- Email: [email protected]
Anti-inflammatory effects of levosimendan in decompensated heart failure: Impact on weight loss and anemia
edge of the endocardium using harmonic imaging. Measurements were obtained by a single observer and averaged over 3 cardiac cycles to decrease beat-to-beat variability. (4) The 2-dimensional echocardiographic features of patients with IDC and NC were compared during a 3-year period at a single tertiary care hospital in India. (5) The presence of additional congenital and valvular defects in patients with NC, referred to as nonisolated NC, has been cited on several occasions.5–7 In our study, aortic valve lesions were seen in 3 patients and mitral valve prolapse was seen in 2 patients. Mild mitral regurgitation was seen in 8 patients without identifiable abnormalities in the mitral leaflets. Because few patients in the group had nonisolated NC, we compared the features of isolated and nonisolated NC as a single group with those of IDC. (6) No patient had overt clinical features of neuromuscular dysfunction at presentation, except 2 patients with marked proximal girdle metabolic myopathy. (7) Information regarding the pattern and the number of segments analyzed in each wall are detailed in the report. No correlation was seen between the number of segments with NC and the extent of spherical remodeling. (8) The infrequent occurrence of NC in the midseptal region in adult patients in our study is similar to observations in earlier studies, including those of Dr. Stöllberger.8 (9) The detection of thrombi in 2 patients with NC was incidental. Both thrombi were mobile and the patients were treated with oral anticoagulant therapy. The thrombi resolved without an embolic event. (10) Most of our patients with NC presented with congestive heart failure. Their lower mean LV ejection fractions compared with that in the study by Stöllberger et al8 probably reflects differences in the patient populations, the referral patterns, and the selection criteria used for defining NC. A low ejection fraction in patients with NC has been reported in earlier series. However, we confirm that, despite a structurally different myocardium, the ejection fractions of patients with NC were
nearly double those of patients with IDC. Partho P. Sengupta, Jagdish C. Mohan, Vimal Mehta, Vineet Jain, Ramesh Arora,
MD MD MD MD MD
New Delhi, India Natesa G. Pandian,
MD
Boston, Massachusetts Bijoy K. Khanderia,
MD
Rochester, Minnisota 28 September 2004
1. Sedmera D, Pexieder T, Vuillemin M, Thompson RP, Anderson RH. Developmental patterning of the myocardium. Anat Rec 2000;258:319 –337. 2. Weiford BC, Subbarao VD, Mulhern KM. Noncompaction of the ventricular myocardium. Circulation 2004;109:2965–2971. 3. Oechslin EN, Attenhofer Jost CH, Rojas JR, Kaufmann PA, Jenni R. Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000;36:493–500. 4. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufimann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001;86:666 – 671. 5. Cavusoglu Y, Ata N, Timuralp B, Gorenek B, Goktekin O, Kudaiberdieva G, Unalir A. Noncompaction of the ventricular myocardium: report of two cases with bicuspid aortic valve demonstrating poor prognosis and with prominent right ventricular involvement. Echocardiography 2003;20:379 –383. 6. Sasse-Klaassen S, Probst S, Gerull B, Oechslin E, Nurnberg P, Heuser A, Jenni R, Hennies HC, Thierfelder L. Novel gene locus for autosomal dominant left ventricular noncompaction maps to chromosome 11p15. Circulation 2004;109:2720 –2723. 7. Stollberger C, Finsterer J. Left ventricular hypertrabeculation/noncompaction. J Am Soc Echocardiogr 2004;17:91–100. 8. Stollberger C, Finsterer J, Blazek G. Left ventricular hypertrabeculation/noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am J Cardiol 2002;90:899 –902.
