John E. Willard

Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both

BACKGROUND In humans, the use of cocaine and cigarette smoking each increase the hearts metabolic need for oxygen but may also decrease the supply of oxygen. As cocaine abuse has proliferated, cocaine-associated chest pain, myocardial infarction, and sudden death have occurred, especially among smokers. We assessed the influence of intranasal cocaine and cigarette smoking, alone and together, on myocardial oxygen demand and coronary arterial dimensions in subjects with and subjects without coronary atherosclerosis. METHODS In 42 smokers (28 men and 14 women; age, 34 to 79 years; 36 with angiographically demonstrable coronary artery disease), we measured the product of the heart rate and systolic arterial pressure (rate-pressure product) and coronary arterial diameters before and after intranasal cocaine at a dose of 2 mg per kilogram of body weight (n = 6), one cigarette (n = 12), or intranasal cocaine at a dose of 2 mg per kilogram followed by one cigarette (n = 24). RESULTS No patient had chest pain or ischemic electrocardiographic changes after cocaine use or smoking. The mean (+/- SE) rate-pressure product increased by 11 +/- 2 percent after cocaine use (n = 30, P < 0.001), by 12 +/- 4 percent after one cigarette (n = 12, P = 0.021), and by 45 +/- 5 percent after both cocaine use and smoking (n = 24, P < 0.001). As compared with base-line measurements, the diameters of nondiseased coronary arterial segments decreased on average by 7 +/- 1 percent after cocaine use (P < 0.001), by 7 +/- 1 percent after smoking (P < 0.001), and by 6 +/- 2 percent after cocaine use and smoking (P < 0.001). The diameters of diseased segments decreased by 9 +/- 2 percent after cocaine use (n = 18, P < 0.001), by 5 +/- 5 percent after smoking (n = 12, P = 0.322), and by 19 +/- 4 percent after cocaine use and smoking (n = 12, P < 0.001). The increase in the rate-pressure product and the decrease in the diameters of diseased segments caused by cocaine use and smoking together were greater (P < 0.001 and P = 0.037, respectively) than the changes caused by either alone. CONCLUSIONS The deleterious effects of cocaine on myocardial oxygen supply and demand are exacerbated by concomitant cigarette smoking. This combination substantially increases the metabolic requirement of the heart for oxygen but simultaneously decreases the diameter of diseased coronary arterial segments.

Assessment of Left-to-Right Intracardiac Shunting by Velocity-Encoded, Phase-Difference Magnetic Resonance Imaging A Comparison With Oximetric and Indicator Dilution Techniques

BACKGROUND Velocity-encoded, phase-difference magnetic resonance imaging (MRI) has been shown to provide an accurate assessment of shunt magnitude in patients with large atrial septal defects, but its ability to determine shunt magnitude in patients with intracardiac left-to-right shunts of various locations and sizes has not been evaluated in a prospective and blinded manner. The objective of the present study was to determine whether velocity-encoded, phase-difference MRI can assess the magnitude of intracardiac left-to-right shunting in humans. METHODS AND RESULTS Twenty-one subjects (15 women and 6 men; age range, 15 to 72 years) underwent velocity-encoded, phase-difference MRI measurements of flow in the proximal aorta and pulmonary artery, followed immediately by cardiac catheterization. The presence of left-to-right intracardiac shunting was assessed with hydrogen inhalation, after which shunt magnitude was measured by the oximetric and indocyanine green techniques. Of the 21 patients, 12 had left-to-right intracardiac shunting detected by hydrogen inhalation. There was a good correlation (r = .94) between the invasive and MRI assessments of shunt magnitude. In comparison to oximetry and indocyanine green, MRI correctly identified the 12 patients with a ratio of pulmonary to systemic flow (Qp/Qs) of < 1.5 (9 without intracardiac shunting and 3 with small shunts) and the 9 patients with a Qp/Qs of > or = 1.5 (6 with atrial septal defect, 1 with ventricular septal defect, 1 with patent ductus arteriosus, and 1 with both atrial septal defect and patent ductus arteriosus). CONCLUSIONS Compared with measurements obtained during cardiac catheterization, velocity-encoded, phase-difference MRI measurements of flow in the proximal great vessels can reliably assess the magnitude of intracardiac left-to-right shunting.

