Canadian Journal of Cardiology 30 (2014) 155e158
Editorial
Exploring the Role of Aldosterone in Right Ventricular Function Alexis Harrison, MD, Brent D. Wilson, MD, PhD, and John J. Ryan, MD, FAHA, FACC Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah, USA
See article by Gregori et al., pages 188-194 of this issue. It has been more than 60 years since aldosterone (originally electrocortin) was first identified by Simpson et al.1 Aldosterone, a mineralocorticoid, is produced in the zona glomerulosa of the adrenal cortex and is critical in volume homeostasis, primarily regulated by the neurohormonal renin-angiotensinaldosterone system (RAAS) through downstream regulation of epithelial Naþ channels, Kþ channels, and Naþ/Kþ-ATPase.2 It is via this classical pathway that aldosterone was found to have a pathophysiologic role in hypertension. A new paradigm for the role of aldosterone in human health and disease continues to emerge. Chronically elevated levels of plasma aldosterone are being found to contribute to cardiac, vascular, renal, and metabolic complications independent of the effects on blood pressure.3 In the 1940s, with the work of Selye, aldosterone was also seen to have an association with myocardial necrosis and fibrosis.4 The concept that there are myocardial effects of aldosterone was resurrected and expanded on in the 1990s by re-examining aldosterone’s local effects in the myocardium leading to the hypothesis that hyperaldosteronism can result in left ventricular hypertrophy and cardiac remodelling.5 The clear benefit of inhibiting hyperaldosteronism in symptomatic chronic systolic left ventricular heart failure is well established and is reflected in recent American College of Cardiology Foundation/American Heart Association and European Society of Cardiology heart failure guidelines.6,7 The Randomized Aldactone Evaluation Study (RALES), published in 1999, examined the appropriateness and complications of spironolactone in combination with standard medical therapy in systolic heart failure, enrolling New York Heart Association class III and class IV systolic heart failure patients with a left ventricular ejection fraction of < 35%.8 The addition of spironolactone resulted in a 30% reduction in all-cause mortality after 2 years of therapy. The effect of aldosterone Received for publication December 23, 2013. Accepted December 23, 2013. Corresponding author: Dr John J. Ryan, Assistant Professor, Division of Cardiovascular Medicine, University of Utah Health Science Center, 30 North 1900 East, Room 4A100, Salt Lake City, Utah 84132, USA. Tel.: þ1801-585-2341; fax: þ1-801-587-5874. E-mail: [email protected] See page 157 for disclosure information.
blockade has been observed in patients with symptomatic left ventricular systolic dysfunction secondary to acute myocardial infarction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial, in which the addition of the aldosterone antagonist, eplerenone, resulted in a 15% relative risk reduction for allcause mortality.9 More recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study has shown similar benefits of adding eplerenone to treatment in patients with systolic heart failure and mild symptoms (New York Heart Association class II).10 However, aldosterone inhibition might promote clinically significant hyperkalemia, especially in the presence of existing renal dysfunction or potassium supplementation. For example, in the RALES trial, in which patients were excluded if creatinine was greater than 2.5 mg/dL (221 mmol/L), hyperkalemia developed in 2% of patients. However, hyperkalemia is more frequent in clinical practice, thereby requiring particular attention to be paid regarding proper patient selection and close laboratory monitoring.11 The role of aldosterone in right ventricular function and dysfunction has only recently been evaluated. Although the right ventricle (RV) has distinct embryology and physiology, compared with the left ventricle (LV), there are relevant lessons to be learned from treatment and pathophysiology of LV failure.12 Both ventricles respond to increases in afterload with a shift toward glycolysis,13,14 downregulation of breceptors,15,16 and a reduction in capillary density.17,18 Similar to the LV, overactivation of the RAAS has been recognized in patients with pulmonary arterial hypertension (PAH) and RV remodelling.19 Increasingly, appreciation of the interplay between the RV and pulmonary circulation has reconceptualized pulmonary hypertension management acknowledging a more integral role of RV pathophysiology in the disease process and potentially offering new neurohormonal targets for intervention.20 There is a great need for therapeutic targets for RV failure in light of the significant morbidity and mortality associated with this condition, with in-patient mortality for RV failure approaching 15%.21 Importantly, current treatment guidelines for decompensated right heart failure recommend the use of aldosterone antagonists, although its effectiveness has never been investigated in randomized controlled trials.22
