Prof. J.P.Das Oration HEART FAILURE

1

22nd Annual Conference OfINDIAN COLLEGE OF

CARDIOLOGY ,PATNA, BIHAR

PROF. J.P.DAS ORATION : HEART FAILURE

Orator: Prof. U. C. Samal

2

graduated with honours from SCB Medical College, Cuttack in 1956. He went to U.K. in 1960 for higher studies and passed the membership examination of the Royal College of Physicians of Edinburg in 1962. He joined the teaching faculty at SCB Medical College in 1962 in the department of Medicine and later joined the Christian Medical College, Vellore where he did his doctorate degree in Cardiology. While at Vellore he worked with a team of pioneers in Cardiology in India like Prof. Kamala Vithilingam, Prof. George Cherian, Prof. I.P. Sukumar and Prof. S.C. Munsi.

On his return to Orissa he pioneered the first cardiology department in Orissa at SCB Medical College, Cuttack where he started the ICCU, the Cardiac Cath Laboratory, Cardiac Pacing, Electrophysiology, Endomyocardial biopsy, and 2D Doppler echocardiography in the nineteen seventies. SCB medical Cardiology department became a landing centre of cardiology in Eastern India. Prof. Das also visited and worked at various cardiac centers aboard in UK, Holland, Moscow.

He is a fellow of the Royal College of Physicians of Edinburg, National Academy of Medical Sciences, India, American College of Cardiology, International Medical Science Academy, Cardiological society of India, Indian College of Physicians and the Indian College of Cardiology.

Prof. Das is an eminent medical teacher and has been an examiner in cardiology at various universities and the National Board of Examinations, He has volumes of work and publications on endomyocaridal biopsy in diabetic cardiomyopathy & aorto- arteritis. In 1967 he was the first in CMC, Vellore to defibrillate a case of atrial fibrillation successfully and he had a series of it.

His loving students have been working at various institutions in Indian and abroad and Prof. Das is proud of their achievements. Besides being a distinguished Cardiologist in the Country. Prof. Das is an eminent painter who has held solo painting exhibitions at Bhubaneswar, Calcutta, and Bangalore.

Utakal University, The Primer and oldest University Odisa has decorated Prof. J.P.Das with the honour of Doctor of Science which is a new feather to his cap.

Outstanding doctor, medical teacher, scientist, philosopher , poet & painter …

3

Heart Failure Management Timeline and New

Paradigm as viewed beyond 2015...

Prof. U. C. SamalMD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS

Ex- Prof. Cardiology & Ex-HOD Medicine Patna Medical College, Patna, Bihar

Past President, Indian College of CardiologyPermanent & Chief Trustee, ICC-Heart Failure Foundation

National Convener , Heart Failure Sub Specialty -CSI Full Member of HFSA/HFA-ESC

Dr. J.P. Das Heart Failure Oration“Advances to the applications”

4

Heart Failure Paradigm from Hippocrates to the Modern Era.

Spectrum of Heart Failure Syndromes.Reduced Ejection Fraction (HFrEF) with

neurohumoral activation inhibition.HFrEF with neurohumoral modulation.Under explored world of Heart Failure with

Preserved Ejection Fraction (HFpEF/HFNEF)

Plan

5

Heart Failure Paradigm from Hippocrates to the Modern

Era.

6

THOMAS KUHN AND THE PARADIGM SHIFT

"The Structure of Scientific Revolutions" , describes scientific progress in terms of a series of paradigm shifts.

When the new data and concepts are sufficiently revolutionary to invalidate the foundations of the former normal science, a paradigm takes place.

Crossovers Between Functional and Proliferative Signaling in the Pathogenesis of Heart Failure: Arnold M. Katz, MD

“Paradigm shift could cause seeing the same information in an entirely different way”

7

T.S.Kuhn (1922-96),US Philosopher of Science

Rubin’s vase

Young maidOld woman

Duck

Rabb

it

Two

diff

eren

t fa

ces

Rubin Vases

8

According to Hippocrates, pleural effusions are caused when an excess of the cold humor (phlegm) moves form the brain to the chest. This paradigm, which was supported by Galen, lasted almost 2000 years, until Harvey's description of the circulation in 1628 stimulated a paradigm shift that overthrew this explanation of heart failure.

Paradigm Shifts in Heart Failure500 BC – 1628 AD

Phlegm to Hemodynamics


Hemodynamics

Phlegm (Cold Humor)

Hippocrates5th Century BC

Galen2nd Century

AD

Harvey

1628

9

Paradigm Shifts in Heart Failure1628 -1940

Rise, Decline and Reemergence of Hemodynamics, Rise and Decline of

Hypertropy

Throughout the 19 th Century, emphasis on the mechanisms responsible for heart failure focused on changes in the size and shape of diseased hearts. The progressive nature of dilatation (remodeling) was well understood by the middle of this century, which ended with a clear understanding that hypertrophy too was progressive. This emphasis on changes in the size and shape of the failing heart ended after publication of Starling's Law of the Heart returned attention to the hemodynamics of this syndrome.

Phlegm (Cold Humor)

Hemodynamics

Harvey

1628

Vieussens

1714

Starling

1917

Mayow

1674

Lancisi

1745

Morgagni

1759

Corvisart

1801

Flint Paul Osler

1870 1884 1892

Dilatation

Hypertrophy

Dilation vs.

Hypertrophy

Progression

10


Rise and Decline of the Kidney, Emergence of contractility

Discovery of the diuretic properties of organic mercurials in 1920 stimulated research in renal physiology that led to the development of thiazide and loop diuretics. At the same time, basic research in cardiac hemodynamics , followed by the introduction of cardiac catheterization,provided the basis for modern cardiac surgery. The increasing pace of discovery continued with the description of myocardial contractility in 1955, recognition that myocardial contractility isdepressed in the failing heart in 1967, and the identification of the first molecular abnormality in the failing heart in 1962.

