Matthew L. Springer

Inhalable products marketed as reduced-harm alternatives to combustible cigarettes, including e-cigarettes, heated tobacco products, and marijuana, produce rapid and sustained adverse cardiovascular effects. Even brief exposure impairs cardiac function and enhances platelet aggregation, whereas prior exposure increases myocardial susceptibility to ischemia-reperfusion injury, resulting in larger infarcts following myocardial infarction. These findings challenge the perception that noncombustible or “reduced-harm” products are cardiovascularly benign.

Introduction: Ultrasonic vaping devices like SURGE are marketed as safer alternatives to conventional coil-based electronic cigarettes like JUUL due to their lower operating temperatures. However, their impact on cardiovascular health has not been fully characterized. Methods: Sprague–Dawley rats were exposed daily for 9 weeks to aerosol generated from SURGE, JUUL, or clean air. Heart rate variability was continuously monitored via implanted telemetry. Cardiac fibrosis was quantified using histological analysis. Temperature profiles of SURGE, JUUL, and Nautilus (a coil-based tank device) were recorded. Aerosol samples were analyzed for carbonyl compounds using high-performance liquid chromatography. Results: Both SURGE and JUUL exposures significantly reduced heart rate variability (high frequency and total power) compared with air. JUUL exposure significantly increased cardiac fibrosis; SURGE showed a similar mean fibrosis level but greater variability, resulting in a non-significant difference. SURGE devices operated at lower peak temperatures (~131°C) than JUUL (~239°C) and Nautilus (~160–170°C). Despite having the lowest temperature, SURGE emitted higher levels of carbonyl compounds than JUUL, although still substantially lower than Nautilus. Conclusions: Although SURGE operates without coils and at lower temperatures than coiled vaping devices, it generates higher levels of carbonyls than some coiled devices and impairs cardiac autonomic regulation, and it can cause cardiac fibrosis comparable with JUUL although with high variability; that is, SURGE does not reliably avoid the increase in fibrosis caused by conventional electronic cigarettes. These findings suggest that non-thermal mechanisms predominate in mediating cardiovascular toxicity associated with ultrasonic vaping, challenging the assumption that coil-free designs are inherently safer. Implications: Despite its lower operating temperature and coil-free design, the SURGE ultrasonic vaping device impaired cardiac autonomic function and promoted fibrosis at a mean level comparable to that of JUUL. These findings challenge claims of reduced harm from coil-less vaping technologies and suggest that non-thermal mechanisms may drive toxicity. Regulatory evaluations should consider device emissions and physiological outcomes—not just hardware features. Physicians and policymakers should be aware that coil-less systems may still pose cardiovascular risks, and marketing these devices as inherently safer may mislead users and undermine tobacco harm reduction efforts.

Importance: Recreational and medicinal cannabis legalization has led to increased cannabis use. To understand the consequences for vascular health, we initiated the CANnabis: Does It Damage Endothelium (CANDIDE) study.Objective: To investigate whether cannabis use is associated with vascular endothelial dysfunction.Design, Setting, and Participants: In this cross-sectional study, age-matched healthy adults, aged 18 to 50 years, living in the San Francisco Bay Area, California, who neither smoke tobacco nor vape and were not frequently exposed to secondhand smoke were recruited into 3 cohorts: 2 chronic cannabis user groups (marijuana smokers and tetrahydrocannabinol [THC]–edible users) and 1 nonuser group. Participants were recruited from October 25, 2021, through August 1, 2024; analysis was completed September 2024. Participants’ arterial flow-mediated dilation (FMD) and carotid-femoral pulse wave velocity (PWV) were measured. Human umbilical vein endothelial cells (HUVECs) were exposed to participant sera with and without vascular endothelial growth factor (VEGF) to assess the effects of user serum on endothelial nitric oxide production.Main Outcomes and Measures: FMD and PWV were direct physiological measurements, and VEGF-stimulated nitric oxide production was measured from HUVECs incubated in user serum samples.Results: Among 55 participants (20 female [37%]; 35 male [63%], mean age, 31.3 [SD, 8.4] years) arterial FMD was significantly lower among the marijuana smokers (mean, 6.0% [SD, 2.6%]; P = .004) and lower among THC-edible users (mean, 4.6% [SD, 3.7%]; P = .003) than among nonusers (mean, 10.4% [SD, 5.2%]). VEGF-stimulated nitric oxide levels in endothelial cells treated with participants’ sera were significantly lower for the marijuana smoker group (mean, 1.1 nmol/L [SD, 0.3 nmol/L] ) than for the nonuser group (mean, 1.5 nmol/L [SD, 0.3 nmol/L]; P = .004) but were unaffected among the THC-edible users group compared with the nonusers (mean, 1.5 nmol/L [SD, 0.3 nmol/L]; P = .81). FMD was inversely correlated with smoking frequency (r = −0.7; P < .001) and the amount of THC ingested (r = −0.7; P = .03). Other vascular properties showed no differences.Conclusions: This cross-sectional study found that chronic cannabis smoking and THC ingestion were associated with endothelial dysfunction similar to that observed in tobacco smokers, although apparently occurring via distinct mechanisms.

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.

Heart failure (HF) remains a global public health burden and often results following myocardial infarction (MI). Following injury, cardiac fibrosis forms in the myocardium which greatly hinders cellular function, survival, and recruitment, thus severely limits tissue regeneration. Here, we leverage biophysical microstructural cues made of hyaluronic acid (HA) loaded with the anti-fibrotic proteoglycan decorin to more robustly attenuate cardiac fibrosis after acute myocardial injury. Microrods showed decorin incorporation throughout the entirety of the hydrogel structures and exhibited first-order release kinetics in vitro. Intramyocardial injections of saline (n = 5), microrods (n = 7), decorin microrods (n = 10), and free decorin (n = 4) were performed in male rat models of ischemia-reperfusion MI to evaluate therapeutic effects on cardiac remodeling and function. Echocardiographic analysis demonstrated that rats treated with decorin microrods (5.21% ± 4.29%) exhibited significantly increased change in ejection fraction (EF) at 8 weeks post-MI compared to rats treated with saline (−4.18% ± 2.78%, p < 0.001) and free decorin (−3.42% ± 1.86%, p < 0.01). Trends in reduced end diastolic volume were also identified in decorin microrod-treated groups compared to those treated with saline, microrods, and free decorin, indicating favorable ventricular remodeling. Quantitative analysis of histology and immunofluorescence staining showed that treatment with decorin microrods reduced cardiac fibrosis (p < 0.05) and cardiomyocyte hypertrophy (p < 0.05) at 8 weeks post-MI compared to saline control. Together, this work aims to contribute important knowledge to guide rationally designed biomaterial development that may be used to successfully treat cardiovascular diseases.

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. 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). 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. Galectin-3-mediated pathways driving fibrosis in the infarcted myocardium. MI triggers the increased secretion of galectin-3 by inflammatory cells that contribute to myofibroblast activation via the TGF-β pathway, the increased expression of arginase-1 via the M2-macrophage alternative pathway that activates a galectin-3 positive feedback loop, and the galectin-3 mediated up-regulation of iNOS via the IKKβ/NF-κB pathway. The inhibition of galectin-3 by Gal-3C regulates these post-MI inflammatory profibrotic signalling cascades, resulting in therapeutic benefits in acute MI models of young and aged hearts.

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.