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.12.025
156
The concept of hyperaldosteronism playing a part in vascular remodelling and RV dysfunction in PAH has been systematically described in preclinical data. In 2 experimental animal models of PAH, Maron and colleagues showed that elevated levels of the vasoconstrictor endothelin (ET)-1 stimulated plasma aldosterone and aldosterone-induced reactive oxygen species. In turn, aldosterone-induced reactive oxygen species oxidized the ETB receptor in pulmonary arterial endothelial cells to inhibit ETB-dependent synthesis of the potent vasodilator and antimitogenic molecule nitric oxide. In that study, decreased levels of bioavailable nitric oxide in the pulmonary vasculature mediated by aldosterone were associated with pulmonary vascular dysfunction, increased pulmonary hypertension, and unfavourable RV remodelling. In turn, pharmacological inhibition of aldosterone with eplerenone or spironolactone prevented and reversed pulmonary arteriole remodelling to improve pulmonary systolic pressure, pulmonary vascular resistance, and RV function.23 A retrospective analysis of spironolactone in the Pulmonary Arterial Hypertension, Randomized, Double-Blind, PlaceboControlled, Multicenter, Efficacy Study (ARIES)-1 and ARIES-2 trials showed a trend toward improved 6-minute walk time and B-type natriuretic peptide concentration with the combination of ambrisentan and spironolactone vs ambrisentan alone.24 Increased understanding of the role aldosterone plays in RV remodelling will provide further insight as to whether the clinical effects observed in ARIES-1 and -2 are secondary to the effects of spironolactone on the pulmonary vasculature or the RV itself. The study by Gregori and colleagues presented in this issue of the Canadian Journal of Cardiology adds to the emerging body of evidence linking aldosterone to the RV and to our understanding of the potential role of neurohormonal activity in RV remodelling and dysfunction.25 In this small, prospective study, the authors report their findings on 104 untreated patients with newly diagnosed systemic hypertension referred to a specialized hypertensive clinic for evaluation for secondary causes of hypertension. Secondary hypertension was being considered because of these patients’ younger age, variable blood pressure values, electrolyte abnormalities, and family history of kidney disease, and symptoms or signs of secondary hypertension. Patients with clinical conditions that could predispose to pulmonary hypertension were excluded. The investigators evaluated levels of renin (via plasma renin activity) and aldosterone (via plasma aldosterone concentrations) on standing and then subsequently with lying down. The study participants also underwent a fixed sodium diet before participation, 24-hour ambulatory blood pressure monitoring, electrocardiogram, and an echocardiogram. Normally renin and aldosterone should be suppressed with supination and can be increased with standing via a sympathetic reflex. Gregori and colleagues have previously shown that an inadequate suppression of the RAAS was noted to be more prevalent in patients with increased left ventricular hypertrophy and decreased left ventricular systolic function.26 In the current study, the authors show that inadequate suppression of the RAAS with supination correlates with a decreased RV myocardial performance index on echocardiography, a measure of RV dysfunction. Impressively, elevated renin and aldosterone without proper supine suppression correlated significantly with a worsening in measures of RV
Canadian Journal of Cardiology Volume 30 2014
