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Cardiovascular Manifestations of Cocaine Abuse
cardiology practice today
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Cardiovascular Manifestations of Cocaine Abuse* A Case of Recurrent Dilated Cardiomyopathy Howard.J. Willens , M .D ,; Sim on C. Chakko, MD .; and Kenn eth M. Kessler, MD . The medical complications of cocaine abuse are being encounte red by clinicians with increasing frequency. The cardiovas cular manifestations of coca ine abuse include chest pain, myocardial ischemia and infarction, congestive he art failure, arrhythmias, inf ective en docarditis, and aortic dis section. Th e pathogenesis of thes e cardiovascular complications has not been fully elucidated but may be related to a combination of the
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ocaine lise can (:ause potenti ally Iife-threa~cning effec ts on the cardiovascular system, 1-3 Th e widespread abuse of this drug durin g the last decad e in the United States has served as the imp etu s for intensive investigation into the mechanisms of cocaine cardiotoxicity. Despit e the significant adva nces in our und erstanding of the actions of cocaine on the cardiovasc ular system, the pr ecise path ogenic basis of the cardiovascular complications associated with cocaine use rem ains und efined , Th e following is a report of a patient with severe chronic dilated cardiom yopathy presum ably caused by the long-term use of freebase cocaine, Th is case will serve as the basis for a discussion of the effects of cocaine on the cardi ovascula r system, CAS E REPORT
A 56-year-old wh ite man was admi tted to the hospital with progressive d yspnea and peda l ede ma of 2 months' durati on, Approximately 12 years before hospital admission, the patient began using coca ine intermittentl y, interspersed with peri ods of daily use, He initially used coca ine by nasal insufflation followed by smoking freebase cocaine in amounts varyi ng between 0,25 g and 2 g. Six years prior to adm ission, he was hospitalized with anasarca and d yspnea, due to adva nced bivent ricular congestive heart failure , A m ultiple gated acqu isition scan demon stra ted cliff use hypokinesis of the left ventricle with an ejection frac tion of 25 perc en t. He was treated wit h intravenous diuretics and lost 20 kg. He was discharged from the hospital and ma intained on a regimen of digoxin, lasix, and an angiotensin-converting enzyme inhibitor. Duri ng the next 6 years, he remained clinically stable without symptoms of congestive heart failur e and dem onstrated sustained radiog raphic improvem ent (Fig I, top and center). Although he abstaine d from dru g use for about 1 year, he then hegan smoking freebase cocaine once per week. On e year prior to hospital ad mission, he began increasing the frequ ency *From the Division of Cardiology, Departm ent of Medicine, University of Miam i School of Medicine, the Card iologv Section, Med ical Service, Depar tment of Veterans Affairs Medical Center, Miami , Fla, and Memorial Hospital, Hollywood , Fla. Repr int requests: Dr, Kessler, VA M edical Center, Cardiology ( IlIA), 1201 LVW 16t h Street , Miam i SSI ?5
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sympathomimetic and membrane anaesthetic effects of cocaine. We present th ese concepts in a cas e discussion (Ch est 1994; 106:594-600) format. -
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M.Vo2=m yocardial oxygen consumpt.ion ..
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Key words: Cocaine abuse; congestive heart failur e; dilated card iomy opathy and amount of cocaine he ingested . Two mon ths before admission, he noted dyspnea on exertion and subseq uently pedal edema, Th e patient did not respond to intensification of his outpatient medic al regimen and was hospit alized , Th e patient had a history of exogenous obesity, a 60-pack-year history of cigarett e smoking, a 2-year history of lype 2 adult onset diabetes mellitu s that was well controlled with oral hypoglycem ic agen ts, and a history of infreq uen t use of sma ll amo unts of alcohol. Th ere was no histor y of chest pain, myocardi al infarction, hypertension, hyperlipidem ia, thyroid disease, rece nt vira l illness, or family history of heart d isease, On ph ysical examination, he was in mod erate respiratory distr ess due to congestive heart failure, Th e electr ocardi ogram revealed sinu s tachycard ia and a nonspecific intra ventricular cond uction def ect. Chest radi ograph y demons trat ed severe ca rdiom egaly with a cardiothoracic ratio of 0.63, a mark ed increase from earlier chest radiograph s (Fig I) , A multi ple gated acq uisition scan revealed an ejection fraction of 18 percen t. Cardiac catheterization and coronary angiograp hy revealed severe pulmonar y art erial and venou s hypert ension with a pulmonary artery pressure of 60/30 rnm Hg and a pulm onary capillary wedg e pressure of 35 mm Hg, a ma rkedl y depr essed cardiac index of 1.4 L /min /m 2 , severe diffuse left vent ricular hypok inesia, and a 40 percent stenotic lesion of the left circumflex arter y, Th e patient was treated with intravenou s d iur etics, vasodilators, and inotro pic agents , and he lost 8 kg. He was discharged from the hospit al with compensated congestive heart failur e, Th e patient refused to ente r a d rug counseling program , Regarding the clinica l manif estat ions of cocaine abuse, the following appl y: 1. Cocaine use results in more emerge ncy depa rtm ent visits by substance abusers than any other illicit dru g, (T / F ) 2, Serious noncardiac complications of coca ine abuse include the following: a. seizures b. cerebro vascular accident s c. noncardi ogen ic pulmonary edema d. abnorm al carbo n monoxide diffusing ca paci ty e, intestinal ischemia F. rh abdomyolysis with ac ute renal fa ilure g all of the above Cardiovascutar Manifestatioins of Cocaine Abuse (Willens. Chakko.
Kessler)
A NSW EHS
FIGURE 1. Chest radiographs (posteroanterior) showing the following: top, cardiomegaly at presentation (1987) durin g cocaine use; center, normalization of card iac size durin g abstinence from cocaine (1987); and bott om , recurr ent cardiomegaly when the patient "rechallenged" himself with cocaine use (1993). See text for clinical details.
3. More than 90 percent of the patients who are evaluated for chest pain following cocaine use are ultimately found to have myocardial ischemia or infarction. (T I F) 4. Cardiovascular complications of cocaine abuse include the following: a. acute myocardial infarction b. amyloid heart disease c. premature coronary artery disease d. ventricular tachyarrhythrnias e. bradyarrh ythmias f. mitral stenosis g. congestive heart failure
1. Tru e. D uring th e last 15 yea rs, new purification techniq ues hav e resu lted in less expe nsive and ph ar macologically more potent form s of cocaine, suc h as fr eebase an d crack. Th ese d evelopments have been associa ted with an increased recreati on al use of coca ine a nd an increase in the m edi cal co m plications resu ltin g from illicit use of th is drug.4 ,5 At th e pr esent tim e , cocaine use ca uses more emerge ncy d epartment visits by substa nce ab users tha n a ny othe r dru g." 2. A ll of th e above. Alth ou gh th e maj ority of medical complications related to cocaine use are ca rd iovascular, serious diso rders involving othe r mul tiple organ syste ms hav e been d escri bed .4,5,7 Ne ur opsy chiatric symptoms a nd disord ers ar e th e seco nd mos t fr equent com plica tio ns relat ed to coca ine use." Minor neuropsychi atric problem s incl ud e anxiety, tr em ors, headaches, confusion, d izziness, an d paresth esias. More ser ious co mplications include seizures, sta tus ep ilepticus, isch emic a nd hem orrhagic ce re brov asc ular accide n ts, an d sub arachnoid hem orrhage oft en com plicating a preexisting berr y a ne urysm or a rte riove nous rnalformation .v! " An incr ease in pulmonary co m plica tions has acco m pa nied th e incr eased avail abilit y of freebase and crack coca ine, both of which ca n be smo ked because of a low er melting point and grea ter heat sta b ility com pare d with coca ine h ydrochl oride.V' Cocaine use has been associated with a n exacerba tion of sym ptoms in asthm atics, noncardi ogen ic pulmon ary edema, and a synd ro me of diffuse pulmonar y infiltrates and hem optysis ca lled crac k lung,5,l l Ad d itiona lly, gas exchange abnorma lities as measured by ca rbo n mon oxid e diffusing ca pacity wer e noted in 10 of 19 fr eeb ase users. 12 Local otola ry ngologic problem s ar e co m m on in cocaine use rs. These include rhinit is, sin usitis, epista xis, mucosal h yp ertrophy, and septal perforations. Cocaine ab use has been associa ted with in travascular thrombosis and ischem ia in m ultip le orga n systems . Besides the card iovascu lar and cen tral nervo us syste ms , severa l cases of in testin al isch emi a ha ve been rep orted. P '!" Renal inf arction due to renal a rte ry th rombosis has a lso been associated with coca ine use,1 5 Rhabdom yolysis is a ser ious complica tio n of cocaine abuse. In one ser ies, 24 percent of pati ents ad m itte d to th e hospita l for cocaine -related problem s wer e found to have rh abdom yolysis.l " In anothe r study of 39 coc a ine users with rh abdom yolysis, one th ird d evelop ed acute ren al Failure.!" 3. False. Th e ca rd iovascula r com p lica tions of coc a ine ab use ar e occ ur ri ng with incr easing fr equen cy. C hes t pain followi ng coca ine use ofte n requires hospita liza tion to ru le ou t acute m yoca rdi al isch emia or necro sis. Although th ere ar e discr epan cies between stud ies, man y patients wit h chest pain following the use of cocain e have not been foun d to have m yocardial necrosis or ischem ia. In a stu dy of 101 patients ad m itte d to the hospital with coca ine -rela ted chest pain , none of the subjects of the study were reported to have e vide nce of m yocardi al in far cti on .l" In a co ntras ting CHEST / 106/ 2/ AUGUST, 1994