Influence of labetalol on cocaine-induced coronary vasoconstriction in humans

PURPOSE Although labetalol is sometimes given to patients with cocaine-associated chest pain, its influence on cocaine-induced coronary vasoconstriction is unknown. PATIENTS AND METHODS In 15 patients (7 men, 8 women, aged 40 to 79 years) undergoing catheterization for chest pain, heart rate, mean arterial pressure, and coronary arterial area (by computer-assisted quantitative angiography) were measured (1) at baseline, (2) 15 minutes after intranasal cocaine, 2 mg/kg, then (3) 5 minutes after intravenous saline (n = 6) or labetalol, 0.25 mg/kg (n = 9). RESULTS Of 40 coronary arterial segments analyzed, cocaine induced a 13% +/- 10% (mean +/- standard deviation) decrease in coronary arterial area in 32. Subsequently, no variable changed after saline administration. Although labetalol reduced mean arterial pressure (117 +/- 14 mm Hg after cocaine, 110 +/- 11 mm Hg after labetalol; p < 0.05), it induced no change in the coronary arterial area (3.47 +/- 1.37 mm2 after cocaine, 3.37 +/- 1.32 mm2 after labetalol; p = NS). CONCLUSION Labetalol reverses the cocaine-induced rise in mean arterial pressure, but does not alleviate cocaine-induced coronary vasoconstriction.

Assessment of Coronary Arterial Flow and Flow Reserve in Humans With Magnetic Resonance Imaging

BACKGROUND The noninvasive measurement of absolute epicardial coronary arterial flow and flow reserve would be useful in the evaluation of patients with coronary circulatory disorders. Phase-contrast magnetic resonance imaging (PC-MRI) has been used to measure coronary arterial flow in animals, but its accuracy in humans is unknown. METHODS AND RESULTS Twelve subjects (7 men, 5 women: age 44 to 67 years) underwent PC-MRI measurements of flow in the left anterior descending coronary artery or one of its diagonal branches at rest and after administration of adenosine (140 microgram . kg(-1) . min (-1) IV). Immediately thereafter, intracoronary Doppler velocity (IDV) and flow measurements were made during cardiac catheterization at rest and after intravenous administration of adenosine. For the 12 patients, the correlation between MRI and invasive measurements of coronary arterial flow and coronary arterial flow reserve was excellent: coronary flow (MRI) (mL/min)= 0.85 x coronary flow (IDV) (mL/min)+17 (mL/min), r=.89, and coronary flow reserve (MRI) =0.79 x coronary velocity reserve (IDV) + 0.34, r=.89. For the range of coronary arterial flows (18 to 161 mL/min) measured by MRI, the limit of agreement between MRI and catheterization measurements of flow was -13+/-30 mL/min; for the range of coronary reserves (0.7 to 3.7) measured by MRI, the limit of agreement between the two techniques was 0.1+/-0.4. CONCLUSIONS Cine velocity-encoded PC-MRI can noninvasively measure absolute coronary arterial flow in the left anterior descending artery in humans. PC-MRI can detect pharmacologically induced changes in coronary arterial flow and can reliably distinguish between those subjects with normal and abnormal coronary artery flow reserve.

