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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Concl3usions
  8. References

J Clin Hypertens (Greenwich). 2011;13:744–749. ©2011 Wiley Periodicals, Inc.

Despite the increased risk of myocardial infarction, aortic dissection, and arrhythmias in patients with hypertension who use cocaine, the hemodynamic and arrhythmogenic effects of cocaine use have not been well characterized in this population. The authors hypothesized that patients with hypertension demonstrate extreme, transient changes in arterial pressures as well as new arrhythmic activity during cocaine use. Ambulatory blood pressures, heart rates, and electrocardiograms (AECGs) were recorded for 48 hours in 10 patients with a history of hypertension who smoke cocaine. Active cocaine use was identified through patient diaries and manual activation of the blood pressure cuff. Of the 10 patients studied (6 men, 7 African Americans, age 49±8 years), 8 were taking antihypertensive medications. The mean blood pressure prior to cocaine use was 126/77 mm Hg and average increase in systolic, diastolic, and mean arterial pressure after use was 74 mm Hg, 30 mm Hg, and 45 mm Hg, respectively (P<.0001 for all). There was no significant change in heart rate. AECGs demonstrated arrhythmic activity during cocaine use, including 6 patients with increased atrial and ventricular ectopy, 2 patients with episodes of nonsustained atrial tachycardia, and 1 patient with 3 episodes of nonsustained monomorphic ventricular tachycardia. Cocaine use resulted in extreme elevations in arterial pressures in patients with hypertension taking medication. Cocaine use was also associated with an increase in arrhythmic activity. These findings may underlie the heightened risk of myocardial infarction, aortic dissection, and potentially lethal arrhythmias in patients with hypertension who use cocaine.

Cocaine is the second most abused illicit drug and the most frequent cause of drug-related deaths in the United States.1 It is estimated that more than 14 million people worldwide and 0.3% of the global population aged 15 to 64 years abuse cocaine regularly.2 According to data from the Drug Abuse Warning Network from 2005, cocaine is also the most frequently cited illicit drug in emergency department visits in the United States, responsible for more than 448,000 visits annually.3

Cocaine-related morbidity is due to its deleterious effects on the cardiovascular (CV) system. Cocaine exerts its sympathomimetic and arrhythmogenic effects primarily by two mechanisms: via blockade of presynaptic reuptake of monoamine neurotransmitters and through impedance of the fast inward sodium channels responsible for phase 0 depolarization, similar to class I antiarrhythmic agents.4,5 Cocaine is also responsible for epicardial coronary vasoconstriction, enhanced platelet aggregation, and premature coronary atherosclerosis.6 The physiologic effects of cocaine use are associated with life-threatening CV events including acute coronary syndromes, sudden cardiac death, and hypertensive crises leading to stroke and aortic dissection.6

Hypertension is the most important CV risk factor worldwide, contributing to one half of all coronary heart disease and approximately two thirds of the cerebrovascular disease burden.7 It is estimated that nearly 30% of the US population 18 years and older carries the diagnosis of hypertension, and among those affected, up to 50% have not reached goal blood pressure (BP) measurements according to national guidelines.8,9 Although long-term cocaine use has not been associated with the development of chronic hypertension, the prevalence of hypertension in the cocaine-using population remains as high as 18% in some studies.10,11 Additionally, cocaine use in hypertensive patients has been associated with increased incidence of acute myocardial infarction, aortic dissection, renal failure, and intracerebral hemorrhage.12–17

Despite these associations, the hemodynamic and arrhythmogenic effects of cocaine use have not been well described in the hypertensive population. The purpose of this study was to characterize variations in BP, heart rate, and ambulatory electrocardiograms (AECGs) in patients with hypertension during cocaine use.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Concl3usions
  8. References

Study Population

This was a single-center, prospective, observational study that included 10 patients from the cardiology and internal medicine clinics at San Francisco General Hospital (San Francisco, CA). Recruitment was performed through posted flyers throughout clinic locations or by referral from clinic providers not involved in the study. Eligible patients were required to have a diagnosis of hypertension for >1 year as confirmed by chart review and also report regularly smoking cocaine. Exclusion criteria were patients unwilling to record a daily diary or wear and correctly operate the monitoring equipment. The protocol was approved by the institutional review board of the University of California, San Francisco, and all patients provided written informed consent prior to study enrollment.

Protocol

On the initial day of the study, pertinent medical and social history, resting vital signs, and 12-lead electrocardiograms (ECGs) were collected. Patients were provided with a 48-hour diary and instructed to record daily activities including medication administration, physical activity, and illicit drug use. Patients were then outfitted with a Zymed DigiTrak 3-channel 48-hour digital Holter recorder (Philips, Andover, MA) and Spacelabs ambulatory BP monitor (ABPM) (Redmond, WA). The ABPM was programmed to automatically record arterial pressures and heart rates every 30 minutes. Additionally, patients were instructed to activate the ABPM device during cocaine use by pressing the manual recording button.