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study of 70 patients hospitalized for cocaine-related chest pain, 31 percent had an acute myocardial infarction and another 13 percent had evidence of lschemia.l'' The differential diagnosis of patients presenting with cocainerelated chest pain is problematic, and the disposition of these patients has significant economic consequences. The initial clinical assessment is limited by the frequent occurrence of electrocardiographic abnormalities in these patients due to early repolarization abnormalities and left ventricular hypertrophy, and by the presence of an elevated creatinine phosphokinase value due to rhabdomyolysls .f" Most investigators recommend admitting patients with cocaine-related chest pain to screen for myocardial ischemia and necrosis . At the same time, caution is advised in the use of thrombolytic therapy, since seizures, cerebral hemorrhage, and severe hypertension may complicate cocaine abuse. 4. a, C, d, e, and g Are Correct. While it appears that chest pain in cocaine users is frequently noncardiac, the relationship between cocaine use and myocardial infarction has been well established. A close temporal association between cocaine use and the development of myocardial infarction has been reported in 114 patients.F' In those patients who had myocardial infarction following cocaine use who were studied by coronary angiography or autopsy, approximately one half have had significant coronary artery disease or intimal hyperplasia. One third have had totally normal coronaries. 3.21,22 Approximately one third of patients have had a thrombotic occlusion, although this could conceivably be an underestimation because of spontaneous lysis of clot prior to study.22,23 Myocardial infarction has occurred with smoking, nasal inhalation, and intravenous use of cocaine and appears to be unrelated to the total dose of cocaine. Myocardial infarction has occurred in first-time users as well as in habital users of cocaine.F" In addition to myocardial infarction, there is also evidence linking cocaine use to myocardial ischemia. Eight of 21 patients in an inpatient cocaine treatment program were found to have recurrent significant ST segment elevation during Holter monitoring. The authors concluded that the periods of ST segment elevation were episodes of silent myocardial ischemia possibly caused by coronary spasm. 25 In autopsy and angiographic studies of cocaine users, the frequent findings of significant coronary artery disease in an unusually young population has led to speculation that cocaine causes accelerated atherosclerosis. In an autopsy study of cocaine users in which the mean age was 32 years, 36 percent of the patients had significant narrowing of their coronary arteries.F" In an angiographic study of cocaine users with cardiac symptoms in which the mean age was 37 years, 40 percent of the patients had at least one coronary artery 2: a 70 percent stenotic lesion, while another 20 percent of patients had lesser degrees of coronary atherosclerosis.f" Although both studies were of selected populations, the data do suggest that cocaine use may accelerate the atherosclerotic process. The clinical observations that link cocaine abuse to arrhythmias and cardiomyopathy are not as extensive as the data linking cocaine use and myocardial infarction. Nev596
ertheless, there is substantial evidence that suggests that cocaine can cause cardiomyopathy. Congestive heart failure in cocaine users may be the result of extensive or recurrent myocardial infarction. In addition, several patients with global ventricular dysfunction in the absence of ischemia or infarction have been described. 28-3o Interestingly, despite the severity of the ventricular dysfunction in these patients, reversibility has been noted with abstinence from cocaine in some patients.29.30 Additional evidence for cocaine-related cardiomyopathy comes from a study of 33 cocaine users who were evaluated by coronary angiography because of cardiac symptoms. Eighteen patients (55 percent) had ejection fractions <50 percent. Of these, 12 had coronary artery disease and regional wall motion abnormalities. Six patients had normal coronary arteries associated with diffuse left ventricular dysfunction. Four of these six had ejection fractions <30 percent.F Both sudden death and arrhythmias have been associated with cocaine use. Although sudden death may be due to respiratory failure from central nervous system depression, status epilepticus or cerebral hemorrhage, presumably some cases of sudden death after cocaine abuse are caused by fatal arrhythmias. Many of the reported cases of arrhythmia associated with cocaine use have been in patients with myocardial ischemia or infarctlon.f However, cocaine may have arrhythmogenic properties that contribute importantly to the development of arrhythmias in the setting of ischemia. Additionally, a few cases of primary tachyarrhythmias and primary bradyarrhythmias have been associated with cocaine use without evidence of myocardial ischemia or necrosis. In patients receiving cocaine as a local anesthetic for laryngoscopy, an increased frequency of ventricular premature contractions was noted. 31 Benchimol et al32 reported a case of accelerated idioventricular rhythm after cocaine use. Nanji and Filipenko33 reported a patient who was found to be in asystole after using cocaine and then developed ventricular fibrillation following an epinephrine bolus during resuscitation efforts. Om and colleagues-" described one case that developed Mobitz type I atrioventricular block after cocaine use, and in a second where sinus arrest with escape of an ectopic atrial rhythm occurred following cocaine ingestion. Miscellaneous cardiovascular disorders associated with cocaine use include aortic dissection, left ventricular hypertrophy, and infective endocarditis. 3,35,36 Regarding the pharmacologic and pathophysiologic basis for the cardiac toxicity of cocaine: 5. The pharmacologic effects of cocaine that appear to be related to its cardiovascular toxicities include the following : a. f3-adrenergic receptor blockade b. inhibition of catecholamine reuptake at presynaptic sites in the central and peripheral sympathetic nervous system c. stimulation of a-adrenergic receptors in the systemic and coronary vasculature d. calcium antagonism e. local membrane anesthesia f. increased calcium flux into smooth muscle cells g. increased platelet aggregation and production of Cardiovascular Manifestalioins of Cocaine Abuse (Willens. Chakko, Kessler)
6. 7.
8.
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mediators h. increased adventitial mast cells in the coronary arteries The diverse pharmacologic activities of cocaine are always synergistic in their cardiovascular effects. (T / F) The actions of cocaine in conscious and sedated animal models are always the same . (T / F) Approximately what percentage of patients with myocardial infarction associated with cocaine use have normal coronary arteries? a. 5 percent b. 10 percent c. 33 percent d. 75 percent Although the precise mechanism by which cocaine causes myocardial infarction is unknown, possible factors include the following: a. increased myocardial oxygen consumption (MVo 2 ) b. coronary vasoconstriction c. coronary artery dissection d. thrombosis e. endothelial cell dysfunction Which of the following histologic diagnoses have been found at autopsy or with endomyocardial biopsy specimens in the hearts of patients who use cocaine. a. myocarditis b. contraction band necrosis c. hemochromatosis d. sarcoid granulomas e. Trypanosoma cruzi The e1ectrophysiologic actions of cocaine include the following: a. blockade of the rapid sodium channel b. prolongation of the PR interval c. shortening of the QRS interval d. shortening of the QTc interval e. inducing triggered activity ANSWERS
5. b, c, e, f, g, and h Are Correct. Although the mechanisms by which cocaine causes these cardiovascular disorders are not fully understood, the pathophysiologic condition may be related to some of the well-known pharmacologic properties of cocaine. Cocaine has two major pharmacologic actions . Cocaine blocks the reuptake of neurotransmitters norepinephrine, dopamine, and serotonin at presynaptic sites in the central and peripheral sympathetic nervous system . A related effect is the increased release of epinephrine from the adrenal medulla. This results in an excess of catecholamines at the postsynaptic receptors. Exposure of the l3-adrenergic receptors in myocardial tissue to increased catecholamines produces a positive inotropic and chronotropic effect. Stimulation of the a-adrenergic receptors in the systemic and coronary vasculature by increased catecholamines results in an elevation of the systemic blood pressure and an increase in coronary vascular resistance.P The second major pharmacologic property of cocaine is powerful local membrane anesthesia. Cocaine reduces the permeability of sodium ions at the rapid sodium channel
in the cell membrane. This results in a slowing of rapid depolarization of the action potential. This property is similar to the electrophysiologic actions of class 1 antiarrhythmic drugs.f Besides a sympathomimetic effect and local membrane anesthetic properties, other less well-studied actions of cocaine have been proposed to explain to the cardiac toxicity of cocaine. These include the following: (1) an increase of calcium flux into smooth muscle cells;37 (2) activation of the parasympathetic nervous system causing coronary vasoconstriction.s'' (3) increased platelet aggregation and production of medlatorsj" and (4) an increase in the adventitial mast cells of the coronary arteries.t"
6. False. 7. False. Relating the pharmacologic properties of cocaine to the observed clinical syndromes has been problematic for several reasons. First, the multiple pharmacologic actions of cocaine often have competing effects on the cardiovascular system which offset each other.v' Second , the observed differences between the effects of cocaine on the cardiovascular system in conscious and sedated animals has confounded the study of cocaine in animal models. In conscious animal preparations, the sympathomimetic effects of cocaine are predominant, while in sedated preparations the local membrane anesthetic effect on the sodium channel is more important.V Third, the effects of cocaine on the cardiovascular system vary markedly according to the dose of cocaine administered. Despite these limitations, certain conclusions can be drawn from the large body of research that has been carried out. Probably several pharmacologic actions of cocaine contribute to the pathogenesis of myocardial ischemia and infarction; thus, different pharmacologic properties can be the dominant causative factor in different patients. Myocardial ischemia and infarction are the result of an imbalance between myocardial oxygen supply and demand. In the presence of significant coronary artery stenosis, an increase in MVo 2 , such as occurs with an increase in the rate-pressure product, can lead to inadequate supply and subsequent ischemia or infarction. Conceptually, cocaine would be expected to consistently increase the double product by an increase in myocardial l3-adrenergic stimulation and an increase in a-adrenergic stimulation of the systemic arteries. In controlled human studies, acute intravenous or intranasal doses of cocaine have caused an increase in heart rate and blood pressure.f'' In experimental models , however, contradictory effects have been noted. Both Wilkersont'' and Fraker et al 44 have observed an increase in heart rate and blood pressure in conscious animals. No increase in either parameter was noted in animals sedated with general anesthesia.42,44 In conscious animals or humans, the sympathomimetic effects may dominate the response to cocaine administration. General anesthesia may blunt catecholamine release allowing the local membrane anesthetic effect to be predominant and offset any increase in heart rate and blood pressure caused by 13- and a-adrenergic stimulation. This experimental observation has relevance for the treatment of patients with cardiovascular complications associated with cocaine intoxication. Wilkerson f has conCHEST 1106/ 21 AUGUST, 1994
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elude d that the cardiovascular toxiciti es of cocai ne are only full y expressed wh en the centra l and peripher al ner vous syste m is fully activat ed. Th us, seda tive hypn otics to suppr ess cent ral and peripher al ner vous syste m acti vit y are usef ul therap eut ic age nts for the managem ent of the ca rd iovascular com plications of coca ine int oxicati on .F" 8. c, 33 percen t.
