Trials / Terminated

TerminatedNCT03166787

Hookah Smoking, Carbon Monoxide, and Coronary Endothelial Function

Status: Terminated
Phase: Phase 1
Study type: Interventional
Enrollment: 60 (actual)

Sponsor: Cedars-Sinai Medical Center · Academic / Other
Sex: All
Age: 21 Years – 49 Years
Healthy volunteers: Accepted

Summary

Detailed description

Hookah (water pipe) smoking is a new global epidemic. The World Health Organization wants to prohibit all claims that hookah is less harmful than cigarettes and wants hookah products to bear the same warning labels as cigarettes. But there is little scientific evidence to substantiate this proposal. Cigarettes, cigars, medicinal nicotine, and e-cigarettes all acutely impair brachial artery endothelial function (flow-mediated dilation, FMD). Also, cigarettes cause both acute and chronic impairment in coronary endothelial function, but the comparative effects of hookah are unknown. Hookah tobacco is heated with burning charcoal. So, the smoke contains "tar" and nicotine plus charcoal combustion products. These include carbon monoxide (CO) and proatherogenic oxidants (especially carbon-rich nanoparticles) that the study team expected to impair endothelial function. Surprisingly, in young hookah smokers, the study team found that hookah smoking is a potent acute stimulus to augment-not impair-FMD. And the enhanced FMD is caused by one or more charcoal combustion products: when the study team replaced charcoal in the hookah with a supposedly healthier electronic heat source ("e-coal"), FMD became acutely impaired just as with cigarettes. But brachial artery FMD is a poor index of coronary endothelial function. With hookah, the CO boost (10-fold larger than cigarettes) decreases hemoglobin (Hb) O2-carrying capacity, which will decrease myocardial O2 delivery unless offset by increased myocardial blood flow (MBF). Accordingly, the study team now turn our attention to acute and chronic effects of hookah smoking on coronary endothelial function. BACKGROUND/SIGNIFICANCE Carbon monoxide (CO) is an endogenously produced gas that play important physiological roles in the circulation. Traditionally considered a poisonous gas that causes tissue hypoxia, CO produced by vascular cells as a byproduct of heme catabolism, also functions to regulate blood flow by inhibiting vasomotor tone, smooth muscle cells proliferation, and platelet aggregation. These vascular effects are thought to be mediated by cyclic guanosine monophosphate (cGMP) because both clinical observations and experimental data provide precedent that CO, like nitric oxide, constitutes a cGMP-dependent vasodilator. Drugs that upregulate the endogenous production of CO by heme oxygenase, such as CO releasing molecules (CORMs), are being developed to treat several vascular diseases. The toxicity of CO is dependent on the: (1) gas concentration; (2) duration of exposure; and (3) whether exposures are intermittent or continuous. After CO is inhaled by the lungs, it reaches the blood stream where it is bound by hemoglobin, forming carboxyhemoglobin. Thus, serum carboxyhemoglobin levels, as a percentage of total hemoglobin, is a determining factor that correlate with the degree of CO intoxication and severity of symptoms. Continuous CO inhalation is fatally toxic at concentrations of 800 parts per million (ppm) or 0.08% in the air. Based on environmental science literature (not controlled clinical research studies), death occurs from continuous CO inhalation for 2-3 hours as with gas-fired kitchen ranges. Studies conducted in controlled research setting have demonstrated that intermittent CO inhalation for 1 hour at low doses (\<250 ppm) offers protection against inflammation and ischemic injury in the heart, liver, and kidney. According to a recent study published in Nature, repeated exposures of 250 ppm of CO for 1 hour inhibit experimental atherosclerosis by a cGMP-dependent process in rats. Other studies have also demonstrated that exogenous CO causes cGMP-dependent vasodilation in isolated vascular rings, and, in intact animals, can augment nitric oxide-dependent vasodilation. Initial studies by our group allowed us to discover that, in young healthy hookah smokers, hookah smoking is a potent acute stimulus to augment-not impair-endothelial function measured by brachial artery flow mediated dilation (FMD). The data implicate a pivotal mechanistic role of one or more charcoal combustion products in the augmented endothelial function: when burning charcoal was replaced with a healthier electronic heat source ("e-coal"), FMD became acutely impaired just as with cigarettes and almost all other known tobacco products including electronic-cigarettes. Interestingly, the CO boost after our hookah subjects smoked charcoal-heated hookah tobacco was \~10-fold higher than after smoking a cigarette (25+11 vs. 3+2 ppm). Tobacco literature provide evidence that the repeated CO exposure from cigarette smoking is associated with a reduced risk of pre-eclampsia (associated with pathological vasoconstriction) in pregnant women as compared with both non-smokers or users of smokeless tobacco (snuff) which does not generate CO. Recently published studies by our study consultants showed that intermittent 0.12-0.15% CO inhaled by healthy smokers, to achieve mean carboxyhemoglobin 5+1% (which is equivalent to exhaled CO levels of 30 ppm), had no significant effect on blood pressure, heart rate, plasma catecholamines, platelet aggregation or C-reactive protein, a marker of inflammation. Similarly, acute CO inhalation clinical research literature conducted in healthy subjects show that levels of 0.05-1.2% CO are safe and produced no symptoms, no adverse effects and no change in standard physiological measures such as blood pressure and heart rate (Table 1). The effects of low levels of CO on human endothelial function has yet to be determined.

Conditions

Interventions

Type	Name	Description
OTHER	Charcoal hookah	The Myocardial Blood Flow (MBF) will be measured at rest and during the last minute of a 3-minute bout of handgrip at 30% Maximal voluntary contraction. This sequence will be performed before and after 12 young hookah smokers are randomized to smoke the same popular Starbuzz tobacco product heated with either charcoal for 30 min each.
OTHER	E-coal hookah	The Myocardial Blood Flow (MBF) will be measured at rest and during the last minute of a 3-minute bout of handgrip at 30% Maximal voluntary contraction. This sequence will be performed before and after 12 young hookah smokers are randomized to smoke the same popular Starbuzz tobacco product heated with electrically (Global First "e-coal," ) for 30 min each.
OTHER	Cigarette	The Myocardial Blood Flow (MBF) will be measured at rest and during the last minute of a 3-minute bout of handgrip at 30% Maximal voluntary contraction. This sequence will be performed before and after 12 young cigarette smokers smoke 2 cigarettes down to the stub over 30 min (to simulate real-world use).
DRUG	Carbon Monoxide inhalation	A subset (n=8) of the young hookah smokers will return on a later day and will be randomized to have coronary endothelial function assessed before and after inhaling 0.3 CO gas from a Douglas bag.
OTHER	Room Air inhalation	A subset 8 of the young hookah smokers will return on a later day and will be randomized to have coronary endothelial function assessed before and after inhaling room air from a Douglas bag.
DRUG	vitamin C	in a subset of 6 subjects the study team will repeat the Myocardial Contrast Echocardiography and speckle tracking studies after pretreatment with either i.v. vitamin C .
DRUG	tadalafil	in a subset of 6 subjects the study team will repeat the Myocardial Contrast Echocardiography and speckle tracking studies after pretreatment with one dose of oral tadalafil.

Timeline

Start date: 2017-08-15
Primary completion: 2020-04-15
Completion: 2020-10-15
First posted: 2017-05-25
Last updated: 2021-04-09

Locations

1 site across 1 country: United States

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT03166787. Inclusion in this directory is not an endorsement.