1. PATHOPHYSIOLOGY HF/AHF Disease Awareness

2. HF=heart failure; LV=left ventricular 1. Alla et al. Heart Fail Rev 2007;12:91–5; 2. Gheorghiade et al. Am J Cardiol 2005;96:11G–17G The pathophysiology of heart failure results in an increasingly downward spiral Acute decompensated HF is associated with frequent hospitalizations 1 With each hospitalization, there is likely myocardial and renal damage that contributes to progressive LV or renal dysfunction, leading to an inevitable downward spiral 2 Cardiac function and quality of life Hospitalizations Time Chronic HF Acute decompensation Cardiac and renal damage/ incomplete recovery More rapid decline in chronic HF Increased risk of decompensations

3. Clinical classification of acute heart failure reflects a spectrum of overlapping presentations ACS=acute coronary syndrome; AHF=acute HF; HF=heart failure; JVP=jugular venous pressure; LV=left ventricular; MI=myocardial infarction; SBP=systolic blood pressure 1. Gheorghiade et al. Circulation 2005;112:3958–68; 2. Dickstein et al. Eur Heart J 2008;29:2388–442 Hypertensive AHF Cardiogenic shock ACS and HF Pulmonary edema Right HF Acutely decompensated chronic HF 70% incidence 1 Usually a history of progressive worsening of chronic HF on treatment and evidence of systemic and pulmonary congestion 2 Unknown incidence 1 Low output syndrome in the absence of pulmonary congestion, increased JVP and low LV filling pressures 2 >50% incidence for ↑ SBP 1 Mainly pulmonary rather than systemic congestion 1 Many patients have preserved ejection fraction 1 <3% incidence 1 Clinical characteristics: severe dyspnea, tachypnea, tachycardia and hypoxemia, which may require immediate airway intervention 1 Unknown incidence 1 Many patients have signs and symptoms of ACS that resolve after initial therapy or resolution of ischemia 1 Acute HF frequently precipitated by or associated with an arrhythmia 2 <1% incidence 1 Primarily complicating acute MI, fulminant myocarditis 1 Tissue hypoperfusion after adequate correction of preload and major arrhythmia 2

4. The Short-term and long-term Pathophysiogical consequences of AHF ‡ NT-pr Preload Afterload Congestion NT- proBNP Vaso- constriction Decreased cardiac function Fluid overload Myocardial overload and renal dysfunction Organ damage and dysfunction Hemodynamic abnormalities Neurohormonal activation Oxidative stress Inflammation O 2 supply-demand mismatch ‡Proposed schematic of acute heart failure pathophysiology Biolo et al. Circ Heart Fail 2010;3:44–50; Bott-Flügel et al. Eur J Heart Fail 2008;10:129–32; Cotter et al. Am Heart J 2008;155:9–18; Cotter et al. Eur J Heart Fail 2008;10:165–69; Feng & Wang. J Geriatr Cardiol 2008;5:1–6; Hunt et al. J Am Coll Cardiol 2009;53:e1–e90; Oikonomou et al. Hellenic J Cardiol 2011;52:30–40; Tsutsui et al. Am J Physiol Heart Circ Physiol 2011;301:H2181–90 Processes mediating long-term effects Amplification phase Processes mediating short-term effects Initiation phase Renal dysfunction as shown by ↑ Cystatin C, ↑ Creatinine, ↑ BUN Renal damage as shown by ↑ uric acid Myocardial fibrosis and remodelling as shown by ↑ fibroblast proliferation and activation Myocardial damage as shown by ↑ hs-cTnT

5. Patterns of ventricular remodelling are different for HFrEF and HFpEF HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction Adapted from Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008; Grossman et al. In: Perspectives in Cardiovascular Research; Myocardial Hypertrophy and Failure. Vol 7. Edited by Alpert NR. New York: Raven Press;1993:1–15 Increased systolic pressure Increased systolic wall stress Parallel addition of new myofibrils Wall thickening Concentric hypertrophy Pressure overload Volume overload Increased diastolic pressure Increased systolic wall stress Series addition of new sarcomeres Chamber enlargement Eccentric hypertrophy HFpEFHFrEF HFpEF – a condition of pressure overload characterized by concentric hypertrophic growth results in normal sized LV cavity with thickened walls and preserved systolic function Left ventricle normal Left ventricle pressure overload Left ventricle volume overload HFrEF – a condition of volume overload characterized by eccentric hypertrophy results in globular heart with thinning of the LV walls, decreased systolic function and enlarged left ventricular volume

6. Long-term Consequences of AHF: Higher NT- proBNP levels are associated with increased risk of mortality in patients with AHF NT-proBNP levels increase Quartile of NT-proBNP Hazard Ratio95% CI p value 1 st 1.0Reference 2 nd 1.70.7–4.40.247 3 rd 2.51.0–6.00.043 4 th 4.31.9–9.9<0.001 Hazard ratio AHF=acute heart failure; CI=confidence interval; NT-proBNP=N-terminal-pro-B-type natriuretic peptide ‡Analysis of data from 568 patients hospitalized for AHF in the Biomarkers in Acute Heart Failure (BACH) study †The NT-proBNP cutoffs were 2,248, 5,017, and 10,455 pg/mL for the 25th, 50th and 75th percentiles, respectively 1. Biolo et al. Circ Heart Fail 2010;3:44–50; 2. Maisel et al. J Am Coll Cardiol 2010;55:2062–76 Higher levels of NT-proBNP are associated with increased risk of mortality by 90 days in patients hospitalized for AHF ‡2 During episodes of AHF 1

7. Long-term Consequences of AHF: Cardiac troponin, a marker of myocyte injury/death, is commonly elevated in AHF and is associated with increased mortality Elevated troponin is associated with poor outcomes in AHF 1 Troponin is often released in patients with AHF 1 Cardiac troponin T (g/L) AHF=acute heart failure ‡Analysis of data from 364 patients hospitalized for AHF from the Finnish Acute Heart Failure (FINN-AKVA) study 1. Kociol et al. J Am Coll Cardiol 2010;56:1071–8; 2. Ilva et al. Eur J Heart Fail 2008;10:772–9 Higher levels of troponin T predict greater mortality in patients with AHF ‡2 All-cause mortality at 6 months (%) P=0.002 P=0.007

8. Long-term Consequences of AHF: Worsening renal function in patients hospitalized for AHF predicts poor outcomes >0.5 mg/L increase in cystatin C ≤0.5 mg/L increase in cystatin C 0.5 0.4 0.3 0.2 0.1 0 1. Maggioni et al. Eur J Heart Fail 2010;12:1076–84; 2. Rudiger et al. Eur J Heart Fail 2005;7:662–70; 3. Forman et al. J Am Coll Cardiol 2004;43:61–7; 4. Akhter et al. Am J Cardiol 2004;94:957–60; 5. Lassus et al. Eur Heart J 2010;31:2791–98 AHF=acute heart failure †Renal impairment defined as an estimated glomerular filtration rate <50 mL/min/1.73 m2 or creatinine clearance <50 mL/min; #Worsening of renal function defined as an increase in serum creatinine of >0.3 mg/dL or >0.5 mg/dL; ‡Analysis of data from 292 patients hospitalized for AHF from the Finnish Acute Heart Failure (FINN-AKVA) study Further worsening of renal function occurs in ~25% of patients hospitalized for AHF #3,4 ~30–40% of patients hospitalized for AHF have renal impairment †1,2 An increase in cystatin C in the first 48 hours following hospitalization for AHF is associated with poor prognosis ‡5 0100200300400 Days Cumulative mortality Item Code: 153049 Copyright © Novartis Pharma AG.