Cardiovascular Community Research Articles

DR CHIP, EDUC,& COSEHC: a triple public health strategy to reduce mortality in a high cardiovascular risk community

DR CHIP, EDUC,& COSEHC: a triple public health strategy to reduce mortality in a high cardiovascular risk community

Dr. Jeffrey M. Isner 1947–2001

View Large Image | View Hi-Res Image | Download PowerPoint SlideWe have lost a leader in cardiovascular gene therapy and therapeutic angiogenesis. Jeffrey M. Isner died on October 31, 2001, at his home in Weston, Massachusetts, at the age of 53. The cause was a heart attack.Jeff Isner was an interventional cardiologist who worked at St. Elizabeth's Hospital for two decades and was on the faculty of Tufts University. Jeff developed an early interest in the clinical syndrome of restenosis, the process by which a smooth muscle cell-rich lesion redevelops within the site of angioplasty dilatation 3 to 6 months after the initial procedure. When I met Jeff in 1989, he had spent several years exploring the role of intravascular laser devices to treat restenosis, but to no avail. He was firmly committed to alternative strategies to treat vascular diseases and quickly saw the promise of gene transfer. On numerous occasions, we discussed applications of gene transfer to blood vessel diseases and visited each other's laboratories, sharing methods and data from our respective vascular gene transfer studies. Jeff was firmly committed to developing the technology and to clinical applications.In the early 1990s, Jeff turned his attention to the burgeoning field of angiogenesis. He and others reasoned that vascular endothelial growth factor (VEGF) could induce new blood vessel growth in patients with peripheral vascular disease. After a series of proof-of-principle experiments in rabbits, Jeff put the idea to the test in 1994, being the first to coat angioplasty catheters with plasmid DNA encoding VEGF and to treat patients with peripheral vascular lesions. He coined the term “therapeutic angiogenesis,” and over the past 7 years he treated over 200 patients in various protocols for myocardial and peripheral angiogenesis.Many questions still need answers before gene therapy becomes standard treatment for vascular disease. Although his studies were promising, Jeff faced significant hurdles. A demonstration that intact collateral vessels—rather than leaky capillaries—were formed following treatment is lacking. Evidence that increased blood flow persisted for many months is not yet obtained. Jeff's early successes also placed him in the middle of the debate regarding the role of physicians conducting clinical studies sponsored by companies in which they had a financial interest.Last year, the Food and Drug Administration temporarily suspended the research conducted by Jeff, Vascular Genetics (a company he founded), and St. Elizabeth's, claiming that the researchers had failed to properly report the death of two patients participating in a study. Jeff said that the two patients had died of underlying cardiovascular disease, rather than the treatments. But the company acknowledged administrative problems with the research and corrected the situation. Jeff resumed his studies this past spring, and recently received a Center of Excellence in Gene Therapy grant from the National Heart, Lung, and Blood Institute. His patients gathered this summer at St. Elizabeth's to acknowledge his pioneering work and to encourage its continuation. Jeff was undaunted in spirit and vowed to continue his work.In addition to his clinical studies in angiogenesis, Jeff made other important scientific contributions. He was one of the first researchers to demonstrate the presence of endothelial cell progenitors in the bone marrow, and subsequent studies have established the role of endothelial cell progenitors in the process of angiogenesis.Jeff will be remembered as a courageous and committed physician. He cared deeply for his patients, and he was passionate in his desire to bring gene therapy to viable clinical treatments. The gene therapy and cardiovascular communities will miss his creativity and energy. Jeff was not only an innovator, he also inspired many trainees to pursue clinical research. It is tragic indeed that his life ended before he witnessed his and others’ research come to fruition—angiogenesis therapies on the market and routinely used to treat patients with atherosclerosis. This will be his legacy, and one that he would have thoroughly enjoyed.

Cardiovascular News

Cardiovascular News

Design issues in the combination of international data from two rural community cardiovascular intervention programs

To compare and contrast two rural cardiovascular community intervention programs (CCIP) in northern Sweden and the US by discussing the methods used to select and combine similar data from two separately designed and implemented CCIP in order to describe and evaluate their effectiveness in reducing cardiovascular risk. Two rural intervention populations and their reference populations were compared. A comparison was made of the intensity and duration of the intervention programs using an overall intervention intensity score. Population-based surveys were conducted at 5-year intervals in both countries. The methods used for data pooling and comparison are described. A description of statistical analyses using a mixed analysis of variance model is provided. The data were pooled. taking into consideration comparable ages. New variables were created in order to define the relationship between similar data that did not permit direct comparison. Combination and comparison of international data from two programs allowed evaluation of community intervention programs that were developed independently for similar communities. The effectiveness of interventions can be compared using such methods.

