Chronic E-Cigarette Use Impairs Endothelial Function on the Physiological and Cellular Levels.

BACKGROUND: The harmful vascular effects of smoking are well established, but the effects of chronic use of electronic cigarettes (e-cigarettes) on endothelial function are less understood. We hypothesized that e-cigarette use causes changes in blood milieu that impair endothelial function. METHODS: Endothelial function was measured in chronic e-cigarette users, chronic cigarette smokers, and nonusers. We measured effects of participants' sera, or e-cigarette aerosol condensate, on NO and H2O2 release and cell permeability in cultured endothelial cells (ECs). RESULTS: E-cigarette users and smokers had lower flow-mediated dilation (FMD) than nonusers. Sera from e-cigarette users and smokers reduced VEGF (vascular endothelial growth factor)-induced NO secretion by ECs relative to nonuser sera, without significant reduction in endothelial NO synthase mRNA or protein levels. E-cigarette user sera caused increased endothelial release of H2O2, and more permeability than nonuser sera. E-cigarette users and smokers exhibited changes in circulating biomarkers of inflammation, thrombosis, and cell adhesion relative to nonusers, but with distinct profiles. E-cigarette user sera had higher concentrations of the receptor for advanced glycation end products (RAGE) ligands S100A8 and HMGB1 (high mobility group box 1) than smoker and nonuser sera, and receptor for advanced glycation end product inhibition reduced permeability induced by e-cigarette user sera but did not affect NO production. CONCLUSIONS: Chronic vaping and smoking both impair FMD and cause changes in the blood that inhibit endothelial NO release. Vaping, but not smoking, causes changes in the blood that increase microvascular endothelial permeability and may have a vaping-specific effect on intracellular oxidative state. Our results suggest a role for RAGE in e-cigarette-induced changes in endothelial function.

Impairment of Endothelial Function by Cigarette Smoke Is Not Caused by a Specific Smoke Constituent, but by Vagal Input From the Airway.

BACKGROUND: Exposure to tobacco or marijuana smoke, or e-cigarette aerosols, causes vascular endothelial dysfunction in humans and rats. We aimed to determine what constituent, or class of constituents, of smoke is responsible for endothelial functional impairment. METHODS: We investigated several smoke constituents that we hypothesized to mediate this effect by exposing rats and measuring arterial flow-mediated dilation (FMD) pre- and post-exposure. We measured FMD before and after inhalation of sidestream smoke from research cigarettes containing normal and reduced nicotine level with and without menthol, as well as 2 of the main aldehyde gases found in both smoke and e-cigarette aerosol (acrolein and acetaldehyde), and inert carbon nanoparticles. RESULTS: FMD was reduced by all 4 kinds of research cigarettes, with extent of reduction ranging from 20% to 46% depending on the cigarette type. While nicotine was not required for the impairment, higher nicotine levels in smoke were associated with a greater percent reduction of FMD (41.1±4.5% reduction versus 19.2±9.5%; P=0.047). Lower menthol levels were also associated with a greater percent reduction of FMD (18.5±9.8% versus 40.5±4.8%; P=0.048). Inhalation of acrolein or acetaldehyde gases at smoke-relevant concentrations impaired FMD by roughly 50% (P=0.001). However, inhalation of inert carbon nanoparticles at smoke-relevant concentrations with no gas phase also impaired FMD by a comparable amount (P<0.001). Bilateral cervical vagotomy blocked the impairment of FMD by tobacco smoke. CONCLUSIONS: There is no single constituent or class of constituents responsible for acute impairment of endothelial function by smoke; rather, we propose that acute endothelial dysfunction by disparate inhaled products is caused by vagus nerve signaling initiated by airway irritation.

Comparable Impairment of Vascular Endothelial Function by a Wide Range of Electronic Nicotine Delivery Devices.

INTRODUCTION: Electronic nicotine delivery systems (ENDS; ie, vaping devices) such as e-cigarettes, heated tobacco products, and newer coil-less ultrasonic vaping devices are promoted as less harmful alternatives to combustible cigarettes. However, their cardiovascular effects are understudied. We investigated whether exposure to aerosol from a wide range of ENDS devices, including a new ultrasonic vaping device, impairs endothelial function. AIMS AND METHODS: We measured arterial flow-mediated dilation (FMD) in rats (n = 8/group) exposed to single session of 10 cycles of pulsatile 5-second exposure over 5 minutes to aerosol from e-liquids with and without nicotine generated from a USONICIG ultrasonic vaping device, previous generation e-cigarettes, 5% nicotine JUUL pods (Virginia Tobacco, Mango, Menthol), and an IQOS heated tobacco product; with Marlboro Red cigarette smoke and clean air as controls. We evaluated nicotine absorption and serum nitric oxide levels after exposure, and effects of different nicotine acidifiers on platelet aggregation. RESULTS: Aerosol/smoke from all conditions except air significantly impaired FMD. Serum nicotine varied widely from highest in the IQOS group to lowest in USONICIG and previous generation e-cig groups. Nitric oxide levels were not affected by exposure. Exposure to JUUL and similarly acidified nicotine salt e-liquids did not affect platelet aggregation rate. Despite lack of heating coil, the USONICIG under airflow conditions heated e-liquid to ~77°C. CONCLUSIONS: A wide range of ENDS, including multiple types of e-cigarettes with and without nicotine, a heated tobacco product, and an ultrasonic vaping device devoid of heating coil, all impair FMD after a single vaping session comparably to combusted cigarettes. IMPLICATIONS: The need to understand the cardiovascular effects of various ENDS is of timely importance, as we have seen a dramatic increase in the use of these products in recent years, along with the growing assumption among its users that these devices are relatively benign. Our conclusion that a single exposure to aerosol from a wide range of ENDS impairs endothelial function comparably to cigarettes indicates that vaping can cause similar acute vascular functional impairment to smoking and is not a harmless activity.

