From the Department of Internal Medicine (Cardiovascular Division),
University of Texas Southwestern Medical Center, and the Cardiac
Catheterization Laboratory, Parkland Memorial Hospital, Dallas, Tex.
Correspondence to Richard A. Lange, MD, Room CS 7.102, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9047.
Methods and Results—In 20 patients (14 men and 6 women aged 39 to
72 years) referred for cardiac catheterization for the
evaluation of chest pain, we measured heart rate, systemic
arterial pressure, LV pressure and its first derivative
(dP/dt), and LV volumes and ejection fraction before and during the
final 2 to 3 minutes of a 15-minute intracoronary infusion of
saline (n=10, control subjects) or cocaine hydrochloride 1 mg/min
(n=10). No variable changed with saline. With cocaine, the drug
concentration in blood obtained from the coronary sinus was
3.0±0.4 (mean±SD) mg/L, similar in magnitude to the blood cocaine
concentration reported in abusers dying of cocaine intoxication.
Cocaine induced no significant change in heart rate, LV dP/dt (positive
or negative), or LV end-diastolic volume, but it caused an
increase in systolic and mean arterial pressures,
LV end-diastolic pressure, and LV end-systolic
volume, as well as a decrease in LV ejection fraction.
Conclusions—In humans, the intracoronary infusion of
cocaine sufficient in amount to achieve a high drug concentration in
coronary sinus blood causes a deterioration of LV
systolic and diastolic performance.
In previously published studies,6 we showed that
the intracoronary infusion of cocaine in humans (1) was safe,
(2) caused no change in coronary arterial blood
flow, and (3) allowed us to achieve a large "local"
(intracoronary) cocaine concentration, similar in magnitude to
that reported in cocaine abusers dying of intoxication, with minimal
systemic effects. With this in mind, we designed the present study
to assess the effects of a direct intracoronary infusion of
cocaine on LV systolic and diastolic
performance in humans. On the basis of previously published
data from anesthetized and conscious
dogs,1 2 3 4 we hypothesized that the attainment of
a high intracoronary cocaine concentration would cause a
substantial deterioration of LV systolic function (dP/dt and
ejection fraction) as well as an increase in LV
end-diastolic pressure.
Experimental Protocol
Once all catheters were positioned appropriately, heart rate, systemic
arterial pressure (phasic and mean), and LV pressure and
its first derivative (dP/dt) were recorded, and single-plane left
ventriculography was performed in the 30° right anterior oblique
projection with 50 to 55 mL of nonionic contrast material. Then, 15
minutes was allowed to elapse so that all variables returned to
baseline. Each patient was then randomly assigned to receive a
15-minute intracoronary infusion of saline (group 1, control
subjects, n=10) or cocaine hydrochloride (10% solution at 1 mg/min;
total dose, 15 mg) (group 2, n=10). During the final 2 to 3 minutes of
the 15-minute intracoronary infusion,
hemodynamic measurements and left ventriculography were
repeated, and blood was procured from the femoral artery and
coronary sinus for measurement of cocaine concentration.
Subsequently, each subject received nitroglycerin 0.4
mg sublingually, and selective coronary angiography was
completed.
Statistical Methodology
Intracoronary saline (n=10) induced no change in any
variable (Table
In previously published studies in dogs, a large dose of
intravenous cocaine (4 to 10 mg/kg) caused an immediate and
profound decrease in LV contractile
performance1 2 and ejection
fraction3 4 as well as an increase in LV
end-diastolic pressure.2 3 In
anesthetized dogs, the intravenous infusion of
cocaine (0.5 mg · kg-1 ·
min-1) increased systemic arterial
pressure and LV end-diastolic pressure and decreased LV
ejection fraction3 ; heart rate, LV dP/dt, and
coronary arterial dimensions were unchanged. In a
similar experimental preparation (anesthetized dogs) in which
heart rate and systemic arterial pressure were held
constant, cocaine 0.25 mg · kg-1 ·
min-1 IV caused a fall in positive and negative
LV dP/dt and a rise in LV end-diastolic
pressure,1 suggesting that the drug had direct
cardiotoxic effects. Also in anesthetized dogs, Hale et
al2 compared the effects of an
intravenous bolus of cocaine (10 mg/kg) with those of a
10-minute intravenous cocaine infusion (10 mg/kg). Both
preparations induced a decrease in LV dP/dt, an increase in
echocardiographically determined LV
diastolic and systolic dimensions, and an increase
in LV end-diastolic pressure. More recently, Fraker et
al4 gave intravenous cocaine (4
mg/kg) to conscious and sedated dogs. In conscious dogs, heart rate and
systemic arterial pressure rose, and
echocardiographically determined regional LV ejection
fraction fell precipitously. In sedated dogs, heart rate and systemic
arterial pressure did not change; nonetheless, LV ejection
fraction fell dramatically. In short, large amounts of
intravenous cocaine in anesthetized and conscious
dogs, resulting in peak blood concentrations of
3.5,3 4.1,4 and
7.51 mg/L, caused a substantial deterioration of
LV systolic performance as well as a rise in LV
end-diastolic pressure.
