Increased vulnerability to atrial and ventricular arrhythmias caused by different types of inhaled tobacco or marijuana products

HuiliangQiuMD, PhD∗HaoZhangMD, PhD∗Daniel D.HanBA∗RonakDerakhshandehMS∗XiaoyinWangMD∗NatashaGoyalMBBS∗MinaNavabzadehPharmD∗PoonamRaoMBBS∗Emily E.WilsonMS∗LeilaMohammadiMD, PhD∗Jeffrey E.OlginMD, FHRS∗†Matthew L.SpringerPhD∗†‡

∗ Division of Cardiology, University of California, San Francisco, San Francisco, California

† Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California

‡ Center for Tobacco Control Research and Education, University of California, San Francisco, San Francisco, California

Available online 15 November 2022.

Background

The emergence of a plethora of new tobacco products marketed as being less harmful than smoking, such as electronic cigarettes and heated tobacco products, and the increased popularity of recreational marijuana have raised concerns about the potential cardiovascular risk associated with their use.

Objective

The purpose of this study was to investigate whether the use of novel tobacco products or marijuana can cause the development of proarrhythmic substrate and eventually lead to arrhythmias.

Methods

Rats were exposed to smoke from tobacco, marijuana, or cannabinoid-depleted marijuana, to aerosol from electronic cigarettes or heated tobacco products, or to clean air once per day for 8 weeks, following by assays for blood pressure, cardiac function, ex vivo electrophysiology, and histochemistry.

Results

The rats exposed to tobacco or marijuana products exhibited progressively increased systolic blood pressure, decreased cardiac systolic function with chamber dilation, and reduced overall heart rate variability, relative to the clean air negative control group. Atrial fibrillation and ventricular tachycardia testing by ex vivo optical mapping revealed a significantly higher susceptibility to each, with a shortened effective refractory period and prolonged calcium transient duration. Histological analysis indicated that in all exposure conditions except for air, exposure to smoke or aerosol from tobacco or marijuana products caused severe fibrosis with decreased microvessel density and higher level of sympathetic nerve innervation.

Conclusion

These pathophysiological results indicate that tobacco and marijuana products can induce arrhythmogenic substrates involved in cardiac electrical, structural, and neural remodeling, facilitating the development of arrhythmias.

Keywords

Arrhythmogenic substrateAtrial fibrillationHeart rate variabilityMarijuanaTobaccoVapingVentricular tachycardia

Introduction

The effect of conventional tobacco cigarette smoking on the pathophysiology of coronary artery disease is relatively well defined; however, the effects on cardiac arrhythmia and proarrhythmic mechanism are less well understood. The situation has become more complex recently with the advent of modern tobacco products such as electronic cigarettes (e-cigs) and heated tobacco products (HTPs), and the increased popularity of legalized marijuana,1, 2, 3, 4 all of which are popularly assumed to be safer than tobacco cigarettes. Although nonconventional tobacco products and marijuana may represent an emerging threat to cardiovascular health,5, 6, 7, 8 current knowledge regarding the mechanism by which smoking/vaping leads to cardiac arrhythmias remains limited.

An enhanced substrate for both atrial and ventricular arrhythmias has been shown to result from any combination of cardiac neural, electrical, and structural remodeling. Neural control of the heart, which involves both sympathetic and parasympathetic nerves, plays a vital role in the initiation and perpetuation of arrhythmia diseases due to its regulation of automaticity and triggered activity.9 Electrical remodeling refers to alterations in ion channels and connexins that promote the development of arrhythmias by affecting action potential duration (APD) and reentrant activity.10 Structural remodeling is an advanced process that progressively affects myocytes and the myocardial interstitium, resulting in myocyte hypertrophy, interstitial fibrosis, and cardiac chamber enlargement, and eventually promotes reentry.11,12