Design issues in the combination of international data from two rural community cardiovascular intervention programs

Objectives: To compare and contrast two rural cardiovascular community intervention programs (CCIP) in northern Sweden and the US by discussing the methods used to select and combine similar data from two separately designed and implemented CCIP in order to describe and evaluate their effectiveness in reducing cardiovascular risk. Methods: Two rural intervention populations and their reference populations were compared. A comparison was made of the intensity and duration of the intervention programs using an overall intervention intensity score. Population-based surveys were conducted at 5-year intervals in both countries. The methods used for data pooling and comparison are described. A description of statistical analyses using a mixed analysis of variance model is provided. Results: The data were pooled, taking into consideration comparable ages. New variables were created in order to define the relationship between similar data that did not permit direct comparison. Conclusions: Combination and comparison of international data from two programs allowed evaluation of community intervention programs that were developed independently for similar communities. The effectiveness of interventions can be compared using such methods.

Time Course and Extent of Improvement of Dysfunctioning Myocardium in Patients with Coronary Artery Disease and Severely Depressed Left Ventricular Function after Revascularization: Correlation with Positron Emission Tomographic Findings

Time Course and Extent of Improvement of Dysfunctioning Myocardium in Patients with Coronary Artery Disease and Severely Depressed Left Ventricular Function after Revascularization: Correlation with Positron Emission Tomographic Findings

Future perspectives and potential implications of cardiac myocyte apoptosis.

Recent advances in the understanding of the molecular mechanisms of apoptosis has gained increasing interest in the cardiovascular research community. Apoptotic myocyte loss has been detected in different cardiac disease states such as ischemic heart disease and congestive heart failure. In addition, some evidence for the molecular mechanisms in cardiac myocyte apoptosis has been evolving, although at present the implications thereof for clinical cardiac disease are not known in most of the cases. Based on these new insights, it is the intention of this article to highlight some topics in apoptosis research that might be of particular interest to define the future role and potentials of new therapeutic approaches aimed at preventing myocyte apoptosis.

Tissue engineering a blood vessel substitute: the role of biomechanics.

The engineering of a functional blood vessel substitute has for a quarter of a century been a "holy grail" within the cardiovascular research community. Such a substitute must exhibit long term patency, and the critical issues in this area in many ways are influenced by biomechanics. One of the requirements is that it must be non-thrombogenic, which requires an "endothelial-like" inner lining. It also must have mechanical strength, i.e. a burst pressure, sufficient to operate at arterial pressures. Ideally, however, it must be more than this. It also must have viscoelastic properties that match those of the native vessel being replaced. Finally, if it is to be able to adapt to changing blood flow conditions, it must exhibit vasoactivity, a function which in and of itself can be viewed as biomechanical in nature. To achieve this requires having, as part of the construct, vascular smooth muscle cells, which are contractile in nature and oriented in a circumferential direction. Only if an engineered blood vessel substitute possesses all of these functional characteristics, can one say that the functionality exhibited by a native vessel is being mimicked.

Harriet Pearson Dustan.

On June 27, 1999, the world of medicine, the entire cardiovascular community and, in particular, our hypertension clinical and research field lost a tireless leader, advocate, and worker with the passing of Harriet Pearson Dustan⇓ from our midst. Certainly, my family lost a valued and devoted “member” and, I, a close and dear friend and colleague. After a long-standing and energy-depleting illness, she finally succumbed to lung cancer, but not without planning for the acknowledged eventuality. Indeed, the week before her death, she systematically called her friends to inquire as to their families and work and to extend her personal farewells. How typical this was of this most selfless and very private person. Figure 1. Doctor Dustan was born in the very small and remote community of Craftsbury Common, Vermont, where she received her early education at the Craftsbury Academy as well as from her mother who had an extensive knowledge of literature. She then went on to receive her undergraduate and medical education at the University of …

Evolution of the Filmless Cardiac Angiography Suite: Promise and Perils of the Evolving Digital Era