Hypertrophy

Starling

1917

Wiggers

1920s

Cournand & Richards

1941

(Forssmann, 1929)

Harkin & Bailey, 1948

(Souttar, 1925)

Hemodynamics

Catherization Mitral Comissuroto

my

Open Heart Surger

y

Contractility

Saxl and Heilig1920

ThiazidesLoop Diuretics

Braunwald

1967

Sarnoff

1955Salt and water Retention

Alpert & Gordon1962

11


Rise of Vasodilators and Fall of Inotropes The Cardiomyopathy of Overload

During the 1970s and 1980s, the short-term benefits of new inotropic agents stimulated efforts to increase contractility in the failing heart. The importance of hemodynamics was highlighted by short-term improvement following administration of several classes of vasodilators, and a survival benefit for a vasodilators reported in V-Heft I, and CONSENSUS I. The end of this era was heralded by evidence that inotropic therapy worsened prognosis. The maladaptive features of hypertrophy attracted little attention until 1990, when evidence began to emerge that heart failure was exacerbated by the growth response in overloaded hearts, that angiotensin II evoked a proliferative response, and that myosin mutations caused hypertrophic cardiomyopathy.

Hypertrophy

Hemodynamics

Contractility

Re-Expression of the Fetal Phenotype

Remodeling and

Cell Death

Cardiomyopathy of Overload Angiotensin as Growth Factor

Myosin Mutations in FHC

VasodilatorsV-Heft

ICONSENSU

S I

Amrinone

Milrinone Promise

12


Maladaptive Growth and Cell Death

Evidence that proliferative signaling caused by mediators of the neurohumoral response is a major cause of the poor prognosis in heart failure came from clinical trials which showed that most vasodilators worsen prognosis, and that b blockers, in spite of their negative inotropic effects, improve survival.

Hypertrophy

Cytokines

Apoptosis and

Necrosis Cell

Elongation

TRANSCRIPTIONAL REGULATION:

PK-C, Gβγ, cAMP, JAK/STATCytoskeleton,MAP KinasesMyogenic Determinanats,

Calcinerulin

Crossovers between

Functional and

Proliferative Signaling

Hemodynamics

Contractility

Cardiomyopathy of Overload

Nifedipine

Ditiazem Flosequinon

Prostacyclin Moxonidi

neVasodilator Trials

Ibopamine

Promise Trial Vest Trial

Carvedilol

Β- Blocker Trials

CIBIS

MERIT

COPERNICUS

Neurohormones•Norepinephrine•Renin•Angiotensin II•Copeptin•Endothelin

Vascular system•Homocysteine•Adhesion molecules•(ICAM, P-selectin)•Endothelin•Adiponectin•C-type natriuretic peptide

Inflammation•C-reactive protein•sST2•Tumor necrosis factor•FAS (APO-1)•GDF-15•Pentraxin 3•Adipokines•Cytokines•Procalcitonin•Osteoprotegerin

Myocardial stress•BNP/ NT proBNP•M-R proANP•pro-adrenomedullin•Neuregulin•sST2

Myocardial injury•Cardiac troponins•High sensitivity cardiac troponins•Myosin light-chain kinase 1•Heart-type fatty acid binding protein•Pentraxin 3

Matrix and cellular

remodeling•Galectin-3•sST2•GDF-15•MMPs•TIMPs•Collagen propeptides•Osteopontin

Cardio-renal syndrome

•Creatinine•Cystatin C•NGAL•ß-Trace protein

Oxidative stress•Oxidized LDL•Myeloperoxidase•Urinary biopyrrins•Urinary and plasma isoprostanes•Plasma malondialdehyde

HF: A systemic illness / Syndrome…?

13

Nature Review Cardiology Vol.9 June 12 pg 349

BNP Not Breathing Probarly, 2001, Januzi/ MaiselBiomarkers

Braunwald 1978

Differences between short-term and long-term effects of drugs used to treat heart failure can be attributed to different

consequences of functional and proliferative signaling.

SHORT-TERM EFFECT LONG-TERM EFFECTVasodilatorsDirect acting(Minoxidil, short-acting Ca blockers, prazocin, prostacyclin, ibopamine, PDE Inhibitors, moxonidine)ACE inhibitors

AT1 receptor blockers

Afterload reduction(functional Signaling)



Transcriptional activation(Proliferative signaling)

Transcriptional inhibition(Proliferative signaling)

Transcriptional inhibition(Proliferative signaling)

InotropesB-agonists(Xamoterol, dubutamine)PDE inhibitors(Milrinone, vesnarinone, pimobendan etc)

Cardiac Output(functional Signaling)

Cardiac output (functional Signaling)

Transcriptional activation (Proliferative signaling)

Transcriptional activation(Proliferative signaling)

B-Blockers Cardiac output(functional Signaling)

Transcriptional inhibition (Proliferative signaling)

Spironolactone Diuresis (functional Signaling) ? Transcriptional inhibition(Proliferative signaling)


14

15

Functional signaling, which modifies the behavior of preexisting structures by post-translational modifications, enables an organism to survive using such responses as fight or flight. In the case of proliferative signaling, transcriptional changes make it possible for an organism to grow its way out of trouble.

Katz, Physiology of the Heart (3rd Ed), Philadelphia, Lippincott/Williams & Wilkins, 2001.

Chronotropic, Inotropic Lusitropic stimulation of the heart

hypertrophic response, cell elongation, apoptosis, leading to remodeling and progression of HF.

