cardiotoxic breast cancer meds: air pollution increases cardiac problems

 A recent study found that women with breast cancer who were on cardiotoxic chemotherapy (anthracyclines and/or trastuzumab) had worse cardiac remodeling and function if they had subsequent exposure to air pollution (see breast cancer air pollution dec cardiac function JAMA2025 in dropbox, or doi:10.1001/jamanetworkopen.2025.52323)

 

Details:

-- 580 female patients were included in this longitudinal prospective cohort study using data from the Cardiotoxicity of Cancer Therapy randomized clinical trial done at multiple sites

    -- this trial enrolled women diagnosed with breast cancer between July 1, 2010, and November 1, 2018, from the Abramson Cancer Center at the University of Pennsylvania. All participants were initiating anthracyclines and/or trastuzumab

    -- air pollution exposure assessment, which was done prior to chemotherapy: three-year average census tract–level concentrations of fine particulate matter with diameter of 2.5 μm or less (PM_2.5), particulate matter with diameter of 10 μm or less (PM₁₀), nitrogen dioxide (NO₂), and ozone (O₃).  there were annual averages for PM_2.5, PM₁₀, and NO₂ , but for O₃ they assessed the average of the daily maximum 8-hour moving value from May through September (warm-season ozone concentration). In the final analysis, there were approximately 350 geographic covariates assessed at each location (eg, traffic densities, land use, and satellite-based indicators) that were incorporated at each location.

-- baseline exposure to PM_2.5 was divided into tertilies: tertile 1 (least pollution, 193 patients), tertile 2 (194 patients), tertile 3 (most pollution, 193 patients); the below baseline data were very similar between tertiles unless noted otherwise

-- overall demographics: age 50, 25% Black (from 13% in tertile 1 to 40%  in tertile 3), white (from 80% in tertile 1 to 53% in tertile 3), BMI 27 (28 in tertile vs 26 in tertile 3)

-- social vulnerability index (SVI, score 0 to 1, with higher values indicating more vulnerability): 0.3 average (0.24 in tertile 1 vs 0.40 in tertile 3)

    -- this SVI was determined by the participant's baseline residential address, linked to the corresponding census tract identifier (there was 445 unique census tract identifiers) and matched to the SVI data from the CDC

-- cancer stage: stage I in 22%, stage II in 54%, stage III in 23%, stage IV in 2%

-- cancer treatment: doxorubicin in 59%, trastuzumab in 31%, both in 10%; radiotherapy in 71%​ with left-sided radiotherapy in 38% (important because of these women getting the adverse addition of cardiotoxic medicines along with cardiotoxic ionizing radiation therapy; for a fuller discussion on ionizing radiation, see https://gmodestmedblogs.blogspot.com/2026/01/age-based-low-dose-lung-ct-but-more.html )

-- cardiovascular history/risk factors: current or prior smoking 38%, current alcohol 55%, sufficient physical activity 12%, hypertension 30% (varied from 26% in tertile 1 to 36%  in tertile 3), dyslipidemia 24% (31% in tertile 1, 21% tertile 3; no specific definition of dyslipidemia), obesity 33%

-- cardiovascular meds: ACE/ARB in 15%, statin 14% (20% in tertile 1 vs 10%  in tertile 3);  b-blocker 9% (6% in tertile 1 vs 10% in tertile 3)

-- blood pressure 125/76, resting heart rate 78

-- baseline echocardiographic data (prior to the  cardiotoxic meds):

    -- left ventricular (LV) systolic function:

        -- left ventricular ejection fraction: 56% (59% tertile 1 vs 54% tertile 3)

        -- longitudinal LV strain: 18% (20% tertile 1 vs 16% tertile 3)

        -- LV circumferential strain: 27% (29% tertile 1 vs 25% tertile 3)

        -- LVEDV, left ventricular end-diastolic volume: 55 ml/m³ (50 tertile 1 vs 60 tertile 3)

        -- LVESV, left ventricular end-systolic volume: 24 ml/m³ (21 tertile 1 vs 28 tertile 3) 

        -- LV mass: 66 g/m³ (51 tertile 1 vs 73 tertile 3)

        -- relative wall thickness: 0.36 (0.35 tertile 1 vs 0.36  tertile 3)

    -- left ventricular diastolic function:

        -- E/e': 7.2 (7.2 tertile 1 vs 7.1 tertile 3)

