Secondhand Tobacco Smoke and Cardiovascular Disease

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.

• Mean Left Ventricular Mass [Time frame: Baseline, approximately 1 day]
• Mean Left Ventricular Volume [Time frame: Baseline, approximately 1 day]
• Change in Mean Angiotensin Converting Enzyme (ACE) Level [Time frame: Up to 10 weeks]
• Change in Mean C-Reactive Protein (CRP) Level [Time frame: At baseline assessment (V1); 4th week of V2 (placebo/losartan) treatment period; and 4th week of V3 (placebo/losartan) treatment period]
• Change in Mean Endothelin-1 Level [Time frame: Up to 10 weeks]
• Change in Mean P-selectin Level [Time frame: Up to 10 weeks]
• Change in Mean Fibrinogen Level [Time frame: Up to 10 weeks]
• Change in Mean von Willebrand Factor (VWF) [Time frame: Up to 10 weeks]
• Change in Mean Maximum Workload [Time frame: Up to 10 weeks]
• Change in Mean Maximum Oxygen Pulse [Time frame: Up to 10 weeks]
• Change in Mean Slope of Systolic Blood Pressure (SBP) [Time frame: Up to 10 weeks]
• Change in Mean Slope of Diastolic Blood Pressure (DBP) [Time frame: Up to 10 weeks]