Elio Melillo

Microalbuminuria and endothelial dysfunction in essential hypertension

Microalbuminuria (urinary albumin excretion between 20 and 200 micrograms/min) and endothelial dysfunction coexist in patients with essential hypertension. To evaluate whether the two phenomena are related and the determinants of that association, we recruited 10 untreated males with essential hypertension and microalbuminuria without diabetes to be compared with an equal number of matched patients with essential hypertension excreting albumin in normal amounts and 10 normal controls. The status of endothelial function was inferred from circulating von Willebrand Factor antigen (vWF), a glycoprotein secreted in greater amounts when the vascular endothelium is damaged. vWF concentrations were higher in hypertensive patients with microalbuminuria than in hypertensive patients without and controls. Individual vWF and urine albumin-excretion values were correlated (r = 0.55, p < 0.002). Blood pressure correlated with both urinary albumin excretion and vWF. Left ventricular mass index and minimal forearm vascular resistances were comparable in patients with hypertension and higher than in controls; total and low-density lipoprotein cholesterol, triglycerides, lipoprotein-a, Factor VII, and plasminogen activator inhibitor-1 did not differ. Fibrinogen was higher and creatinine clearance lower in microalbuminurics. Albuminuria in essential hypertension may reflect systemic dysfunction of the vascular endothelium, a structure intimately involved in permeability, haemostasis, fibrinolysis, and blood pressure control. This abnormality may have important physiopathological implications and expose these patients to increased cardiovascular risk.

Amlodipine, Enalapril, and Dependent Leg Edema in Essential Hypertension

Calcium channel blockers (CCBs) blunt postural skin vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing. To evaluate the dose-response relation between this pharmacological interference and dependent edema, a frequent side effect of CCBs during antihypertensive treatment, skin blood flow (laser Doppler flowmetry) at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, and leg weight (Archimedes principle) were measured at baseline, during increasing doses of the dihydropyridine amlodipine (5 and 10 mg UID each for 2 weeks), and after drug withdrawal in 10 hypertensive men. Because angiotensin-converting enzyme inhibitors may attenuate ankle swelling by CCBs, those parameters were evaluated according to a similar design during amlodipine (10 mg UID) and enalapril (20 mg UID) combined (n=10). As a control, the effect of enalapril monotherapy (10 and 20 mg UID for 2 weeks each) was evaluated in a third series of patients (n=8). Amlodipine (5 mg UID) increased leg weight without modifying postural vasoconstriction (the percent skin blood flow decrease from horizontal to dependent position), which indicates that extravascular fluid shift was independent of postural skin vasoconstriction. At 10 mg UID, however, amlodipine blunted postural vasoconstriction and increased leg weight further, which suggests that skin blood flow autoregulation limited additional fluid transfer. Both parameters normalized after drug withdrawal. Enalapril per se did not affect cutaneous vasomotion or leg weight but reduced the amount of dependent fluid extravasation by the CCB despite a persistent antagonism for postural vasoconstrictor responses.

Women and peripheral arterial disease: same disease, different issues.

Objectives Atherosclerosis is a multifactorial disease and, thus, its clinical manifestations are likely to present gender-specific differences with respect to their development, course, symptom complexes and prognosis. The present study aimed to examine sex differences in peripheral arterial disease (PAD) and its clinical correlates. Methods PAD severity, quality of life (assessed by ST-22), cardiovascular risk factors, inflammatory profile and comorbidity were assessed in 163 men and 68 women who were consecutively diagnosed with PAD at three Italian University vascular centres. Results Compared to men, women showed a higher prevalence of critical limb ischemia (P = 0.018), but had a less impaired quality of life (assessed by ST-22), and were less likely to have a history of lower extremity revascularization. Furthermore, women tended to be older (P = 0.058), and more likely to present hypercholesterolemia (P = 0.053), diabetes mellitus (P = 0.001), body mass index ≥ 30 kg/m2 (P = 0.003) and metabolic syndrome (P = 0.001). Conversely, C-reactive protein plasma levels were similar in the two groups. No gender-specific difference was observed in cardiovascular comorbidity; however, the condition showing the strongest association with coronary artery disease was diabetes mellitus in women (odds ratio = 4.96, P = 0.021), and smoking in men (odds ratio = 2.66, P = 0.008). Conclusion In PAD, there are several sex differences in baseline characteristics, especially with respect to the weight and significance of cardiovascular risk factors. Knowledge of these differences may help achieve optimal gender-specific cardiovascular risk prevention.