Quantitation of cardiac output with velocity-encoded, phase-difference magnetic resonance imaging

Velocity-encoded, phase-difference magnetic resonance imaging (MRI) previously has been used to measure flow in the aorta, as well as in the pulmonary, carotid, and renal arteries, but these measurements have not been validated against currently accepted invasive techniques. To determine the accuracy of velocity-encoded, phase-difference MRI measurements of cardiac output, 23 subjects (11 men and 12 women, aged 15 to 72 years) underwent velocity-encoded, phase-difference MRI measurements of cardiac output in the proximal aorta, followed immediately by cardiac catheterization, with measurement of cardiac output by the Fick principle and by thermodilution. For MRI, Fick, and thermodilution measurements, stroke volume was calculated by dividing cardiac output by heart rate. The magnetic resonance images were acquired in 1 to 3 minutes. For all patients, the agreement between measurements of stroke volume was 3 +/- 9 ml for MRI and Fick, -3 +/- 11 ml for MRI and thermodilution, and 0 +/- 8 ml for MRI and the average of Fick and thermodilution. Compared with standard invasive measurements, velocity-encoded, phase-difference MRI can accurately and rapidly determine cardiac output.

Influence of intranasal cocaine on plasma constituents associated with endogenous thrombosis and thrombolysis

PURPOSE As cocaine abuse has become widespread, catastrophic cocaine-associated cardiovascular events have been noted with increasing frequency. Although these incidents are thought to be caused by drug-induced vasoconstriction and/or arterial thrombosis, the influence of cocaine on the plasma constituents involved in endogenous thrombosis and thrombolysis has not been characterized. PATIENTS AND METHODS In 22 patients (8 men, 14 women, ages 32 to 62 years) undergoing cardiac catheterization, blood samples were procured before and 15 minutes after the administration of intranasal saline (n = 8, controls) or cocaine, 2 mg/kg (n = 14), and the plasma concentrations of fibrinogen, plasminogen, and lipoprotein(a), as well as tissue plasminogen activator activity and plasminogen activator inhibitor (PAI-1) activity, were measured. RESULTS No variable changed with the use of intranasal saline, whereas the use of cocaine resulted in an increase in PAI-1 activity (0.48 + 0.06 [mean + SD] nmol/L at baseline, 0.53 + 0.05 nmol/L after cocaine, P = 0.011). CONCLUSION Intranasal cocaine administration is associated with an increase in plasma PAI-1 activity. This may be important in recreational users of cocaine who experience vascular thrombosis.

Left ventricular hypertrophy associated with chronic cocaine abuse.

BackgroundThis study was performed to determine whether chronic cocaine abuse is associated with left ventricular hypertrophy in humans. Methods and ResultsA consecutive series of 40 chronic cocaine abusers 23–44 years old who were enrolled in an inpatient drug rehabilitation program were considered for the study. Subjects with elevated resting blood pressure (n = −4) or a history of hypertension (n = 3) were excluded. Technically adequate two-dimensional echocardiograms were obtained in 30 cocaine abusers and 30 age- and race-matched nornmal control subjects. All subjects were men, and the groups were similar with regard to resting blood pressure, height, weight, and body surface area. All echocardiograms were read in blinded fashion, and left ventricular mass was calculated by the area-length method. Left ventricular cavity dimensions and wall motion were normal in all subjects. Left ventricular mass index was higher in the cocaine group (103 ± 24 versus 77 ± 14 g/m2, p = .0001). Posterior wall thickness was increased (1.2 cm or more) in 13 cocaine abusers (43%) compared with four controls (p = 0.0099). ConclusionsChronic cocaine abuse is associated with increased left ventricular niass index and wall thickness. Left ventricular hypertrophy may provide a substrate facilitating the development of myocardial ischemia and/or arrhythmias in cocaine abusers.