        -- LA, left atrial, volume: 26.1 ml/m³ (22 tertile 1 vs 34 tertile 3)

        -- diastolic function grade:

            -- normal: 66% (74% tertile 1 vs 76% tertile 3)

            -- grade 1: 9% (7% tertile 1 vs 11% tertile 3)

            -- grade 2: 15% (19% tertile 1 vs 13% tertile 3)

    -- ventricular-arterial coupling:

        -- Ea/Ees: 0.90 (.79 tertile 1 vs 1.01  tertile 3)

-- PM_2.5 exposure: median 9.26 μg/m³ (8.06 tertile 1 vs 10.40 tertile 3)

main outcomes: echocardiography-derived measures of cardiac remodeling and function, and the incidence of cardiac dysfunction, defined as a left ventricular ejection fraction (LVEF) decline of 10% or more from baseline to less than 50%

-- multivariable linear regression to assess the relationship of air pollution with measures of cardiac remodeling and function

-- adjusted associations between air pollution and cardiac dysfunction

 

--followup a median of 3.1 years

Results:

 --3642 echocardiograms were done over the median of 3.1 years

-- prior to the chemotherapy, there were baseline cross-sectional associations of PM_2.5, NO₂, and O₃ with measures of cardiac function (LVEF, longitudinal strain, and circumferential strain), LV structure (LVEDV, LVESV, and LV mass), LV diastolic function (LA volume), and VA coupling

(Ea/Ees). 

    -- also, prior to chemotherapy, each baseline IQR-increment increase in PM_2.5 concentration (1.68 μg/m³) was associated with worse LVEF of −2.9% (−3.6% to −2.3%), longitudinal strain of −2.0% (−2.4% to −1.6%), circumferential strain of −1.6%  (−2.3% to −0.8%); higher LVEDV of 5.2 mL/m² (3.8 to 6.6 mL/m²), LVESV of 3.9 mL/m² (3.1 to 4.7 mL/m²), and higher LV mass of 11.5 g/m² (9.2 to 13.7 g/m²); and greater VA coupling with Ea/Ees of 0.11 (0.07 to 0.14) (all of these with P < .001)

-- after chemotherapy, cardiac dysfunction (defined as LVEF decline of 10% or more from baseline to less than 50%): 98 of 574 participants (17.1%)

    -- concentrations of PM_2.5 (median 9.26 μg/m³ [IQR, 8.49-10.17 μg/m3 ]); altogether 579 participants (99.8%) were exposed to  PM_2.5 levels that exceeded the WHO's guideline limit of 5 μg/m³; those who were younger, more often Black individuals, and having the highest SVI index and were more likely to reside in the highest tertile of PM_2.5 exposure (tertile 3: 9.80-12.44 μg/m³)

        -- each IQR-increment increase in PM_2.5 (1.68 μg/m³), was associated with a mean LVEF change of -1.3% (-1.8% to -0.8%), worse longitudinal strain of -1.0% (-1.3% to -0.7%), left ventricular mass increase of 4.8gm (3.1 to 6.5gm), worse LVEDV of 2.1 mL/m² (1.3 to 3.0 mL/m²), worse LVESV of 1.4 mL/m²(0.7- to 2.0 mL/m²).

            -- all of these measurement were statistically significant at P < .001, indicative of worse LV function and remodeling

        -- patients in the highest tertiles of PM_2.5 , adjusted for clinical and sociodemographic factors, were at a significantly higher risk of cardiac dysfunction compared with those in the lowest tertile, adjusted HR], 2.03; (1.17 to  3.52) 

    -- concentrations of O₃ (median, 47.00 parts per billion [ppb] [IQR, 45.50-48.19 ppb])

        -- each IQR-increment increase in O₃ (2.69 ppb) was associated with a mean LVEF change of −1.4% (−1.8% to −1.0%), p<0.001; worse longitudinal strain of -1.1% (-1.3% to -0.8%); worse left ventricular mass increase of 3.2gm (2.1 to 4.3gm); worse LVEDV of 1.3 mL/m2 (0.4 to 2.1 mL/m²; P = .004); and worse  LVESV of 1.1 mL/m² (0.5 to 1.7 mL/m², P < .001)

        -- patients in the highest tertiles of O₃ exposure were at a significantly higher risk of cardiac dysfunction compared with those in the lowest tertile, aHR, 2.15 (1.23 to 3.78)