16

Spectrum of Heart Failure Syndromes

HFpEF HFrEF

Age Usually >60yrs Any

Sex Predominance Women Men

Common comorbidities

Hypertension +++ ++

Diabetes +++ ++

CAD or Previous MI +/++ +++

Renal Failure ++ +

Obesity ++ +

Atrial Fibrillation ++ +

Chronic Lung disease ++ -

Ventricular Structure/ Atrial Size(i.e. increase LV mass and LA size)

Usually concentric LV remodeling or hypertrophy

Usually eccentric remodeling or hypertrophy

Dyspnea & Fatigue ++ ++

Exercise intolerance ++ ++

Systolic dysfunction + ++

Diastolic dysfunction ++ ++

Secondary pulmonary hypertension R/V Failure ++ ++

Benefit from ACEIs & ARBs - ++

Benefit from B-Blockers ? ++

Benefit from aldosterone ? ++

Benefit from ICD/CRT ? ++

Similarities and differences in HFpEF/ HFNEF & HFrEF

Modified from Barry A. Borlaug, Mayo Clinic Cardiology, 201317

Fundamental Pathophysiologic Mechanism

HFrEF HFpEFMyocyte loss of

Infarct/ inflamationInfectious/ Toxin

Old ParadigmHypertension

Contractile DysfunctionGenetic/ Toxin

Concentric RemodelingLVH/Fibrosis/ Diastolic Dysf

Eccentric Remodeling NH Activation

NH Activation Most unlikely … Needs New Paradigm

18

Patterns of cardiac myocyte hypertrophyA, Morphology of cardiac myocytes in response to hemodynamic pressure and volume overloading. Phenotypically distinct changes in the morphology of myocyte occur in response to the type of hemodynamic overload that is superimposed. When the overload is predominantly due to an increase in pressure, the increase in systolic wall stress leads to the parallel addition of sarcomeres and widening of the cardiac myocytes. When the overload is predominantly due to an increase in ventricular volume, the increase in diastolic wall stress leads to the series addition of sarcomeres, and thus lengthening of cardiac myocytes.

B, The pattern of cardiac remodeling that occurs in response to hemodynamic overloading depends on the nature of the inciting stimulus. When the overload is predominantly due to an increase in pressure (e.g., with systemic hypertension or aortic stenosis), the increase in systolic wall stress leads to the parallel addition of sarcomeres and widening of the cardiac myocytes, resulting in concentric cardiac hypertrophy. When the overload is predominantly due to an increase in ventricular volume, the increase in diastolic wall stress leads to the series addition of sarcomeres, lengthening of cardiac myocytes, and LV dilation, which is referred to as eccentric chamber hypertrophy.

Douglas l. Mann, G. Michelael Felkar, Heart Failure, 3rd Edition

19

20

Reduced Ejection Fraction (HFrEF) with neurohumoral

activation inhibition.

Damage to the myocytes and to the extracellular matrix leads to changes in the size, shape and function of the left ventricle and the heart more generally (a process term remodeling).

These changes, in turn, lead to electrical instability, systemic process resulting in many effects on other organs and tissues and further damage to heart.

The cycle along with intercurrent events, such as myocardial infarction, is believed to cause progressive worsening of heart failure syndrome over time.

Pathophysiology of systemic heart failure

Modified N Engl J Med 2010;362:228-38.Heart-failure syndrome

Electrical, ventilator, vascular, muscle, renal, hematologic and other

effects

Neurohumoral imbalance, increased cytokine

expression, immune and inflammatory

changes, altered fibrinolysis

Apoptosis, altered gene expression,

energy starvation, oxidative

stress

Injury to myocytes

and extracellular matrix

Ventricular

remodeling

“ Evolving Concepts of Heart Failure:Cooling Furnace, Malfunctioning Pump,

Enlarging Muscle.” 21

22

Neuroendocrine Activation and Mortality

Swedberg K, et al. Circulation. 1990;82(5);1730-1735

Adverse Neurohormonal Activation in Heart Failure has Formed the Basis for Evidenced Based Pharmacologic Therapy

23Adapted form Cohn JN. Cardiolgy;1997;88 (suppl 2)2-6

24

Renin - Angiotensin - Aldosterone System

ACE = angiotensin converting enzyme

25

Heart Failure : A State of "Neurohumoral Imbalance"

ARB = angiotensin –receptor blocker;SOC = system of care

ACE inhibitors considered 1st line standard of care treatment in Heart

Failure

26

Swedberg K et al for the CONSENSUS Trail Study Group. Circulation 1990;82;1730-1736. The SOLVD investigators N Eng J Med 1991;325 293-302

Pharmacological treatments indicated in potentially all patients with symptomatic (NYHA functional class II–IV) systolic heart failure

Recommendations Class

Level

An ACE inhibitor is recommended, in addition to a beta-blocker, for all patients with an EF ≤40% to reduce the risk of HF hospitalization and the risk of premature death.

I A

A beta-blocker is recommended, in addition to an ACE inhibitor (or ARB if ACE inhibitor not tolerated), for all patients with an EF ≤40% to reduce the risk of HF hospitalization and the risk of premature death.

I A

An MRA is recommended for all patients with persistingsymptoms (NYHA class II–IV) and an EF ≤35%, despite treatment with an ACE inhibitor (or an ARB if an ACE inhibitor is not tolerated) and a beta-blocker, to reduce the risk of HF hospitalization and the risk of premature death.

I A

27ESC Guidelines: European Heart Journal (2012) 33, 1787–1847

28

Demonstrated Comparative efficacy & benefits of GDMT

Fonarow GC, Yancy CW, Hernandez AF, et al Am Heart J 2011; 161:1024.

Guideline-recommended

therapy

Relative risk reductions in

pivotal randomized

clinical trial(s) (%)

Number needed to treat for mortality

benefit (standardized to 12

m)

Relative risk reduction in

meta-analysis

Angiotensin converting enzyme inhibitor OR angiotensin II receptor blocker

17 77 20%

Beta-blocker therapy (carvedilol, bisoprolol, extended release metoprolol succinate)

34 28 31%

Aldosterone antagonist 30 18 25%

Hydralazine plus nitrate 43 21 Not available

Cardiac resynchronization therapy

36 24 29/22%

Implantable cardioverter defibrillator

23 70 26%

Single Agent (drug) that reduce mortality in Heart Failure with Reduced Ejection Fraction

29

Combinational outcome : 25 Years of Progress in Chronic HF

30

Mentz, Felker, Mann. Heart Failure a companion to Braunwald’s Heart Disease, 2014

HFrEF with neurohumoral modulation.