Calcium Channel Blockers Blunt Postural Cutaneous Vasoconstriction in Hypertensive Patients

The aim of this work was to test whether calcium channel blockers interfere with skin vasoconstrictor reflexes that minimize postural increases in capillary pressure and avoid fluid extravasation and eventually subcutaneous edema. Studies were conducted in 23 untreated mild to moderate essential hypertensives; drugs, either calcium channel blockers or not, were given for 2 weeks according to a crossover, sequence-randomized design. Skin blood flow was measured by laser Doppler flowmetry in two skin areas: (1) the dorsum of the foot, where arteriovenous anastomoses are poorly represented, and (2) the plantar surface of the great toe, where those anastomoses are predominant. Determinations were obtained both with the foot at heart level and with it placed passively 50 cm below the heart level; percent flow changes from the horizontal to the dependent position were the measure of postural vasoconstriction. Two dihydropyridine derivatives, amlodipine (10 mg UID) and nifedipine (60 mg UID), and verapamil (240 mg BID), a chemically unrelated compound, diminished to similar extents the postural fall in skin blood flow at the dorsum of the foot. Blockade of alpha1-adrenergic and AT-1 subtype angiotensin II receptors by doxazosin (4 mg UID) and losartan (50 mg UID), respectively, exerted no effect. Postural skin blood flow responses at the plantar surface of the great toe were unmodified during the pharmacological trials. Thus, calcium channel blockers of different chemical origins antagonized postural skin vasoconstriction at the dorsum of the foot. The data indicate altered postural capillary blood flow regulation, since arteriovenous anastomoses are anatomically absent at this site; the effect was independent of either alpha1-adrenoceptor or angiotensin II receptor antagonism. Interference with skin postural vasoconstrictor mechanisms may result in net filtration of fluid to the extravascular compartment. This mechanism might explain the as yet unknown pathogenesis of ankle edema during treatment with calcium antagonists.

Acetylcholine-mediated vasodilatation and tissue-type plasminogen activator release in normal and hypertensive men.

Muscarinic agents release tissue plasminogen activator (t-PA) in the forearm circulation of normal subjects, but no information exists about their effect in those hypertensive patients in whom the response to endothelial-mediated vasodilators is blunted. Acetylcholine, an endothelium-dependent vasodilator and a muscarinic agonist that releases t-PA from in-vitro systems, and sodium nitroprusside, an endothelium-indepen dent vasodilator, were infused into the brachial artery at rates calculated to cause a similar degree of vasodilatation. The study was performed in five elderly, smoking hyper tensive patients in whom the clustering of detrimental factors for endothelial function permitted prediction of defective endothelial-mediated vasorelaxation, and five young, normotensive, nonsmoking male volunteers. Forearm blood flow was assessed by venous plethysmography; t-PA and plasminogen activator inhibitor 1 (PAI-1) antigen values were expressed as flow-dependent (net release, the product of venoarterial concentration gradient and forearm blood flow) or independent (absolute and fractional concentration gradients) indices. In patients, acetylcholine did not change flow and net release and concentration gradients of t-PA, suggesting that vasodilatation as such, possibly by increasing fluid shear stress, may induce t-PA release in human forearm. In normal subjects, acetylcholine and sodium nitroprusside increased t-PA antigen net release at the highest infusion rate, an effect attributable to forearm hyperperfusion, since absolute and fractional gradients did not change significantly. PAI-1 antigen did not change during either infusion in both controls and patients, indicating the absence of an endothelial pool to be mobilized acutely.

Forearm blood flow reserve and cardiac and renal indexes of pressure load in normotensive and hypertensive individuals.

In response to hypertension, arterioles remodel their structure, the heart develops myocardial hypertrophy, and the kidney reduces creatinine clearance and increases albuminuria. To better understand the interrelations among the target organs involved in hypertension, we evaluated minimal forearm vascular resistances--a hemodynamic index of arteriolar structure derived from mean blood pressure and maximal postischemic forearm blood flow--the echocardiographic indexes of cardiac structure, and urinary albumin excretion and creatinine clearance in 29 male mild to moderate non-macroalbuminuric essential hypertensive patients on no drugs and 11 age- and sex-matched normotensive control subjects. Minimal forearm resistances were elevated in hypertensive patients and correlated with left ventricular mass, wall thickness, and mean arterial pressure. Patients with abnormal minimal forearm resistances (2 SD above normal) were characterized by higher pressure, greater wall thickness, lower creatinine clearance, and higher albumin excretion, suggesting that maximal forearm flow capacity does relate to the hemodynamic load exerted on both the kidney and heart. However, the correlation with cardiac structure and mean arterial pressure explained only part of the variability of minimal forearm resistances. Furthermore, no correlation among these parameters was found when hypertensive patients were evaluated separately from normotensive subjects, possibly because of heterogeneous factors active on arteriolar structure and unrelated to the pressor load. Overall, the data suggest that the development of abnormal minimal forearm resistances in the course of the hypertensive process is related to the pressor load, but its details need further understanding.

Transcutaneous oxygen and carbon dioxide levels with iloprost administration in diabetic critical limb ischemia.

