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The past as prologue
EDITORIAL The past as prologue Timothy F. Christian, MD
See related article on p. 644 For such as we are made of, such we be William Shakespeare, Twelfth Night, Act 2, Scene 2 Left ventricular (LV) remodeling after reperfused myocardial infarction (MI) is complex, multifactorial, and variable, but it can be simplified into 2 main processes. The large loss in myocyte contractility generates a cycle of ventricular dilatation and compensatory noninfarct zone hypertrophy with subsequent increases in wall tension, which appear to respond to alterations in hemodynamics. The second process is the changes now known to occur in the extracellular matrix from activation of metalloproteinases and collagen turnover, which decrease wall tensile strength and promote LV dilation.1 Markers of matrix activity have been shown to correlate with progressive LV dilation after MI.2 One such marker is carboxy-terminal telopeptide of type I procollagen (ICTP), which is associated with collagen degradation. Brain natriuretic peptide (BNP) is released from stretch receptors within the atria and ventricles, causing a net excretion of serum sodium. Consequently, it has gained acceptance as a marker for the failing heart. Because there is no evolutionary land-based advantage to waste sodium for survival to reproduction (all systems have evolved to avidly retain volume during blood loss), this is likely a vestigial endocrine system from a time when life was ocean based and sodium balance fluctuated with changes in salinity.3 BNP levels are high during fetal gestation within the amniotic fluid but become negligible after birth, only to reappear later in life for those in whom cardiac pathology develops. BNP levels are dynamic in patients with LV remodeling, with peak values seen in the days after the index infarct—presumably on the basis of increased wall tension and stretch. The study by Cerisano et al4 in this issue of the Journal suggests that BNP may not be just an observer during postinfarction LV remodeling but may be an active particFrom the College of Medicine, University of Vermont, Burlington, Vt. Reprint requests: Timothy F. Christian, MD, College of Medicine, University of Vermont, Baird 191, MCHV, 111 Colchester Ave, Burlington, VT 05401; [email protected]. J Nucl Cardiol 2008;15:613-4. 1071-3581/$34.00 Copyright © 2008 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2008.07.003
ipant in the process. They divide a cohort with acute MI and severe LV dysfunction into 2 groups based on plasma BNP levels on the third day after MI. Despite similar infarct size measures by single photon emission computed tomography techniques and LV function at baseline, only patients with elevated BNP levels at day 3 went on to have LV dilatation develop over the ensuing month. After the authors controlled for infarct size and LV wall tension, BNP was an independent predictor of subsequent LV dilation. They make a second important observation: there is an interaction between BNP and the collagen marker ICTP on subsequent LV dilation. Interaction terms are uncommon in clinical articles and can be confusing. They show that given variables a and b impact on dependent variable c independently but, when considered together (a ⫻ b), have another independent effect. Flower color and sunshine may be independent predictors of honey production, but considered together, they produce a stronger impact on production than either alone (presumably as the bee can distinguish flower types better in strong light). In the current study LV dilation is most marked in the setting of sustained BNP release and elevated ICTP levels. This suggests a cyclical interplay between collagen degradation and LV stretch. There are certainly issues that can be raised regarding the results. Collagen degradation is widespread in the body, and so, targeted cardiac molecular imaging will be necessary to localize the source of ICTP. The authors do not perform the complete analysis of determining whether the interaction term between BNP and ICTP is an independent predictor of ventricular dilation but do show that it is at least a univariate predictor. The relationship between infarct size by single photon emission computed tomography and subsequent LV volume changes has been much closer in prior studies using higher-resolution techniques,5 which may reflect the lower reproducibility of cardiac volumes by 2-dimensional echocardiography.6 The cohort with elevated BNP levels appears to be an overall sicker group in this study, with trends for larger and more severe infarcts and LV volumes at baseline, double the prevalence of diabetes and multivessel disease, and a significantly lower post-MI LV ejection fraction. Because this is a small post-MI cohort of 34 patients, it is possible that, with a larger sample size, most of these variables would reflect significant differences at baseline and also impact the multivariate analysis. Still, as a small-sample study, the results are provocative. The interaction of BNP and ICTP draws together the 2 paradigms of remodeling in a single study. ICTP elevation 613
614
Christian The past as prologue
only occurred in the presence of sustained BNP release, suggesting a cause-and-effect relationship. Because the amount of myocardial damage was similar between groups, the elevated BNP levels, presumably from increased wall tension, may trigger a change in extracellular matrix collagen degradation and a consequent weakening of the tensile strength of the myocardial wall in the infarct zone. Like Viola in Twelfth Night, BNP may be an active agent in disguise. But if the damage is similar, why do some patients produce sustained BNP levels whereas others do not? The authors suggest that the risk area was larger for these patients but have no measure of it. Perhaps it reflects the extent of the development (or lack of evolutionary regression) of the BNP system in individual patients. Perhaps it is a function of the underlying collagen formation in individuals that predisposes them to increased wall tension. The answer is uncertain, but it is likely a combination of factors, including that tiny proportion of the ocean that we still carry within us from the past, such as we are made of. Acknowledgment The author has indicated he has no financial conflicts of interest.
