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Diagnostic and therapeutic implications in post–myocardial infarct patients with raised brain natriuretic peptide levels
Correspondence [2] Akpinar H, Kural AR, Tufek I, et al. Spontaneous ureteral rupture: is immediate surgical intervention always necessary? Presentation of four cases and review of the literature. J Endourol 2002;16:179-83. [3] Cooke GM, Bartucz JP. Spontaneous extravasation of contrast medium during intravenous urography: report of fourteen cases and a review of the literature. Clin Radiol 1974;25:87-93. [4] Diamond DA, Marshall FF. The diagnosis and management of spontaneous rupture of the ureter. J Urol 1982;128:808-10.
Diagnostic and therapeutic implications in post– myocardial infarct patients with raised brain natriuretic peptide levels To the Editor, Despite the fact that survivors of ST-segment elevation myocardial infarct with diastolic dysfunction had significantly (P = .01) higher median levels of brain natriuretic peptide (BNP), compared with counterparts without diastolic dysfunction, subjects with BNP greater than 500 pg/mL, nevertheless had significantly (P = .003) lower left ventricular ejection fraction (LVEF; mean value 37%) than counterparts with BNP less than 500 pg/mL (in whom the mean value was 48%) [1]. This was probably a reflection of the fact that in some post–myocardial infarction (post-MI) subjects, exemplified, in one study, by a subgroup of 18 subjects with mean LVEF as low as 36.9%, severe left ventricular diastolic dysfunction may coexist with systolic dysfunction and, hence, subnormal LVEF [2]. That this should be the case is consistent with the observation that in the animal model of post-MI, survival myocardial fibrosis in the noninfarcted region is the histologic correlate of systolic as well as diastolic dysfunction [3]. Even in the early stages of post-MI heart failure [4], despite background prevalence of 78.8% for hypertension (a recognized risk factor for diastolic dysfunction) [5] and background prevalence of 49.6% for diabetes mellitus (also a risk factor for diastolic dysfunction) [6], mean LVEF may be as low as 39.11% [4], again probably reflecting the fact that LVEF may not be truly representative of the coexistence of diastolic dysfunction and its severity in subjects with subnormal LVEF. In the latter study, despite early initiation of angiotensin-converting enzyme (ACE) inhibitor therapy, there was only a modest (P b .05) “protective short term effect on mortality” [4], which, arguably, might have been considerably enhanced, had an aldosterone antagonist been coprescribed with the ACE inhibitor, as in the EPHESUS study (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and Survival Study), which enrolled subjects with LVEF less than 40% [7]. It has been already shown that outside the post-MI context, the substitution of torasemide, a loop diuretic with antialdosterone properties, for frusemide as an addition to existing ACE inhibitor or angiotensin receptor blocker therapy significantly (P b .01) reduces the collagen volume fraction (the fraction of myocardial volume occupied by collagen) on
237 an 8-month follow up, not only in patients with diastolic heart failure but also in those with systolic heart failure [8]. In the latter study [8], as well as in a study exclusively enrolling heart failure subjects with intact LVEF, the success of antialdosterone therapy in significantly (P = .006) attenuating the progressive increase in markers of collagen turnover (which reflect myocardial fibrosis) might, arguably, have been attributable to its coprescription with either ACE inhibitors or angiotensin receptor blockers [9], given the fact that in the animal model of post-MI survival, the severity of myocardial fibrosis can be significantly (P b .01) attenuated either by ACE inhibitor therapy or by aldosterone blockade [3]. Accordingly, in subjects such as the ones reported in the recent study, the advocacy for the use of “agents that antagonize the renin angiotensin aldosterone system” for the purpose of conferring clinical benefit in patients with ST-segment elevation myocardial infarction who have increased BNP levels [1] should comprise coprescription of ACE inhibitors and aldosterone antagonists regardless of baseline LVEF, so as to optimize the opportunity to mitigate the severity of post-MI myocardial fibrosis. Other benefits of coprescription of ACE inhibitors and aldosterone antagonists include a loop diuretic– sparing effect [10], which, in the context of loop diuretic– related activation of the renin-angiotensin-aldosterone system (RAAS) [11], might mitigate the risk of renin-angiotensinaldosterone system–related myocardial fibrosis, a phenomenon in which the role of diuretics has not been explored even in studies that report the occurrence of myocardial fibrosis in heart failure patients on background diuretic therapy [8,9]. Oscar M.P. Jolobe MB, ChB, DPhil Manchester Medical Society C/o John Rylands University Library Manchester M13 9PP, UK E-mail address: [email protected] doi:10.1016/j.ajem.2010.10.004
References [1] Neyou A, O'Neill B, Berman AD, Boura JA, McCullough PA. Determinants of markedly increased B-type natriuretic peptide in patients with ST-segment elevation myocardial infarction. Am J Emerg Med 2010. doi:10:1016/j.ajem 2009.08.003. [2] Khumri TM, reid KJ, Kosiborod M, Spertus JA, Main ML. Usefulness of left ventricular diastolic dysfunction as a predictor of one-year rehospitalization in survivors of acute myocardial infarction. Am J Cardiol 2009;103:17-21. [3] Zhang Y-L, Zhou S-X, Lei J, Yuan G-Y, Wang J-F. Blockades of angiotensin and aldosterone reduce osteopontin expression and interstitial fibrosis infiltration in rats with myocardial infarction. Chin Med J 2008;121:2192-6. [4] Nunez-Gil IJ, Garcia-Rubira J, Luaces M, et al. Mild heart failure is a mortality marker after non–ST-segment acute myocardial infarction. Eur J Intern Med 2010;21:439-43. [5] Mcmurray JJ, Carson PE, Komajda M, et al. Heart failure with preserved ejection fraction: clinical characteristics of 4113 patients enrolled in I-PRESERVED trial. Eur J Heart Fail 2008;10:149-56.