31

32

A Paradigm Shift :From “Neurohumoral Inhibition” to “Neurohumoral Modulation”

33

Aim of PARADIGM-HF Trial

Prospective comparision of ARNI with ACEI to Determine Impact on Global Mortality and morbidity

in Heart Failure trial (PARADIGM-HF)

Specifically designed to replace current use of ACE Inhibitors and Angiotensin Receptor Blockers as the

Cornerstone of the treatment of Heart Failure

8422 Cases/ 27 months Largest ever in the last 15 years of Heart Failure Trials

LCZ696- A first-in-class Angiotensin Receptor Neprilysin Inhibitor- Simultaneously inhibits NEP and the RQS

34

(ENTRESTO)

PARADIGM-HF : Primary outcome

35

Prospective comparison of ARNI with ACEI to determine impact on Global Mortality and morbidity in Heart Failure

Trial

McMurray, Packer et al NEJM 2014

36

PARADIGM-HF : Primary outcomeProspective comparison of ARNI with ACEI to determine

impact on Global Mortality and morbidity in Heart Failure Trial

McMurray, Packer et al NEJM 2014

Angiotensin Neprilysin Inhibition with LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin- Angiotensin System

37

The incredible & consistent benefits of LCZ696 on all outcomes in HF

Compared with ENALAPRIL, pts on LCZ696 are :

Less likely to die of a cardiovascular cause or any cause Less likely to die suddenly Less likely to be hospitalized for HF for any reason Less likely to show symptomatic deterioration Less likely to need intensification of oral therapy / addition of IV therapy Less likely to show deterioration in renal function Less likely to visit ER Less likely to go to ICU and Less likely to need IV inotropic therapy Less likely to require devices / surgery for worsening/end stage heart failure Less likely to show biomarker evidence of cardiac wall stress and myocyte injury

38

PARADIGM - HF : Absolute benefitsSwitching 1000 patients from an ACE inhibitor/ARB to LCZ696 avoided :

47 primary endpoints 31 cardiovascular deaths 28 patients hospitalized for HF 37 patients hospitalized for any reason 53 admissions for HF 111 admissions for any reason

Over a median treatment period of 27 months

39

40

PARADIGM-HF Trial is poised to change clinical Practise in Heart Failure

MineralocoricoidReceptor

antagonists

Beta-adrenergic blockers

ACE inhibitors orAngiotensin receptor

blockers


antagonists


Angiotensin receptor-Neprilysin inhibition

[LCZ 696]

Finerenone[ARTS:HF]

THE PRESENT THE NEAR FUTURE

ZS-9: Harmonize , Patiromer : PEARL HF

Under explored world of Heart Failure with Preserved Ejection

Fraction (HFpEF/HFNEF)

41

Prevalence of HF-PEF13 Community Based Studies

1997- 2006

0

20

40

60

80

100

HF-

PE

F P

reva

lenc

e (%

)

Median = 52% Mean = 55%

Reviewed by Hogg K et al, 2004 and Owan T et al, 2005, Owan T, NEJM, 2006; Bursi F, JAMA, 2006 42

Secular Trends in the Prevalence of Heart Failure with Preserved Ejection Fraction

Redfield MM. Trends in Prevalence and Outcome of Heart Failure with Preserved Ejection Fraction. Heart Failure.2006;251259.

43

Less than 45% EF(54.42%)

45% & above EF(45.58%)

HF-CBS-SRS9800 Case based registry

Ongoing Study ... Samal UC, Raghu TR et. al44

Upto 44 years10.23%

45 to 54 years18.60%

55 to 64 years35.35%

65 to 74 years19.53%

75 & abov

e years16.28

%

Age group of Heart Failure Patients

HF-CBS-SRS9800 Case based registry

45Ongoing Study ... Samal UC, Raghu TR et. al

Recommendations COR LOESystolic and diastolic blood pressure should be controlled according to published clinical practice guidelines I B

Diuretics should be used for relief of symptoms due to volume overload I C

Coronary revascularization for patients with CAD in whom angina or demonstrable myocardial ischemia is present despite GDMT IIa

C

Management of AF according to published clinical practice guidelines for HFpEF to improve symptomatic HF

IIa C

Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF IIa C

ARBs might be considered to decrease hospitalizations in HFpEFIIb B

Nutritional supplementation is not recommended in HFpEFIII: No Benefit C

Management of ACCF 2013

46

Clinical Trials in HF with Preserved Ejection Fraction

TRIAL MEAN AGE DRUG EF RESULTS

DIG Study 63 Digoxin >45 No reduction in composite of death or HF hospitalization (HR 0.82; 95% CI 0.63-1.07)

CHARM-P 67 Candesartan >40 No mortality benefit (HR 0.89; 95% CI 0.77-1.03; P = 0.118); ↓ 3-yr hospitalizations (P = 0.017)

SWEDIC 67 Carvedilol >45 No significant change in composite diastolic LV function; → E/A (P ≤ 0.05)

PEP-CHF 75 Perindopril ≥40No mortality benefit was seen over 2.1 yr (HR 0.92; 95% CI 0.70-1.21, P = 0.545), ↓ 1-yr hospitalizations (HR 0.628; 95% CI 0.408-0.966; P = 0.033)

SENIORS 76 Nebivolol ≥35No reduction in composite all-cause mortality or CV hospitalizations (HR (0.81; 95% CI 0.63-1.04; P = 0.720)

I-PRESERVE 72 Irbesartan ≥40No reduction over 49.5 months of follow-up in composite all-cause mortality or CV hospitalizations (HR 0.95; 95% CI 0.86-1.05; P = 0.35)

RAAM-PEF 70 Eplerenone ≥50 No improvement (P = 0.91) in 6MWDELAND 66 Nebivolol >45 No improvement (P = 0.094) in 6MWD

TOPCAT 69 Spironolactone ≥45

No reduction in composite CV mortality, aborted cardiac arrest, or HF admission (HR 0.89, 95% CI 0.77-1.04, P = 0.14); HF admissions reduced (HR 0.83, 95% CI 0.69-0.99, P = 0.04)

RELAX 69 Sildenafil <50 No improvement in exercise capacity or clincal status47

Mortality Benefit HFrEF VS HFpEF

48

HFpEF – Mortality Reduction By treatment

D J Holland, JACC 2011;57:1676

49

ŀ

JAMA. 2008;300(4):431-433.

