Gary E. McVeigh

Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus.

SummaryThe endothelium plays a pivotal role in modulating the reactivity of vascular smooth muscle through the formation of several vasoactive substances. We examined the effects of endothelium-dependent and independent vasodilators on forearm blood flow in 29 patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 21 control subjects, using venous occlusion plethysmography. Via a brachial artery cannula, increasing amounts of acetylcholine and glyceryl trinitrate were infused in doses of 60, 120, 180 and 240 mmol per min and 3, 6 and 9 nmol per min respectively. NG monomethyl-l-arginine, a stereospecific inhibitor of endothelium derived relaxing factor, was infused to inhibit basal and stimulated release of this dilator substance. Reactive hyperaemic forearm blood flow did not differ between groups. Forearm blood flow responses to each dose of acetylcholine were significantly greater in control than diabetic subjects (p<0.01 for all doses). NG monomethyl-l-arginine attenuated forearm blood flow from maximal stimulated values when responses were compared with the natural decline to acetylcholine in forearm flow in both control and diabetic subjects (p<0.05 for both groups), but had no effect on basal blood flow responses. Forearm blood flow responses to each dose of glyceryl trinitrate were significantly greater in control than diabetic subjects (p<0.05 for all). These data provide evidence for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications.

Noninvasive Pulse Wave Analysis for the Early Detection of Vascular Disease

A noninvasive technique has been developed and validated for calculating capacitive and oscillatory systemic arterial compliance with the use of pulse wave analysis and a modified Windkessel model. Application of the technique to subjects with hypertension, postmenopausal women with symptomatic coronary artery disease, and appropriate control subjects has confirmed a reduction of oscillatory compliance in the disease states and an increase in capacitive and oscillatory compliances in response to vasodilator drugs. This method should be useful in screening subjects for early evidence of vascular disease and in monitoring the response to therapy.

Age-related abnormalities in arterial compliance identified by pressure pulse contour analysis : Aging and arterial compliance

The objective of this study was to evaluate age-related changes in pulsatile arterial function. Aging alters arterial pulsatile function and produces consistent changes in the pressure pulse contour. A reduced systemic arterial compliance that can be derived from analysis of the pulse contour is regarded as the best clinical index of impaired pulsatile arterial function and may mark the presence of early vascular damage. We analyzed intra-arterial brachial artery waveforms in 115 healthy normotensive volunteers (83 men, 32 women) and radial artery waveforms obtained with the use of a calibrated tonometer device in 212 healthy volunteers (147 women, 65 men). A computer-based assessment of the diastolic pressure decay and a modified Windkessel model of the circulation were used to quantify changes in arterial waveform morphology in terms of large artery or capacitive compliance, oscillatory or reflective compliance in the small arteries, inertance, and systemic vascular resistance. Large artery compliance and oscillatory compliance correlated negatively with age for both invasive and noninvasive groups (r=-0.50 and r=-0.55; r=-0.37 and r=-0.66; P<0.001 for all). The slopes of the regression lines for the decline in oscillatory compliance with age were significantly steeper than those recorded for large artery compliance estimates. The change in blood pressure with age independently contributed to the decrease in large artery compliance but not oscillatory compliance in both groups. Consistent age-related changes were found in the pressure pulse contour by analysis of waveforms obtained invasively or noninvasively from the upper limb. The change in the oscillatory or reflective compliance estimate was independent of blood pressure change and may represent a better marker than large artery or capacitive compliance of the degenerative aging process in altering pulsatile arterial function.

Dietary fish oil augments nitric oxide production or release in patients with Type 2 (non-insulin-dependent) diabetes mellitus

SummaryDecreased release of nitric oxide from damaged endothelium is responsible for the impaired endothelium-dependent vasodilator responses found in animal models of vascular disease. Dietary supplementation with fish oils has been shown to augment endothelium-dependent relaxations, principally by improving the release of nitric oxide from injured endothelium. Using forearm venous occlusion plethysmography we studied vascular responses to 60, 120, 180 and 240 nmol/min of acetylcholine (an endothelium-dependent vasodilator) and 3, 6 and 9 nmol/min of glyceryl trinitrate (an endothelium-independent vasodilator) infused into the brachial artery in 23 patients with Type 2 (non-insulin-dependent) diabetes mellitus. NG monomethyl-l-arginine was employed to inhibit stimulated and basal release of nitric oxide from the endothelium. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double-blind crossover fashion for 6 weeks followed by a 6-week washout period and a final 6-week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the active treatment periods at 6 and 18 weeks. Fish oil supplementation significantly improved forearm blood flow responses to each dose of acetylcholine when compared to the vasodilator responses recorded at baseline and after olive oil administration (p<0.01). Neither fish oil nor olive oil supplementation produced any significant changes in forearm blood flow to the incremental infusions of glyceryl trinitrate when compared with responses recorded during the baseline studies. NG monomethyl-l-arginine significantly reduced forearm blood flow from maximal stimulated values to acetylcholine when compared to the uninhibited decline in flow to acetylcholine infusions at comparable time points (p<0.01). Treatment with fish oils improved endothelium-dependent responses to acetylcholine without altering endothelium-independent responses to glyceryl trinitrate. By increasing stimulated nitric oxide release from the endothelium fish oils may afford protection against vasospasm and thrombosis in patients with diabetes mellitus.

