HEART FAILURE

1
 DEFINITION
• 2013 ACC/ AHA DEFNITION-
– Heart Failure is defined as “ a complex clinical
syndrome that results from any structural or
functional impairment of ventricular filling(diastole)
or ejection of blood. (systole) ”

2
 CLASSIFICATION BY
DEFINITION
• SYSTOLIC HEART FAILURE
– Characterized by reduced ejection fraction and
enlarged ventricle size. Clinically present with left
ventricular failure and marked cardiomegaly.
• DIASTOLIC HEART FAILURE
– Characterized by increased resistance to filling due
to increased filling pressures. Clinically present
with pulmonary congestion with normal or slightly
enlarged ventricles .
3
4
 CLASSIFICATION BASED ON
EJECTION FRACTION
• Heart Failure with reserved Ejection Fraction
HFrEF – Ejection fraction < 40% .
– These patients will have systolic dysfunction and
concomitant diastolic dysfunction. Coronary artery
disease is the major cause.
• Heart Failure with Preserved Ejection Fraction
HFpEF – Ejection Fraction > 50%.
– These patients can be diagnosed by 1)clinical signs
and symptoms and 2)evidence of pEF or normal EF or
previously rEF 3)evidence of abnormal LV diastolic
dysfunction (echo / LV catheterisation)
5
 CLASSIFICATION BASED ON CARDIAC OUTPUT

• HIGH OUTPUT FAILURE-

– The normal heart fails to maintain normal or
increased output in conditions like anemia,
hyperthyroidism, pregnancy.
– Usually right sided failure occurs followed by left sided
failure with presence of shortened circulatory time.
• LOW OUTPUT FAILURE-
– Heart fails to generate adequate output in conditions
like cardiomyopathy, valvular heart disease,
tamponade and bradycardia.
6
 RIGHT AND LEFT SIDED HEART FAILURE

• Right sided heart failure is characterised by the

presence of peripheral edema, raised JVP and
hypotension and congestive hepatomegaly.
• Left sided heart failure – pulmonary edema is the
striking feature. Other signs are tachypnea,
tachycardia, third heart sound, pulsus alternans,
cardiomegaly.
• Congestive Cardiac Failure – Characterised by
combination of both left and right sided heart
failure.
7
8
FORWARD AND BACKWARD HEART FAILURE

• FORWARD HEART FAILURE-

– This results from inadequate discharge of blood
into arterial system leading to poor tissue
perfusion and excess Na+ reabsorption through
RAAS.
• BACKWARD HEART FAILURE-
– This results from failure of one or both ventricles
to fill normally and discharge its contents, causing
back pressure on the atria and venous system.
9
 ACCF/AHA FUNCTIONAL CLASSIFICATION

• Stage A – At high risk of HF but witout

structural hear disease.
• Stage B – Structural heart disease without
signs or symptoms of HF.
• Stage C – Structural heart disease with prior
HF or current HF.
• Stage D – Refractory HF requiring special
interventions.
10
 NYHA FUNCTIONAL CLASSIFICATION

• Stage 1 – no limitation of ordinary physical

activity.
• Stage 2 – slight limitation of ordinary physical
activity.
• Stage 3 – marked limitation of ordinary
physical activity, but comfortable at rest.
• Stage 4 – unable to carry out physical activity,
symptomatic at rest.
11
 RISK FACTORS
• Epidemiology –
– Worldwide 2 crore people are affected by heart
failure. Approximate 2 % prevalence in developed
countries. Women have better survival than men.
– Coronary artery disease is the major cause for
heart failure. (60 – 75%)
• Etiology and Risk Factors –
– Any condition that leads to alteration of LV
structure and function can lead to heart failure
12
 ETIOLOGIES OF HEART
FAILURE
• HFrEF (EF < 40%) –
– Coronary Artery Disease (Infarction/Ischemia)
– Chronic Pressure Overload (Hypertension/
Valvular Heart Disease - Stenotic)
– Chronic Volume Oveload(Valvular Heart Disease-
Regurgitant/ Intracardiac shunting)
– Non ischemic DCM (Familial/ Infiltrative/
Endocrine/ Toxic/ Inflammatory/ Peripartum/
Stress)
13
THE PATHOPHYSIOLOGY OF HFREF
Damage to cardiac myocytes and extracellular matrix leads to changes in
the size, shape and function of the
heart and cardiac wall stress

Systemic neurohormonal overactivation

Vasoconstriction, fibrosis, apoptosis, hypertrophy,

cellular and molecular alterations, myotoxicity

Maladaptive remodeling and

Hemodynamic alterations,
progressive worsening
salt and water retention
of LV function

Morbidity and mortality: HF symptoms:

arrhythmias, pump failure dyspnea, edema, fatigue
14
 ETIOLOGIES OF HEART
FAILURE
• HFpEF (EF 40 – 50%)-
– Hypertrophic Cardiomyopathy
– Hypertensive heart disease
– Restrictive Cardiomyopathy(Amyloidosis /
Sarcoidosis / Hemochromatosis)
– Fibrosis / Endomyocardial Disorders / Aging
• Right Heart diseases-
– Cor pulmonale
– Pulmonary Vascular disorders
15
 ETIOLOGIES OF HEART
FAILURE

