James N. Ross

Clinical, echocardiographic, and neurohormonal effects of a sodium-restricted diet in dogs with heart failure.

The use of low-sodium diets in dogs with heart failure is common practice, but randomized, double-blind studies have not been conducted to examine the benefits or problems with this approach. The purpose of this study was to determine the effects of a low-sodium diet on clinical, echocardiographic, and neurohormonal parameters in dogs with heart failure. Dogs with stable chronic heart failure were fed exclusively a low-sodium (LS) and a moderate-sodium (MS) diet for 4 weeks each in a randomized, double-blind, crossover design. At days 0, 28, and 56, echocardiography and thoracic radiography were performed, and blood was analyzed for electrolytes and neurohormones. Fourteen dogs completed the study (9 with chronic valvular disease and 5 with dilated cardiomyopathy). Electrolyte abnormalities were common during the study, and serum sodium and chloride concentrations decreased significantly on the LS diet. Neurohormones did not change significantly between diet groups. Maximum left atrial (P = .05) and standard left atrial (P = .09) size decreased on the LS diet. For dogs with chronic valvular disease, vertebral heart score (P = .05), left ventricular internal dimension in diastole (P = .006) and systole (P = .02), standard left atrial dimension (P = .03), maximum left atrial dimension (P = .02), end-diastolic volume index (P = .02), and end-systolic volume index (P = .04) decreased significantly on the LS diet compared to the MS diet. Although analysis of these data suggests some benefits of a low-sodium diet, future studies with improved study design are needed to further evaluate the advantages and disadvantages of sodium restriction in dogs with heart failure.

Cocaine-induced microvascular spasm in Yucatan miniature swine. In vivo and in vitro evidence of spasm.

The purpose of the present study was to determine the maximal coronary flow reserve (CFR) before and after the administration of successive cocaine doses (0.1, 0.5, 3, and 7 mg/kg IV) for 2 minutes at 10-minute intervals in eight miniature swine. CFR was assessed by the administration of adenosine (0.03, 0.3, and 3 mg IC). Hemodynamic and flow measurements were performed 3 minutes after each dose. Coronary flow (CF) was measured with a Doppler-tipped wire in the proximal left anterior descending coronary artery (LAD). Also, microvessels were dissected, and vessel diameters were measured by a videoelectronic dimension analyzer. In vivo, LAD CF increased fourfold, CFR increased twofold, and coronary vascular resistance (CVR) decreased fourfold after the administration of adenosine. In contrast, LAD CF decreased threefold, CFR decreased onefold, and CVR increased sixfold 3 minutes after the administration of cocaine. Adenosine (3 mg) was repeated 4 minutes after the administration of cocaine, and LAD CF increased 1.4-fold, CVR increased 2.5-fold, and CFR decreased onefold. Thus, adenosine partially reversed the potent cocaine constrictor effect. In vitro, 10(-9) mol/L cocaine decreased the diameter of the coronary microvessels from 129 +/- 12 to 127 +/- 12 microns, and 10(-4) mol/L cocaine decreased coronary microvessel diameter to 114 +/- 15 microns (P < .05). In conclusion, cocaine in vivo decreases CFR, and consistent with the in vivo effect, cocaine in vitro produced constriction of vessels < 200 microns. These results indicate that cocaine can produce profound microvascular spasm. This may contribute to the ischemia/infarction reported in patients who abuse cocaine and who are subsequently found to have normal epicardial coronary arteries.

Acute and chronic cocaine exposure can produce myocardial ischemia and infarction in Yucatan swine

The purpose of this study was to determine whether the acute and chronic administration of cocaine could induce myocardial infarction. Twenty-five minipigs were studied before and 4 months after balloon angioplasty of the left anterior descending artery (LAD) and balloon denudation of the left circumflex artery (LCx). Minipigs received cocaine in the initial and in the 4-month study (0.1, 0.5, and 3 mg/kg i.v.). Minipigs were randomized to group I (high-cholesterol diet + daily cocaine; 500 mg i.m.; n = 8), group II (high-cholesterol diet + no i.v. cocaine; n = 5), group III (chow diet + daily cocaine; 500 mg i.m.; n = 6), group IV (chow diet + no i.v. or i.m. cocaine; n = 6). In vivo, coronary flow significantly decreased and vascular resistance significantly increased after the administration of cocaine. Histamine significantly decreased the luminal diameters (LAD and LCx) in groups I, II and III. There were a total of five acute and 16 chronic infarctions among the three groups that received either short- or long-term cocaine; however, no infarct occurred in group IV. The combination of daily cocaine abuse with a cholesterol-rich diet enhanced coronary vasoreactivity in vivo and in vitro. We conclude that long-term or sporadic cocaine abuse can induce myocardial infarction.

