Hallvard Lilleng

Creatine kinase activity and blood pressure in a normal population: the Tromso study

Objectives In the vast majority of cases the cause for hypertension is not known. On the basis of observations from black and multiethnic populations, it has been hypothesized that a genetically high tissue creatine kinase activity may be an independent factor responsible for primary hypertension. If the relation between creatine kinase and blood pressure is causal, it is reasonable to believe that it will be independent of ethnicity and present in different populations. In this cross-sectional study, we examined whether creatine kinase was associated with blood pressure in a large Caucasian normal population. Methods and results Data on creatine kinase and blood pressure were analyzed in a random sample of 12 776 men and women (65% of those eligible), aged 30–87 years from a normal population in the municipality of Tromsø, Norway. We used linear regression to model the association between creatine kinase and blood pressure. Creatine kinase was independently associated with blood pressure. A one unit increase in log CK was associated with a 3.3 (95% CI 1.4–5.2) mmHg increase in systolic blood pressure and a 1.3 (95% CI 0.3–2.3) mmHg increase in diastolic blood pressure, after adjustment for age, sex, body mass index, s-glucose, s-creatinine, physical activity and alcohol consumption. The creatine kinase effect on blood pressure was independent of antihypertensive medication, and no difference in creatine kinase level was found between those with controlled and uncontrolled hypertension (geometric mean 101 vs. 104 IU/l, P = 0.1). Conclusion Creatine kinase was associated with blood pressure in this population.

Creatine Kinase as Predictor of Blood Pressure and Hypertension. Is It All About Body Mass Index? A Follow‐Up Study of 250 Patients

The correlation between creatine kinase (CK) and blood pressure (BP) was examined prospectively in 120 patients with persistent high CK and 130 individuals with normal CK. Hypertension was defined as systolic BP (SBP) ≥140 mm Hg or diastolic BP (DBP) ≥90 mm Hg or current use of antihypertensive medication. Baseline CK was weakly correlated with SBP (r=0.11, P=.07) and DBP (r=0.16, P=.01) at follow‐up. Persons with persistent high CK had higher SBP (140.8 mm Hg vs 138.2 mm Hg) and DBP (83.2 mm Hg vs 81.0 mm Hg, P=.06) values and were more likely to have hypertension (66.7% vs 55.5%, P=.05) than individuals with normal CK. In age‐ and sex‐adjusted analysis, a 1‐unit change in logCK was associated with a 4.9‐mm Hg higher SBP, a 3.3‐mm Hg higher DBP, and a 2.2‐higher odds for having hypertension at follow‐up (P=.1, .07, and .06, respectively). When including body mass index (BMI) to the model, BMI was a strong and independent predictor for SBP, DBP, and hypertension at follow‐up and the CK effect on blood pressure was substantially attenuated. This study showed that the CK effect on blood pressure is clearly modified by BMI.

Seasonal Variation of Migraine in an Arctic Population

Objectives.— To investigate seasonal variation of migraine headache in a population residing in an extreme Arctic locale.

Are the currently used reference intervals for creatine kinase (CK) reflecting the general population? The Tromsø Study

Abstract Background: Laboratory reference intervals are not necessarily reflecting the range in the background population. This study compared creatine kinase (CK) reference intervals calculated from a large sample from a Norwegian population with those elaborated by the Nordic Reference Interval Project (NORIP). It also assessed the pattern of CK-normalization after standardized control analyses. Methods: New upper reference limits (URL) CK values were calculated after exclusion of individuals with risk of hyperCKemia and including individuals with incidentally detected hyperCKemia after they had completed a standardized control analysis. After exclusion of 5924 individuals with possible causes of hyperCKemia, CK samples were analyzed in 6904 individuals participating in the 6th survey of The Tromsø Study. URL was defined as the 97.5 percentile. Results: New URL in women was 207 U/L. In men <50 years it was 395 U/L and in men ≥50 years 340 U/L. In individuals with elevated CK, normalization grade after control analysis was inversely correlated to the CK level (p<0.04). Conclusions: URL CK values in women and in men <50 years of age were in accordance with URL CK values given by the NORIP. In men ≥50 years, a higher URL was found and the findings suggest an upward adjustment of URL in this age group.

