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Circulation. 2004;110:e333-e336
doi: 10.1161/01.CIR.0000143625.56882.5C
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(Circulation. 2004;110:e333-e336.)
© 2004 American Heart Association, Inc.


Special Report

Left Ventricular Form and Function

Scientific Priorities and Strategic Planning for Development of New Views of Disease

Gerald D. Buckberg, MD; Myron L. Weisfeldt, MD; Manel Ballester, MD; Raphael Beyar, MD; Daniel Burkhoff, MD, PhD; H. Cecil Coghlan, MD; Mark Doyle, BSc, PhD; Neal D. Epstein, MD; Morteza Gharib, PhD; Ray E. Ideker, MD, PhD; Neil B. Ingels, PhD; Martin M. LeWinter, MD; Andrew D. McCulloch, PhD; Gerald M. Pohost, MD; Leslie J. Reinlib, PhD; David J. Sahn, MD; George Sopko, MD, MPH; Francis G. Spinale, MD, PhD; Henry M. Spotnitz, MD; Francisco Torrent-Guasp, MD; Edward P. Shapiro, MD

From the University of California, Los Angeles (G.D.B.); The Johns Hopkins University, Baltimore, Md (M.L.W., E.P.S.); University of Lleida, Lleida, Spain (M.B.); Technion-Israel Institute of Technology, Technion City, Israel (R.B.); Columbia University, New York, NY (D.B., H.M.S.); University of Alabama at Birmingham (H.C.C., R.E.I.); Allegheny-Singer Research Institute, Pittsburgh, Pa (M.D.); National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md (N.D.E., L.J.R., G.S.); California Institute of Technology, Pasadena, Calif (M.G.); Palo Alto Medical Foundation, Palo Alto, Calif (N.B.I.); The University of Vermont, Burlington, Vt (M.M.L.); University of California, San Diego (A.D.M.); University of Southern California, Los Angeles, Calif (G.M.P.); Oregon Health Sciences University, Portland, Ore (D.J.S.); The Medical University of South Carolina, Charleston, SC (F.G.S.); and Denia, Spain (F.T.-G.).

Correspondence and reprint requests to Edward P. Shapiro, MD, Division of Cardiology, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Baltimore, MD 21224. E-mail eshapiro{at}jhmi.edu


*    Introduction
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*Introduction
down arrowUnderstanding Normal and...
down arrowAdvancing Imaging
down arrowAdvancing Therapeutics Through...
down arrowReferences
 
Heart failure continues to be one of the most costly and prevalent medical problems. The increasing age of our population and the increased survival of patients with diseases that lead to heart failure will no doubt further magnify this very serious health problem at a staggering cost, both monetary and human.1 To address this public health concern, a fuller understanding of what constitutes normal cardiac function is essential to recognize optimal goals for restoration after disease disrupts stability. From micro to macro, our limited understanding of the heart’s function continues to represent an obstacle to our ability to design strategies for effective treatment of heart failure. Thus, there is a critical need to address the existing and emerging issues in this area to develop new safe and effective strategies to address the clinical challenges facing cardiologists and cardiothoracic surgeons. As a result of this need, the National Heart, Lung, and Blood Institute convened a workshop entitled "Form and Function: New Views on Development, Diseases, and Therapies for the Heart" on April 25 to 26, 2002, in Bethesda, Maryland. The objective was an effort to understand the importance of structure/function relationships of the intact ventricles from both the basic science and clinical perspectives, to define where progress is most urgently needed, and to plan research programs that will most effectively integrate understanding of functional geometry into therapy of human heart disease.

There has been a remarkable growth in the understanding of cellular myocardial function at the genetic/molecular level with development of the ability to perform genetic manipulation of cardiac and other cells within the heart. It is critically important to recognize that the complex molecular machinery that enables the heart to fulfill its role in the circulatory system can only function effectively within an architectural design that allows the contractile apparatus to perform with optimal mechanical efficiency, determined by appropriate integration of the vectors of force generated by cardiac sarcomeres. Integration of new genetic techniques and advances in imaging technology must be matched with a new understanding of the importance of shape and fiber architecture to provide insights into disease that can lead to new therapies.

A shift in emphasis from concepts of ventricular function that consider only contractile state and load to those that also incorporate interaction and dynamic rearrangement of myocardial layers2 is needed. A starting point for discussion at the workshop was the anatomic concept that has been proposed by Torrent-Guasp,3 in which both ventricles are considered to consist of a single myofiber band extending from the right ventricular muscle just below the pulmonary artery to the left ventricular muscle where it attaches to the aorta, twisted and wrapped into a double helical coil during evolutionary and embryological development. In this construct, sequential activation and contraction beginning in fibers near the pulmonary artery and spreading toward the aortic end of the band might explain the pattern of ejection and suction needed for ventricular output and filling. This model is an example of an emphasis that relates fiber architecture to chamber shape and mechanics and has implications for improved understanding of electrical, electromechanical, and mechanical determinants of cardiac function. Disease resulting from ischemic, non-ischemic, and valvular mechanisms may produce architectural distortion and create a more spherical ventricular shape. The conceptual underpinning of management may therefore involve restoration of the normal structural scaffold, so that successful interventions can be designed to achieve normalization of fiber orientation.