Although cineangiography has been in use for 35 years, it has important limitations. Films are expensive to produce, cannot be readily copied or transmitted electronically, are bulky, and require a large storage space. Digital angiography will soon replace film for archiving cardiac catheterization images, ultimately offering powerful new capabilities at a reduced cost. The transition toward the filmless angiogram is characterized by both great promise and important risks. Current nonfilm archiving systems (such as super-VHS videotape or analog optical disks) have not met the needs of the cardiovascular community, owing to poor image quality and resolution inferior to that of cine films. Analog storage media can result in a standard error in lesion measurements exceeding 1 mm and have a suboptimal signal-to-noise ratio. While digital media record adequate image detail, proprietary formats preclude the universal compatibility supplied by cine film. As a consequence of incompatibility, referred patients must undergo repeat catheterization prior to surgery or intervention. To resolve the compatibility problem, a committee established by the American College of Cardiology in conjunction with manufacturers (DICOM) has developed a standardized digital recording format using CD-ROM to transfer images between medical centers. The availability of this standardized interchange medium will have a positive impact on research as well as on patient care by eliminating barriers to image exchange throughout the cardiovascular community. Support for the DICOM approach by practitioners is vital to the transition to digital future. (Am J Cardiol 1996;78(suppl 3A):41–44)

901–114 Women Have a Higher Response Rate than Men to the Antihypertensive Calcium Channel Blocker Amlodipine

There is a lack of data on gender difference in response to the newer antihypertensive medicines. The Amlodipine Cardiovascular Community Trial was designed to determine the blood pressure (BP) response of patient subgroups with mild-moderate hypertension to amlodipine besylate monotherapy (5–10 mg/day). After a 2 week placebo phase, patients received amlodipine for a 4 week efficacy/titration phase followed by a 12 week maintenance phase. Goal BP was defined as a decrease in diastolic BP by 10 mmHg or more plus a diastolic BP of less than 90 mmHg. Baseline systolic BP in mmHg was 153 ± 16 and 155 ± 16 and diastolic BP 101 ± 4 and 100 ± 4 for males (n = 702) and females (n = 382), respectively. Decreases in BP at 4 weeks were greater in females than males for both systolic (-19 vs -15 mmHg, p < 0.0001) and diastolic BP (-14 vs -12 mmHg, p < 0.0001). Results were maintained at 12 weeks. Ninety-one percent of females achieved goal BP compared to 83% of men (p = 0.001). The greater response to amlodipine by women remained significant after adjusting for: age, weight, dose (mg/kg), baseline BP. and drug compliance (99% in both women and men). There was no difference in decrease in systolic and diastolic BP for women on hormone replacement (–18 and–14 mmHg) versus those not on hormone replacement (–19 and–14 mmHg). Thus, hormone replacement in women did not account for the gender difference in BP response. Women reported edema more frequently than men. In conclusion, women demonstrated a greater antihypertensive effect to amlodipine than men; the mechanism for this observation remains to be determined.

Myocardial hibernation in terms of the flow-function relationship.

In the northern part of the United States, hibernation is a very real phenomenon. It refers, of course, to the dormant condition in which some types of animals pass through the trying conditions of winter. In fact, the Latin word from which the word derives is hibernus which refers to wintry conditions. In contrast to various woodland creatures who can sleep through the winter largely oblivious to its rigors, the human inhabitants of the North have to stay awake through winter no matter how much they would like to hibernate for several months. With our usual penchant for giving simple, catchy nicknames to very complicated concepts, the cardiovascular research community has adopted the word hibernation to describe the myocardium’s response to coronary inflow restriction that is not severe enough to compromise viability. Faced with the “wintry” circumstances posed by inappropriately low oxygen availability, the idea is that the myocardium “hibernates” to protect itself against the consequences of prolonged supply/demand imbalance.

Program evaluation strategies for community-based health promotion programs: perspectives from the cardiovascular disease community research and demonstration studies.

