John C. Giacomini

Anger report predicts coronary artery vasomotor response to mental stress in atherosclerotic segments

To determine the effects of anger on coronary artery vasoconstriction, 12 patients with symptomatic myocardial ischemia were studied during cardiac catheterization. During catheterization, the patients were asked to recall a recent event that had produced anger. One narrowed and 2 non-narrowed arterial segments were selected using predetermined criteria. Patients also completed various self-report measurements upon entering the catheterization laboratory before any procedures, after completion of the clinical angiogram and after the anger recall stressor. There was a significant increase in subject reports of anger (F[1,6] = 21.94, p < 0.01) and arousal (F [2,6] = 5.49, p < 0.05) during the anger stressor. There were no significant changes in heart rate, systolic or diastolic blood pressure, or heart rate x systolic blood pressure product during the anger stressor. A total of 27 arterial segments (9 narrowed and 18 non-narrowed) were selected and analyzed using quantitative angiographic techniques. Repeated-measures analysis of variance (baseline vs anger stressor) found no significant group differences with regard to changes in arterial diameter between conditions or among segments. Reported anger was significantly correlated with a decrease in both mean (r = -0.76, p < 0.05) and minimal (r = -0.82, p < 0.05) diameter changes in narrowed arteries. Vasoconstriction only occurred with high levels of anger. There were no significant correlations between anger report and diameter change in non-narrowed arteries. Thus, anger may produce coronary vasoconstriction in previously narrowed coronary arteries.

Reduction of ischemic depolarization by the calcium channel blocker diltiazem. Correlation with improvement of ventricular conduction and early arrhythmias in the dog.

Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effects on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic injury potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15–25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 ± 2.7 mV before diltiazem and 6.1 ± 1.6 mV afterward (P ± 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P ± 10–5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocdusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.

Two- to three-year follow-up of patients with single-vessel coronary artery disease randomized to PTCA or medical therapy (results of a VA cooperative study)

Despite increasing use of percutaneous transluminal coronary angioplasty (PTCA) to treat stenotic coronary artery disease, there are relatively few prospective studies evaluating its long-term effectiveness. We prospectively randomized 212 stable patients with provocable myocardial ischemia and single-vessel subocclusive coronary disease to receive primary therapy with either PTCA or medical therapy. This report presents the clinical follow-up of these patients at a mean, after randomization, of 2.4 years for interview and 3.0 years for exercise testing. Of the 212 patients originally randomized, 175 received an extended follow-up interview, and 132 underwent exercise testing; 62% of patients in the PTCA group were angina free compared with 47% of patients in the medical group (p <0.05). Furthermore, exercise duration as measured by treadmill testing was prolonged by 1.33 minutes over baseline in the PTCA group, whereas it decreased by 0.28 minutes in the medical group (p <0.04). Although the angina-free time on the treadmill was not different (p=0.50), fewer patients in the medical group developed angina on the treadmill at 3 years than those in the PTCA group (p=0.04). By 36 months, excluding the initial randomized PTCA, use of PTCA and use of coronary artery bypass surgery were not different in the 2 treatment groups. These data indicate that some of the early benefits derived from PTCA in patients with single-vessel coronary artery disease are sustained, making it an attractive therapeutic option for these patients.

Administration of heparin causes in vitro release of non-esterified fatty acids in human plasma