Previous studies have suggested that conventional tobacco smoking can lead to the imbalance of cardiac autonomic control by causing sympathetic overinnervation and parasympathetic withdrawal.13 A recent study revealed that e-cigs also can promote the imbalance of cardiac automatic control and further the inducibility of ventricular tachycardia (VT).14 Nicotine-mediated fibrosis and activation of nicotinic acetylcholine receptors are considered to be the common proarrhythmogenic substrate caused by all nicotine-containing products.15,16 However, the increased risk of arrhythmias caused by non-nicotine products such as marijuana suggests unexpected effects that cannot be fully explained by nicotine. The impacts of chronic smoking and vaping of this wide range of tobacco and marijuana products on the formation of arrhythmogenic substrate, including cardiac neural, electrical, and structural remodeling, have not been fully determined. The overall goal of this study was to test the hypothesis that smoking/vaping of these tobacco products or marijuana may increase the susceptibility to inducible tachycardia including atrial fibrillation (AF) and VT comparably to smoking conventional tobacco cigarettes, and to investigate potentially related cardiac electro-pathophysiologic modifications.

Methods

Animals

Sprague-Dawley rats (age 8–10 weeks, of both sexes) were used for this study. Group sizes varied from 5–16 depending on the experiment, a situation resulting from complications of the COVID-19 laboratory shutdowns, although sufficient power was still achieved for an α of 0.05, 2-tailed testing, and power of 0.8 (for details see Supplemental Methods). Animal procedures were approved and monitored by the Institutional Animal Care and Use Committee of the University of California, San Francisco. The research reported in this paper adhered to the ARRIVE guidelines for reporting animal research and the National Academies of Sciences, Engineering, and Medicine Guide for the Care and Use of Laboratory Animals.

Smoke/aerosol generation and animal exposure

To mimic human active smoking/vaping, conscious rats in restrainers (Braintree Scientific, Braintree, MA) were exposed to pulsatile smoke/aerosol commencing after at least 3 days of acclimation to the restrainers, by which time the rats tolerated being held, as determined by breathing smoothly and not struggling. Each rat was exposed 5 days per week for 2 months, 1 session per day, with each session consisting of 10 cycles spread over 5 minutes, to approximate the consumption of a single cigarette or a single vaping session.17 Two of 18 initial animals in the tobacco cigarette group died on days 1 and 14 of exposure and were replaced; no other mortalities occurred.

Rats were exposed to one of the following products: Marlboro Red tobacco cigarettes (CIG); HTPs (IQOS); e-cigs (JUUL, Virginia Tobacco flavor, 5% nicotine); marijuana (MJ, ∼10% delta-9-tetrahydrocannabinol [THC]); or “Placebo marijuana” (pb-MJ, cannabinoid-depleted marijuana, <0.01% THC). Marijuana was provided by the National Institute on Drug Abuse Drug Supply Program. All required federal, state, and institutional approvals for acquisition and possession of marijuana and exposure of rodents were obtained.18 Air exposure was used as control. Group size was 8–16 animals.

Pathophysiological assessments

Systolic blood pressure (SBP), echocardiography, electrocardiographic telemetry, arrhythmia inducibility testing, and optical mapping were assayed during or after exposure as described previously (see Supplemental Methods).19, 20, 21, 22, 23, 24 We measured conscious SBP by tail cuff on the first exposure day and at the end of the 2nd, 4th, 6th, and 8th weeks to determine progressively chronic effects. On each measurement day, SBP was measured twice, both before and after that day’s single exposure, to determine that day’s acute effect. Eight weeks postexposure, ex vivo heart optical mapping was performed as described previously to test the susceptibility to arrhythmias originating from the left and right atria and ventricles and to evaluate their electrophysiological characteristics.19 Action potential duration at 80% repolarization (APD80) and calcium transient duration at 80% repolarization (CATD80) were measured after a series of 20 × S1 pacing trains at pacing cycle lengths of 150, 130, 120, 110, 100, 90, 80, and 70 ms. The effective refractory period (ERP) and the susceptibility to both AF and VT were tested via programmed stimulations including extrastimuli and overdrive pacing. AF was diagnosed as fast and irregular beating lasting >2 seconds, whereas VT was determined as at least 6 nondriven consecutive ventricular premature beats.23,24