9. a, b, d, and e Are Correct .
sis lead ing to endothelial dam age and dysfunction. This endo thelial d ysfun ction may further pr edi spose to spas m, thrombosis, and accelerat ed athe rosclerosis ultimately lead ing to coro na ry occ lusio n.'
10. a- Myocardit is and b- Contraction Band Necrosis. Although the pathogen esis of ca rd iomyopathy associated with coca ine use is less well un derstood than the relation of cocaine to myocardi al ischemia , some preliminar y insigh ts may be obta ined and hypotheses formulat ed fr om the existing dat a. In vitro and in vivo , anima l studies have documented a direct m yocar di al d epressant effect of coca ine that is inde pe nde nt of increase d MVo 2, reduced coro na ry blood flow, and load ing conditions.44,52..53 Th e relevan ce of thi s acut e m yocardial depressant effect to the developm ent of card iomyo pa thy , however, is unknown becau se th e d epression noted is extreme ly tr an sient. .52 Additionall y, human volunteers given intr anasal cocaine had an incr ease in left ventricul ar dP / d t..54 Alte rna tive theori es have been suggested by the autopsy and endo my ocardial biopsy stud ies of cocain e users. In an autopsy study of 40 pati ent s ~ ho used coca ine, eight patients (20 per cent) wer e found to have m yocarditis..55 In another autopsy study, a large percentage of coca ine users we re foun d to have contrac tio n band necrosis, a findin g also observed in th e m yocardial disease associated with pheochromocy torna.P" Althoug h it is not clea r how these find ings relat e to the developm ent of ca rdiom yopathy , th e studi es do ind icat e tha t m yocyte injur y ind ep endent of ischem ia occurs in pa tien ts who use coca ine .
Accord ing to autopsy and ang iography stud ies, app roximat ely one th ird of th e pa tien ts who have had myocardial infa rction in associa tion with coca ine use have normal corona ry ar te ries.3.21 Although an incr ease in MVo 2 ca used by cocai ne may explain th e developm ent of m yocardial infarc tion and ischemia in pati ent s with significant coronary arte ry disease, anothe r mechani sm mu st be hyp othesized for pati ent s with normal corona ry arte ries. Myoca rdi al infarc tion with angiographicall y normal coronary art eri es has been well describ ed in pati ents wh o do not use cocaine . In these patients , an int era ction betw een coronary arte ry spasm and thrombosis leading to total cor onary artery occlusion has been prop osed as th e mechani sm by whic h m yocardial inf ar cti on occ urs .P Presumably, the path ogenesis of m yocardial inf ar cti on in pat ients wh o use coca ine and have angiog ra phica lly norm al coronary arteri es could be the same . Seve ral case report s suppo rt thi s hypoth esis. Zimm erman et al46 described a young pati en t with cli nica l and electrocard iographic evide nce of recurrent corona ry artery spasm following cocai ne use who was observed to have thrombotic occl usion of the left anterior descend ing artery by coronary angiogra phy . Ascher et al 47 described a patient wh o sustain ed an acu te m yocardial infar ct ion afte r coca ine use an d was found to have spontan eous foca l spasm of his left anter ior descen di ng artery b y coronar y ang iogra phy . Despit e these rep ort s, ergonovine testin g is consisten tly negative in coca ine abusers sugges ting differ ences between th em and pat ient s with Prinzmetal 's variant ang ina. In an ima l models, a modest diffu se vasoconstrictor effect has been noted after cocaine administrati on .48.49 In human volunteers given small doses of intranasal cocai ne , the diamet er of th e left anteri or descending decr eased by 8 to 12 per cent.i" Thi s effect is consist ent with the know n action of coca ine as an a-adrene rgic stim ulant and ca n be blocked by the a -adre nergic blocking age nt ph entolam ine. Th e sam e investiga tors found that in hu man voluntee rs stud ied by ang iogra phy , ther e was incr eased vasoconstric tion of atherosclerotic coronary ar ter y segme nts com pared with norm al segme nts (13 vs 29 percen t) after the adm inistr ation of coca ine int ran asally..50 Prelimi na ry dat a sugges t th at there may be other ph ar macologic act ions of cocai ne that contrib ute to the path ogenesis of m yocardi al infa rc tion. In vitro coca ine enhanced plat elet agg regation and th romboxan e prod uction in response to arachido nic acid .38 Anot her study has found that prostac yclin production by endothelial ce lls in rab bit s is reduced by th e ad min istra tion of coca ine.s i Thus, cocaine may up set the delicat e ba lance bet ween endo thelial and plat elet-deri ved vasoac tive and plat elet-acti ve substa nces in favor of th e medi at ors of vasoconstriction, pla telet agg regation, and thrombosis. Kloner et al3 has proposed a unif ying theor y of m yocardial infa rc tion in cocai ne users. Recurrent spasm may ca use local thrombo-
Th e arrhyt hmias that have been observ ed with coca ine abuse are proba bly caused by m ultiple factors, including myoca rd ial ischem ia, hyp erthermia, aci dosis seco nda ry to seizures, and hyp oxia seconda ry to respirat or y depression. Nevertheless, ther e is strong exp erime ntal evide nce suggesting that cocaine is pr oarrh ythm ic and conditions the m yocardial elect rophysiologic subs tra te to int er act with these othe r der angem ents result ing in arrhy thmias. Both the sym pa thomime tic effec ts of coca ine and th e local mem brane an estheti c effects on cellular ion transport ma y contribute to the gen esis of arrhythmias by cocaine. Int er estin gly, as was pr eviously noted with regard to the effect of cocaine on heart rat e, blood pr essure, and contrac tility, the sym pa thomime tic effects and membran e anesthe tic effects of coca ine on ca rd iac electro physiology are often oppos ing and may coun te rac t eac h othe r."! Inoue and Zipes.5 7 stud ied the sym pathom ime tic effects of coca ine on arrhy thm ias in dogs. Th ey observe d that cocai ne ca used a fur the r shorten ing of the ventric ular effec tive refr actory peri od in response to norepinephrine infusion com pa red wit h norepinephrine inf usion alone. Additionally, cocaine facil itated the ind ucti on of ventr icular tachyarrh ythmias by progr am med stimulation in dogs with experimentally induced infarctions that were recei ving norepinephrine inf usions. Th ese au thors con cluded that coca ine 's potentiation of the shortening of the effective refract ory per iod by norepinephrin e or sym pa thetic dri ve was arrhy thmogenic in the sett ing of m yocardial infar ction. Th ey postulated that the areas of ischemia or necros is are sym pathetic ally dener vat ed and un abl e to respond to th e cocaine and ca tec holamine- induce d shorte n-
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Cardiovascular Manifestatioins of Cocaine Abuse (Willens, Chakko, Kessler)
11. a, b, and e Are Correct .
