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(Circulation. 1997;95:766-770.)
© 1997 American Heart Association, Inc.
Articles |
Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on Heart Failure Research
the National Heart, Lung, and Blood Institute, Bethesda, Md (S.C.M., L.R.). See "Appendix" for a list of the members of the SEP on Heart Failure Research.
Correspondence to Leslie Reinlib, PhD, National Heart, Lung, and Blood Institute, Rockledge Center Two, 6701 Rockledge Dr, MSC 7940, Bethesda, MD 20892. E-mail LR25V@NIH.GOV.
Key Words: cardiovascular diseases • heart diseases • heart failure
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Introduction |
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Top
Introduction
Perform Studies Designed to...Heart failure is the final common pathway of most primary cardiovascular diseases, including coronary atherosclerosis, hypertension, cardiomyopathy, myocarditis, diabetes, and valvular and congenital heart malformations. Most treatments slow the course of these primary diseases but do not abolish them. As a result, an increasing proportion of the US population is living with heart disease and is at risk for heart failure. Approximately 400 000 new cases of heart failure occur annually, and recent estimates (1993) of its prevalence demonstrate the enormous burden exacted on the public: 4.7 million patients, with 1.5 million people younger than 65 years of age, and direct healthcare costs (drugs, nursing home care, professional services) totaling $17.8 billion each year. These numbers will likely increase as the US population ages.
In recognition of this national health problem, the National Heart, Lung, and Blood Institute (NHLBI) convened a Task Force on Research in Heart Failure and released the findings in 1994 to chart the course for future research. Given the explosion of new information and ideas, a Special Emphasis Panel (SEP) on Heart Failure Research was held on May 20, 1996, in Bethesda, Md, to follow up and focus the broad task force recommendations. The framework to conduct future research as recommended by these expert panels of extramural scientists is essential to promoting the needs of the biomedical community and properly committing the Institute's scarce resources.
The SEP members were experts representing a broad range of biomedical disciplines and were charged to consider an array of emerging ideas to approach heart failure. The SEP made recommendations to serve as the basis of a balanced research blueprint to guide the NHLBI. Four broad goals were identified for an ideal plan: (1) An improved national network of clinicians and scientists would be created to interact optimally to determine the underlying causes of heart failure and develop practical, effective solutions; (2) promising basic science approaches, such as those discussed below that either are lacking or would benefit from improved emphasis and those to help define and respond to the clinical manifestations of heart failure, would be encouraged; (3) new techniques would be developed and existing ones exploited to assist the research field as it moves into the 21st century. These will likely include varied pursuits such as utilization of the wealth of data flowing from the Human Genome Project and Rat Genome Project, gene transfer technology, and better cell isolation and tissue preservation techniques; and (4) special efforts would be implemented to attract and retain established and young scientists to the problems of heart failure research and encourage interactions and sharing of ideas and resources among complementary disciplines.
The SEP identified several clinical and basic research directions ripe for investigation. Elucidation of the roles of apoptosis and cardiomyocyte cell cycle was identified as a particularly attractive area of investigation. In particular, high priority was placed on learning how to control cell life and death cycles and growth in the heart. The adult cardiac myocyte is extraordinarily refractory to cell division, and it seems clear that very little division occurs. Although a great deal is known about cell cycle regulation in many cell types, studies of cardiac myocytes are just beginning. Similarly, apoptosis, whose role in other cell types has been established, has relevance to the heart, but clarification of its influence on failure is lacking. Focusing the latest concepts and investigators' talents on the cell biology of the myocyte and its role in heart failure would provide novel clues to the origins of the syndrome and offer attractive original approaches. Several exciting themes are emerging from investigation of cardiac development that are leading to alternative views of heart function and treatment of heart failure. New avenues for treatment are suggested by the success of cardiac cell grafting between animals and of transgenic mice displaying enhanced cardiac performance. These studies are in their infancy, but the potential utility is tremendous. Advances in the relative science will depend largely on the development of appropriate new research tools. Finally, resolution of certain controversial areas would be helpful in providing clear directions for new advances. For example, various notions of the impact of structural and pathological alterations on failure need to be standardized and unified.
