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

Citation

Qiu, Huiliang et al. (2022), Increased vulnerability to atrial and ventricular arrhythmias caused by different types of inhaled tobacco or marijuana products, Dryad, Dataset, https://doi.org/10.7272/Q66W98B3

Abstract

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 an increased popularity of recreational marijuana, has raised concerns about the potential cardiovascular risk associated with their use.

Objective: The present study aimed to investigate whether the use of novel tobacco products or marijuana can cause the development of proarrhythmic substrate and eventually lead to arrhythmias.

Methods and results: Rats exposed to smoke from tobacco, marijuana, or cannabinoid-depleted marijuana, or to aerosol from electronic cigarettes or heated tobacco products, once per day for 8 weeks 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 a higher level of sympathetic nerve innervation.

Conclusions: 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.

Methods

Animals. Sprague-Dawley rats, 8–10 weeks old, of both genders, were used for this study. 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, <.01% THC). All required federal, state, and institutional approvals for acquisition and possession of marijuana and exposure of rodents were obtained. Air exposure was used as control. Group size was 8–16.

Pathophysiological assessments. Systolic blood pressure, echocardiography, ECG telemetry, arrhythmia inducibility testing, and optical mapping were assayed during or after exposure as described previously (see Supplemental Materials).  We measured conscious SBP by tail cuff on the first exposure day and at the end of the 2nd, 4th, 6th, and 8th week 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 post-exposure, ex vivo heart optical mapping was performed as described previously to test the susceptibility to arrhythmias originating from left and right atria and ventricles and to evaluate their electrophysiological characteristics. The APD at 80% repolarization and calcium transient duration at 80% repolarization were measured after a series of 20×S1 pacing trains at the pacing cycle lengths of 150, 130, 120, 110, 100, 90, 80, and 70 ms. The effective refractory period and the susceptibility to both AF and VT were tested via programmed stimulations including extra-stimuli and overdrive pacing. AF was diagnosed as fast and irregular beating lasting more than 2 seconds, whereas VT was determined as at least 6 non-driven consecutive ventricular premature beats. For histological analysis, hearts were weighed, fixed, and embedded in O.C.T compound for the following histological analyses. Heart coronal or transverse cryosections were stained with Sirius red/fast green to assess fibrosis or fluorescently stained for the 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. To visualize 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, slides were incubated with biotinylated Griffonia simplicifolia I lectin and then labeled with Alexa Fluor 488 Streptavidin (Invitrogen) as we previously described. 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.

Statistics. Data are shown as mean ± SD. P<.05 was required for significance. 

Funding

California TRDRP, Award: T29IP0490

American Heart Association, Award: 20POST35120455

Elfenworks Foundation

Roy E Thomas Medical Foundation

FDA Center for Tobacco Products, Award: U54 HL147127

National Institutes of Health, Award: U54 HL147127