Breast Cancer and Atrial Fibrillation: A 'Multiple-Hit Phenomenon'?

Patrice Wendling

January 29, 2019

Women with breast cancer have a higher incidence of atrial fibrillation (AF) than the general population, but risk varies by age and with time, suggest new findings.

A nationwide study in Denmark showed that women younger than 60 years had more than double the risk for new-onset AF in the first 6 months after their breast cancer diagnosis (hazard ratio [HR], 2.10; 95% CI, 1.25 - 3.44) and an 80% higher risk from 6 months to 3 years (HR, 1.80; 95% CI, 1.37 - 2.35).

Women older than 60 years, however, had short-term risk similar to that of women without cancer (HR, 1.13; 95% CI, 0.95 - 1.34) and a marginally elevated risk from 6 months to 3 years (HR, 1.14; 95% CI, 1.05 - 1.25) in multivariable analysis.

"Oftentimes, you see that younger patients are treated more aggressively with chemotherapy and radiation," lead investigator Maria D'Souza, MD, Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte, told theheart.org | Medscape Cardiology. "These treatments can be cardiotoxic, so if you have a higher frequency of younger patients being treated, we may also see a higher frequency having side effects."

Although these differences can partially explain the findings, she said that a number of comorbidities known to be risk factors for AF, such as hypertension, ischemic heart disease, and heart failure, were also associated with AF in the study population. Given that AF is associated with a higher risk for thromboembolism and ischemic stroke, in particular, the higher incidence of AF in breast cancer patients merits further study.

The findings were published online today in Heart Rhythm.

D'Souza and colleagues used data from four nationwide Danish registries to match, by age, 74,155 patients diagnosed with breast cancer from 1998 to 2015 with 222,465 women from the general population. The median age was 62 years and the two groups had similar comorbidities and pharmacologic treatments.

During follow-up, 987 patients with breast cancer (1.33%) and 3019 women from the background population (1.36%) developed AF, and 9445 (12.74%) and 10,408 (4.68), respectively, died.

The oldest patients had the highest 3-year cumulative incidence of AF, which aligns with research showing that advanced age is a predominant risk factor for AF, the authors note.

Further, baseline hypertension (HR, 1.38), ischemic heart disease (HR, 1.35), heart failure (HR, 1.71), chronic kidney disease (HR, 1.46), peripheral arterial disease (HR, 1.80), chronic obstructive pulmonary disease (HR, 1.86), and chronic liver disease (HR, 1.65) were all tied to a higher incidence of AF in multivariable analysis.

Emerging evidence has shown that both breast cancer and related treatments are associated with risk factors important for the development of AF through the mechanism of systemic inflammation and altered cardiovascular regulation, the authors note.

In addition, a bidirectional relationship between breast cancer and AF has been observed, with the Women's Health Initiative reporting a 19% higher risk of invasive breast cancer in women with prevalent AF.

Although this bidirectional association is not well understood, advancing age is the most potent risk factor for AF, and breast cancer also increases with age, Ankur A. Karnik, MD, Department of Cardiovascular Medicine, Boston University School of Medicine, and colleagues, observe in an accompanying editorial. Obesity is another prominent risk factor for both.

"Inflammation may be a common process that increases risk for both conditions," they write.

This study "provides valuable insights from a large nationwide cohort, with results generalizable to women of European ancestry. However, a few limitations should be mentioned," the editorialists write.

Specifically, the 3-year follow-up might be too short for the cardiotoxic effects of breast cancer treatment to fully manifest. The analysis also did not account for confounding from body mass index and the competing risk for death.

The investigators argue that the higher death rate observed in patients with breast cancer could have caused an underestimation of AF risk in patients. "Our estimates were conservative, and we expect that this issue would only support the direction of our conclusion."

Ultimately, the cumulative incidence of AF at 3 years was "low and similar for women with and without breast cancer," at about 0.4% vs 0.2% before age 60 years and 2.2% vs 2.4% after 60 years, the editorialists point out.

D'Souza agreed the data is not there to support such an approach, but based on the findings: "We'd encourage practitioners to be aware of these patients and to be aware of this increased incidence to be able to diagnose and treat as soon as possible."

The study suggests several substantive research questions, according to the editorialists, such as whether there are subsets of women with breast cancer at sufficient risk for AF to merit more intensive monitoring and whether the risk for AF in patients with breast cancer can be explained by shared risk factors.

And, "is it a multiple-hit phenomenon in which a proinflammatory state and breast cancer treatments add insult to injury? A study design that accounts for multiple confounders is important in future endeavors," Karnik and colleagues say.

This study was funded by the Danish Heart Foundation and the VELUX Foundations. D'Souza has received grants from both organizations. Karnik reports no conflicts of interest.

Heart Rhythm. Published online January 29, 2019. Abstract, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org, follow us on Twitter and Facebook.

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