Preserved EF with heart failure (HF pef) 50% 5 year survival. Both have type 2 diabetes Both have hypertension Both have normal ejection fractions

Transcription

1 Research companies Government / University research

2 Preserved EF with heart failure (HF pef) 50% 5 year survival Both have type 2 diabetes Both have hypertension Both have normal ejection fractions

3 Introduction

4 Translational considerations in vascular risk factors

5 No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HF-PEF. ESC Guidelines 2016 Symptom relief-diuretics Possible mortality morbidity reduction and symptom relief-- SGLT2 inhibitors Translational considerations in heart failure: normal ejection fraction

6 Concluding comments

7 Type 2 diabetes and inflammation Immune system are altered in obesity and type 2 diabetes Most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the cardiovascular system and circulating leukocytes Altered levels of specific cytokines and chemokines Nat Rev Immunol Feb;11(2):98-107

8 Right ventricule Septum LV

9 In 2015 it affected about 40 million people globally Structural considerations Molecular considerations In the year after diagnosis the risk of death is about 35% after which it decreases to below 10% each year

10 Heart failure syndrome: symptoms and signs

11 Brain natriuretic peptide (BNP) >100 pg/ml or N-terminal pro-bnp >360 pg/ml

12 Completed trials: historical perspective of diabetes related heart failure

13 HEART FAILURE PREVALENCE IN SELECTED T2DM TRIALS Average percent of patients with heart failure in T2DM trials UKPDS 33-NR ADVANCE-NR ACCORD-4.3% VADT-NR SAVOR-13% TECOS-18% EXAMINE-28% EMP-Reg-10% CANVAS-14% LEADER-14% ELIXA-22% EXSCEL-16% 0 Glucose lowering trials DPP4 inhibitors SGLT2 inhibitors GLP-1 agonist Chilton-pending publication

14 T2DM PREVALENCE IN SELECTED HEART FAILURE TRIALS Average percent Chilton-pending publication RELAX-AHF (2)-47% ASCEND-HF-42.6% TRUE-AHF-39% EVEREST-39% I-Preserve-27% PEP-CHF-21% DIG-PEF-29% CHARM-Preserved-28% TOPCAT-33% Acute HF HF pef HF ref Normal EF PARADIGM-HF-35% SHIFT-30% EchoCRT-41% HF-ACTION-32% SENIORS-26% MERIT-HF-25% CHARM-Added-29% DIG-REF-28% Low EF

15 No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HF-PEF ESC HF 2016 guideline Lower filling pressure to LV (reduce pulmonary edema) Reduce BNP Quality of life Rhythm Heart rate Wall stress Reduce MVO2 Reduce demand Both? CV death / events

16 Acute treatment options for diabetes patients with heart failure and normal EF

17 Normal (reduced) filling pressures LA RV Left atrium pressure Increased PCW Post capillary-lv dysfunction High filling pressures Modified Mayo

18 Clinical outcome trials for preserved EF with heart failure overview

19 Primary outcome NEJM 2014;320:1383 TOPCAT

20 TOPCAT BNP

21 Type 2 diabetes : EMPA reg

22 ALL CAUSE MORTALITY IN HEART FAILURE TRIALS: FOCUS ON TYPE 2 DIABETES HFrEF Drug Significant increase adjusted all cause mortality in T2DM Significant increase in adjusted CV mortality in T2DM PARADIGM-HF Sacubitril/valsartan 1.4 Hazard ratio 1.54 HR Echo-CRT CRT 2.08 HR 1.79 SOLVD Enalapril 1.29 HR NA Chilton-pending publication

23 Candian study of lvedlp

24 Translational biology

25 Structural heart changes

26 High glucose induced myocardial fibrosis Diabetes Control Animal LVH Increased matrix STZ-treated rats High glucose Green Massons stain Collagenous matrix deposition Circ Res 49: Heart Fail Rev (2014) 19:15 23

27 Symptoms improve and less pulmonary congestion / SOB 10 Diuretics SGLT2 inhibitors

28 DIASTOLIC DYSFUNCTION: VERY STIFF, NON COMPLIANT LEFT VENTRICULE LARGER LEFT ATRIAL SIZE HFpEF LVEDP PCW BNP Olmsted County (Minn) residents without cardiovascular disease (n617) Circulation. 2007; 115:

29 Volume Clin. Cardiol. Vol. 16 (Suppl. 11), (1993) Myocardial fibrosis

30 CASE 1 38 y/o obese woman SOB / Atypical chest pain BMI-48 Type 2 DM-metformin HT 300 NS over 15 minutes-developed SOB Baseline

31 Molecular considerations Fuel / energy / ATP Mitochondria Cell membrane Heart fuel sources Glucose FFA Ketones (liver produces) Human heart horsepower 0.75 to 1

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33 CHRONIC ELEVATED GLUCOSE Oxidative stress Diabetes Reduced ATPs Swollen ballooned mitochondria Reduced numbers MRI Normal EF Severe systolic dysfunction Dysfunctional myofibrils 2-5 watts of mechanical power Beats about 40 million times a year

34 ELECTRON MICROSCOPE-MITOCHRONDRIA Diabetes caused mitochondrial swelling and crista fragmentation (yellow arrow) Control Diabetes Diabetes led to myocyte dissolution, muscular fiber twists and Z line disappearance, the effects of which were reversed by empagliflozin Diabetes + EMPa Redox Biology 15 (2018)