238 [6] Aronson D, Musallam A, Lessick J, et al. Impact of diastolic dysfunction on the development of heart failure in diabetic patients after acute myocardial infarction. Circ Heart Fail 2010;3:125-31. [7] Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21. [8] Lopez B, Querejeta R, Gonzalez A, et al. Effects of loop diuretics on myocardial fibrosis and collagen Type I turnover in chronic heart failure. J Am Coll Cardiol 2004;43:2028-35. [9] Mak GJ, Ledwidge MT, Watson C, et al. Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. J Am Coll Cardiol 2009;54:1674-82. [10] Ikram H, Webster MWI, Nicholls MG, et al. Combined spironolactone and converting enzyme inhibitor therapy for refractory heart failure. Aust N Z J Med 1986;16:61-3. [11] Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-Wilson P. Untreated heart failure: clinical and neuroendocrine effects on introducing diuretics. Br Heart J 1987;57:17-22.
Correspondence Cardiology class I recommendation [1-3]. The effectiveness of aldosterone antagonism in patients with diastolic dysfunction is currently being evaluated in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [4] trial. Patients with STEMI, markedly elevated BNP levels, and systolic dysfunction with or without superimposed diastolic dysfunction will most likely benefit from aldosterone receptor antagonists based on the totality of evidence available at this time. We await the results of future trials of such therapy and other agents that use baseline BNP measurement in risk stratification. We anticipate management approaches in the future that will call for natriuretic peptide measurement upon admission in patients presenting with acute coronary syndromes [5]. Ariane Neyou MD Department of Internal Medicine William Beaumont Hospital Royal Oak Royal Oak, MI 48073, USA
Response to letter to the editor To the Editor, In our study of 91 patients admitted for acute ST-segment elevation myocardial infarction (STEMI), we found that elevated brain natriuretic peptide (BNP) (median N500 pg/ mL) was predictive of increased mortality, diastolic dysfunction, left anterior descending artery culprit, and multivessel disease. Although we concluded that elevated BNP levels are significantly associated with diastolic dysfunction, the mean ejection fraction was significantly lower in the group of patients with elevated BNP levels (N500 pg/mL) compared with the group of patients with lower BNP (b500 pg/mL) (37% ± 12% vs 48% ± 12%, P = .0003). This certainly is a reflection of a combination of systolic and diastolic dysfunction, with those most severely ill having restrictive physiology. The Randomized Aldactone Evaluation Study and the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study established that spironolactone increased survival in patients with advanced systolic heart failure and in patients after acute myocardial infarction with heart failure or reduced ejection fraction, respectively. As a result of these studies, aldosterone receptor antagonists were given an American Heart Association/American College of
Peter A. McCullough MD, MPH St. John Providence Health System Providence Park Heart Institute Novi, MI 48374, USA doi:10.1016/j.ajem.2010.10.006
References [1] Maron BA, Leopold JA. Aldosterone receptors antagonists. Effective but often forgotten. Circulation 2010;121:934-9. [2] Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al, For the Randomized Aldactone Evaluation Study Investigators. The effects of spironolactone in patients with severe heart failure. N Engl J Med 1999;341:709-17. [3] Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348(14):1309-21. [4] TOPCAT trial: treatment of preserved cardiac failure with an aldosterone antagonist. www.topcatsudy.com. [5] McCullough PA, Peacock WF, O'Neil B, de Lemos JA, Lepor NE, Berkowitz R. An evidence-based algorithm for the use of B-type natriuretic testing in acute coronary syndromes. Rev Cardiovasc Med 2010;11(Suppl 2):S51-S65.
