Ambient Air Pollution Linked to Mortality After Heart Transplant

Stephanie Edwards

December 12, 2019

New retrospective data show an association between long-term exposure to particulate matter <2.5 µm in diameter (PM2.5) and all-cause mortality among heart transplant recipients.

A contemporary cohort taken from the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) registry showed that for heart transplant recipients living in ZIP code areas where air pollution was above the acceptable level set by the National Ambient Air Quality Standards (NAAQS), mortality rates were higher than for those living in areas where the air quality was at or below that threshold.

"This study shows that there is a robust association, 26% increase in mortality relative risk after adjusting for multiple factors," said senior author Sanjay Rajagopalan, MD, Harrington Heart and Vascular Institute, University Hospitals, and Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio. "We would add cardiac transplantation as another entity or a susceptible population subset to the effects of air pollution."

The study was published online December 10 in the Journal of the American College of Cardiology.

High-Risk Procedure

More than 2000 heart transplants are performed in the United States each year. Although the authors point out that heart transplant is the preferred treatment for patients with heart failure, post-transplant mortality remains as high as 50%.

The authors write that exposure to PM2.5 has been shown to induce systemic immune activation. In this study, the investigators aimed to determine whether there is a relationship between ambient PM2.5 and mortality among transplant recipients in the United States.

The study used data from the Standard Transplant Analysis and Research (START) files from UNOS from 21,800 patients listed in the UNOS/OPTN registry, which has collected data on all solid organ transplants performed in the United States since 1987, the authors note. All adults aged ≥18 years who underwent heart transplant between January 1, 2004, and September 30, 2015, were included.

The mean age at the time of transplant was 53 years, 75% were men, 69% were white, and 39% had heart failure of ischemic etiology. A total of 21.9% of patients were living in areas where the mean annual exposure of PM2.5 was ≥12 µg/m3, which is above NAAQS limits. Mean annual exposure to PM2.5 was 10.6 ± 2.3 mg/m3.

Patients were classifed on the basis of average PM2.5 into tertiles and were compared using a chi-square test. Cox proportional hazard models were constructed to assess the association between PM2.5 and mortality, and four models for covariates were increasingly adjusted throughout follow-up.

Exposure to PM2.5 was treated as a time-varying covariate. PM2.5 levels are available on an annual basis. Each participant was assigned a level of exposure from the transplant date, and that level was updated on January 1 of each subsequent calendar year until death or right censoring.

At a median follow-up of 4.8 years, 5208 patients (23.9%) had died.

The estimated mortality hazard ratio (HR) for each incremental increase in annual PM2.5 exposure was 1.43 (95% confidence interval [CI], 1.21 – 1.49).

After adjustment for 30 donor, recipient, and neighborhood variables, the researchers found that each 10 µg/m3 increase in annual exposure to PM2.5 was associated with a 26% higher risk for mortality (HR, 1.26; 95% CI, 1.11 – 1.43).

The findings were consistent across subgroups with respect to age, sex, race, diabetes, bridging to transplant using mechanical circulatory support, year of transplant, and heart failure etiology, the authors note.

With respect to causes of death, the authors write, "we found an association between PM2.5 and mortality from infections in transplant patients. Unfortunately, the UNOS database does not collect additional data on cause-specific infection mortality."

Table. Increased Mortality Risk by Cause of Death (Fully Adjusted, Per 10 mg/m3 PM2.5)

Cause of Death HR 95% CI P Value
Graft failure 1.36 0.97 – 1.90 .073
Cardiovascular 1.04 0.76 – 1.42 .82
Cardiovascular or graft failure 1.18 0.94 – 1.49 .15
Infection 1.54 1.12 – 2.14 .009
Pulmonary 1.03 0.60 – 1.77 .91
Cerebrovascular 0.92 0.52 – 1.64 .78
Hemorrhage 0.99 0.37 – 2.64 .98
Malignancy 1.56 0.97 – 2.52 .068


"As a vulnerable group, transplant recipients are highly susceptible to infections due to immunosuppression," they add. "PM2.5 is recognized as a factor in enhancing susceptibility to infection. Indeed, several cohort studies have also shown an association between air pollution with incidence and mortality from infections."

"It's very clear that the environment has a robust effect on outcomes and, in fact, collectively conspires with other genetic factors," Rajagopalan said.

In future studies, Rajagopalan suggested that "research might need to be focused on personal measures to mitigate air pollution effects, and those should be directed, really, to vulnerable and susceptible populations."

The authors note some limitations. As a retrospective study, the quality of data cannot be ascertained for all patients. Exposure misclassification is possible owing to the possibility that the ZIP code in which the transplant took place may not be the primary residence. Time-varying estimates of cardiometabolic risk factors were not accounted for, and variables associated with air pollution exposure and outcomes could not be determined.

Timing of Vulnerability

In an accompanying editorial, C. Arden Pope III, PhD, Department of Economics, Brigham Young University, Provo, Utah, and Aruni Bhatnagar, PhD, Division of Environmental Medicine, Department of Medicine, University of Louisville, Kentucky, call this finding "robust" and "notably large."

They speculate on why transplant patients may be sensitive to air pollution. "The investigators argue that air pollution exposure results in activation of oxidant and inflammatory responses, and increases blood pressure and insulin resistance due to the activation of the sympathetic-adrenal-medullary axis," they write. However, air pollution can also affect immune responses, "which may be particularly devastating in immunosuppressed transplant patients.

"Indeed, the investigators found that PM2.5 was associated with mortality from infections, suggesting that exposure to air pollution may increase the risk of fatal infections," they add. "Moreover, their results suggest that effects of air pollution were insensitive to time after transplantation, which implies that a combination of effects may be at play."

This insensitivity of effects to time after transplant suggests that air pollution "contributes to multiple time-variant causes of mortality in transplant patients, and points to pervasive systemic effects that await unambiguous identification," they note. Identifying specific time windows of high vulnerability to air pollution and the contribution of risk factors such as hypertension and hyperlipidemia in modifying that vulnerability "will be important in minimizing the risk imposed by air pollution in an already vulnerable patient population."

Pope and Bhatnagar note that this study "makes an important contribution to our understanding of the health effects of air pollution."

"Given the large baseline mortality risk in cardiac transplant recipients, the relatively large excess mortality risk associated with PM2.5 air pollution is remarkable," they conclude. "These results may demonstrate the broader risks of chronic exposure to air pollution in diminishing health and further complicating those who already have chronic illness."

The study was supported in part by National Institutes of Health and the Health Resources and Services Administration. The editorialists have disclosed no relevant financial relationships.

J Am Coll Cardiol. Published online December 9, 2019. Abstract, Editorial

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