systolic and diastolic dysfunction, namely a decreased tricuspid annular plane systolic excursion, an increased tissue Doppler-derived right ventricular myocardial performance index, and a reduced E/A transtricuspid ratio. In this setting, it is intriguing to speculate that chronic exposure to pathophysiologically relevant aldosterone levels with supination could modulate decreased RV function, in particular in the setting of Group 2 pulmonary hypertension (PH).27 Important limitations to this study include the fact that neither the tricuspid annular plane systolic excursion nor the RV myocardial performance index met American Society of Echocardiography criteria for RV dysfunction, thus the ultimate significance of this finding for the clinician is not known.28 Similarly, follow-up was limited and no outcomes data regarding progression to RV failure was available. Another limitation must be the consideration for the presence of LV dysfunction in these same patients, which can affect RV function. The optimism for the effects of aldosterone antagonism on the RV should be tempered, of course, by the simple fact that the RV is not the LV. Established RV and pulmonary vasculature medicines such as endothelin receptor antagonists and phosphodiesterase V inhibitors have failed to show clinical benefit in LV pathology.29,30 Preclinical work has also shown that spironolactone failed to improve RV performance in an animal model of Group 2 PH secondary to myocardial infarction.31 Furthermore, RAAS blockade with angiotensin receptor blocker plus eplerenone failed to improve RV function in an animal model of pulmonary artery banding.32 Additionally, although the work presented here by Gregori and colleagues and elsewhere argues for a role of aldosterone antagonism in treating the failing RV, preclinical and registry data supported the hypothesis that spironolactone could be beneficial in diastolic heart failure.33 With the aforementioned success and impressive mortality benefit seen in symptomatic systolic left ventricular dysfunction, investigators studied aldosterone blockade in left ventricular diastolic heart failure, a disease that has a mortality and hospitalization rate equaling systolic heart failure.34 The hope was that aldosterone blockade would prove to be the first drug to show some benefit because previous trials have shown minimal benefit. However, the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)(Clinicaltrials.gov identifier: NCT00094302) trial found that spironolactone vs placebo in patients with symptomatic heart failure with preserved ejection fraction failed to have an effect on the primary end point of cardiovascular mortality, aborted cardiac arrest, and hospitalization for heart failure management. A secondary end point, reduction in heart failure hospitalizations, was reduced by 2%, although this benefit was countered by a substantial increase in hyperkalemia and hospitalizations for renal failure. Hyperaldosteronism has an established role in left ventricular systolic dysfunction, a less clear role in left ventricular diastolic dysfunction, and an unknown but promising role in right ventricular remodelling and dysfunction. The study by Gregori and colleagues reinforces the burgeoning theory that aldosterone and its attendant neurohormonal pathways play an understudied role in RV dysfunction. To explore the role that aldosterone antagonism might have in the prevention or treatment of RV dysfunction, it is time to perform adequately sized randomized controlled trials in well-defined patient
Harrison et al. Aldosterone in the Right Ventricle
157
populations, such as Group 2 PH with RV failure, using robust clinical end points.
16. Bristow MR, Minobe W, Rasmussen R, et al. Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J Clin Invest 1992;89:803-15.
Disclosures The authors have no conflicts of interest to disclose.
17. Sabri A, Samuel JL, Marotte F, et al. Microvasculature in angiotensin IIdependent cardiac hypertrophy in the rat. Hypertension 1998;32:371-5.
References
18. Bogaard HJ, Natarajan R, Henderson SC, et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 2009;120:1951-60.
1. Simpson SA, Tait JF, Wettstein A, et al. Isolation from the adrenals of a new crystalline hormone with especially high effectiveness on mineral metabolism [in undetermined language]. Experientia 1953;9:333-5.
19. de Man FS, Tu L, Handoko ML, et al. Dysregulated renin-angiotensinaldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:780-9.
2. Williams JS, Williams GH. 50th anniversary of aldosterone. J Clin Endocrinol Metab 2003;88:2364-72.
20. Maron BA. Targeting neurohumoral signaling to treat pulmonary hypertension: the right ventricle coming into focus. Circulation 2012;126: 2806-8.
