Editorial Commentary Statin Therapy in Heart Failure Is It Time for a Second Look? Ali Javaheri, Daniel J. Rader, Shahrokh Javaheri See related article, pp 1041–1049
C
ongestive heart failure (CHF) is a common end-stage clinical presentation of coronary artery disease or 2 of its major risk factors, hypertension and diabetes mellitus. Because of this, patients with CHF are often prescribed 3-hydroxy3-methylglutaryl coenzyme-A inhibitors (statins) that not only prevent cardiovascular events such as myocardial infarction, but also reduce the risk of incident heart failure. In concept, statin therapy could benefit patients with CHF by multiple mechanisms, including reduction in further ischemic events, decreased sympathetic activity, or improved endothelial function. However, once heart failure has developed, from either ischemic or nonischemic heart disease, the benefit of statin therapy is more controversial. In the present issue of the Journal, Haack et al1 present a well-executed series of experiments showing that simvastatin treatment significantly improved respiratory variability and arrhythmia observed in a postinfarction rat CHF model. This improvement was associated with amelioration of enhanced peripheral arterial chemosensitivity, a major mechanism mediating periodic breathing and central sleep apnea (CSA) in CHF.2,3 Rats with CHF exhibited increased respiratory variability with reduced tidal volume and augmented ventilatory responses to hypoxia but not hypercapnia. Simvastatin mediated downregulation of the exaggerated hypoxic ventilatory response and carotid nerve discharge. These changes were associated with upregulation of Kruppel-like factor 2 and endothelial NO synthase within the carotid body and nucleus tractus solitarii, a group of respiratory neurons within the dorsal respiratory group that receive afferent input from the peripheral chemoreceptors. In essence, these findings demonstrate that the increased carotid body chemosensitivity, respiratory instability, and cardiac arrhythmias observed in CHF are ameliorated by simvastatin treatment in rats. In CHF, periodic breathing and CSA are prevalent comorbidities4 associated with increased mortality.3,5,6 One mechanism mediating CSA in patients with CHF is the enhanced sensitivity of the peripheral and central chemoreceptors, resulting in augmented ventilatory responses to hypoxia The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Divisions of Cardiology (A.J.) and Translational Medicine and Human Genetics (D.J.R.), University of Pennsylvania, Philadelphia; and Emeritus Professor of Medicine, University of Cincinnati, OH (S.J.). Correspondence to Shahrokh Javaheri, 6461 Pepperell Lane, Cincinnati, OH 45236. E-mail [email protected] (Hypertension. 2014;63:909-910.) © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.113.02703
and hypercapnia.2,3,7,8 Furthermore, the severity of CSA correlates with the degree of sensitivity to CO2.7 Therefore, it is surprising that in the present study, CO2 chemosensitivity remained unchanged. Given the increased morbidity and mortality associated with CSA in CHF, could statins represent a pharmacological therapy in CHF that would be of clinical benefit? Indeed, effective treatment of CSA improves survival of patients with heart failure.6 In 1 study, patients with the highest burden of CSA9 were the least likely to have their CSA suppressed with continuous positive airway pressure therapy. If statins dampen chemosensitivity, perhaps continuous positive airway pressure–nonresponsive patients with heightened chemosensitivity may respond to continuous positive airway pressure with statin adjunctive therapy. Given the high prevalence of CSA in heart failure and that effective treatment of CSA improves survival, one might hypothesize that statin treatment would reduce mortality in heart failure. However, 2 large randomized controlled clinical trials failed to show benefit in improving survival. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)10 and Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico Heart Failure (GISSI-HF)11 trials each randomized patients with CHF attributable to either ischemic or nonischemic cause to rosuvastatin or placebo, and mortality was not reduced in either study. How do we reconcile the findings of the present study with the randomized trial evidence? Interestingly, data from a meta-analysis suggest that simvastatin and atorvastatin, but not rosuvastatin, may be associated with improved survival in CHF.12 Simvastatin and atorvastatin are lipophilic statins that readily cross the blood–brain barrier.13,14 In contrast, both GISSI-HF and CORONA used rosuvastatin, a hydrophilic statin that