Secondhand Tobacco Smoke and Cardiovascular Disease
Secondhand Tobacco Smoke and Cardiovascular Disease
This is a double-blind randomized placebo-controlled crossover clinical trial of efficacy and
 safety of an FDA-approved angiotensin receptor blocker (losartan) to improve cardiopulmonary
 outcomes in individuals with pre-Chronic Obstructive Pulmonary Disease (COPD) due to
 prolonged exposure to secondhand tobacco smoke.
Secondhand tobacco smoke (SHS) remains a major public health problem.This is important
 particularly as the generations that endured the highest amount of SHS exposure are aging,
 which could potentially accentuate the SHS-related occult health problems that may have been
 previously too subtle to be recognized. Although acute and subacute health effects of
 exposure to SHS have been studied, its long-term consequences have been more difficult to
 examine in part due to challenges with exposure assessment. Nonsmoking flight attendants (FA)
 who worked on commercial aircrafts before the enactment of the smoking ban were exposed to
 heavy SHS in aircraft cabin for many years, in a range similar to the nicotine exposure
 burden experienced by "light" smokers. The regularity of this intense exposure in the cabin
 work environment lends itself to relatively accurate SHS exposure quantification through
 employment history, and makes the exposed FA a unique population in which the long-term
 health effects of previous exposure to SHS could be examined as a form of "natural"
 experiment that is also generalizable to other SHS exposed populations.

 Over the past several years, the investigators recruited a nonsmoking cohort of FA with such
 history of cabin SHS exposure who had subclinical signs and symptoms of pulmonary disease.
 Furthermore, while the FA in this cohort had no history of known cardiovascular disease, and
 were able to perform well on maximum effort exercise testing, they had an abnormal
 cardiovascular (hypertensive) response to exercise (HRE) that was associated with their cabin
 SHS exposure. Subtle abnormal cardiovascular response to exercise in the absence of overt
 disease, such as what the investigators observed in this cohort, has been described in other
 populations with likely subclinical disease and is suggested to be associated with impaired
 cardiovascular function with potential future adverse outcomes. However, the underlying
 mechanisms that contribute to these abnormal cardiovascular responses are unclear, and the
 rationale for initiation of preventative medical interventions in this setting remains
 unproven. Thus, the nature and clinical significance of these subtle abnormalities demands
 further investigation.

 The hypothesis of this study is that:

 1. Prolonged exposure to secondhand tobacco smoke (SHS), even when remote, is associated
 with occult cardiovascular disease as determined by (a) abnormal cardiac structure and
 function, (b) abnormal vascular structure and function, and (c) abnormal circulatory
 mediators, which altogether generate a hypertensive response to exertion and limit
 exercise capacity.

 2. Management of hypertensive response to exercise (HRE) via blocking of the
 renin-angiotensin system, using an angiotensin-converting enzyme (ACE) receptor blocker,
 reduces the hypertensive response and improves exercise capacity, proxies for long-term
 cardiovascular health outcomes.

 The investigators will investigate the above hypothesis through the following specific aims:

 Specific Aim 1- Determine whether hypertensive response to exercise (HRE) is associated with
 abnormal cardiac and/or vascular structure and function in flight attendants (FA) with
 prolonged cabin SHS exposure but without overt cardiovascular disease. The investigators will
 perform cardiac magnetic resonance imaging (MRI) to measure myocardial dimensions and
 function including left ventricular (LV) mass, volume, ejection fraction (LVEF), and
 diastolic function. The investigators will also measure aortic stiffness by regional pulse
 wave velocity (PWV) measurement in the thoracic aorta from the MRI. The investigators will
 then examine the associations of these outcomes with SHS exposure and HRE.

 Specific Aim 2- Determine whether HRE is associated with abnormal circulatory markers of
 cardiovascular disease in those with prolonged SHS exposure but without overt disease. The
 investigators will examine subjects' peripheral blood samples for circulatory markers of
 systemic inflammation, vascular function, and prothrombotic state including ACE, C-reactive
 protein (CRP), endothelin-1 (ET-1), P-selectin, fibrinogen, and von Willebrand Factor (vWF).
 Moreover, the investigators will perform molecular phenotyping of peripheral blood monocytes,
 an important culprit in atherogenesis, using mass cytometry in search for a proinflammatory
 profile associated with cardiovascular disease. The investigators will then examine the
 associations of these outcomes with HRE and SHS exposure.

