Abstract
Despite extensive study, the extent to which cocaine use predisposes to cardiac injury remains unknown. We hypothesized that chronic cocaine binging would increase susceptibility to a subsequent cardiac insult, even in the absence of demonstrable effects on baseline hemodynamics. We studied progression of dilated cardiomyopathy (DCM) induced by rapid ventricular pacing (240 beats per minute) in five conscious, chronically instrumented dogs, after exposure to repetitive cocaine binging (COC) in the form of four consecutive 1 mg/kg i.v. boluses daily for 8 days, to simulate human cocaine abuse. We compared the results with nine control dogs (CON) undergoing the exact pacing protocol, without prior cocaine exposure. Baseline hemodynamics were not significantly altered by chronic cocaine exposure. Following 2 weeks of pacing, COC dogs exhibited accelerated progression to DCM, depressed plasma nitric oxide levels (CON, 17 ± 2 μM; COC, 10 ± 2 μM, p < 0.05), and a significantly greater increase in plasma epinephrine (CON, 33 ± 6 pg/ml; COC, 104 ± 24 pg/ml). After only 2 weeks of pacing, COC dogs demonstrated progressive DCM of a magnitude comparable with end-stage pacing-induced DCM. Chronic cocaine binging increases susceptibility to a subsequent myocardial insult and accelerates progression of DCM in conscious dogs following rapid pacing. These data suggest that although chronic cocaine use alone may not affect myocardial function, it predisposes to greater susceptibility to a superimposed insult.
Cocaine is responsible for the greatest number of hospitalizations in United States attributable to illicit drug use. According to a survey, it was reported that more than 25 million people had used cocaine at some time in their life, and 1.5 million were chronic users. The effects of cocaine on the cardiovascular system are multifaceted and remain incompletely understood. Cardiovascular manifestations of cocaine abuse include chest pain, myocardial ischemia and infarction, arrhythmias, infective endocarditis, aortic dissection and development of dilated cardiomyopathy, and heart failure (Wiener et al., 1986; Kloner et al., 1992; Mouhaffel et al., 1995). There have been increasing numbers of reports of dilated cardiomyopathy in cocaine abusers. Wiener et al. (1986) were the first to describe the occurrence of DCM in the absence of atherosclerotic coronary artery disease in two patients who were cocaine abusers.
Chronic cocaine use in young men who were normotensive and had no symptoms or signs of heart diseases had electrocardiographic and echocardiographic abnormalities including LV hypertrophy (54%), LVEF <0.45 (4%), increased QRS voltage (23%), and episodes of ST-segment elevation on ambulatory monitoring (33%) (Chakko and Myerburg, 1995). However, the mechanism whereby chronic cocaine use predisposes to myocardial injury remains incompletely understood.
There has been both confusion and controversy as to whether cocaine use predisposes to decreased myocardial contractility. Much of the evidence of cocaine-induced myocardial depression comes from studies in anesthetized animals. Prior studies from our laboratory (Stambler et al., 1993; Shannon et al., 1996) have failed to demonstrate adverse effects of acute cocaine administration (1 mg/kg) in conscious dogs. The major effects of cocaine under the circumstances are mediated by increased sympathetic nervous system activation. Moreover, we and others have demonstrated that tolerance develops to the LV and systemic hemodynamic effects of cocaine when administered in a binge fashion (Fischman and Schuster, 1982; Fischman et al., 1985; Ambre et al., 1991; Foltin and Fischman, 1991; Shannon et al., 1996; Tella et al., 1999). Similarly, we have shown that cocaine produces rapid and exaggerated chronotropic, inotropic, and coronary vasoconstrictor responses in conscious dogs with established dilated cardiomyopathy induced by rapid pacing (Mathier et al., 2002). However, relatively few studies have examined the effects of repetitive cocaine exposure over time as consumed by human cocaine users.
Thus, the purpose of the present study was to determine the cardiovascular consequences of chronic cocaine binging in conscious dogs using dose and frequency of administration that mimic human use. A second goal was to determine whether chronic cocaine binging predisposes to or accentuates the cardiovascular effects of a superimposed insult and by what mechanisms.