Vascular abnormalities in non-insulin-dependent diabetes mellitus identified by arterial waveform analysis

PURPOSE The arterial pressure waveform is derived from the complex interaction of the left ventricular stroke volume and the physical properties of the arterial circulation. Widespread abnormalities in the physical characteristics of the arterial vessels associated with diabetes mellitus can produce consistent changes in the shape of the pressure pulse waveform, providing information about arterial structure and tone that can be quantitated by pulse contour analysis. PATIENTS AND METHODS We analyzed intraarterial brachial artery waveforms in 28 patients with non-insulin-dependent diabetes mellitus and 22 control subjects matched for age and sex. A computer-based assessment of the diastolic pressure decay and a modified Windkessel model of the circulation were employed to quantify changes in arterial waveform morphology in terms of the large-artery compliance (C1), the oscillatory diastolic waveform (C2), inertance, and systemic resistance. RESULTS No differences were found in heart rate, mean arterial pressure, cardiac output, or stroke volume between groups. The mean oscillary arterial compliance estimate was significantly reduced in diabetic subjects versus controls: 0.02 (95% confidence interval [CI], 0.01 to 0.03) mL/mm Hg versus 0.08 (95% CI, 0.04 to 0.12) mL/mm Hg (p < 0.001). Oscillatory compliance values were uniformly reduced in the diabetic subjects regardless of the presence or absence of physical complications of the disease. No differences in large-artery compliance, inertance, or systemic resistance were found between groups. No positive correlations were found between indices of glycemic control, the known duration of diabetes, and any of the hemodynamic variables. CONCLUSIONS Quantitative changes in the arterial pressure pulse waveform, reflected by a reduced oscillatory compliance estimate, were found in patients with non-insulin-dependent diabetes mellitus. This estimate appears to act as an early marker for the vascular abnormalities associated with diabetes before complications of the disease become clinically apparent. By contrast, no changes in large-artery compliance were found in this patient population free from clinically obvious macrovascular disease.

Vascular abnormalities associated with long-term cigarette smoking identified by arterial waveform analysis.

PURPOSE Consistent changes in the arterial pulse contour are found with aging and disease states that impair the compliance characteristics of blood vessels that buffer pulsatile phenomena in the arterial tree. We assessed whether vascular adaptation in structure or tone of blood vessels associated with long-term cigarette smoking would influence steady state or pulsatile hemodynamics at a preclinical stage. PATIENTS AND METHODS We analyzed intraarterial brachial artery waveforms in 35 healthy long-term cigarette smokers and 32 nonsmoking control subjects matched for age and gender. The diastolic pressure decay was segmented into two components: an exponential decay that reflects the compliance characteristics of the large arteries and an oscillatory diastolic waveform generated principally by pulse-wave reflections from small arteries and arterioles. RESULTS Resting heart rate was higher in smokers than nonsmokers, mean +/- SD (66 +/- 9 versus 60 +/- 10; P < 0.05). Systolic, diastolic, and mean arterial pressures were lower in smokers compared with nonsmokers (P < 0.01 for all). No differences in cardiac output, large artery compliance, or systemic vascular resistance estimates where apparent between groups. A decrease in the amplitude and duration of the diastolic wave, produced by peripheral pulse-wave reflections in the arterial system, was found in smokers compared with nonsmokers (0.04 +/- 0.02 versus 0.7 +/- 0.03; P < 0.001). CONCLUSIONS Quantitative changes in the arterial waveform were found in long-term smokers compared with nonsmoking control subjects. The altered arterial wave shape marks the presence of abnormal structure or tone in the peripheral vasculature that affects pulsatile arterial function. This measure of vascular injury is detectable at a preclinical stage and may relate to the subsequent risk of morbid events in chronic smokers and aid in clinical risk stratification.

