Dennis Johnston

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.

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.

Microcirculatory hemodynamics and endothelial dysfunction in systemic lupus erythematosus.

Objective—Impaired flow-mediated dilation (FMD) occurs in disease states associated with atherosclerosis, including SLE. The primary hemodynamic determinant of FMD is wall shear stress, which is critically dependent on the forearm microcirculation. We explored the relationship between FMD, diastolic shear stress (DSS), and the forearm microcirculation in 32 patients with SLE and 19 controls. Methods and Results—DSS was calculated using (mean diastolic velocity×8×blood viscosity)/baseline brachial artery diameter. Doppler velocity envelopes from the first 15 seconds of reactive hyperemia were analyzed for resistive index (RI), and interrogated in the frequency domain to assess forearm microvascular hemodynamics. FMD was significantly impaired in SLE patients (median, 2.4%; range, −2.1% to 10.7% versus median 5.8%; range, 1.9% to 14%; P<0.001). DSS (dyne/cm2) was significantly reduced in SLE patients (median, 18.5; range, 3.9 to 34.0 versus median 21.8; range, 14.1 to 58.7; P=0.037). A strong correlation between FMD and DSS, rs=0.65, P=0.01 was found. Postischemic RI was not significantly different between the 2 groups; however, there were significant differences in the power-frequency spectrums of the Doppler velocity envelopes (P<0.05). Conclusions—These data suggest that in SLE, altered structure and function of the forearm microcirculation contributes to impaired FMD through a reduction in shear stress stimulus.

Drug-patient interactions and their relevance in the treatment of heart failure

The effects of congestive heart failure (CHF) on drug disposition and elimination are many and varied. Indeed, the pharmacokinetics of many of the drugs used to treat CHF are significantly altered by the patients underlying condition. Reduced gastric emptying in CHF delays absorption and decreases the peak plasma concentrations of furosemide, bumetanide, and digoxin. Moreover, drugs that have a high hepatic extraction ratio (organic nitrates, morphine, prazosin, and hydralazine) achieve higher than expected plasma concentrations in patients with CHF. In contrast, drugs requiring biotransformation to active forms, e.g., angiotensin-converting enzyme (ACE) inhibitors such as enalapril, perindopril, quinapril, and ramipril, generally have lower than expected plasma concentrations. Nevertheless, ACE inhibitors can impair renal function in CHF, leading to an actual increase in plasma concentrations. However, decreases in absorption and first-pass metabolism are often offset by reduced hepatic and renal clearance. The overall absorption of lisinopril may be reduced in some CHF patients; consequently, the onset of effect is delayed but is often more prolonged.

The effect on endothelial function of vitamin C during methionine induced hyperhomocysteinaemia

BackgroundManipulation of total homocysteine concentration with oral methionine is associated with impairment of endothelial-dependent vasodilation. This may be caused by increased oxidative stress. Vitamin C is an aqueous phase antioxidant vitamin and free radical scavenger. We hypothesised that if the impairment of endothelial function related to experimental hyperhomocysteinaemia was free radically mediated then co-administration of vitamin C should prevent this.MethodsTen healthy adults took part in this crossover study. Endothelial function was determined by measuring forearm blood flow (FBF) in response to intra-arterial infusion of acetylcholine (endothelial-dependent) and sodium nitroprusside (endothelial-independent). Subjects received methionine (100 mg/Kg) plus placebo tablets, methionine plus vitamin C (2 g orally) or placebo drink plus placebo tablets. Study drugs were administered at 9 am on each study date, a minimum of two weeks passed between each study. Homocysteine (tHcy) concentration was determined at baseline and after 4 hours. Endothelial function was determined at 4 hours. Responses to the vasoactive substances are expressed as the area under the curve of change in FBF from baseline. Data are mean plus 95% Confidence Intervals.ResultsFollowing oral methionine tHcy concentration increased significantly versus placebo. At this time endothelial-dependent responses were significantly reduced compared to placebo (31.2 units [22.1-40.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo). Endothelial-independent responses were unchanged. Co-administration of vitamin C did not alter the increase in homocysteine or prevent the impairment of endothelial-dependent responses (31.4 [19.5-43.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo)ConclusionsThis study demonstrates that methionine increased tHcy with impairment of the endothelial-dependent vasomotor responses. Administration of vitamin C did not prevent this impairment and our results do not support the hypothesis that the endothelial impairment is mediated by adverse oxidative stress.