doi:10.1016/j.amjcard.2004.09.056
Anti-inflammatory Effects of Levosimendan in Decompensated Heart Failure: Impact on Weight Loss and Anemia
Levosimendan is a novel positive inotropic agent that acts by enhancing calcium sensitivity of cardiac myofilaments. Besides improving myocardial contractility, it also causes peripheral vasodilation, without increasing myocardial oxygen demands and promoting arrhythmiogenesis.1 In addition, we have recently shown that levosimendan administration in patients with decompensated heart failure is followed by a significant reduction
of serum interleukin-6, soluble Fas and soluble Fas ligand, hence bearing potential anti-inflammatory and antiapoptotic properties.2 Bearing this in mind, von Haehling et al,3 in their recently published Reader’s Comment discuss the potential role of levosimendan in improving cachexia and anemia in patients with heart failure, speculating about the time frame over which these changes should be encountered. Levosimendan has an elimination half-life of 1 hour, whereas its 2 circulating metabolites, OR-1855 and its acetylated form OR-1896, have half-lives of about 70 to 80 hours and reach their maximum concentration 2 days after withdrawal of a 24-hour intravenous infusion.4 Given that the metabolite OR-1896 has hemodynamic properties similar to those of the parent agent, the hemodynamic effects of levosimendan are expected to persist for 7 to 10 days after its intravenous infusion. According to our unpublished personal data, derived by repetitive levosimendan administration in patients with decompensated heart failure, a reduction in serum interleukin-6 levels is seen until 10 days after the intravenous infusion of the drug. Within the next 14 to 20 days, a novel increase in interleukin-6 is encountered, but this increase never reaches the baseline levels observed before to the initial levosimendan administration. During this time, a significant weight loss is also encountered, apparently due to the reduction of congestion. Moreover, there is also a trend toward an increase in hemoglobin levels within 7 to 10 days after levosimendan infusion, whereas after 4 repetitive administrations, patients with a satisfactory overall response also show a significant hemoglobin increase. Besides the reduction in circulating blood volume and the improvement in renal function, anemia reduction may be attributed to the anti-inflammatory effects of levosimendan, through the potential improvement of bone marrow resistance to erythropoietin. These and other similar findings may serve as a start point for randomized clinical trials that will hopefully provide a solid body of READERS’ COMMENTS
923
evidence on the exact role of levosimendan in improving collateral, inflammation-induced abnormalities, such as cachexia and anemia, in patients with chronic heart failure. John T. Parissis, Dimitrios Farmakis, Dimitrios T. Kremastinos,
MD MD MD
Athens, Greece 18 November 2004
1. Kivikko M, Antila S, Eha J, Lehtonen L, Penti-
kainen PJ. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol 2002;42:43–51. 2. Parissis JT, Adamopoulos S, Antoniades C, Kostakis G, Rigas A, Kyrzopoulos S, Iliodromitis E, Kremastinos D. Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. Am J Cardiol 2004;93:1309 – 1312. 3. von Haehling S, Diller GP, Anker SD. Impact of levosimendan treatment on chronic heart failure [letter]. Am J Cardiol 2004;94:1105. 4. Poder P, Eha J, Sundberg S, Antila S, Heinpalu M, Loogna I, Planken U, Rantanen S, Lehtonen L. Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study. J Clin Pharmacol 2004;44:1143–1150. doi:10.1016/j.amjcard.2004.11.018
Angiotensin-Converting Enzyme Inhibitors and Myocardial Infarction: A Class Effect?
The case-control analysis of Sauer and colleagues1 demonstrated that the risk of nonfatal myocardial infarction (MI) did not correlate with the degree of angiotensin-converting enzyme (ACE) inhibitor lipophilicity (tissue affinity). This study should be exam-
ined further in view of a number of recent secondary prevention trials that demonstrated variable efficacy among different ACE inhibitors. Lipophilicity is but 1 pharmacologic characteristic of a drug that has never been shown to predict clinical outcomes within this medication class. One retrospective study demonstrated lower 1-year mortality among 7,512 Canadian patients treated with either ramipril and perindopril, compared with other ACE inhibitors after acute MI.2 Although this study corroborates Sauer and colleagues1 finding that drug lipophilicity, per se, is not predictive of efficacy, it also suggests that not all drugs within the ACE inhibitor class are equally effective. Similar results were reported in a cohort of 6,381 patients hospitalized with ST-segment elevation MI,3 wherein therapy with ramipril was independently associated with a lower 21-day mortality rate versus other ACE inhibitors (hazard ratio 0.54, 95% confidence interval 0.32 to 0.90). The finding of differential efficacy among specific ACE inhibitors appears to also extend to coronary artery disease (CAD) patients without a history of acute MI. Once again, in this population, only ramipril and perindopril have been prospectively shown to reduce cardiovascular morbidity and mortality.4,5 A very recent prospective randomized trial of trandolopril in 8,290 patients with stable CAD demonstrated no reduction in the primary composite end point of cardiovascu-
924 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 95
APRIL 1, 2005
lar death, MI, or coronary revascularization (hazard ratio for trandolopril 0.96; 95% confidence interval 0.88 to 1.06, p ⫽ 0.43). Taken together, these trials suggest that a “class effect” may not exist among ACE inhibitors, at least with regard to the treatment of stable CAD. In this population, treatment with either 8 mg/day of perindopril or 10 mg/ day of ramipril4,5 remains the only evidenced-based strategy, notwithstanding the minimal lipophilicity attributed to these agents.2 Mori J. Krantz, MD Raymond O. Estacio Philip S. Mehler, MD Denver, Colorado 30 November 2004
1. Sauer WH, Baer JT, Berlin JA, Kimmel SE. Class effect of angiotensin converting enzyme inhibitors on prevention of myocardial infarction. Am J Cardiol 2004;94:1171–1173. 2. Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg MJ, Rahme E. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after myocardial infarction: a class effect? Ann Intern Med 2004;141:102–12. 3. Wienbergen H, Schiele R, Gitt A, et al. Impact of ramipril versus other angiotensin-converting enzyme inhibitors on outcome of unselected patients with ST-elevation acute myocardial infarction. Am J Cardiol 2002;90:1045–1049. 4. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000;342:145–153. 5. Fox KM, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo controlled, multicenter trial. The EUROPA Study. Lancet 2003;362:782–788.
