1. Prof. U. C. Samal gave the Dr. J.P. Das Heart Failure Oration at the 22nd Annual Conference of the Indian College of Cardiology in Patna, Bihar. 2. He discussed the evolution of the understanding of heart failure from ancient theories of humors to modern knowledge of hemodynamics, neurohormonal activation, and the importance of both functional and proliferative signaling in the pathogenesis and treatment of heart failure. 3. He highlighted advances in differentiating heart failure with reduced ejection fraction from heart failure with preserved ejection fraction, as well as new insights into neurohormonal modulation and understudied areas of HFpEF/HFNEF.

1. 22nd Annual Conference Of
INDIAN COLLEGE OF CARDIOLOGY ,
PATNA, BIHAR
Orator:
Prof. U. C. Samal 1

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. 2

3. Prof. U. C. Samal
MD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS
Ex- Prof. Cardiology & Ex-HOD Medicine
Patna Medical College, Patna, Bihar
Past President, Indian College of Cardiology
Permanent & 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
3
“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)
4

5. Heart Failure Paradigm from
Hippocrates to the Modern Era.
5

6.  "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
6

7. “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 maid
Duck
Twodifferentfaces
RubinVases

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.
500 BC – 1628 AD
Phlegm to Hemodynamics
Crossovers Between Functional and Proliferative Signaling in the Pathogenesis of Heart Failure: Arnold M. Katz, MD
Hemodynamics
Phlegm (Cold Humor)
Hippocrates
5th Century BC
Galen
2nd Century AD
Harvey
1628
8

9. 1628 -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
9

10. 1920 -1970
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 is
depressed 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
Comissurotomy
Open
Heart
Surgery
Contractility
Saxl and Heilig
1920 Thiazides
Loop Diuretics
Braunwald
1967
Sarnoff
1955
Salt and water Retention
10
Alpert & Gordon
1962

11. 1970 -1991
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
Vasodilators
V-Heft I CONSENSUS I
Amrinone Milrinone
Promise
11

12. 1990 -2000
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/STAT
Cytoskeleton,MAP Kinases
Myogenic Determinanats, Calcinerulin
Crossovers
between
Functional
and
Proliferative
Signaling
Hemodynamics
Contractility
Cardiomyopathy
of Overload
Nifedipine Ditiazem
Flosequinon Prostacyclin
Moxonidine
Vasodilator Trials
Ibopamine
Promise Trial
Vest Trial
Carvedilol Β- Blocker Trials
CIBIS MERIT COPERNICUS
12

13. 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
13
Nature Review Cardiology
Vol.9 June 12 pg 349
BNP Not Breathing Probarly, 2001, Januzi/ Maisel
Biomarkers
Braunwald 1978

14. 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 EFFECT
Vasodilators
Direct acting
(Minoxidil, short-acting Ca
blockers, prazocin, prostacyclin,
ibopamine, PDE Inhibitors,
moxonidine)
ACE inhibitors
AT1 receptor blockers
Afterload reduction(functional Signaling)
Afterload reduction(functional Signaling)
Afterload reduction(functional Signaling)
Transcriptional activation
(Proliferative signaling)
Transcriptional inhibition
(Proliferative signaling)
Transcriptional inhibition
(Proliferative signaling)
Inotropes
B-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)
Crossovers Between Functional and Proliferative Signaling in the Pathogenesis of Heart Failure: Arnold M. Katz, MD 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.
15

16. Spectrum of Heart Failure Syndromes
16

17. 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, 2013
17

18. Fundamental Pathophysiologic Mechanism
HFrEF HFpEF
Myocyte loss of
Infarct/ inflamation
Infectious/ Toxin
Old Paradigm
Hypertension
Contractile Dysfunction
Genetic/ Toxin
Concentric Remodeling
LVH/Fibrosis/ Diastolic Dysf
Eccentric Remodeling NH Activation
NH Activation Most unlikely
… Needs New Paradigm
18

19. Patterns of cardiac myocyte hypertrophy
A, 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.
20

21.  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. 22
Neuroendocrine Activation and Mortality
Swedberg K, et al. Circulation. 1990;82(5);1730-1735

