Genetic factors associated with heart failure in patients who underwent HCT

ATLANTA — Patients with variation in the MRP2, RAC2 and HFE genes had up to a threefold higher risk of developing heart failure following hematopoietic stem cell transplantation compared with controls, according to study results presented at the 2012 ASH Annual Meeting and Exposition.

Hematopoietic stem cell transplantation (HCT) survivors are at an increased risk of developing congestive heart failure. This is primarily due to their exposure to pre-HCT treatment with anthracyclines. Transplant survivors tend to develop heart failure earlier than the general population. The OS rate following diagnosis of heart failure is less than 50% after 2 years, according to background information in the study.

Smita Bhatia

“These patients are at increased risk of metabolic disorders such as hypertension and diabetes,” Smita Bhatia, MD, MPH, Ruth Ziegler Chair of Population Sciences at City of Hope in Duarte, Calif., said during a presentation. “These particular factors tremendously increase the risk of congestive heart failure.”

Researchers conducted a nested case-control study to try to determine how genetics can influence the risk for developing heart failure.

They evaluated the impact of functional single nucleotide polymorphisms (SNPs) in genes thought to be associated with anthracycline-related congestive heart failure.

The investigators identified genetic pathways that could make transplant survivors more sensitive to pre-transplant chemotherapy toxicities, Bhatia said.

Bhatia and colleagues evaluated 77 patients with leukemia, lymphoma and myeloma who developed congestive heart failure after undergoing HCT at City of Hope between 1988 and 2007.

The patients’ median age at the time of HCT was 47.5 years (range, 16-68.6 years). The median time to congestive heart failure was 2.8 years (range, 0.1-12.7 years). Patients received a median 300 mg/m² dose (range, 60-650mg/mg²) of anthracycline.

Another 178 transplant survivors who did not experience heart failure served as controls.

The cumulative incidence of congestive heart failure reached 6% at 15 years after transplantation, according to study results.

When compared with controls, patients who experienced congestive heart failure were more likely to be female (55.8% vs. 34%, P<0.01). They also were more likely to have received chest radiation prior to HCT (14.3% vs. 5.1%, P=0.01) and have had hypertension following HCT (28.6% vs. 14.6%, P<0.01).

The researchers studied genes responsible for the breakdown of anthracyclines into toxic byproducts (CBR1, CBR3, NQ01, MRP1, MRP2); the defense from oxidative stress (NCF4, RAC2, CYBA, SOD); iron overload (HFE); and blood pressure and heart regulation (AGT, AGTR1, ACE, ADRB1, ADRB2).

Results from a multivariate conditional logistic regression analysis indicated an increased risk of congestive heart failure in patients with variations in the genes RAC2 (P<0.01), HFE (P=0.01) or MRP2 (P<0.01).

Female HCT survivors with ≥2 SNPs had the highest risk of congestive heart failure (OR=17.1; 95% CI, 4.63-63.36).

Saro Armenian

“Following this study, we now have a much better profile of those transplant survivors who are likely to develop heart failure,” Saro Armenian, DO, MPH, the study’s lead author and medical director of the Pediatric Survivorship Clinic in the Childhood Cancer Survivorship Program at City of Hope, said in a press release. “Armed with these insights, we can now create better screening measures and perhaps even tailor intervention strategies based on a patients’ genetic makeup, minimizing long-term transplant-related toxicity and making a tremendous difference in the long-term health of these patients.”

For more information:

Armenian S. Abstract #589. Presented at: the 2012 ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta.

Disclosure: The researchers report no relevant financial disclosures.