For histologic analysis, hearts were weighed, fixed, and embedded in optimal cutting temperature (O.C.T.) compound for the following histologic analyses.21 Heart coronal or transverse cryosections were stained with Sirius red/fast green to assess fibrosis or fluorescently stained for assessment of the intrinsic cardiac nervous system (ICNS) and cardiac microvessels. ICNS as the autonomic nerve system inside the heart is vital for cardiac function and maintenance of normal heart rhythm.25 To visualize the ICNS, we performed immunofluorescence staining for sympathetic and parasympathetic nerves. In order to quantify microvessels, including capillaries and small precapillary arterioles with a cross-area of 10–314 μm2,26 slides were incubated with biotinylated Griffonia simplicifolia I lectin (GS-I, Sigma-Aldrich, St. Louis, MO) and then labeled with Alexa Fluor 488 Streptavidin (Invitrogen, Waltham, MA) as previously described.27 Microvessel density (count/mm2 tissue) and area percentage were calculated. Ten views were taken randomly from subepicardium, midmural, and subendocardium for each section to calculate mean optical area that represented the average intensity level using Fiji ImageJ.28

Most procedures were analyzed by a blinded investigator. Some functional measurements were partially blinded due to constraints imposed by the pandemic laboratory shutdowns (see Study limitations).

Statistical analysis

Data are given as mean ± SD. P <.05 was considered significant (for details see Supplemental Methods).

Results

Exposure to smoke or aerosol of tobacco and marijuana products increased SBP

Exposure to all non-air conditions altered SBP acutely (pre- vs post-exposure) (Figure 1A). Tobacco cigarette smoke, JUUL aerosol, and IQOS aerosol acted similarly in substantially increasing SBP (>10 mm Hg) at the first exposure, with relatively moderate acute increases in SBP on subsequent days. However, in contrast to tobacco products, marijuana (10% THC) decreased SBP during each acute exposure. pb-MJ did not lower SBP and actually increased it, similar to the tobacco products. Charting changes in the pre-exposure values reveals that chronic exposure to all products progressively elevated baseline SBP to >130 mm Hg after 2 weeks of exposure, to >140 mm Hg after 4 weeks of exposure, and steady increases continued through the 8th week (Figure 1B). Serum concentrations of norepinephrine, but not of angiotensin, were significantly different in rats exposed to tobacco or marijuana products compared to air at 8 weeks postexposure (P <.001) (Figure 1C).

Left ventricular systolic function was reduced and cardiac chamber enlarged after chronic exposure

To determine whether exposure to tobacco and marijuana smoke/aerosol affected cardiac function, echocardiography was performed. Exposure for 8 weeks progressively reduced both ejection fraction and fractional area change in all non-air groups compared to their baseline levels (Figure 2). Left ventricular (LV) end-systolic volume and LV end-diastolic volume were gradually increased in non-air groups. By 8 weeks post-exposure, LV end-systolic volume and LV end-diastolic volume were enlarged significantly in all non-air groups compared to baseline (P <.05), along with an increase in LV mass compared to baseline and to the air group (P <.001). Moreover, exposure to all conditions except air resulted in an enlargement of left atrial (LA) diameter by the 4th week of exposure, and the enlargement continued to increase through the 8th week. These findings suggest that exposure to tobacco and marijuana products led to reduced LV function and enlarged cardiac chambers, indicating LV dysfunction and remodeling associated with smoking/vaping.

Chronic use of tobacco, e-cigs, HTPs, or marijuana reduced overall heart rate variability