Pharmacokinetic profiles of single and repeat doses of lisinopril and enalapril in congestive heart Failure

T his study was undertaken to determine whether the presence of congestive heart failure (CHF) would alter absorption, firstpass metabolism, and drug elimination and result in different pharmacokinetic profiles for lisinopril and enalapril. Lisinopril is pharmacologically active after oral administration and does not require hepatic activation. Bioavailability is low and the time to peak concentration is prolonged, mainly due to poor absorption. The drug undergoes renal elimination and has a duration effect of > 24 hours.’ Enalapril is a prodrug that requires conversion in the liver to its active form, enalaprilat. Enalaprilat is then excreted by the kidney and has a duration effect of about 24 hours.2 Medication was administered on day 1 and days 3-8; no drug was given on day 2 to allow for plasma concentration measurement after the first dose. Blood samples were taken after the first dose to determine levels of serum lisinopril, enalapril, and enalaprilat predose, hourly for 12 hours and at 24, 32, and 48 hours. Hepatic blood flow was measured before the first and last dose, using indocyanine green clearance.3 Blood pressures and heart rate were measured at baseline and 2,4,6,8,12, and 24 hours after dosing. Serum and urine concentrations of lisinopril, enalapril, enalaprilat, and angiotensin II were measured by radioimmunoassay. Six patients received lisinopril (mean age 70 years; weight 71.8 kg) and 7 received enalapril (mean age 69 years; weight 73.7 kg). One patient

Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator NO and harmful superoxide free radicals. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering the membrane association of these molecules, statins affect intracellular positioning and hence activity of a multitude of substances. These include eNOS(endothelial NO synthase), which produces NO (inhibited by Rho), and NADPH oxidase, which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of NO while decreasing superoxide production. A total of 40 hypercholesterolaemic patients were randomized to treatment with either atorvastatin or placebo; 20 normolipidaemic patients were also studied. Platelet nitrite, NO and superoxide were examined as was the cellular distribution of the GTPases Rho and Rac at baseline and after 8 weeks of treatment.Following atorvastatin therapy, platelet NO was increased (3.2 pmol/10(8) platelets) and superoxide output was attenuated [-3.4 pmol min(-1) (10(8) platelets)(-1)] when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets, implying reduced activity. In conclusion, the results of the present study show altered NO/superoxide production following statin therapy. A potential mechanism for this is the change in the distribution of intracellular GTPases, which was considered to be secondary to decreases in isoprenoid intermediates, suggesting that the activity of the former had been affected by atorvastatin.

Effect of low versus conventional dose cyclopenthiazide on platelet intracellular calcium in mild essential hypertension.

Platelet free intracellular calcium levels were measured during a double-blind, placebo-controlled parallel study to investigate the antihypertensive activity of 50 micrograms, 125 micrograms, and 500 micrograms cyclopenthiazide, in mild essential hypertension. Cytosolic free calcium levels were significantly higher in established hypertensive patients (135 +/- 28 nmol/l, P less than 0.001) but not in borderline hypertensive patients (123 +/- 26 nmol/l) compared with normotensive controls (111 +/- 9 nmol/l). A positive correlation between platelet free calcium level and systolic and diastolic blood pressure was confirmed (n = 68; r = 0.309 P = 0.01; r = 0.405 P less than 0.001, respectively). The 125-micrograms and 500-microgram doses of cyclopenthiazide produced mean decrements in blood pressure of 18/10 mmHg and 23/8 mmHg, respectively, (P less than 0.05 for both), after 8 weeks of therapy. The 50-microgram dose displayed no useful antihypertensive activity. Platelet free calcium levels fell by a similar amount in the four groups. The fall in blood pressure produced by the 125 and 500-microgram doses of cyclopenthiazide did not correlate with changes in platelet [Ca2+]i (r = 0.166 systolic and r = 0.169 diastolic). These findings do not support the hypothesis that changes in platelet cytosolic calcium levels are determined by the same factors that control blood pressure.