doi:10.1016/j.amjcard.2004.12.007
nearly double those of patients with IDC. Partho P. Sengupta, Jagdish C. Mohan, Vimal Mehta, Vineet Jain, Ramesh Arora,
MD MD MD MD MD
New Delhi, India Natesa G. Pandian,
MD
Boston, Massachusetts Bijoy K. Khanderia,
MD
Rochester, Minnisota 28 September 2004
1. Sedmera D, Pexieder T, Vuillemin M, Thompson RP, Anderson RH. Developmental patterning of the myocardium. Anat Rec 2000;258:319 –337. 2. Weiford BC, Subbarao VD, Mulhern KM. Noncompaction of the ventricular myocardium. Circulation 2004;109:2965–2971. 3. Oechslin EN, Attenhofer Jost CH, Rojas JR, Kaufmann PA, Jenni R. Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000;36:493–500. 4. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufimann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001;86:666 – 671. 5. Cavusoglu Y, Ata N, Timuralp B, Gorenek B, Goktekin O, Kudaiberdieva G, Unalir A. Noncompaction of the ventricular myocardium: report of two cases with bicuspid aortic valve demonstrating poor prognosis and with prominent right ventricular involvement. Echocardiography 2003;20:379 –383. 6. Sasse-Klaassen S, Probst S, Gerull B, Oechslin E, Nurnberg P, Heuser A, Jenni R, Hennies HC, Thierfelder L. Novel gene locus for autosomal dominant left ventricular noncompaction maps to chromosome 11p15. Circulation 2004;109:2720 –2723. 7. Stollberger C, Finsterer J. Left ventricular hypertrabeculation/noncompaction. J Am Soc Echocardiogr 2004;17:91–100. 8. Stollberger C, Finsterer J, Blazek G. Left ventricular hypertrabeculation/noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am J Cardiol 2002;90:899 –902.
doi:10.1016/j.amjcard.2004.09.056
Anti-inflammatory Effects of Levosimendan in Decompensated Heart Failure: Impact on Weight Loss and Anemia
Levosimendan is a novel positive inotropic agent that acts by enhancing calcium sensitivity of cardiac myofilaments. Besides improving myocardial contractility, it also causes peripheral vasodilation, without increasing myocardial oxygen demands and promoting arrhythmiogenesis.1 In addition, we have recently shown that levosimendan administration in patients with decompensated heart failure is followed by a significant reduction
of serum interleukin-6, soluble Fas and soluble Fas ligand, hence bearing potential anti-inflammatory and antiapoptotic properties.2 Bearing this in mind, von Haehling et al,3 in their recently published Reader’s Comment discuss the potential role of levosimendan in improving cachexia and anemia in patients with heart failure, speculating about the time frame over which these changes should be encountered. Levosimendan has an elimination half-life of 1 hour, whereas its 2 circulating metabolites, OR-1855 and its acetylated form OR-1896, have half-lives of about 70 to 80 hours and reach their maximum concentration 2 days after withdrawal of a 24-hour intravenous infusion.4 Given that the metabolite OR-1896 has hemodynamic properties similar to those of the parent agent, the hemodynamic effects of levosimendan are expected to persist for 7 to 10 days after its intravenous infusion. According to our unpublished personal data, derived by repetitive levosimendan administration in patients with decompensated heart failure, a reduction in serum interleukin-6 levels is seen until 10 days after the intravenous infusion of the drug. Within the next 14 to 20 days, a novel increase in interleukin-6 is encountered, but this increase never reaches the baseline levels observed before to the initial levosimendan administration. During this time, a significant weight loss is also encountered, apparently due to the reduction of congestion. Moreover, there is also a trend toward an increase in hemoglobin levels within 7 to 10 days after levosimendan infusion, whereas after 4 repetitive administrations, patients with a satisfactory overall response also show a significant hemoglobin increase. Besides the reduction in circulating blood volume and the improvement in renal function, anemia reduction may be attributed to the anti-inflammatory effects of levosimendan, through the potential improvement of bone marrow resistance to erythropoietin. These and other similar findings may serve as a start point for randomized clinical trials that will hopefully provide a solid body of READERS’ COMMENTS