Materials and Methods
Instrumentation. Fourteen mongrel dogs of either sex weighing 14 to 19 kg were instrumented as described below. Dogs were premedicated with a combination of intramuscular injection of Atropine (0.05 mg/kg) and Acepromazine (0.1–0.5 mg/kg). After approximately 20 min, Pentothal (5% of 1 g) was administered intravenously for induction and intubation. Inhalational anesthesia was maintained by isoflurane (1.0–1.5%) with 2 liters of 100% oxygen.
Using sterile technique through a left atrial thoracotomy, Tygon catheters were implanted in the descending thoracic aorta and right and left atrium. A Silastic catheter was implanted in the coronary sinus. A solid-state miniature pressure transducer (Konigsberg Instruments Inc., Pasadena, CA) was implanted in the apex to measure LV pressures. A sutureless pacing lead was attached to the right ventricular free wall, and stainless steel pacing leads were attached to the left atrial appendage. The left circumflex coronary artery was dissected free for a distance of ∼3 cm, taking care not to damage the vessel adventitia and surrounding nerves. Transonics transit time-flow probes (Transonic Systems Inc., Ithaca, NY) were implanted around the circumflex coronary artery for measuring coronary blood flow and around the proximal aorta to measure aortic flow. Ultrasonic dimension crystals were placed in the long and short axis across the endocardial surface on the left ventricle. Following completion of the instrumentation, catheters and wires were tunneled subcutaneously and externalized intracapsularly. The thoracotomy was closed in layers.
The dogs were allowed to recover from the surgical procedure for 2 weeks, during which time they were trained to lie quietly on the experimental table in a conscious, unrestrained state. Hemodynamic measurements were made with the dogs fully awake, lying quietly on their right side. Animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animal Resources [DHHS Publication No. (National Institutes of Health) 86–23, revised 1996] and the guidelines of the Institutional Animal Care and Use Committee at Allegheny General Hospital.
Experimental Measurement. Aortic and left atrial pressures were recorded from the implanted catheters using Triton System 6-model 200 (Triton Technology, San Diego, CA), calibrated on the day of each experiment using a mercury manometer. Left ventricular pressure was measured using the implanted solid-state micromanometer. The micromanometer was calibrated in vitro using a mercury manometer and in vivo using the aortic and left atrial catheters. Coronary and aortic blood flows were measured using a Transonics flowmeter (T206 Series; Transonics Systems). Measurements of plasma norepinephrine and epinephrine concentration were made using a commercially available high-pressure liquid chromatography kit (Chromosystems Instruments and Chemicals, Munich, Germany). Plasma NO levels were carried out using a kit purchased from R&D Systems, Inc. (Minneapolis, MN).
Two weeks after surgery, five of the dogs (n = 5, COC) were administered cocaine hydrochloride (1 mg/kg over 1 min), dissolved in normal saline, for four doses in a day with 20 min in-between the doses. Drug was administered via the right atrial catheter. The individual dose was chosen as the maximally tolerated dose in a conscious dog that did not result in uncontrollable agitation based on our prior studies (Shannon et al., 1993, 1995; Stambler et al., 1993). This protocol was repeated for total of 8 days (4 days a week for 2 weeks in continuation). Nine dogs served as a control. Hemodynamic data were recorded daily during the binge administration and compared prior to and following the chronic cocaine exposure.
Three days after completion of the binging protocol, rapid ventricular pacing was instituted at 240 beats/min in both groups of dogs (CON and COC) using a programmable pacemaker (Pace Medical, Waltham, MA) worn externally in a protective vest. Pacing was continued until the dogs developed signs and symptoms of severe heart failure. Hemodynamic measurements were made during sinus rhythm after the pacer had been discontinued for at least 30 min.
