Clin. Cardiol. 15, 141-142 (1992)
Editor‘s Note Ventricular Remodeling and Prognosis after Myocardial Infarction Prognosis after myocardial infarction relates to numerous factors. At the top of the list is left ventricular function.’ To determine the best assessment of prognosis based on left ventricular function, it is important to make sure that the ventricle is working under optimal conditions at the time of prognostication. Left ventricular dysfunction resulting from stunned or hibernating myocardium may have no relevance to prognosis. By definition, left ventricular function will improve over time in patients with stunned myocardium and, in patients with hibernating myocardium, left ventricular function improves if coronary perfusion can be increased.2 Thus, if one wants to use ventricular function as a prognostic indicator in the individual patient, efforts should be made to optimize hemodynamics in order to obtain the optimum assessment of ventricular performance. Another point to be made is that prognostication in the individual patient is not a single event occurring at one point in time but rather a continuous variable. Intuitively, one would expect a second myocardial infarction to result in a worsening of LV function and, as a result, a poorer prognosis could be predicted. Where does ventricular remodeling fit into all this? In recent years there have been numerous reports of “ventricular remodeling” in animals and in patients following an acute myocardial infarction. I sense there is some confusion about what is meant by the term “ventricular remodeling.” It certainly has been confused in my mind! The dictionary defines remodeling as follows: “to make over, to reshape, to refashion, or to redesign.” I like to think of remodeling of the ventricle as a change in ventricular geometry. But what does a change in ventricular geometry have to do with prognosis? When myocardial infarction or any form of injury to the heart occurs, there is compensatory cardiac growth which is referred to pathologically as hypertrophy.3This is a complex response which includes an increase in adult muscle proteins. It is also associated with a re-expression of genes that are active during the embryonic and fetal stages but which have long since been suppressed. Studies of ventricles in intact animals, hypertrophied as a result of pressure overload, reveal an expression of several protoncogenesthat clearly qualify as growth factors and may play a role in growth response! ffeffer writes that long-term therapy with ACE inhibitors can attenuate ventricular enlargement and improve survival in animals recovering from experimental myocardial infarcti~n.~ In these experiments an angiotensin-converting enzyme inhibitor was administered 14 days after the experimental coronary artery ligation. Thus, the improved survival in the animals recovering from experimental myocardial infarction suggests that the beneficial effect is the result of preserving ventricular geometry and performance rather than of limiting infarction size. He writes further that the observations reported are highly suggestive that the improved outcome following myocardial infarction by treatment with ACE inhibitors is a result of decreasing ventricular enlargement and dysfunction of the ventricle. Clinically, remodeling of the myocardium after a myocardial infarction consists of left ventricular wall thinning which is probably due to cell slippage in the infarction area, ventricular chamber dilatation, and a compensatory hypertrophy of the uninfarcted portion of the myocardium> Thinning and chamber dilatation occur within 24 hours of the infarction and, initially, may be a physiologic change to maintain the pump function of the heart. If the infarction is large-for example, an anterior myocardial infarction-increased work of the noninfarcted area can change the physiologic process to a pathologic process resulting in further thinning and dilating of the infarcted zone. Left ventricular wall thinning can be recognized easily by echocardiographyas a lengthening of the noncontractile region of the infarction. In contrast, the area that has not been infarcted will undergo some lengthening that would be consistent with the volume overload. This volume overload may be static, but in many instances may be progressive. All of these
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changes can be influenced by the size of the myocardial infarction, the rate of healing of the myocardial infarction, and the stress put upon the ventricular wall.7 Drugs such as nitroglycerin may attenuate infarction expansion and thus influence prognosis. Jugdutt and colleagues were able to show that prolonged nitroglycerin therapy decreased infarct expansion and infarct thinning and demonstrated improved hemodynamics, decreased LV volume and asynergy, and increased ejection fraction compared with the effect of placebo.8 Similarly, angiotensin-converting enzyme inhibitors can alter the hemodynamics of the left ventricle and slow down or prevent ventricular enlargement. Conversely, drugs that increase afterload or slow healing will have the