923
evidence on the exact role of levosimendan in improving collateral, inflammation-induced abnormalities, such as cachexia and anemia, in patients with chronic heart failure. John T. Parissis, Dimitrios Farmakis, Dimitrios T. Kremastinos,
MD MD MD
Athens, Greece 18 November 2004
1. Kivikko M, Antila S, Eha J, Lehtonen L, Penti-
kainen PJ. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol 2002;42:43–51. 2. Parissis JT, Adamopoulos S, Antoniades C, Kostakis G, Rigas A, Kyrzopoulos S, Iliodromitis E, Kremastinos D. Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. Am J Cardiol 2004;93:1309 – 1312. 3. von Haehling S, Diller GP, Anker SD. Impact of levosimendan treatment on chronic heart failure [letter]. Am J Cardiol 2004;94:1105. 4. Poder P, Eha J, Sundberg S, Antila S, Heinpalu M, Loogna I, Planken U, Rantanen S, Lehtonen L. Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study. J Clin Pharmacol 2004;44:1143–1150. doi:10.1016/j.amjcard.2004.11.018
Angiotensin-Converting Enzyme Inhibitors and Myocardial Infarction: A Class Effect?
The case-control analysis of Sauer and colleagues1 demonstrated that the risk of nonfatal myocardial infarction (MI) did not correlate with the degree of angiotensin-converting enzyme (ACE) inhibitor lipophilicity (tissue affinity). This study should be exam-
ined further in view of a number of recent secondary prevention trials that demonstrated variable efficacy among different ACE inhibitors. Lipophilicity is but 1 pharmacologic characteristic of a drug that has never been shown to predict clinical outcomes within this medication class. One retrospective study demonstrated lower 1-year mortality among 7,512 Canadian patients treated with either ramipril and perindopril, compared with other ACE inhibitors after acute MI.2 Although this study corroborates Sauer and colleagues1 finding that drug lipophilicity, per se, is not predictive of efficacy, it also suggests that not all drugs within the ACE inhibitor class are equally effective. Similar results were reported in a cohort of 6,381 patients hospitalized with ST-segment elevation MI,3 wherein therapy with ramipril was independently associated with a lower 21-day mortality rate versus other ACE inhibitors (hazard ratio 0.54, 95% confidence interval 0.32 to 0.90). The finding of differential efficacy among specific ACE inhibitors appears to also extend to coronary artery disease (CAD) patients without a history of acute MI. Once again, in this population, only ramipril and perindopril have been prospectively shown to reduce cardiovascular morbidity and mortality.4,5 A very recent prospective randomized trial of trandolopril in 8,290 patients with stable CAD demonstrated no reduction in the primary composite end point of cardiovascu-
924 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 95
APRIL 1, 2005
lar death, MI, or coronary revascularization (hazard ratio for trandolopril 0.96; 95% confidence interval 0.88 to 1.06, p ⫽ 0.43). Taken together, these trials suggest that a “class effect” may not exist among ACE inhibitors, at least with regard to the treatment of stable CAD. In this population, treatment with either 8 mg/day of perindopril or 10 mg/ day of ramipril4,5 remains the only evidenced-based strategy, notwithstanding the minimal lipophilicity attributed to these agents.2 Mori J. Krantz, MD Raymond O. Estacio Philip S. Mehler, MD Denver, Colorado 30 November 2004
1. Sauer WH, Baer JT, Berlin JA, Kimmel SE. Class effect of angiotensin converting enzyme inhibitors on prevention of myocardial infarction. Am J Cardiol 2004;94:1171–1173. 2. Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg MJ, Rahme E. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after myocardial infarction: a class effect? Ann Intern Med 2004;141:102–12. 3. Wienbergen H, Schiele R, Gitt A, et al. Impact of ramipril versus other angiotensin-converting enzyme inhibitors on outcome of unselected patients with ST-elevation acute myocardial infarction. Am J Cardiol 2002;90:1045–1049. 4. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000;342:145–153. 5. Fox KM, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo controlled, multicenter trial. The EUROPA Study. Lancet 2003;362:782–788.
doi:10.1016/j.amjcard.2004.12.007