This post-attack damage is greatest among higher-risk populations – elderly and diabetic patients – making it a problem of particular concern for the VA, whose researchers are taking what they know about mitochondrial malfunctioning and looking for ways to modulate it at the molecular level. It might be a new drug, Lesnefsky said, but “obviously the quickest pathway from laboratory bench to the coronary care unit would be for us to discover a currently approved drug can be successfully used to reduce this component of mitochondrial injury.”

Because most heart failure involves the left ventricle (LV) of the heart, that’s where most research is focused. But while it occurs less often, failure of the right ventricle (RV) – which pumps deoxygenated blood back to the lungs for oxygenation – is nevertheless a serious disease, and poorly understood. The traditional assumption that it can be treated in the same way as LV failure is being proven wrong, according to Dr. Anthony Baker, a research biologist at the San Francisco VAMC and professor of medicine at the University of California, San Francisco School of Medicine.

“Studies from our lab and others,” Baker said, “have suggested that actually the right ventricle has distinctive properties that are different from the LV.” How RV failure damages a heart cell is a complicated process, involving the release of an enzyme that destroys certain intracellular structures. Baker and his team have discovered that levels of this enzyme are markedly reduced in animal models with RV failure that receive a particular adrenergic drug – a medicine that stimulates the release of neurotransmitters from the adrenal gland – targeting specific receptors in heart cells.

“We’ve found that in experimental models of RV failure, when we chronically treat animals with a drug that specifically stimulates the alpha-1A adrenergic receptor,” said Baker, “there is an improvement in RV function and there is less injury to the RV.” Baker and his team hope further studies of animal models, now in the developmental phase, may eventually lead to new therapies for patients with RV failure.

The most common cause of heart disease is atherosclerosis – the narrowing or blockage of blood vessels that supply blood to the heart. Dr. Lisa Tannock, chief of endocrinology and molecular medicine for University of Kentucky Healthcare and a physician researcher for the Lexington VAMC, is leading investigations into the causes of atherosclerosis, with the goal of identifying biomarkers or mechanisms that could suggest new methods of reducing risk.

Because risk factors for cardiovascular disease, such asserum amyloid A, or SAA, are often observed to accumulate over a period of years, much VA research is aimed at interventions that can lower these risks and prevent heart failure – and some of this research has challenged the medical profession’s working assumptions.

“My focus,” said Tannock, “is on how elevated lipids, or dyslipidemia, impacts cardiovascular disease.” Though her ultimate aim is to answer a big-picture question – “Are we identifying people a little bit too late in the disease, and therefore missing opportunities to intervene earlier when we actually really could prevent disease?” – her current investigations drill down to a particular molecule: serum amyloid A (SAA), a protein that binds with lipids to form lipoproteins. Considered an “acute phase reactant,” SAA is normally seen at low levels in a healthy person, but spikes – up to 100 or 1,000 percent – in a person with an infection, or who has just undergone surgery.

Interestingly, chronic inflammatory conditions associated with increased heart attack risk, such as obesity, diabetes, lupus, or rheumatoid arthritis – are also associated with chronically elevated levels of SAA – in many cases, the acute-phase reactant is elevated for a period of decades. “So my question is,” said Tannock, “instead of being just a biomarker, is SAA actually causing atherosclerosis?”

Tannock and a team of investigators have demonstrated that overexpression of SAA in animal models causes atherosclerosis. Her current project focuses on the physical location of SAA in the body. Typically, it’s attached to high-density lipoproteins (HDL) – the “good” cholesterol – suggesting that HDL may function, in part, to sequester or neutralize SAA. But other research data suggests that in people with insulin resistance, SAA is prone to hopping onto the low-density lipoprotein, the “bad” cholesterol, especially just after eating. Tannock’s study will examine blood samples taken from obese and diabetic human subjects, before and after consumption of a high-fat meal, to try to learn more about how, why, and in whom SAA makes this critical shift from HDL to LDL molecules.

 

Risk Management, Treatments, and Outcomes

The prevention and management of heart failure, despite many innovations and new therapies, remains a significant issue for the American health care system overall and the VA’s in particular. Many VA researchers are focused on optimizing therapies and care to deliver the highest possible quality of life for heart patients. Dr. Patricia Kelley, a registered nurse and portfolio manager for care of complex chronic conditions in the VA’s Health Services Research and Development (HSR&D) Service, described this research as multimodal, collecting data from throughout the VA’s health care system. “We look at the patient-level data, patient outcomes and satisfaction,” she said. “Health Services looks at the effectiveness of interventions, and the effective improvement on patient outcomes, as well as different innovative ways of delivering health care delivery to this complex patient population.”