Data Analysis. A digital instrumentation cassette recorder (PC216Ax, Sony Magnescale; Sony Manufacturing Systems America Inc., Lake Forest, CA) was used to record hemodynamic data. The first derivative of left ventricular pressure (dP/dt) was derived continuously from the LV pressure signal using an online differentiator calibrated against a triangular wave signal of known slope. Mean arterial pressure was derived continuously from the phasic aortic pressure signal using as online electric filter. Stroke volume (SV) = 1000 × CO/HR, left ventricular ejection fraction (LVEF) = 100 × (SV/LVEDV), left ventricular end-diastolic volume (LVEDV) = (LVEDD3)/1000, and systemic vascular resistance (SVR) = 80 × (MAP-right atrial pressure/CO) were derived using shown equations.
Statistical Analysis. All data are expressed as mean ± standard error of the mean. Comparisons of measured parameters between groups were made using repeated measures analysis of variance on a SPSS software program (SPSS Inc., Chicago, IL).
Results
The Effects of Chronic Cocaine Binging on LV and Systemic Hemodynamics.Figure 1 summaries the effects of repetitive cocaine binging on left ventricular systolic (LVP), LV end-diastolic (LVEDP), and mean arterial pressures (MAP) as well as LV dP/dt. The data are summarized based on response to the cocaine binging on days 1, 4, and 8 of the protocol. The first dose of cocaine caused a marked increase in LVP, LVEDP, and MAP that was transient, returning toward but not back to baseline within 20 min. Subsequent doses of cocaine demonstrated an attenuated response, such that by the fourth dose, there was little hemodynamic response. A similar pattern was observed on days 4 and 8. Notably, the chronic exposure to the binging protocol did not alter the baseline measures (Table 1). A similar pattern was observed with LV dP/dt, where the first dose of cocaine was associated with a marked positive inotropic effect while tolerance developed to the subsequent doses. The pattern was identical on days 4 and 8 of the protocol. Notably, there was no evidence that chronic cocaine exposure over 8 days leads to depressed myocardial contractility or altered systemic or ventricular hemodynamics (Table 1). Table 2 reveals that there was no statistically significant change in baseline resting hemodynamics including LV systolic and diastolic function in the dogs exposed to chronic cocaine binging when compared with same dogs before cocaine administration.
The Hemodynamic Effects of Rapid Ventricular Pacing (RVP) following Chronic Cocaine Binging.Figure 2 illustrates the effects of rapid ventricular pacing on LVP, LVEDP, LV dP/dt, and MAP in control and dogs exposed to chronic cocaine binging. The decrease in the LVP after initiation of pacing was more rapid and of a greater magnitude in cocaine exposed dogs compared with control dogs. Similar observations were also evident for LV dP/dt and MAP. An increase in LVEDP was of a greater magnitude at 2 weeks in the dogs exposed to chronic cocaine binging. Figure 3 shows the effects of rapid pacing on heart rate, stroke volume, and posterior wall thickness. The compensatory tachycardia occurred more rapidly and was of a greater magnitude in dogs exposed to chronic cocaine binging compared with control dogs.
Although the decline in CO was not statistically different in the two groups at 2 weeks of RVP (CON, 2.2 ± 0.3 to 1.9 ± 0.2 versus COC, 2.6 ± 0.3 to 2.2 ± 0.3, p = 0.43), stroke volume fell to a significantly greater extent in dogs exposed to chronic cocaine binging compared with control (CON, 27 ± 4 to 20 ± 3 versus COC, 29 ± 3 to 17 ± 2, p < 0.05). The failure to observe a difference in the CO responses was attributed to greater compensatory tachycardia in dogs exposed to chronic cocaine binging compared with control (CON, 85 ± 4 to 99 ± 6 versus COC, 91 ± 6 to 131 ± 6, p < 0.05).
Regional posterior wall thickness decrease to a much greater extent during 2 weeks of pacing in the cocaine-treated animals (Table 3). With respect to global ventricular function, LVEF (CON, 44 ± 7 to 26 ± 3 versus COC, 50 ± 3 to 22 ± 3) declined significantly in both groups and to a greater extent in the cocaine-treated dogs, but the difference was p = 0.056. Although the decrease in the coronary blood flow was not statistically significant at the end of 2 weeks of pacing, coronary blood flow/beat, and coronary perfusion pressure were decreased to a significantly greater extent in dogs exposed to chronic cocaine binging compared with control.
The Neurohormonal Effects of Rapid Ventricular Pacing (RVP) following Chronic Cocaine Binging.Table 3 illustrates that there was no difference in baseline catecholamines and nitric oxide (NO) between control dogs and dogs exposed to chronic cocaine binging prior to pacing. Figure 4 illustrates the alterations in plasma catecholamines and NO during sustained rapid pacing. Norepinephrine levels increased modestly in both groups following 2 weeks of RV pacing. Notably, the relative increase in plasma norepinephrine was comparable between groups. However, cocaine-treated animals demonstrated a very significant increase in plasma epinephrine levels. RVP was associated with greater decrease in NO (CON, 17 ± 2; COC, 10 ± 2 μM, p < 0.05) at 2 weeks.
Discussion
In the present study, we examined whether chronic cocaine binging was associated with the development of LV and systemic hemodynamic abnormalities in conscious dogs. We observed no significant abnormalities in baseline hemodynamics despite repetitive administrative of cocaine over a 2-week period. However, chronic cocaine binging predisposed to an accelerated course of dilated cardiomyopathy following rapid pacing in these dogs. These data demonstrate for the first time that although cocaine binging may itself not cause hemodynamic perturbations, it may predispose to accelerated courses following superimposed cardiac insults.
Prior studies have demonstrated conflicting results with respect to whether continuous cocaine administration leads to altered cardiac contractility as the signature feature of dilated cardiomyopathy (Sutliff et al., 1996; Moritz et al., 2003b). Many of these differences can be reconciled based upon different experimental models used. Under circumstances in which anesthetized animal models have been studied, acute cocaine administration has been shown to be a myocardial depressant (Bedotto et al., 1988; Hale et al., 1989, 1991; Fraker et al., 1990; Hayes et al., 1991). In contrast, several laboratories, including our own, have demonstrated that in conscious, chronically instrumented dogs, cocaine has a sympatho-stimulatory effect in increasing myocardial contractility and heart rate (Wilkerson, 1988; Kiritsy-Roy et al., 1990, Knuepfer and Branch, 1992; Shannon et al., 1993, 1995, 1996, 2000; Stambler et al., 1993). The critical dependence of cocaine on the integrity of sympathetic nervous system likely reconciles these differences. In contrast, under anesthetized conditions when sympathetic tone is altered, the effects are predominantly those of its local anesthetic properties leading to depressed contractility (Przywara and Dambach, 1989; Crumb and Clarkson, 1990; Wilkerson et al., 1991).
Most prior studies have also examined the acute effects of cocaine or have administered cocaine in a continuous fashion, intraperitoneally (Mortiz et al., 2003b), subcutaneously, or intravenously (Nunez et al., 1997; Tella et al., 1999). However, these protocols do not closely recapitulate the habitual use of cocaine by humans. The study attempted to recapitulate recreational binging by giving multiple, repetitive doses of cocaine over a 2-h period and then repeating this every day for a total of 8 days. On any specific day, we observed that cocaine was associated with an initial stimulatory effect (hypertension, tachycardia, and positive inotropy) followed by the development of tolerance. Prior studies have suggested that cocaine self-administration occurs every 20 to 30 min to recapitulate the “high” (Fischman and Schuster, 1982). Our goal was to mimic this administration. Our laboratory has previously described the mechanism of this tolerance as involving depressed central sympathetic stimulation (Shannon et al., 1996). Notably, this is the first report of tolerance occurring on multiple days following the repetitive administrative of cocaine. Importantly, there is no sensitization that occurs following chronic cocaine binging and no effect on resting hemodynamics. We did not attempted to overcome hemodynamic tolerance by increasing the dose, as 1 mg/kg is the near maximal dose of cocaine tolerated by a conscious dog without agitation and seizures (Shannon et al., 1993; Stambler et al., 1993).
In addition, this is the first report that demonstrates that chronic cocaine binging appears to predispose to accelerated course of dilated cardiomyopathy following the imposition of a subsequent cardiovascular insult. In this particular series of studies, we use a well described reproducible model of rapid ventricular pacing, which has been used extensively in our laboratory (Nikolaidis et al., 2001, 2004; Mathier et al., 2002). Prior studies from our laboratory have demonstrated that dogs undergoing rapid ventricular pacing developed progressive dilated cardiomyopathy over a 4-week period (Nikolaidis et al., 2001). When acute cocaine was administered to conscious dogs with established DCM, they develop more marked hemodynamic abnormalities than when acute cocaine was administered to a normal dog (Mathier et al., 2002). In this study, we conducted experiments in which the chronic cocaine binging predisposed to an accelerated course of cardiomyopathy. We observed that conscious, chronically instrumented dogs develop severe end-stage cardiomyopathy within 2 weeks of rapid ventricular pacing when the usual course takes 4 weeks (Nikolaidis et al., 2001). Furthermore, the development of dilated cardiomyopathy in dogs exposed to chronic cocaine binging was associated with increase in epinephrine at an earlier time point. Notably, plasma norepinephrine levels increased similarly in both groups as reported previously (Nikolaidis et al., 2001). Taken together, these data suggest that dilated cardiomyopathy in chronic cocaine users may represent the cumulative effects of chronic cocaine predisposing to an accelerated course following the superimposition of a cardiovascular insult such as rapid pacing.
We used the highly reproducible model of pacing induced dilated cardiomyopathy because of the consistent and time-dependent course of cardiac decompensation. Although not a common cause of human cardiomyopathy, tachycardia induced DCM is a recognized cause of demand-related LV dysfunction (Gillette et al., 1985; Grogan et al., 1992).
The mechanism by which chronic cocaine binging predisposes to an accelerated course remains unknown. We have shown previously (Nikolaidis et al., 2001) that dilated cardiomyopathy may be accelerated by inhibition of nitric oxide synthesis and lower plasma NO levels. Although basal nitric oxide levels were not different, it is conceivable that nitric oxide production (Roig et al., 2000) or metabolism may be altered by chronic cocaine binging. Alternatively, chronic cocaine binging might alter signaling pathways downstream of NO production such as cyclic GMP. Finally, cocaine binging may alter nitroso-redox balance (Devi and Chan, 1996; Fineschi et al., 2001; Moritz et al., 2003a, 2004; Pacifici et al., 2003; Kovacic, 2005) by increasing oxidative stress.
Determining the cellular mechanisms associated with the chronic cocaine-induced predisposition to development of DCM is the subject of ongoing investigation. Nonetheless, this study is the first to document a relationship between chronic cocaine use and the development of an accelerated course of DCM following superimposed insult in a conscious large animal model.
Limitations. We did not measure plasma cocaine levels during the acute binging protocols, and we acknowledge this limitation. We have, however, in previous studies published from our laboratory following similar protocol, proved that there was a progressive increase in both baseline plasma cocaine levels and plasma cocaine responses during the binge protocol (Shannon et al., 1996).
Footnotes
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This work was supported in part by U.S. Public Health Service Grant DA-10480.
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doi:10.1124/jpet.105.088161.
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ABBREVIATIONS: DCM, dilated cardiomyopathy; LV, left ventricle; LVEF, LV ejection fraction; NO, nitric oxide; COC, cocaine; CON, control; dP/dt, first derivative of LV pressure with respect to time; SV, stroke volume; CO, cardiac output; HR, heart rate; LVEDD, LV end-diastolic diameter; SVR, systemic vascular resistance; LVP, LV systolic pressure; LVEDP, LV end-diastolic pressure; MAP, mean arterial pressure(s); RVP, rapid ventricular pacing.
- Received April 19, 2005.
- Accepted August 24, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
References
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