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VA Research Currents archive
October 6, 2016
Vietnam Veteran Ralph Syrcle's heart condition was helped by a diuretic, or water pill, called spironolactone, which has been studied in Dr. Shawn Bender's lab at the Columbia (Missouri) VA Medical Center. (Photo courtesy of Columbia VAMC)
Ralph Syrcle experienced combat first-hand. He served for a year in Vietnam as a U.S. Army infantryman and fought north of Saigon, before moving to the Ho Chi Minh trail and an area along the Cambodian border.
He witnessed plenty of blood and saw some of his buddies die.
"I have flashbacks of what happened in Vietnam, violent dreams, nightmares," Syrcle says. "Somebody's shooting a weapon, and I hit the ground. I can close my eyes and smell it."
Today, Syrcle, who lives in the rural town of Griggsville, Illinois, near the Missouri border, is battling diastolic dysfunction, one of the most common defects of heart function in the United States and a condition that is prevalent in the VA patient population.
Diastolic dysfunction is a weakness in the heart's ability to relax between beats. It causes a buildup of fluid in the lungs and surrounding body tissues, leading to heart attacks, strokes, and possibly sudden cardiac death.
Obesity and diabetes can trigger diastolic dysfunction, and Syrcle, who is 67 and stands 5-foot-9, once weighed as much as 340 pounds. He's also a borderline diabetic who is insulin-resistant. His symptoms included swelling of the heart; edema, an abnormal accumulation of fluid in body tissues; and a shortness of breath upon exertion.
"The old guard of mineralocorticoid receptor antagonists has paved the way for newer, more specific, and safer drugs targeting this critical mechanism of cardiovascular disease."
But Syrcle, who also has atrial fibrillation, a quivering or irregular heartbeat, is now on the mend from diastolic dysfunction thanks to a diuretic drug called spironolactone, which is often used in managing chronic heart failure. The medication has helped his heart relax, allowing his ventricles to fill with blood properly, and he no longer has shortness of breath. Spironolactone is one of a handful of mineralocorticoid receptor antagonists (MR antagonists) available in the United States.
Syrcle's case is just one example of anecdotal evidence that spironolactone can help patients with obesity and diabetes who are suffering from diastolic dysfunction. But medical experts lack hard evidence from clinical trials.
Dr. Shawn Bender's work on treating obesity-related diastolic dysfunction with the diuretic spironolactone earned a "Top Paper" award from the journal Hypertension.
To help address the gap, researchers at the Harry S. Truman Memorial Veterans' Hospital in Columbia, Missouri, set out to study spironolactone in a preclinical lab setting. As a result of the work, they were able to show that patients like Syrcle who are obese and insulin-resistant may have improved heart function from the drug. While spironolactone is, in fact, used for people with diastolic dysfunction, its value for this particular group of patients has been poorly understood and underappreciated.
Working with obese and insulin-resistant rats, the VA researchers showed that diastolic dysfunction could be treated with spironolactone at doses low enough to not cause changes in potassium levels—a side effect that can be harmful in patients. (Elevated potassium is a common side effect from spironolactone.) They also determined that the diuretic largely corrected obesity-associated impairments related to diastolic dysfunction and improved the function of the vessels that provide blood to the heart, while also reducing markers of inflammation and tissue damage.
The VA-funded lab testing has allowed for a better understanding of how to treat diastolic dysfunction, even if well-established MR antagonism drugs such as spironolactone eventually fall out of use, according to the study's lead author, Dr. Shawn Bender, a research health scientist at the VA hospital in Columbia. He says the future for researching obesity-associated diastolic dysfunction looks very promising, noting that studies by his group and others lend support to the use of a new generation of MR antagonists.
"Studies like ours utilizing first-and second-generation mineralocorticoid receptor antagonists have revealed an important role for mineralocorticoid receptor activation in numerous cardiovascular pathologies, including those associated with obesity," Bender says. "These drugs, however, despite their efficacy, come with a risk of hyperkalemia, a potentially harmful ion imbalance."
An ion, or electrolyte, imbalance can stem from too little or too much of key minerals that help keep nerves and muscles working properly and keep fluid levels in check. It can cause problems like dark urine, nausea, fatigue, irregular heartbeat, and seizures.
Based on the results of older MR antagonists, newer antagonists that do not cause hyperkalemia are now being tested in clinical trials, according to Bender.
"So the old guard of mineralocorticoid receptor antagonists has paved the way for newer, more specific, and safer drugs targeting this critical mechanism of cardiovascular disease," he says.
Bender says his clinical colleagues are excited about the results of his study.
"They were particularly excited at the prospect of having a therapeutic option for diastolic heart failure, a condition for which there are currently no [established] treatments," he says. "I tend to agree with some of my colleagues who view the MR drug as a master regulator of various cardiovascular diseases."
Dr. Mozow Zuidema, a cardiologist at the VA hospital in Columbia who has provided care for Ralph Syrcle, says the results of Bender's research are "exciting as far as a new medication to treat diastolic dysfunction that is not currently in our practice guidelines."
"There are current clinical trials for new antagonists," Zuidema adds. "So the fact that we have a case study in Ralph to show that [spironolactone] is beneficial in this disease population, then perhaps the new wave of MR antagonists could also have the same benefits and potentially more benefits in the same patient population."
For his work, the American Heart Association (AHA) honored Bender with one of two 2015 "Top Paper Awards" in the basic science category for AHA's prestigious journal Hypertension, in which the study was published. Bender's paper was titled, "Mineralocorticoid Receptor Antagonism Treats Obesity-Associated Cardiac Diastolic Dysfunction."
Dr. Kenute Myrie, a scientific program manager with VA's Office of Research and Development, says Bender's research has helped the medical and scientific community "understand the mechanisms underlying obesity-associated hypertension, the impact of hypertension on the vasculature of the heart, and ultimately cardiovascular disease. These findings point the scientific community in a direction for therapeutic studies that could result in new treatment and management of Veterans' health."
Myrie is an official with VA's Career Development Program, which helped fund Bender's work.
The research may also help explain the results of some recent clinical trials. For example, in 2014, a major clinical study—the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial—had cast doubt on the effectiveness of spironolactone. In the large international trial, the drug failed to show universal benefit for diastolic dysfunction.
©iStock/ambassador806
TOPCAT included patients with symptomatic diastolic heart failure from the United States, Canada, Argentina, Brazil, Russia, and Georgia. Those from the Western countries were a higher-risk group than the other participants with regard to parameters such as age and diabetes. A post-hoc analysis revealed that spironolactone improved patient outcomes in the higher-risk population but not the Russia-Georgia cohort.
"So while the overall trial was indeed negative, a positive effect of MR antagonism was, at a minimum, suggested by the post-hoc analysis for higher-risk patients," Bender says. "More controlled trials will be needed in the future to further evaluate these questions."
Meanwhile, Ralph Syrcle is more than 50 pounds lighter than his high of 340 and says he is feeling better, as he lives in retirement after working as a farmer for nearly four decades. He hopes other Veterans will benefit from spironolactone as researchers learn more about the drug.
"My heart has leveled out," he says. "It was once all over the place and jumping up and down. Now, I can't feel it beating really hard or fast."