does not cross the blood–brain barrier.13,14 It is therefore conceivable that the effects of simvastatin noted in the present study were, at least in part, mediated centrally. Another key difference is that the present study was performed in a rat model of acute heart failure, versus the chronic CHF studied in the GISSI-HF and CORONA trials. In a subgroup analysis of patients with ischemic systolic CHF, patients with low levels of biomarkers such as N-terminal probrain natriuretic peptide and galectin-3, a marker of fibrosis, had a significant benefit with rosuvastatin (hazard ratio, 0.33; 95% confidence interval, 0.16–0.67).15 It could be hypothesized that the beneficial effect of this hydrophilic statin was in part related to improvement in CSA via a peripheral effect on carotid bodies decreasing hypoxic chemosensitivity or via possible antifibrotic effects. Although post hoc analysis of these studies is only hypothesis provoking, biomarkers may
Downloaded from http://hyper.ahajournals.org/ at909 California Institute of Technology on May 26, 2015
910 Hypertension May 2014 help identify a key subpopulation of patients with CHF with less advanced disease and less CSA burden who may benefit from statin therapy. Patients with a high-fibrotic burden as evidenced by high level of galectin-3 may be at too advanced a degree of fibrosis to benefit. Altogether, it is possible that certain subgroups of patients with CHF may benefit from statin therapy and that it may matter which statin and what dose is used with regard to clinical benefit in heart failure.13,14 Identifying subgroups that may benefit, whether it be the 30% to 40% of patients with CHF with CSA or perhaps patients in an earlier stage of disease with lower CSA burden, will require careful study. In addition, mechanistic details of physiological effects in humans and animal models will require further investigation using different statins of varying lipophilicity to determine which drug to test in clinical studies. Given the key differences between the animal studies, human physiological studies, and randomized trial data, we suggest that it is too soon to give up on statin therapy for patients with CHF and that more research is needed to determine whether a statin should be part of the treatment of this increasingly prevalent and ultimately fatal form of heart disease.
Disclosures D.J. Rader has received consulting fees from Merck and Pfizer. The other authors report no conflicts.
References 1. Haack KKV, Marcus NJ, Rio RD, Zucker IH, Schultz HD. Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure. Hypertension. 2014;63:1041–1049. 2. Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3:141–163. 3. Ponikowski P, Anker SD, Chua TP, Francis D, Banasiak W, Poole-Wilson PA, Coats AJ, Piepoli M. Oscillatory breathing patterns during wakefulness
in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity. Circulation. 1999;100:2418–2424. 4. Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol. 2006;106:21–28. 5. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol. 2007;49:2028–2034. 6. Arzt M, Floras JS, Logan AG, Kimoff RJ, Series F, Morrison D, Ferguson K, Belenkie I, Pfeifer M, Fleetham J, Hanly P, Smilovitch M, Ryan C, Tomlinson G, Bradley TD; CANPAP Investigators. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115:3173–3180. 7. Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med. 1999;341:949–954. 8. Solin P, Roebuck T, Johns DP, Walters EH, Naughton MT. Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure. Am J Respir Crit Care Med. 2000;162:2194–2200. 9. Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation. 2000;101:392–397. 10. Kjekshus J, Apetrei E, Barrios V, et al; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–2261. 11. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of rosuvastatin in patients with chronic heart failure (the gissi-hf trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–1239. 12. Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, Abbate A, Vrtovec B, Khan BV, Vetrovec GW. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol. 2009;104:1708–1716. 13. Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS. Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood- brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J Alzheimers Dis. 2011;23:307–318. 14. Millar PJ, Floras JS. Statins and the autonomic nervous system. Clin Sci (Lond). 2014;126:401–415. 15. Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P, Adourian A, Böhm M, van Veldhuisen DJ, Komajda M, Cleland JG, Wikstrand J, McMurray JJ, Aukrust P; CORONA Study Group. Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Eur Heart J. 2012;33:2290–2296.