    -- in addition, LA volume increased: 2.1mL/m² [1.3 to 3.0 mL/m²] for PM_2.5 and 1.5 mL/m² [0.7 to 2.2 mL/m²] for O₃

    -- neither PM₁₀ (aHR 0.84 (0.49 to 1.44)) nor NO₂ (aHR, 0.92 (0.50 to 1.70)) showed significant associations with cardiac dysfunction

 

 

-- the median time to cardiac dysfunction was 0.7 years (IQR, 0.4-1.3 years)

-- findings from the 1-year air pollution exposure analysis showed cross-sectional and longitudinal associations consistent with those from the primary 3-year model for measures of both cardiac structure and function

Commentary:

-- it is certainly true that we have made great strides in improving breast cancer survival. However, some of the important agents, especially anthracyclines and trastuzumab, are associated with adverse cardiac remodeling, declines in left ventricular function and development of heart failure

-- in this light, it is important to assess other potential factors that are possibly reversible/avoidable in further increasing the likelihood of cardiovascular disease, especially beyond the medical ones of hypertension, diabetes, and dyslipidemia that are typically addressed

-- this study was done to see if air pollution might be a risk factor for worsening cardiac function, since it is clearly associated with cardiovascular disease in many studies over many decades, eg: https://gmodestmedblogs.blogspot.com/2016/06/air-pollution-and-heart-disease.html

    -- air pollution is associated with increased systemic inflammation (including increased CRP levels) in many studies (eg doi.org/10.1038/s41598-025-24690-5), and this increased inflammation is associated with several medical problems including lung disease (eg COPD exacerbations), atrial fibrillation, diabetes, and hypertension and several cancers including lung, breast, bladder, upper and lower digestive tract (small intestine, colon, rectum, appendix, and anus), liver, gall bladder, pancreas, female and male genital, and lymphohematopoietic: https://aacrjournals.org/cebp/article/25/5/839/71066/Cancer-Mortality-Risks-from-Long-term-Exposure-to

-- in fact, air pollution in a 2019 assessment was found to be associated with almost 6.7 million deaths worldwide:  Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019 - The Lancet

-- studies have found that PM_2.5, PM₁₀, nitrogen dioxide NO₂, and O₃ are associated with worse cardiovascular outcomes, adverse cardiac remodeling, and diastolic dysfunction; it seems that of these pollutants PM_2.5 (fine particulate matter with a diameter of 2.5 μm or less) has the best evidence of an association with these adverse cardiovascular effects

    -- one study found that each 10 μg/m³ increase in PM_2.5 was associated with a 74.8% higher risk of heart failure (Effect of Air Pollution on Heart Failure: Systematic Review and Meta-Analysis - PubMed ); another found a 1.32-fold higher cardiovascular mortality that was worse in women receiving chemotherapy or radiation

-- this current study found that the fine pollutant PM_2.5 and O₃ exposure were independently associated with worse cardiac remodeling and function in patients with breast cancer treated with cardiotoxic therapy. The other pollutants studied (PM₁₀ and NO₂) did not play a significant role, as depicted in the figure above

-- it was notable but not surprising that even before receiving the cardiotoxic meds, those in tertile 3 had worse baseline echocardiographic findings, likely reflecting increased air pollution exposure but also other causes of chronic inflammation (stress, depression, and the higher blood pressure, diabetes, smoking alcohol intake and less physical activity in those in tertile 3). and we know that chronic inflammation if linked to decreased LV ejection fraction, worse NYHA functional class, and that chronic inflammation is both and cause and consequence of heart failure: https://www.jacc.org/doi/10.1016/j.jacc.2020.01.014

-- PM_2.5 promotes inflammation, mitophagy (selective autophagic degradation of damaged or stressed mitochondria), oxidative stress and accelerated aging, and increases of the generation of reactive oxygen species. the combination of these adverse effects likely reinforces a worsening of systemic inflammation and thereby increases adverse cardiac remodeling; systolic and LV dilation (precursors to cardiomyopathy and heart failure); and also the myriad of systemic diseases associated with this inflammation/immune activation such as diabetes, cancer, likely depression and several other chronic conditions

-- O₃ has also been found to increase mortality from risk from ischemic heart disease, and even short-term spikes in O₃ are associated with acute hospital admissions for MI and heart failure