Journal of Nuclear Cardiology September/October 2008
References 1. Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough? Circulation 2003;108:1395-403. 2. Radovan J, Vaclav P, Petr W, Jan C, Michal A, Richard P, et al. Changes of collagen metabolism predict the left ventricular remodeling after myocardial infarction. Mol Cell Biochem 2006; 293:71-8. 3. Inoue K, Naruse K, Yamagami S, Mitani H, Suzuki N, Takei Y. Four functionally distinct C-type natriuretic peptides found in fish reveal evolutionary history of the natriuretic peptide system. Proc Natl Acad Sci U S A 2003;100:10079-84. 4. Cerisano G, Valenti R, Sciagrà R, Pucci PD, Tommasi M, Raspanti S, et al. Relationship of sustained brain natriuretic peptide release after reperfused acute myocardial infarction with gated SPECT infarct measurements and its connection with collagen turnover and left ventricular remodeling. J Nucl Cardiol 2008;15:644-54. 5. Chareonthaitawee P, Christian TF, Hirose K, Gibbons RJ, Rumberger JA. Relation of initial infarct size with the extent of left ventricular remodeling in the year after acute myocardial infarction. J Am Coll Cardiol 1995;25:567-73. 6. Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000;2:271-8.
See related article on p. 644 For such as we are made of, such we be William Shakespeare, Twelfth Night, Act 2, Scene 2 Left ventricular (LV) remodeling after reperfused myocardial infarction (MI) is complex, multifactorial, and variable, but it can be simplified into 2 main processes. The large loss in myocyte contractility generates a cycle of ventricular dilatation and compensatory noninfarct zone hypertrophy with subsequent increases in wall tension, which appear to respond to alterations in hemodynamics. The second process is the changes now known to occur in the extracellular matrix from activation of metalloproteinases and collagen turnover, which decrease wall tensile strength and promote LV dilation.1 Markers of matrix activity have been shown to correlate with progressive LV dilation after MI.2 One such marker is carboxy-terminal telopeptide of type I procollagen (ICTP), which is associated with collagen degradation. Brain natriuretic peptide (BNP) is released from stretch receptors within the atria and ventricles, causing a net excretion of serum sodium. Consequently, it has gained acceptance as a marker for the failing heart. Because there is no evolutionary land-based advantage to waste sodium for survival to reproduction (all systems have evolved to avidly retain volume during blood loss), this is likely a vestigial endocrine system from a time when life was ocean based and sodium balance fluctuated with changes in salinity.3 BNP levels are high during fetal gestation within the amniotic fluid but become negligible after birth, only to reappear later in life for those in whom cardiac pathology develops. BNP levels are dynamic in patients with LV remodeling, with peak values seen in the days after the index infarct—presumably on the basis of increased wall tension and stretch. The study by Cerisano et al4 in this issue of the Journal suggests that BNP may not be just an observer during postinfarction LV remodeling but may be an active particFrom the College of Medicine, University of Vermont, Burlington, Vt. Reprint requests: Timothy F. Christian, MD, College of Medicine, University of Vermont, Baird 191, MCHV, 111 Colchester Ave, Burlington, VT 05401; [email protected]. J Nucl Cardiol 2008;15:613-4. 1071-3581/$34.00 Copyright © 2008 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2008.07.003
ipant in the process. They divide a cohort with acute MI and severe LV dysfunction into 2 groups based on plasma BNP levels on the third day after MI. Despite similar infarct size measures by single photon emission computed tomography techniques and LV function at baseline, only patients with elevated BNP levels at day 3 went on to have LV dilatation develop over the ensuing month. After the authors controlled for infarct size and LV wall tension, BNP was an independent predictor of subsequent LV dilation. They make a second important observation: there is an interaction between BNP and the collagen marker ICTP on subsequent LV dilation. Interaction terms are uncommon in clinical articles and can be confusing. They show that given variables a and b impact on dependent variable