Acute heart failure syndromes: clinical challenges. Pathophysiology. ESC Congress August. Paris, France. Marco Metra

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1 ESC Congress August. Paris, France. Acute heart failure syndromes: clinical challenges. Pathophysiology Marco Metra Cardiology, Dept. Of experimental and applied medicine. University of Brescia. Italy

2 DECLARATION OF CONFLICT OF INTEREST Received honoraria from Bayer, Corthera, Novartis

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5 Causes of Acute Heart Failure (ESC 2008) Acute decompensation of pre-existing chronic HF Acute coronary syndromes With large areas of myocardial ischaemia or infarction AMI mechanical complications RV infarction Hypertensive crisis Acute arrhythmias Valvular regurgitation Endocarditis, rupture of chordate tendinae Worsening of pre-existing VR Severe aortic valve stenosis Acute myocarditis Post-partum cardiomyopathy Tako-Tsubo cardiomyopathy Aortic dissection Cardiac tamponade Pulmonary embolism High otput syndromes Septicemia Thyrotoxicosis Severe anaemia Shunt syndromes Metra, Brutsaert, Dei Cas, Gheorghiade. ESC Intensive Acute Cardiac Care textbook

6 Metra, Brutsaert, Dei Cas, Gheorghiade. ESC Intensive Acute Cardiac Care textbook

7 Patient Comorbidities in ADHERE Patient comorbidities % of patients Insulin treated diabetes 16.6 Non insulin treated diabetes 24.9 Hypertension 70.9 Atrial arrhythmia 30.8 Ventricular arrhythmia 5.5 Previous cerebrovascular accident or TIA 15.5 Liver disease 1.6 Chronic kidney disease 19.6 Chronic pulmonary disease 27.6 Peripheral vascular disease 13.6 Anemia 17.6 Fonarow, G. C. et al. Arch Intern Med 2008;168:

8 Factors influencing clinical presentations & prognosis of AHF Fluid overload Blood pressure (peripheral perfusion) Myocardial ischemia Kidney dysfunction Each may or may not be present, with different relative importance, in each patient

9 Factors influencing clinical presentations & prognosis of AHF Fluid overload Blood pressure (peripheral perfusion) Myocardial ischemia Kidney dysfunction Each may or may not be present, with different relative importance, in each patient

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11 Spectrum of AHFS pathophysiological mechanisms Main mechanism of onset Main cause of symptoms Vascular (peripheral / diastolic) afterload and/or predominant LV diastolic dysfunction Fluid redistribution to the lungs Cardiac (central/ systolic) contractility Sodium and water renal retention Fluid accumulation Gain in body weight No Yes Onset Rapid (hours) Gradual (days) Main symptom Dyspnoea Fatigue Systolic BP Normal to high Normal to low LV filling pressure High In a few cases may be low with CO LVEF & Cardiac output Normal Low Metra, Brutsaert, Dei Cas, Gheorghiade. ESC Intensive Acute Cardiac Care textbook

12 Pathophysiologic mechanisms in acute heart failure LV afterload Cardiac dysfunction systolic diastolic Metra, Brutsaert, Gheorghiade, Dei Cas. ESC Intensive Acute Cardiac Care textbook

13 Pathophysiologic mechanisms in acute heart failure LV afterload Cardiac dysfunction systolic diastolic Fluid redistribution to the lungs Lung congestion LV wall stress Metra, Brutsaert, Gheorghiade, Dei Cas. ESC Intensive Acute Cardiac Care textbook

14 Pathophysiologic mechanisms in acute heart failure LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Renal changes / renal dysfunction Fluid redistribution to the lungs Lung congestion LV wall stress Neurohormonal activation RAA SNS - ADH Inflammatory activation Na-H 2 O retention Congestion LV preload Metra, Brutsaert, Gheorghiade, Dei Cas. ESC Intensive Acute Cardiac Care textbook

15 tachycardia coronary perfusion pressure Myocardial ischemia MVO 2 Pathophysiologic mechanisms in acute heart failure LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Neurohormonal activation RAA SNS - ADH Inflammatory activation Diuretic use Diuretic resistance Renal changes / renal dysfunction Na-H 2 O retention Congestion Fluid redistribution to the lungs Lung congestion LV wall stress LV preload Metra, Brutsaert, Gheorghiade, Dei Cas. ESC Intensive Acute Cardiac Care textbook

16 Changes in epad Systolic heart failure Diastolic heart failure Circulation 2008;118:

17 Probability of an HF event for 261 patients during a 6-month period in relation to chronic daily epad Copyright 2010 American Heart Association Stevenson, L. W. et al. Circ Heart Fail 2010;3:

18 Fraction of patients Fraction of patients Prognostic value of NT-ProBNP at discharge in patients hospitalised for AHF 1 Cardiac mortality 1 Cardiac mortality or CV Hospitalizations Patients at risk NT-ProBNP: P< Discharge NT-ProBNP <6078 Discharge NT-ProBNP > Days Patients at risk NT-prBNP: P< Discharge NT-ProBNP <3275 Discharge NT-ProBNP >3275 < < > > Days Metra Dei Cas. Eur J Heart Fail. 2007;9:

19 Cumulative Number of HF Hospitalizations CHAMPION: Wireless PA monitoring in HF: a randomised controlled trial Treatment Control p < 0.001, based on Negative Binomial Regression Months 15 Months At Risk Treatment Control Days from Implant Abraham WT et al. Lancet Feb 19;377(9766):

20 Weight changes after HF hospitalization are predictive of subsequent re-hospitalization but not of mortality: results from EVEREST Blair, J. E.A. et al. Eur Heart J :

21 Factors influencing clinical presentations & prognosis of AHF Fluid overload Blood pressure (peripheral perfusion) Myocardial ischemia Kidney dysfunction Each may or may not be present, with different relative importance, in each patient

22 Clinical significance of high blood pressure in AHF Cause of AHF Afterload mismatch Consequence of AHF neurohormonal activation cardiac function

23 SBP in AHF Registries ADHERE, AHJ patients from 282 hospitals Mean SBP, 144 mmhg SBP >140: 50% of pts OPTIMIZE-HF, JAMA patients from 259 hospitals Mean SBP, mmhg SBP >140: 50% of pts Italian Survey, EHJ patients from 206 cardiology centers Mean SBP, mmhg, WHF, de novo SBP >140: 43%; 38% WHF, 49% de novo EFICA, EJHF patients from 60 centers Mean SBP, mmhg; 139 without CS pts Courtesy of M. Gheorghiade

24 In-Hospital Mortality Rates by Admission Systolic Blood Pressure Deciles (n = ) Gheorghiade, M. et al. JAMA 2006;296:

25 Risk Stratification Data Points in ED Patients With Suspected Acute Heart Failure Peacock, W. F. et al. J Am Coll Cardiol 2010;56:

26 Acute HF treatment strategy according to SBP Oxygen /NIV, loop diuretic + vasodilator Clinical evaluation SBP >100 mmhg SBP mmhg SBP <90 mmhg Vasodilator (NTG, nitroprusside, nesiritide), levosimendan Vasodilator and/or inotrope (dobutamine, PDEI, levosimendan) Consider preload correction with fluids or inotrope (dopamine) Good response stabilize & initiate oral diuretics, ACEI/ARB, β-blocker Poor response inotrope, vasopressor, mechanical support, consider PAC ESC 2008 guidelines

27 Influence of baseline blood pressure on symptoms improvement with relaxin in AHF Pre-Relax-AHF study Teerlink et al. Eur Heart J 2009 ; 30 ( Abstract Supplement ), 164

28 tachycardia coronary perfusion pressure Myocardial ischemia MVO 2 Pathophysiologic mechanisms in acute heart failure LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Neurohormonal activation RAA SNS - ADH Inflammatory activation Diuretic use Diuretic resistance Renal changes / renal dysfunction Na-H 2 O retention Congestion Fluid redistribution to the lungs Lung congestion LV wall stress LV preload Metra, Brutsaert, Gheorghiade, Dei Cas. ESC Intensive Acute Cardiac Care textbook

29 Factors influencing clinical presentations & prognosis of AHF Fluid overload Blood pressure (peripheral perfusion) Myocardial ischemia / damage Kidney dysfunction Each may or may not be present, with different relative importance, in each patient

30 AHF Hemodynamic abnormalities + neurohormonal activation Low CO / hypotension LVEDP / wall stress Heart rate Inotropic agents Coronary perfusion Pulmonary congestion O 2 uptake myocardial VO 2 Myocardial damage / necrosis Metra, Brutsaert, Dei Cas, Gheorghiade. ESC Intensive Acute Cardiac Care textbook

31 Prevalence of Detectable (>0.01 pg/ml)troponin T in patients with AHF with daily blood sampling 46% Coronary artery disease 26% Idiopathic dilated cardiomyopathy 26% TnT (1 sample) TnT (>1 sample) No TnT 28% 60% TnT (1 sample) TnT (>1 sample) No TnT 14% Metra et al., Eur J Heart Fail. 2007;9:776-86