3. Guichard JL, Clark D 3rd, Calhoun DA, Ahmed MI. Aldosterone receptor antagonists: current perspectives and therapies. Vasc Health Risk Manag 2013;9:321-31. 4. Selye H. The general adaptation syndrome and the diseases of adaptation. J Allergy 1946;17:231, 289, 358. 5. Rossi GP, Sacchetto A, Visentin P, et al. Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension 1996;27:1039-45. 6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2013;62:e147-239. 7. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-847. 8. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med 1999;341: 709-17. 9. Pitt B, Williams G, Remme W, et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 2001;15:79-87. 10. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21. 11. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 2004;351:543-51. 12. Srivastava D, Olson EN. A genetic blueprint for cardiac development. Nature 2000;407:221-6. 13. Rich S, Pogoriler J, Husain AN, et al. Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest 2010;138:1234-9. 14. Schwartz A, Lee KS. Study of heart mitochondria and glycolytic metabolism in experimentally induced cardiac failure. Circ Res 1962;10: 321-32. 15. Piao L, Fang YH, Parikh KS, et al. Grk2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation 2012;126: 2859-69.
21. Campo A, Mathai SC, Le Pavec J, et al. Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension. Eur Respir J 2011;38:359-67. 22. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34: 1219-63. 23. Maron BA, Zhang YY, White K, et al. Aldosterone inactivates the endothelin-b receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension. Circulation 2012;126:963-74. 24. Maron BA, Waxman AB, Opotowsky AR, et al. Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). Am J Cardiol 2013;112:720-5. 25. Gregori M, Tocci G, Giammariolo B, et al. Abnormal regulation of renin angiotensin aldosterone system is associated with right ventricular dysfunction in hypertension. Can J Cardiol 2014;30:188-94. 26. Gregori M, Tocci G, Marra A, et al. Inadequate RAAS suppression is associated with excessive left ventricular mass and systo-diastolic dysfunction. Clin Res Cardiol 2013;102:725-33. 27. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation task force on expert consensus documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573-619. 28. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685-713 [quiz: 786-8]. 29. Packer M. Multicentre, double-blind, placebo-controlled study of longterm endothelin blockade with bosentan in chronic heart failured results of the REACH-1 trial (abstract). Circulation 1998;98(suppl 17): I-3. 30. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309: 1268-77. 31. Chabot A, Jiang BH, Shi Y, Tardif JC, Dupuis J. Role of aldosterone on lung structural remodelling and right ventricular function in congestive heart failure. BMC Cardiovasc Disord 2011;11:72.
158
32. Borgdorff MA, Bartelds B, Dickinson MG, Steendijk P, Berger RM. A cornerstone of heart failure treatment is not effective in experimental right ventricular failure. Int J Cardiol 2013;169:183-9. 33. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with
Canadian Journal of Cardiology Volume 30 2014 preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA 2013;309:781-91. 34. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251-9.