Diagnostic and therapeutic implications in post– myocardial infarct patients with raised brain natriuretic peptide levels To the Editor, Despite the fact that survivors of ST-segment elevation myocardial infarct with diastolic dysfunction had significantly (P = .01) higher median levels of brain natriuretic peptide (BNP), compared with counterparts without diastolic dysfunction, subjects with BNP greater than 500 pg/mL, nevertheless had significantly (P = .003) lower left ventricular ejection fraction (LVEF; mean value 37%) than counterparts with BNP less than 500 pg/mL (in whom the mean value was 48%) [1]. This was probably a reflection of the fact that in some post–myocardial infarction (post-MI) subjects, exemplified, in one study, by a subgroup of 18 subjects with mean LVEF as low as 36.9%, severe left ventricular diastolic dysfunction may coexist with systolic dysfunction and, hence, subnormal LVEF [2]. That this should be the case is consistent with the observation that in the animal model of post-MI, survival myocardial fibrosis in the noninfarcted region is the histologic correlate of systolic as well as diastolic dysfunction [3]. Even in the early stages of post-MI heart failure [4], despite background prevalence of 78.8% for hypertension (a recognized risk factor for diastolic dysfunction) [5] and background prevalence of 49.6% for diabetes mellitus (also a risk factor for diastolic dysfunction) [6], mean LVEF may be as low as 39.11% [4], again probably reflecting the fact that LVEF may not be truly representative of the coexistence of diastolic dysfunction and its severity in subjects with subnormal LVEF. In the latter study, despite early initiation of angiotensin-converting enzyme (ACE) inhibitor therapy, there was only a modest (P b .05) “protective short term effect on mortality” [4], which, arguably, might have been considerably enhanced, had an aldosterone antagonist been coprescribed with the ACE inhibitor, as in the EPHESUS study (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and Survival Study), which enrolled subjects with LVEF less than 40% [7]. It has been already shown that outside the post-MI context, the substitution of torasemide, a loop diuretic with antialdosterone properties, for frusemide as an addition to existing ACE inhibitor or angiotensin receptor blocker therapy significantly (P b .01) reduces the collagen volume fraction (the fraction of myocardial volume occupied by collagen) on
237 an 8-month follow up, not only in patients with diastolic heart failure but also in those with systolic heart failure [8]. In the latter study [8], as well as in a study exclusively enrolling heart failure subjects with intact LVEF, the success of antialdosterone therapy in significantly (P = .006) attenuating the progressive increase in markers of collagen turnover (which reflect myocardial fibrosis) might, arguably, have been attributable to its coprescription with either ACE inhibitors or angiotensin receptor blockers [9], given the fact that in the animal model of post-MI survival, the severity of myocardial fibrosis can be significantly (P b .01) attenuated either by ACE inhibitor therapy or by aldosterone blockade [3]. Accordingly, in subjects such as the ones reported in the recent study, the advocacy for the use of “agents that antagonize the renin angiotensin aldosterone system” for the purpose of conferring clinical benefit in patients with ST-segment elevation myocardial infarction who have increased BNP levels [1] should comprise coprescription of ACE inhibitors and aldosterone antagonists regardless of baseline LVEF, so as to optimize the opportunity to mitigate the severity of post-MI myocardial fibrosis. Other benefits of coprescription of ACE inhibitors and aldosterone antagonists include a loop diuretic– sparing effect [10], which, in the context of loop diuretic– related activation of the renin-angiotensin-aldosterone system (RAAS) [11], might mitigate the risk of renin-angiotensinaldosterone system–related myocardial fibrosis, a phenomenon in which the role of diuretics has not been explored even in studies that report the occurrence of myocardial fibrosis in heart failure patients on background diuretic therapy [8,9]. Oscar M.P. Jolobe MB, ChB, DPhil Manchester Medical Society C/o John Rylands University Library Manchester M13 9PP, UK E-mail address: [email protected] doi:10.1016/j.ajem.2010.10.004
References [1] Neyou A, O'Neill B, Berman AD, Boura JA, McCullough PA. Determinants of markedly increased B-type natriuretic peptide in patients with ST-segment elevation myocardial infarction. Am J Emerg Med 2010. doi:10:1016/j.ajem 2009.08.003. [2] Khumri TM, reid KJ, Kosiborod M, Spertus JA, Main ML. Usefulness of left ventricular diastolic dysfunction as a predictor of one-year rehospitalization in survivors of acute myocardial infarction. Am J Cardiol 2009;103:17-21. [3] Zhang Y-L, Zhou S-X, Lei J, Yuan G-Y, Wang J-F. Blockades of angiotensin and aldosterone reduce osteopontin expression and interstitial fibrosis infiltration in rats with myocardial infarction. Chin Med J 2008;121:2192-6. [4] Nunez-Gil IJ, Garcia-Rubira J, Luaces M, et al. Mild heart failure is a mortality marker after non–ST-segment acute myocardial infarction. Eur J Intern Med 2010;21:439-43. [5] Mcmurray JJ, Carson PE, Komajda M, et al. Heart failure with preserved ejection fraction: clinical characteristics of 4113 patients enrolled in I-PRESERVED trial. Eur J Heart Fail 2008;10:149-56.
