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Cardiovascular I - Acute Ischemic Coronary Syndromes

 

Background

The pathology of acute ischemia is typically related to plaque instability, thrombus formation, and coronary flow obstruction resulting in myocardial damage.  The intervention is targeted to restore patency, whether through use of thrombolytic agents or direct revascularization.  The relevant biomarker would be related to a patency and/or perfusion assessment.  Patency can be assessed directly by angiography or indirectly by perfusion techniques.

 

Moderators:   Victor Dzau, M.D., Brigham and Women’s Hospital

                        Judith Hochman, M.D., Columbia University College of Physicians and Surgeons

 

Agenda

 

Targeted Topics: Acute Myocardial Infarction, Acute Heart Failure, Unstable Angina

Clinical Trials Challenges

David L. DeMets, Ph.D., University of Wisconsin, Madison

Angiography

David O. Williams, M.D., Brown University and Rhode Island Hospital

Jeffrey Popma, M.D., Brigham and Women’s Hospital

Myocardial Imaging

Frans Wackers, M.D., Yale School of Medicine

Pamela S. Douglas, M.D., Beth Israel Hospital  

Myocardial Viability

Nathaniel Reichek, M.D., Medical College of Pennsylvania and MCP Hahnemann University

Robert Bonow, M.D., Northwestern University Medical School

Plaque

Ward Casscells, M.D., University of Texas Medical School and Hermann Hospital

Zahi Fayed, Ph.D., Mount Sinai School of Medicine

 

Markers: ECG Serum

Bernard R. Chaitman, M.D., St. Louis University Medical Center

Allan Jaffe, M.D., State University of New York Health Sciences Center, Syracuse

Discussant:            Robert R. Fenichel, M.D., Ph.D., Center for Drug Evaluation and Research, U.S. Food and Drug Administration

 

ABSTRACTS

Atherosclerotic Plaque Imaging by Magnetic Resonance Imaging

Zahi A. Fayad, Ph.D., and Valentin Fuster, M.D., Ph.D.

There has been increasing focus on the importance of the composition of atherosclerotic plaque, rather than the degree of luminal narrowing, as the major risk factor for acute coronary syndromes.  However, current imaging modalities are limited at evaluating the wall and characterization of the plaque.  Magnetic resonance imaging (MRI) methods are currently being employed to noninvasively characterize the arterial wall and the "vulnerable" atherosclerotic plaque in vivo.  We are using in vivo MRI to characterize carotid arteries and aortic plaques in patients.  New techniques for coronary artery wall imaging and plaque characterization are being tested.   These techniques also have been adapted for the study of plaques in different animal models.  For example, we have recently demonstrated that MRI can characterize plaques in apolioprotein E knockout mice using in vivo magnetic resonance microscopy.  We can follow in vivo progression, regression, and plaque stabilization in these animal models.  These methods will allow the study of the pathogenesis of atherosclerotic plaques, as well as the influence of genetics or drugs on plaque development.  In patients, successful application of these methods should allow the early identification of the "vulnerable" plaques.  This opens up whole new areas for diagnosis, prevention, and treatment (e.g., lipid-lowering drug regimens).

 

Key References

Fayad ZA, Fallon JT, Shinnar M, Wehrli S, Dansky HM, Poon M, Badimon JJ, Charlton SA, Fisher EA, Breslow JL, Fuster V. Noninvasive in vivo high-resolution magnetic resonance imaging of atherosclerotic lesions in genetically engineered mice. Circulation 1998;98:1541‑1547.

Fayad ZA, Tamana N, Badimon JJ, Goldman M, Weinberger J, Fallon JT, Aguinaldo G, Shinnar M, Chesebro JH, Fuster V. Circulation 1998;98;1‑515.

Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326:242‑250 (part 1) and 310‑318 (part 2).

Fuster V, Fallon JT, Badimon JJ, Nemerson Y. The unstable atherosclerotic plaque: clinical significance and therapeutic intervention. Thrombosis Haemostasis 1997; 78:247‑255.

