The impact of cardiovascular co-morbidities and duration of diabetes on the association between microvascular function and glycaemic control.

BACKGROUND: Good glycaemic control in type 2 diabetes (T2DM) protects the microcirculation. Current guidelines suggest glycaemic targets be relaxed in advanced diabetes. We explored whether disease duration or pre-existing macrovascular complications attenuated the association between hyperglycaemia and microvascular function. METHODS: 743 participants with T2DM (n = 222), cardiovascular disease (CVD = 183), both (n = 177) or neither (controls = 161) from two centres in the UK, underwent standard clinical measures and endothelial dependent (ACh) and independent (SNP) microvascular function assessment using laser Doppler imaging. RESULTS: People with T2DM and CVD had attenuated ACh and SNP responses compared to controls. This was additive in those with both (ANOVA p < 0.001). In regression models, cardiovascular risk factors accounted for attenuated ACh and SNP responses in CVD, whereas HbA1c accounted for the effects of T2DM. HbA1c was associated with ACh and SNP response after adjustment for cardiovascular risk factors (adjusted standardised beta (ß) -0.096, p = <0.008 and -0.135, p < 0.001, respectively). Pre-existing CVD did not modify this association (ß -0.099; p = 0.006 and -0.138; p < 0.001, respectively). Duration of diabetes accounted for the association between HbA1c and ACh (ß -0.043; p = 0.3), but not between HbA1c and SNP (ß -0.105; p = 0.02). CONCLUSIONS: In those with T2DM and CVD, good glycaemic control is still associated with better microvascular function, whereas in those with prolonged disease this association is lost. This suggests duration of diabetes may be a better surrogate for "advanced disease" than concomitant CVD, although this requires prospective validation.

Microvascular abnormalities in patients with vibration white finger.

In vivo nailfold capillary microscopy was performed on 10 men with vibration white finger (VWF) and 10 age-matched male controls. The observed nailfold capillaries required adaptation of Maricq's classifications and addition of new morphological scoring systems. These new classifications produced numerical scores for assessing capillary: dropout, tortuosity, elongation, visualization of subpapillary venular plexus, and the degree of disarrangement of nailfold capillary polarity. Application of these new scores showed, for the first time, a complex pattern of abnormal-nailfold capillaries in patients with VWF. Capillary dropout was evident in 7/10 patients, with an associated disarrangement in nailfold capillary polarity in five. All 10 controls had normal capillary morphology. Tortuosity of the capillary loops and elongation of their length was observed in 30% of patients. These significant morphological alterations seen in VWF suggest a local small-vessel vasculitis.

Impaired skin vasomotor reflexes in patients with erythromelalgia.

Erythromelalgia (EM) is a chronic disorder characterized by intermittent burning pain, warmth and erythema of the extremities. Increasing the local temperature and dependency of the affected limb(s) precipitates the symptoms, whereas direct cooling and elevation of the limb(s) can provide partial relief. Our previous findings showed that patients with EM have enhanced cutaneous vascular tone at rest and during stimulation, which may be due to an increase in sympathetic neural activity. To test this, we measured skin vasoconstrictor responses to contralateral arm cold challenge (CC) and inspiratory gasp (IG) using laser Doppler flowmetry at the toe pulp and fingertip. These areas were chosen because of their dense sympathetic innervation. An index of the vasoconstrictor response (between 0 and 1) was calculated from the change in skin perfusion from baseline following CC and IG. In control subjects, vasoconstrictor responses to CC at the toe and fingertip were both 0. 70+/-0.02 (mean+/-S.E.M.), which were significantly greater (P<0. 001) than corresponding values in patients with EM (0.37+/-0.04 and 0.45+/-0.04 respectively). Similarly, vasoconstrictor responses to IG were significantly greater (P<0.001) at the toe and fingertip in control subjects (0.70+/-0.03 and 0.70+/-0.02 respectively) compared with values in EM patients (0.27+/-0.03 and 0.45+/-0.15 respectively). These data show that, in contrast with control subjects, patients with EM have diminished sympathetic vasoconstrictor responses to both CC and IG. Denervation supersensitivity may play a part by increasing vasoconstrictor responses to circulating catecholamines, leading to a reduction in skin blood flow. Therefore an interplay between neural and vasoactive agents may be involved in the pathophysiology of EM.

