Creatine kinase, sodium retention, and blood pressure: Is there a link?

Creatine kinase (CK), also known as creatine phosphokinase, is the central regulatory enzyme of energy metabolism and is reported to be a potential causal factor in primary hypertension (HTN). It consists of a dimer molecule and can be present in 3 distinct isoenzymes (MM, MB, and BB). CK is expressed by various tissues and cell types, including muscle, brain, and kidney and its concentration parallels to the metabolic and energy demands of the tissues. The skeletal muscle has the highest concentration of CK of all the tissues.1 At these locations, CK fuels high‐energy demanding processes such as Na+/K+‐ATPase at cell membranes and myosin kinase at the contractile proteins in the skeletal muscles. CK does so by catalyzing the production of high‐energy adenosine triphosphate (ATP) via the transfer of a phosphoryl group from creatine phosphate (the major storage reservoir of energy during muscle rest) to adenosine diphosphate.

Clinically, CK is widely used to detect muscle injury.2 If the serum CK activity is high, the isoenzyme distribution is usually assessed. A high serum CK‐MB activity is suggestive of cardiac muscle injury and is still used to assess acute myocardial injury under select circumstances. In resting subjects without overt muscle damage, serum CK activity is considered a measure of tissue CK activity.3 Substantial evidence linking serum (systemic) and tissue CK activity to blood pressure (BP) has emerged over the last two decades, linking high tissue CK activity to a greater risk of HTN.

High tissue CK precedes the onset of hypertension and antihypertensive therapy lowers high tissue CK in animal models.4 CK inhibition lowers blood pressure in spontaneously hypertensive rats and decreases human vascular contractility.5, 6 Serum CK activity after rest has been independently associated with blood pressure (BP) levels in a random sample of a multiethnic population in the Netherlands.7 These data were replicated in another cross‐sectional population study from Norway.8 The latter group of investigators also demonstrated this effect during a longitudinal follow‐up, though the relationship was substantially weakened by obesity, as expressed by body mass index (BMI).9 It has been speculated that a relative predominance of muscle fiber type with higher CK phenotype (muscle fiber type II) may be a biological factor predisposing to both HTN and obesity. Moreover, CK activity after rest is hypothesized to be a predictor of failure of HTN treatment.10 There is no evidence regarding HTN directly causing increased CK activity by decreasing its clearance or damaging endothelial or cardiac cells.11 In addition, normal CK isoenzymes have been detected in subjects with higher CK values and uncomplicated HTN.

Thus, available evidence from animal and human studies has raised the question about a possible causal relationship between CK and BP. How could CK activity cause or contribute to an increased BP? It has been hypothesized that high tissue CK activity, whether induced or constitutive, could generate a greater ATP buffer capacity and subsequently increase cardiac contractility, vascular resistance, and sodium retention as well as decrease nitric oxide bioavailability.12 At the level of the kidney, high activity of CK, that is located near the basolateral Na+/K+‐ATPase, might provide increased availability of ATP necessary for sodium reabsorption. Sodium intake is a major determinant of blood pressure with higher sodium intake being associated with higher BP values and an increased cardiovascular risk,13 especially in salt sensitive individuals. Factors involved in inter‐individual sodium retention and subsequent intravascular volume expansion and increased BP are not completely understood.

In this current paper, featured in this journal, Brewster et al14 explored, for the first time, the potential association between plasma CK activity and sodium retention after a high sodium intake in 60 healthy men, aged 18‐50. The study population was half Caucasian (European) and half of African Continental ancestry. These inclusion criteria were chosen based on known higher CK activity in men versus women and in subjects from African ancestry versus Caucasians.15 The participants were normotensive or (8 out of 60) with uncomplicated and untreated essential primary HTN. Subjects with secondary forms of HTN, with diseases, or taking medications that could affect plasma CK activity were excluded from the study. In particular, hypothyroidism, a known cause of both elevated CK and a risk factor for HTN, was excluded by a careful medical history evaluation and thyroid stimulated hormone testing. Study participants were asked to avoid heavy exercise for 3 days prior to obtaining baseline serum CK activity. They were then assigned to a low sodium (LS) intake (<50 mmol of sodium daily) for 7 days, followed by 3 days of high sodium (HS) intake (>200 mmol of sodium daily), under the supervision of a dietician. The primary outcome was to assess predictors of urinary sodium excretion after a HS diet. Baseline, LS, and HS period variables for body weight, sitting BP, heart rate, and 24‐hour urinary sodium excretion were studied.