Shinnar M, Fayad ZA, Fallon JT, Fuster V. in Fuster V., eds. The Vulnerable Atherosclerotic Plaque: Understanding, Idenfication, and Modification, Armonk, NY: Futura Publishing, 1999, pp.155‑162.

Toussaint JF, LaMuraglia GM, Southern JF, Fuster V, Kantor HL. Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo. Circulation 1996;94:932‑938.

Vallabahajosula S, Fuster VJ. Nucl Med 1997;38:1788‑1796.

Myocardial Viability

Nathaniel Reichek, M.D.

A variety of potential cardiac imaging biomarkers are available for assessment of myocardial viability in acute and chronic ischemic heart disease.  These include positron emission tomography for assessment of myocardial perfusion and metabolism; single photon emission computerized tomography imaging using thallium 201; and dobutamine wall motion studies using echocardiography, magnetic resonance imaging, or computerized tomography.  Additional candidate approaches include contrast echocardiography, proton MRI contrast imaging and tissue tagging, 31P NMR spectroscopy, sodium MRI, and proton MRI to detect myocardial production of O17 water.  However, none of these approaches permits rigorous quantitation of the amount of viable myocardium routinely in humans.  Lack of reliable transmural resolution of necrotic versus viable myocardium is a particular problem.  Although the general relationship between salvage of myocardium and clinical outcomes is well described, no simple algorithms exist to permit quantitative extrapolation from any viability biomarkers to affect clinical outcome.  It is also unclear in acute myocardial infarction whether the characteristics and outcome of viable myocardium generated by various reperfusion strategies are similar or different.  Finally, the ultimate fate of viable myocardium is also determined by vascular outcomes that cannot be assessed by viability biomarkers, such as thrombotic reocclusion, restenosis, and bypass graft closure.

 

Key References

Baumgartner H, Porenta G, Lau YK, Wutte M, Klaar U, Mehrabi M, Siegel RJ, Czernin J, Laufer G, Sochor H, Schelbert H, Fishbein MC, Maurer G. Assessment of myocardial viability by dobutamine echocardiography, positron emission tomography and thallium‑201 SPECT: Correlation with histopathology in explanted hearts. J Am Coll Cardiol 1998 Nov15;32(6):1701‑1708.

Beller GA, Ragosta M. Extent of myocardial viability in regions of left ventricular dysfunction by rest‑redistribution thallium‑201 imaging: A powerful predictor of outcome. J Nucl Cardiol 1998;5:445‑448.

Bonow RO. Identification of viable myocardium. Circulation 1996;94:2674‑2680.

Geskin G, Kramer CM, Rogers WJ, Theobald TM, Pakstis D, Hu Y‑L, Reichek N. Quantitative assessment of myocardial viability post‑infarction by dobutamine magnetic resonance tagging. Circulation 1998;98:217‑223.

Grandin C, Wijns W, Melin JA, Bol A, Robert AR, Heyndrickx GR, Michel C, Vanoverschelde JL. Delineation of myocardial viability with PET. J Nucl Med 1995;36:1543‑1552.

Kloner RA, Bolli R, Marban E, Reinlib L, Braunwald E. Medical and cellular implications of stunning, hibernation and preconditioning. An NHLBI Workshop. Circulation 1998;97:1848‑1867.

Rogers WJ, Kramer CM, Geskin G, Hu YL, Theobald TM, Vido DA, Petruolo S, Reichek N. Early contrast‑enhanced MRI predicts late functional recovery after reperfused myocardial infarction. Circulation 1999;99:744‑751.

Smart SC, Sawada S, Ryan T, Segar D, Atherton L, Berkovitz K, Bourdillon PDV, Feigenbaum H. Low‑dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation 1993;88:405‑415.

Tillisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern M, Phelps M, Schelbert H. Reversibility of cardiac wall‑motion abnormalities predicted by positron tomography. N Engl J Med 1986;314:884.

 

Echocardiography in Acute Coronary Syndromes

Pamela S. Douglas, M.D.