POCUS for Thrombus: Emphasizing the Importance of Initial Point-of-Care Ultrasound in the Management of Pulmonary Thromboembolism.

Pulmonary embolism (PE) constitutes a substantial health burden among individuals in the United States. It ranks as the third most common cause of cardiovascular death aside from stroke and myocardial infarction. Diagnostic errors are common with PE as patients can present with non-specific symptoms or could be completely asymptomatic with PE being an incidental finding. Diagnostic errors can result in missed or late diagnosis of PE, which, in turn, increases health care costs, morbidity, and mortality rates. Hence, early diagnosis is crucial. Computed tomography pulmonary angiography (CTPA) remains the gold standard in PE diagnosis, despite exposure to high doses of radiation. Point-of-care ultrasound (POCUS) is an underutilized, non-invasive technique that aids in the early diagnosis of PE and can safely reduce the radiation from CTPA in cases where contraindication exists. POCUS has been shown to have a high sensitivity and specificity for early diagnosis of PE.

Platypnea Orthodeoxia Syndrome Secondary to a Persistent Eustachian Valve.

Platypnea-Orthodeoxia syndrome (POS) is a rare and poorly understood syndrome characterized by platypnea and oxygen desaturation in the upright position that is relieved by recumbency. Here, we report a case of an 84-year-old woman who had chronic hypoxia in an upright position despite using home oxygen. The patient presented for hypoxia evaluation and was noted to have a restrictive pattern on pulmonary function tests (PFT). An echocardiogram showed a prominent eustachian valve extending from inferior to superior vena cava with contrast approaching the interatrial septum. The patient had a complete resolution of her platypnea following the closure of the patent foramen ovale.

Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers.

BACKGROUND: Marijuana leaf vaporizers, which heat plant material and sublimate Δ-9-tetrahydrocannabinol without combustion, are popular alternatives to smoking cannabis that are generally perceived to be less harmful. We have shown that smoke from tobacco and marijuana, as well as aerosol from e-cigarettes and heated tobacco products, impair vascular endothelial function in rats measured as arterial flow-mediated dilation (FMD). METHODS AND RESULTS: We exposed 8 rats per group to aerosol generated by 2 vaporizer systems (Volcano and handheld Yocan) using marijuana with varying Δ-9-tetrahydrocannabinol levels, in a single pulsatile exposure session of 2 s/min over 5 minutes, and measured changes in FMD. To model secondhand exposure, we exposed rats for 1 minute to diluted aerosol approximating release of uninhaled Volcano aerosol into typical residential rooms. Exposure to aerosol from marijuana with and without cannabinoids impaired FMD by ≈50%. FMD was similarly impaired by aerosols from Yocan (237 °C), and from Volcano at both its standard temperature (185 °C) and the minimum sublimation temperature of Δ-9-tetrahydrocannabinol (157 °C), although the low-temperature aerosol condition did not effectively deliver Δ-9-tetrahydrocannabinol to the circulation. Modeled secondhand exposure based on diluted Volcano aerosol also impaired FMD. FMD was not affected in rats exposed to clean air or water vapor passed through the Volcano system. CONCLUSIONS: Acute direct exposure and modeled secondhand exposure to marijuana leaf vaporizer aerosol, regardless of cannabinoid concentration or aerosol generation temperature, impair endothelial function in rats comparably to marijuana smoke. Our findings indicate that use of leaf vaporizers is unlikely to reduce the vascular risk burden of smoking marijuana.

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

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.

Inhibition of galectin-3 post-infarction impedes progressive fibrosis by regulating inflammatory profibrotic cascades.