c independently but, when considered together (a ⫻ b), have another independent effect. Flower color and sunshine may be independent predictors of honey production, but considered together, they produce a stronger impact on production than either alone (presumably as the bee can distinguish flower types better in strong light). In the current study LV dilation is most marked in the setting of sustained BNP release and elevated ICTP levels. This suggests a cyclical interplay between collagen degradation and LV stretch. There are certainly issues that can be raised regarding the results. Collagen degradation is widespread in the body, and so, targeted cardiac molecular imaging will be necessary to localize the source of ICTP. The authors do not perform the complete analysis of determining whether the interaction term between BNP and ICTP is an independent predictor of ventricular dilation but do show that it is at least a univariate predictor. The relationship between infarct size by single photon emission computed tomography and subsequent LV volume changes has been much closer in prior studies using higher-resolution techniques,5 which may reflect the lower reproducibility of cardiac volumes by 2-dimensional echocardiography.6 The cohort with elevated BNP levels appears to be an overall sicker group in this study, with trends for larger and more severe infarcts and LV volumes at baseline, double the prevalence of diabetes and multivessel disease, and a significantly lower post-MI LV ejection fraction. Because this is a small post-MI cohort of 34 patients, it is possible that, with a larger sample size, most of these variables would reflect significant differences at baseline and also impact the multivariate analysis. Still, as a small-sample study, the results are provocative. The interaction of BNP and ICTP draws together the 2 paradigms of remodeling in a single study. ICTP elevation 613
614
Christian The past as prologue
only occurred in the presence of sustained BNP release, suggesting a cause-and-effect relationship. Because the amount of myocardial damage was similar between groups, the elevated BNP levels, presumably from increased wall tension, may trigger a change in extracellular matrix collagen degradation and a consequent weakening of the tensile strength of the myocardial wall in the infarct zone. Like Viola in Twelfth Night, BNP may be an active agent in disguise. But if the damage is similar, why do some patients produce sustained BNP levels whereas others do not? The authors suggest that the risk area was larger for these patients but have no measure of it. Perhaps it reflects the extent of the development (or lack of evolutionary regression) of the BNP system in individual patients. Perhaps it is a function of the underlying collagen formation in individuals that predisposes them to increased wall tension. The answer is uncertain, but it is likely a combination of factors, including that tiny proportion of the ocean that we still carry within us from the past, such as we are made of. Acknowledgment The author has indicated he has no financial conflicts of interest.
Journal of Nuclear Cardiology September/October 2008
References 1. Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough? Circulation 2003;108:1395-403. 2. Radovan J, Vaclav P, Petr W, Jan C, Michal A, Richard P, et al. Changes of collagen metabolism predict the left ventricular remodeling after myocardial infarction. Mol Cell Biochem 2006; 293:71-8. 3. Inoue K, Naruse K, Yamagami S, Mitani H, Suzuki N, Takei Y. Four functionally distinct C-type natriuretic peptides found in fish reveal evolutionary history of the natriuretic peptide system. Proc Natl Acad Sci U S A 2003;100:10079-84. 4. Cerisano G, Valenti R, Sciagrà R, Pucci PD, Tommasi M, Raspanti S, et al. Relationship of sustained brain natriuretic peptide release after reperfused acute myocardial infarction with gated SPECT infarct measurements and its connection with collagen turnover and left ventricular remodeling. J Nucl Cardiol 2008;15:644-54. 5. Chareonthaitawee P, Christian TF, Hirose K, Gibbons RJ, Rumberger JA. Relation of initial infarct size with the extent of left ventricular remodeling in the year after acute myocardial infarction. J Am Coll Cardiol 1995;25:567-73. 6. Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000;2:271-8.