Community-based programs are being widely adopted in the struggle to prevent chronic disease. Program evaluation of community-based programs involves a particular set of problems stemming from the variety of activities being undertaken simultaneously, the multiple intermediate goals of the programs and the rapidity with which the programs evolve. An analysis of the experience of four large community-based cardiovascular disease research and demonstration studies (Stanford Five-City Project, Minnesota Heart Health Program, Pawtucket Heart Health Program and the German Cardiovascular Prevention Project) provides valuable models, methodologies and strategies for planning and conducting evaluations of public health programs or community studies. By comparing and combining their experiences, the four programs have identified eight categories of evaluation for community studies, including formative evaluation, quality assurance, assessment of delivered dose, assessment of received dose, component program impact, intermediate outcomes, community impact and cost analysis. This paper presents information on the strategies by which each of the four programs addressed these evaluation categories.

Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute Workshop)

Idiopathic dilated cardiomyopathy (IDC) is the primary indication for cardiac transplantation, with associated costs of approximately $177 million per year. Recognizing the economic implications of IDC, the increasing incidence, and the limited information on pathogenesis and prognosis, the National Heart, Lung, and Blood Institute convened a workshop on the Prevalence and Etiology of Idiopathic Dilated Cardiomyopathy on June 13 to 14, 1991. The difficulties of studying the disease were reviewed, including its relatively low prevalence, its potentially pluricausal nature, and the fact that it is often a diagnosis of exclusion. Still, it presents significant challenges to the cardiovascular scientific community, since the mechanism of myocardial damage and related etiologic and prognostic factors are virtually unknown. The development of more reliable measures of immune-mediated damage and noninvasive measures of impaired cardiac function present new research opportunities in this disorder. Standardized diagnostic criteria for use in observational and interventional trials were developed, and priorities for future research were proposed. Population-based registries and nested case-control studies, where feasible, are appropriate study designs for tracking incidence and prevalence, and for identifying risk factors, respectively. Interventional studies should focus on secondary prevention, through modifying immunemediated damage in clinically evident dilated cardiomyopathy, and through prevention of sudden death in patients with the disorder. Primary prevention trials must await the identification of modifiable risk factors and of appropriate and effective interventions.

Heart valve legislation and regulation

During 13 years of regulation by the FDA under the Medical Device Amendments of 1976, the process by which replacement heart valves have been developed and modified has changed. Some of these changes have been good for the public, whereas other changes are of questionable value. Conditions will never be as they were 25 years ago, but they could be closer to what was expected in 1976. As the FDA constantly seeks to improve its performance and Congress focuses on possible changes to the Act, the cardiovascular community of practitioners, inventors, and manufacturers should offer their assistance. I believe the creative spirit that enables you as pioneers to reflect on your accomplishments and contemplate even greater innovations for the future should again be applied to the process of helping the FDA improve the way it serves us—the public.

The Stanford Five-City Project: design and methods.

The Stanford Five-City Project is a large experimental field study of community health education for the prevention of cardiovascular disease. It will provide data on fundamental questions in cardiovascular disease epidemiology, communication, health education, behavior change, and community organization, and will also test the ability of a potentially cost-effective program to prevent cardiovascular disease at the community level. This paper describes the purposes, hypotheses, design, and methods of the Five-City Project as a reference for future papers describing results. It is hypothesized that a 20% decrease in cardiovascular disease risk will lead to a significant decline in cardiovascular disease event rates in two treatment communities compared with three reference communities as a result of a six-year intervention program of community-wide health education and organization. Risk factor change will be assessed through four surveys of independent samples and in a repeatedly surveyed cohort. Cardiovascular disease event rates will be assessed through continuous community surveillance of fatal and nonfatal myocardial infarction and stroke.

Coronary risk factors and socioeconomic status in Eastern Finland

Known CHD risk factors are strongly related to behavior and are rooted in cultural and social patterns. For any preventive community program, it is essential to clarify the connection between these risk factors and the socioeconomic situation of the given population. Before launching a comprehensive cardiovascular community program in North Karelia, a county in Eastern Finland with the world's highest known incidence rates of CHD, a large baseline survey was carried out on a representative sample of the population with a participation rate of 90%. Lower socioeconomic status (rural living, lower educational level and income, heavy physical work) was generally associated with CHD risk factors, i.e., smoking, high serum cholesterol, and high blood pressure, although with regard to blood pressure, the association was weak for men. The main departure was observed among women, where smoking in general was rare and was mainly associated with higher socioeconomic status. The findings are in agreement with current knowledge about the occurrence of the disease in the same population. The findings in Eastern Finland are discussed in the light of previous studies and possible social change during the last year.