Clinical impact of persistent hyperCKemia in a Norwegian general population: A case-control study

In this case-control study we assessed the clinical impact of persistent hyperCKemia in a Norwegian general population. HyperCKemia was defined according to the NORIP- references (women 35-210 U/L, men <50 years 50-400 U/L, and men ≥50 years 40-280 U/L). We compared the frequency of muscular symptoms and function, neuromuscular diseases and risk factors between 120 cases with persistent hyperCKemia and 130 age- and sex-matched controls with normal CK values, all recruited from the single-centre, population-based prospective Tromsø Study. The participants underwent a standardized interview assessing muscle symptoms, physical activity, use of statins and presence of other CK risk factors, prior to clinical neurological and neurophysiological examination. Knee extensor muscle strength (Cybex NORM dynamometer) and dominant hand grip strength (Martin Vigorimeter) was assessed. A total of 85 cases (71%) reported either muscle pain, muscle stiffness or cramps, compared to 70 controls (54%) (p=0.017) There were no differences in muscle strength between the groups. In men, weight, Body Mass Index and muscle symptoms were significantly higher in the group with persistent hyperCKemia. In women, no differences between the groups were detected. Use of statins was similar in cases and controls. We diagnosed 3 women with previously unknown myopathy, all in the group with persistent hyperCKemia. This study support that CK may be used as a marker of muscular symptoms in the general population.

Reply: creatine kinase, overweight, and hypertension--the issue is more complex than we thought.

Dear Editor: In referral to our paper, Haan and colleagues argue that adjusting the creatine kinase (CK) effect on blood pressure for body mass index (BMI) may introduce overadjustment bias because CK is believed to play a causal role in both hypertension and obesity. However, there are reasons to question whether the association between CK and overweight is causal. Moreover, the direction of this association is also unclear. A number of cross-sectional studies have found low proportions of type I fibers and high proportions of type IIb fibers in populations with high body fat stores. These results have led investigators to hypothesize that the underlying differences in substrate oxidation capacities of certain fiber types may predispose individuals to obesity. However, worldwide obesity has doubled since 1980 while the muscle fiber distribution must be assumed to have been pretty fixed. The fundamental cause of obesity and overweight is an energy imbalance between calories consumed and calories expended, not muscle fiber distribution. Even though people with type II fiber dominance may more easily gain weight, this can hardly explain the overweight epidemic, which is independent of ethnicity and muscle fiber type. In contrast, findings from several studies comparing obese, post-obese, and never-obese patients do not support the contention that muscle fiber composition is important for the development of obesity. Instead, differences in muscle metabolism between overweight and nonoverweight individuals may be caused by differences in their fitness levels rather than an innate metabolic phenotype. In conclusion, these data suggest that smaller fiber areas and lower enzyme activities, ie, markers of aerobic capacity of skeletal muscle, but not fiber composition, may be factors predisposing to obesity. In our opinion, muscle fiber distribution cannot be considered the cause for overweight but at best a risk factor. It is also possible that the relationship between overweight and high CK levels goes in the opposite direction. Obese persons develop higher levels of CK as an effect of increased muscular strain. Reduction in blood flow in the overweight state may be related to compromised capillary beds and, in turn, to fat infiltration to the muscle, which may ultimately reduce blood circulation and/or oxygen extraction. In a previous casecontrol study, we found that men, but not women, with persistent hyperCKemia had more muscle symptoms and higher body weight and BMI than controls with normal CK levels. Obesity has been consistently associated with hypertension and increased cardiovascular risk. Based on population studies, risk estimates indicate that at least two thirds of the prevalence of hypertension can be directly attributed to obesity. Neuroendocrine mechanisms and factors derived from adipose are thought to play a major role. Obesity raises blood pressure by promoting insulin and leptin resistance, increasing renal tubular reabsorption, impairing pressure natriuresis, and causing volume expansion as a result of activation of the sympathetic nervous system and renin-angiotensin-aldosterone system and by physical compression of the kidneys, especially when visceral obesity is present. As muscle fiber phenotype cannot be considered the cause for overweight, and overweight may cause hypertension through mechanisms independent of CK, it seems justified to take BMI into consideration when studying the effect of CK on blood pressure.