238 [6] Aronson D, Musallam A, Lessick J, et al. Impact of diastolic dysfunction on the development of heart failure in diabetic patients after acute myocardial infarction. Circ Heart Fail 2010;3:125-31. [7] Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21. [8] Lopez B, Querejeta R, Gonzalez A, et al. Effects of loop diuretics on myocardial fibrosis and collagen Type I turnover in chronic heart failure. J Am Coll Cardiol 2004;43:2028-35. [9] Mak GJ, Ledwidge MT, Watson C, et al. Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. J Am Coll Cardiol 2009;54:1674-82. [10] Ikram H, Webster MWI, Nicholls MG, et al. Combined spironolactone and converting enzyme inhibitor therapy for refractory heart failure. Aust N Z J Med 1986;16:61-3. [11] Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-Wilson P. Untreated heart failure: clinical and neuroendocrine effects on introducing diuretics. Br Heart J 1987;57:17-22.
Correspondence Cardiology class I recommendation [1-3]. The effectiveness of aldosterone antagonism in patients with diastolic dysfunction is currently being evaluated in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [4] trial. Patients with STEMI, markedly elevated BNP levels, and systolic dysfunction with or without superimposed diastolic dysfunction will most likely benefit from aldosterone receptor antagonists based on the totality of evidence available at this time. We await the results of future trials of such therapy and other agents that use baseline BNP measurement in risk stratification. We anticipate management approaches in the future that will call for natriuretic peptide measurement upon admission in patients presenting with acute coronary syndromes [5]. Ariane Neyou MD Department of Internal Medicine William Beaumont Hospital Royal Oak Royal Oak, MI 48073, USA
Response to letter to the editor To the Editor, In our study of 91 patients admitted for acute ST-segment elevation myocardial infarction (STEMI), we found that elevated brain natriuretic peptide (BNP) (median N500 pg/ mL) was predictive of increased mortality, diastolic dysfunction, left anterior descending artery culprit, and multivessel disease. Although we concluded that elevated BNP levels are significantly associated with diastolic dysfunction, the mean ejection fraction was significantly lower in the group of patients with elevated BNP levels (N500 pg/mL) compared with the group of patients with lower BNP (b500 pg/mL) (37% ± 12% vs 48% ± 12%, P = .0003). This certainly is a reflection of a combination of systolic and diastolic dysfunction, with those most severely ill having restrictive physiology. The Randomized Aldactone Evaluation Study and the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study established that spironolactone increased survival in patients with advanced systolic heart failure and in patients after acute myocardial infarction with heart failure or reduced ejection fraction, respectively. As a result of these studies, aldosterone receptor antagonists were given an American Heart Association/American College of
Peter A. McCullough MD, MPH St. John Providence Health System Providence Park Heart Institute Novi, MI 48374, USA doi:10.1016/j.ajem.2010.10.006
References [1] Maron BA, Leopold JA. Aldosterone receptors antagonists. Effective but often forgotten. Circulation 2010;121:934-9. [2] Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al, For the Randomized Aldactone Evaluation Study Investigators. The effects of spironolactone in patients with severe heart failure. N Engl J Med 1999;341:709-17. [3] Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348(14):1309-21. [4] TOPCAT trial: treatment of preserved cardiac failure with an aldosterone antagonist. www.topcatsudy.com. [5] McCullough PA, Peacock WF, O'Neil B, de Lemos JA, Lepor NE, Berkowitz R. An evidence-based algorithm for the use of B-type natriuretic testing in acute coronary syndromes. Rev Cardiovasc Med 2010;11(Suppl 2):S51-S65.