Iloprost, a prostacyclin analogue, is a treatment option for surgically unsuitable diabetic chronic critical limb ischemia (CLI), although its outcome is difficult to be anticipated clinically. Whether transcutaneous (tc) oxygen tension (PO2) predicts the response to iloprost in diabetic CLI is unclear at this point and, in that same context, the prognostic role of tc carbon dioxide tension (PCO2), another ischemia-sensitive parameter, is unknown. Supine and dependent tcPO2 and tcPCO2 were measured at baseline and after 4 weeks of iloprost treatment in 31 limbs of 26 type-2 diabetic arteriopaths with CLI not amenable to surgery. Success was defined as pain relief and significant reduction of analgesics. Clinical outcome was stratified by baseline tcPO2 and tcPCO2 tertiles, and likelihood ratios (LR) quantified the increase from pretest chances given a certain result. Iloprost succeeded in 16 (52%) and failed in 15 limbs (48%) and post-treatment tcPO2 followed a parallel course. Failures increased by ascending baseline tcPCO2 and descending tcPO2 tertiles; successes behaved specularly. Predictions of failure based on elevated tcPCO2 (>53 mm Hg) were more efficient than relying on depressed tcPO2 (LR 10.7 vs 3.6); success was almost certain when tcPO2 was >23 mm Hg (LR = 17.8). Dependent determinations were less useful than supine measurements for prognostic use. Elevated tcPCO2 predicted failure efficiently and high tcPO2 was a useful prognostic tool for success of iloprost, suggesting that their combined use may allow better prognostic stratification and improve the therapeutic approach to diabetic CLI.

Transcutaneous Oxygen and Carbon Dioxide Measurement in Peripheral Vascular Disease

Combined transcutaneous oxygen tension (tcPO2) and transcutaneous carbon dioxide tension (tcPCo2) measurements were carried out at both the subclavicular and metatarsal level in 29 controls and 100 patients with peripheral arterial obstructive disease (PAOD) (intermittent claudication: n = 40, critical limb ischemia: n = 60). Interindividual variation coefficients of arterial and subclavicular tcPCO2 (n = 94 subjects) were superimposable, while tcPo2 variability was twice the arterial value. Furthermore, arterial tensions were better predicted by tcPCO2 than by tcPO2 measurement. In the 75 limbs with an ABI < 0.9 of patients with intermittent claudication, tcPCO2 did not differ significantly from controls (n = 58 limbs), but it was elevated in those with critical limb ischemia (n = 74 limbs), although control and pathological values overlapped widely even in this latter group. At variance with tcPCO2, tcPQ2 was lower in intermittent claudication than in controls, and undetectable in most of the symptomatic limbs with critical ischemia, irrespective of concomitant diabetes. In the overall sample (n = 255 limbs), tcPCO2 did not show significant changes for tcPo2 values ranging from 80 to 10 mmHg, and it increased markedly in several—but not all—patients whose tcPo2 values were below that limit. To evaluate further the biological significance of an increase in tissue tcPCO2, another sample of 24 subjects underwent acute forearm ischemia for a period of thirteen minutes, a maneuver that increased tcPCO2 markedly, indicating that this parameter is indeed a correlate of drastic reductions in limb perfusion. Thus, tcPCO2 is methodologically less variable than tcPo2 and more predictive of arterial values. However, the wide overlap with control values restrains its use as an isolated diagnostic tool to substantiate PAOD, even in the most advanced stages of disease. Marked elevations in tCPCO2 can be found in patients with critical limb ischemia, although normal values may coexist with low or negligible tcPO2 levels for reasons to be clarified. Further work is needed to establish the extent to which tcPcO2 determination may complement tcPO2 to differentiate extreme from less severe degrees of critical limb ischemia.

Noninvasive Transcutaneous Monitoring in Long-Term Follow-Up of Patients With Thromboangiitis Obliterans Treated With Intravenous Iloprost:

We evaluated the effectiveness of intravenous iloprost (IVI) in outpatients with thromboangiitis obliterans (TAO) and lower limb noninvasive transcutaneous monitoring (TCM) at follow-up (FU). Ten consecutive patients with TAO underwent IVI therapy. Transcutaneous oxygen (TcPo 2) and carbon dioxide (TcPco 2) determination and laser Doppler flowmetry (LDF) were performed before and after IVI at 3, 6, and 12 months of FU. Clinical response was positive in 7 patients, whereas 3 nonresponders underwent a second IVI cycle with 1 showing a late positive clinical response. After 12 months of FU, all patients were alive without amputations. Supine and dependent TcP2 levels significantly improved (P < .005). Hallux LDF values showed significant change with the maximal hyperemic test at 44°C (P < .005). Forefoot maximal hyperemic test at 44°C LDF (P < .005) and improved venous arterial reflex (P < .05) showed statistically significant time evolution. We demonstrated some degree of IVI effectiveness and evaluated TCM in patients with TAO.