AIMS: Acute myocardial infarction (MI) causes inflammation, collagen deposition, and reparative fibrosis in response to myocyte death and, subsequently, a pathological myocardial remodelling process characterized by excessive interstitial fibrosis, driving heart failure (HF). Nonetheless, how or when to limit excessive fibrosis for therapeutic purposes remains uncertain. Galectin-3, a major mediator of organ fibrosis, promotes cardiac fibrosis and remodelling. We performed a preclinical assessment of a protein inhibitor of galectin-3 (its C-terminal domain, Gal-3C) to limit excessive fibrosis resulting from MI and prevent ventricular enlargement and HF. METHODS AND RESULTS: Gal-3C was produced by enzymatic cleavage of full-length galectin-3 or by direct expression of the truncated form in Escherichia coli. Gal-3C was intravenously administered for 7 days in acute MI models of young and aged rats, starting either pre-MI or 4 days post-MI. Echocardiography, haemodynamics, histology, and molecular and cellular analyses were performed to assess post-MI cardiac functionality and pathological fibrotic progression. Gal-3C profoundly benefitted left ventricular ejection fraction, end-systolic and end-diastolic volumes, haemodynamic parameters, infarct scar size, and interstitial fibrosis, with better therapeutic efficacy than losartan and spironolactone monotherapies over the 56-day study. Gal-3C therapy in post-MI aged rats substantially improved pump function and attenuated ventricular dilation, preventing progressive HF. Gal-3C in vitro treatment of M2-polarized macrophage-like cells reduced their M2-phenotypic expression of arginase-1 and interleukin-10. Gal-3C inhibited M2 polarization of cardiac macrophages during reparative response post-MI. Gal-3C impeded progressive fibrosis post-MI by down-regulating galectin-3-mediated profibrotic signalling cascades including a reduction in endogenous arginase-1 and inducible nitric oxide synthase (iNOS). CONCLUSION: Gal-3C treatment improved long-term cardiac function post-MI by reduction in the wound-healing response, and inhibition of inflammatory fibrogenic signalling to avert an augmentation of fibrosis in the periinfarct region. Thus, Gal-3C treatment prevented the infarcted heart from extensive fibrosis that accelerates the development of HF, providing a potential targeted therapy.

Sociodemographic Factors Associated with Adolescents' and Young Adults' Susceptibility, Use, and Intended Future Use of Different E-Cigarette Devices.

Numerous studies have identified sociodemographic factors associated with susceptibility, ever-use and past-30-day use of e-cigarettes, including JUUL. However, it remains unknown which sociodemographic factors are associated with adolescents' and young adults' (AYA) use of the entire spectrum of different types of e-cigarette devices (e.g., disposables, pod/cartridge-based, and other e-cigarettes, like mods or tanks). The aim of this study was to examine the relationship between sociodemographic factors and use, future use intent and susceptibility to use different e-cigarette device types. We conducted a national online survey using a convenience sample of 13-24-year-olds, 50:50 e-cigarette ever- to never-users and sex and race/ethnicity balanced per the U.S. Census (n = 4351). Sociodemographic factors were not associated with ever use of disposables among AYAs or generally with intent to use e-cigarette devices in the future. However, sociodemographic factors were related to the use of pod/cartridge-based and other e-cigarette devices. LGBTQ+ AYAs were more likely to use pod/cartridge-based devices and to be susceptible to using all device types compared to other AYAs. Young adults, males, and other/multiracial non-Hispanic AYAs were more likely to report past-30-day-use of all devices and AA/Black non-Hispanic AYAs were more likely to report past-30-day use of pod/cartridge-based and other devices compared to former users. AA/Black non-Hispanic AYAs were more likely to be susceptible to using all devices and other/multiracial non-Hispanic AYAs were susceptible to using other devices (compared to White non-Hispanic AYAs). AYAs under 21 who were former users were more likely to intend using other devices in the future compared to AYAs 21 years or above. These findings may inform targeted prevention efforts to curb the growing popularity of different devices among AYAs.

JUUL and Combusted Cigarettes Comparably Impair Endothelial Function.

OBJECTIVES: JUUL and earlier generation electronic cigarettes (e-cigs) are promoted as being less hazardous than cigarettes. While JUUL Labs, in particular, claims that switching from smoking to vaping has beneficial impacts, the health effects of such products are not well understood. We investigated whether exposure to JUUL and previous generation e-cig aerosol impairs endothelial function comparably to cigarette smoke. METHODS: We exposed rats to aerosol from Virginia Tobacco flavor JUUL, an e-cig tank system using unflavored freebase nicotine e-liquid, Marlboro Red combustible tobacco cigarettes, or clean air for 10 cycles of 2 second inhalation over 5 minutes. Endothelial function (FMD) was measured pre- and post-exposure. Blood was collected 20 mins post-exposure for serum nicotine analysis. RESULTS: Aerosol/smoke from JUUL, previous generation e-cigs, and cigarettes all impaired FMD. The extent of impairment ranged from 34%-58%, although the differences between groups were insignificant. Nicotine was highest in serum from the JUUL group; for the other e-cig and cigarette groups, nicotine levels were lower and comparable to each other. CONCLUSIONS: Aerosol from JUUL and previous generation e-cigs impairs endothelial function in rats, comparable to impairment by cigarette smoke.