A recurrent theme in the discussions was to encourage mechanisms to induce teams with diverse expertise to work together on common problems. The panel recognized the need for greater cooperation in the community to apply molecular, cellular, physiological, and clinical approaches to the study on heart failure. The recent funding of five Specialized Centers of Research (SCOR) in Heart Failure represents an initial step in this direction. The next step should take advantage of the extensive expertise and resources available across the country. Ideally, established basic and clinical investigators—where necessary, from diverse locations—would collaborate to develop a clearly targeted hypothesis-driven project, drawing on multiple disciplines to address major issues, mechanisms, and treatments for heart failure. As an example, the driving question might be based on observations of histological and patient data suggesting a family of overexpressed genes controlling hypertrophic remodeling. This hypothesis could be addressed by characterizing alterations in gene family expression; related candidate transcription factors; subsequent protein products; biochemical measures of these proteins' activities; studies of effects in transgenic or knockout animals; tests of patient samples; and correlations with histological, immunologic, and biochemical examination in patient biopsies and explanted tissue. It would be necessary for the investigators to share results and ideas at each step to ensure smooth progress. The design of such projects would encourage closer clinical and basic interactions and, it is hoped, provide for greater synergy.
Recommendations of the SEP in specific research areas are listed below, followed by brief discussions and some specific goals.
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Perform Studies Designed to Understand and Regulate Cardiac Apoptosis |
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Loss of cardiac myocytes may be a fundamental part of the myocardial process that initiates and/or aggravates heart failure and leads to premature death. Two different phenomena are known: necrosis and apoptosis. Myocyte necrosis—characterized by surface membrane disruption, inflammation, and fibrotic replacement—is a common inciting event caused by infarction, infection, or toxicity. Apoptosis occurs without disruption of the surface membrane, is associated with pinocytosis of cell contents and phagocytosis by neighboring cells, and may be an unwanted secondary occurrence of a hormonal, paracrine, or autocrine response. Although apoptosis in the heart was not detected in earlier studies, improved assay methods have provided support for it, and recent reports have indicated elevated levels of apoptosis in tissue from heart failure patients. The stimuli for this process, its consequences on neighboring cells and organ function, and the long-term effects of irrevocable cell loss have yet to be established in animal models or humans.
Apoptosis appears to be mediated by multiple factors and occurs in normal mammalian development, as in postnatal degeneration of mammalian right ventricle. It is, for example, activated by superoxides, which are induced by physical stretch and, in dilated myocardium, may explain the loss of myocytes and progressive ventricular deterioration. Many neurohumoral agents also influence apoptosis. An essential goal of understanding the impact of apoptosis on heart failure is to determine the physiologically relevant neurohumoral and local hormone activators and inhibitors. Improved assay systems to study these effects need to be developed.
The data on apoptosis in the setting of human heart failure are fragmentary, and critical questions at the molecular level have not been resolved. However, a large body of work exists from studies of the apoptotic signaling pathway in other cell types that could be related to the normal and failing heart. Such studies include the effects of anoxic and ischemic conditions and definition of gene families and their products that, if known, could favorably affect the understanding of heart failure. Targeting cardiac cells with appropriate gene transfer vectors is a high priority, because these studies could lead to new approaches to slow down undesirable processes. It will be critical to develop appropriate tools, techniques, and reagents to unequivocally address the role of apoptosis versus necrosis in the onset of heart failure. Current assays are limited in their capacities to distinguish between apoptosis and necrosis in myocytes. Improved assays and techniques appropriate for cardiac cells are critical, and a combination of cultured cell, transgenic, and gene targeting approaches should be considered.
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Examine the Cardiac Cell Cycle and Determine How to Control Cell Proliferation and Growth |
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Several studies suggest that restoration of the proliferative capacity of adult myocytes could serve as potential therapy in a variety of settings, including acute myocardial infarction and heart failure. Limited cardiac myocyte proliferation has been observed under conditions of abnormal stress, but it is clearly not of sufficient magnitude to have a significant functional impact. Defining and removing the blocks to cell division could lead to production of new cells. However, a growing body of evidence suggests multiple checkpoints may be responsible for the maintenance of the terminally differentiated phenotype in cardiac and skeletal muscle cells, and it may be necessary to implement several steps or procedures to restore the proliferative capacity of myocytes.