ing of the effective refractory period leading to further dispersion of refractoriness. This sets th e stage for reentrant arrhythmias.P" Other investigators have em phasized th e local m embrane an esth etic properties of cocaine in the genesis of arrhythmias. In several anim al models using both electrocardiography and electrophysiology techniques, cocaine has been dem on str at ed to hav e effects on myocardial cond uction and repol ari zation that ar e sim ilar to th e class I antiarrh ythmic drugs. Cocaine has been shown to prolong th e PR , QRS, and QT int ervals as well as th e ventricular effective refractory period, AH and HV int ervals.58- 6o Clarkson et al 60 not ed th at th e prolongation of th e QTc inte rval in th eir anim al model was due to cocain e 's effect on th e QRS int erval. The ST int erval was unchanged . Thus, th ey speculat ed th at cocaine beh aved like a cla ss IB antiarrhythmic age nt with fast onset-offset kinetics of sodium channel blockad e.60 The prolongation of conduction caused by cocaine could provide th e substrate for re-entrant a rrhy thm ias. However , Kimura et al6 1 have sugg ested that prolonged cond uct ion is most likely to produce re-entrant arrhythm ias in hearts with heterogen eou s conduction a nd repolarization du e to localiz ed ischemia, infarction, or fibrosis. They suggest that other mechanisms of arrhythmia gen er ation by coca ine need to be studied to explain arrh ythm ias observed in patients with normal hearts. In th eir study , cocaine had elect rophysiologic properties that wer e sim ilar to th e class IA antiarrhythmic agents with prolongation of both conduction and repolarization. At the cellular level, cocaine prol ong ed action po tential duration and caused ea rly afte r-depola rizations with trigger ed activ ity . Th ese electrophysiologic effects of cocaine wer e ca used by slowing of the outward K+ cur re nt. The a ut hors speculated th at thi s might be an alt ernative mechanism by which cocaine was arrhythmogenic.v! The pr ecise m echanism by which cocaine causes ar rh ythmias is unknown. However, th e incr eased sensitivity to catech olamines and th e prolongat ion of conduction and repol ar izati on du e to th e 'slowing of Na + and K+ m em brane cha nne ls, in conjunct ion with oth er ph ysiologic ab normaliti es associated with cocai ne intoxication, provide a strong th eoretic basis for th e gen eration of arrhythmias by cocaine. Several serious car diovascular disord er s, including dilat ed cardiomyopathy, hav e been observ ed to be associated with cocaine abuse. H owever , if in fact coca ine is a ca usative fact or in th e pathogenesis of cardiom yopathy, th e number of re ported cases of dilated cardiom yopathy complicating cocain e abuse is sur prising ly small considering th e wid espread use of this d ru g in this country. Th e association of cocaine use and cardiom yopathy is particularly striking in our patient because he initially developed a dilated card iomy opathy whil e using cocaine and th en had signific an t clinical and radiographic improvem ent during a period of abstinence. Subsequently, th er e was severe recurrence of cong esti ve heart failure wh en he, in effect, " rec ha lleng ed" him self with th e suspected causati ve ag ent by again using cocaine. With th e exce ption of a relatively bri ef histor y of diabet es mellitus, th er e was nothing in his m edi cal history that would pr edispose to th e de velopment of card iomy opa thy. Th e answe r to th e
qu estion as to wh y only certain patients who use cocaine will develop dil at ed cardiomyopathy or othe r cardiovascular complications awaits further research. R EFEHENCES
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Valladares BK, Lemberg L. The Miami vices in the CCU : I. Cardiac manifestations of cocaine use. Heart Lung 1987; 16: 456-58 Isner JM, Estes NAM III, Thompson I'D , Costanzo-Nordin MR, Subrama nian R, Miller G, et al. Acute card iac events temporally related to cocaine abuse. N Engl J Med 1986; 315:438-43 Kloner RA, Hale S, Alker K, Rezkalla S. Th e effects of acute and chronic cocaine use on the heart. Circulation 1992; 85:407-19 Creg ler LL, Mark H . Medical complications of cocaine abuse. N Engl J Med 1986; 315:1495-1500 Warner EA. Cocaine abuse. Ann Intern Med 1993; 119:226-35 Macdonald DI. Cocaine heads ED drug visits. JAMA 1987; 258:2029 Brody SL, Slovis CM, Wr enn KD. Cocaine-related medical pr oblem s: consecutive ser ies of 233 patients. Am J Med 1990; 88:325-3 1 Lichtenfeld PJ, Rubin DB, Feldm an RS. Subara chnoid hemorrhage precipit ated by cocaine snorting. Arch Ne urol 1984; 41:223-24 Levine SR, WashingtonJM, Jefferson MF , Kieran SN, Moen M, Feit H , et al. "Crack" cocaine-associated stroke. Ne urology 1987; 37:1849-53 Golbe Ll , Merkin MD. Cerebr al infarction in a user of free-base cocaine ('crack'). Neurology 1986; 36:1602-04 Cucco RA, Y00 OH , Cre gler L, Chang [C. Nonfatal pulmon ar y ede ma after 'freebase' cocaine smoking. Am Rev Respir Dis 1987; 136:179-81 Itkonen J, Schnoll S, Glassroth J. Pulm onar y dysfunction in 'freebase' cocaine users. Arch Intern Med 1984; 144:2195-97 Nalbandian H, Sheth N, Dietrich R, Georgiou J. Intestinal ischemia caused by cocaine ingestion: report of two cases. Surgery 1985; 97:374-76 Mizrahi S, Laor D, Stamler B. Intestinal ischem ia indu ced by cocaine abuse [letter]. Arch Surg 1988; 123:394 Wohlm an RA. Renal artery thrombosis and embolization associated with intravenous cocaine injection. South Med J 1987; 80:928-30 Welch RD, Todd HK, Krause GS. Incid ence of cocaine-associated rhabd omyolysis. Ann Emerg Med 1991; 20:154-57 Roth D, Alarcon FJ, Fernandez j A, Preston RA, Bourgoignie JJ. Acute rhabdom yolysis associated with cocaine intoxication. N Engl J Med 1988; 319:673-77 Gitter MJ, Goldsmith SR, Dunbar D, Sharkey SW. Cocaine and chest pain: clinical features and outcome of patients hospitalized to rule out my ocardi al inf arction. Ann Intern Med 1991; 115:277-82 Amin M, Gabelm an G, Karpel J, Buttr ick P. Acute myocardi al infarction and chest pain syndromes afte r cocaine use. Am J Cardiol 1990; 66:1434-37 Rubin RB, Ne ugarten J. Cocaine-ind uced rhabdom yolysis masqueradin g as myocardi al ischemia. Am J Med 1989; 86: 551-53 Minor RL, Scott BD, Brown DD , Winniford MD. Cocaine-ind uced myocardial infarction in patient s with norm al coronary art eries. Ann Intern Med 1991; 115:797-806 Rezkalla SH, Hale S, Kloner RA. Cocaine-induced heart diseases. Am Heart J 1990; 120:1403-07 Smith HWB III, Liberm an HA, Brody SL, Batte y LL, Donahue BC, Morris De. Acute m yocardial infarction temporally related to cocaine use: clinical, angiograp hic and pathophysiologic observations. Ann Intern Med 1987; 107:13-8 CHEST / 106 /2 / AUGUST, 1994
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24 Goldfrank LR, Hoffman RS. Th e cardiovascular effects of cocaine. Ann Emerg Med 1991; 20:165-75 25 Nadema nee K, Gorelick DA, Josephson MA, Ryan MA, Wilkins JA, Rober tson HA,'et aL Myocardial ischemia during cocaine withdrawal. Ann Intern Med 1989; 111:876-80 26 Dressler FA, Malekzad eh S, Roberts We. Quantitative analysisof amou nts of coronary arterial nar rowing in cocaine addicts. Am J Car diol 1990; 65:303-08 27 Om A, Warner M, Sabri N, Cecick L, Vetrovec G. Freq uency of coronary artery d isease and left ventricular dysfuncti on in cocaine users. Am J Ca rdiol 1992; 69:1549-52 28 Wiener RS, Lockhart JT, Schwartz RG. Dilated cardiomyop athy and cocaine abuse: report of two cases. Am J Med 1986; 81:699-701 29 Om A, Ellahham S, Orn ato JP. Reversibility of cocaine-induced cardiomyo pathy. Am Heart J 1992; 124:1639-41 30 Chokshi SK, Moore R, Pandi an NG, Isner JM. Reversible cardiomyopath y associated with cocaine int oxication. Ann Intern Med 1989; 111:1039-40 31 Orr D, Jones I. Anesthesia for lar yngoscopy. Anesthesia 1968; 23:194 32 Benchimol A, Bartall H, Desser KB. Accelerated ventricular rhyth m and cocaine abu se. Ann Intern Med 1978; 88:519-20 33 Nanji AA, Filipenko JD . Asystole and ventricular fibrillation associated with cocaine intoxication. Chest 1984; 85:132-35 34 Om A, Ellenbogen KA, Vetrovec GW . Cocaine-induced bradya rrhythmias. Am Heart J 1992; 124:232-34 35 Om A, Ellahham S, Vetrovec GW, Gua rd C, Reese S, Nixon JV. Left ventricular hype rtrophy in normotensive cocaine users. Am Hea rt J 1993; 125:1441-43 36 Chakko S, Fernandez A, Mellman T A, Milanes FJ, Kessler KM, Myerburg RJ. Cardiac manifes tations of cocaine abuse: a cross-sectional study of asymp tomatic men with a history of long-term abuse of 'crack' cocaine: J Am Coil Cardiol 1992; 20:1168-74 37 Isner JM, Chokshi SK. Cardiovascular complications of cocaine. Curr Probl Cardiol 1991; 64:94-123 38 Shannon RP, StarnbIer BS, Komamura K, Ihara T, Vatner SF. Cholinergic modulation of the coronary vasoconstriction ind uced by cocaine in conscious dogs. Circulation 1993; 87:93949. 39 Togna G, Tem pesta E, Togna AR, Dolici N, Cebo B, Caprino L. Platelet responsiveness and biosynthesis of thromboxan e and prostacyclin in response to in vit ro cocaine treatmen t. Haem ostasis 1985; 15:100-07 40 Kolodgie FD , Virmani R, Cornhill JF, Herd erick EE, Smialek J. Increase in atherosclerosis and adventitial mast cells in cocaine abusers:an alternative mechanism of cocaine associated coronary vasospasm and thrombosis. J Am Coil Ca rdiol 1991; 17:1553-60 41 Kloner RA, Hale S. Unraveling the comp lex effects of cocaine on the hear t. Circulation 1993; 87:1046-47 42 Wilkerson RD. Cardiovascular effects of cocaine in conscious dogs: impo rtance of fully func tional auto nomic and central nervous systems. J Pharmacol Exp Th er 1988; 246:466-71 43 Lange RA,Cigarroa RG, YancyCW, Willard JE, Popma lJ ,Sills MN, et aL Cocaine-ind uced coronary-arte ry vasoconstriction. N Engl J Med 1989; 32 1:1557-62 44 Fra ker TD , Temesy-Arrnos PN, Brewster PS, Wilkerson RD.