To advance the understanding of the relationship between form and function of the intact heart and to integrate these findings into therapy, we recommend intensive study along the following pathways.


*    Understanding Normal and Abnormal Shape and Fiber Mechanics
up arrowTop
up arrowIntroduction
*Understanding Normal and...
down arrowAdvancing Imaging
down arrowAdvancing Therapeutics Through...
down arrowReferences
 


*    Advancing Imaging
up arrowTop
up arrowIntroduction
up arrowUnderstanding Normal and...
*Advancing Imaging
down arrowAdvancing Therapeutics Through...
down arrowReferences
 

Specific imaging methods with potential for defining fiber orientation and electromechanical sequences in microscopic preparations and small animal models include (1) two photon confocal microscopy7 and/or optical computed tomography for optical imaging of fiber orientation and mechanics and (2) high field magnetic resonance imaging (MRI) development,8 particularly using diffusion tensor imaging,9 tissue tagging, and strain assessment in 2-dimensional and 3-dimensional space. The utility of iron and chelate markers for MRI tracking of cells10 or even gene activity11 should be studied. Specifically, chimeric mouse models in which some cells have been tagged in this manner and can be tracked to study the dynamic geometry of fibers might define fiber architecture and how it changes throughout the cycle. Similarly, labeled stem cells might be introduced into remodeled ventricles to assess the factors that determine their eventual orientation. In larger animal and clinical studies, optimization of MRI at existing and expected higher magnetic field strengths has potential to define normal and abnormal structure (fiber orientation via diffusion tensor imaging), systolic and diastolic function (strain or strain rate via tagging or tissue velocity measurement), and perfusion (oxygen saturation using blood-oxygen level-dependent or other methods).
The development and more frequent use of methods that provide long-lasting tagging of myocardium, persisting for months or years, should be encouraged. For example, this method might make use of the implantation of radiopaque or other sensors for high-speed cine imaging or recording to study geometry change and even fiber realignment and systolic/diastolic dimensional change after restoration of appropriate geometry by surgery over extended observation periods.
In the long term, configuration changes in transmembrane proteins following electrical or mechanical events might provide signals that could be detected with noninvasive imaging modalities such as MRI or spectroscopy. Lastly, although ultrasound has limitations for myocardial characterization, new high-resolution methods12 have recently been introduced. Because it is portable, cardiac ultrasound is ideally suited to use in interventional settings and/or surgery. Therefore, improvement in ultrasound methods for characterization of myocardial function and perfusion would be highly desirable.


*    Advancing Therapeutics Through Surgery and Devices
up arrowTop
up arrowIntroduction
up arrowUnderstanding Normal and...
up arrowAdvancing Imaging
*Advancing Therapeutics Through...
down arrowReferences
 

The aforementioned animal models of heart failure should allow assessment of surgical strategies like the surgical ventricular restoration technique,13 alone and in combination with valve repair or replacement. Improved imaging methods should allow visualization of "reverse remodeling" or "restoration" that might occur after these procedures. New operations may be developed to allow apposition of layers containing different fiber orientations, restoring a more natural scaffold of architectural form. Successful tissue bioengineering using stem cells, which tend to orient along normal fiber directions, might then produce an intact matrix of cardiomyocytes, angiogenesis, fibrous tissue, neural connections, and other focal components.
Human trials of surgical ventricular restoration should be accompanied by in-depth noninvasive studies of changes in geometry (by MRI and 3-dimensional echo) and fiber angle (by diffusion tensor MRI) and invasive (biopsy-derived) studies of changes in neurohormonal and cytokine levels, collagen dynamics (eg, c-propeptide and c-telopeptide assays), and alteration in transmembrane proteins and sarcoplasmic reticulum calcium dynamics.
Guided by advances in the understanding of shape and fiber dynamics, new devices that alter the synchronization of depolarization and repolarization should be developed and tested. In the long term, studies in which cultured Purkinje cells are introduced into hearts with seriously impaired intraventricular activation should be planned.

The panel agreed that much research has been done in this area, much of which has served to highlight the need for further understanding. Thus, many needs remain to be met. The area of cardiac imaging of structure and function at both the molecular and organ level to study their interaction was considered as a new frontier to be developed with a unique opportunity to use novel tools to study previously unexplored physiological and pathological states. It would also provide a clear benchmark for testing other technologies, now in the developmental stages, that could supplant current techniques in the near future, and will provide a firm foundation for developing new diagnostic and therapeutic strategies in cardiac disease states.