Cardiac echocardiography is an important part of the management of acute coronary syndromes, and much research has gone into identifying prognostic features.  Echocardiography is therefore a useful tool in risk stratification, with high‑quality research indicating excess mortality in patients with lower global left ventricular function (ejection fraction), more extensive regional abnormalities, moderate or severe mitral valve regurgitation and acute left ventricular dilation, and longer term remodeling.  Unfortunately, such studies have wide confidence intervals; few analyses have been done to determine the predictive power of these variables for cardiac events or death; and no studies have yet demonstrated causal relationships between echocardiographic findings and subsequent events.  A promising echocardiographic tool, myocardial perfusion assessment by the use of intravenous microbubble injection, is currently in development.  Only one multicenter assessment of test performance has been reported, indicating poor sensitivity for segmental perfusion defects (compared with single photon emission computerized tomography sestamibi), with reasonable specificity.  This technique is not yet sufficiently refined to replace angiography in determining coronary patency.

 

Key References

DeMaria AN, Cotter B, Ohmori K. Myocardial contrast echocardiography: Too much, too soon? (editorial) J Am Coll Cardiol 1998;32(5):1270‑1271.

Lehmann KG, Francis CK, Dodge HT. Mitral regurgitation in early myocardial infarction. Incidence, clinical detection, and prognostic implications. TIMI Study Group. Ann Intern Med 1992;117(1):10‑17.

Marwick TH, Brunken R, Meland N, Brochet E, Baer FM, Binder T, Flachskampf F, Kamp O, Nienaber C, Nihoyannopoulos P, Pierard L, Vanoverschelde JL, van der Wouw P, Lindvall K. Accuracy and feasibility of contrast echocardiography for detection of perfusion defects in routine practice: Comparison with wall motion and technetium‑99m sestamibi single‑photon emission computed tomography. The Nycomed NC100100 Investigators. J Am Coll Cardiol 1998;32(5):1260‑1269.

Popovic AD, Neskovic AN, Marinkovic J, Thomas JD. Acute and long‑term effects of thrombolysis after anterior wall acute myocardial infarction with serial assessment of infarct expansion and late ventricular remodeling. Am J Cardiol 1996;77(7):446‑450.

St. John Sutton M, Pfeffer MA, Plappert T, Rouleau JL, Moye LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, et al. Quantitative two‑dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation 1994;89(1):68‑75.

Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G. Determinants of 6‑month mortality in survivors of myocardial infarction after thrombolysis. Results of the GISSI‑2 data base. The Ad hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)‑2 Data Base. Circulation 1993;88(2):416‑429.  

Acute Ischemic Coronary Syndromes:  Electrocardiogram

Bernard R. Chaitman, M.D. and Allan S. Jaffe, M.D.

In clinical trials, sample size can be reduced by identifying high‑risk patient subsets at entry.  The magnitude of risk can be related to clinical characteristics and the extent of electrocardiographic (ECG) abnormalities.  Novel lead configurations, more frequent ECG acquisition, and use of selected coding criteria have the potential to further enhance identification.  Definitions of Q or non‑Q wave myocardial infarction vary considerably in trials of acute coronary syndrome (ACS).  Cardiac serum markers (i.e., serial CK‑MB and cardiac troponins) identify the presence of myocyte injury.  Appropriate cutpoints for the definition of myocardial infarction have become problematic of late with the advent of more sensitive markers, especially in patients with heart failure and hypertension and those after interventional and cardiac surgical procedures.  Sampling frequency, the type of assay used, missing samples, and determination of myocardial infarction represent challenges to clinical trial design.  Estimates of myocardial infarction size have been considered as a surrogate endpoint for mortality, enhancing the specificity of this composite endpoint, but have become more problematic in the area of recanalization.  Myocardial infarction definitions in clinical trials of ACS will undoubtedly represent tradeoffs between sensitivity versus specificity.  Standardized definitions should be used for reporting purposes and comparability among studies.