Measurements

Forty-eight hours of continuous ambulatory Holter monitoring were loaded onto Philips Zymed Holter 2.9.2 software for analysis by a single, blinded examiner. Only Holter recordings with <20% artifact per 24-hour period were used for final data analysis. Timing of cocaine use as recorded in patient diaries was located on the Holter report and concurrent surface activity was collected for both the hour surrounding cocaine use and for the hour prior to use. Similarly, times in which the ABPM recording button was activated or the patient recorded cocaine use in the diary were identified on the ABPM data by the same blinded examiner. Arterial pressures and heart rates were collected both at the time of cocaine use and for non-cocaine measurements recorded within 30 minutes prior to use. For clinically significant arrhythmias detected by the Holter monitor or severe hypertension detected on ABPM (systolic BP ≥180 mm Hg or diastolic BP ≥110 mm Hg), patients were notified by letter to contact their physicians for follow-up.

Statistical Analysis

Statistical analysis was performed with the use of a commercially available software package (http://www.graphpad.com, GraphPad, La Jolla, CA). Patient characteristics were summarized as mean ± standard deviation for continuous variables and counts and percentages for categorical variables. Differences between the mean values of two sets of measurements were analyzed by univariate analyses, and a two-tailed P value <.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Concl3usions
  8. References

Patient Characteristics

A total of 10 patients were enrolled in the study and 7 returned Holter monitors with analyzable data. The clinical features of the study cohort are listed in Table I. Of the 10 patients studied, 6 were men, 7 were African American, and the average age was 49±8 years. All of the 10 patients had a diagnosis of hypertension and 8 of 10 were currently taking prescribed antihypertensive medications as confirmed by documentation in patient diaries. The most commonly used antihypertensive was hydrochlorothiazide (4 of 8) whereas 3 of 8 patients were using angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs). No patients were using β-blockers. A total of 8 participants were current tobacco smokers, and 7 endorsed regular use of alcohol. All participants smoked cocaine, and 2 patients additionally injected cocaine. On average, patients reported using cocaine 5 times per week for a mean duration of 18 years (range 10–30 years).

Table I.   Patient Characteristics (N=10)
VariableAverage±SD or No. (%)
  1. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; SD, standard deviation.

Age, y49±8
Sex
 Male6 (60)
 Female4 (40)
Race
 African American7 (70)
 White2 (20)
 Hispanic1 (10)
Hypertension10 (100)
Dyslipidemia3 (30)
Coronary artery disease1 (10)
Previous myocardial infarction1 (10)
Heart failure0 (0)
Diabetes mellitus2 (20)
Family history of CAD2 (20)
Currently taking hypertension medications8 (80)
Type of hypertension medication
 Thiazide4 (40)
 ACE inhibitor/ARB3 (30)
 Dihydropyridine calcium channel blocker1 (10)
 Clonidine1 (10)
 β-Blocker0 (0)
Average use of cocaine (per week)5±5
Average duration of cocaine use, y18±7
Current use of other illicit drugs7 (70)
Current tobacco use8 (80)
Average tobacco, pack-years27±25
Current alcohol use7 (70)

Ambulatory BP Monitoring

During the 48-hour study period, a total of 23 BP measurements were recorded during cocaine use for the entire patient cohort. Patients on average smoked cocaine 2 times during the total period of observation, and all episodes of cocaine use occurred during daytime hours. These measurements were compared with singular BP recordings collected within 30 minutes of each cocaine use (Figure 1). An example of an ambulatory BP recording demonstrating transient changes during cocaine use from a single patient is shown in Figure 2. The average BP within 30 minutes prior to cocaine use was 126/77 mm Hg and the average increase in systolic, diastolic, and mean arterial pressures after cocaine use were 74 mm Hg, 30 mm Hg, and 45 mm Hg, respectively. The mean heart rate within 30 minutes prior to cocaine use was 80 beats per minute and the average increase after cocaine use was 9 beats per minute. When compared with periods of no cocaine use, all observed differences were significant except for heart rate (P<.0001 for systolic, diastolic, and mean arterial pressures; P=.239 for heart rate) (Table II).

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Figure 1.  Systolic and diastolic blood pressure measurements before and during cocaine use. SBP indicates systolic blood pressure; DBP, diastolic blood pressure.

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Figure 2.  Example of a 24-hour recording from a patient’s ambulatory blood pressure monitor. Note the elevations in systolic, diastolic, and mean arterial pressures during episodes of cocaine use (designated by *).

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Table II.   Arterial Pressures and Heart Rate in Patients Before and During Cocaine Use
 No Cocaine Use+ Cocaine UseMean DifferenceP Value
  1. Abbreviations: BP, blood pressure; bpm, beats per minute; MAP, mean arterial pressure.