Abstract The objective of this study was to investigate the extent to which in vitro hydrolysis of endogenous triglycerides contributes to the elevated concentrations of non-esterified fatty acids (NEFAs) which have been reported after heparin administration. Heparin is known to induce the release of lipases which hydrolyze endogenous substrate both in vivo and in vitro . Four patients undergoing diagnostic cardiac catheterization, who routinely receive heparin, were studied. Blood samples were obtained before and at 5 and 30 minutes after an intravenous bolus of heparin (46 U/kg) was administered. Determinations of NEFAs in plasma were carried out immediately and again various times after the samples had incubated at 24°C and at 0°C. In addition, an aliquot of each sample was frozen quickly, stored for 5–7 days, thawed, and incubated at 24°C for 180 minutes. As expected, there were no significant increases after incubation in the concentrations of NEFAs in the samples obtained before heparin administration. In contrast, in the samples obtained after heparin administration, incubation at 24°C produced significant increases in the concentrations of NEFAs. For example, in the plasma samples obtained 5 minutes after administration of heparin, concentrations of NEFAs increased 50, 160 and 300% after 5, 60, and 180 minutes of incubation compared to pre-heparin concentrations. When assayed immediately, the concentrations of NEFAs increased only 15% over pre-heparin concentrations. Incubating the samples at 0°C slowed lipase activity. Freezing the samples stopped the lipase activity; however, when the thawed samples were incubated at 24°C, concentrations of NEFAs continued to rise. This study suggests that much of the reported increases in the in vivo concentrations of NEFAs after administration of heparin may be due to in vitro formation from continued lipase activity on endogenous substrate. Moreover, studies relating increases in the concentrations of NEFAs after administration of heparin to changes in drug binding to plasma proteins should be re-examined for possible in vitro artifacts.

A pilot study of l-arginine supplementation on functional capacity in peripheral arterial disease

Peripheral arterial disease (PAD) impairs walking capacity and is often associated with a profound endothelial vasodilator dysfunction, characterized by reduced bioactivity and/or synthesis of endothelium-derived nitric oxide (NO). Previous studies have suggested that dietary supplementation of L-arginine, the precursor of NO, improves endothelium-dependent vasodilation, limb blood flow and walking distance. However, these studies have been small, and have used large intravenous doses of L-arginine. The optimal dose of L-arginine has not been determined. Accordingly, this pilot study was conducted to establish the lowest effective oral dose of L-arginine to improve walking distance in preparation for the definitive study. Patients with PAD and intermittent claudication (n = 80) participated in this study. Eligibility criteria included: (1) ankle-brachial index (ABI) at rest ≤0.90; (2) post-exercise reduction in ABI ≥25%; and (3) difference in absolute claudication distance of ≤25% between two consecutive treadmill tests. Treadmill testing was performed using the Skinner-Gardner protocol and community-based walking was assessed using the walking impairment questionnaire. Patients were randomly assigned to oral doses of 0, 3, 6 or 9 g of L-arginine daily in three divided doses for 12 weeks. Treadmill testing was performed prior to administration of the study drug and again after 12 weeks of treatment. The study drug was well tolerated, with no significant adverse effects of L-arginine therapy. The safety laboratory studies were unremarkable, except for a statistically significant reduction in hematocrit in the L-arginine-treated groups. There was no significant difference observed in absolute claudication distance between the groups. However, a trend was observed for a greater increase in walking distance in the group treated with 3 g L-arginine daily, and there was a trend for an improvement in walking speed in patients treated with L-arginine. This pilot study provided data for safety, for power calculation and for dosing for the larger definitive trial that is now underway.

Antiarrhythmic Agent Amiodarone Possesses Calcium Channel Blocker Properties

Amiodarone possesses multiple pharmacologic properties, including peripheral and coronary vasodilatation, negative inotropy, and negative chronotropic and dromotropic effects. These properties are shared by the group of drugs termed calcium channel blockers. We examined the interaction of amiodarone with receptors for the 1,4-dihydropyridine (DHP) calcium blockers in rat and rabbit myocardial membrane particulates. Amiodarone displaced specifically bound [3H]nitrendipine in both rat and rabbit preparations in a competitive, concentration-dependent manner at a single class of binding sites (Ki approximately 0.27 micxroM). Calcium channel activity was determined pharmacologically in a tissue bath with electrically stimulated rabbit right ventricular strips, KCl-induced aortic ring contraction, and 45Ca2+ uptake in K(+)-depolarized cultured rat cardiomyocytes. Amiodarone completely inhibited myocardial contraction (EC50 = 1.7 microM), completely antagonized depolarization-induced aortic ring contraction (EC50 = 24 nM), and significantly reduced (29% vs. control) 45Ca2+ uptake into cultured cells. The calcium channel blocking effects of amiodarone may contribute significantly to its pharmacologic profile.

