Just as human brain cells were long presumed never to regenerate after injury, a similar dogma posits that cardiac muscle cells cannot stage a comeback following a heart attack. "Traditional views have concluded that once the heart is damaged by a heart attack, functional muscles are replaced by nonfunctioning scar tissue," noted Christopher Reinhard, president and CEO of Collateral Therapeutics (San Diego, California).
In September 2000, Collateral exclusively licensed patents from the University of Texas Southwestern Medical Center (Dallas, Texas) covering certain human genes discovered by molecular biologists at the university. They co-authored an article, titled "Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor," in the June 23 issue of the journal Cell. The paper reports preclinical studies showing that myocardin, a novel and potent gene-regulating protein, is expressed specifically in heart and smooth-muscle cells, and can switch on other cardiac-specific genes in non-muscle cells. It is apparently essential for forming heart cells in embryos of Xenopus laevis, the African clawed frog. The co-authors found that during embryogenesis, myocardin was expressed in heart muscle cells and a subset of smooth-muscle cells. This proceeded in step with expression of muscle genes dependent on SRF – serum response factor – which regulates transcription of many muscle and growth factor-inducible genes.
Specifically, myocardin increased the expression of several cardiac-specific genes in fibroblasts. These are nonmuscle cells involved in the formation of scar tissue after a heart attack. The proprietary protein may potentially act as a gene switch, transforming fibroblasts into cardiomyocytes – functioning, contracting heart muscle cells.
An estimated 1.1 million people a year in the U.S. suffer heart attacks, which kill 40% of them. Soon after such an onslaught, white blood cells deployed by the immune system migrate into the area of infarction and remove the dead heart muscle cells. Fibroblasts then proliferate, and form a fibrous collagen scar in the affected region. The injured heart's ability to maintain normal function will depend on the site and size of damaged tissue.
Current therapeutic post-attack treatments focus on acute measures, notably clot-dissolving drugs to restore blood flow to the heart. Surviving patients are prescribed medication to forestall future episodes, and advised to adopt lifestyle changes, such as altering diet, increasing exercise and quitting smoking. The Cell paper's authors suggest that myocardin up-regulated genes might provide opportunities for converting noncardiac cells into human cardiac muscle cells for heart repair through nonsurgical gene therapy.
Type 2 diabetes is study focus
A new study involving many of the nation's leading research institutions will evaluate ways to prevent death in people with both Type 2 diabetes and coronary heart disease, the No.1 killer of people with Type 2 diabetes. Named BARI 2D (for Bypass Angioplasty Revascularization Investigation 2 Diabetes), the study will follow 2,800 patients across the U.S. and Canada over five years and evaluate the effectiveness of various treatments for individuals with Type 2 diabetes and coronary heart disease, including rosiglitazone maelate (Avandia), an insulin sensitizer for the treatment of Type 2 diabetes. The BARI 2D trial is funded by the National Heart, Lung and Blood Institute and National Institute of Diabetes and Digestive & Kidney Diseases of the National Institutes of Health (Bethesda, Maryland).
The study may provide critical information for patients who have Type 2 diabetes and blockages in coronary arteries, and who are considered at high risk for heart attacks, strokes or death. This research is intended to aid the 14 million Americans with type 2 diabetes who are at risk for heart disease, thus accounting for 80% of all deaths among those with Type 2 diabetes.
One of the study's principal investigators, Richard Nesto, MD, chairman of the Lahey Clinic's cardiovascular medicine department and associate professor of medicine at Harvard Medical School (both Boston, Massachusetts), noted that most patients with Type 2 diabetes die from cardiovascular disease that develops from diabetes rather than from the diabetes itself. "Diabetes is a powerful risk factor for cardiac death – as powerful as a history of prior heart attack in a person without diabetes," he said. "Our hope is that this study will help prolong the lives of people with Type 2 diabetes in the future, by examining and comparing innovative treatment approaches that rely on surgery or diabetes medications, such as Avandia."
The principal investigator for the study, Katherine Detre, MD, DrPH, of the University of Pittsburgh (Pittsburgh, Pennsylvania), said, "We now know that insulin resistance is a key contributor to cardiovascular disease and are beginning to use this knowledge to see if we can reduce the risk of cardiac events, such as heart attacks, in Type 2 diabetes patients. In the BARI 2D study, we're testing the hypothesis that treating diabetes with drugs that lower insulin resistance, such as Avandia, as compared to providing the body with more insulin, will result in a lower rate of cardiac deaths." She added, "Because the prevalence of diabetes is reaching epidemic proportions, this research has become urgent so that we may prevent a corresponding rise in cardiac events."
In the BARI 2D trial, patients with both Type 2 diabetes and documented coronary artery disease amenable to revascularization will be assigned at random to receive initial elective revascularization, either coronary angioplasty or bypass surgery, coupled with aggressive medical treatment of diabetes and cardiovascular risk factors or to receive aggressive medical treatment alone. In addition, in order to compare the results of different strategies of the glycemic control of diabetes, patients will also simultaneously be assigned at random to receive an insulin-providing agent or an insulin sensitizer, such as Avandia. With either form of treatment, the goal will be to lower blood glucose close to normal. The primary outcome of the study is the prevention of all-cause mortality. The study will run for a seven-year period with regular follow-up intervals.
Depression, anxiety not hypertension risks
In a study with a somewhat unexpected conclusion, researchers in Texas reported in the July issue of the American Journal of Hypertension that symptoms of depression and anxiety are not related to changes in blood pressure or the onset of hypertension. Michael Weber, MD, an editor of the journal, noted the high level of interest in the potential relationship between depression/hypertension and chronic diseases such as hypertension, asthma, cancer and diabetes, but he said the new findings "are contrary to the belief held by many that depression and anxiety are independent risk factors for the future development of hypertension or elevated blood pressure in initially normotensive individuals." He also noted that the researchers themselves were surprised by the findings. "However, the study population was sufficiently large enough, as was the study duration of four years," he added.
Lead investigator of the study was Eileen Huh Shinn, PhD, of the department of behavioral science at the University of Texas-M.D. Anderson Cancer Center (Houston, Texas). She said that previous studies had shown mixed results due to insufficient follow-up time, inadequate study samples and lack of validated standardized measures. Shinn and colleagues analyzed four years of prospective data from the Reno Diet Heart Study on 433 people whose blood pressure was less than 140/90 mm Hg and not taking anti-hypertensive medication before study entry. The investigators did not find a link between depression and anxiety symptoms and the onset of hypertension in their analyses.