To know more visit HeartFailure.com Pathophysiology highlights To know more visit HeartFailure.com © 2015 Novartis Pharma AG, May 2015, GLCM/HTF/0028

Heart failure pathophysiology Silent underlying neurohormonal imbalance results in continued disease progression In patients with heart failure, left ventricular remodeling leads to changes in cardiac volume and wall thickness. The abnormality in cardiac structure or function contributes to1: Inadequate cardiac output Poor organ perfusion Activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) Activation of the RAAS gives rise to1,2: Vasoconstriction Increased sodium and water retention Fibrosis Hypertrophy Increased blood pressure Activation of the SNS leads to2: Increased heart rate and myocardial contractility Sodium retention Renin release Natriuretic peptides help counter the effects of the RAAS and SNS in chronic heart failure but this balancing effect is diminished as heart failure progresses. Sustained overactivation of the RAAS and SNS with attenuation of the effects of the natriuretic peptide system leads to neurohormonal imbalance in heart failure.2-4 1. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 2. Boerrigter G, Costello-Boerrigter L, Burnett JC Jr. Alterations in renal function in heart failure. In: Mann DL, ed. Heart Failure: A Companion to Braunwald's Heart Disease. 2nd ed. St Louis: Saunders; 2011. 3. McMurray J, Komajda M, Anker S, Gardner R. Heart failure: epidemiology, pathophysiology and diagnosis. In: Camm AJ, Lüscher TF, Serruys PW, eds. ESC Textbook of Cardiovascular Medicine, 2nd ed. New York: Oxford University Press; 2009. 4. Mann DL, Zipes DP, Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia: Saunders; 2015.

Heart failure pathophysiology Underlying neurohormonal imbalance results in continued disease progress ARE CHRONIC HEART FAILURE PATIENTS SILENTLY PROGRESSING? Even when heart failure symptoms are stabilised by current treatments and it may seem that patients are doing well, the neurohormonal imbalance underlying heart failure is still silently occurring, resulting in sustained progression of cardiac structure and function abnormalities.1 MYOCARDIAL INJURY Worsening systolic dysfunction and cardiac remodeling1 RAAS and SNS are overactivated to support heart function1 PROGRESSION OF HEART FAILURE Sustained neurohormonal imbalance leads to ongoing decline1 Beneficial compensatory effects of NPs are diminished2-4 RAAS = Renin-angiotensin-aldosterone system SNS = Sympathetic nervous system NPs = Natriuretic peptides 1. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 2. Boerrigter G, Costello-Boerrigter L, Burnett JC Jr. Alterations in renal function in heart failure. In: Mann DL, ed. Heart Failure: A Companion to Braunwald's Heart Disease. 2nd ed. St Louis: Saunders; 2011. 3. McMurray J, Komajda M, Anker S, Gardner R. Heart failure: epidemiology, pathophysiology and diagnosis. In: Camm AJ, Lüscher TF, Serruys PW, eds. ESC Textbook of Cardiovascular Medicine, 2nd ed. New York: Oxford University Press; 2009. 4. Mann DL, Zipes DP, Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia: Saunders; 2015.

HEART FAILURE IS A PROGRESSIVE DISEASE2 Heart failure pathophysiology Underlying neurohormonal imbalance results in continued disease progress Heart failure is a complex deteriorating condition driven by neurohormonal imbalance, leading to a spiral of worsening disease and punctuated by acute episodes that result in poor outcomes for patients.1 HEART FAILURE IS A PROGRESSIVE DISEASE2 Chronic decline CARDIAC FUNCTION Hospitalisations for acute decompensation episodes DISEASE PROGRESSION From Gheorghiade M, et al. Am J Cardiol. 2005. 1. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 2. Boerrigter G, Costello-Boerrigter L, Burnett JC Jr. Alterations in renal function in heart failure. In: Mann DL, ed. Heart Failure: A Companion to Braunwald's Heart Disease. 2nd ed. St Louis: Saunders; 2011.

Heart failure pathophysiology Underlying neurohormonal imbalance results in continued disease progress Natriuretic peptides may potentially be an important therapeutic target due to their ability to counterregulate the RAAS and SNS.2,3 PHYSIOLOGY OF THE THREE MAIN TYPES OF NATRIURETIC PEPTIDES IN HEART FAILURE3,4,6* BNP = B-type natriuretic peptide ANP = Atrial natriuretic peptide CNP = C-type natriuretic peptide CNS = Central nervous system NT-proBNP = N-terminal-proBNP TGF = Transforming growth factor *Neprilysin is the major enzyme responsible for degrading the natriuretic peptides ANP, BNP, and CNP.3 1. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 2. Boerrigter G, Costello-Boerrigter L, Burnett JC Jr. Alterations in renal function in heart failure. In: Mann DL, ed. Heart Failure: A Companion to Braunwald's Heart Disease. 2nd ed. St Louis: Saunders; 2011. 3. McMurray J, Komajda M, Anker S, Gardner R. Heart failure: epidemiology, pathophysiology and diagnosis. In: Camm AJ, Lüscher TF, Serruys PW, eds. ESC Textbook of Cardiovascular Medicine, 2nd ed. New York: Oxford University Press; 2009. 4. Mann DL, Zipes DP, Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia: Saunders; 2015. 5. Gheorghiade M, De Luca L, Fonarow GC, et al. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol. 2005;96(6A):11G-17G. 6. Goetze JP, Friis-Hansen L, Rehfeld JF, Nilsson B, Svendsen JH. Atrial secretion of B-type natriuretic peptide. Eur Heart J. 2006;27(14):1648-1650.

Heart failure pathophysiology Underlying neurohormonal imbalance results in continued disease progress Natriuretic peptides may potentially be an important therapeutic target due to their ability to counterregulate the RAAS and SNS.2,3 PHYSIOLOGY OF THE THREE MAIN TYPES OF NATRIURETIC PEPTIDES IN HEART FAILURE3,4,6* BNP = B-type natriuretic peptide ANP = Atrial natriuretic peptide CNP = C-type natriuretic peptide CNS = Central nervous system NT-proBNP = N-terminal-proBNP TGF = Transforming growth factor *Neprilysin is the major enzyme responsible for degrading the natriuretic peptides ANP, BNP, and CNP.3 1. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 2. Boerrigter G, Costello-Boerrigter L, Burnett JC Jr. Alterations in renal function in heart failure. In: Mann DL, ed. Heart Failure: A Companion to Braunwald's Heart Disease. 2nd ed. St Louis: Saunders; 2011. 3. McMurray J, Komajda M, Anker S, Gardner R. Heart failure: epidemiology, pathophysiology and diagnosis. In: Camm AJ, Lüscher TF, Serruys PW, eds. ESC Textbook of Cardiovascular Medicine, 2nd ed. New York: Oxford University Press; 2009. 4. Mann DL, Zipes DP, Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia: Saunders; 2015. 5. Gheorghiade M, De Luca L, Fonarow GC, et al. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol. 2005;96(6A):11G-17G. 6. Goetze JP, Friis-Hansen L, Rehfeld JF, Nilsson B, Svendsen JH. Atrial secretion of B-type natriuretic peptide. Eur Heart J. 2006;27(14):1648-1650.