World Trade Center Particulate Matter Induced Cardiorespiratory and Vascular Dysfunction: a MultiOmic Approach (CaRVD)

World Trade Center Particulate Matter Induced Cardiorespiratory and Vascular Dysfunction: a MultiOmic Approach (CaRVD)

Particulate matter (PM) associated cardiorespiratory and vascular dysfunction (CaRVD) poses a significant global health burden. The World Trade Center (WTC) destruction on September 11, 2001 led to an intense deposition of particulate matter (WTC-PM) into aerodigestive system. WTC associated morbidities include respiratory, gastrointestinal, chronic rhinosinusitis, cancer, mental health concerns and more recently a focus has been on cardiovascular disease. This proposal will investigate the development of WTC-cardiorespiratory and vascular dysfunction (WTC-CaRVD) which is firmly within the purview of the James Zadroga 9/11 Health and Compensation Act.

WTC-PM exposure causes heterogeneous obstructive airways disease (OAD) patterns, which include airway hyperreactivity (AHR) and loss of FEV1. Early diagnosis and therapeutic options are few, in part due to limited understanding of their pathogenesis. While pulmonary vascular changes are classically thought to occur due to the hypoxemia of late OAD, recent investigations show that vascular dysfunction occurs early in OAD. This vascular hypothesis of OAD postulates that pulmonary vasculature remodeling leads to loss of lung function. Early evidence of WTC-CaRVD includes increased prevalence of cardiovascular disease risk factors such as metabolic syndrome, elevated pulmonary artery/aorta ratio, and cardiovascular biomarkers (such as CRP). Murine models of WTC-PM exposure show inflammation, AHR both acutely and persistently and reflect what is seen in FDNY 1st responders. Airway and cardiac remodeling were also persistent features of WTC-PM exposure in the study team's murine models. Therefore, the study team will focus on Heme Oxygenase-1 (HO-1), a mediator of oxidative stress, known to stimulate collagen formation and is also induced after WTC-PM exposure. Furthermore, pathways and mechanisms of WTC-CaRVD warrant further study and are the focus of the 5-year proposal.

The HYPOTHESIS is that WTC-PM exposure causes WTC-CaRVD mediated by HO-1. First responders with AHR will have features of WTC-CaRVD, and will demonstrate a unique biomarker profile compared to controls.

Inclusion Criteria:

1. Age 21-90
2. FDNY rescue and recovery worker
3. Documented WTC exposure
4. Consented/Enrolled member of the WTC-HP
5. Subjects are willing and able to consent for themselves to study enrollment
6. Subjects are willing and able to participate in study procedures
7. Are able to perform their activities of daily living independently
8. Are either light duty or retired FDNY Firefighters
9. Spirometry available within the last 24 months, and at a post-9/11 visit.
10. Have means to accommodate transportation to/from in-person visit Are able to attend a single visit at the CTSI (462 1st Avenue, C & D 4th Floor)
11. Pre-9/11 spirometry with FEV1%predicted ≥LLN and if not available 1st -post 9/11 spirometry with an FEV1 >80% predicted.
12. No recorded positive AHR testing prior to 9/11
13. Exposure at the WTC-site within 2 weeks of 9/11/2001
14. Entered WTC-HP before the site closure on 7/24/2002
15. Serum from their first post 9/11 WTC-HP visit is available in the biorepository and may be assayed
16. Are not currently being treated for malignancy
17. Subjects will either need to be defined as having WTC-AHR or be designated controls

Exclusion Criteria:

1. Unwilling to complete an informed consent.
2. Not enrolled in the WTC-HP
3. Do not meet eligibility criteria or did not have serum available in the biorepository from the first post 9/11 WTC-HP visit.
4. Have pre-existing and documented conditions or concurrent diagnoses, including (and not necessarily limited to) active cancer, severe heart disease, significant cognitive impairment, eating disorders, significant psychiatric illness, end-stage COPD, severe pulmonary hypertension, or organ transplant.
5. High dose steroid (>20mg prednisone or equivalent) or other hormonal treatments/chemotherapy use in the last month, including testosterone supplementation.
6. Life-expectancy < 6 months