AFAR: Proceedings of the 2009 Aging Heart Conference

An American Federation for Aging Research Conference

Oct. 6, 2009

Conference Overview

Heart disease remains the leading killer of older people, Dr. Jay Edelberg told about 75 researchers and clinicians gathered at Manhattan's Union Club on Oct. 6, 2009, for The Aging Heart: A Roadmap to Cardiac Independence, organized by the American Federation for Aging Research (AFAR).

"The vast majority of us will still succumb to cardiovascular diseases," Dr. Edelberg, group director of clinical biomarkers, discovery medicine and clinical pharmacology at Bristol-Myers Squibb Co. and an AFAR board member, said in his opening remarks.

To better understand the biological processes underlying changes in heart function, 11 prominent scientists from around the country discussed research on the links between aging and cardiovascular diseases along with new approaches to treating the aging heart.

Dr. Edelberg emphasized AFAR's role as a "pioneering organization" with a "long-standing history" of supporting young researchers-he himself had received an AFAR grant years earlier. For AFAR's president, Dr. Terrie Fox Wetle, associate dean of medicine for public health at Brown University, the conference gave scientists a chance to discuss "exciting new findings in both basic and translational research."

"Advances in basic research have improved our understanding of both age-related changes in the function of the heart and circulatory system, as well as age-related diseases of the heart," she said.

In his keynote speech, Dr. Edward G. Lakatta, founder and director of the Laboratory of Cardiovascular Science at the National Institute on Aging, raised profound questions about aging per se: What is it? Why do we age? And he pointed out that while aging is a major risk factor for cardiovascular diseases, it is often ignored because it is thought to be "nonmodifiable." Hypertension rises with age as does the incidence of stroke and heart failure. To understand the link between these requires an approach that integrates multiple cell and molecular mechanisms.

As genes and their environment work together to keep the organism in a steady state, there are changes in the system over time, Dr. Lakatta said, such as cumulative mutations, oxidative damage, cell death or atrophy. Time-dependent changes in cardiovascular DNA and environment alter the cardiovascular substrate with which disease processes interact. For instance, certain age-associated changes, such as arterial stiffness and pulse wave velocity, are independent risk factors for cardiovascular disease.

Aging is a shift in an organism's reality. Dr. Lakatta made it clear that disease and aging, while related, are not synonymous. Rather, aging arteries are fertile soil for the seeds of arterial disease to flourish, and those who age unsuccessfully are more at risk for developing disease.

As Dr. Lakatta expressed, the good news is that exercise and drug therapies can help retard arterial aging and thus make people less susceptible to cardiovascular disease.

Because mice can be readily used to test ways to protect the heart, Dr. Peter S. Rabinovitch, professor in the department of pathology at the University of Washington in Seattle, and his colleagues use them to study cardiac aging. Specifically, they look at the relationship of cardiac aging to mitochondrial free radicals and how mitochondrial antioxidants might protect us from cardiac aging and disease.

In previous research, Dr. Rabinovitch has shown that the over-expression of catalase targeted to mitochondria (mCAT) prolongs median life span of mice by about 20 percent.

Cardiac aging in mice is accompanied by a series of changes, such as accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations and deletions. Cardiac function in mice, evaluated by echocardiography, declines with age in a fashion that is similar to that seen in humans, including substantial increases in diastolic dysfunction. All of these changes were significantly retarded in mCAT mice.

Since aging is accompanied by elevated levels of intracardiac angiotensin II (AngII), Dr. Rabinovitch hypothesized that mitochondrial reactive oxygen species (ROS) might mediate the effects of AngII.

In contrast to mice that over-express wild-type peroxisomal catalase, mCAT mice are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by angiotensin II, showing there is indeed a relationship.

Treatment of mice with the peptide SS-31 provided protection from AngII that was similar to that of mCAT. Thus, Dr. Rabinovitch concluded that mitochondrial-targeted antioxidants might someday prove useful for prevention and treatment of age-related cardiomyopathy.

With new methods available to analyze cardiac function in Drosophila, Dr. Rolf Bodmer, professor and program director of the Development and Aging Program at the Burnham Institute for Medical Research, and colleagues have studied the genetic control of heart function as it deteriorates with age in flies.

They found that exercise-induced cardiac arrest or fibrillation (a form of "heart failure") increases with age. In addition, the regularity of the myogenic heart in aging flies is disturbed, resulting in more arrhythmias.

Dr. Bodmer and his colleagues looked at several potassium channels in fly heart function and demonstrated their roles in protecting against arrhythmias and hypoxia/ischemia. He discussed, for example, the product of dSUR is associated with K-ATP channel function, which protects the heart against hypoxia/ischemia in flies and mammals. This protection seems to be reduced with age.

Modulating insulin/TOR signaling pathways is well known to affect overall aging in many organisms, Dr. Bodmer said. Manipulating insulin/TOR-signaling within the myocardium dramatically alters the age-dependent decline in cardiac performance, he found.

Dr. Bodmer's presentation communicated the importance of the fly heart for cardiac aging research, as it is emerging as a promising genetic model for studying the age-dependent decline in cardiac function.