• High output states

– Thyrotoxicosis
– Nutritional – Beriberi
– Anemia

16
 LV REMODELING
• DEFINITION – It refers to change in LV Mass ,
Volume or Shape or the Composition of the heart
after Cardiac injury or index event.
• Progress of HF associated with changes in
geometry of remodeled LV
• Changes that occur include –
– LV dilatation
– LV thinning
– Increase in LV end diastolic volume
– Decrease in stroke volume
17
 LV REMODELING
– Subendocardial hypoperfusion
– Increased oxidative stress and free radical
generation
– Stress activated hypertrophic signaling pathways
– Incompitence of mitral valve apparatus and
functional MR

18
 CLINICAL FEATURES
• Important symptoms –
– Fatigue
– Exertional Breathlessness
• Cause of breathlessness is multifactorial
– Pulmonary congestion due to LVF
– Accumulation of interstitial and intra alveolar fluid
, stimulating juxta capillary J receptors, causing
Rapid Shallow breathing
– Decreased pulmonary compliance
– Increased airway resistance 19

– Respiratory fatigue and Anemia

 CLINICAL FEATURES
• Orthopnea –
– Dyspnea in recumbent position
– Occurs due to redistribution of fluid from
splanchnic circulation and lower extremities
– Causes increase in pulmonary capillary pressure.
– Nocturnal cough is usually asociated with this
symptom
– Relieved by sitting upright .
– This symtom is more common in patients with co
morbid obesity or ascites
20
 CLINICAL FEATURES
• Paroxysmal Nocturnal Dyspnea-
– Defnition – it refers to acute episode of shortness of
breath and coughing that generally occur at night and
awken patient from sleep usually 1 – 3 hours after
recline.
– Associated with coughing or wheeze
– Mechanism – increased pressure in bronchial arteries
leading to airway compression (+) interstitial
pulmonary edema = increased airway resistance.
– Orthopnea symptoms resolve after upright posture,
but symptoms of PND persist even after upright
posture.
21
 CLINICAL FEATURES
• Cheyne stokes respiration
– Also called periodic / cyclic respiration
– It is present in nearly 40 % cases of HF
– It is caused by decreased sensitivity of
RESPIRATORY CENTRE to PaCO2.
– Due to transient fall in PaO2 , rise in PaCO2 there
is an apneustic phase. PaCO2 rises steadily till it
stimulates depressed respiratory centre and
causes hyperventilation and hypocapnia (low
PaCO2).
22
 CLINICAL FEATURES
• Other symptoms like
– Anorexia
– Nausea
– Early satiety
– Abdominal pain
– Abdominal fullness
– Congestive hepatomegaly
– Confusion , disorientation, sleep disturbances,
– Nocturia 23
 PHYSICAL EXAMINATION
• Patient will present with laboured breathing in an
acute LVF. He/she may not be able to finish the
sentence due to shortness of breath. He / she
may have difficulty to talk due to shortness of
breath.
• Blood pressure may be normal or high in early HF
, may decrease consequently and is usually low.
• Low pulse pressure (reduced stroke volume)
• Sinus tachycardia (increased sympathetic activity)
cool peripheries, cyanosis of tips of fingers and
nail bed.
24
 PHYSICAL EXAMINATION
• Jugular venous pressure –
– Indicates right atrial pressure
– It is measured in terms of (cm of H2O)
– Normal < 8 cm of H2O
– Method – measure highest point of JVP vertically
from sternal angle and add 5 cm of H2O
– Positive Abdomino- Jugular reflex

25
 PHYSICAL EXAMINATION
• Respiratory system
– Bilateral rales/crepitations may be present as a
result of transudate of fluid from intravascular
space to intraalveolar space.
– May be accompanied by expiratory wheeze
(cardiac asthma).
– Pleural effusion may/may not be present.
(common in CCF)

26
 PHYSICAL EXAMINATION
• Cardiovascular system
– Apical impulse may shift inferiorly / laterally.
– Sustained apical impulse is felt in severe LVH.
– S3 gallop (protodiastolic gallop) can be heard.
– Left parasternal impulse in cases if severe RVH
– S4 gallop is usually present in diastolic dysfunction.
– MR or TR may be present additionally.

27
 PHYSICAL EXAMINATION
• Per abdomen
– Hepatomegaly is present (tender / pulsatile)
– Pulsations in liver indicate tricuspid regurgitation
– Ascites , Jaundice , raised liver enzymes
– Peripheral edema can be pre tibial or pre sacral
edema
• Cardiac cachexia
– Cause for cachexia is multifactorial
• Elevation of BMR
• Elevated circulating cytokines like TNF
• Congestion of intestinal veins
28
 OTHER IMPORTANT COMORBIDITIES IN
HF
• Atrial Fibrillation
• Anemia
• Depression
• Others
– Diabetes
– Arthritis
– CKD
– COPD
29
30
BIOMARKERS IN HEART FAILURE

