The Endocrine and Neurohormonal Dysregulation in Heart Failure.

Transcription

1 European Society of Cardiology and the Argentine Society of Cardiology Chronic Heart Failure - Beyond the Left Ventricle The Endocrine and Neurohormonal Dysregulation in Heart Failure. Enrique Fairman; MD Clínica Santa Isabel y Bazterrica Buenos Aires Argentina No potential conflicts of interest

2 Heart Failure Pathophysiology A complex multiorgan disease Excess Neurohormonal Activation Multiple Endocrine Defficiency

3 Heart Failure Pathophysiology A complex multiorgan disease Multiple Endocrine Defficiency Insulin Resistance Thyroid hormone Anabolic Hormones Growth hormone Insulin-like growth factor 1 Anabolic steroids Testosterone DHEA

4 Incidence, Cases/1000 Person-years at Risk Insulin Resistance and Heart Failure Incidence of Heart Failure Prognostic Significance Ingelsson et al. JAMA 2005;294:334 Doehner et al. JACC 2005; 46:1019

5 Insulin Resistance and Heart Failure Heart Failure and Insulin Resistance Swan et al JACC :527 Witteles et al JACC 2004; 44:78

6 Pathophysiologycal link Hypertension Coronary disease Insulin Resistance Intracellular Glucose FFA Energetic Deficit Myocardial Damage Heart Failure Sympathetic Activity Tissue perfusion

7 Insulin Resistance Insulin Resistance and Heart Failure Inflammatory Mechanisms Adipose Tissue Inflammatory Mediators Tumor Necrosis Factor Interferon C-RP Interleuquina 6 Adiponectin Resistin Heart Failure

8 Energetic Consequences of Insulin Resistance Witteles Jacc 2008; 51:93-102

9 Pathophysiologycal link Hypertension Coronary disease Insulin Resistance Intracellular Glucose FFA Energetic Deficit Myocardial Damage Heart Failure Sympathetic Activity Tissue perfusion

10 Insulin Resistance and Heart Failure A potential therapeutic target Diabetic Medications Metformin TZD (Increase risk of heart failure?) Incretin System (GLP-1 DPP4 (-) ) Metabolic Modulators Trimetazidine

11 Metformin vs Other Treatments All Cause Hospital Admissions at one year Study (Treatment Control) Eurich / /773 Odds ratio (95%CI) ( ) Masoudi / / ( ) Total ( 95% CI) ( ) Eurich D et al. BJM 2007;335:497

12 Insulin Resistance and Heart Failure A potential therapeutic target Diabetic Medications Metformin TZD (Increase risk of heart failure?) Incretin System (GLP-1 DPP4 (-) ) Metabolic Modulators Trimetazidine

13 GLP-1 Infusion Metaanalisis Study or subgroup Halbirk et al Sokos et al Mean difference IV, fixed, 95% CI BNP Total (95%CI Favours control Favours experimental Study or subgroup Halbirk et al Nikolaidis et al Sokos et al Total (95%CI Mean difference IV, fixed, 95% CI Ey Fraction Munaf et al Int J Pept ; 2012: 2012: Favours control Favours experimental

14 Insulin Resistance and Heart Failure A potential therapeutic target Diabetic Medications Metformin TZD (Increase risk of heart failure?) Incretin System (GLP-1 DPP4 (-) ) Metabolic Modulators Trimetazidine At present there is not enough evidence

15 Low IGF-1 in HF patients GH ILGF-1 Low IGF-1 ressembles HF Low IGF-1 predicts HF cardiac performance peripheral vascular resistance exercise capacity Low IGF-1 in HF is associated with poor outcome

16 IGF-1 level Heart Failure and Growth Factor H Failure Controls Broglio et al 135±47(n:39) 194±64(n:42) Anker et al 124±9(n:21) 151±9(n:26) Al-Obaidi et al 121±18(n:12) 108±15(n:21) Anwar et al 83±(5(n:60) 95±5(n:103) Saeki et al 101±34(n:18) 173 ±27(n:15) Konteleon et al 124± 49(n:23) 236± 66(n:23) Mankowska et al 208±(n:183) 299(n:366) Weighted mean No trial with GH or IGF-1 in HF demostrated beneficial effects

17 Hypothyroidism in Heart Failure % N: 132 Ascheim D et al Thyroid ;12:511

18 Significance of Low T 3 n: 573 Iervasi et al. Circulation 2003;107:708

19 TH and DITPA in Heart Failure Author/year N Drug Results Adv Eff Moruzzi T4 (1month) SVR CO LVEY EXERCISE TOLERANCE Moruzzi T4(3 months) Hamilton T3 SVR CO No Malik T4 CI PCWP No Iervasi T3 SVR CO No Pingitore T3 NA Aldosterone LVEDV NTproBNP Goldman DITPA SVR CI Poorly tolerated No No Gerdes; Circulation 2010;122:385

20 DHEA Testosterone Anabolic Steroids in Heart Failure Testosterone and Exercise Capacity Jankowsa E et al. Circulation 2006; 114:1829 Toma et al. Circ Heart Fail. 2012;5:315