The Nancy Renick Memorial Lecture
Age-Associated Chronic Heart Failure in Women: Is Her Strength Her Weakness?

Heart failure increases with age, especially among women, said Dr. Jeanne Y. Wei, chair of the department of geriatrics and executive director of the Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences.

Scientists have observed a series of changes in the aging heart that can lead to diastolic dysfunction, especially in women. Left ventricular hypertrophy is a "prevailing co-morbidity" in women, Dr. Wei explained, which can result in heart failure.

The role estrogen plays in this process is complex. Higher estrogen levels in older women are shown to be associated with higher mortality. But cardiomyopathy in many postmenopausal women may be due to cardiovascular over-activation, induced by emotional stress in the setting of low estrogen. Depression, low self-efficacy and social isolation are known to be risk factors for people after heart attacks. Studies have shown that even positive subliminal words can reduce systolic blood pressure.

Calcium blockers and exercise, including gentle exercise like tai chi, appear to help improve function, as does ensuring that older women are living in a setting that reduces isolation and makes them feel useful, Dr. Wei said.

Dr. Richard Shannon, professor and chairman in the department of medicine at the University of Pennsylvania, affirmed the association of aging with insulin resistance throughout the body and in the heart. However, the amount of insulin resistance contributing to accelerating heart failure and whether overcoming this process would slow the progression of heart failure are both unknown.

Using a group of older beagles matched with younger beagles that had had the same diet and training regimen, Dr. Shannon and his colleagues documented the nature and extent of insulin resistance and its pathogenesis in the heart.

They found the older dogs had greater insulin resistance, higher levels of arterial and cardiac norepinephrine and an accumulation of fat deposits in the heart. Thus, it appears that in the absence of conventional risk factors such as inactivity and obesity, advanced age is associated with insulin resistance in beagles, Dr. Shannon said.

The cellular basis of insulin resistance in the heart is different from that in skeletal muscle, Dr. Shannon explained. Heart mitochondria showed an increase in reactive oxygen species (ROS) and calcium sequestration, which leads to an accelerated course of heart failure.

Dr. Shannon's research also explored the impact of anti-diabetic drugs on the aging heart. He found that giving some of the older beagles Rosiglitazone markedly improved their insulin sensitivity and slowed their progression to heart failure.

Despite many therapies, congestive heart failure remains a progressive disease, said Dr. Roger Hajjar, director of the Cardiovascular Research Center at Mount Sinai School of Medicine in Manhattan. There is therefore a desperate need for innovative therapies to reverse the course of ventricular dysfunction.

Dr. Hajjar described how recent advances in understanding the molecular basis of myocardial dysfunction and the evolution of increasingly efficient gene transfer technology have placed heart failure within reach of gene-based therapies.

One of the key abnormalities in heart failure is a defect in sarcoplasmic reticulum (SR) function, which is responsible for abnormal intracellular Ca2+ handling. Scientists have identified deficient SR Ca2+ uptake during relaxation in failing hearts and it has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a). Restoring SERCA2a levels has been shown to improve function, metabolism and survival, Dr. Hajjar said.

Over the last 10 years, Dr. Hajjar and his colleagues have targeted important calcium cycling proteins in experimental models of the heart by somatic gene transfer. This has led to the recent completion of the first human Phase I clinical trial of gene therapy for heart failure, using an adeno-associated vector (AAV) type 1 to carry SERCA2a. In this trial, Dr. Hajjar saw clinically meaningful improvements in functional status and/or cardiac function. A Phase II trial was launched last year and the results should be available spring of next year.

Dr. Hajjar said the research has shown: 1) AAV- based therapy is safe even in severely ill patients, 2) about 40 percent of patients must be excluded from the clinical trials because of neutralizing antibodies (Nab) to various AAV serotypes in the general population and 3) delivering the therapy via catheter works well.

Dr. Hajjar's research now directly addresses the limitations of AAV vectors by generating mutated AAV vectors that will go the target tissue, can be grown at high titers and escape the pre-existing NAbs for naturally occurring AAVs. He explained that these new vectors will be the basis for a second generation gene therapy trial.

Many patients who suffer from atherosclerosis need bypass surgery, said Dr. Laura Niklason, a professor at Yale University in biomedical engineering and anesthesia. Treating diseases such as kidney failure also requires arterial grafts.

Unfortunately, autologous veins and arteries are in short supply. This has led many to develop tissue-engineered arteries, which may one day end the need to harvest veins or arteries from patients for bypass operations, she said.

Dr. Niklason and her colleagues use a set of strategies to engineer vessels: a polymer scaffolding to guide vessel growth, in vitro bioreactors that mimic aspects of the heart's pumping function, and tailored culture media that supply critical growth factors and nutrients to support arterial regeneration.

Over about eight weeks, the cells replicate and secrete extracellular matrix to form an artery, while the polymer scaffold is simultaneously degrading. In the end, a tissue-like artery is formed. Dr. Niklason illustrated how this worked well when the cells have come from young and healthy animals, but attempts to use the same approach with cells derived from older human with vascular disease has been less successful.