-- NO₂ was associated with cardiac dysfunction in this cohort prior to receiving their cardiotoxic meds, including abnormal LV function, structural indices, and longitudinal strain. but, for unclear reasons, persistent longitudinal exposure to NO₂ did not result in increased risk of cardiac dysfunction. NO₂ is pretty clearly associated with pulmonary dysfunction vs cardiac dysfunction in other studies

Limitations:

-- there were pretty significant differences in baseline medical therapy between the groups. for example, though dyslipidemia was prevalent (31% in tertile 1 vs 21% in tertile 3), statin use was only 20% in tertile 1 vs 10% in tertile 3. Statins not only treats the hyperlipidemia (which was not defined further in this study), but have a significant role in lowering systemic inflammation, an important component to developing heart disease

    -- and one might think that having breast cancer, which itself raises the systemic inflammatory state, plus getting cardiotoxic drugs which constitutes a significant additional cardiovascular risk factor, would have led to higher levels of statin use.... This underuse of statins may well sway the results a bit.

-- the assessment done in this study was observational, thereby limiting the outcome to associations and not to causality. to determine causality, there would need to be a randomized controlled study, such as one that involved several communities sharing many similarities, some randomized to aggressive pollution decreases and comparing them to areas without this intervention in order to establish a role for pollution (an unlikely study to happen)

-- the pollution measures were assessed at baseline in this study and might not reflect the continued conditions over the 3-year period (though the 1-year analysis did have the same results). eg, some individuals may have moved out of these areas over the course of the study, affecting the results found

-- this study was done in a small area in the US and might not reflect other areas in the US or globally

-- there could be detection bias: those getting known cardiotoxic chemotherapy had lots of echocardiograms and may therefore have had more detection of abnormalities than in other patient groups

-- there was only 3.1 years followup on a potentially long-term cardiovascular effect; we may well need a longer study to assess the cumulative effect of pollution on clinically important cardiovascular outcomes....

-- and the measurements were echocardiographic and not the all-important clinical outcome of heart failure. we know from many studies that assessing surrogate markers of disease does not necessarily reflect clinical outcomes: https://gmodestmedblogs.blogspot.com/2024/06/using-surrogate-markers-for-disease-are.html . And, though in broad strokes a reduced LVEF is a pretty good predictor of clinical heart failure, there are certainly patients with very reduced ejection fraction with minimal symptoms and conversely patients with only mild decreases in ejection fraction with pretty severe symptoms

so, this study did suggest a few important findings that should affect our approach to cardiovascular disease:

-- it is clear that the risk factors for cardiovascular disease are far broader than the standard issues (lipids, blood pressure, diabetes, cigarette smoking): https://gmodestmedblogs.blogspot.com/2023/10/update-ascvd-risk-factor-critique.html

    -- it is increasingly clear that other very important risk factors play a very significant role: our social environment (stress, depression, etc), pollution (air/water/land; microplastics, etc), chronic inflammatory diseases (eg controlled HIV, chronic infections, chronic rheumatologic diseases, etc), other atherosclerotic disease (peripheral arterial disease, etc), alcohol, unhealthy diet, sedentary life, and likely more to be found (eg, there is increasing information documenting that low renin levels are associated with higher levels of inflammation and that we should target patients with low renin to receive meds to increase their renin levels: https://gmodestmedblogs.blogspot.com/2025/12/hyperaldosteronism-targeting-renin-level.html

-- this study of women receiving cardiotoxic meds for their breast cancer reinforces the specific importance of environmental exposures (pollution) in increasing cardiovascular disease and the importance of addressing them aggressively in order to mitigate cardiovascular disease risk.

    -- this study noted that the combination of cardiac toxins (meds plus pollution), not surprisingly, leads to more deleterious heart effects: it was clear in this study that women living in areas with higher air pollution at baseline had worse echocardiograms, and those subsequently given cardiotoxic medications had significant further deterioration of their echocardiograms

    -- and it is clear that if we want to decrease major causes of morbidity and mortality, we need to focus on the public health interventions necessary to prevent or mitigate these conditions that affect air/water/land quality, promote healthy diets/exercise venues, decrease toxic occupational exposures, reinstate and invigorate the Clean Air Act that has been largely decimated under the current political leadership, and provide increased support for public health as an integral part of having a healthy, happy, and productive population