However, simple induction of proliferation is not a guarantee of improved cardiac activity.
Indeed, a functional advantage of new cells rather than hypertrophied existing cells would be necessary to justify attempts to stimulate cell division. It will be critical to determine the parameters for enhanced function so that proliferation and growth can be implemented to produce optimal benefits. Such characteristics might include increased sarcomeres laid down in series or parallel orientation, resulting in increased myocyte length or larger cross-sectional area. In addition, it may be desirable to develop strategies to genetically engineer dividing cells. Molecular studies suggest ways to design cells to improve cardiac contraction. For example, transgenic mice demonstrate enhanced cardiac performance when the gene knockout technique is used to deplete the sarcoplasmic reticular protein phospholamban. Selective manipulation of phospholamban levels or activity could alter the contractile parameters of de novo cells in a preconceived way.
In addition, new approaches for molecular therapy should be considered. A host of evidence suggests the importance of inflammatory cytokines in the setting of heart failure, and the potential exists to neutralize their activity by a variety of approaches. Identifying the beneficial or detrimental effects on cardiac growth and function of growth factors and cytokines is to be encouraged. Creating assay systems to search for novel secreted factors is of interest. Such studies are expected to eventually lead to forms of intervention to treat heart failure.
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Foster Studies Encompassing Physiological, Molecular, Biochemical, and Multiorgan Factors |
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Heart failure is a complex syndrome that involves the interaction of multiple organ systems and cell types. A purely reductionistic approach for the study of heart failure, although important for many issues, may overlook critical interactions that occur in the intact organism or tissue. Therefore, organ, tissue, and cellular dysfunction in heart failure need to be examined in the context of the integrated environment in which the abnormality occurs. The roles of the renin-angiotensin and sympathetic nervous systems have been studied extensively in heart failure, and therapeutic approaches influencing these systems are clinically useful. However, the mechanisms stimulating these systems in heart failure are incompletely understood. The numerous alterations in autocrine and paracrine signaling present in hypertrophied and failing myocardium need to be understood comprehensively in both humans and relevant animal models. For example, hemodynamic overload and heart failure are associated with altered or de novo expression in the myocardium of signaling molecules, including peptide growth factors, cytokines, and nitric oxide, which have the potential to exert profound effects on the phenotype of myocytes, fibroblasts, vascular smooth muscle cells, and endothelial cells. There probably are multiple levels of autocrine and paracrine interactions resulting from positive and negative feedback loops; therefore, studies in isolated cells may not replicate the in vivo environment. Better understanding of cell and tissue regulation, targets, and signaling systems may elucidate the origins of heart failure or its progress.
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Nurture New Technologies to Develop Improved Animal Models of Heart Failure |
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Genetically engineered mice are extremely valuable in elucidating mechanisms underlying normal and deranged cardiovascular function, and the strategy of transgenics is encouraged so far as to determine candidate genes and mechanisms relevant to the origins of heart failure and its decompensation. The broad range of such mice available or on the horizon offers opportunities to test a wide variety of hypotheses. However, despite the tremendous insights granted by use of genetically engineered mice, there is still a need for large-animal models of heart failure.
To overcome the limitations imposed by mouse models, considerable interest is invested in large animals to allow more complete integrative study of cells and organs and couple molecular physiology and transgenic manipulations with extensive experience in observing cardiovascular function. The principal disadvantages are cost, limited selective times of estrus (excepting rabbits), smaller litter sizes, and longer periods of development and aging. Despite these barriers, genetically engineered large-animal models are likely to be of tremendous value. Desirable characteristics for large-animal models of heart failure include a clear-cut phase of compensation displaying little evidence of cardiac structural and/or functional abnormalities and the absence of pulmonary or systemic congestion, followed by a period of worsened contractile depression associated with circulatory congestion. Models should provide low surgical mortality, reproducibility, and high similarities to humans. One critical goal will be to develop more successful in vitro and in vivo models of cardiac hypertrophy and failure, including postinfarct animal models. These models should optimize the ability to explore combined alterations to point to new directions for gene targeting, clinical, or pharmacological studies. The issues require critical examination of feasibility, cost, and implementation by a panel with expertise in both genetic engineering of large and small animals and application of animals in physiological and pharmacological settings.