Editorial
Exploring the Role of Aldosterone in Right Ventricular Function Alexis Harrison, MD, Brent D. Wilson, MD, PhD, and John J. Ryan, MD, FAHA, FACC Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah, USA
See article by Gregori et al., pages 188-194 of this issue. It has been more than 60 years since aldosterone (originally electrocortin) was first identified by Simpson et al.1 Aldosterone, a mineralocorticoid, is produced in the zona glomerulosa of the adrenal cortex and is critical in volume homeostasis, primarily regulated by the neurohormonal renin-angiotensinaldosterone system (RAAS) through downstream regulation of epithelial Naþ channels, Kþ channels, and Naþ/Kþ-ATPase.2 It is via this classical pathway that aldosterone was found to have a pathophysiologic role in hypertension. A new paradigm for the role of aldosterone in human health and disease continues to emerge. Chronically elevated levels of plasma aldosterone are being found to contribute to cardiac, vascular, renal, and metabolic complications independent of the effects on blood pressure.3 In the 1940s, with the work of Selye, aldosterone was also seen to have an association with myocardial necrosis and fibrosis.4 The concept that there are myocardial effects of aldosterone was resurrected and expanded on in the 1990s by re-examining aldosterone’s local effects in the myocardium leading to the hypothesis that hyperaldosteronism can result in left ventricular hypertrophy and cardiac remodelling.5 The clear benefit of inhibiting hyperaldosteronism in symptomatic chronic systolic left ventricular heart failure is well established and is reflected in recent American College of Cardiology Foundation/American Heart Association and European Society of Cardiology heart failure guidelines.6,7 The Randomized Aldactone Evaluation Study (RALES), published in 1999, examined the appropriateness and complications of spironolactone in combination with standard medical therapy in systolic heart failure, enrolling New York Heart Association class III and class IV systolic heart failure patients with a left ventricular ejection fraction of < 35%.8 The addition of spironolactone resulted in a 30% reduction in all-cause mortality after 2 years of therapy. The effect of aldosterone Received for publication December 23, 2013. Accepted December 23, 2013. Corresponding author: Dr John J. Ryan, Assistant Professor, Division of Cardiovascular Medicine, University of Utah Health Science Center, 30 North 1900 East, Room 4A100, Salt Lake City, Utah 84132, USA. Tel.: þ1801-585-2341; fax: þ1-801-587-5874. E-mail: [email protected] See page 157 for disclosure information.
blockade has been observed in patients with symptomatic left ventricular systolic dysfunction secondary to acute myocardial infarction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial, in which the addition of the aldosterone antagonist, eplerenone, resulted in a 15% relative risk reduction for allcause mortality.9 More recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study has shown similar benefits of adding eplerenone to treatment in patients with systolic heart failure and mild symptoms (New York Heart Association class II).10 However, aldosterone inhibition might promote clinically significant hyperkalemia, especially in the presence of existing renal dysfunction or potassium supplementation. For example, in the RALES trial, in which patients were excluded if creatinine was greater than 2.5 mg/dL (221 mmol/L), hyperkalemia developed in 2% of patients. However, hyperkalemia is more frequent in clinical practice, thereby requiring particular attention to be paid regarding proper patient selection and close laboratory monitoring.11 The role of aldosterone in right ventricular function and dysfunction has only recently been evaluated. Although the right ventricle (RV) has distinct embryology and physiology, compared with the left ventricle (LV), there are relevant lessons to be learned from treatment and pathophysiology of LV failure.12 Both ventricles respond to increases in afterload with a shift toward glycolysis,13,14 downregulation of breceptors,15,16 and a reduction in capillary density.17,18 Similar to the LV, overactivation of the RAAS has been recognized in patients with pulmonary arterial hypertension (PAH) and RV remodelling.19 Increasingly, appreciation of the interplay between the RV and pulmonary circulation has reconceptualized pulmonary hypertension management acknowledging a more integral role of RV pathophysiology in the disease process and potentially offering new neurohormonal targets for intervention.20 There is a great need for therapeutic targets for RV failure in light of the significant morbidity and mortality associated with this condition, with in-patient mortality for RV failure approaching 15%.21 Importantly, current treatment guidelines for decompensated right heart failure recommend the use of aldosterone antagonists, although its effectiveness has never been investigated in randomized controlled trials.22