23. 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. 24
Renin - Angiotensin - Aldosterone System
ACE = angiotensin converting enzyme

25. 25
Heart Failure : A State of "Neurohumoral Imbalance"
ARB = angiotensin –receptor blocker;SOC = system of care

26. ACE inhibitors considered 1st line standard
of care treatment in Heart Failure
26
Swedberg K et al for the CONSENSUSTrail StudyGroup. Circulation 1990;82;1730-1736. The SOLVD
investigators N Eng J Med 1991;325 293-302

27. Pharmacological treatments indicated in potentially all patients with
symptomatic (NYHA functional class II–IV) systolic heart failure
Recommendations Class Level
AnACE 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 persisting
symptoms (NYHA class II–IV) and an EF ≤35%, despite treatment with
an ACE inhibitor (or anARB 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
27
ESC Guidelines: European Heart Journal (2012) 33, 1787–1847

28. 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 (standardi
zed 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%

29. SingleAgent (drug) that reduce mortality in Heart Failure with
Reduced Ejection Fraction
29

30. Combinational outcome : 25 Years of Progress in Chronic HF
30
Mentz, Felker, Mann. Heart Failure a companion to Braunwald’s Heart Disease, 2014

31. HFrEF with neurohumoral
modulation.
31

32. 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
33
8422 Cases/ 27 months
Largest ever in the last 15 years of Heart Failure Trials

34. LCZ696- A first-in-classAngiotensin Receptor Neprilysin Inhibitor-
Simultaneously inhibits NEP and the RQS
34
(ENTRESTO)

35. PARADIGM-HF : Primary outcome
35
Prospective comparison of ARNI with ACEI to determine impact on
Global Mortality and morbidity in Heart FailureTrial
McMurray, Packer et al NEJM 2014

36. 36
PARADIGM-HF : Primary outcome
Prospective comparison of ARNI with ACEI to determine impact on
Global Mortality and morbidity in Heart FailureTrial
McMurray, Packer et al NEJM 2014

37. Angiotensin Neprilysin Inhibition with LCZ696 Doubles Effect on Cardiovascular
Death of Current Inhibitors of the Renin-Angiotensin System
37

38. 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

39. PARADIGM - HF : Absolute benefits
Switching 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
Mineralocoricoid
Receptor
antagonists
Beta-adrenergic
blockers
ACE inhibitors or
Angiotensin receptor
blockers
Mineralocoricoid
Receptor
antagonists
Beta-adrenergic
blockers
Angiotensin receptor-
Neprilysin inhibition
[LCZ 696]
Finerenone
[ARTS:HF]
THE PRESENT THE NEAR FUTURE
ZS-9: Harmonize ,
Patiromer : PEARL HF
40

41. Under explored world of Heart
Failure with Preserved Ejection
Fraction (HFpEF/HFNEF)
41

42. Prevalence of HF-PEF
13 Community Based Studies
1997- 2006
0
20
40
60
80
100
HF-PEFPrevalence(%)
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

43. 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 Fa
2006;251259.
43

44. Less than
45% EF
(54.42%)
45% &
above EF
(45.58%)
HF-CBS-SRS
9800 Case based registry
Ongoing Study ... Samal UC, Raghu TR et. al44

45. Upto 44
years
10.23%
45 to 54
years
18.60%
55 to 64
years
35.35%
65 to 74
years
19.53%
75 & above
years
16.28%
Age group of Heart Failure Patients
HF-CBS-SRS
9800 Case based registry
45Ongoing Study ... Samal UC, Raghu TR et. al

46. Recommendations COR LOE
Systolic 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 HFpEF
IIb B
Nutritional supplementation is not recommended in HFpEF
III: No Benefit C
Management of ACCF 2013
46

47. 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 ≥40
No 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 ≥35
No 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 ≥40
No 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 6MWD
ELAND 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

