Anthracycline Containing Chemotherapy Associated With Valvular Dysfunction in Long Term Lymphoma Survivors

Anthracycline containing chemotherapy (ACCT) alone was significantly associated with valvular dysfunction in lymphoma survivors, according to results of a cross-sectional national multi-center survey conducted in Norway.¹

From March 2012 to March 2014, researchers evaluated 274 patients who were lymphoma survivors, matched with controls (1:1 on age, gender, systolic blood pressure, and BMI), selected from a clinical echocardiographic database. Lymphoma survivors originally underwent treatment, including autologous stem cell transplantation, from 1987 to 2008. Controls had no diagnoses of cardiovascular disease, hypertension, or diabetes.

After excluding lymphoma survivors already diagnosed with cardiovascular disease, hypertension, or diabetes, valvular dysfunction was observed in 16.7% of patients treated with ACCT alone, which corresponded to a 3-fold increased risk (odds ratio [OR]: 2.9; 95% confidence interval [CI]: 1.5-5.8; P=.002) compared with controls. Increased aortic valve degeneration after ACCT was also increased in lymphoma survivors compared with controls (13.0% vs 2.9%; P<.001).

In total, 82 dysfunctional valves were observed in 61 lymphoma survivors, of which 59 were left-sided, and valvular regurgitations comprised 86.6% of all valvular dysfunction.

Researchers identified female gender, age of more than 50 years at cancer diagnosis, and at least 3 lines of chemotherapy pre auto-hematopoietic stem cell transplantation as independent risk factors.

“The underlying mechanism for valvular dysfunction after ACCT has not been previously reported,” the authors noted. “…It is conceivable that the most likely cause of valvular dysfunction (ie, MR [mitral regurgitation] and TR [tricuspid regurgitation]) in the ACCT group was a combination of reduced LV/RV systolic function and a mild left ventricular remodeling, a phenomenon previously observed in Hodgkin lymphoma survivors after ACCT.”

In an accompanying editorial, Michael H. Crawford, MD, chief of Clinical Cardiology at University of California at San Francisco Medical Center, wrote that when mitral regurgitation was compared to controls, there was no difference, but aortic and tricuspid regurgitation significantly increased in the ACCT-alone group.²

“Although this is a cross-sectional study with no report of prior echoes [echocardiograms], the data supporting the hypothesis that anthracycline containing chemotherapy can cause direct valve injury is compelling,” Dr Crawford wrote.

He expands by pointing out that “direct drug induced valve disease has been observed with agents that increase fibrosis and collagen deposition by stimulating a specific serotonin receptor (5HT2B) in valve tissue…These drugs can produce valve thickening that resembles carcinoid heart valve disease.”

However, it is difficult to prove an association with these drugs, because valve regurgitation is common as people grow older, and most patients who have been studied to not have prior echocardiograms. Nonetheless, Dr Crawford suggests it seems wise to consider valve disease in long term lymphoma survivors, particularly in high dose chemotherapy or radiation.

The study authors conferred: “The majority of valvular dysfunction observed was moderate, and longer observation time is necessary for further clarification of the clinical significance of these findings.”

References

1. Murbraech K, Wethal T, Smeland KB, et al. Valvular dysfunction in lymphoma survivors treated with autologous stem cell transplantation—a national cross-sectional study. JACC Cardiovasc Imaging. 2016. doi: 10.1016/j.jcmg.2015.06.028.
2. Crawford MH. Chemotherapy induced valvular heart disease. JACC Cardiovasc Imaging. 2016. doi: 10.1016/j.jcmg.2015.07.019.