By Michael Crawford, MD
Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: Long-term lymphoma survivors were noted to experience valvular regurgitation out of proportion to reductions in left ventricular function and degenerative valve stenosis. The most evidence appeared in those who received radiation therapy in addition to chemotherapy.
SOURCE: 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;9:230-239.
Radiation therapy for lymphoma patients is known to be associated with late heart valve damage. Chemotherapy, especially with anthracyclines, has been associated with left ventricular dysfunction and valve disease. It has been assumed that chemotherapy-induced myocardial depression and heart failure was the cause of the valve dysfunction (secondary or functional valve regurgitation). However, data to support this assumption are sparse. Thus, investigators from Norway performed a cross-sectional national study of 274 adult lymphoma survivors who underwent chemotherapy followed by bone marrow transplantation from 1987-2008. They were examined by echocardiography and compared to healthy age- and sex-matched controls. Mean cumulative anthracycline dose was 316 mg/m2 and 35% had received radiation therapy to the anterior chest. Mean time that had elapsed since therapy was 13 years. Valve disease, which was defined as regurgitation more than mild or any stenosis or the presence of a prosthetic valve, occurred in 22% of the population. In 87%, valve disease was regurgitation alone. Severe valve disease was unusual, occurring in nine patients, of whom seven experienced aortic stenosis, and six of seven also had heart radiation. Of those only treated with an anthracyclines, 17% presented with valve disease, which was three-fold higher than that observed in the controls. Aortic valve degeneration was seen in 13% of the anthracycline alone patients vs. 3% in the controls (P < 0.001). The incidence of mitral regurgitation was not different in the two groups, but aortic and tricuspid regurgitation were increased in the chemotherapy-alone group. Left ventricular function decreased compared to controls, but this difference was modest (54 vs. 58%; P < 0.01). In a multivariate analysis, all patients who were > 50 years of age, female, underwent three lines or more of chemotherapy, and received high-dose radiation therapy to the heart were significantly associated with valve disease. The authors concluded that anthracycline chemotherapy alone is associated with valve degeneration in long-term lymphoma survivors.
COMMENTARY
Drug-induced valve injury has been observed in humans with agents that increase fibrosis by stimulating specific serotonin receptors in valve tissue. Example drugs include ergot alkaloids (methysergide, ergotamine), ergot-derived dopaminergic agonists (pergolide, ecstasy), and drugs metabolized into norflurane (fenfluramine, dexfenfluramine). These drugs can produce valve leaflet thickening that appears similar to that seen in carcinoid syndrome. Reports of toxicity with such drugs describe regurgitation in early stages, before echocardiography detects obvious valve thickening. The difficulty with these observations is that progressive valve regurgitation can occur with normal aging and other diseases (rheumatic, endocarditis). Since most patients suspected of having drug-induced valve disease have not undergone prior echoes, assigning a cause becomes problematic. This observational study suffers from the same limitation.
On the other hand, the data supporting a causative role of chemotherapy are compelling. There were 177 patients who received chemotherapy alone, and they were compared to 274 matched controls. Blinded investigators read the echocardiograms. The difference in left ventricular ejection fraction was modest (mean 58% controls vs. 55% chemo alone) and is unlikely to explain the difference in valve disease observed. Also, left ventricular end-diastolic volume was nearly identical (67 vs. 66, mL/m2). In addition, co-morbidities between the two groups that may affect valve function were not different between the groups (e.g., hypertension). Finally, more than three lines of chemotherapy was an independent predictor of valve disease. Since chemotherapy can damage mature cells that do not divide frequently, such as the myocardium, perhaps valve endothelial cells can be damaged as well. In fact, there was an association between decreased left ventricular function and degenerative aortic valve disease in the chemotherapy group.
Until further data are obtained, it would seem prudent to pay attention to the possibility of valve and myocardial dysfunction in lymphoma survivors and consider a screening echo perhaps every five years, especially in those who received both therapies. Obviously, if there are symptoms or signs of valve or myocardial disease, an echo is indicated. Indeed, this is another example why large medical centers specializing in cancer therapy have developed cardio-oncology specialties.