32 Prediction of Cardiac Death: CART analysis 107 patients discharged after AHF P< NT-proBNP <6078pg/mL n= 76; 1-year survival, 91% NT-proBNP >6078 pg/ml n= 31; 1-year survival, 34% P=0.021 NYHA class I/II n= 61; 1-year survival, 95% NYHA class III/IV n= 15; 1-year survival, 71% P=0.018 ctnt undetectable n= 40; 1-year survival, 100% ctnt detectable n= 21; 1-year survival, 78% Metra et al., Eur J Heart Fail. 2007;9:776-86

33 Fraction of patients Freedom from Death or CV Hospitalization and ctnt plasma levels in Acute Heart Failure Fraction of patients 1 Cardiac mortality Cardiac mortality or CV hospitalizations P< No ctnt detectable ctnt detectable Days P<0.01 No ctnt detectable ctnt detectable Patients at risk Patients at risk: No ctnt No ctnt ctnt ctnt Metra et al., Eur J Heart Fail. 2007;9: Days

34 Usefulness of both BNP and Cardiac Troponin Levels to Predict In-Hospital Mortality in ADHERE Fonarow et al. Am J Cardiol 2008; 101:

35 Post-discharge mortality and HF readmissions in patients subdivided on the basis of troponin and BNP at discharge Xue Y et al. Eur J Heart Fail 2011;13:37-42

36 Factors influencing clinical presentations & prognosis of AHF Blood pressure (peripheral perfusion) Fluid overload Myocardial ischemia Kidney dysfunction Each may or may not be present, with different relative importance, in each patient

37 Potential impact of kidney dysfunction on outcomes of patients with AHF length of hospitalization Need of higher furosemide doses Contraindication to ACEi/ ARBs neurohormonal activation & inflammatory activity Anemia

38 Kidney dysfunction in heart failure

39 The Cardio-Renal Syndrome Gheorghiade, M. et al. J Am Coll Cardiol 2009;53:

40 The effect of an increase in cystatin C on mortality in patients with a small rise in creatinine during hospitalization for acute heart failure. 48% Creat>0.3 mg/ Cys-C>0.2 Cys-C<0.2, / Creat<0.3 Cys-C >0.2 Lassus J P et al. Eur Heart J 2010;31:

41 Mortality and/or Heart Failure Hospitalization in ADHF Patients Without Advance Kidney Dysfunction Beta trace protein Cystatin C Manzano-Fernandez, S. et al. J Am Coll Cardiol 2011;57:

42 Clinical outcome of renal tubular damage in chronic heart failure Damman K et al. Eur Heart J 2011;eurheartj.ehr190

43 Pathophysiology of AHF Cardiac dysfunction Blood pressure Fluid overload Neuro-hormonal (& Inflammatory?) activation Myocardial ischemia Kidney dysfunction

44 Event-free survival Development of Circulatory-Renal limitations (CRLimit) to ACE inhibitors identifies patients with severe heart failure and early mortality CR Limit, no inotropes, n=45 16 CR Limit, on inotropes, n=14 On ACEi, n= I 3 CRLimit vs. on ACE: HR, 2.8 (1.8 to 4.4; p<0.0001) adjusted for age, SBP, creatinine Inotropes vs. no inotropes: p= I I I I I I I I I I I I I Months from hospitalization Kittleson, M. et al. J Am Coll Cardiol 2003;41:

45 Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET HR, 1.59; 95%CI, HR, 1.30; 95%CI, Metra et al., Eur J Heart Fail 2007; 9:

46 Carvedilol use at discharge after a HF hospitalization is associated with improved survival: an analysis from OPTIMIZE-HF Fonarow et al. Am Heart J 2007;153:82.e1282.e11

47 Biomarkers in patients admitted for HF and/or acute dyspnea No. NPs ctni CgA CRP Low ly% Zairis, X X X Alonso-Martines, X Mueller, X Milo-Cotter, X Pascual-Figal, X X X Januzzi, JACC X X Manzano-Fernandez, X Rehman et al. JACC X X X Shah, X van Kimmenade, X Dieplinger et al., X X X ST2

48 Association of a low lymphocyte ratio to a poor survival: analysis from Pre-RELAX-AHF Milo-Cotter et al. Cardiology 2010; 117:190-6

49 Multimarker Testing with ST2 and BNP and Rates of Death After Acute Heart Failure Rehman, S. U. et al. J Am Coll Cardiol 2008;52:

50 Knowing the pathophysiology of AHFS, i.e. transforming an iceberg in a mountain we can safely climb