Downloaded from http://hyper.ahajournals.org/ at California Institute of Technology on May 26, 2015
Statin Therapy in Heart Failure: Is It Time for a Second Look? Ali Javaheri, Daniel J. Rader and Shahrokh Javaheri Hypertension. 2014;63:909-910; originally published online February 10, 2014; doi: 10.1161/HYPERTENSIONAHA.113.02703 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/63/5/909
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/
Downloaded from http://hyper.ahajournals.org/ at California Institute of Technology on May 26, 2015
C
ongestive heart failure (CHF) is a common end-stage clinical presentation of coronary artery disease or 2 of its major risk factors, hypertension and diabetes mellitus. Because of this, patients with CHF are often prescribed 3-hydroxy3-methylglutaryl coenzyme-A inhibitors (statins) that not only prevent cardiovascular events such as myocardial infarction, but also reduce the risk of incident heart failure. In concept, statin therapy could benefit patients with CHF by multiple mechanisms, including reduction in further ischemic events, decreased sympathetic activity, or improved endothelial function. However, once heart failure has developed, from either ischemic or nonischemic heart disease, the benefit of statin therapy is more controversial. In the present issue of the Journal, Haack et al1 present a well-executed series of experiments showing that simvastatin treatment significantly improved respiratory variability and arrhythmia observed in a postinfarction rat CHF model. This improvement was associated with amelioration of enhanced peripheral arterial chemosensitivity, a major mechanism mediating periodic breathing and central sleep apnea (CSA) in CHF.2,3 Rats with CHF exhibited increased respiratory variability with reduced tidal volume and augmented ventilatory responses to hypoxia but not hypercapnia. Simvastatin mediated downregulation of the exaggerated hypoxic ventilatory response and carotid nerve discharge. These changes were associated with upregulation of Kruppel-like factor 2 and endothelial NO synthase within the carotid body and nucleus tractus solitarii, a group of respiratory neurons within the dorsal respiratory group that receive afferent input from the peripheral chemoreceptors. In essence, these findings demonstrate that the increased carotid body chemosensitivity, respiratory instability, and cardiac arrhythmias observed in CHF are ameliorated by simvastatin treatment in rats. In CHF, periodic breathing and CSA are prevalent comorbidities4 associated with increased mortality.3,5,6 One mechanism mediating CSA in patients with CHF is the enhanced sensitivity of the peripheral and central chemoreceptors, resulting in augmented ventilatory responses to hypoxia The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Divisions of Cardiology (A.J.) and Translational Medicine and Human Genetics (D.J.R.), University of Pennsylvania, Philadelphia; and Emeritus Professor of Medicine, University of Cincinnati, OH (S.J.). Correspondence to Shahrokh Javaheri, 6461 Pepperell Lane, Cincinnati, OH 45236. E-mail [email protected] (Hypertension. 2014;63:909-910.) © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.113.02703
and hypercapnia.2,3,7,8 Furthermore, the severity of CSA correlates with the degree of sensitivity to CO2.7 Therefore, it is surprising that in the present study, CO2 chemosensitivity remained unchanged. Given the increased morbidity and mortality associated with CSA in CHF, could statins represent a pharmacological therapy in CHF that would be of clinical benefit? Indeed, effective treatment of CSA improves survival of patients with heart failure.6 In 1 study, patients with the highest burden of CSA9 were the least likely to have their CSA suppressed with continuous positive airway pressure therapy. If statins dampen chemosensitivity, perhaps continuous positive airway pressure–nonresponsive patients with heightened chemosensitivity may respond to continuous positive airway pressure with statin adjunctive therapy. Given the high prevalence of CSA in heart failure and that effective treatment of CSA improves survival, one might hypothesize that statin treatment would reduce mortality in heart failure. However, 2 large randomized controlled clinical trials failed to show benefit in improving survival. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)10 and Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico Heart Failure (GISSI-HF)11 trials each randomized patients with CHF attributable to either ischemic or nonischemic cause to rosuvastatin or placebo, and mortality was not reduced in either study. How do we reconcile the findings of the present study with the randomized trial evidence? Interestingly, data from a meta-analysis suggest that simvastatin and atorvastatin, but not rosuvastatin, may be associated with improved survival in CHF.12 Simvastatin and atorvastatin are lipophilic statins that readily cross the blood–brain barrier.13,14 In contrast, both GISSI-HF and CORONA used rosuvastatin, a hydrophilic statin that does not cross the blood–brain barrier.13,14 It is therefore conceivable that the effects