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Mechanism of cocaine-indu ced myocard ial depression in dogs. Circulation 1990; 81:1012-16 Lindsay V, Pichard A. Acute myocardial infa rction with normal coronary arteries [editorial]. Am J CardioI 1984; 54:902-04 Zimmerman FH, Gustafson GM, Kem p HG. Recurre nt m yocardia l infarc tion associated with cocaine abuse in a young man with norma l coronary arteries: eviden ce for coronary artery spasm culmina ting in th rombosis. J Am Coil Ca rdiol 1987; 9:964-68 Ascher EK, Stauffer JCE, Gaasch WHoCoronary artery spasm, cardiac ar rest, transient elec trocardiographic Q waves and stunned myocard ium in cocaine-associated acute myocard ial infarction. Am J Cardi ol1988; 61:939-41 Hale SL, Alker KJ, Rezkalla S, Figures G, Kloner RA. Adve rse effects of cocaine on cardiovascular dynami cs, myocardial blood flow, and corona ry artery d iam eter in an experimental model. Am Heart J 1989; 118:927-33 Kuhn FE, Johnson MN, Gillis RA, Visner MS, Schaer GL, Gold C, et al. Effect of cocaine on the coronary circulation and systemic hem odynamic in dogs.J Am CoilCardiol 1990;16:1481-91 Flores ED, Lange RA, Cigarroa RG, Hillis LD. Effect of cocaine on coronary artery dim ensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significant stenoses. J Am Coil Cardiol 1990; 16:74-9 Eickhorn EJ, Demian SE, Willard JE, Molina S, Bartul a LL , Alvarez LG, et aL Cocaine use redu ces prostacyclin in rabbit aorta [abstract]. J Am Coil Cardiol 1991; 17:349A Liu C-P, Tu nin C, Kass DA. Transient time course of cocaineinduced cardiac dep ression versus sustained peripheral vasoconstric tion. J Am Coil Car diol 1993; 21:260-68 Morcos NC, Fairhurst AS, Henr y WL. Direct b ut reversible effects of cocaine on the m yocard ium [abstract ]. J Am Coil Cardiol 1988; 11:71A Boehr er JD, Moliterno DJ, WillardJE, Snyde r RW, Hort on RP, Glama nn B, et al. Hemodynamic effects of intranasal cocaine in hum ans. J Am Coil Cardiol 1992; 20:40-3 Virmani R, Robinowitz M, Smialek JE, Smyt h DF . Ca rdiovascular effects of cocaine: an au topsy study of 40 patients. Am Heart J 1988; 115:1068-75 Tazelaar HD , Karch SB, Stephe n BG, Billingham ME. Cocaine and the hear t. Hum Path o11987; 18:195-99 Inoue H, Zipes DP. Cocaine-indu ced supersensitivity and arrhythmogenesis. J Am Coil Cardiol 1988; 11:867-74 Hale SL, Lehmann MH , Kloner RA. Electrocardiographic abnormalities aft er acut e adm inistration of cocaine in the rat. Am J Cardiol 1989; 63:1529-30 Beckman KJ, Park er RB, Hariman RJ, Gallastegiu JL, [avaid JI, Baum an JL. Hemodynamic and electrophysiological actions of cocaine: effects of sodium bicarb onat e as an antidote in dogs. Circu lation 1991; 83:1799-1807 Clarkson CW, Chang C, Stolfi A, George WJ, Yam asaki S, Pickoff AS. Electrophysiologic effects of high cocaine concentrations on intact canine heart : evidence for modulation by both heart rate and autonomic nervous system. Circulation 1993; 87:950-62 Kimura S, Bassett AL, Xi H, Myerburg RJ. Early afterdepo larizations and triggered activit y induced by cocaine: a possible mechanism of cocaine arrhythmogenesis. Circulation 1992; 85:2227-35
Cardiovascular Manifestatio ins of Cocaine Abuse (Willens, Chakko, Kessler)
•
Cardiovascular Manifestations of Cocaine Abuse* A Case of Recurrent Dilated Cardiomyopathy Howard.J. Willens , M .D ,; Sim on C. Chakko, MD .; and Kenn eth M. Kessler, MD . The medical complications of cocaine abuse are being encounte red by clinicians with increasing frequency. The cardiovas cular manifestations of coca ine abuse include chest pain, myocardial ischemia and infarction, congestive he art failure, arrhythmias, inf ective en docarditis, and aortic dis section. Th e pathogenesis of thes e cardiovascular complications has not been fully elucidated but may be related to a combination of the
C
ocaine lise can (:ause potenti ally Iife-threa~cning effec ts on the cardiovascular system, 1-3 Th e widespread abuse of this drug durin g the last decad e in the United States has served as the imp etu s for intensive investigation into the mechanisms of cocaine cardiotoxicity. Despit e the significant adva nces in our und erstanding of the actions of cocaine on the cardiovasc ular system, the pr ecise path ogenic basis of the cardiovascular complications associated with cocaine use rem ains und efined , Th e following is a report of a patient with severe chronic dilated cardiom yopathy presum ably caused by the long-term use of freebase cocaine, Th is case will serve as the basis for a discussion of the effects of cocaine on the cardi ovascula r system, CAS E REPORT
A 56-year-old wh ite man was admi tted to the hospital with progressive d yspnea and peda l ede ma of 2 months' durati on, Approximately 12 years before hospital admission, the patient began using coca ine intermittentl y, interspersed with peri ods of daily use, He initially used coca ine by nasal insufflation followed by smoking freebase cocaine in amounts varyi ng between 0,25 g and 2 g. Six years prior to adm ission, he was hospitalized with anasarca and d yspnea, due to adva nced bivent ricular congestive heart failure , A m ultiple gated acqu isition scan demon stra ted cliff use hypokinesis of the left ventricle with an ejection frac tion of 25 perc en t. He was treated wit h intravenous diuretics and lost 20 kg. He was discharged from the hospital and ma intained on a regimen of digoxin, lasix, and an angiotensin-converting enzyme inhibitor. Duri ng the next 6 years, he remained clinically stable without symptoms of congestive heart failur e and dem onstrated sustained radiog raphic improvem ent (Fig I, top and center). Although he abstaine d from dru g use for about 1 year, he then hegan smoking freebase cocaine once per week. On e year prior to hospital ad mission, he began increasing the frequ ency *From the Division of Cardiology, Departm ent of Medicine, University of Miam i School of Medicine, the Card iologv Section, Med ical Service, Depar tment of Veterans Affairs Medical Center, Miami , Fla, and Memorial Hospital, Hollywood , Fla. Repr int requests: Dr, Kessler, VA M edical Center, Cardiology ( IlIA), 1201 LVW 16t h Street , Miam i SSI ?5
594
sympathomimetic and membrane anaesthetic effects of cocaine. We present th ese concepts in a cas e discussion (Ch est 1994; 106:594-600) format. -
- -- - - - - _ ._ -- ~
~ __ ._ -
M.Vo2=m yocardial oxygen consumpt.ion ..
~_.