Systolic BP, mm Hg126±27201±2974±32<.0001
Diastolic BP, mm Hg77±18107±2330±33<.0001
MAP, mm Hg94±20138±1945±28<.0001
Heart rate, bpm80±2088±299±34.239

Resting and Ambulatory ECGs

Resting 12-lead ECGs demonstrated one patient with right bundle branch block, 1 patient with Sokolow-Lyon voltage criteria for left ventricular hypertrophy, and 1 patient with evidence of an old inferior infarct. There were no recorded arrhythmias at rest. When compared with the hour prior, patients experienced an increase in premature atrial and/or ventricular depolarizations with cocaine use, and 3 patients recorded premature atrial and/or ventricular depolarizations not observed during the hour prior to cocaine use. Two patients experienced episodes of nonsustained atrial tachycardia: one with heart rates up to 160 lasting 12 seconds, the second with heart rates up to 165 lasting 10 seconds. Additionally, one patient recorded 3 episodes of nonsustained monomorphic ventricular tachycardia, each episode lasting up to 3 seconds. Of the study group, only 1 patient showed no change in AECGs during cocaine use (Table III).

Table III.   Resting and Ambulatory ECGs Before and During Cocaine Use
PatientResting ECGAECG Before Cocaine UseAECG During Cocaine Use
  1. Abbreviations: AECG, ambulatory electrocardiogram; NSR, normal sinus rhythm; NSVT, nonsustained ventricular tachycardia; PAC, premature atrial contraction; PVC, premature ventricular contraction; RBBB, right bundle branch block.

1NSR2 PVCs40 PACs, atrial tachycardia to 160 lasting 12 seconds, 335 PVCs, 447 couplets, 3 episodes of NSVT each lasting up to 3 seconds
2RBBB1 PVC79 PACs, 23 PVCs, 4 couplets, 3 triplets
3NSRNSR2 PACs, lateral ST-segment depressions
4NSRNSRNSR
5NSR2 PACs44 PACs, atrial tachycardia to 165 lasting 10 seconds, 2 PVCs
6NSR1 PAC242 PACs, 71 PVCs
7NSRNSR5 PACs

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Concl3usions
  8. References

The results of this study demonstrate that smoking cocaine has a pronounced effect on arterial pressures among individuals with hypertension, despite the use of antihypertensive medication. Cocaine use was also associated with increased arrhythmic activity, but did not cause a significant change in heart rate, even though none of the individuals studied were taking atrioventricular nodal-blocking agents.

Cocaine is a powerful sympathomimetic agent that causes acute elevations in arterial pressures. The major mechanism of action is through blockade of peripheral norepinepherine reuptake and direct stimulation of central sympathetic activity.18–20 In addition, cocaine induces arterial vasoconstriction through preferential stimulation of α-adrenergic receptors and alteration in endothelial production of endothelin and nitric oxide.6,18 The net effect on systolic and diastolic pressures in the general population that has been described is an increase of 20 mm Hg and 10 mm Hg, respectively.4,21 These are modest increases in BP that are equivalent to mild exercise and are not alone believed to be sufficient to result in the CV complications observed in healthy users.22 Likely, coexisting changes to the coronary vasculature, primarily that of premature atherosclerosis, in addition to the prothrombotic effects of cocaine use underlie the development of the CV complications observed in long-term users.

Cocaine use in patients with hypertension is associated with end-organ damage not commonly observed in the general population of users, but more typically observed during acute hypertensive crises. In a retrospective study of 38 cases of aortic dissection performed by our group, 14 cases were associated with cocaine use and, of those, 11 had a previous diagnosis of hypertension.13 In addition, one half of patients with known coronary artery disease who presented to 29 community acute care hospitals with cocaine-associated myocardial infarctions carried the diagnosis of hypertension.12 Acute cocaine use has also been associated with the development of renal failure and intracerebral hemorrhage in patients with long-standing hypertension.14–16

The extreme increases in arterial pressures after cocaine use that we observed in this cohort is likely accountable for the higher incidence of CV emergencies among individuals with hypertension. Cocaine use resulted in an average increase in systolic and diastolic BPs of 74 mm Hg and 30 mm Hg, respectively, with 8 of 10 patients reaching diastolic pressures ≥110 mm Hg. These dramatic elevations in BP were observed despite the majority of our patient population being treated with antihypertensive medications and having well-controlled BPs at baseline.

One possible explanation for the high BPs observed is that all individuals in our study smoked crack cocaine. In contrast to other modes of administration of cocaine, the onset of action of crack cocaine is within seconds after ingestion with a peak effect occurring in 1 to 3 minutes.6 Many of the initial studies of cocaine use were performed in the setting of the cardiac catheterization laboratory in which cocaine was administered intravenously.23,24 The short half-life of crack cocaine may also predispose abusers to use crack cocaine repeatedly and at higher doses, which, in turn, may exacerbate the hemodynamic effects. Additionally, a phenomenon called sensitization exists that may serve as a model for humans and repeated drug use.25 Sensitization was demonstrated in rodents who, when repeatedly given a stimulant, exhibited greater responses compared with stimulant-naive rodents. In a subsequent rodent study, repeated administration of cocaine following drug-free intervals resulted in increases in BP but not in heart rate, similar to our findings in humans.26,27 A human study of repeated smoked cocaine in experienced cocaine users also resulted in increases in baseline and peak systolic pressures in addition to heart rates.28

In addition to using crack cocaine, all of the study patients had chronic hypertension. Autonomic dysregulation has long been suggested in the pathophysiology of essential hypertension. Andersen and colleagues demonstrated increased rates of sympathetic fiber activity in peroneal nerves of borderline hypertensive patients,29 and hypertensive patients have been found to have elevated levels of total plasma norepinepherine levels as well as excessive renal release of catecholamines.30,31 It has also been suggested that altered adrenergic receptivity underlies the development of hypertension.32,33 Thus, it is possible that cocaine use creates increases in plasma catecholamines, which, when superimposed on a hyperexcitable autonomic nervous system, result in the marked elevations in arterial pressures that were observed in the current study.

Our patient cohort demonstrated increased arrhythmic activity during the hour surrounding cocaine use that was not observed in the hour prior to use. All but 1 patient demonstrated increased frequency of atrial and/or ventricular premature depolarizations during cocaine use. In addition, 1 patient with no known coronary artery disease or cardiac risk factors besides hypertension experienced 3 episodes of nonsustained monomorphic ventricular tachycardia with cocaine use.

Cocaine is a known cardiac toxin that has been associated with nearly every cardiac tachyarrhythmia.34 These rhythm disturbances are likely responsible for the heightened prevalence of sudden cardiac death among cocaine users previously observed in a study by our group.35 Experimental models by O’Leary and colleagues36 demonstrated cocaine’s ability to block fast inward sodium channels responsible for phase 0 depolarization, similar to the pharmacokinetics of class I antiarrhythmic agents, while also disrupting cardiac potassium and calcium channels. ECG findings recorded during cocaine use include prolongation in PR, QRS, and QTc intervals, changes in ST-segment morphology, and development of a Brugada-like pattern.34,37 Cocaine is also responsible for accelerated atherosclerosis, dilated cardiomyopathy, left ventricular hypertrophy, and coronary spasm, all of which result in the formation of a vulnerable substrate for arrhythmogenesis.6,38–40 Hypertension is an independent risk factor for cardiac arrhythmias and sudden cardiac death through the promotion of ventricular hypertrophy and cardiac remodeling. Combined with cocaine’s ability to induce tachycardia and ischemia, it is not surprising that patients with hypertension who abuse cocaine are largely susceptible to both benign and malignant arrhythmias.

All of the patients in our study developed an increase in heart rate during cocaine use, although the degree of change was not significant. Previous studies have demonstrated an average rise in heart rate during cocaine use of 20 to 30 beats per minute in patients with a resting heart rate of approximately 60 beats per minute.4,21,22 The average baseline heart rate in our study cohort was notably higher than in these previous studies, and heart rates achieved during cocaine use were similar in absolute magnitude. The increase in baseline heart rate may have been a result of chronic cocaine use as previously described in a similar population of experienced users.28 Of note, despite the majority of our patients taking antihypertensive medications, none reported use of direct atrioventricular nodal-blocking agents.

Limitations

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Concl3usions
  8. References

There are several limitations of this study. First, due to the difficulty of reliably studying this patient population in the ambulatory setting, only a small number of patients were included in the study. Patients used “street cocaine,” which may contain various amounts of active cocaine and contaminants. Furthermore, given the nature of continuous ambulatory monitoring, 3 patients were excluded from Holter data analysis due to substantial artifact on recordings. Patients in this study also served as their own control group, limiting our ability to account for confounding variables. Finally, additional data during episodes of cocaine use may have been missed as patients may not have properly recorded episodes of cocaine use either in the provided diary or through manual activation of the ABPM.

Concl3usions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Concl3usions
  8. References

Cocaine use resulted in marked elevations in arterial pressures in patients with well-controlled hypertension taking antihypertensive medications. Cocaine use was also associated with increased arrhythmic activity. These associations are likely responsible for the increased risk of myocardial infarction, aortic dissection, and malignant arrhythmias in patients with hypertension who use cocaine. Given this susceptibility to potentially lethal CV emergencies, clinicians should prioritize cessation of cocaine use in patients with hypertension in addition to aggressively controlling BP.

Disclosure:  Grant support: None.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Concl3usions
  8. References