50

HFpEF: Cardiovascular Fallout of Chronic Systemic Inflammation

Myocardial Microvascular inflammation in HFPEF: In HFPEF myocardium, there is high expression of adhesion molecules high

oxidative stress, low NO bioavailability and very low cGMP content. What drive LV remodeling in HFPEF:

Myocardial overload or metabolic comorbidities ? Metabolic comorbidities are more important for LV

remodeling in HFpEF that myocardial overload. It is seen in ALL-HAT trials in the incidence of higher BMI in HFPEF, is significantly associated with HFPEF than HFREF, and there is no difference for the other co-founders, like SBP. DBP, Previous MI or Stroke, DM and BMI.

What reduces LV compliance in HFPEF : titin or collagen There is only a modest increase in fibrosis in HFPEF. During physiological stretches, 2/3 of RT is titin dependent and 1/3

collagen dependent. A phosphorylation deficit of titin and ultrastructural changes in titin

(faster degradation ?) contribute to the high RT of failing myocardium.

Walter J Paulus, 2014

• Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in HFpEF.

• A new paradigm for HFpEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations.

52

53

Microvascular Rarefaction in

HFpEF

Mohammed SF et. Circ 2015,131;55054

Comorbidities Drive Myocardial Dysfunction and remodeling in HFpEF

Comorbidities induce a systemic proinflammatory state with elevated plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, sST2, and pentraxin3.

Coronary microvascular endothelial cells reactively produce reactive oxygen species (ROS), vascular cell adhesion molecule (VCAM), and E-selectin.

Production of ROS leads to formation of peroxynitrite (ONOO) and reduced nitric oxide (NO) bioavailability, both of which lower soluble guanylate cyclase (sGC) activity in adjacent cardiomyocytes.

Lower sGC activity decreases cyclic guanosine monophosphate concentration and protein kinase G (PKG) activity. Low PKG activity increases resting tension (Fpassive) of cardiomyocytes because of hypophosphorylation of titin and removes the brake on prohypertrophic stimuli inducing cardiomyocyte hypertrophy.

VCAM and E-selectin expression in endothelial cells favors migration into the subendothelium of monocytes. These monocytes release transforming growth factor β (TGF-β). The latter stimulates conversion of fibroblasts to myofibroblasts, which deposit collagen in the interstitial space.

Walter J. Paulus, JACC 201355

Myocardial Remodeling in HFpEF, HFrEF, and Advanced HFrEF

Endotheliu

m

Cardiomyocy

tes56

Targeting Microvascular Infalmmation and Impaired cGMP-PKG signaling

• Anti-ischemic or pro-angiogenic therapies• Anti-inflammatory therapies• Enhance cGMP-PKG signaling

– NO-sGC-cGMP– NP-pGC-cGMP

57

Senni M & Pieske B. Eur Heart J 2014

Drug Enhancing cGMP- PKG signaling

58

vericiguat

PDE5

Beet Root Juice and Nitroxyl

59

Ongoing and may be completed in 2019.

(Valsartan/Sacubitril)

60

Summary:


antagonists


ACE inhibitors orAngiotensin receptor

blockers


antagonists


Angiotensin receptor-Neprilysin inhibition

[LCZ 696]

Finerenone[ARTS:HF]

THE PRESENT THE NEAR FUTURE

ZS-9: Harmonize , Patiromer : PEARL HF

However, this expectation has not reached the guidelines though claimed it has been the part of Canadian guidelines of Heart Failure. At present, it is difficult to accept because of the formidable cost. Though, the evidence is convincing for those who can afford, till then enarapril/ LCZ696( Entresto) will be taken in the face value of Kuhn Cartoons i.e. duck and rabbit or young maiden and old lady, so there is a paradigm shift.

I’ve learned that people will forget what you said,

people will forget what you did, but people will never

forget how you made them Feel!.

Thank You ……. What the take home message means to me?

Damsels of Future Paradigm…

Beet Root juice

BendaviaAlagebrium

Nitroxyl

iron

VariciaugatAticiaguat

62

63

64

65

66

SOLVD: Deaths, Causes of Death, Development of Heart Failure According to Treatment Group

Cause of Death or Type of Event

Placebo (%) (N =

2117)

Enalapril (%)

(N . 2111)

Reduction in

Risk (95% Cl)

Z Score

P Value

Death All causes 334 (15.8) 313 (14.8) 8 (-8 to 21) 1.02 .30Cardiovascular causes 298 (14.1) 265 (12.6) 12 (-3 to 26) 1.57 .12 Cardiac 271 (12.8) 238 (11.3) 13 (-3 to 27) 1.63 .10 Arrhythmia without worsening

105 (5.0) 98(4.6) 7 (-22 to 30) 0.54 NS

Progressive heart failure* 106 (5.0) 85(4.0) 21 (-5 to 41) 1.64 .10Noncardiovascular causes 36(1.7) 48(2.3) - - NDMorbidity and combined outcomesDevelopment of CHF 640 (30.2) 438 (20.7) 37 (28-44) 7.47 <.001Development of CHF and anti-CHF Therapy

477 (22.5) 293 (13.9) 43 (33-50) 7.59 <.001

First hospitalization for CHF 273 (12.9) (8.7) 36 (22-46) 4.65 <.001Multiple hospitalizations for CHF 102 (4.8) 58(2.7) 44 (23-59) 3.61 <.001

Death or development of CHF 818 (38.6) 630 (29.8) 29 (21-36) 6.55 <.001

Death or hospitalization for CHF 518 (24.5) 434 (20.6) 20 (9-30) 3.46 <.001CHF = congestive heart failure ; C; = confidence interval; NS = not significant ; ND = not doneThe SOLVD Investigators. N Engl J Med. 1992;327(10);685-691 67

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00% 87.4

4%

65.5

8%

45.1

2%

42.7

9%

38.7

9%

36.7

4%

36.2

8%

25.3

7%

23.2

6%

13.0

2%

3.26

%

0.93

%

0.47

%

0.47

%

Use of Medicines in HF Patients

Perc

enta

ge o

f Hea

rt Fa

ilure

Pat

ient

s

68

Take home message… • New Paradigm brings upfront the importance of co-

morbidites and microvascular inflammation and endothelial dysfunction as future target. – Anti-ischemic or pro-angiogenic therapies– Anti-inflammatory therapies– Enhance cGMP-PKG signaling

• No-sGc-cGMP• NP-pGC-cGMP

• Example of such drugs already in use : – phosphodiesterase 5 inhibitors; sidelnafil (RELAX Trail);– Angotensin- Neprilysin Inhibitor (LCZ696, ENTRESTO),

PARAMOUNT Study (Phase-II trial) – Statins

• There are may other promising molecules targeting novel pathways are already making a head way with hopeful mosaicism as shown next slide. 69

What drives HFpEF Development ? Obesity or Arterial Hypertension ?

