Falko Skrabal

Autonomic dysfunction and hemodynamics in vitamin B12 deficiency

Orthostatic hypotension in patients with cobalamin (Cbl) deficiency has been reported previously in isolated cases but we are not aware of detailed systematic studies of hemodynamic and autonomic nervous system function in patients with cobalamin deficiency. We investigated hemodynamic and autonomic responses to 60 degrees passive head up tilt (HUT) in 21 patients with vitamin B12 deficiency, 21 healthy age-matched control subjects and 9 age-matched patients with diabetes mellitus (DM) and established diabetic neuropathy. To systematically assess hemodynamic and autonomic nervous system function, we performed measurements of heart rate, beat-to-beat systolic and diastolic blood pressure, stroke index, cardiac index, total peripheral resistance index, total power, low (LF) and high (HF) frequency oscillatory component of heart rate variability, LF/HF ratio and spontaneous baroreflex sensitivity. As compared to controls, we found a significant fall of systolic blood pressure during 60 consecutive beats directly after head up tilt; furthermore, a significantly blunted fall of stroke index, cardiac index and a lack of increase of total peripheral resistance index for the duration of tilt in patients with diabetes mellitus and in patients with vitamin B12 deficiency. As compared to controls, we observed an altered response of spectral indices of sympathetic activation and vagal withdrawal and an impaired modulation of baroreflex sensitivity during head up tilt suggestive of a complex modification in the neural control activities in patients with cobalamin deficiency, which was comparable to that observed in patients with diabetes mellitus and established autonomic neuropathy. The results suggest that vitamin B12 deficiency causes autonomic dysfunction with similar hemodynamic consequences and patterns of autonomic failure as seen in diabetic autonomic neuropathy. Defective sympathetic activation may be the cause for orthostatic hypotension, which is occasionally seen in patients with vitamin B12 deficiency. It is concluded that patients with orthostatic hypotension should be screened for cobalamin deficiency.

In human hypercholesterolemia increased reactivity of vascular smooth muscle cells is due to altered subcellular Ca2+ distribution

There is evidence that, besides an attenuated endothelium-dependent relaxation, functional changes in smooth muscle contractility occur in experimental hypercholesterolemic animals. Unfortunately, little is known of the situation in human arteries, and the intracellular mechanisms involved in the modulation of vascular smooth muscle function in human hypercholesterolemia are still unclear. Thus, besides acetylcholine-induced endothelium-dependent relaxation, smooth muscle reactivity to KCl, norepinephrine (NE) and phenylephrine (PE) was evaluated in uterine arteries from 34 control individuals (CI) and 22 hypercholesterolemic patients (HC). Contractions to KCl, norepinephrine and phenylephrine were enhanced by 1.3-, 2.1- and 3.5-fold in vessels from HC. Furthermore, the Ca(2+) signaling in the perinuclear cytosol, which promotes cell contraction, and that of the subplasmalemmal region, which contributes to smooth muscle relaxation, were examined in freshly isolated smooth muscle cells. In cells from HC, increases in perinuclear Ca(2+) concentration ([Ca(2+)](peri)) in response to 30 mM KCl and 300 nM NE were increased by 67 and 93%, respectively. In contrast, the increase in the subplasmalemmal Ca(2+) concentration ([Ca(2+)](sub)) to 10 microM NE was reduced in cells from HC by 33%. No further differences in perinuclear and subplasmalemmal Ca(2+) signaling were found in cultured smooth muscle cells from CI and HC (primary culture 4-6 weeks after isolation). These data indicate a significant change in the subcellular Ca(2+) distribution in smooth muscle cells from HC. In addition, production of superoxide anions (O(2)(-)) was increased 3.8-fold in uterine arteries from HC. Treatment of smooth muscle cells with the O(2)(-)-generating mixture xanthine oxidase/hypoxanthine mimicked hypercholesterolemia on smooth muscle Ca(2+) signaling. From these findings, we conclude that during hypercholesterolemia, besides a reduced endothelium-dependent relaxation, changes in smooth muscle reactivity take place. Thereby, smooth muscle contractility is increased possibly due to the observed changes in subcellular Ca(2+) signaling. The observed increased O(2)(-) production in HC might play a crucial role in the alteration of smooth muscle function in hypercholesterolemia.

Gefäßelastizität, Hochdruck und Hochdrucktherapie

SummarySemi-automated methods for pulse wave analysis enable the early diagnosis of changes in the elasticity of large and small blood vessels. Currently two methods are in routine use: (a) the augmentation index and (b) the compliance of the large and the small blood vessels (C1, C2). It has been shown that both measurements are able to predict cardiovascular mortality independent of other established risk factors. It remains to be shown whether antihypertensive therapy with drugs which improve compliance, in addition to lowering blood pressure, are superior to drugs which only lower blood pressure without affecting compliance. An increase of pulse pressure represents a later stage in the development of atherosclerosis and is therefore less sensitive than the above named elasticity measurements. Changes in elasticity occur very early in the development of atherosclerosis; therefore, these methods should prove very useful in preventive medicine. It is to be hoped that these methods will be increasingly used for detecting incipient atherosclerosis.ZusammenfassungAus der Pulswellenanalyse lassen sich z. B. mittels des Augmentationsindex oder der errechneten Complianceparameter der großen und kleinen Gefäße (C1, C2) Veränderungen der Arterienwand im Sinne eines Vorstadiums der Atherosklerose erkennen. Für diese Untersuchungstechnik wurde in prospektiven Untersuchungen gezeigt, dass sich das kardiovaskuläre Risiko inklusive Mortalität unabhängig von anderen etablierten Risikofaktoren abschätzen lässt. Auch eine Erhöhung der Blutdruckamplitude ist durch eine gestörte Gefäßelastizität verursacht, nur ist diese Amplitudenzunahme erst zu einem viel späteren Zeitpunkt zu beobachten. Eine Abnahme der Gefäßelastizität als Vorläufer der Atherosklerose lässt sich bereits zu einem Zeitpunkt erkennen, wenn noch keine manifeste Gefäßerkrankung vorliegt, diese Untersuchungstechnik sollte also vermehrt in der Präventivmedizin eingesetzt werden. Es muss zusätzlich in Hinkunft gezeigt werden, dass Antihypertensiva, die zusätzlich zu ihrer blutdrucksenkenden Eigenschaft auch die Compliance verbessern günstiger sind als Antihypertensiva, die keinen oder sogar einen negativen Einfluss auf die Gefäßcompliance haben.