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.12.025
156
The concept of hyperaldosteronism playing a part in vascular remodelling and RV dysfunction in PAH has been systematically described in preclinical data. In 2 experimental animal models of PAH, Maron and colleagues showed that elevated levels of the vasoconstrictor endothelin (ET)-1 stimulated plasma aldosterone and aldosterone-induced reactive oxygen species. In turn, aldosterone-induced reactive oxygen species oxidized the ETB receptor in pulmonary arterial endothelial cells to inhibit ETB-dependent synthesis of the potent vasodilator and antimitogenic molecule nitric oxide. In that study, decreased levels of bioavailable nitric oxide in the pulmonary vasculature mediated by aldosterone were associated with pulmonary vascular dysfunction, increased pulmonary hypertension, and unfavourable RV remodelling. In turn, pharmacological inhibition of aldosterone with eplerenone or spironolactone prevented and reversed pulmonary arteriole remodelling to improve pulmonary systolic pressure, pulmonary vascular resistance, and RV function.23 A retrospective analysis of spironolactone in the Pulmonary Arterial Hypertension, Randomized, Double-Blind, PlaceboControlled, Multicenter, Efficacy Study (ARIES)-1 and ARIES-2 trials showed a trend toward improved 6-minute walk time and B-type natriuretic peptide concentration with the combination of ambrisentan and spironolactone vs ambrisentan alone.24 Increased understanding of the role aldosterone plays in RV remodelling will provide further insight as to whether the clinical effects observed in ARIES-1 and -2 are secondary to the effects of spironolactone on the pulmonary vasculature or the RV itself. The study by Gregori and colleagues presented in this issue of the Canadian Journal of Cardiology adds to the emerging body of evidence linking aldosterone to the RV and to our understanding of the potential role of neurohormonal activity in RV remodelling and dysfunction.25 In this small, prospective study, the authors report their findings on 104 untreated patients with newly diagnosed systemic hypertension referred to a specialized hypertensive clinic for evaluation for secondary causes of hypertension. Secondary hypertension was being considered because of these patients’ younger age, variable blood pressure values, electrolyte abnormalities, and family history of kidney disease, and symptoms or signs of secondary hypertension. Patients with clinical conditions that could predispose to pulmonary hypertension were excluded. The investigators evaluated levels of renin (via plasma renin activity) and aldosterone (via plasma aldosterone concentrations) on standing and then subsequently with lying down. The study participants also underwent a fixed sodium diet before participation, 24-hour ambulatory blood pressure monitoring, electrocardiogram, and an echocardiogram. Normally renin and aldosterone should be suppressed with supination and can be increased with standing via a sympathetic reflex. Gregori and colleagues have previously shown that an inadequate suppression of the RAAS was noted to be more prevalent in patients with increased left ventricular hypertrophy and decreased left ventricular systolic function.26 In the current study, the authors show that inadequate suppression of the RAAS with supination correlates with a decreased RV myocardial performance index on echocardiography, a measure of RV dysfunction. Impressively, elevated renin and aldosterone without proper supine suppression correlated significantly with a worsening in measures of RV
Canadian Journal of Cardiology Volume 30 2014
systolic and diastolic dysfunction, namely a decreased tricuspid annular plane systolic excursion, an increased tissue Doppler-derived right ventricular myocardial performance index, and a reduced E/A transtricuspid ratio. In this setting, it is intriguing to speculate that chronic exposure to pathophysiologically relevant aldosterone levels with supination could modulate decreased RV function, in particular in the setting of Group 2 pulmonary hypertension (PH).27 Important limitations to this study include the fact that neither the tricuspid annular plane systolic excursion nor the RV myocardial performance index met American Society of Echocardiography criteria for RV dysfunction, thus the ultimate significance of this finding for the clinician is not known.28 Similarly, follow-up was limited and no outcomes data regarding progression to RV failure was available. Another limitation must be the consideration for the presence of LV dysfunction in these same patients, which can affect RV function. The optimism for the effects of aldosterone antagonism on the RV should be tempered, of course, by the simple fact that the RV is not the LV. Established RV and pulmonary vasculature medicines such as endothelin receptor