All – HAT Trial – Circulation 2008; 118 : 2259

70

Treatment options for pts with chronic symptomatic systolic HF (NYHA class II–IV).

71

ESC Guidelines: European Heart Journal (2012) 33, 1787–1847

a. Diuretics may be used as needed to relieve the signs and symptoms of congestion , but they have not been shown to reduce hospitalization or death.

b. Should be titrated to evidence-based dose or maximum tolerated dose below the evidence-based dose.

c. Asymptomatic patients with an LVEF ≤35% and a history of myocardial infarction should be considered for an ICD.

d. If mineralocorticoid receptor antagonist not tolerated, an ARB may be added to an ACE inhibitor as an alternative.

e. European Medicines Agency has approved ivabradine for use in patients with a heart rate ≥75 b.p.m. May also be considered in patients with a contraindication to a beta-blocker or beta-blocker intolerance.

f. Indication differs according to heart rhythm, NYHA class, QRS duration, QRS morphology and LVEF.

g. Not indicated in NYHA class IV.h. Digoxin may be used earlier to control the

ventricular rate in patients with atrial fibrillation—usually in conjunction with a beta-blocker.

i. The combination of hydralazine and isosorbide dinitrate may also be considered earlier in patients unable to tolerate an ACE inhibitor or an ARB.

ab

b

cb,d

e

f g

h i

cc

72

Demonstrated Comparative efficacy & benefits of GDMT

Fonarow GC, Yancy CW, Hernandez AF, et al Am Heart J 2011; 161:1024.

Guideline-recommended

therapy

Relative risk reductions in

pivotal randomized

clinical trial(s) (%)

Number needed to treat for mortality

benefit (standardized to 12

m)

Relative risk reduction in

meta-analysis

Angiotensin converting enzyme inhibitor OR angiotensin II receptor blocker

17 77 20%

Beta-blocker therapy (carvedilol, bisoprolol, extended release metoprolol succinate)

34 28 31%

Aldosterone antagonist 30 18 25%

Hydralazine plus nitrate 43 21 Not available

Cardiac resynchronization therapy

36 24 29/22%

Implantable cardioverter defibrillator

23 70 26%

Devices

ICDsb-Blockers

Sensing Devices

CRT, CRT-DMR-Antagonists

Ivabradine

Eras of Heart Failure Management Timeline

Pre-1980

Neurohormonal Drugs

1980s1990s

2000s 2010s

Palliative Drugs

Digitalis Diuretics

ACE-I

2015

ARNI

ARNI

73

74

CARDIOMYOPATHIES

Konstam MA. J Card Failure, 2003

Overview of Left Ventricular RemodelingAlterations in Myocyte Biology

Excitation contraction couplingMyosin heavy chain (fetal) gene expressionΒ-adrenergic desensitizationHypertrophyMyocytolysisCytoskeletal ProteinsMyocardial ChangesMyocyte loss• Necrosis• Apoptosis• AutophagyAlternations in extracellular matrix• Matrix degradation• Myocardial fibrosisAlternations in Left Ventricular Chamber GeometryLeft Ventricular (LV) dilationIncreased LV sphericityLV wall thinningMitral valve incompetence

75

Why no positive results in RCTs ?

• Wrong selection of patients : Patients with many different comorbid conditions or mimicking illnesses might have been included• Wrong choice of drugs : B Blockers may worsen chronotropic incompetence• Including patients with advanced disease process • HFpEF is a heterogenous disease• Trying to test drugs useful in HFrEF in a patho-

physiologically different HFpEF76

The systemic renin-angiotensin system. The systemic RAS consists of liver-derived AGT, kidney-derived renin, and endothelium-derived ACE. The latter is particularly abundant in pulmonary endothelial cells. Sequential action of renin and ACE on AGT produces the octapeptide Ang II in the circulation. Ang II acts via binding to AGTR1 and AGTR2, which generally produce opposite effects. AGTR1 is the predominant receptor in adult tissues. The systemic RAS is involved in acute effects to maintain salt and water homeostasis and blood pressure. 77

Homeostatic regulation of contractile function. Adrenergic drive acts as a servo-control regulator of normal cardiac contractile function. When cardiac contractile function is adequate to sustain normal homeostasis, adrenergic drive is low or reduced. In contrast, when contractile function is inadequate to support homeostasis, cardiac adrenergic drive increases to a commensurate degree. Adapted from Port JD, Bristow MR: Altered β-adrenergic receptor gene regulation and signaling in chronic heart failure. J Mol Cell Cardiol 33:887–905, 2001.

78

Pathphysiology and Therapeutical Implications

- Paradigm Shifts in Heart Failure -

Year Pathophysiology

ModelPrimary Defects

Therapeutical Cosequences

before 1970 salt and water

retentionOedema Reduction of NaCl

diuretics

from 1985Pump failure,

role of peripheryReduces force

of contraction

Digitalis and other positive inotropic

drugs

from 1990neurohumoral activation,

cellular defects

Calcium signalling, SERCA, Ca/Na Exchanger

ACE-inhibitors and β- blockers in addition to diuretics and digitalis

from 2000Apoptosis cellular

regenerationGrowth factors, Cytokines, bone marrow defects

Inhibitors of apoptosis Stem cell

therapy Genomics & Epigenetics

2010 & Beyond B L O C K B U S T E R ?