In humans, long-term cocaine use has been reported to cause LV
systolic dysfunction. Wiener et al7
described dilated cardiomyopathy in two long-term
cocaine abusers, after which others8 9 reported
an association of cocaine use and LV systolic dysfunction.
Chokshi et al9 described a young woman with
reversible, profound myocardial depression after binge cocaine use.
They hypothesized that the observed LV dysfunction was due to a direct
cardiotoxic effect of the drug rather than drug-induced
catecholamine excess10 or
metabolic derangements (eg, hypoxia or acidosis).
Bertolet et al11 found evidence of LV
systolic dysfunction (by radionuclide ventriculography) in 7%
of asymptomatic long-term cocaine users. These and other
reports provide evidence that repetitive cocaine exposure may depress
LV systolic function. However, the effects of short-term
cocaine administration on LV performance in vivo have not been
well characterized in that no study has examined the immediate effects
of a large dose of cocaine on LV systolic and
diastolic function in humans.
In our study, we infused cocaine directly into the left
coronary artery in humans to achieve a relatively high
"local" (intracoronary) drug concentration. The cocaine
concentration in coronary sinus blood in our 10 group 2
subjects averaged 3.0±0.4 mg/L, similar in magnitude to the peak blood
concentration in dogs reported by Bedotto et al3
and Fraker et al4 and in drug abusers dying of
cocaine intoxication12 ; the corresponding
systemic concentration averaged 0.17±0.06 mg/L. Similar to the results
obtained in dogs, high-dose intracoronary cocaine in humans
exerted a deleterious effect on LV systolic
performance, as reflected by a rise in LV end-systolic
volume and a fall in ejection fraction (Table
Our study has limitations. First, we did not assess the effects
of a high systemic cocaine concentration on LV function. The systemic
infusion of cocaine in doses of sufficient size to achieve a drug
concentration comparable to those reported in experimental animals is
not feasible in human volunteers. However, we achieved a high cocaine
concentration in the coronary circulation via direct
intracoronary infusion. It is possible that high systemic
concentrations of the drug, with associated secondary effects (ie,
elevated catecholamines or systemic arterial
pressure), may cause an even greater degree of LV dysfunction. Second,
we observed that cocaine altered LV compliance (eg, increased LV
end-diastolic pressure without altering LV
end-diastolic volume), but we assessed only one measure of
LV diastolic function, -dP/dt, which was not changed with
cocaine administration. LV -dP/dt reflects events that occur early in
diastole.15 In the future, the
measurement of
In conclusion, in humans, the intracoronary infusion of cocaine
sufficient in amount to achieve a high concentration of drug in the
coronary circulation causes a deterioration of LV
systolic and diastolic function.
Received August 28, 1997;
revision received November 5, 1997;
accepted December 1, 1997.
2.
Hale SL, Alker KJ, Rezkalla S, Figures G, Kloner
RA. Adverse effects of cocaine on cardiovascular
dynamics, myocardial blood flow, and coronary artery diameter
in an experimental model. Am Heart J. 1989;118:927–933.[Medline]
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3.
Bedotto JB, Lee RW, Lancaster LD, Olajos M, Goldman S.
Cocaine and cardiovascular function in dogs: effects on
heart and peripheral circulation. J Am Coll
Cardiol. 1988;11:1337–1342.[Abstract]
4.
Fraker TD Jr, Temesy-Armos PN, Brewster PS, Wilkerson
RD. Mechanism of cocaine-induced myocardial depression in dogs.
Circulation. 1990;81:1012–1016.
5.
Boehrer JD, Moliterno DJ, Willard JE, Snyder RW II,
Horton RP, Glamann DB, Lange RA, Hillis LD. Hemodynamic
effects of intranasal cocaine in humans. J Am Coll
Cardiol. 1992;20:90–93.[Abstract]
6.
Daniel WC, Lange RA, Landau C, Willard JE, Hillis LD.
Effects of the intracoronary infusion of cocaine on
coronary arterial dimensions and blood flow in
humans. Am J Cardiol. 1996;78:288–291.[Medline]
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7.
Wiener RS, Lockhart JT, Schwartz RG. Dilated
cardiomyopathy and cocaine abuse: report of two
cases. Am J Med. 1986;81:699–710.[Medline]
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8.