All of the normal-to-normal RR intervals (NN intervals) of all conditions superimposed in Supplemental Figure 1 showed the same RR intervals distribution pattern in the form of a Poincaré plot, which plots each pair of RR intervals between 2 consecutive beats and thus quantifies the distribution pattern of heart rate mapping. Data in Figure 3A indicated only exposure to JUUL led to a shortened average NN interval. Surprisingly, chronic exposure to smoke of CIG, IQOS, MJ, and pb-MJ did not shorten the NN interval and actually prolonged it. Use of a time-domain method to directly evaluate the degree of dispersion of NN interval revealed that exposure to tobacco and marijuana products compared to air caused a significant reduction of the overall heart rate variability (HRV) indicators (Figures 3B–3E), including the average of 2-minute standard deviation of NN intervals (SDNN), root mean square of successive differences between normal heartbeats (RMSSD), number of pairs of successive NN intervals that differ by >9 ms (NN9), and proportion of NN9 divided by the total number of NN intervals (pNN9), which suggests depressed parasympathetic function. Frequency-domain method for HRV analysis, an indirect method that reflects sympathetic and parasympathetic function, showed that all of these products decreased overall HRV, especially the sympathetic modulations (Figures 3F–3J). Compared to air, most of the conditions had lower total power (P <.05 except JUUL), very-low-frequency (VLF) band (P <.05), low-frequency (LF) band (P <.05 except IQOS), and ratio of low-frequency/high-frequency (LF/HF) (P <.05 except IQOS). Both LF and HF were depressed by IQOS exposure, but apparently HF was influenced more, which resulted in an increased LF/HF value. As very-low frequency and LF are mainly driven by sympathetic activity, RMSSD, NN9, pNN9, and HF are driven by parasympathetic activity, and SDNN reflects overall HRV, these results suggest that all of these products decreased overall HRV, especially the sympathetic modulations.

Increased susceptibility, shortened ERP and APD80, and prolonged CaTD80

Tachyarrhythmias were tested using programmed stimulation and burst pacing ex vivo. One heart from the JUUL group failed to connect to the Langendorff system due to technical difficulties. All tobacco products caused a significant increase in overall AF inducibility compared to air (Figures 4A and 4B, and Table 1). An overall AF inducible rate of 37.5% was observed in rats exposed to MJ and 50% in pb-MJ rats, whereas AF remained uninducible in rats exposed to air. VT inducible rates were 0%, 62.5%, 71.43%, 37.5%, 75%, and 37.5% in air, CIG, JUUL, IQOS, MJ, and pb-MJ, respectively, reaching significance (P <.05) for CIG, JUUL, and MJ. More than 50% of tachycardia events were induced by overdrive pacing. Non-air groups developed shorter ERPs in the LA, right atrium (RA), and LV (Figures 4C–4E). Compared to air control, non-air conditions resulted in shorter APD80 and longer CaTD80 at different pacing cycle lengths (Figure 5). As a result, a larger difference of CaTD80 – APD80 was found in the non-air groups.

Table 1. Inducibility of AF or VT

Exposure conditions: CIG = conventional combustible tobacco cigarettes; IQOS = heated tobacco products; JUUL = e-cigarettes; MJ = marijuana; pb-MJ = cannabinoid-depleted placebo marijuana. Parameters for analysis: AF = atrial fibrillation; LAF = left atrial pacing-induced atrial fibrillation; RAF = right atrial pacing-induced atrial fibrillation; VT = ventricular tachycardia.

Values are given as %.

Higher deposition of interstitial fibrosis and less microvessel density

To determine whether different smoking/vaping products may induce cardiac fibrosis, heart sections were stained for interstitial fibrosis in red and cardiomyocytes in green. Interstitial fibrosis in LA, RA, and LV was significantly increased in all non-air groups compared to the air group (P <.001) (Figure 6). There was no significant difference among non-air groups. Measurement of fibrotic biomarkers, including galectin-3 (Gal-3) and matrix metalloproteinase-9 (MMP-9) and its endogenous tissue inhibitor of metalloproteinase-1 (TIMP1), showed only MMP-9 was reduced comparably in all non-air groups, identifying MMP-9 potentially as the main mediator. Transverse sections stained with GS-I were analyzed to assess changes in microvessels. Both density and area percentage of microvessels were significantly decreased in non-air groups, suggesting adverse effects on the microcirculation (Figure 7).

Intrinsic cardiac neural remodeling

The densities of tyrosine hydroxylase (as sympathetic marker)–positive nerves within LA, RA, LV, and right ventricle were higher in rats exposed to tobacco or marijuana products than to air (Figure 8). Conversely, densities of choline acetyltransferase (as parasympathetic marker)–positive nerves were relatively lower in non-air groups. These data suggest a potential cardiac neural remodeling of sympathetic hyperinnervation and parasympathetic withdrawal.