48. Mortality Benefit HFrEF VS HFpEF
48

49. HFpEF – Mortality Reduction By treatment
D J Holland, JACC 2011;57:1676
49

50. ŀ
JAMA. 2008;300(4):431-433.
50

51. 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

52. • 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. 53

54. Microvascular Rarefaction in
HFpEF
Mohammed SF et. Circ 2015,131;550
54

55. 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 2013
55

56. Myocardial Remodeling in HFpEF, HFrEF,
and Advanced HFrEF
56

57. 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

58. 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)
59

60. Summary:
Mineralocoricoid
Receptor
antagonists
Beta-adrenergic
blockers
ACE inhibitors or
Angiotensin receptor
blockers
Mineralocoricoid
Receptor
antagonists
Beta-adrenergic
blockers
Angiotensin receptor-
Neprilysin inhibition
[LCZ 696]
Finerenone
[ARTS:HF]
THE PRESENT THE NEAR FUTURE
ZS-9: Harmonize ,
Patiromer : PEARL HF
60
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.

61. 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?

62. Damsels of Future Paradigm…
Beet Root
juice
Bendavia
Alagebrium
Nitroxyl
iron
Variciaugat
Aticiaguat
62

63. 63

64. 64

65. 65

66. 66

67. SOLVD: Deaths, Causes of Death, Development
of Heart Failure According to Treatment Group
Cause of Death orType of Event Placebo (%)
(N = 2117)
Enalapril (%)
(N . 2111)
Reduction in
Risk (95% Cl)
Z Score PValue
Death
All causes 334 (15.8) 313 (14.8) 8 (-8 to 21) 1.02 .30
Cardiovascular 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 .10
Noncardiovascular causes 36(1.7) 48(2.3) - - ND
Morbidity and combined outcomes
Development of CHF 640 (30.2) 438 (20.7) 37 (28-44) 7.47 <.001
Development of CHF and anti-CHFTherapy 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 <.001
Multiple 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 <.001
CHF = congestive heart failure ; C; = confidence interval; NS = not significant ; ND = not done
The SOLVD Investigators. N EnglJ Med. 1992;327(10);685-691 67

68. 0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
87.44%
65.58%
45.12%
42.79%
38.79%
36.74%
36.28%
25.37%
23.26%
13.02%
3.26%
0.93%
0.47%
0.47%
PercentageofHeartFailurePatients
Use of Medicines in HF Patients 68

69. 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

70. What drives HFpEF Development ?
Obesity or Arterial Hypertension ?
All – HATTrial – Circulation 2008; 118 : 2259 70

71. Treatment options for pts withchronic 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.
a
b
b
c
b,
d
e
f g
h i
c
c

72. 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 (standardi
zed 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%

73. Devices
ICDs
b-Blockers
Sensing
Devices
CRT, CRT-D
MR-Antagonists
Ivabradine
Eras of Heart Failure Management
Timeline
Pre-1980
Neurohormonal
Drugs
1980s 1990s 2000s 2010s
Palliative
Drugs
Digitalis
Diuretics
ACE-I
2015
ARNI
ARNI
73

74. 74
CARDIOMYOPATHIES
Konstam MA. J Card Failure, 2003

75. Overview of Left Ventricular
RemodelingAlterations in Myocyte Biology
Excitation contraction coupling
Myosin heavy chain (fetal) gene expression
Β-adrenergic desensitization
Hypertrophy
Myocytolysis
Cytoskeletal Proteins
Myocardial Changes
Myocyte loss
• Necrosis
• Apoptosis
• Autophagy
Alternations in extracellular matrix
• Matrix degradation
• Myocardial fibrosis
Alternations in LeftVentricular Chamber Geometry
LeftVentricular (LV) dilation
Increased LV sphericity
LV wall thinning
Mitral valve incompetence
75

76. 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 HFpEF
76

77. 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

78. 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

79. Pathphysiology and Therapeutical
Implications
- Paradigm Shifts in Heart Failure -
Year
Pathophysiology
Model
Primary
Defects
Therapeutical
Cosequences
before 1970
salt and water
retention
Oedema Reduction of NaCl
diuretics
from 1985
Pump failure,
role of periphery
Reduces force
of contraction
Digitalis and other
positive inotropic
drugs
from 1990
neurohumoral
activation, cellular
defects
Calcium
signalling,
SERCA, Ca/Na
Exchanger
ACE-inhibitors and
β- blockers in
addition to
diuretics and
digitalis
from 2000
Apoptosis cellular
regeneration
Growth
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