Duell PB. Chronic cocaine abuse and dilated
cardiomyopathy. Am J Med. 1987;83:601. Letter.[Medline]
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9.
Chokshi SK, Moore R, Pandian NG, Isner JM.
Reversible cardiomyopathy associated with cocaine
intoxication. Ann Intern Med. 1989;111:1039–1040.
10.
Lam JB, Shub C, Sheps SG. Reversible dilatation of
hypertrophied left ventricle in pheochromocytoma: serial two
dimensional echocardiographic observations. Am
Heart J. 1985;109:613–615.[Medline]
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11.
Bertolet BD, Freund G, Martin CA, Perchalski DL,
Williams CM, Pepine CJ. Unrecognized left ventricular
dysfunction in an apparent healthy cocaine abuse population. Clin
Cardiol. 1990;13:323–328.[Medline]
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12.
Escobedo LG, Ruttenber AJ, Agocs MM, Anda RF, Wetli CV.
Emerging patterns of cocaine use and the epidemic of cocaine overdose
deaths in Dade County, Florida. Arch Pathol Lab Med. 1991;115:900–905.[Medline]
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13.
Smith VE, Zile MR. Relaxation and
diastolic properties of the heart. In: Fozzard HA, Haber E,
Jennings RB, Katz AM, Morgan HE, eds. The Heart and
Cardiovascular System. 2nd ed. New York, NY: Raven
Press, Ltd; 1992:1353–1367.
14.
Perreault CL, Hague NL, Ransil BJ, Morgan JP. The
effects of cocaine on intracellular Ca2+ handling
and myofilament Ca2+ responsiveness of ferret
ventricular myocardium. Br J
Pharmacol. 1990;101:679–685.[Medline]
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15.
Grossman W. Evaluation of systolic and
diastolic function of the myocardium. In: Baim
DS, Grossman W, eds. Cardiac Catheterization,
Angiography, and Intervention. 5th ed. Baltimore, Md: Williams &
Wilkins; 1996:333–355.
16.
Ritchie JM, Greene NM. Local anesthetics. In: Gilman
AG, Goodman LS, Rall TW, Murad F, eds. The Pharmacologic Basis of
Therapeutics. 7th ed. New York, NY: Macmillan;
1985:309–310.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Effects of the Intracoronary Infusion of Cocaine on Left Ventricular Systolic and Diastolic Function in Humans
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—In dogs, a large
amount of intravenous cocaine causes a profound
deterioration of left ventricular (LV) systolic
function and an increase in LV end-diastolic pressure. This
study was done to assess the influence of a high intracoronary
cocaine concentration on LV systolic and diastolic
function in humans.
Key Words: cocaine • ventricles • systole • diastole
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
In dogs, a
large amount of intravenous cocaine (4 to 10 mg/kg) causes
a worsening of left ventricular (LV) systolic
function (decline in LV dP/dt1 2 and ejection
fraction3 4 ) and a rise in LV
end-diastolic pressure.2 3 In
contrast, in humans, a small amount of intranasal cocaine (2 mg/kg)
induces a modest increase in LV contractility, as
reflected by the first derivative of LV pressure
(dP/dt),5 and LV end-diastolic
pressure is unchanged. The influence of a large amount of cocaine on LV
systolic and diastolic performance in
humans is unknown.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Population
We studied 20 patients (14 men and 6 women aged 39 to 72 years)
undergoing cardiac catheterization for the evaluation
of chest pain. None had an unstable cardiac condition or other acute
medical illness, active congestive heart failure, or valvular
heart disease, and none admitted to previous cocaine use. Patients with
50% luminal diameter narrowing of the left main coronary
artery were not enrolled in the study. The protocol was approved by the
Human Subjects Review Committee of the University of Texas Southwestern
Medical Center, and all subjects gave written informed consent.
Medications that could influence LV function (ß-adrenergic blockers,
calcium antagonists, and long-acting nitrates) were
discontinued >12 hours before study. All subjects were studied in the
fasting state after premedication with oral diazepam 5 to 10 mg.
Under local anesthesia with marcaine, an 8F
sheath was inserted percutaneously in the right femoral
artery, through which a Judkins catheter was advanced to the ostium of
the left coronary artery. A single angiogram was performed with
nonionic contrast material to exclude left main coronary artery
disease, after which the catheter was removed. After infiltration with
marcaine, a 6F sheath was inserted percutaneously in
the left femoral artery, and a cutdown was performed in the right
antecubital fossa for isolation of a basilic vein. An 8F Goodale-Lubin
catheter was advanced to the coronary sinus via the right
basilic vein; its position was confirmed fluoroscopically and
oximetrically, and it was secured in place for the duration of the
study. A 7F micromanometer-tipped pigtail catheter
(Millar Instruments) was advanced to the left ventricle via the right
femoral artery, and a 6F Judkins catheter was advanced to the ostium of
the left coronary artery via the left femoral artery. Systemic
arterial pressure was measured through the side-port
extension of the right femoral arterial sheath, and heart
rate was determined electrocardiographically.