Discussion

This study showed that 8 weeks of daily exposure to smoke or aerosol from tobacco cigarettes, e-cigs, HTPs, or marijuana can cause comparable pathophysiological changes, consequently leading to hypertension, cardiac dysfunction, and arrhythmias. Cardiac electrical, structural, and neural remodeling all are involved in inducible AF and VT caused by smoking or vaping. It is notable that these adverse effects resulted from a single smoking/vaping session per day, with each session reflecting a relatively modest exposure mimicking 10 “puffs” over 5 minutes, that is, we did not use an extreme exposure model. We have used the same conditions to study the acute effects of a single session of cigarette smoking, IQOS use, and multiple types of e-cigarette vaping sessions.17,29,30 During the course of these studies, we have validated the relevance of our exposure conditions to human real-world application by (1) using nose cone pulsatile exposure to enable immediate switching between brief pulses of undiluted smoke/aerosol and interim periods of clean air; (2) showing that circulating plasma nicotine and cotinine levels after a single session of exposure to Marlboro Red cigarette smoke were comparable to circulating levels in humans after smoking 1 cigarette; and (3) confirming an approximate dose–response relationship between the number of exposure cycles in one session and resulting plasma nicotine levels.17

Smoking/vaping tobacco and marijuana products elevated SBP

Exposure to tobacco and marijuana products progressively increased pre-exposure SBP. Within each individual measurement day, tobacco products and cannabinoid-depleted marijuana acutely increased SBP. In contrast, regular marijuana acutely reduced SBP but not all the way to baseline day 0 values, indicating that cannabinoids have a blood pressure–lowering effect that may be not sufficient to counteract the prohypertensive effect of marijuana smoke. The increased norepinephrine levels in all non-air groups, with no change in angiotensin levels, suggest that sympathetic neural drive may be more important in smoking-caused hypertension, rather than the renin-angiotensin system. Thus, beta-blockers may be better than angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for the treatment of smoking-related hypertension.

Smoking or vaping led to alterations in autonomic nerve activity and cardiac neural remodeling

Autonomic nerve function is an important determinant of arrhythmogenesis.25 It is intriguing that chronic exposure to e-cigs, HTPs, and marijuana all caused reduced overall HRV, of which both sympathetic and parasympathetic nerve function were downregulated as indicated by the results from the time-domain method and change of LF band from the frequency-domain method. Previous studies have also suggested that chronic and acute tobacco smoking are associated with reduced overall HRV.13 A recent study suggested that exposure to vanillin-flavored e-cig aerosol for 10 weeks also influences autonomic nerve activity by increasing the predominance of sympathetic nerve function in mice.14 The reduced HRV is independently associated with the arrhythmogenesis of both AF and VT and is involved in the development of hypertension.31, 32, 33 Moreover, in the present study, we observed cardiac sympathetic hyperinnervation and parasympathetic withdrawal in rats exposed to tobacco and marijuana products. Cardiac neural remodeling plays an important role in arrhythmogenesis by inducing triggered activity and changing the automaticity of cardiomyocytes.34 The overinnervation of sympathetic nerves is associated with the arrhythmogenesis of both AF and VT.25 Both the extrinsic cardiac nervous system (ECNS) and the ICNS are equally important in maintaining a normal cardiac physiology. Without ECNS control, pathologic change of the ICNS itself could be proarrhythmogenic.35 Our observed cardiac sympathetic hyperinnervation and parasympathetic withdrawal may be the cause of the subsequent cardiac electrical remodeling. Although we did not directly link neural remodeling to electrical remodeling, previous studies have demonstrated that sympathetic hyperinnervation in the ICNS can promote Ca2+-initiated triggered activity.36 One reasonable explanation for the shortened APD80 and prolonged CaTD80 is that sympathetic nerves activate intracellular Ca2+ transients, whereas parasympathetic nerves activate IKAch, leading to triggered activity due to late phase 3 early afterdepolarizations.25,36

