The researchers linked the genetic variant to a reduction in the left ventricle's ejection fraction, a measurement cardiologists make of how much blood the heart pumps with each beat. The variant, or polymorphism, involves peroxisome proliferator-activated receptor-alpha (PPAR), a transcription factor that regulates the use of fatty acids within cells.
Transcription factors such as PPAR are proteins that switch on other genes. Scientists have studied PPAR extensively because it is fundamental to cellular metabolism. Most of these studies, however, are in the context of diabetes. The Duke team found that a particular variant of PPAR, a polymorphism called PPAR-I7, is associated with reduced function of the left ventricle.
If additional studies confirm this association between PPAR-I7 and the weakening of the heart's pumping strength, future therapies might be developed to interfere with the molecular pathways that PPAR regulates, the researchers said.
"We found that in a broad sample that PPAR-I7 is associated with lower ejection fractions in heart patients," said Duke cardiologist Mark Donahue, M.D., who presented the results of the Duke analysis Nov. 9, 2004, during the American Heart Association's annual scientific sessions in New Orleans.
"Furthermore, we found that this adverse association is additive," Donahue continued. "Inheriting the polymorphism from one parent is bad, and inheriting it from both parents is even worse. The results of our analysis suggest that the PPAR signaling pathway in general may play an important role in the potential development of heart failure."
Also known as congestive heart failure, heart failure is a condition characterized by the thickening of the walls of the heart. Over time this thickening restricts the heart's ability to pump enough blood to the body's tissues, and thereby to provide them with oxygen and nutrients. An estimated 4.7 million Americans suffer from the condition, with 400,000 new cases reported each year. Half of the patients die within five years of the diagnosis.
"We have always been intrigued by heart patients who appear to have very similar clinical characteristics but markedly different outcomes," Donahue said. "We thought genetics might play an important role. We hypothesized that the PPAR variant, since it plays a key role in regulating metabolism, might make heart muscle cells less efficient when stressed by disease."
The researchers collected clinical data and DNA samples from 973 patients treated in the Duke system to document any correlations between the PPAR-I7 polymorphism and ejection fraction.
The polymorphism is caused by a single alteration in one DNA base pair at a single location on the PPAR gene. In this instance, a guanine (G) is replaced by a cytosine (C). A patient who inherited the polymorphism, or allele, from one parent would have a GC base pair at that location, while a patient who inherited the allele from both parents would have a CC base pair.
"Our statistical analysis showed that the number of PPAR-I7 alleles was significantly associated with ejection fraction in heart patients after adjusting for such factors as age, gender, ethnicity and diabetes," Donahue said. "Additionally, gender and diabetes were also independently associated with ejection fraction."
An ejection fraction measures the percentage of blood pumped out of the left ventricle with each of the chamber's contractions. Cardiologists consider normal any reading above 55, which means 55 percent of the blood in the chamber was pumped out, Donahue said.
Patients without diabetes in the study had an average ejection fraction of 53, compared to 50 for those with one allele and 42 for those with two alleles. Diabetic patients without the polymorphism had an ejection fraction of 49, compared to 45 for those with one allele and 38 for those with two.
The same trends held when the patients were analyzed by gender. Men without the polymorphism had an ejection fraction of 50, compared to 46 for men with one allele and 40 for men with two alleles. Women without the polymorphism had an ejection fraction of 56, compared to 53 for women with one allele and 42 for women with two alleles.
"Myocytes, or heart muscle cells, are constantly turning over and remodeling themselves in response to their environment," Donahue explained. "It is possible that the PPAR polymorphism, because it is so crucial to metabolism within these cells, could modify the course of this renewal process and lead to the physical changes in heart muscle characteristic of heart failure."
Donahue plans future studies to determine whether other variants of PPAR are also involved in declining heart function. Ultimately, he hopes genetic research will help physicians predict at an early stage which patients are at greatest risk for developing heart failure, and to treat them more effectively.
Donahue's analysis was supported by the Duke Clinical Research Institute and Duke's Center for Human Genetics. Other members of the Duke team were Matthew Wolf, Jonathan Jennings, Bonnie Pedersen, Elizabeth Hauser, Ph.D., Douglas Marchuk, Ph.D., Howard Rockman, MD, and William Kraus, M.D.