Hookah Smoking, Carbon Monoxide, and Coronary Endothelial Function

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.

Inclusion Criteria:

- 21-25 y/o hookah smokers: smoked hookah > 12 times in the last 12 months.

- 21-25 y/o cigarette smokers: smoked >100 cigarettes and smoked in the last 30 days.

- 35-49 y/o hookah smokers: smoke hookah at least once per week for > 20 years.

- 35-49 y/o cigarette smokers: have > 20 pack-year cigarette smoking history.

- All subjects must have:

- no history of illicit drug use or marijuana.

- no evidence of cardiopulmonary disease by history or physical.

- no diabetes with fasting blood glucose <100 mg/dl.

- BP<140/90 mmHg.

- resting heart rate<100 bpm.

- BMI<30kg•m2.

- no prescription medication.

- normal EKG and echocardiogram.

Exclusion Criteria:

- suboptimal echocardiographic window.

- exhaled CO>10 ppm (smoking non-abstinence).

- positive pregnancy test.

- psychiatric illness.

- other conditions deemed unsafe to participate.