The design of new models should take advantage of emerging technologies and the tremendous amount of material appearing from such efforts as the Human Genome Project. Another powerful tool is the growing body of human expressed sequence tags currently being deposited into the public domain. These DNA probes provide opportunities to monitor expression of candidate genes and proteins in disease progression and development. Information arising from these efforts will need to be processed and made available for practical use by investigators.
When advanced methods are applied, in vitro and in vivo assay systems should be designed to display fidelity to key end points that can be related to the human failing heart phenotype. In this regard, finding molecular surrogates that are closely linked to the pathophysiological status is an important goal. Better methods to isolate and culture developing and adult heart cells while preserving the in vivo integrity also will be central to testing hypotheses deriving from models of heart failure.
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Determine the Contribution of Energy Depletion to Heart Failure |
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Energy stores are not grossly depleted in failing myocardium, but more subtle limitations in energy transfer may be present and could be important in causing myocyte failure either directly, by limiting the amount of work performed by the myocyte, or indirectly, by activation of gene expression programs that contribute to structural and functional abnormalities. The cause of energetic defects is not understood but might relate to physical limitations in blood flow, especially in the subendocardium, impaired energy transfer (eg, increased capillary/myocyte distance), alterations in the expression or function of key energy-regulating enzymes (eg, creatine kinase), or altered structure or function of myocytes and organelles (eg, mitochondria). Newly discerned determinants of depressed energy reserves might improve early detection assays and therapies for heart failure. Directions for work to expand the database of heart failure based on these concepts are best resolved by a panel of experts in bioenergetics and imaging techniques.
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Determine the Factors Leading to Fatal Arrhythmias |
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Arrhythmias frequently lead to mortality in heart failure patients. Considerable new research advances enhance our understanding of the causes and prevention of fatal arrhythmias. Molecular genetic studies of patients with long-QT syndrome have identified multiple mutant genes that produce structurally and functionally abnormal sodium and potassium channels in the myocyte membrane that contribute to disordered electrical function of the heart. Similar types of "channelopathies" have been identified in myocytes obtained from the failing heart, with some particularly exciting information on the transient outward current (Ito) in cells from animals with heart failure. Furthermore, "M" cells, which have unique repolarization characteristics involving increased Ito, have been identified in human hearts and could contribute to repolarization heterogeneity and secondary fatal arrhythmias. Thus, the area of channel dysfunction is a prime suspect as a contributing factor in the development of malignant arrhythmias. It is essential to identify specific ion channels and associated signaling pathways contributing to arrhythmias in heart failure. Additional factors associated with an increased likelihood of fatal arrhythmias in failure should be investigated: myocardial scarring and fibrosis, ventricular ectopy, ischemia, autonomic imbalance, low heart rate variability, overt and covert T-wave alternans, temporal dispersion of ventricular refractoriness, and electrolyte imbalance.
The track record of antiarrhythmic drugs is disappointing in the prevention of fatal arrhythmias. However, other measures are encouraging in dealing with electrical cardiac disturbances. For example, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) indicated a 54% reduction in total mortality with the implanted cardioverter-defibrillator in a defined subset of high-risk coronary patients. Other types of electrical therapy may be useful as an "antiarrhythmic agent" or in optimizing the timing of electrical depolarization. These encouraging results require extension and confirmation.
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Study Regression of Heart Failure Abnormalities With Left Ventricular Assist Devices |
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Until the advent of cardiac transplantation and powerful drugs, such as ß-blockers and ACE inhibitors, heart failure patients were generally treated with bed rest to unload the left ventricle, which reportedly improved such variables as heart rate, heart size, and contraction. However, prolonged hospital rest is incompletely effective, reduces quality of life, and is not economically feasible. Cardiac transplantation, a last resort, is limited by an insufficient number of donors, the high cost, and the fact that only select patients are eligible for surgery.
An alternative treatment is implantation of an left ventricular assist device (LVAD) to largely unload the left ventricle. Existing data indicate that LVAD use for >30 days in patients awaiting transplantation consistently enhances ventricular function and shows overall improvement.