Fibrosis and microvessel change

The development of fibrosis and the decrease in capillary density in post-smoking/vaping hearts may be the consequence of elevated SBP. In nonischemic conditions, cardiac fibrosis leads to hypertension, cardiac hypertrophy, or heart failure with preserved ejection fraction, the latter often accompanied by microvascular rarefaction.37 This provides an important indication that smoking or vaping may cause multiple aspects of cardiovascular disease (CVD) beyond arrhythmias, because the latter could be a symptom of other severe CVD; and the pathologic findings, including changes in fibrosis, microvessels, and nerves, may cause more problems than we observed. Moreover, the increased ratio of TIMP1/MMP9 or the decreased MMP9 is known to accelerate fibrosis and microvessel remodeling.38 Accordingly, the increase of MMP9 may be able to inhibit fibrosis and restore the vascular network.38 Therefore, the present study identified the important role of MMP9 in smoking-related cardiac fibrotic and microvessel remodeling.

Potential clinical applications

Smoking/vaping-related CVD affects countless people but is not named as a disease. Given the increasing use of marijuana and novel tobacco products, including e-cigs and HTPs, and common perceptions that these products are relatively free of health risks, our results indicate that all of these products may still carry substantial risk of development of cardiac disease. Our findings may provide clues to treat smoking/vaping-related CVD by preventing hypertension, targeting HRV, intracellular calcium handling, and fibrosis. Improvement of calcium regulation may benefit heart function and reduce susceptibility to arrhythmia. In addition, because neural remodeling of the heart, which here mainly refers to increased sympathetic innervation, is highly associated with CVD development, nerve ablation or stimulation may be a potential therapeutic measure applied to such pathophysiological changes. Improvement of HRV by multiple interventions (eg, aerobic training,39 beta-blockers,40 and calcium channel blockers41) may be accompanied by improvements of sympathovagal rebalance and calcium handling.

Study limitations

A limitation is that although most procedures underwent completely blinded analysis, only 1 investigator was able to access the laboratory during the COVID-19 shutdown, so the exposures and the cardiac function and SBP data collection were performed by the same person. Those data were subsequently coded and randomized, and the investigator analyzed the data at least 2 weeks later, now blinded to the identity of each animal. Another limitation is that our study used entirely young, healthy rats; age or comorbidities presumably result in a more complex physiological effect. Whether smoking-related cardiac nerve activity correlates with frequency of arrhythmia episodes requires further investigation. This study was not designed to assess the effects of lifelong product use, so we do not know whether the adverse effects that we observed were at their saturation point or would have continued to worsen with continued chronic exposure.

Conclusion

A single daily smoking/vaping session with tobacco cigarettes, e-cigs, HTPs, or marijuana cigarettes results in an increased susceptibility to AF and VT with reduced HRV, cardiac sympathetic hyperinnervation, interstitial fibrosis, and electrophysiological changes in otherwise healthy rats. These pathophysiological changes may be secondary to the increase in blood pressure caused by chronic exposure.

Data Availability Statement

Raw data are accessible at https://doi.org/10.7272/Q66W98B3.

Appendix. Supplementary data

Download : Download Acrobat PDF file (212KB)

Supplemental Material.

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Cited by (0)

Funding Sources: This research was supported by Grant U54 HL147127 from the NIH and FDA Center for Tobacco Products; California Tobacco-Related Disease Research Program of the University of California, Grant Number T29IP0490 to Dr Springer; AHA Postdoctoral Fellowship 20POST35120455 to Dr Qiu; and generous support from the Elfenworks Foundation (in memory of Deb O’Keefe) and the Roy E Thomas Medical Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the FDA.

Disclosures: The authors have no conflicts of interest to disclose. Daniel D. Han’s current affiliation is School of Medicine and Dentistry, University of Rochester, Rochester, New York. Dr Poonam Rao’s current affiliation is CHRISTUS Good Shepherd/Texas A&M University Internal Medicine Residency Program, Longview, Texas.

© 2022 Heart Rhythm Society.

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Posted: November 15, 2022

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Link to original study: Increased vulnerability to atrial and ventricular arrhythmias caused by different types of inhaled tobacco or marijuana products