21 Anabolic Defficiency and Survival Jankowsa E et al. Circulation 2006; 114:1829

22 Multiple Endocrine Defficiency Reaffirms HF is a complex multiorgan disease. MED is: Just a biomarker not mechanistically linked to HF. Useful only for staging and monitoring Adaptative response. LEAVE THE STATUS QUO Negative consequence of HF. SEARCH AND CORRECT Possible therapeutic target, but still, no clear evidence

23 Heart Failure Pathophysiology A complex multiorgan disease Excess Neurohormonal Activation Multiple Endocrine Defficiency

24 Models of heart failure Cardiorenal Hemodynamic Neurohormonal

25 Mechanisms of heart failure Index Event Cardiac Disfunction Ventricular Remodelling Neurohormonal Activation Salt and H20 retention Vasoconstriction Structural Myocardial Damage

26 Neurohormonal Mechanisms in heart failure Trigger (cardiac damage) Vascular Underfilling Inadequate baroreceptor and chemoreceptors response Autonomic Imbalance Counterbalance Mechanisms (protective?) Natriuretic Peptides Prostaglandins Nitric Oxide Sympathetic tone Parasympathetic Neurohormonal Activation (compensatory and deletereous) Catecholamines RAAS AVP (irrespective of osmotic conditions) Endothelins

27 Death or Hospitalizacion for CHF (%) Therapeutic Application of the neurohormonal model p=0.001 Consensus Trial The Consensus Study Group N Engl J Med 1987; 316:1429 SOLVD Investigators N Engl J Med 1991; 325: SOLVD Investigators N Engl J Med 1992; 327: SOLVD Treatment Trial SOLVD Prevention Trial

28 Therapeutic Application of the neurohormonal model Copernicus Merit HF Cibis II MERIT-HF Study Group. Lancet 1999;353: CIBIS II Investigators Lancet 1999;353:9-13. Packer M et al. Circulation 2002;106: Capricorn Investigators Lancet 2011; 357: Capricorn

29 Clinical Application of the neurohormonal model Rales Emphasis Pitt et al.rales investigators N Engl J Med 1999; 341:709 Pitt et al. N Eng J Med 2003; 348:1309 Zannad et al. Emphasis HF Study Group N Engl J Med 2011; 364:11-21 Ephesus

30 Neurohormonal model based Trials CONSENSUS Positive Trials SOLVD AIRE SAVE TRACE RALES EPHESUS EMPHASIS CHARM ALTERNATIVE VALHEFT CHARM ADDED CIBIS II MERIT COPERNICUS CAPRICORN

31 Probability of Event Combination of ACE inhibitors and Angiotensin II receptor blockers Valsartan Valsartan and captopril Captopril Months Valiant Trial. NEJM 2003; 349:1963.

32 Death or rehospitalization for Heart Failure at 30 days. (% pts) Nesiritide in acute heart failure Placebo Nesiritide P=0.31 Hazard ratio 0.93 (95% CI ) Death or Rehospitalization for Heart Failure Death Rehospitalization For Heart Failure -0.7 (-2.1 to 0.7) -0.4 (-1.3 to 0.5) -0.1(-1.2 to 1.0) n:7141 Ascend HF Trial O`Connor et al. NEJM 2011; 365:32

33 %Event free survival Omapatrilat in heart failure Omapatrilat Enalapril P:0, Months Overture Trial Circulation 2002; 106: 920

34 ProportionWithout Event Proportion Surviving Tolvaptan in Heart Failure All-Cause Mortality Cardiovascular Mortality or Heart Failure Hospitalization Months in study Tolvaptan Placebo Months in Study N:4133 EVEREST Trial JAMA 2007; 297:1391

35 Central Sympathetic Inhibition % 5,5 p= ,1 4 3,4 moxonidina placebo Mortality Progress HF Moxcon Trial n:1934 Cohn et al. Eur J Heart Fail 2003;5:659

36 Neurohormonal model based Trials BEST MOXCON EVEREST ASCEND-HF OVERTURE RITZ IV FIRST VALIANT ENABLE RECOVER RENAISSANCE RENEWAL Positive Trials CONSENSUS SOLVD AIRE SAVE TRACE RALES EPHESUS EMPHASIS CHARM ALTERNATIVE Neutral or Negative Trials VALHEFT CHARM ADDED CIBIS II MERIT COPERNICUS CAPRICORN

37 Although excess neurohormonal activation is harmful, some degree may be neccesary

38 Limits of the NH blockade strategy Importance of hypotension Pre- and posttitration daytime and nocturnal diastolic hypotensive episodes Hypotension may be a pharmacotherapeutic ceiling Mak et al. J Cardiac Fail 2008;14:555

39 Are there limits to the neurohormonal model? Placebo ACE inhibitors βblockers except Bucindolol Bucindolol Omapatrilat Etanercept Moxonidine Endothelin Antagonists Angiotensin Receptor Antagonist Mehra et al. JACC 2003; 41:1606

40 We must stop assuming that the body s compensatory actions to chronic HF are harmful; we do not understand enough physiology to know why they are often needed. S Gottlieb. JACC 2003;41:1458.

41 Limits of the NH blockade strategy application Pathophysiology Therapy learning

42 Patagonia, Argentina