opposite effect. Perhaps the best way to prevent pathologic ventricular remodeling is to limit the infarction size by the early use of thrombolytic agents in combination with beta adrenergic receptor blockers, nitrates, and ACE inhibitors. The use of thrombolytic agents in the treatment of acute myocardial infarction may have a beneficial effect related to reduction of myocardial expansion and increase in ventricular volume, and thus exert a significant positive effect because of this influence on left ventricular remodeling. Although early reperfusion of infarcting myocardium seems the best way to preserve ventricular function, some evidence exists that suggests that late reperfusion may also limit infarct expansion and slow down or prevent pathologic ventricular expansion and remodeling in the post-infarction patient? Thus, thrombolytic therapy, open coronary arteries, and adjunctive drug therapy may prevent or at least modify the abnormal remodeling of ventricular myocardium in the post-infarction patient. C. Richard Conti, M.D. Editor-in-Chief
References 1. Kostuk WJ, Kazamias TM, Gander MP, Simon AL, Ross J: Left ventricular size after acute myocardial infarction: Serial changes and their prognostic significance. Circulation 47, 1174-1179 (1973) 2. Conti CR: The stunned and hibernating myocardium: A brief review. Clin Cuniiol 14,708-712 (1991) 3. Mares A, Towbin J, Bies RD, Roberts R: Molecular biology for the cardiologist. Curr Prob Curdiol 12(1), 21-22 (1992) 4. Muluagh SL, Michael LH, Perryman MB, Roberts R Hernodynamic load in in vivo induces cardiac expression of the cellular oncogene, c-myc. Biochem Siophys Res Comm 147,627-636 (1987) 5. Pfeffer MA: ACE inhibitors and ventricular remodeling following myocardial infarction. Choices in Cardio/6(suppl I), 4-6 (1991) 6. Firth BG,Dunnmon PM: Left ventricular dilatation and failure post-myocardial infarction: Pathophysiology and possible pharmacologic interventions. Curdiovasc Drugs and Ther 4(5), 1263-1274 (1990) 7. Pfeffer MA, Braunwald E: Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81(4), 1161-1172 (1990) 8. Jugdutt BI, Michorowski BL, Tymchak WJ: Improved left ventricular function and topography by prolonged nitroglycerin therapy after acute myocardial infarction. Z Kardiol78(suppl2), 127-129; 142-144 (1989) 9. Bonaduce D, Petretta M, Villara B, Breglio R, Conforti G, Montemurro MV, Lanzillo T, Morgano G Effects of late administration of tissue-type plasminogen activator on left ventricular remodeling and function after myocardial infarction. J Am Coll Curdiol 16(7), 1561-1568 ( 1990)
Editor‘s Note Ventricular Remodeling and Prognosis after Myocardial Infarction Prognosis after myocardial infarction relates to numerous factors. At the top of the list is left ventricular function.’ To determine the best assessment of prognosis based on left ventricular function, it is important to make sure that the ventricle is working under optimal conditions at the time of prognostication. Left ventricular dysfunction resulting from stunned or hibernating myocardium may have no relevance to prognosis. By definition, left ventricular function will improve over time in patients with stunned myocardium and, in patients with hibernating myocardium, left ventricular function improves if coronary perfusion can be increased.2 Thus, if one wants to use ventricular function as a prognostic indicator in the individual patient, efforts should be made to optimize hemodynamics in order to obtain the optimum assessment of ventricular performance. Another point to be made is that prognostication in the individual patient is not a single event occurring at one point in time but rather a continuous variable. Intuitively, one would expect a second myocardial infarction to result in a worsening of LV function and, as a result, a poorer prognosis could be predicted. Where does ventricular remodeling fit into all this? In recent years there have been numerous reports of “ventricular remodeling” in animals and in patients following an acute myocardial infarction. I sense there is some confusion about what is meant by the term “ventricular remodeling.” It certainly has been confused in my mind! The dictionary defines remodeling as follows: “to make over, to reshape, to refashion, or to redesign.” I like to think of remodeling of the ventricle as a change in ventricular geometry. But what does a change in ventricular geometry have to do with prognosis? When myocardial infarction or any form of injury to the heart occurs, there is compensatory cardiac growth which is referred to pathologically as hypertrophy.3This is a complex response which includes an increase in adult muscle proteins. It is also associated with a re-expression of genes that are active during the embryonic and fetal stages but which have long since been suppressed. Studies of ventricles in intact animals, hypertrophied as a result of pressure overload, reveal an expression of several protoncogenesthat clearly qualify as growth factors and may play a role in growth response! ffeffer writes that long-term therapy with ACE inhibitors can attenuate ventricular enlargement and improve survival in animals recovering from experimental myocardial infarcti~n.