Gender differences in perception of PAD: a pilot study.

Patients with peripheral arterial disease (PAD) report profound limitations in all domains of quality of life that are worse than those for patients with chronic pulmonary disease and moderate to severe heart failure. While claudication has detrimental effects on quality of life, little is understood about the factors that influence quality of life and whether these determinants are similar for men and women with PAD and claudication. The purpose of the present investigation was to evaluate the effect of claudication on quality of life in 71 men and 26 women (mean age 72 and 73 years respectively) with PAD. Disease severity as assessed by ankle brachial index (ABI) and community-based walking was similar for men and women, although men reported greater comorbid conditions than women. Despite the similarity in disease severity, women reported decreased physical functioning (p = 0.01), more bodily pain (p = 0.04) and greater mood disturbance (p = 0.012) than men. Claudication and PAD had a greater impact on women than on men and may result from the higher prevalence of mood disturbance and bodily pain reported by women.

Suboptimal intensity of risk factor modification in PAD

This study extends earlier trials indicating that atherosclerosis risk factors are underdetected and undertreated in peripheral arterial disease (PAD) patients. Recognition and treatment of hyperlipidemia and hypertension in PAD patients is suboptimal. Diabetes appears to be detected more frequently although glycemic control is still suboptimal. The use of antiplatelet therapy is particularly underutilized. Additionally, despite the demonstrated efficacy of regular exercise in PAD patients, almost half of the study sample was sedentary. Approximately one third of the current study sample was overweight and nearly one third was obese by ATP-III guidelines. Only 31% of subjects were taking dietary measures to improve their cardiovascular health, and even fewer were physically active. To rectify suboptimal management of risk factors, there is a need for increased public awareness of PAD, reimbursement and implementation of screening programs and more aggressive treatment. Future studies are needed to examine innovative interventions for identification and management of cardiovascular risk factors in patients with PAD.

The pharmacokinetics and pharmacodynamics of d- and dl-verapamil in rabbits

Summary: The pharmacokinetics and pharmacodynamics of d- and dl-verapamil were studied in conscious rabbits in randomized cross-over fashion. Following a single intravenous dose, there was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic properties of the compounds. The mean (±SD) clearances of d- and dl-verapamil were 0.13 ± 0.03 and 0.12 ± 0.05 L/min/kg, respectively. The mean (±SD) steady-state volume of distribution was 9.7 ± 5.2 L/kg for d-verapamil and 8.1 ± 4.1 L/kg for dl-verapamil. No difference was observed between the compounds in their binding to plasma proteins. The mean (±SD) half-life in plasma was 98.7 ± 63.8 min for d-verapamil and 96.3 ± 38.0 min for dl-verapamil. In contrast to the lack of stereoselective differences in the pharmacokinetic properties of verapamil, there were marked differences in the pharmacodynamics of d- and dl-verapamil. dl-Verapamil appeared to prolong the PR interval to a greater degree than did d-verapamil, consistent with the more potent calcium channel effects of the l-enantiomer. Similarly, dl-verapamil had more potent hypotensive effects compared with the d-enantiomer, which produced no effects on systemic arterial pressure. Chronotropic effects, judged to be caused by autonomic reflexes in response to the hypotensive effects of the compound, were also statistically greater for dl-verapamil than for d-verapamil. These results demonstrate stereoselective pharmacodynamic effects in vivo of verapamil.

Bronchial imaging in humans using xenon K-edge dichromography

Abstract This report describes the initial use of K-edge xenon dichromography for imaging the bronchial tree in humans. The subjects inhale an anatomic dead-space volume of a mixture of 80% xenon and 20% oxygen, following which a dichromographic line-scan image is recorded using two monochromatic synchrotron radiation beams closely bracketing the k-edge of xenon (34.56 keV). Images of airways, from main-stem bronchi to fourth-order branches, are recorded with a pixel resolution of 0.5×0.5 mm. The scanning rate is 12 cm/s, the line exposure time is 4 ms, the skin dose to the exposed area (125 mm × 150 mm) is