Creatine kinase is associated with blood pressure during pregnancy.

OBJECTIVE: Hypertensive disorders in pregnancy pose a major burden during pregnancy and are also associated with an increased risk for hypertension later in life. Plasma creatine kinase activity is identified in the general population as an independent risk factor for hypertension. We hypothesize that plasma creatine kinase activity is similarly associated with blood pressure during pregnancy. METHODS: Women who participated in the 'Amsterdam Born Children and their Development-study' were eligible for the current study. The associations between plasma creatine kinase activity and blood pressure measurements during pregnancy, and between plasma creatine kinase activity and hypertensive disorders in pregnancy (gestational hypertension, HELLP, preeclampsia and eclampsia) were evaluated using multiple linear regression and logistic regression models. RESULTS: In 3619 pregnant women, plasma creatine kinase activity was significantly associated with all blood pressure outcomes. This was most pronounced for the mean SBP throughout pregnancy, with a regression coefficient of 3.48 mmHg (CI 1.67-5.28, P < 0.001) per 1-unit logCK. With respect to the hypertensive disorders in pregnancy, we found a significant association between severe gestational hypertension diagnosed before 34 weeks of gestation (OR 9.16, CI 1.32-63.86, P = 0.025) per 1-unit logCK activity. HELLP and preeclampsia were not significantly associated. CONCLUSION: Our data show that plasma creatine kinase activity measured in early pregnancy is associated with blood pressure during pregnancy and associated with severe gestational hypertension diagnosed before 34 weeks of gestation, whereas no significant association was found between creatine kinase and other hypertensive disorders in pregnancy.

Creatine kinase and blood pressure in women with a history of early-onset preeclampsia.

OBJECTIVES: High plasma creatine kinase (CK) activity is associated with hypertension in the general and pregnant population. We hypothesize that women with a history of early-onset preeclampsia are prone to hypertension due to a high CK activity level. STUDY DESIGN: Nine to 16 years after pregnancy, serum CK activity and blood pressure were measured in 117 women with a history of early-onset preeclampsia and 50 women with a history of an uncomplicated pregnancy. MAIN OUTCOME MEASURES: CK activity levels of the two groups were compared using the Mann-Whitney U test. The association between CK activity and blood pressure was evaluated by means of multivariable regression analysis. RESULTS: There was no significant difference in median (interquartile range) CK activity between women with a history of early-onset preeclampsia and an uncomplicated pregnancy (59.00 [47.00-85.00] vs. 58.00 [46.50-75.25], respectively, p = 0.774). The association between CK and systolic blood pressure was significant in women with a pregnancy history of early-onset preeclampsia (regression coefficient [95% confidence interval]: 0.123 mmHg [0.020-0.226], p = 0.019), and a trend was found for diastolic blood pressure (p = 0.069). CK and blood pressure were not significantly associated in women with a history of an uncomplicated pregnancy. CONCLUSIONS: Median CK did not significantly differ between the two groups. Serum CK activity was significantly associated with systolic blood pressure in women with a history of early-onset preeclampsia. These data suggest that CK is not a predominant factor in the increased risk of hypertension in women with a history of early-onset preeclampsia.

The acute effect of beta-guanidinopropionic acid versus creatine or placebo in healthy men (ABC-Trial): A randomized controlled first-in-human trial.

AIMS: Increasing evidence indicates that the ATP-generating enzyme creatine kinase (CK) is involved in hypertension. CK rapidly regenerates ATP from creatine phosphate and ADP. Recently, it has been shown that beta-guanidinopropionic acid (GPA), a kidney-synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure-lowering agent, we assessed the tolerability of a sub-therapeutic GPA dose in healthy men. METHODS: In this active and placebo-controlled, triple-blind, single-centre trial, we recruited 24 healthy men (18-50 years old, BMI 18.5-29.9 kg m-2 ) in the Netherlands. Participants were randomized (1:1:1) to one week daily oral administration of GPA 100 mg, creatine 5 g, or matching placebo. The primary outcome was the tolerability of GPA, in an intent-to-treat analysis. RESULTS: Twenty-four randomized participants received the allocated intervention and 23 completed the study. One participant in the placebo arm dropped out for personal reasons. GPA was well tolerated, without serious or severe adverse events. No abnormalities were reported with GPA use in clinical safety parameters, including physical examination, laboratory studies, or 12-Lead ECG. At day 8, mean plasma GPA was 213.88 (SE 0.07) in the GPA arm vs. 32.75 (0.00) nmol l-1 in the placebo arm, a mean difference of 181.13 (95% CI 26.53-335.72). CONCLUSION: In this first-in-human trial, low-dose GPA was safe and well-tolerated when used during 1 week in healthy men. Subsequent studies should focus on human pharmacokinetic and pharmacodynamic assessments with different doses.

The acute effect of beta-guanidinopropionic acid versus creatine or placebo in healthy men (ABC Trial): study protocol for a randomized controlled trial.

BACKGROUND: Despite adequate treatment, up to 30% of treated antihypertensive patients with primary, uncomplicated hypertension remain uncontrolled. We proposed that high intracellular activity of the ATP regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, we found that plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population. In addition, the creatine analog and competitive oral creatine kinase inhibitor beta-guanidinopropionic acid effectively and safely reduced blood pressure in the spontaneously hypertensive rat. However, to our knowledge there are no human data on the safety of oral supplementation with this substance. Therefore, we will assess the tolerability of beta-guanidinopropionic acid in men, compared to creatine and placebo. METHODS/DESIGN: This is a randomized, active and placebo controlled, triple blind, double dummy, single center clinical intervention trial in 24 healthy male volunteers, 18 to 50 years old, recruited in the Netherlands. The intervention consists of one week of daily oral administration of beta-guanidinopropionic acid 100 mg, creatine 5 gram, or placebo. The primary outcome is the tolerability of beta-guanidinopropionic acid as a descriptive measure, in an intent-to-treat analysis. Other outcomes include the placebo-adjusted differences with baseline in biochemical and hemodynamic parameters, including plasma markers of muscle tissue damage, urine sodium excretion, resting sitting systolic and diastolic brachial blood pressure, supine systolic and diastolic central blood pressure, pulse wave velocity and augmentation index, heart rate, cardiac contractility, cardiac output, and total peripheral resistance. DISCUSSION: There is an unfulfilled need for new conservative options to treat resistant hypertension. This study will provide first-in-men data on creatine kinase inhibition as a potential new class of antihypertensive drugs. TRIAL REGISTRATION: The Netherlands National Trial Register Trialregister.nl (identifier NTR 4444) , registered 9 March 2014.

Creatine and creatine analogues in hypertension and cardiovascular disease.

BACKGROUND: The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention. OBJECTIVES: To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease. SEARCH METHODS: Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction. SELECTION CRITERIA: Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery. DATA COLLECTION AND ANALYSIS: The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change. MAIN RESULTS: Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia. AUTHORS' CONCLUSIONS: This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.