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Key words: Cocaine abuse; congestive heart failur e; dilated card iomy opathy and amount of cocaine he ingested . Two mon ths before admission, he noted dyspnea on exertion and subseq uently pedal edema, Th e patient did not respond to intensification of his outpatient medic al regimen and was hospit alized , Th e patient had a history of exogenous obesity, a 60-pack-year history of cigarett e smoking, a 2-year history of lype 2 adult onset diabetes mellitu s that was well controlled with oral hypoglycem ic agen ts, and a history of infreq uen t use of sma ll amo unts of alcohol. Th ere was no histor y of chest pain, myocardi al infarction, hypertension, hyperlipidem ia, thyroid disease, rece nt vira l illness, or family history of heart d isease, On ph ysical examination, he was in mod erate respiratory distr ess due to congestive heart failure, Th e electr ocardi ogram revealed sinu s tachycard ia and a nonspecific intra ventricular cond uction def ect. Chest radi ograph y demons trat ed severe ca rdiom egaly with a cardiothoracic ratio of 0.63, a mark ed increase from earlier chest radiograph s (Fig I) , A multi ple gated acq uisition scan revealed an ejection fraction of 18 percen t. Cardiac catheterization and coronary angiograp hy revealed severe pulmonar y art erial and venou s hypert ension with a pulmonary artery pressure of 60/30 rnm Hg and a pulm onary capillary wedg e pressure of 35 mm Hg, a ma rkedl y depr essed cardiac index of 1.4 L /min /m 2 , severe diffuse left vent ricular hypok inesia, and a 40 percent stenotic lesion of the left circumflex arter y, Th e patient was treated with intravenou s d iur etics, vasodilators, and inotro pic agents , and he lost 8 kg. He was discharged from the hospit al with compensated congestive heart failur e, Th e patient refused to ente r a d rug counseling program , Regarding the clinica l manif estat ions of cocaine abuse, the following appl y: 1. Cocaine use results in more emerge ncy depa rtm ent visits by substance abusers than any other illicit dru g, (T / F ) 2, Serious noncardiac complications of coca ine abuse include the following: a. seizures b. cerebro vascular accident s c. noncardi ogen ic pulmonary edema d. abnorm al carbo n monoxide diffusing ca paci ty e, intestinal ischemia F. rh abdomyolysis with ac ute renal fa ilure g all of the above Cardiovascutar Manifestatioins of Cocaine Abuse (Willens. Chakko.
Kessler)
A NSW EHS
FIGURE 1. Chest radiographs (posteroanterior) showing the following: top, cardiomegaly at presentation (1987) durin g cocaine use; center, normalization of card iac size durin g abstinence from cocaine (1987); and bott om , recurr ent cardiomegaly when the patient "rechallenged" himself with cocaine use (1993). See text for clinical details.
3. More than 90 percent of the patients who are evaluated for chest pain following cocaine use are ultimately found to have myocardial ischemia or infarction. (T I F) 4. Cardiovascular complications of cocaine abuse include the following: a. acute myocardial infarction b. amyloid heart disease c. premature coronary artery disease d. ventricular tachyarrhythrnias e. bradyarrh ythmias f. mitral stenosis g. congestive heart failure
1. Tru e. D uring th e last 15 yea rs, new purification techniq ues hav e resu lted in less expe nsive and ph ar macologically more potent form s of cocaine, suc h as fr eebase an d crack. Th ese d evelopments have been associa ted with an increased recreati on al use of coca ine a nd an increase in the m edi cal co m plications resu ltin g from illicit use of th is drug.4 ,5 At th e pr esent tim e , cocaine use ca uses more emerge ncy d epartment visits by substa nce ab users tha n a ny othe r dru g." 2. A ll of th e above. Alth ou gh th e maj ority of medical complications related to cocaine use are ca rd iovascular, serious diso rders involving othe r mul tiple organ syste ms hav e been d escri bed .4,5,7 Ne ur opsy chiatric symptoms a nd disord ers ar e th e seco nd mos t fr equent com plica tio ns relat ed to coca ine use." Minor neuropsychi atric problem s incl ud e anxiety, tr em ors, headaches, confusion, d izziness, an d paresth esias. More ser ious co mplications include seizures, sta tus ep ilepticus, isch emic a nd hem orrhagic ce re brov asc ular accide n ts, an d sub arachnoid hem orrhage oft en com plicating a preexisting berr y a ne urysm or a rte riove nous rnalformation .v! " An incr ease in pulmonary co m plica tions has acco m pa nied th e incr eased avail abilit y of freebase and crack coca ine, both of which ca n be smo ked because of a low er melting point and grea ter heat sta b ility com pare d with coca ine h ydrochl oride.V' Cocaine use has been associated with a n exacerba tion of sym ptoms in asthm atics, noncardi ogen ic pulmon ary edema, and a synd ro me of diffuse pulmonar y infiltrates and hem optysis ca lled crac k lung,5,l l Ad d itiona lly, gas exchange abnorma lities as measured by ca rbo n mon oxid e diffusing ca pacity wer e noted in 10 of 19 fr eeb ase users. 12 Local otola ry ngologic problem s ar e co m m on in cocaine use rs. These include rhinit is, sin usitis, epista xis, mucosal h yp ertrophy, and septal perforations. Cocaine ab use has been associa ted with in travascular thrombosis and ischem ia in m ultip le orga n systems . Besides the card iovascu lar and cen tral nervo us syste ms , severa l cases of in testin al isch emi a ha ve been rep orted. P '!" Renal inf arction due to renal a rte ry th rombosis has a lso been associated with coca ine use,1 5 Rhabdom yolysis is a ser ious complica tio n of cocaine abuse. In one ser ies, 24 percent of pati ents ad m itte d to th e hospita l for cocaine -related problem s wer e found to have rh abdom yolysis.l " In anothe r study of 39 coc a ine users with rh abdom yolysis, one th ird d evelop ed acute ren al Failure.!" 3. False. Th e ca rd iovascula r com p lica tions of coc a ine ab use ar e occ ur ri ng with incr easing fr equen cy. C hes t pain followi ng coca ine use ofte n requires hospita liza tion to ru le ou t acute m yoca rdi al isch emia or necro sis. Although th ere ar e discr epan cies between stud ies, man y patients wit h chest pain following the use of cocain e have not been foun d to have m yocardial necrosis or ischem ia. In a stu dy of 101 patients ad m itte d to the hospital with coca ine -rela ted chest pain , none of the subjects of the study were reported to have e vide nce of m yocardi al in far cti on .l" In a co ntras ting CHEST / 106/ 2/ AUGUST, 1994
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study of 70 patients hospitalized for cocaine-related chest pain, 31 percent had an acute myocardial infarction and another 13 percent had evidence of lschemia.l'' The differential diagnosis of patients presenting with cocainerelated chest pain is problematic, and the disposition of these patients has significant economic consequences. The initial clinical assessment is limited by the frequent occurrence of electrocardiographic abnormalities in these patients due to early repolarization abnormalities and left ventricular hypertrophy, and by the presence of an elevated creatinine phosphokinase value due to rhabdomyolysls .f" Most investigators recommend admitting patients with cocaine-related chest pain to screen for myocardial ischemia and necrosis . At the same time, caution is advised in the use of thrombolytic therapy, since seizures, cerebral hemorrhage, and severe hypertension may complicate cocaine abuse. 4. a, C, d, e, and g Are Correct. While it appears that chest pain in cocaine users is frequently noncardiac, the relationship between cocaine use and myocardial infarction has been well established. A close temporal association between cocaine use and the development of myocardial infarction has been reported in 114 patients.F' In those patients who had myocardial infarction following cocaine use who were studied by coronary angiography or autopsy, approximately one half have had significant coronary artery disease or intimal hyperplasia. One third have had totally normal coronaries. 3.21,22 Approximately one third of patients have had a thrombotic occlusion, although this could conceivably be an underestimation because of spontaneous lysis of clot prior to study.22,23 Myocardial infarction has occurred with smoking, nasal inhalation, and intravenous use of cocaine and appears to be unrelated to the total dose of cocaine. Myocardial infarction has occurred in first-time users as well as in habital users of cocaine.F" In addition to myocardial infarction, there is also evidence linking cocaine use to myocardial ischemia. Eight of 21 patients in an inpatient cocaine treatment program were found to have recurrent significant ST segment elevation during Holter monitoring. The authors concluded that the periods of ST segment elevation were episodes of silent myocardial ischemia possibly caused by coronary spasm. 25 In autopsy and angiographic studies of cocaine users, the frequent findings of significant coronary artery disease in an unusually young population has led to speculation that cocaine causes accelerated atherosclerosis. In an autopsy study of cocaine users in which the mean age was 32 years, 36 percent of the patients had significant narrowing of their coronary arteries.F" In an angiographic study of cocaine users with cardiac symptoms in which the mean age was 37 years, 40 percent of the patients had at least one coronary artery 2: a 70 percent stenotic lesion, while another 20 percent of patients had lesser degrees of coronary atherosclerosis.f" Although both studies were of selected populations, the data do suggest that cocaine use may accelerate the atherosclerotic process. The clinical observations that link cocaine abuse to arrhythmias and cardiomyopathy are not as extensive as the data linking cocaine use and myocardial infarction. Nev596
