Magnesium Metabolism, Vitamin D and Interleukins in Cardiovascular Disease

A magnesium deficiency is known to be involved in the pathogenesis of cardiovascular diseases. In patients with essential hypertension intima media thickness is increased in about 70% (ELSA Study). In our study, we investigated 21 patients (10 female, 11 male, average age 56.3 ± 6.6 years) with untreated essential hypertension (grades I and II according to WHO guidelines). All patients had a hypomagnesiaemia in serum (1.57 ± 0.11 mg%). In all patients we found a significant increase in intima media thickness of arteria carotis communis (0.97 ± 0.08 mm) (r=-0.869, p<0.0001). The results show that a magnesium deficiency in patients with essential hypertension may be of special pathogenetic importance. In addition, the role of magnesium deficiency in the development of arteriosclerosis has to be discussed. Furthermore, we demonstrated a connection between magnesium deficiency and an increased intima media thickness. In this context, calcium antagonist therapy or magnesium supplementation may be of advantage when treating intima media thickness in hypertension. In addition in essential hypertensives with diabetes mellitus type IIb showing lowered magnesium (1.72 ± 0.08 mg/ dl) and vitamin D (9.55 ± 4.74 ng/ml) levels interleukine 6 concentrations were 8.57 ± 4.14 pg/ml (p<0.01 vs. controls) being a risk factor for metabolic disorder, e. g. arteriosclerosis.


Introduction
Cardiovascular epidemiology has expanded from studies focusing only on cardiovascular risk factors to include research on causes and consequences of atherosclerosis and associated arterial wall abnormalities. In a large number of studies, techniques have been used that enable non-invasive assessment of vascular characteristics to study early functional and structural wall changes. Examples of these measurements are coronary artery calcium levels, arterial stiffness, brachial endothelial function, aortic augmentation index (Aix) and carotid intima-media thickness (CIMT). One of the reasons for an increased attention on these indicators is that the availability of adequate noninvasively assessed measurements of functional and structural arterial characteristics allows for studies among children, adolescents and young adults. Such studies may greatly enhance our insight in causes, development and pathophysiological mechanisms of cardiovascular disease. Furthermore, these measurement extend research into middle aged and elderly subjects who are yet free from symptomatic cardiovascular disease [1].
Several new studies have focused on the role of CIMT in predicting future vascular events [1,2].
Studies performed in the general population consistently showed a gradual graded increase in risk with increased CIMT. The magnitude of association differed somewhat by age but in general was remarkably similar across studies.
CIMT may help, in addition to established risk factors, in identifying those individuals that will suffer from cerebrovascular and coronary heart disease [3][4][5].
In this context changes in magnesium metabolism have been implicated in the pathogenesis of hypertension . Therefore it was of interest to study magnesium deficient patients with essential hypertension concerning CIMT and arteriosclerosis and vitamin D disorder.

Subjects and Methods
Subjects 21 patients were studied, 11 male and 10 female. The average age was 56.3 ± 6.6 years. All patients had a normal renal function (serumcreatinine 0.85 ± 0.4 mg%). In all patients cholesterol and triglyceride concentrations were significantly increased.
In a second additional study 11 different hypertensive patients with diabetes mellitus type IIb with magnesium loss and lowered vitamin D status were investigated concerning interleukine 6 levels.
All patients were informed about the aim of the study according to the Helsinki Charter and had given written consent at the time of investigation.

Methods
The analysis of serum magnesium concentrations was performed by a Hitachi analyser. Measurements of intima media thickness were performed in the arteria carotis communis with a GE apparatus Vivid 5, Solingen, Germany.

Statistical Analysis
Statistical analyses was performed using ANOVA.
The results are given as means ± SD, a p<0.05 was considered significant. The reported p values are two-tailed.