Effects of Long-Term Cigarette Smoking on Endothelium-Dependent Responses in Humans

Endothelial injury is a central feature of vascular disease induced by cigarette smoking and may act as a precursor for future atherosclerosis. Using forearm occlusion plethysmography, we studied the vascular responses to methacholine (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator) infused into the brachial artery of 35 long-term cigarette smokers and 16 nonsmoking subjects. NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide production, was used to inhibit synthesis of nitric oxide in the endothelium. The reactive hyperemic response at peak and during recovery to the temporary interruption of forearm blood flow was also compared between groups. Smokers had elevated carboxyhemoglobin levels compared with nonsmokers (5.1 +/- 2.1% vs 0.8 +/- 0.4%; p < 0.001). No differences were found in the peak or late hyperemic responses between groups. In smokers, the incremental infusions of methacholine and sodium nitroprusside increased forearm blood flow from 3.6 +/- 1.2 to 12.9 +/- 9.0 ml.min-1 x 100 ml-1 and from 4.0 +/- 1.5 to 9.3 +/- 4.0 ml.min-1 x 100 ml-1, respectively, compared with 3.2 +/- 1.0 to 13.5 +/- 5.6 ml.min-1 x 100 mL-1 and from 2.9 +/- 0.7 to 8.6 +/- 4.2 ml.min-1 x 100 ml-1 in nonsmoking subjects (p = NS). L-NMMA (4 mumol/min for 5 minutes) significantly reduced forearm blood flow in both smokers and nonsmokers from 4.1 +/- 1.4 to 3.4 +/- 1.2 ml.min-1 x 100 ml-1 and 3.8 +/- 0.7 to 2.3 +/- 0.5 mL.min-1 x 100 ml-1, respectively (p < 0.01 for both); and the decrement in forearm blood flow in nonsmokers was significantly greater than that recorded in smoking subjects (p < 0.05). In this study, long-term cigarette smokers exhibited an impairment in basal, but not stimulated, nitric oxide-mediated vasodilation.

Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure.

Background—Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O2·−), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O2·−. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF. Methods and Results—We employed the platelet as a compartmentalized ex-vivo model to examine O2·− and NO production. When eNOS is functioning normally, incorporation of N&ohgr;-Nitro-l-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O2·− detection, as inhibition of NO production prevents NO scavenging of O2·−. This was observed in controls and 9 of the CCF patients, in whom O2·− detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O2·− production by 39%, indicating O2·− production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8±1.4 versus 0.9±0.4 pmol/108 platelets, P =0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling. Conclusions—This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.

A randomised interventional trial of ω-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus

Objective: To determine the clinical effect of dietary supplementation with low-dose ω-3-polyunsaturated fatty acids on disease activity and endothelial function in patients with systemic lupus erythematosus. Methods: A 24-week randomised double-blind placebo-controlled parallel trial of the effect of 3 g of ω-3-polyunsaturated fatty acids on 60 patients with systemic lupus erythematosus was performed. Serial measurements of disease activity using the revised Systemic Lupus Activity Measure (SLAM-R) and British Isles Lupus Assessment Group index of disease activity for systemic lupus erythematosus (BILAG), endothelial function using flow-mediated dilation (FMD) of the brachial artery, oxidative stress using platelet 8-isoprostanes and analysis of platelet membrane fatty acids were taken at baseline, 12 and 24 weeks. Results: In the fish oil group there was a significant improvement at 24 weeks in SLAM-R (from 9.4 (SD 3.0) to 6.3 (2.5), p<0.001); in BILAG (from 13.6 (6.0) to 6.7 (3.8), p<0.001); in FMD (from 3.0% (−0.5 to 8.2) to 8.9% (1.3 to 16.9), p<0.001) and in platelet 8-isoprostanes (from 177 pg/mg protein (23–387) to 90 pg/mg protein (32–182), p = 0.007). Conclusions: Low-dose dietary supplementation with ω-3 fish oils in systemic lupus erythematosus not only has a therapeutic effect on disease activity but also improves endothelial function and reduces oxidative stress and may therefore confer cardiovascular benefits.

Thiazolidinediones: effects on insulin resistance and the cardiovascular system

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) primarily in adipose tissue. PPAR‐γ receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor‐alpha (TNF‐α), plasminogen activator inhibitor‐1(PAI‐1) and interleukin‐6 (IL‐6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima‐media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR‐α/γ agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured.