Epidemiological studies have identified a potential temporal link between marijuana use and myocardial infarction
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In light of accumulating data suggesting prevalent use of marijuana, including among patients with established cardiovascular disease, it is important to integrate screening, counseling, and testing when appropriate into clinical care......A broad range of cardiac electrical effects, including atrial fibrillation/flutter, atrioventricular block/asystole, sick sinus syndrome, ventricular tachycardia, and Brugada pattern, have been described with marijuana use.....Cerebrovascular events have also been reported in association with marijuana use (36-39), including with SCBs.....Thrombosis and ischemia of other vascular beds have also been reported......Cannabis use has been associated with myocardial dysfunction, independent of coronary artery disease......Early studies had shown that cannabinoids contribute to weight gain in patients with human immunodeficiency virus, leading to the rationale for use of dronabinol as an appetite stimulant......Cannabinoids can interfere with the action of multiple classes of cardiovascular therapies by inhibiting the cytochrome P (CYP) 450 family. Additional pharmacokinetic interactions may occur at the level of membrane transporters.....Cannabidiol is a substrate of CYP3A4 and CYP2C19 and is a more potent inhibitor of CYP3A and CYP2D6 compared with other cannabinoids (Table 3) (10). It also influences uridine 5'-diphospho (UDP)-glucuronosyltransferases......THC and CBN are substrates of CYP2C9 and CYP3A4, and both similarly inhibit a variety of CYP450 enzymes.....Cannabinoids affect key classes of cardiovascular medications including antiarrhythmics, calcium-channel blockers, statins, β-blockers, and warfarin (Table 4) (10,14,63-65). The anticipated changes in drug levels are described, but limited clinical data are available guiding the need for dose or therapeutic changes.
Marijuana use continues to increase nationally in light of changing policies around legalization. We estimate that >2 million patients with cardiovascular disease report current or prior use of marijuana. Observational studies have suggested a potential association between marijuana and a range of cardiovascular risks, although the level of evidence has not been robust. Few randomized clinical trials have been conducted or are planned to examine effects of marijuana on cardiovascular risk, due in part to its Schedule I federal designation as a controlled substance. Acknowledging the modest strength of current evidence, screening and testing for use of marijuana in select cardiovascular settings is encouraged. Furthermore, patients who are at highrisk of cardiovascular events should be counseled to avoid or at least minimize marijuana use. It is imperative to conduct rigorous scientific research evaluating marijuana to inform recommendations for patient care and to provide a framework for the cardiovascular community.
Marijuana Use in Patients With Cardiovascular Disease
JACC Review Topic of the Week
Routine Cannabis Screening in CVD Patients: Have We Hit a Tipping Point?
January 21, 2020
With 11 recreational-marijuana states, 33 medical-use states, and a groundswell of state marijuana ballot initiatives teed up, researchers and cardiologists are questioning what this means for Americans with cardiovascular disease (CVD).
Patients are asking as well, said Muthiah Vaduganathan, MD, MPH, a cardiologist at Brigham and Women's Hospital and Harvard Medical School in Boston, and coauthor of a new marijuana review article, published in the January 28 issue of the Journal of the American College of Cardiology.
"This was actually a multidisciplinary team of general cardiologists, pharmacists, transplant physicians, transplant cardiologists, and interventional cardiologists and, in each of our practices, we had independently seen patients coming into either our clinics or the hospital setting and asking us about the safety of marijuana use in the context of their cardiovascular conditions," Vaduganathan said in an interview.
"We felt responsible as medical researchers, as well as cardiologists, in promoting the best level of science and in conveying the best information. So that was what prompted, initially at a patient level, this particular review."
The authors call for "routine screening for marijuana use" and a "broad commitment" from government and researchers to pursue marijuana-related research to clarify the CV safety profile. They cite the increasing use and potency of marijuana and a spike in reported cannabis-related adverse health effects.
In 2016 and 2017, more than 39 million Americans reported using marijuana within the previous year, according to the annual National Survey on Drug Use and Health. Still, the number of users is shifting with the changing legalization landscape. In the first 12 days of 2020, for example, sales of newly legal recreational marijuana reached $19.7 million in the state of Illinois alone.
Observational studies have suggested an association between marijuana use and a broad range of CV risks, such as myocardial infarction (MI), arrhythmias, and cerebrovascular events, but "the level of evidence has not been robust," the authors conclude.
Using NHANES data, the authors estimate that of the 90 million adults who reported ever using marijuana or hashish in 2015 and 2016, 2 million had cardiovascular disease.
That number hit 2.7 million in 2013 to 2014, up from 1.7 million users with CVD in 2007 to 2008.
"For the first time, there are more marijuana users in the United States that are estimated than cigarette smokers," Vaduganathan told theheart.org | Medscape Cardiology. "While public health resources and interventions have successfully targeted cigarette smoking and as we commonly ask about cigarette smoking in cardiovascular clinics, we often neglect marijuana."
"When you actually look at the chemical toxin profile of the combustion products of marijuana compared with tobacco when both are smoked, it's actually quite comparable," he said. "So we would anticipate that the cardiovascular and pulmonary effects may also be similar."
When marijuana is used in other forms, including edibles and oils, it may have physiologic effects that still affect the cardiovascular system, Vaduganathan observed. For instance, it may enhance sympathetic nervous system response and increase heart rate and blood pressure, which can be problematic in patients with cardiovascular diseases, especially those with known hypertension or arrhythmias.
Concerns have also been raised about potential interactions with commonly used cardiovascular drugs and cannabinoids, including THC and CBD, which are metabolized by the cytochrome P450 enzymatic (CYP) pathway in the liver.
The published report includes a chart citing potential changes in drug levels of statins, anti-arrhythmics, calcium-channel blockers, β-blockers, and warfarin. But Vaduganathan said it's too soon for marijuana sales to be accompanied by drug-drug interaction safety labels.
"We know that there's an interaction and that these drug levels are expected to increase," he said. "What we don't know is the duration of time they'll increase or if various modalities of marijuana use actually would have differential effects on drug levels."
For drugs that can be monitored, like warfarin and tacrolimus, Vaduganathan said more frequent monitoring is recommended, but "for ones where we don't have a clear ability to monitor drug levels, we don't know how best to guide those decisions."
To theheart.org | Medscape Cardiology, Salim Virani, MD, PhD, a cardiologist at Baylor College of Medicine and the Michael DeBakey VA Medical Center in Houston, said that the issue of marijuana use is on the radar of cardiologists but that there's always this question about the strength of the evidence.
"As the authors very clearly point out in this review article, the evidence we have is all observational," he said. "Is it causal or not and, if it's causal, what is the effect size or the magnitude of that effect? That is what we really want to know."
Nevertheless, "I would like to point out that, even if the harms are small compared to some of the other risk factors that we may be aware of, like diabetes or smoking, if such a large proportion of the population is using it, then even a small effect size in terms of a detrimental impact can be really, really big at the population level," said Virani, who also chairs the American College of Cardiology (ACC) Prevention of Cardiovascular Disease Section.
Although the American Heart Association (AHA) has issued scientific statements dedicated to hookah smoking and e-cigarettes, neither the AHA nor the ACC has issued a similar statement on marijuana, likely because of the paucity or limited scope of the data, suggest Virani and Vaduganathan.
Right now, the only scenarios the authors could identify in guidelines or key documents where screening for marijuana is routinely done or mandated is before transplantation and before consideration for advanced therapies for patients with advanced heart failure, Vaduganathan told theheart.org | Medscape Cardiology.
"In all other circumstances - even at the time, for instance, of myocardial infarction or new heart failure presentations or new atrial arrhythmias, and despite all these scenarios being higher risk and potentially associated with marijuana use - there's no regimented screening pathways and certainly cardiologists aren't routinely doing it in practice," he said.
The authors say cardiology specialists should be aware of local regulations and the legal status of marijuana products in their state and, whenever possible, ask about frequency, quantity, and method of use.
"I think a risk-based screening makes sense as a first step, as we learn more," Vaduganathan said. "Our highest-risk patients for recurrent events are those who have been recently hospitalized for acute CV events, like myocardial infarction or new heart failure presentation. And these patients should not only be screened but, in our opinion, counseled to lower or stop use of marijuana, especially during this high-risk window."
Vaduganathan currently screens his patients, especially younger patients, who newly present with CVD. In the Partners YOUNG-MI registry of patients with a first MI before age 50, marijuana use was reported in 6% and associated with twice the hazard of death, even after adjustment for tobacco use.
"In these patients, I think urine toxicology screening makes sense," he said. "In other patients, I think you need to have an open conversation and, in general, patients are willing to discuss this openly."
Explaining that marijuana may affect levels of key heart drugs is often enough of a rationale for most patients to overcome privacy concerns and open up, Vaduganathan observed.
Physicians, however, may struggle with these conversations in the absence of definitive evidence that marijuana use is detrimental to cardiovascular health, Virani said. Still, they should consider screening in young patients who present with CVD of unknown etiology and those taking multiple CV medications that may interact with marijuana.
Although the AHA's recent announcement of a $20 million grant initiative to tackle youth vaping is a positive step, both men lamented the lack of dedicated research on marijuana and CV health.
"This review article definitely brings up a lot of those questions that we're having out there," Virani said. "In terms of research, I think one aspect is getting the knowledge base stronger, and the second is, well, okay that's great, but then how do we take this information back to our patients?"
Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst; has served on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, and Relypsa; and has participated on clinical end-point committees for studies sponsored by Novartis and the National Institutes of Health. Virani reports grant support from the Department of Veterans Affairs, World Heart Federation, American Heart Association, and American Diabetes Association; and honoraria from the American College of Cardiology.
J Am Coll Cardiol. 2020;75:320-332. Abstract
Marijuana Use in Patients With Cardiovascular Disease
JACC Review Topic of the Week
Jan 3 2020 -Ersilia M. DeFilippis, Navkaranbir S. Bajaj, Amitoj Singh, Rhynn Malloy, Michael M. Givertz, Ron Blankstein, Deepak L. Bhatt and Muthiah Vaduganathan
• We estimate that >2 million U.S. adults who have reported ever using marijuana have cardiovascular disease.
• Observational studies have suggested an association between marijuana use and a range of cardiovascular risks.
• Marijuana is becoming increasingly potent, and smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco.
• Few randomized clinical trials have been conducted or are planned to explore the effects of marijuana on cardiovascular risk.
• Screening and testing for use of marijuana are encouraged in clinical settings, especially in the care of young patients presenting with cardiovascular disease.
Marijuana use is increasing as more states are legalizing cannabis for both medicinal and recreational purposes. National survey data estimate that >2 million Americans with established cardiovascular diseases currently use or have used marijuana in its variety of forms, including inhalation and vaping. Cannabinoid receptors are distributed in multiple tissue beds and cells, including platelets, adipose tissue, and myocytes. Observational data suggest associations between marijuana and a broad range of adverse cardiovascular risks. Marijuana is becoming increasingly potent, and smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco. Synthetic cannabinoids have been linked to more sustained and deleterious pharmacodynamic effects. Marijuana is classified as a Schedule I substance, thus limiting its rigorous study for cardiovascular health effects. This review summarizes cardiovascular considerations related to marijuana use, pharmacological interactions, and future steps to provide clearer guidance regarding its cardiovascular safety. Screening for marijuana use is encouraged, especially in young patients presenting with cardiovascular disease.
The effects of marijuana are mediated through the endocannabinoid system (11,12). Cannabinoid (CB) receptors are distributed in multiple tissue beds and cell types (Figure 1). CB-1 receptors are present in high concentrations in the central and peripheral nervous systems, but also exist on platelets, adipose tissue, myocytes, liver, pancreas, and skeletal muscle (11). Therefore, exogeneous cannabinoids can exert effects on multiple systems (Table 1) (12). In settings of tissue injury, endocannabinoids are generated in excess with enhanced CB-1 receptor signaling. CB-2 receptors are present on immune cells, osteoclasts, and osteoblasts.
The potency of marijuana has been steadily increasing over time (13). Synthetic cannabinoids (SCB), including “Spice” and “K2,” have existed for more than a decade, during which they may have undergone potentially dangerous pharmacological alteration. These SCBs are not under specific federal regulation (14). SCBs may be up to 100-fold more potent than THC and have been linked to more sustained and deleterious downstream pharmacodynamic effects (15,16). Similarly, hydroponic methods of cultivation used in small-scale recreational production may include potentially harmful plant growth regulators and produce more potent marijuana.
Coronary artery disease
Mechanistically, marijuana use may pose potential cardiovascular risk in patients with atherosclerotic cardiovascular disease, especially early after acute coronary syndromes (23,24). In the acute setting, cannabis smoking can lead to increases in heart rate and blood pressure, secondary to sympathetic nervous system activation (25), augmenting myocardial oxygen demands (8). Aronow and Cassidy (26) determined that exercise time until angina onset was reduced after smoking a single marijuana cigarette compared with placebo in a small experiment of 10 patients with coronary artery disease. Chronic use promotes tolerance and may be associated with less pronounced physiological effects (27). Other postulated mechanisms include production of oxidant gases resulting in cellular stress, platelet activation, increased oxidized low-density lipoprotein cholesterol formation, and induction of an inflammatory response.
Epidemiological studies have identified a potential temporal link between marijuana use and myocardial infarction. In a meta-analysis of 36 studies, the top 3 triggers of myocardial infarction included use of cocaine, eating a heavy meal, and smoking marijuana (28). Furthermore, in a systematic analysis of 33 studies, 28 found an increased risk of acute coronary syndromes with marijuana use (25). This observed risk association appears temporally related to recency of use. For instance, among 3,882 patients with myocardial infarction in the Determinants of Myocardial Infarction Onset Study (29,30), 3% smoked marijuana in the prior year; 37 of whom had smoked within 24 h and 9 within 1 h of myocardial infarction (29). Marijuana users were more likely to be men, obese, and current cigarette smokers. In addition, marijuana use, which is more prevalent in younger adults, is not infrequently detected among patients presenting with early-onset myocardial infarction. In the Partners YOUNG-MI registry of patients who presented with first myocardial infarction under the age of 50 years, marijuana use was reported or tested positive in >6% (31). Marijuana use was associated with twice the hazard of death among these patients even after adjusting for tobacco use (31). Another mechanism of coronary pathology is coronary vasospasm in the absence of coronary artery disease.
A broad range of cardiac electrical effects, including atrial fibrillation/flutter, atrioventricular block/asystole, sick sinus syndrome, ventricular tachycardia, and Brugada pattern, have been described with marijuana use (32-34). Increased catecholamines and β-adrenergic stimulation with THC may theoretically increase arrhythmogenicity (35). In an NIS study from 2010 to 2014, Desai et al. (32) found that 66,179 of 2,459,856 (3%) of those with reported marijuana use experienced arrhythmias (mostly atrial fibrillation).
Cerebrovascular events have also been reported in association with marijuana use (36-39), including with SCBs (40). Mechanisms related to potential cerebrovascular risks include direct vasculotoxic effects, alterations in hemodynamics, or incident atrial fibrillation/flutter (36,41). Furthermore, even transient exposure to marijuana smoke can induce endothelial dysfunction (42). One population survey found that individuals who had smoked marijuana in the past year experienced a 3.3× higher rate of cerebrovascular events (37). A case series described 14 patients with ischemic stroke who had exposure to cannabis during or before symptoms began, with 5 experiencing recurrent stroke with re-exposure (38). Among 334 patients who experienced acute ischemic stroke under the age of 45 years over a 9-year period, 17% were cannabis users. These patients were typically younger and were more likely to be men (43).
Peripheral artery disease
Thrombosis and ischemia of other vascular beds have also been reported (44). Delta-8 and delta-9-tetrahydrocannabinols can induce peripheral vasoconstriction (45). Cannabis arteritis has been reported in young men who developed distal ischemia leading to necrosis of fingers or toes (45-47), commonly with concurrent use of tobacco (47). Arteriographic evaluation reveals anomalies resembling Buerger’s disease (45). Exposure to secondhand smoke from marijuana for 1 min impaired femoral artery flow-mediated dilatation, a measure of endothelial dysfunction, for at least 90 min, which was longer than impairment by tobacco secondhand smoke (42).
Cannabis use has been associated with myocardial dysfunction, independent of coronary artery disease. Rabbits who have received a selective CB2 agonist demonstrate concentration-dependent decreases in cardiac contractility (48). Case reports have suggested associations of cannabis with stress cardiomyopathy (49) and myocarditis/myopericarditis, an entity referred to as “toxic myocarditis” (50,51).
Early studies had shown that cannabinoids contribute to weight gain in patients with human immunodeficiency virus, leading to the rationale for use of dronabinol as an appetite stimulant (52,53). Furthermore, a trial of rimonabant, an endocannabinoid receptor antagonist, demonstrated weight loss and improved metabolic abnormalities (54). However, multiple recent epidemiological studies have suggested that cannabis may be protective against weight gain and related alterations in metabolism (55-57). In 1 study, cannabis users had lower low-density lipoprotein cholesterol; when cannabis was discontinued, a subset had an increase in weight greater than nonusers (55). In 2016, a small randomized double-blind trial showed that in patients with diabetes mellitus, tetrahydrocannabivarin (compared with placebo) significantly decreased fasting plasma glucose levels and improved pancreatic β-cell function (58).
Potential Pharmacological Interactions With Cardiovascular Medications
Cannabinoids can interfere with the action of multiple classes of cardiovascular therapies by inhibiting the cytochrome P (CYP) 450 family (10,59,60). Additional pharmacokinetic interactions may occur at the level of membrane transporters. Glycoprotein P (P-gp) expression is affected by the duration of exposure to cannabinoids (61). With chronic exposure, the expression of P-gp is down-regulated, but with short exposure it is up-regulated. Cannabinoids inhibit breast cancer-resistant protein and increase accumulation of its substrates (62). Additionally, a withdrawal phenomenon has been reported after abrupt discontinuation due to the high affinity of THC to cannabinoid binding receptors (14).