ertheless, there is substantial evidence that suggests that cocaine can cause cardiomyopathy. Congestive heart failure in cocaine users may be the result of extensive or recurrent myocardial infarction. In addition, several patients with global ventricular dysfunction in the absence of ischemia or infarction have been described. 28-3o Interestingly, despite the severity of the ventricular dysfunction in these patients, reversibility has been noted with abstinence from cocaine in some patients.29.30 Additional evidence for cocaine-related cardiomyopathy comes from a study of 33 cocaine users who were evaluated by coronary angiography because of cardiac symptoms. Eighteen patients (55 percent) had ejection fractions <50 percent. Of these, 12 had coronary artery disease and regional wall motion abnormalities. Six patients had normal coronary arteries associated with diffuse left ventricular dysfunction. Four of these six had ejection fractions <30 percent.F Both sudden death and arrhythmias have been associated with cocaine use. Although sudden death may be due to respiratory failure from central nervous system depression, status epilepticus or cerebral hemorrhage, presumably some cases of sudden death after cocaine abuse are caused by fatal arrhythmias. Many of the reported cases of arrhythmia associated with cocaine use have been in patients with myocardial ischemia or infarctlon.f However, cocaine may have arrhythmogenic properties that contribute importantly to the development of arrhythmias in the setting of ischemia. Additionally, a few cases of primary tachyarrhythmias and primary bradyarrhythmias have been associated with cocaine use without evidence of myocardial ischemia or necrosis. In patients receiving cocaine as a local anesthetic for laryngoscopy, an increased frequency of ventricular premature contractions was noted. 31 Benchimol et al32 reported a case of accelerated idioventricular rhythm after cocaine use. Nanji and Filipenko33 reported a patient who was found to be in asystole after using cocaine and then developed ventricular fibrillation following an epinephrine bolus during resuscitation efforts. Om and colleagues-" described one case that developed Mobitz type I atrioventricular block after cocaine use, and in a second where sinus arrest with escape of an ectopic atrial rhythm occurred following cocaine ingestion. Miscellaneous cardiovascular disorders associated with cocaine use include aortic dissection, left ventricular hypertrophy, and infective endocarditis. 3,35,36 Regarding the pharmacologic and pathophysiologic basis for the cardiac toxicity of cocaine: 5. The pharmacologic effects of cocaine that appear to be related to its cardiovascular toxicities include the following : a. f3-adrenergic receptor blockade b. inhibition of catecholamine reuptake at presynaptic sites in the central and peripheral sympathetic nervous system c. stimulation of a-adrenergic receptors in the systemic and coronary vasculature d. calcium antagonism e. local membrane anesthesia f. increased calcium flux into smooth muscle cells g. increased platelet aggregation and production of Cardiovascular Manifestalioins of Cocaine Abuse (Willens. Chakko, Kessler)
6. 7.
8.
9.
10.
11.
mediators h. increased adventitial mast cells in the coronary arteries The diverse pharmacologic activities of cocaine are always synergistic in their cardiovascular effects. (T / F) The actions of cocaine in conscious and sedated animal models are always the same . (T / F) Approximately what percentage of patients with myocardial infarction associated with cocaine use have normal coronary arteries? a. 5 percent b. 10 percent c. 33 percent d. 75 percent Although the precise mechanism by which cocaine causes myocardial infarction is unknown, possible factors include the following: a. increased myocardial oxygen consumption (MVo 2 ) b. coronary vasoconstriction c. coronary artery dissection d. thrombosis e. endothelial cell dysfunction Which of the following histologic diagnoses have been found at autopsy or with endomyocardial biopsy specimens in the hearts of patients who use cocaine. a. myocarditis b. contraction band necrosis c. hemochromatosis d. sarcoid granulomas e. Trypanosoma cruzi The e1ectrophysiologic actions of cocaine include the following: a. blockade of the rapid sodium channel b. prolongation of the PR interval c. shortening of the QRS interval d. shortening of the QTc interval e. inducing triggered activity ANSWERS
5. b, c, e, f, g, and h Are Correct. Although the mechanisms by which cocaine causes these cardiovascular disorders are not fully understood, the pathophysiologic condition may be related to some of the well-known pharmacologic properties of cocaine. Cocaine has two major pharmacologic actions . Cocaine blocks the reuptake of neurotransmitters norepinephrine, dopamine, and serotonin at presynaptic sites in the central and peripheral sympathetic nervous system . A related effect is the increased release of epinephrine from the adrenal medulla. This results in an excess of catecholamines at the postsynaptic receptors. Exposure of the l3-adrenergic receptors in myocardial tissue to increased catecholamines produces a positive inotropic and chronotropic effect. Stimulation of the a-adrenergic receptors in the systemic and coronary vasculature by increased catecholamines results in an elevation of the systemic blood pressure and an increase in coronary vascular resistance.P The second major pharmacologic property of cocaine is powerful local membrane anesthesia. Cocaine reduces the permeability of sodium ions at the rapid sodium channel
in the cell membrane. This results in a slowing of rapid depolarization of the action potential. This property is similar to the electrophysiologic actions of class 1 antiarrhythmic drugs.f Besides a sympathomimetic effect and local membrane anesthetic properties, other less well-studied actions of cocaine have been proposed to explain to the cardiac toxicity of cocaine. These include the following: (1) an increase of calcium flux into smooth muscle cells;37 (2) activation of the parasympathetic nervous system causing coronary vasoconstriction.s'' (3) increased platelet aggregation and production of medlatorsj" and (4) an increase in the adventitial mast cells of the coronary arteries.t"
6. False. 7. False. Relating the pharmacologic properties of cocaine to the observed clinical syndromes has been problematic for several reasons. First, the multiple pharmacologic actions of cocaine often have competing effects on the cardiovascular system which offset each other.v' Second , the observed differences between the effects of cocaine on the cardiovascular system in conscious and sedated animals has confounded the study of cocaine in animal models. In conscious animal preparations, the sympathomimetic effects of cocaine are predominant, while in sedated preparations the local membrane anesthetic effect on the sodium channel is more important.V Third, the effects of cocaine on the cardiovascular system vary markedly according to the dose of cocaine administered. Despite these limitations, certain conclusions can be drawn from the large body of research that has been carried out. Probably several pharmacologic actions of cocaine contribute to the pathogenesis of myocardial ischemia and infarction; thus, different pharmacologic properties can be the dominant causative factor in different patients. Myocardial ischemia and infarction are the result of an imbalance between myocardial oxygen supply and demand. In the presence of significant coronary artery stenosis, an increase in MVo 2 , such as occurs with an increase in the rate-pressure product, can lead to inadequate supply and subsequent ischemia or infarction. Conceptually, cocaine would be expected to consistently increase the double product by an increase in myocardial l3-adrenergic stimulation and an increase in a-adrenergic stimulation of the systemic arteries. In controlled human studies, acute intravenous or intranasal doses of cocaine have caused an increase in heart rate and blood pressure.f'' In experimental models , however, contradictory effects have been noted. Both Wilkersont'' and Fraker et al 44 have observed an increase in heart rate and blood pressure in conscious animals. No increase in either parameter was noted in animals sedated with general anesthesia.42,44 In conscious animals or humans, the sympathomimetic effects may dominate the response to cocaine administration. General anesthesia may blunt catecholamine release allowing the local membrane anesthetic effect to be predominant and offset any increase in heart rate and blood pressure caused by 13- and a-adrenergic stimulation. This experimental observation has relevance for the treatment of patients with cardiovascular complications associated with cocaine intoxication. Wilkerson f has conCHEST 1106/ 21 AUGUST, 1994
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elude d that the cardiovascular toxiciti es of cocai ne are only full y expressed wh en the centra l and peripher al ner vous syste m is fully activat ed. Th us, seda tive hypn otics to suppr ess cent ral and peripher al ner vous syste m acti vit y are usef ul therap eut ic age nts for the managem ent of the ca rd iovascular com plications of coca ine int oxicati on .F" 8. c, 33 percen t.
9. a, b, d, and e Are Correct .
sis lead ing to endothelial dam age and dysfunction. This endo thelial d ysfun ction may further pr edi spose to spas m, thrombosis, and accelerat ed athe rosclerosis ultimately lead ing to coro na ry occ lusio n.'
10. a- Myocardit is and b- Contraction Band Necrosis. Although the pathogen esis of ca rd iomyopathy associated with coca ine use is less well un derstood than the relation of cocaine to myocardi al ischemia , some preliminar y insigh ts may be obta ined and hypotheses formulat ed fr om the existing dat a. In vitro and in vivo , anima l studies have documented a direct m yocar di al d epressant effect of coca ine that is inde pe nde nt of increase d MVo 2, reduced coro na ry blood flow, and load ing conditions.44,52..53 Th e relevan ce of thi s acut e m yocardial depressant effect to the developm ent of card iomyo pa thy , however, is unknown becau se th e d epression noted is extreme ly tr an sient. .52 Additionall y, human volunteers given intr anasal cocaine had an incr ease in left ventricul ar dP / d t..54 Alte rna tive theori es have been suggested by the autopsy and endo my ocardial biopsy stud ies of cocain e users. In an autopsy study of 40 pati ent s ~ ho used coca ine, eight patients (20 per cent) wer e found to have m yocarditis..55 In another autopsy study, a large percentage of coca ine users we re foun d to have contrac tio n band necrosis, a findin g also observed in th e m yocardial disease associated with pheochromocy torna.P" Althoug h it is not clea r how these find ings relat e to the developm ent of ca rdiom yopathy , th e studi es do ind icat e tha t m yocyte injur y ind ep endent of ischem ia occurs in pa tien ts who use coca ine .