?79

Female46.51%Male

53.49%

Heart Failure Patients by Gender

Ongoing Study ... Samal UC, Singh BP and Raghu TR et. al80

Clinical classifications of heart failure severity

NYHA Classification ACC-AHA StagesClass I – no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation or dyspnea

Stage A – at high risk for heart failure, no identified structural or functional abnormality, no signs or symptoms

Class II – Slight limitation of physical activity, comfortable at rest but ordinary physical activity results in fatigue, palpitation or dyspnea

Stage B – Developed structural heart ds, strongly associated with development of heart failure but without signs or symptoms

Class III - Marked limitation of physical activity, comfortable at rest but less than ordinary physical activity results in fatigue, palpitation or dyspnea

Stage C – symptomatic heart failure associated with underlying structural heart ds

Class IV – unable to carry on any physical activity without discomfort, if any physical activity undertaken, discomfort increased

Stage D – Advanced structural heart ds and marked symptoms of heart failure at rest despite maximal medical therapy

81

82

Classes of recommendations

Levels of evidence

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012

Investigation Check list in pts with LV systolic dysfunction and treatment action needed Test & possible finding Action Needed

EchocardiographyPresence/ absence of Organic Heart Disease & Base line LV function

Operative/ device salvage

ElectrocardiographyAtrial fibrillation or flutter

Slow the ventricular rate if it is rapid, consider prophylactic anticoagulation therapy for thromboembolism

QRS duration ≥ 120msec Consider cardiac resynchronization therapy

Sinus bradycardia Administer beta blocker and digoxin with caution

Chest radiographyPulmonary congestion, edema or pleural effusion

Provide adequate diuresis

Primary pulmonary pathology [COPD, fibrosis or tumor] Look for alt. cause of dyspnea and provide specific therapy

Hematolgic testsAnemia

Perform a diagnostic work up, treat iron deficiency, if present

Biochemical testsIncreased creatinine/ Serum Potassium

Administer RAAS blockers with caution

Hypokalemia Add or ↓ the dose of RAAS blockers, consider k+ replacement

Hyponatremia Reduce the dose or discontinue use of thiazide, reduce water intake, consider t/t with tolvaptan, if hyponatremia is severe

Hyperurecemia Consider reducing dose of diuretic as much as possible, administer prophylaxis for gout with xanthine oxidase inhibitor

83

Pharmacokinetics of the Loop Diuretics

84

From Felker GM, Mentz RJ: Diuretics and ultrafiltration in acute decompensated heart failure. J Am Coll Cardiol 59:2145–2153, 2012.

Practical Issues in the Use of Diuretics in Heart Failure

Volume overloaded patient need diuretic to relieve symptoms.

In presence of renal insufficiency, loop diuretic is the choice while torsemide / bumetanide may be superior to furosemide.

Even in the event of furosemide resistance, torsemide would be superior, may be because of increased bioavailability.

And also Torsemide being longer acting will less likely have chance of postdiuretic rebound and sodium retention.

Patient already on oral diuretic on the wake of decompensation the dose should be doubled.

Diuretics has no role in mortality reduction.

Dose response curves of loop diuretics in chronic heart failure (CHF) and chronic renal failure (CRF) patients compared with normal controls.

85

Reproduced from Ellison DH: Diuretic therapy and resistance in congestive heart failure. Cardiology 96:132–143, 2001.

In heart failure patients, higher doses are required to achieve a given diuretic effect and the maximal effect is blunted.

Classes of diuretics and their mechanisms of actions

86

Modified from Wile D: Diuretics: a review. Ann Clin Biochem 49:419–431, 2012.

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00% 75.8

1%

58.6

0%

48.3

7%

43.7

2%

40.0

0%

33.0

2%

24.6

5%

19.0

7%

18.6

0%

18.1

4%

13.9

5%

11.1

6%

Comorbid States

Perc

ent o

f Pat

ient

s Ongoing Study ... Samal UC, Singh BP and Raghu TR et. al Ongoing Study ... Samal UC, Singh BP and Raghu TR et. al

HF-CBS-SRS9800 Registry base

Ongoing Study ... Samal UC, Singh BP and Raghu TR et. al87

88

Pharmacologic Actions of Human BNP

BNP = brain natriuretic peptide


Comorbidities induce a systemic proinflammatory state with elevated plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, sST2, and pentraxin3.


89


Coronary microvascular endothelial cells reactively produce reactive oxygen species (ROS), vascular cell adhesion molecule (VCAM), and E-selectin.


90


Production of ROS leads to formation of peroxynitrite (ONOO) and reduced nitric oxide (NO) bioavailability, both of which lower soluble guanylate cyclase (sGC) activity in adjacent cardiomyocytes.


91


Lower sGC activity decreases cyclic guanosine monophosphate concentration and protein kinase G (PKG) activity. Low PKG activity increases resting tension (Fpassive) of cardiomyocytes because of hypophosphorylation of titin and removes the brake on prohypertrophic stimuli inducing cardiomyocyte hypertrophy.


92


VCAM and E-selectin expression in endothelial cells favors migration of monocytes into the subendothelium. These monocytes release transforming growth factor β (TGF-β) which in turn stimulates conversion of fibroblasts to myofibroblasts, which deposit collagen in the interstitial space.


93

Objectives in the Management of Heart Failure

The objective of Pharmacotherapy is effective treatment to reduce mortality and hospital admission rates, while both reflect, the ability to slow or prevent progressive worsening of Heart Failure, often evidenced by, reverse LV remodeling and reduction in circulating natriuretic peptide concentrations.

Imperatively, the CRT also has been evidenced for these key fundamental outcome i.e. mortality and hospitalization.

The relief of the symptoms and improvement in quality of life, and increase in functional capacity are though utmost importance to the patients , but not have been evidenced in the most primary outcome trials, perhaps, because of diversity in outcomes and survival.