Results
The mean serum magnesium concentration was 1.57 ± 0.11 mg/dl (normal range for serum magnesium: 1.70-2.55 mg/dl). IMT (in mm) was measured 0.97 ± 0.8. The normal range is known to be below 0.7 mm. The correlation coefficient r=-0.869, p<0.0001.
In hypertensive diabetics type II serum magnesium levels were 1.72 ± 0.08 mg/dl, which was in the lower normal range or below. Interleukine 6 concentrations were 8.57 ± 4.14 pg/ml, being significantly increased as compared to controls (p<0.01).
The vitamin D/magnesium ratio was 5.59 ± 2.87 in 11 hypertensive diabetics type IIb, being lower than values of normal range.

Discussion
A role for lowered magnesium concentrations in vascular tone has been postulated in essential hypertension .
On the basis of experimental data, the theoretical mechanisms underlying the Mg ++ -induced vasodilation may be: (a) a modification of the response to vasopressor hormones, and (b) an interaction with cellular Ca ++ handling [32]. These possible mechanisms are supported by 3 lines of recent evidence. First, the extracellular Mg ++ concentration can influence Ca ++ metabolism of vascular smooth muscle by changing the Ca ++ influx through the plasma membrane. Recently, in single myocytes from frog ventricle, the site of interaction between Mg ++ and Ca ++ inward current that is dependent on phosphorylation by cyclic adenosine monophosphatase [33]. Second. Changes in the extracellular Mg ++ concentration induced inverse changes in the Ca ++ content of vascular smooth muscle and in exchangeable Ca ++ [34,35]. Third, a decrease in the intracellular free Mg ++ concentration results in diminished membrane Na + , K + -adenosine triphosphatase and Ca ++ ATPase activities, and, as a corollary, increased Na + -Ca ++ exchange and increased intracellular Na + and Ca ++ concentrations [36]. In addition a sodium magnesium antiport exists in red blood cells and in vascular smooth muscle cells [9]. TRPM (transient receptor potential channel melastin member) type 6 and 7 -channels, recently described, regulate intracellular magnesium stores, too [37,38].
It is well known, that an increased intima media thickness is a marker for cardiovascular morbidity and mortality. Functional and structural arterial measurements confer an increased risk for cardiovascular disease. It has been suggested that the increase in the stiffness of the arterial wall with aging can be explained by a decrease in elastin density (or collagen) [39][40][41][42][43][44][45].
Calcification of arteries is a common phenomenon especially in the elderly [34].
Aortic wall calcium (and phosphorus) contents increase with age. Age linked medial calcification is associated with elastic fibers [34]. Physical factors such as increased intraluminal pressure (e.g. hypertension) that promote elastocalcionis suggested that global degeneration of the arterial wall, of stress on medial elastic fibers and lamellae are followed by fracture. As pulse pressure increases in hypertension (especially so in isolated systolic hypertension), cyclic wall stress is increased and so fracture and elastocalcinosis would be expected to occur earlier. In this context it is well documented that magnesium acts as a physiological calcium antagonist and is necessary for an intact phosphorus metabolism. As described early by our group a magnesium deficiency is involved in the pathogenesis of primary hypertension, the development of elevated pulse pressure values and as shown here in an increased intima media thickening [41,43].
In addition a negative correlation concerning magnesium loss and elevated blood lipid composition was described earlier, even by our group.
It is also of recent interest that antihypertensive drug treatment with calcium antagonist is of special benefit in avoiding intima media thickening and thereby in preventing stroke. Calcium antagonists lower blood pressure and reduce cardiovascular morbidity and mortality [44][45][46][47][48][49].
In addition data presented here show decreased magnesium concentrations and vitamin D levels and increased interleukin levels in hypertensive patients with diabetes mellitus type IIb. IL-6 plays an important role in the development of arterial stiffness and arteriosclerosis in hypertensive patients and in diabetics. The combination of both hypertension and diabetes shows even more arteriosclerotic organe damage in which IL-6 is pathophysiologically involved [28].
These findings favour the development of an increased intima media thickness and the manifestation of arteriosclerosis.
In conclusion, a vitamin D loss in hypertensive patients with diabetes mellitus type IIb has to be corrected immediately. Normally, the daily amount of magnesium is 300-480 mg, vitamin D should be given 1,000 I.E. at least [50].