The working group developed these recommendations, which highlight a number of important and new areas for future research, to address these critical issues. Development of new ideas and directions within all 3 of the above areas will feed into and support each of the other 2. Accomplishing these goals will require a multidisciplinary collaboration of physiologists, biomedical engineers, clinicians, radiologists, and surgeons. In addition, these lines of research are sufficiently complicated to require the cooperation of both theorists and experimentalists; that is, we should encourage the development and validation of new and improved integrative computational models, which provide testable hypotheses concerning myocardial mechanics. Experiments involving genetic and molecular perturbations, or therapeutic interventions including surgery, would then provide tests of model predictions and also develop new parameters to insert into models so that realistic testing can evolve. New funding opportunities should encourage projects with a wide range of scopes, varying from individual grants to multidisciplinary collaborative programs. The highest priority in this endeavor should be to attain a more sophisticated understanding of the contributions of fiber and intracellular architecture to chamber function through the development of improved imaging methods and their creative application, and to investigate the application of these principles to human disease through surgery or other modalities.


*    Acknowledgments
 
We thank Aventis for their support.


*    References
up arrowTop
up arrowIntroduction
up arrowUnderstanding Normal and...
up arrowAdvancing Imaging
up arrowAdvancing Therapeutics Through...
*References
 
1. Rich MW. Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults. J Am Geriatr Soc. 1997; 45: 968–974.[Medline] [Order article via Infotrieve]

2. LeGrice IJ, Takayama Y, Covell JW. Transverse shear along myocardial cleavage planes provides a mechanism for normal systolic wall thickening. Circ Res. 1995; 77: 182–193.[Abstract/Free Full Text]

3. Torrent-Guasp F. La mecanica agonista-antagonista de los segmentos descendente y ascendente de la banda miocardica ventricular. Rev Esp Cardiol. 2001; 54: 1091–1102.[Medline] [Order article via Infotrieve]

4. Ogawa E, Saito Y, Harada M, Kamitani S, Kuwahara K, Miyamoto Y, Ishikawa M, Hamanaka I, Kajiyama N, Takahashi N, Nakagawa O, Masuda I, Kishimoto I, Nakao K. Outside-in signaling of fibronectin stimulates cardiomyocyte hypertrophy in cultured neonatal rat ventricular myocytes. J Mol Cell Cardiol. 2000; 32: 765–776.[CrossRef][Medline] [Order article via Infotrieve]

5. Dong SJ, Hees PS, Siu CO, Weiss JL, Shapiro EP. MRI assessment of LV relaxation by untwisting rate: a new isovolumic phase measure of tau. Am J Physiol Heart Circ Physiol. 2001; 281: H2002–H2009.[Abstract/Free Full Text]

6. Torrent-Guasp F, Kocica MJ, Corno A, Komeda M, Cox J, Flotats A, Ballester-Rodes M, Carreras-Costa F. Systolic ventricular filling. Eur J Cardiothorac Surg. 2004; 25: 376–386.[Abstract/Free Full Text]

7. Potter SM, Wang CM, Garrity PA, Fraser SE. Intravital imaging of green fluorescent protein using two-photon laser-scanning microscopy. Gene. 1996; 173: 25–31.[CrossRef][Medline] [Order article via Infotrieve]

8. Yang Z, French BA, Gilson WD, Ross AJ, Oshinski JN, Berr SS. Cine magnetic resonance imaging of myocardial ischemia and reperfusion in mice. Circulation. 2001; 103: e84.[Medline] [Order article via Infotrieve]

9. Tseng WY, Wedeen VJ, Reese TG, Smith RN, Halpern EF. Diffusion tensor MRI of myocardial fibers and sheets: correspondence with visible cut-face texture. J Magn Reson Imaging. 2003; 17: 31–42.[CrossRef][Medline] [Order article via Infotrieve]

10. Bulte JW, Douglas T, Witwer B, Zhang SC, Strable E, Lewis BK, Zywicke H, Miller B, van Gelderen P, Moskowitz BM, Duncan ID, Frank JA. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol. 2001; 19: 1141–1147.[CrossRef][Medline] [Order article via Infotrieve]

11. Louie AY, Huber MM, Ahrens ET, Rothbacher U, Moats R, Jacobs RE, Fraser SE, Meade TJ. In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotechnol. 2000; 18: 321–325.[CrossRef][Medline] [Order article via Infotrieve]

12. Aristizabal O, Christopher DA, Foster FS, Turnbull DH. 40-MHZ echocardiography scanner for cardiovascular assessment of mouse embryos. Ultrasound Med Biol. 1998; 24: 1407–1417.[CrossRef][Medline] [Order article via Infotrieve]

13. Athanasuleas CL, Stanley AW, Jr., Buckberg GD, Dor V, DiDonato M, Blackstone EH. Surgical anterior ventricular endocardial restoration (SAVER) in the dilated remodeled ventricle after anterior myocardial infarction. RESTORE group. Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical Shape to the LV. J Am Coll Cardiol. 2001; 37: 1199–1209.[Abstract/Free Full Text]


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This Article
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Right arrow Articles by Buckberg, G. D.
Right arrow Articles by Shapiro, E. P.
Related Collections
Right arrow Other Ethics and Policy
Right arrow Structure
Right arrow Contractile function
Right arrow Congestive
Right arrow Remodeling
Right arrow AHA Statements and Guidelines
Right arrow CT and MRI
Right arrow CV surgery: transplantation, ventricular assistance, cardiomyopathy
Right arrowRelated Article