To address this problem Dr. Niklason's lab used young human cells to create robust engineered arteries and then selectively removed the cells from the engineered tissues. This removed most of the antigenicity of the tissues, since extracellular matrix molecules are highly conserved within the species, while cells are highly antigenic. The mechanical characteristics of the artery were also preserved using this technique.

Looking to the future, Dr. Niklason expressed the potential for these non-living acellular tissues to one day be stored on the shelf in hospitals or operating rooms.

The primary function of the autonomic nervous system is to maintain homeostasis, said Dr. Arnold Jacobson, Head, Cardiac Center of Excellence, GE Healthcare Medical Diagnostics. Sympathetic nervous system activity increases with advancing age in sedentary health adults, which could have physiological and patho-physiological effects.

This could represent a favorable adaptation in response to other age-related changes or this could contribute to a number of deleterious changes, including arterial wall hypertrophy, greater central arterial stiffness and elevated systolic blood pressure, Dr. Jacobson said.

Heart failure is associated with abnormalities of sympathetic innervation. Many imaging studies have shown that the poorer the sympathetic nervous system function of the heart, the poorer the clinical outcome. However, in many patients, this function can improve with medical treatment and cardiac resynchronization.

The most extensively studied imaging agent is metaiodobenzylguanidine (mIBG), an analog of norepinephrine. There is a direct relationship between mIBG uptake and long-term clinical outcome in heart failure patients: the lower the uptake, the poorer the outcome.

Two prospective multi-center trials were performed by GE Healthcare to confirm the prognostic significance of this reduced mIBG uptake in heart failure patients to determine who might be at risk of an adverse cardiac event. (Note: mIBG is not approved for cardiac imaging in the United States.) In the two studies, a total of 961 patients with the mean age of 62 who had heart failure and 94 controls, with the mean age of 58, without heart disease were examined. A highly significant decrease in cardiac neuronal uptake was observed in the heart failure patients compared with control subjects, with a similar difference in cardiac sympathetic neuronal function seen for all age groups.

Dr. Jacobson explained how these results suggest that treatments that can improve sympathetic neuronal function are likely to be equally beneficial for decreasing the risk of adverse events in older and younger patients with heart failure.

The aging heart is increasingly susceptible to insults, as it shows a limited ability to repair and regenerate, said Dr. Hazel Szeto, professor of pharmacology at Weill Medical College of Cornell University.

Mitochondrial oxidative stress activates the intrinsic pathway to apoptosis by inducing mitochondrial permeability transition and mitochondrial swelling, she said. This leads to the death of cardiac cells.

For Dr. Szeto, the question is how do we protect the cell from mitochondrial oxidative stress? One possibility is to get antioxidants inside the mitochondria. Yet most antioxidants are not cell-permeable and cannot reach mitochondria, she said.

Dr. Szeto and her colleagues have designed potent antioxidant peptide molecules that target and concentrate inside mitochondria. They reduce reactive oxygen species in mitochondria and protect against mitochondrial permeability transition, swelling and apoptosis.

Dr. Szeto presented evidence that these mitochondria-targeted peptides can protect myocardial function in animal models of heart failure. She described how these peptide molecules are undergoing clinical development for various clinical applications.

Cardiac Progenitor Cells as a Target of Pharmacological Intervention in the Aging Heart

The potential for stem cells to improve or cure heart disease has galvanized scientists to look at using autologous stem cells from a variety of tissues, said Dr. Sean Wu, an assistant professor of medicine at Harvard Medical School and a Principal Faculty at the Harvard Stem Cell Institute.

Dr. Wu referred to recent clinical trials that have shown little improvement and no evidence of new heart cell growth when these stems cells are administered by intracoronary infusion or injected into the heart. These studies illustrate the need to understand how heart cells develop and differentiate, he said.

Dr. Wu and his colleagues have found a set of progenitor cells within the adult mouse heart that is capable of regenerating new cardiomyocytes after injury. Looking at drugs that might help expand the number of these cells, their research identified a class of compounds they named ICPE for "inducer of cardiac progenitor expansion."

Dr. Wu believes that, if ICPE can be successfully used in animals, the elusive goal of triggering an autologous cardiomyogenic progenitor cell population to repair the human heart might be possible.

Dr. Edelberg said the conference highlighted the progress of research on the heart and gave attendees insights into how cardiovascular systems work-and can cease to work. It also communicated a "better understanding of the latest innovations in technology and science."

Dr. Wetle agreed: "Findings such as these are contributing to improved care and healthier behaviors. Among older persons in each age category, we have experienced a steady decline in the rate of cardiovascular deaths over the past decade."

AFAR is a nonprofit organization whose mission is to support biomedical research on aging. It is devoted to creating the knowledge that all of us need to live healthy, productive, and independent lives. Since 1981, AFAR has awarded approximately $124 million to more than 2,600 early and mid-career scientists and medical students as part of its broad-based series of grant programs. Its work has led to significant advances in our understanding of aging processes, age-related diseases, and healthy aging practices. AFAR communicates news of these innovations through its organizational web site www.afar.org and educational web sites Infoaging (www.infoaging.org) and Health Compass (www.healthcompass.org).