antagonists and phosphodiesterase V inhibitors have failed to show clinical benefit in LV pathology.29,30 Preclinical work has also shown that spironolactone failed to improve RV performance in an animal model of Group 2 PH secondary to myocardial infarction.31 Furthermore, RAAS blockade with angiotensin receptor blocker plus eplerenone failed to improve RV function in an animal model of pulmonary artery banding.32 Additionally, although the work presented here by Gregori and colleagues and elsewhere argues for a role of aldosterone antagonism in treating the failing RV, preclinical and registry data supported the hypothesis that spironolactone could be beneficial in diastolic heart failure.33 With the aforementioned success and impressive mortality benefit seen in symptomatic systolic left ventricular dysfunction, investigators studied aldosterone blockade in left ventricular diastolic heart failure, a disease that has a mortality and hospitalization rate equaling systolic heart failure.34 The hope was that aldosterone blockade would prove to be the first drug to show some benefit because previous trials have shown minimal benefit. However, the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)(Clinicaltrials.gov identifier: NCT00094302) trial found that spironolactone vs placebo in patients with symptomatic heart failure with preserved ejection fraction failed to have an effect on the primary end point of cardiovascular mortality, aborted cardiac arrest, and hospitalization for heart failure management. A secondary end point, reduction in heart failure hospitalizations, was reduced by 2%, although this benefit was countered by a substantial increase in hyperkalemia and hospitalizations for renal failure. Hyperaldosteronism has an established role in left ventricular systolic dysfunction, a less clear role in left ventricular diastolic dysfunction, and an unknown but promising role in right ventricular remodelling and dysfunction. The study by Gregori and colleagues reinforces the burgeoning theory that aldosterone and its attendant neurohormonal pathways play an understudied role in RV dysfunction. To explore the role that aldosterone antagonism might have in the prevention or treatment of RV dysfunction, it is time to perform adequately sized randomized controlled trials in well-defined patient
Harrison et al. Aldosterone in the Right Ventricle
157
populations, such as Group 2 PH with RV failure, using robust clinical end points.
16. Bristow MR, Minobe W, Rasmussen R, et al. Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J Clin Invest 1992;89:803-15.
Disclosures The authors have no conflicts of interest to disclose.
17. Sabri A, Samuel JL, Marotte F, et al. Microvasculature in angiotensin IIdependent cardiac hypertrophy in the rat. Hypertension 1998;32:371-5.
References
18. Bogaard HJ, Natarajan R, Henderson SC, et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 2009;120:1951-60.
1. Simpson SA, Tait JF, Wettstein A, et al. Isolation from the adrenals of a new crystalline hormone with especially high effectiveness on mineral metabolism [in undetermined language]. Experientia 1953;9:333-5.
19. de Man FS, Tu L, Handoko ML, et al. Dysregulated renin-angiotensinaldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:780-9.
2. Williams JS, Williams GH. 50th anniversary of aldosterone. J Clin Endocrinol Metab 2003;88:2364-72.
20. Maron BA. Targeting neurohumoral signaling to treat pulmonary hypertension: the right ventricle coming into focus. Circulation 2012;126: 2806-8.
3. Guichard JL, Clark D 3rd, Calhoun DA, Ahmed MI. Aldosterone receptor antagonists: current perspectives and therapies. Vasc Health Risk Manag 2013;9:321-31. 4. Selye H. The general adaptation syndrome and the diseases of adaptation. J Allergy 1946;17:231, 289, 358. 5. Rossi GP, Sacchetto A, Visentin P, et al. Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension 1996;27:1039-45. 6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2013;62:e147-239. 7. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-847. 8. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med 1999;341: 709-17. 9. Pitt B, Williams G, Remme W, et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 2001;15:79-87. 10. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21. 11. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 2004;351:543-51. 12. Srivastava D, Olson EN. A genetic blueprint for cardiac development. Nature 2000;407:221-6. 13. Rich S, Pogoriler J, Husain AN, et al. Long-term effects of epoprostenol on the pulmonary vasculature in idiopathic pulmonary arterial hypertension. Chest 2010;138:1234-9. 14. Schwartz A, Lee KS. Study of heart mitochondria and glycolytic metabolism in experimentally induced cardiac failure. Circ Res 1962;10: 321-32. 15. Piao L, Fang YH, Parikh KS, et al. Grk2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation 2012;126: 2859-69.
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