Two uses are proposed to benefit heart failure patients. First, for end-stage patients, permanent LVAD implantation is suggested to reverse cardiac remodeling. The devices might require replacement at some point, similar to pacemaker upkeep. The other use would be temporary to rest the heart. This might best benefit end-stage patients but could also improve the conditions of many people with more moderate failure. Recovery to an extent allowing permanent removal of the LVAD would be a major advancement in treating heart failure.
Sufficient data exist to support the feasibility of a systematic analysis of the effects of mechanical ventricular unloading. The critical hypotheses to test are as follows: (1) Left ventricular unloading results in a rapid and sustained correction of the neurohumoral and tissue response to heart failure; (2) contractile function progresses with time and is maintained after withdrawal of mechanical support; (3) functional changes are linked to identifiable structural and biochemical changes such as myocyte morphometry, ultrastructure, receptor function, and excitation-contraction coupling; (4) ventricular unloading reprograms the surviving cells to express the fetal phenotype; and (5) expression of the fetal phenotype is a prerequisite for the repair of damaged myocardium, re-expression of the normal, adult cardiac gene program, structural regeneration, and return of normal contractile function.
As a final note, these protocols also create opportunities to serially study dysfunction and recovery in the left ventricle. Myocardial processes can be studied in biopsies or the tissue "plugs" removed during LVAD implantation. It is interesting to note a similar situation in treatment of dilated cardiomyopathies with ß-adrenergic blockers, which often improves intrinsic myocardial function.
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Determine Structural and Functional Alterations of Intact Failing Hearts |
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Despite rapid advancements in our knowledge of molecular mechanisms in the heart and of clinical responses in patients with heart failure, there remains a large gap of information about the progressive structural and functional abnormalities that characterize heart failure. Such critically important issues as the cellular contribution to left ventricular dilation during the remodeling process and its influence on chamber function remain poorly elucidated. In particular, there is a lack of knowledge about changes in myocyte structure, fiber orientation, fiber slippage, and the role of collagen and other interstitial components. Some of these issues are currently being addressed in animal models. For studies of clinically relevant cardiac remodeling processes, it is important to develop models replicating the cardiac response to a clinically relevant insult such as localized myocardial damage or overload.
A series of technical developments would greatly facilitate these forms of research and quantitative cellular, organ, and organism pursuits. For cellular studies, improved methods to isolate myocytes and other cells in their native states, preferably from human biopsy material, would be of great assistance. Problems with heterogeneity of cell size and function require careful study. More widespread use of MRI is encouraged because of its precise quantitative potential to measure myocardial mass, chamber volume, and chamber function. Sequential studies, particularly in response to new interventions, are needed. In addition, new methods are required to better examine and monitor structural changes.
At the molecular level, studies are needed to define the gene expression that leads to myocyte and fibroblast growth and remodeling. The relative role of hemodynamic factors and growth hormones, cytokines, and other paracrine mechanisms must be elucidated. The capacity of the myocardium to reverse its remodeling and the molecular and structural mechanisms contributing to this process are important unresolved issues.
The SEP expressed concern about differences of opinion among morphometrists about the techniques available and the lack of standardized methods in assessing myocyte size, number, and interstitial components. One camp argues that myocardial structure is best examined in disassociated cells. The other view is that classic anatomic methods can be used to identify phenotypic changes. These opposing premises may limit progress in determining the influence of growth factors and pharmacological agents and attaining the quantification necessary in addressing mechanisms such as apoptosis. High priority is placed on a "summit conference" of cardiac pathologists and experts with differing views to provide investigators with recommendations for promising quantitative studies.
The quest to confirm experimentally derived concepts would be greatly facilitated by increased availability of patient and normal subject tissues. Although cell studies indicate specific candidates and suggest underlying mechanisms, understanding cellular function under the various constraints imposed in vivo—load, stretch, neurohumoral, etc—is critical to determining the causes of and solutions to heart failure. Local tissue banks operating in a few transplant centers successfully support research needs and could be extended to other investigators. Discussion of the potential problems in establishing a national tissue bank led to the opinion that groups performing such services should extend their scope instead of creating a de novo system.
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Encourage Mechanistic Studies in Clinical Trials |
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Large-scale clinical trials provide a rich population of patients with left ventricular dysfunction that are monitored over time in a well-defined, standardized protocol. The opportunity to identify molecular, cellular, structural, neurohormonal, electrophysiological, bioenergetic, circulatory, or clinical markers of the progression of the ventricular dysfunction and of its response to the therapeutic interventions should not be lost.
This effort will require the interaction of basic scientists with clinical trial investigators. Future trials of heart failure treatments should plan to consider arrangements for ancillary basic studies and obtain blood, tissue, or other measurements to elucidate mechanisms of the disease and its progression. Modest augmentation of support for trials may allow collection of important clinically relevant information that would not be obtained in single-center studies. This information would form the origins of a database that would meet a critical need to establish the phenotypes and genotypes of the normal and progressively failing hearts.
New insights into mechanisms and treatment must ultimately be tested in humans. Consideration should also be given to more focused clinical trials in which the patient population is more homogeneous. Although this approach may yield data that are viewed to be less broadly applicable, new understanding of a mechanism in a clearly defined subset of patients with heart failure may well be applicable to a larger population.
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Summary |
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The SEP identified priorities to support in future basic and clinical research and pointed out directions likely to result in advances against heart failure. The list is not intended to be all-encompassing and does not address, for example, exciting lines of work already under way. Rather, the recommendations are designed to point out gaps in current knowledge not being adequately addressed and highly promising new directions.
Although the incidence of heart failure continues to grow, emerging lines of research provide hope that research advances will eventually lead to more effective treatment and ultimately to prevention. This research will be well served by bringing the latest multidisciplinary approaches and the best investigators to focus on the problems of heart failure. It is hoped the efforts of distinguished expert entities such as the task force and SEP will be a useful guide in addressing the needs of the biomedical community and assisting in its success.
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Appendix |
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Members of the SEP on Heart Failure Research
Cardiovascular Division, University of Minnesota Medical School, Minneapolis (J.N.C.); Division of Cardiology, Health Sciences Center, University of Colorado, Denver (M.R.B.); Department of Medicine and Center for Molecular Genetics, School of Medicine, University of San Diego, La Jolla, Calif (K.R.C.); Division of Cardiology, Boston (Mass) University Medical Center (W.S.C.); Cullen Cardiovascular Research Laboratories, Texas Heart Institute, Houston (O.H.F.); Department of Molecular, Cell, and Developmental Biology, University of Colorado, Boulder (L.A.L.); Cardiovascular Division, Harvard Medical School, Beth Israel Hospital, Boston, Mass (B.H.L.); Department of Cardiology, School of Medicine and Dentistry, University of Rochester (NY) (A.J.M.); Division of Cardiology, Albert Einstein College of Medicine, The Bronx, NY (E.H.S.); and Cardiovascular Center, Division of Cardiology, University of Cincinnati (Ohio) Medical Center, Cincinnati (R.A.W.).
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M. C. LaPointe, X.-P. Yang, O. A. Carretero, and Q. He Left ventricular targeting of reporter gene expression in vivo by human BNP promoter in an adenoviral vector Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1439 - H1445. [Abstract] [Full Text] [PDF]
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C. Iribarren, A. J. Karter, A. S. Go, A. Ferrara, J. Y. Liu, S. Sidney, and J. V. Selby Glycemic Control and Heart Failure Among Adult Patients With Diabetes Circulation, June 5, 2001; 103(22): 2668 - 2673. [Abstract] [Full Text] [PDF]
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J. H. SUH, E. T. SHIGENO, J. D. MORROW, B. COX, A. E. ROCHA, B. FREI, and T. M. HAGEN Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-{alpha}-lipoic acid FASEB J, March 1, 2001; 15(3): 700 - 706. [Abstract] [Full Text] [PDF]