The key mover of this objectives are the Three neurohumoral antagonists: ACEIs, ARBs and Beta Blockers are essentials to all cases of Heart Failure with reduced Systolic Ejection Fraction. 94

Evidence Based Pharmacologic Treatment Of Heart FailureTreatment Evidence Dosing

Contraindications, Cautions and Averse Events

Starting dose mg

Dose frequency/ day

Target total daily dose mg

Mean total daily dose

achieved in

outcome studies

mgACE inhibitors • Contraindications : History of angioedema/

bilateral renal-artery stenosis/ serum potassium >5.0 mmol/liter, serum creatinine >2.5 mg/dl (220 μmol/liter),or symptomatic hypotension or SBP<90 mm Hg.

• Possible adverse events include cough, angioedema, a rise in creatinine or blood urea nitrogen, hyperkalemia, and symptomatic hypotension.

Captopril SAVE 6.25 3 150 121Enalapril CONSENSUS

SOLVD2.5 2 20-40 16.6

Lisinopril ATLAS 2.5-5 1 20-35 NARamipril AIRE 2.5 1 or

210 8.7

Trandolapril TRACE 1 1 4 3Beta blockers • Asthma and second- or third-degree

atrioventricular block, recent decompensated heart failure and heart rate <55 bpm.

• Possible adverse events include bradycardia and atrioventricular block, bronchospasm, worsening heart failure during initiation of treatment or increase in dosage, and symptomatic hypotension.

Bisoprolol CIBIS-II 1.25 1 10 6.2Carvedillol COMET 3.125 2 50-100 37Metoprolol MERIT-HF 12.5

or 251 200 150

Nevibolol SENIORS 1.25 1 10 7.7

N Engl J Med 2010;362:228-38.

95

Treatment Evidence Dosing

Contraindications, Cautions and Averse Events

Starting

dose

mg

Dose frequency/ day

Target total daily dose mg

Mean total daily dose

achieved in

outcome studies

mgAngiotensin receptor blockers Contraindications include bilateral renal-artery

stenosis. Be alert for serum potassium >5.0 mmol/liter, serum creatinine >2.5 mg/dl, symptomatic hypotension, or systolic blood pressure <90 mm Hg. Possible adverse events include a rise in creatinine or blood urea nitrogen, hyperkalemia, and symptomatic hypotension.

Candesartan CHARM-Alternative CHARM-Added trial

4 1 32 24

Valsartan Val-HeFT 40 2 320 25.4

Losartan HEAAL study 50 1 150 129

Aldosterone blockers Contraindications include serum potassium >5.0 mmol/liter.Be alert for serum potassium >4.5 mmol/liter and serum creatinine >2.0 mg/dl (175 μmol/ liter). Possible adverse events include hyperkalemia, rise in creatinine or blood urea nitrogen, and gynecomastia and breast pain in men (more common with spironolactone).

Eplrenone EMPHASIS-HF

25 1 50 43

Spironolactone RALES 25 1 25-50 26

Hydralazine-isosorbide nitrate Contraindications include lupus syndrome.Be alert for symptomatic hypotension or systolic blood pressure <90 mm Hg. Possible adverse events include headache, symptomatic hypotension, arthralgia, and lupus like syndrome.

Hydralazine V-HeFT I 37.5 3 225 143

Isosorbide nitrate

V-HeFT I 20 3 120 60 96

Other treatments with less-certain benefits in patients with symptomatic (NYHA class II–IV) systolic heart failure

97

Recommendations Class

Level

ARB

Recommended to reduce the risk of HF hospitalization and the risk of premature death in patients with an EF ≤40% and unable to tolerate an ACE inhibitor because of cough (patients should also receive a beta-blocker and an MRA). I A

Recommended to reduce the risk of HF hospitalization in patients with an EF ≤40% and persisting symptoms (NYHA class II–IV) despite treatment with an ACE inhibitor and a beta-blocker who are unable to tolerate an MRA. I A

IVABRADINE

Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB). IIa B

May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35% and a heart rate ≥70 b.p.m. who are unable to tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB). IIb C

DIGOXIN

May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤45% who are unable to tolerate a beta-blocker (ivabradine is an alternative in patients with a heart rate ≥70 b.p.m.). Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB). IIb B

May be considered to reduce the risk of HF hospitalization in patients with an EF ≤45% and persisting symptoms (NYHA class II–IV) despite treatment with a beta-blocker, ACE inhibitor (or ARB), and an MRA (or ARB). IIb B

H-ISDN

May be considered as an alternative to an ACE inhibitor or ARB, if neither is tolerated, to reduce the risk of HF hospitalization and risk of premature death in patients with an EF ≤45% and dilated LV (or EF ≤35%). Patients should also receive a beta-blocker and an MRA.

IIb B

May be considered to reduce the risk of HF hospitalization and risk of premature death in patients in patients with an EF ≤45% and dilated LV (or EF ≤35%) and persisting symptoms (NYHA class II–IV) despite treatment with a beta-blocker, ACE inhibitor (or ARB), and an MRA (or ARB). IIb B

An n-3 PUFAf preparation may be considered to reduce the risk of death and the risk of cardiovascular hospitalization in patients treated with an ACE inhibitor (or ARB), beta-blocker, and an MRA (or ARB).

IIb BESC Guidelines: European Heart Journal (2012) 33, 1787–1847

Recommendations for pharmacological therapy for management of stage C HFrEF [2013 ACCF/AHA Guideline]

98

Yancy CW, Jessup M, Bozkurt B, et al. 2013. J Am Coll Cardiol 2013; 62:e147.

Ivabrad

ine ?

Cumulative benefits of medical therapy on mortality

99

GLOBAL HEART, VOL. 8, NO. 2, 2013 June 2013: 141-170

Chasing a wrong paradigm

Discordance in the treatment benefits of neurohormonal antagonism in HFpEF vs. systolic HF suggests that, despite these 2 conditions sharing a common clinical picture of volume overload, exercise intolerance, and significant mortality, HFpEF does not appear to involve neurohormonal activation as a critical pathophysiologic mechanism.

Mayo clin Proc. June 2011:86(6) 531-539

100

101

102

Health & Medicine

Prof. J.P.Das Oration HEART FAILURE