All results are reported as mean±SD. The two groups were
compared with Student's t test. Within each group, the
changes induced by saline or cocaine were assessed with a repeated
measures ANOVA. For all analyses, a value of P<.05
was considered significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The two groups were similar in age, sex, extent of
coronary artery disease, and LV ejection fraction
(Table
). Among the
hemodynamic variables at baseline, only LV -dP/dt
differed between the groups.
View this table:
[in a new window]
Table 1. Hemodynamic Variables at Baseline and 15
Minutes After Administration of Saline or Cocaine 
). Intracoronary cocaine (n=10) resulted in
an average cocaine concentration in coronary sinus blood of
3.0±0.4 mg/L and in systemic (femoral arterial) blood of
0.17±0.06 mg/L. Of the hemodynamic and
ventriculographic variables measured, heart rate, LV dP/dt
(positive and negative), and LV end-diastolic volume did
not change with cocaine. Systolic and mean arterial
pressures, LV end-diastolic pressure (Fig 1), and LV end-systolic volume
all increased, and LV ejection fraction fell (Fig 2).
View larger version (18K):
[in a new window]
Figure 1. Left ventricular (LV)
end-diastolic pressure before and after an
intracoronary saline (left) or cocaine (right) infusion. Each
line represents the data from one patient, and mean±1 SD
values are shown on either side of each set of lines. LV
end-diastolic pressure increased with intracoronary
cocaine (*P=.001 compared with baseline).
View larger version (16K):
[in a new window]
Figure 2. Left ventricular ejection fraction
before and after an intracoronary saline (left) or cocaine
(right) infusion. Each line represents the data from one
patient, and mean±1 SD values are shown on either side of each set of
lines. Left ventricular ejection fraction decreased with
intracoronary cocaine (*P=.03 compared with
baseline).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In the present study, a high intracoronary cocaine
concentration in humans, achieved via a direct infusion into the left
coronary artery, exerted a deleterious effect on
LV systolic and diastolic performance.
Intracoronary cocaine induced no significant change in heart
rate, LV dP/dt (positive or negative), or LV end-diastolic
volume (Table). At the same time, it caused systolic and mean
arterial pressures, LV end-diastolic pressure,
and LV end-systolic volume to rise (Table, Fig 1) and LV
ejection fraction to fall (Table, Fig 2). , Fig 2). Additionally, it
caused an increase in LV end-diastolic pressure without a
concomitant change in LV end-diastolic volume (Table, Fig 1). Thus, dogs and humans appear similar in the manner in which
their LV systolic performance responds to a high
intracoronary concentration of cocaine; moreover, LV
diastolic function in both species is impaired after drug
administration. Myocardial relaxation occurs when calcium ions
dissociate from contractile proteins and are sequestered by the
sarcoplasmic reticulum.13 In isolated myocardial
tissue, cocaine-induced alterations in calcium ion handling result in
an increase in the intracytosolic calcium concentration, causing
prolongation of the calcium transient and a negative lusitropic
effect.14 Alternatively, cocaine may cause a
change in myofilament calcium ion sensitivity, resulting in impaired LV
systolic or diastolic performance. 
(the time constant of isovolumic pressure decline)
may provide a more sophisticated analysis of the effects of
cocaine on diastolic function. Third, we cannot exclude the
possibility that the modest increase in systemic arterial
pressure after intracoronary cocaine administration contributed
to the observed decline in LV systolic function. Previous
studies have demonstrated that serum cocaine concentrations similar to
those obtained in the present study cause a modest increase in
systemic arterial pressure,5
resulting from inhibition of presynaptic reuptake of
epinephrine and norepinephrine by
peripheral neurons.16 However, we
showed previously5 that LV performance
increases after intranasal cocaine despite an increase in systemic
arterial pressure similar in magnitude to that observed in
the present study. Thus, the small increase in afterload probably
does not explain the decrease in LV systolic function. Our
study also has certain strengths in that it is the first to assess the
direct effects of large amounts of cocaine on myocardial function in
human subjects.
Acknowledgments
This study was supported by a grant from the National Institute
on Drug Abuse (RO-1 DA10064).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Abel FL, Wilson SP, Zhao R, Fennell WH. Cocaine
depresses the canine myocardium. Circ
Shock. 1989;28:309–319.[Medline]
[Order article via Infotrieve]
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