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C. Badorff, B. Fichtlscherer, R. E. Rhoads, A. M. Zeiher, A. Muelsch, S. Dimmeler, and K. U. Knowlton Nitric Oxide Inhibits Dystrophin Proteolysis by Coxsackieviral Protease 2A Through S-Nitrosylation : A Protective Mechanism Against Enteroviral Cardiomyopathy Circulation, October 31, 2000; 102(18): 2276 - 2281. [Abstract] [Full Text] [PDF]
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Y. Moriyama, H. Yasue, M. Yoshimura, Y. Mizuno, K. Nishiyama, R. Tsunoda, H. Kawano, K. Kugiyama, H. Ogawa, Y. Saito, et al. The Plasma Levels of Dehydroepiandrosterone Sulfate Are Decreased in Patients with Chronic Heart Failure in Proportion to the Severity J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1834 - 1840. [Abstract] [Full Text]
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M. O. Boluyt and O. H.L. Bing Matrix gene expression and decompensated heart failure: The aged SHR model Cardiovasc Res, May 1, 2000; 46(2): 239 - 249. [Abstract] [Full Text] [PDF]
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C. H. Redfern, M. Y. Degtyarev, A. T. Kwa, N. Salomonis, N. Cotte, T. Nanevicz, N. Fidelman, K. Desai, K. Vranizan, E. K. Lee, et al. Conditional expression of a Gi-coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy PNAS, April 25, 2000; 97(9): 4826 - 4831. [Abstract] [Full Text] [PDF]
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D. Fatkin, C. MacRae, T. Sasaki, M. R. Wolff, M. Porcu, M. Frenneaux, J. Atherton, H. J. Vidaillet, S. Spudich, U. De Girolami, et al. Missense Mutations in the Rod Domain of the Lamin A/C Gene as Causes of Dilated Cardiomyopathy and Conduction-System Disease N. Engl. J. Med., December 2, 1999; 341(23): 1715 - 1724. [Abstract] [Full Text] [PDF]
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T. Ide, H. Tsutsui, S. Kinugawa, H. Utsumi, D. Kang, N. Hattori, K. Uchida, K.-i. Arimura, K. Egashira, and A. Takeshita Mitochondrial Electron Transport Complex I Is a Potential Source of Oxygen Free Radicals in the Failing Myocardium Circ. Res., August 20, 1999; 85(4): 357 - 363. [Abstract] [Full Text] [PDF]
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C. Perez-Terzic, A. M. Gacy, R. Bortolon, P. P. Dzeja, M. Puceat, M. Jaconi, F. G. Prendergast, and A. Terzic Structural Plasticity of the Cardiac Nuclear Pore Complex in Response to Regulators of Nuclear Import Circ. Res., June 11, 1999; 84(11): 1292 - 1301. [Abstract] [Full Text] [PDF]
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D. J. Peterson, H. Ju, J. Hao, M. Panagia, D. C. Chapman, and I. M.C. Dixon Expression of Gi-2{alpha} and Gs{alpha} in myofibroblasts localized to the infarct scar in heart failure due to myocardial infarction Cardiovasc Res, March 1, 1999; 41(3): 575 - 585. [Abstract] [Full Text] [PDF]
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H. F. Clemo, B. S. Stambler, and C. M. Baumgarten Persistent Activation of a Swelling-Activated Cation Current in Ventricular Myocytes From Dogs With Tachycardia-Induced Congestive Heart Failure Circ. Res., July 27, 1998; 83(2): 147 - 157. [Abstract] [Full Text] [PDF]
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P. Anversa and J. Kajstura Ventricular Myocytes Are Not Terminally Differentiated in the Adult Mammalian Heart Circ. Res., July 13, 1998; 83(1): 1 - 14. [Full Text] [PDF]
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M. O'Rourke and L. Reinlib Priorities in Heart Failure Research • Response Circulation, January 27, 1998; 97(3): 296 - 296. [Full Text]
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J. Leor, H. Prentice, V. Sartorelli, M. J Quinones, M. Patterson, L. K Kedes, and R. A Kloner Gene transfer and cell transplant: an experimental approach to repair a 'broken heart' Cardiovasc Res, September 1, 1997; 35(3): 431 - 441. [Full Text] [PDF]
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P. Liao, D. Georgakopoulos, A. Kovacs, M. Zheng, D. Lerner, H. Pu, J. Saffitz, K. Chien, R.-P. Xiao, D. A. Kass, et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy PNAS, October 9, 2001; 98(21): 12283 - 12288. [Abstract] [Full Text] [PDF]
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A. J. Moss, W. Zareba, W. J. Hall, H. Klein, D. J. Wilber, D. S. Cannom, J. P. Daubert, S. L. Higgins, M. W. Brown, M. L. Andrews, et al. Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction N. Engl. J. Med., March 21, 2002; 346(12): 877 - 883. [Abstract] [Full Text] [PDF]
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