Skin perfusion in patients with erythromelalgia.

BACKGROUND: Erythromelalgia (EM) is a chronic disorder characterized by intermittent pain, warmth and erythema of the extremities. Symptoms can be precipitated by increasing the temperature of the affected limb and can be partially relieved by direct cooling. MATERIALS AND METHODS: Microvascular assessment was conducted under 'hot' (28 degrees C) environmental conditions in 61 EM (EMI) patients and 30 control subjects. Twenty patients with many of the symptoms of EM were enrolled as an active control group (EMII). Using laser Doppler flowmetry, basal skin erythrocyte flux (SkEF) and the hyperaemic response to local heating (44 degrees C) were measured. RESULTS: Compared with control subjects, basal SkEF was reduced at the toe (P < 0.001), index finger (P < 0.05), dorsal and plantar aspects of the foot (P < 0.01) in both patient groups and at the medial mid-calf (P < 0.05) in EMI patients. Both EM groups also had a significantly reduced maximum SkEF at the dorsum of foot and medial mid-calf (all P < 0.001) compared with control values. In a subset of patients and control subjects, transcutaneous carbon dioxide levels were raised in EMI patients (P < 0.02) compared with levels in control subjects. Toe temperature was significantly reduced in both EM groups compared with control subjects (both P < 0. 001). CONCLUSION: Our study indicates for the first time that there is a vasoconstrictor tendency in patients with EM, which may be related to functional or structural changes in skin microvessels. Thus, the previous hypothesis that the pathophysiology of EM relates to vasodilatation is not supported in our patients. We believe that, in EM, vasoconstriction precedes reactive hyperaemia, similar to that seen in Raynaud's phenomenon.

Oral L-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon.

OBJECTIVE: To assess the effects of oral L-arginine supplementation on cutaneous vascular responses in patients with primary Raynaud's phenomenon (RP). METHODS: Double-blind, crossover comparison of placebo versus L-arginine (8 gm/day for 28 days). Cutaneous vascular responses in the fingers were assessed during iontophoresis of acetylcholine and sodium nitroprusside, which are endothelium-dependent and endothelium-independent vasodilators. RESULTS: In comparison with control subjects, patients with primary RP had diminished endothelium-dependent and -independent vasodilatation (P < 0.05, and P < 0.005, respectively, by analysis of variance). At the 3 doses used, vascular responses to acetylcholine were reduced by 71%, 64%, and 63%, respectively, and responses to sodium nitroprusside were reduced by 67%, 73%, and 66%, respectively. L-arginine had no significant effect on cutaneous vascular responses to acetylcholine or sodium nitroprusside in control subjects or patients with primary RP. CONCLUSION: Reduced vasodilator ability in primary RP is unlikely to be due to an impairment in the L-arginine/nitric oxide pathway.

Cutaneous vascular responses to acetylcholine are mediated by a prostanoid-dependent mechanism in man.

Approximately 50% of the forearm vasodilatation to intra-arterial infusions of acetylcholine is mediated by endothelium-derived nitric oxide. These conclusions have been derived from venous occlusion plethysmographic measurements of total forearm blood flow during co-infusions of acetylcholine and NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthase. Since venous occlusion plethysmography measures total limb blood flow, the relative proportion of the measurement from skin cannot be determined precisely. To determine the effects of acetylcholine on skin specifically, we have used laser Doppler flowmetry to measure vascular responses to local iontophoresis of acetylcholine in the forearm of normal male volunteers. To elucidate the possible mechanisms of cutaneous vasodilatation to acetylcholine, vascular responses were measured before and after systemic inhibition of prostanoid production and nitric oxide synthesis by oral aspirin (600 mg daily for 3 days) and intravenous L-NMMA (3 mg/kg for 60 min), respectively. After aspirin administration, dose-dependent vascular responses to acetylcholine were reduced significantly by approximately 53% (p < 0.005, ANOVA). In contrast, intravenous L-NMMA appeared to have no significant effect on cutaneous vascular responses to acetylcholine. While the role of nitric oxide is uncertain, vasodilatation to acetylcholine in the forearm skin is mediated largely by a prostanoid-dependent mechanism. Assessment of cutaneous vascular responses to iontophoresis of acetylcholine may, therefore, be useful in diseases where abnormal endothelium-dependent prostanoid function has been implicated.