Twenty‐four hour urine collections at the end of the LS diet (day 7) and HS diet (day 10) periods confirmed patients’ adherence to diet. High sodium intake led to a significant increase in systolic blood pressure (SBP) and weight as compared to when the subjects were on low sodium intake. Plasma CK activity was inversely correlated with the 24‐hour urinary sodium excretion after high sodium intake. In particular, sodium excretion was 260.4 mmol/24 h after high sodium intake in the high CK tertile versus 415.2 mmol/24 h in the low CK tertile (P < .001). African ancestry was strongly inversely correlated with urinary sodium excretion and directly correlated with CK activity, as shown previously.7 However, ancestry and age did not fully explain the correlation between CK activity and sodium retention. Participants in the high tertile of CK activity experienced a smaller increase in both SBP and diastolic blood pressure (DBP) when exposed to high sodium intake than those in the low tertile of CK. Thus, they were seemingly less sensitive in terms of BP response. This fact is in conflict with the same subjects retaining more sodium after high sodium intake. Whether this is due to chance, because of the relatively small sample size, or to the use of a less accurate method of BP measurement (office BP instead of 24‐hour ambulatory BP monitoring) is unknown. If this finding is confirmed, it would suggest that the increased renal sodium reabsorption is not the sole mechanism by which CK activity may contribute to BP.

As the authors pointed out,14 the association between resting plasma CK activity and sodium retention does not imply any causal relationship, but it certainly adds up to the available findings linking CK activity and BP. Future studies should clarify if there is an association between renal tissue CK and urinary sodium excretion to confirm the assumption that the standardized plasma activity of CK reflects its cellular function. It would also be important to assess the plasma aldosterone and renin activity in the subjects exposed to high sodium intake and see if they differ in CK activity. Recently emerging “gold standard” methods of volume assessment, such as bioimpedance monitoring, would add additional valuable information in future studies, including the ability to assess fluid spaces, volume expansion, and defining the relative proportions of fat and muscle volumes of the subjects,16, 17 moving beyond the current definitions of obesity, such as BMI and waist circumference. It would also be of interest to investigate if the association between resting CK activity and sodium retention is only limited to acute changes in sodium intake, as investigated in the current paper by Brewster et al.14 In addition, it would be interesting to see the effects of diuretic use on the CK activity of subjects exposed to a high sodium diet. Last, the best way to define a causal relationship between CK activity and urinary sodium excretion would be to repeat this experiment assessing BP and urinary sodium excretion after a high sodium diet before and after administering beta‐guanidinopropionic acid, a CK inhibitor that is now available for human use.18 We are looking forward to more studies offering a better understanding on this new and exciting area of clinical HTN. As it was pointed out in an editorial by Dr. Pickering almost a decade ago in this journal, “genetically determined variations in muscle fiber composition could well be of considerable importance in furthering our understanding of the deadly combination of HTN, obesity, and type 2 diabetes”,19 our understanding continues to evolve on this subject.

DISCLOSURES AND CONFLICT OF INTEREST STATEMENT

The authors alone are responsible for the content and writing of the paper. The authors have read and understood the journal's policy on disclosing conflicts of interest and declare that they have none to report. This study did not receive any research funding.

Pisoni R, Hamrahian M, Fülöp T. Creatine kinase, sodium retention, and blood pressure: Is there a link? J Clin Hypertens. 2018;20:342–344. 10.1111/jch.13177