80. Female
46.51%Male
53.49%
Heart Failure Patients by Gender
Ongoing Study ... Samal UC, Singh BP and Raghu TR et. al80

81. Clinical classifications of heart failure severity
NYHA Classification ACC-AHA Stages
Class 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. 82
Classes of recommendations
Levels of evidence
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
2012

83. Investigation Check list in pts with LV systolic dysfunction and treatment action needed
Test & possible finding Action Needed
Echocardiography
Presence/ absence of Organic Heart Disease & Base line
LV function
Operative/ device salvage
Electrocardiography
Atrial 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 radiography
Pulmonary 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 tests
Anemia
Perform a diagnostic work up, treat iron deficiency, if present
Biochemical tests
Increased 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

84. 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.

85. 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.

86. Classes of diuretics and their mechanisms of actions
86
Modified from Wile D: Diuretics: a review. Ann Clin
Biochem 49:419–431, 2012.

87. 0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
75.81%
58.60%
48.37%
43.72%
40.00%
33.02%
24.65%
19.07%
18.60%
18.14%
13.95%
11.16%
PercentofPatients
Comorbid States
Ongoing Study ... Samal UC, Singh BP and Raghu TR et. alOngoing Study ... Samal UC, Singh BP and Raghu TR et. al
HF-CBS-SRS
9800 Registry base
Ongoing Study ... Samal UC, Singh BP and Raghu TR et. al87

88. 88
Pharmacologic Actions of Human BNP
BNP = brain natriuretic peptide

89. 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.
Walter J. Paulus, JACC 2013 89

90. Comorbidities Drive Myocardial Dysfunction and remodeling in HFpEF
 Coronary microvascular endothelial cells
reactively produce reactive oxygen species
(ROS), vascular cell adhesion molecule
(VCAM), and E-selectin.
Walter J. Paulus, JACC 2013 90

91. Comorbidities Drive Myocardial Dysfunction and remodeling in HFpEF
 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.
Walter J. Paulus, JACC 2013 91

92. Comorbidities Drive Myocardial Dysfunction and remodeling in HFpEF
 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.
Walter J. Paulus, JACC 2013 92

93. Comorbidities Drive Myocardial Dysfunction and remodeling in HFpEF
 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.
Walter J. Paulus, JACC 2013 93

94. 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

95. Evidence Based Pharmacologic Treatment Of Heart Failure
Treatment Evidence Dosing
Contraindications, Cautions and Averse
Events
Starting
dose
mg
Dose
freque
ncy/
day
Target
total
daily
dose mg
Mean total
daily dose
achieved
in
outcome
studies mg
ACE 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 3 150 121
Enalapril CONSENSUS
SOLVD
2.5 2 20-40 16.6
Lisinopril ATLAS 2.5-5 1 20-35 NA
Ramipril AIRE 2.5 1 or 2 10 8.7
Trandolapril TRACE 1 1 4 3
Beta 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 6.2
Carvedillol COMET 3.125 2 50-100 37
Metoprolol MERIT-HF 12.5 or
25
1 200 150
Nevibolol SENIORS 1.25 1 10 7.7 N Engl J Med 2010;362:228-38.
95

96. Treatment Evidence Dosing
Contraindications, Cautions and Averse
Events
Star
ting
dose
mg
Dose
frequen
cy/ day
Target
total
daily
dose
mg
Mean
total daily
dose
achieved
in
outcome
studies
mg
Angiotensin 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

97. 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
B
ESC Guidelines: European Heart Journal (2012) 33, 1787–1847

98. 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.

99. Cumulative benefits of medical therapy on mortality
99
GLOBAL HEART, VOL. 8, NO. 2, 2013 June 2013: 141-170

100. 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. 101

102. 102