No Association Between Plasma Lipoprotein(a) Concentrations and the Presence or Absence of Coronary Atherosclerosis in African-Americans

Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with coronary atherosclerosis in Caucasians. Although African-Americans have a higher median plasma Lp(a) concentration than Caucasians, they do not have a greater incidence of coronary atherosclerosis. This study was performed to determine whether the plasma concentration of Lp(a) is associated with coronary atherosclerosis in African-Americans. The fasting plasma concentrations of Lp(a) and lipoproteins were measured in 140 African-American subjects (62 men, 78 women, aged 31 to 80 years) 18 +/- 16 months (mean +/- SD) after they underwent coronary angiography: 72 had angiographically normal coronary arteries and 68 had > 70% luminal diameter narrowing of one or more major epicardial coronary arteries. The groups were similar in age, sex, and other risk factors for atherosclerosis. The subjects with coronary artery disease had higher plasma concentrations of total cholesterol, triglycerides, and VLDL and LDL cholesterol (P = .04) and lower concentrations of HDL cholesterol (P = .0001) than subjects without coronary artery disease, but there was no significant difference in the plasma concentration of Lp(a). The distribution of apolipoprotein(a) alleles by size was also not significantly different between the two groups. These results suggest that the plasma concentration of Lp(a) is not an independent risk factor for coronary artery disease in African-Americans.

Genetic modification of the vessel wall. Comparison of surgical and catheter-based techniques for delivery of recombinant adenovirus.

BACKGROUND Gene transfer can potentially alter vessel wall biology and intervene in the pathogenesis of human disease. Although several methods for vector delivery have been described, systematic comparisons of these methods are unavailable. Therefore, this study compared three catheter-based strategies and a surgical technique to assess efficient and selective gene transfer to the vascular wall. METHODS AND RESULTS The common carotid arteries and internal jugular veins of New Zealand White rabbits were infected with recombinant adenovirus encoding either firefly luciferase or a nuclear-localizing variant of beta-galactosidase. Delivery of recombinant virus was achieved by one of four methods: (1) instillation within a surgically isolated vessel segment (dwell), (2) a double-balloon catheter, (3) a perforated balloon catheter (Wolinsky), or (4) an angioplasty balloon catheter coated with a hydrophilic adsorbent polymer (Hydrogel). Vessel segments were analyzed 4 days after infection for luciferase and beta-galactosidase activity and for the extent of injury to the vessel wall. Luciferase activity in vessels infected using the double-balloon method was substantially greater than that achieved by catheter-based methods (P < .05). The dwell and double-balloon methods yielded selective expression in intimal cells, whereas arteries infected using perforated or Hydrogel-coated balloon catheters demonstrated expression primarily in medial cells. Tissue injury was most pronounced with the perforated balloon catheter. CONCLUSIONS Prototype catheters permit relatively efficient direct gene transfer to vascular endothelium; however, delivery methods for targeting the medial cells are inefficient. Modifications are needed to optimize direct gene transfer and minimize tissue injury.

Adenovirus-mediated transfer of a gene encoding human apolipoprotein A-I into normal mice increases circulating high-density lipoprotein cholesterol.

BackgroundIn animal models of atherosclerosis, augmentation of circulating high-density lipoprotein (HDL) cholesterol exerts a protective effect against development of fatty streaks and promotes plaque regression. Methods and ResultsTo investigate the potential of gene transfer to increase HDL cholesterol, a fusion gene encoding human apolipoprotein A-I (apo A-I) under the control of the human cytomegalovirus (CMV) immediate-early promoter was packaged into a recombinant adenovirus (AdCMV apo A-I). BALB/c mice infected with AdCMV apo A-I by intravenous injection accumulate immunoreactive apo A-I in serum; levels 5 days after infection averaged 168 mg/dL. A 35% increase in HDL cholesterol and a 47% increase in total cholesterol were observed in mice infected with AdCMV apo A-I compared with control viruses. Analysis of size-fractionated lipoproteins revealed that human apo A-I is incorporated into murine HDL particles. Expression of human apo A-I declined to <10% of maximum after 12 days and mRNA encoding apo A-I, prevalent 5 days after infection, was undetectable in the livers of infected mice after 12 days. ConclusionsWe conclude that adenovirus-mediated transfer of a gene encoding apo A-I produces transient elevations of circulating HDL cholesterol of a magnitude correlated with important physiological effects. These observations suggest the potential for gene-based therapeutic strategies to reduce cardiovascular risk.