Accord ing to autopsy and ang iography stud ies, app roximat ely one th ird of th e pa tien ts who have had myocardial infa rction in associa tion with coca ine use have normal corona ry ar te ries.3.21 Although an incr ease in MVo 2 ca used by cocai ne may explain th e developm ent of m yocardial infarc tion and ischemia in pati ent s with significant coronary arte ry disease, anothe r mechani sm mu st be hyp othesized for pati ent s with normal corona ry arte ries. Myoca rdi al infarc tion with angiographicall y normal coronary art eri es has been well describ ed in pati ents wh o do not use cocaine . In these patients , an int era ction betw een coronary arte ry spasm and thrombosis leading to total cor onary artery occlusion has been prop osed as th e mechani sm by whic h m yocardial inf ar cti on occ urs .P Presumably, the path ogenesis of m yocardial inf ar cti on in pat ients wh o use coca ine and have angiog ra phica lly norm al coronary arteri es could be the same . Seve ral case report s suppo rt thi s hypoth esis. Zimm erman et al46 described a young pati en t with cli nica l and electrocard iographic evide nce of recurrent corona ry artery spasm following cocai ne use who was observed to have thrombotic occl usion of the left anterior descend ing artery by coronary angiogra phy . Ascher et al 47 described a patient wh o sustain ed an acu te m yocardial infar ct ion afte r coca ine use an d was found to have spontan eous foca l spasm of his left anter ior descen di ng artery b y coronar y ang iogra phy . Despit e these rep ort s, ergonovine testin g is consisten tly negative in coca ine abusers sugges ting differ ences between th em and pat ient s with Prinzmetal 's variant ang ina. In an ima l models, a modest diffu se vasoconstrictor effect has been noted after cocaine administrati on .48.49 In human volunteers given small doses of intranasal cocai ne , the diamet er of th e left anteri or descending decr eased by 8 to 12 per cent.i" Thi s effect is consist ent with the know n action of coca ine as an a-adrene rgic stim ulant and ca n be blocked by the a -adre nergic blocking age nt ph entolam ine. Th e sam e investiga tors found that in hu man voluntee rs stud ied by ang iogra phy , ther e was incr eased vasoconstric tion of atherosclerotic coronary ar ter y segme nts com pared with norm al segme nts (13 vs 29 percen t) after the adm inistr ation of coca ine int ran asally..50 Prelimi na ry dat a sugges t th at there may be other ph ar macologic act ions of cocai ne that contrib ute to the path ogenesis of m yocardi al infa rc tion. In vitro coca ine enhanced plat elet agg regation and th romboxan e prod uction in response to arachido nic acid .38 Anot her study has found that prostac yclin production by endothelial ce lls in rab bit s is reduced by th e ad min istra tion of coca ine.s i Thus, cocaine may up set the delicat e ba lance bet ween endo thelial and plat elet-deri ved vasoac tive and plat elet-acti ve substa nces in favor of th e medi at ors of vasoconstriction, pla telet agg regation, and thrombosis. Kloner et al3 has proposed a unif ying theor y of m yocardial infa rc tion in cocai ne users. Recurrent spasm may ca use local thrombo-
Th e arrhyt hmias that have been observ ed with coca ine abuse are proba bly caused by m ultiple factors, including myoca rd ial ischem ia, hyp erthermia, aci dosis seco nda ry to seizures, and hyp oxia seconda ry to respirat or y depression. Nevertheless, ther e is strong exp erime ntal evide nce suggesting that cocaine is pr oarrh ythm ic and conditions the m yocardial elect rophysiologic subs tra te to int er act with these othe r der angem ents result ing in arrhy thmias. Both the sym pa thomime tic effec ts of coca ine and th e local mem brane an estheti c effects on cellular ion transport ma y contribute to the gen esis of arrhythmias by cocaine. Int er estin gly, as was pr eviously noted with regard to the effect of cocaine on heart rat e, blood pr essure, and contrac tility, the sym pa thomime tic effects and membran e anesthe tic effects of coca ine on ca rd iac electro physiology are often oppos ing and may coun te rac t eac h othe r."! Inoue and Zipes.5 7 stud ied the sym pathom ime tic effects of coca ine on arrhy thm ias in dogs. Th ey observe d that cocai ne ca used a fur the r shorten ing of the ventric ular effec tive refr actory peri od in response to norepinephrine infusion com pa red wit h norepinephrine inf usion alone. Additionally, cocaine facil itated the ind ucti on of ventr icular tachyarrh ythmias by progr am med stimulation in dogs with experimentally induced infarctions that were recei ving norepinephrine inf usions. Th ese au thors con cluded that coca ine 's potentiation of the shortening of the effective refract ory per iod by norepinephrin e or sym pa thetic dri ve was arrhy thmogenic in the sett ing of m yocardial infar ction. Th ey postulated that the areas of ischemia or necros is are sym pathetic ally dener vat ed and un abl e to respond to th e cocaine and ca tec holamine- induce d shorte n-
598
Cardiovascular Manifestatioins of Cocaine Abuse (Willens, Chakko, Kessler)
11. a, b, and e Are Correct .
ing of the effective refractory period leading to further dispersion of refractoriness. This sets th e stage for reentrant arrhythmias.P" Other investigators have em phasized th e local m embrane an esth etic properties of cocaine in the genesis of arrhythmias. In several anim al models using both electrocardiography and electrophysiology techniques, cocaine has been dem on str at ed to hav e effects on myocardial cond uction and repol ari zation that ar e sim ilar to th e class I antiarrh ythmic drugs. Cocaine has been shown to prolong th e PR , QRS, and QT int ervals as well as th e ventricular effective refractory period, AH and HV int ervals.58- 6o Clarkson et al 60 not ed th at th e prolongation of th e QTc inte rval in th eir anim al model was due to cocain e 's effect on th e QRS int erval. The ST int erval was unchanged . Thus, th ey speculat ed th at cocaine beh aved like a cla ss IB antiarrhythmic age nt with fast onset-offset kinetics of sodium channel blockad e.60 The prolongation of conduction caused by cocaine could provide th e substrate for re-entrant a rrhy thm ias. However , Kimura et al6 1 have sugg ested that prolonged cond uct ion is most likely to produce re-entrant arrhythm ias in hearts with heterogen eou s conduction a nd repolarization du e to localiz ed ischemia, infarction, or fibrosis. They suggest that other mechanisms of arrhythmia gen er ation by coca ine need to be studied to explain arrh ythm ias observed in patients with normal hearts. In th eir study , cocaine had elect rophysiologic properties that wer e sim ilar to th e class IA antiarrhythmic agents with prolongation of both conduction and repolarization. At the cellular level, cocaine prol ong ed action po tential duration and caused ea rly afte r-depola rizations with trigger ed activ ity . Th ese electrophysiologic effects of cocaine wer e ca used by slowing of the outward K+ cur re nt. The a ut hors speculated th at thi s might be an alt ernative mechanism by which cocaine was arrhythmogenic.v! The pr ecise m echanism by which cocaine causes ar rh ythmias is unknown. However, th e incr eased sensitivity to catech olamines and th e prolongat ion of conduction and repol ar izati on du e to th e 'slowing of Na + and K+ m em brane cha nne ls, in conjunct ion with oth er ph ysiologic ab normaliti es associated with cocai ne intoxication, provide a strong th eoretic basis for th e gen eration of arrhythmias by cocaine. Several serious car diovascular disord er s, including dilat ed cardiomyopathy, hav e been observ ed to be associated with cocaine abuse. H owever , if in fact coca ine is a ca usative fact or in th e pathogenesis of cardiom yopathy, th e number of re ported cases of dilated cardiom yopathy complicating cocain e abuse is sur prising ly small considering th e wid espread use of this d ru g in this country. Th e association of cocaine use and cardiom yopathy is particularly striking in our patient because he initially developed a dilated card iomy opathy whil e using cocaine and th en had signific an t clinical and radiographic improvem ent during a period of abstinence. Subsequently, th er e was severe recurrence of cong esti ve heart failure wh en he, in effect, " rec ha lleng ed" him self with th e suspected causati ve ag ent by again using cocaine. With th e exce ption of a relatively bri ef histor y of diabet es mellitus, th er e was nothing in his m edi cal history that would pr edispose to th e de velopment of card iomy opa thy. Th e answe r to th e
qu estion as to wh y only certain patients who use cocaine will develop dil at ed cardiomyopathy or othe r cardiovascular complications awaits further research. R EFEHENCES
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Cardiovascular Manifestatio ins of Cocaine Abuse (Willens, Chakko, Kessler)