factor for cardiovascular disease, chronic kidney disease, and premature death worldwide [1]. The universal biomarker for hypertension is blood pressure, defining the condition and guiding therapeutic approaches. The activity of the ATP-generating enzyme creatine kinase has been identified as a biomarker for hypertension, and since multiple studies have confirmed creatine kinase as a. We aimed to determine the plasma creatine concentrations in a large population-based cohort, in order to prospectively investigate the association of plasma creatine with incident hypertension. Given the established sex differences in the rates of hypertension, and the fact that location of the creatine transporter gene resides on the X-chromosome [19,20,21], we performed sex-stratified analyses.
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