~ In these experiments an angiotensin-converting enzyme inhibitor was administered 14 days after the experimental coronary artery ligation. Thus, the improved survival in the animals recovering from experimental myocardial infarction suggests that the beneficial effect is the result of preserving ventricular geometry and performance rather than of limiting infarction size. He writes further that the observations reported are highly suggestive that the improved outcome following myocardial infarction by treatment with ACE inhibitors is a result of decreasing ventricular enlargement and dysfunction of the ventricle. Clinically, remodeling of the myocardium after a myocardial infarction consists of left ventricular wall thinning which is probably due to cell slippage in the infarction area, ventricular chamber dilatation, and a compensatory hypertrophy of the uninfarcted portion of the myocardium> Thinning and chamber dilatation occur within 24 hours of the infarction and, initially, may be a physiologic change to maintain the pump function of the heart. If the infarction is large-for example, an anterior myocardial infarction-increased work of the noninfarcted area can change the physiologic process to a pathologic process resulting in further thinning and dilating of the infarcted zone. Left ventricular wall thinning can be recognized easily by echocardiographyas a lengthening of the noncontractile region of the infarction. In contrast, the area that has not been infarcted will undergo some lengthening that would be consistent with the volume overload. This volume overload may be static, but in many instances may be progressive. All of these
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changes can be influenced by the size of the myocardial infarction, the rate of healing of the myocardial infarction, and the stress put upon the ventricular wall.7 Drugs such as nitroglycerin may attenuate infarction expansion and thus influence prognosis. Jugdutt and colleagues were able to show that prolonged nitroglycerin therapy decreased infarct expansion and infarct thinning and demonstrated improved hemodynamics, decreased LV volume and asynergy, and increased ejection fraction compared with the effect of placebo.8 Similarly, angiotensin-converting enzyme inhibitors can alter the hemodynamics of the left ventricle and slow down or prevent ventricular enlargement. Conversely, drugs that increase afterload or slow healing will have the opposite effect. Perhaps the best way to prevent pathologic ventricular remodeling is to limit the infarction size by the early use of thrombolytic agents in combination with beta adrenergic receptor blockers, nitrates, and ACE inhibitors. The use of thrombolytic agents in the treatment of acute myocardial infarction may have a beneficial effect related to reduction of myocardial expansion and increase in ventricular volume, and thus exert a significant positive effect because of this influence on left ventricular remodeling. Although early reperfusion of infarcting myocardium seems the best way to preserve ventricular function, some evidence exists that suggests that late reperfusion may also limit infarct expansion and slow down or prevent pathologic ventricular expansion and remodeling in the post-infarction patient? Thus, thrombolytic therapy, open coronary arteries, and adjunctive drug therapy may prevent or at least modify the abnormal remodeling of ventricular myocardium in the post-infarction patient. C. Richard Conti, M.D. Editor-in-Chief
References 1. Kostuk WJ, Kazamias TM, Gander MP, Simon AL, Ross J: Left ventricular size after acute myocardial infarction: Serial changes and their prognostic significance. Circulation 47, 1174-1179 (1973) 2. Conti CR: The stunned and hibernating myocardium: A brief review. Clin Cuniiol 14,708-712 (1991) 3. Mares A, Towbin J, Bies RD, Roberts R: Molecular biology for the cardiologist. Curr Prob Curdiol 12(1), 21-22 (1992) 4. Muluagh SL, Michael LH, Perryman MB, Roberts R Hernodynamic load in in vivo induces cardiac expression of the cellular oncogene, c-myc. Biochem Siophys Res Comm 147,627-636 (1987) 5. Pfeffer MA: ACE inhibitors and ventricular remodeling following myocardial infarction. Choices in Cardio/6(suppl I), 4-6 (1991) 6. Firth BG,Dunnmon PM: Left ventricular dilatation and failure post-myocardial infarction: Pathophysiology and possible pharmacologic interventions. Curdiovasc Drugs and Ther 4(5), 1263-1274 (1990) 7. Pfeffer MA, Braunwald E: Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81(4), 1161-1172 (1990) 8. Jugdutt BI, Michorowski BL, Tymchak WJ: Improved left ventricular function and topography by prolonged nitroglycerin therapy after acute myocardial infarction. Z Kardiol78(suppl2), 127-129; 142-144 (1989) 9. Bonaduce D, Petretta M, Villara B, Breglio R, Conforti G, Montemurro MV, Lanzillo T, Morgano G Effects of late administration of tissue-type plasminogen activator on left ventricular remodeling and function after myocardial infarction. J Am Coll Curdiol 16(7), 1561-1568 ( 1990)