Cocaine-induced microvascular vasoconstriction but differential systemic haemodynamic responses in Yucatan versus Yorkshire varieties of swine.

1 Systemic and coronary haemodynamics were measured in 6 Yorkshire swine and 6 Yucatan miniature swine under isoflurane anaesthesia to investigate the influence of cocaine following its intravenous administration at 1, 3 and 7 mg kg−1. 2 Cocaine in Yorkshire swine decreased mean arterial pressure and rate pressure product (systolic pressure × heart rate), suggesting a cardiac depressant effect, whereas cocaine in Yucatan miniature swine increased these parameters, consistent with a hyperadrenergic state. 3 Cocaine in both Yorkshire swine and Yucatan miniature swine decreased coronary blood flow and coronary flow reserve, and increased coronary vascular resistance. 4 A modest generalized epicardial coronary artery constriction was observed by angiography, without evidence of focal spasm. 5 Our results confirm a marked vasoconstrictor effect of cocaine on the coronary arterial circulation, predominantly distal to the epicardial coronary arteries, but also indicate important differences in the systemic cardiovascular responses to the drug between two closely related strains of animals within the same species. Due to the similarities between the swine and human coronary arterial vasculature, we suggest that vasoconstriction in the coronary microcirculation may produce cardiac toxicity in man.

Effects of cocaine on carotid vascular reactivity in swine after balloon vascular injury.

Background and Purpose The use of cocaine has been associated with stroke. To evaluate carotid vasospasm as a potential mechanism of cocaine-induced stroke, we studied 12 swine immediately and 10 weeks after angioplasty. Methods We compared the short- and long-term vasoconstrictor responses of normal and injured arterial segments to nitroglycerin, histamine, and cocaine in vivo by carotid angiography. We also compared the isometric contractile force responses to different vasoactive substances in normal and injured vascular rings in vivo, and we tested the direct action of cocaine on both arterial segments. Results In in vivo studies, immediately after angioplasty, luminal diameter in the control segment decreased by 30% with histamine 30 μg/kg and by 23% with cocaine 10 mg/kg significantly (P<.001) decreased luminal diameter by 26% in the control and by 34% in the angioplasty segment. Thus, 10 weeks after angioplasty, the transitory loss of carotid vasoconstriction in response to histamine and cocaine reverted, and a moderate generalized vasoconstriction occurred in both segments without localized vasospasm. In vitro, the maximal isometric tension responses to KC1, acetylcholine, histamine, and phenylephrine were similar in vascular rings from normal and angioplasty segments. The median effective doses to histamine and phenylephrine were similar. In contrast, cocaine in concentrations from 10−7 to 10−3 mol/L failed to produce any isometric contraction in vitro. Conclusions Cocaine in vivo produced a generalized carotid vasoconstriction without evidence of localized vaso- spasm; since there was no response to cocaine in vitro, the in vivo effect was most likely mediated by neurohumoral factors rather than by a direct action of cocaine on vascular smooth muscle.

Cocaine-induced transmural myocardial infarction in a Yorkshire swine with normal coronary arteries: Evidence for microvascular and/or epicardial coronary artery spasm☆

Cocaine-induced myocardial infarction with normal coronary arteries is well documented in humans. The exact mechanism of action remains speculative. We report one case of cocaine-induced myocardial infarction with normal coronaries in one swine. Systemic hemodynamics and angiographic, electrocardiographic, echocardiographic, and histopathologic data are presented. Intravenous cocaine (1, 3, 10 mg/kg) produced significant decreases in mean arterial pressure, heart rate, stroke volume, coronary blood flow, and coronary reserve, whereas pulmonary artery diastolic pressure and coronary vascular resistances increased. Left anterior descending and left circumflex coronary artery cross-sectional area decreased by 31% and 64%, respectively, without localized vasospasm. Electrocardiographic changes occurred (3 mm ST elevation in leads II, III, AVF). Peak creatine phosphokinase was 17,220 IU/L. The echocardiogram revealed severe hypokinesis of the inferior wall and normal ventricular function. The animal survived the acute phase of the infarction and the swine was restudied 12 weeks later. Upon rechallenge, systemic and coronary hemodynamics shoved changes similar to those in the previous study. The swine developed ventricular fibrillation and expired after the 10 mg/kg cocaine dose. Macroscopic examination of the external surface of the heart revealed marked diffuse fibrosis in the posteroinferior and lateral left ventricular wall. Our data suggest that the infarct induced by cocaine may have resulted from severe vasoconstriction or spasm at the level of the microcirculation, and/or the epicardial coronary arteries, which shoved slight but significant narrowing throughout their lengths.