35 POTENTIAL BENEFICIAL EFFECTS OF SGLT2 INHIBITORS SGLT 2 inhibition / increased excretion of glucose / H20 / Na Calorie restriction glucagon: insulin ratio Reduced glucogenolysis Increased lipolysis / FFA Increase in b-hydroxybutyrate (ketones) Chilton-pending publication Liver Am J Cardiol Aug 4;80(3A):50A-64A

36 Lungs Capillaries Oxygen saturation=100% Post capillary Pulmonary artery Right ventricle Left atrium Left ventricle

37 Lungs Capillaries Oxygen saturation=100% Post capillary Pulmonary artery Right ventricle Pre capillary Left atrium Left ventricle

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39 PA Systolic 8-20 mm Hg at rest Exercise <30 mmhg Lungs Capillaries Oxygen saturation=100% Post capillary Pulmonary artery Capillaries PRESSURE increases-fluids alveoli Post capillary Pulmonary artery Right ventricle Pre capillary Right ventricle Pre capillary Normal Left atrium (6-10 mm Hg) Left atrium (increased risk for Afib) Pulmonary artery Left ventricle-(lvedp 6-10) Capillaries PRESSURE increases-fluids alveoli Post capillary Left ventricle dysfunction Matrix matters Ischemia-reduced LV function Many diabetes patients have both RV hypertrophy compensates Right ventricle Pre capillary RV hypertrophy decompensates Left atrium Left ventricle

40 HEART FAILURE WITH NORMAL EJECTION FRACTION (HFPEF) : ANNUAL MORTALITY % Yearly mortality 30 Real world studies overestimate True annual mortality PEP-HF N=852 0 Epideminology Mayo N= years Yearly RCT NEJM 355:251 EHJ 27:2338 Lancet 362:777

41 HEART FAILURE WITH NORMAL EF: MORTALITY RATE Percent mortality In hospital 1 month 3 months 6 months 5 years NEJM 355:251 J. Cardiac Failure 9:107

42 Modes of death In heart failure 60-70% die of CV etiologies Sudden death (40-45%) Heart failure 25-30% Stroke 10-15% MI 6-8% other Eur Heart J Mar 7;38(10):

43 TREATMENTS FOR HEART FAILURE WITH NORMAL EJECTION FRACTION Diuretics SGLT2 inhibitor? European Journal of Heart Failure (2018) 20, 16 37

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45 HF WITH NORMAL EJECTION FRACTION (HFPEF) Non cardiac comorbidities Endothelium / glycocalyx ROS & NO Diabetes / obesity Hypertension COPD Growth / remodeling Oxidative stress TGF-b Cardiomyocyte sgc cgmp PKG Concentric remodeling Reduced LV compliance Increase in PCW / LVEDP SOB / pulmonary congestion PRESSURE increases-fluids alveoli Capillaries Post capillary Pulmonary artery Right ventricle Pre capillary Left atrium (increased risk for Afib) Left ventricle dysfunction Matrix matters Ischemia-reduced LV function Many diabetes patients have both Lancet Diabetes Endocrinol Mar; 4(3):

46 HF WITH NORMAL EJECTION FRACTION (HFPEF) Chronic pulmonary congestion Muscularization of pulmonary vessels SMC EC Matrix PPARg Adiponectin Pulmonary artery Lungs Capillaries Proliferation of pulmonary capillaries Oxygen saturation=100% Post capillary Right ventricle Pre capillary Normal Pulmonary Pharmacology & Therapeutics 26 (2013) 420e426 CIrculation 2007;115:1275e84 Left atrium INCREASED Left ventricle end diastolic pressure

47 HF WITH NORMAL EJECTION FRACTION (HFPEF) Normal RVEF is 62% & 65% LV Pulm HT RVEF 34% Lungs Capillaries Oxygen saturation=100% Post capillary Pulmonary artery Right ventricle dysfunction Pre capillary Left atrium RV fails Hypertrophy (compensate) INCREASED Left ventricle end diastolic pressure Circ Res. 2014;115:

48 HF WITH NORMAL EJECTION FRACTION (HFPEF) Septum becomes flattened and less convex to the RV at end-diastole thickness of wall resistance (afterload) Pulmonary artery Capillaries Pre capillary pressure Lungs Oxygen saturation=100% Normal post capillary pressure Right ventricle dysfunction Left atrium Normally the LV pressure exceeds RV pressure during diastole..here you see RV pressure higher flattening the septum Normal left ventricle end diastolic pressure

49 OBESITY AND HFPEF 4000 Plasma volume ml 3907 p< FAT Pericardium Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF Heart volume PCW pericardial restraint R & L ventricular pressures exercise capacity (VO2 max) Circulation July 04; 136(1): Obese HF Non obese HF Control Obese HF Non obese HF Control Epicardial fat volume ml 945 p< Obese HF Non obese HF Control Obese HF Non obese HF Control

50 Right ventricular failure has very high mortality Beta-Blocker Evaluation of Survival Trial (BEST) N=2008 Systolic dysfunction patients Int J Cardiol February 23; 155(1):