 Specific Aim 3- Determine whether short-term treatment with an ACE receptor blocker
 (Losartan) improves HRE and exercise capacity in those with prolonged exposure to SHS but
 without overt cardiovascular disease. The investigators will perform a placebocontrolled
 double-blind randomized controlled trial (RCT) in subjects with HRE but without known
 cardiovascular disease to determine the efficacy (and safety) of blocking the
 reninangiotensin system in reducing HRE and improving exercise capacity, a proxy for improved
 cardiovascular health.
Inclusion Criteria:

 -  Must be able to understand and provide informed consent.

 -  Adults >= 40 years of age.

 -  Must have a history of occupational exposure to secondhand tobacco smoke for at least
 5 years such as flight attendants who worked for airlines before the smoking ban on
 aircrafts went into effect or casino workers who worked at casinos with no smoke-free
 policies.

 -  Must have never smoked or have a remote history of light smoking defined as follows:

 -  Lifetime smoking history equivalent to < 1 pack-year and

 -  No smoking history for >= 20 years at the time of enrollment.

 Exclusion Criteria:

 -  Inability or unwillingness of a participant to give written informed consent or comply
 with study protocol.

 -  Subject is pregnant, breast-feeding, or plans to become pregnant.

 -  Current therapy with angiotensin converting enzyme (ACE) inhibitor or angiotensin
 receptor blocker (ARB).

 -  Known intolerance to ACE inhibitor or ARB.

 -  History of angioedema.

 -  Conventional indication for ACE inhibitor or ARB (e.g., history of myocardial
 infarction, known cardiomyopathy).

 -  Blood pressure less than 90 mm Hg systolic or 60 mm Hg diastolic while standing or
 sitting.

 -  Known unilateral or bilateral renal artery stenosis higher than 70%.

 -  Renal insufficiency (Creatinine Clearance <30 mL/min by Cockcroft-Gault calculation).

 -  Current regular use of NSAIDs defined as daily use on 5 or more days of the week for
 more than one month.

 -  Potassium supplementation or serum potassium level of 5.0 milliequivalents (mEq)/dL or
 higher at V1.

 -  Current use of a potassium sparing diuretic.

 -  History of clinically overt cardiovascular disease including: stable or unstable
 angina; chest discomfort and dyspnea with baseline exertion; symptomatic coronary
 artery disease (as defined by history of abnormal stress test; cardiac catheterization
 showing >70% coronary artery stenosis; history of revascularization; pathologic Q
 waves on EKG); poorly controlled resting hypertension (SBP>160/ DBP>95); congestive
 heart failure (CHF) (as defined by left ventricular ejection fraction (LVEF) <55%;
 physical exam findings of CHF; symptomatic pulmonary edema); significant (>mild)
 valvular heart disease; congenital heart disease; cardiac arrhythmias including
 frequent premature atrial or ventricular contractions (>5 per minute).

 -  History of clinically overt pulmonary disease that may interfere with study
 procedures, including: greater than mild asthma, COPD, emphysema, chronic interstitial
 lung disease, and pulmonary hypertension.

 -  Neuromuscular disorders or physical disability to perform exercise testing using an
 ergometer.

 -  Significant history of recreational drug use other than marijuana as defined by:
 recreational drug use within the last 30 years of recruitment (or) recreational drug
 use at a frequency of more than once a month before 30 years.

 -  Marijuana use more than once a week.

 -  Other uncontrolled chronic illnesses which in the judgment of the study physician
 would interfere with completing study procedures.

 -  Failure to keep screening appointments or other indicators of non-adherence.

 -  Concomitant participation in another interventional study.

 -  Subjects with BMI <15 or >40 kg/m2.

 -  MRI Scan Participation Exclusion Criteria - The participants will be excluded from the
 MRI portion of the study if they have a metallic object embedded or implanted in their
 body that is incompatible with Magnetic Resonance (MR) scanning, including MR
 incompatible pacemaker or defibrillator.