of simvastatin noted in the present study were, at least in part, mediated centrally. Another key difference is that the present study was performed in a rat model of acute heart failure, versus the chronic CHF studied in the GISSI-HF and CORONA trials. In a subgroup analysis of patients with ischemic systolic CHF, patients with low levels of biomarkers such as N-terminal probrain natriuretic peptide and galectin-3, a marker of fibrosis, had a significant benefit with rosuvastatin (hazard ratio, 0.33; 95% confidence interval, 0.16–0.67).15 It could be hypothesized that the beneficial effect of this hydrophilic statin was in part related to improvement in CSA via a peripheral effect on carotid bodies decreasing hypoxic chemosensitivity or via possible antifibrotic effects. Although post hoc analysis of these studies is only hypothesis provoking, biomarkers may
Downloaded from http://hyper.ahajournals.org/ at909 California Institute of Technology on May 26, 2015
910 Hypertension May 2014 help identify a key subpopulation of patients with CHF with less advanced disease and less CSA burden who may benefit from statin therapy. Patients with a high-fibrotic burden as evidenced by high level of galectin-3 may be at too advanced a degree of fibrosis to benefit. Altogether, it is possible that certain subgroups of patients with CHF may benefit from statin therapy and that it may matter which statin and what dose is used with regard to clinical benefit in heart failure.13,14 Identifying subgroups that may benefit, whether it be the 30% to 40% of patients with CHF with CSA or perhaps patients in an earlier stage of disease with lower CSA burden, will require careful study. In addition, mechanistic details of physiological effects in humans and animal models will require further investigation using different statins of varying lipophilicity to determine which drug to test in clinical studies. Given the key differences between the animal studies, human physiological studies, and randomized trial data, we suggest that it is too soon to give up on statin therapy for patients with CHF and that more research is needed to determine whether a statin should be part of the treatment of this increasingly prevalent and ultimately fatal form of heart disease.
Disclosures D.J. Rader has received consulting fees from Merck and Pfizer. The other authors report no conflicts.
References 1. Haack KKV, Marcus NJ, Rio RD, Zucker IH, Schultz HD. Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure. Hypertension. 2014;63:1041–1049. 2. Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3:141–163. 3. Ponikowski P, Anker SD, Chua TP, Francis D, Banasiak W, Poole-Wilson PA, Coats AJ, Piepoli M. Oscillatory breathing patterns during wakefulness
in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity. Circulation. 1999;100:2418–2424. 4. Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol. 2006;106:21–28. 5. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol. 2007;49:2028–2034. 6. Arzt M, Floras JS, Logan AG, Kimoff RJ, Series F, Morrison D, Ferguson K, Belenkie I, Pfeifer M, Fleetham J, Hanly P, Smilovitch M, Ryan C, Tomlinson G, Bradley TD; CANPAP Investigators. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115:3173–3180. 7. Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med. 1999;341:949–954. 8. Solin P, Roebuck T, Johns DP, Walters EH, Naughton MT. Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure. Am J Respir Crit Care Med. 2000;162:2194–2200. 9. Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation. 2000;101:392–397. 10. Kjekshus J, Apetrei E, Barrios V, et al; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–2261. 11. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of rosuvastatin in patients with chronic heart failure (the gissi-hf trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–1239. 12. Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, Abbate A, Vrtovec B, Khan BV, Vetrovec GW. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol. 2009;104:1708–1716. 13. Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS. Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood- brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J Alzheimers Dis. 2011;23:307–318. 14. Millar PJ, Floras JS. Statins and the autonomic nervous system. Clin Sci (Lond). 2014;126:401–415. 15. Gullestad L, Ueland T, Kjekshus J, Nymo SH, Hulthe J, Muntendam P, Adourian A, Böhm M, van Veldhuisen DJ, Komajda M, Cleland JG, Wikstrand J, McMurray JJ, Aukrust P; CORONA Study Group. Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Eur Heart J. 2012;33:2290–2296.
Downloaded from http://hyper.ahajournals.org/ at California Institute of Technology on May 26, 2015
Statin Therapy in Heart Failure: Is It Time for a Second Look? Ali Javaheri, Daniel J. Rader and Shahrokh Javaheri Hypertension. 2014;63:909-910; originally published online February 10, 2014; doi: 10.1161/HYPERTENSIONAHA.113.02703 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/63/5/909
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/
Downloaded from http://hyper.ahajournals.org/ at California Institute of Technology on May 26, 2015