31
 NT-PROBNP AND HS-TNT ARE ESTABLISHED BIOMARKERS IN HF

• BNP and NT-proBNP are the gold standard biomarkers for diagnosis and
prognosis in patients with HF1
• These biomarkers:
o Increase in response to myocardial wall stress and cardiac congestion2
o Are modified by HF therapy
o Are endorsed by HF clinical guidelines
o Can be used to predict future outcomes and guide HF therapy
• High BNP and NT-proBNP levels are readouts of cardiac congestion and
anticipate CV risk (mortality and HF worsening)
• Small increases in hs-TnT can reflect an increased risk of disease
progression in HF
32
BNP AND NT-PROBNP MEASUREMENT IS USEFUL FOR THE
DIAGNOSIS OF HFREF

Clinical examination, ECG,

chest X-ray, echocardiography

Natriuretic peptides

BNP <100 pg/mL BNP 100–400 pg/mL BNP >400 pg/mL

NT-proBNP <400 pg/mL NT-proBNP 400–2,000 pg/mL NT-proBNP >2,000 pg/mL

Chronic HF unlikely Uncertain diagnosis Chronic HF likely

▪ Clinical usefulness of BNP and NT-proBNP testing in patients with chronic HF:
• diagnosis of chronic HF in patients with dyspnea
• prognosis and risk stratification
• screening for chronic HF in high-risk populations
• monitoring and guiding treatment
• treatment with recombinant BNP
33
MANAGEMENT OF HEART FAILURE

34
 MANAGEMENT OPTIONS IN HFREF:

● Pharmacotherapy
● Devices
● Surgical management
● Cardiac transplant
● Stem cell/ Gene therapy

35
 GOALS OF TREATMENT

● To reduce symptoms
● Prolong survival
● Improve the quality of life
● Prevent disease progression

36
 PHARMACOLOGICAL MANAGEMENT

PROGNOSIS SYMPTOMS

● ACE inhibitors ● Diuretics

● ARBs ● Digoxin
● Beta Blockers ● Ivabradine*
● MRAs
● Hydralazine+nitrate*
37
 THE POTENTIAL DRUGS FOR HF-REF

• Diuretic
• Angiotensin Converting Enzyme Inhibitor
• Aldosterone Antagonist
• Angiotensin Receptor Antagonist
• Beta-adrenoreceptor Antagonists
• Digoxin
• Hydralazine/Nitrate
• Ivabradine
• Sacubutril-Valsartan

38
STAGES OF HEART FAILURE

39
 GUIDELINES RECOMMEND SEVERAL CORE THERAPIES
FOR PATIENTS WITH HFREF
▪ Most patients with chronic HF should be routinely managed with a combination of a RAAS
inhibitor, a β-blocker and a diuretic

Therapy Recommendation
LVEF ≤40% to reduce risk of mortality and HF hospitalization (unless
ACEIs contraindicated or not tolerated)

β-blockers LVEF ≤40% to reduce risk of mortality and HF hospitalization

Persisting symptoms (NYHA class II–IV*) and LVEF ≤35%, despite treatment with
Aldostero
an ACEI (or ARB if an ACEI is not tolerated) and a β-blocker, to reduce risk of
ne
mortality and HF hospitalization
antagonis
ts

LVEF ≤40% unable to tolerateACEI therapy to reduce risk of mortality and HF

hospitalization
ARBs
Persisting symptoms (NYHA class II–IV*) and LVEF ≤40%, despite treatment with
an ACEI and a β-blocker, who are unable to tolerate aldosterone antagonist
therapy
As needed to relieve signs and symptoms of congestion (have not been shown40to
Diuretics reduce risk of mortality and HF hospitalization)

McMurray et al. Eur Heart J 2012;33:1787–847

TREATMENT ALGORITHM AS PER ESC 20
GUIDELINES

41
 BETA BLOCKER
• HF activation of autonomic nervous system, adrenergic
activities (alfa ἀ 1, ß 1 & ß 2)
• ß ßlockers - Metoprolol,Carvidilol ,bisoprolol
• Should be started at low dose and titrated very slowly 1-2
weekly, because initiation and increase in dosing may
produce fluid retention due to abrupt withdrawal of
adrenergic support from heart and circulation. So better to
start and optimize the diuretic before starting BB and ACE-I.
• Combination of BB and ACE-I at lower tolerated dose is
better than individual drug at higher dose.
• Even after BB if HR remain >70 bpm or if BB is
contraindicated, Ivabradin is indicated. >>low BP, BA.

42
 BENEFITS OF BETA BLOCKERS

• Long-term treatment with beta blockers can

• Lessen the symptoms of HF
• Improve pt’s clinical status and
• Enhance pt’s overall sense of well-being
• Reduce the risk of death and the combined
risk of death or hospitalization
• Benefits irrespective of CAD,DM,Sex and race
43
 BETA BLOCKERS : INITIATION AND
MAINTENANCE
• Initiated at very low doses
• Gradual increments in dose if lower doses have been well
tolerated
• Vital signs and symptoms – monitored closely
• 85% of pts able to tolerate and achieve max planned trial
dose with this approach
• Can be safely started before discharge even in patients
hospitalized for HF
• Long-term treatment should be maintained, even if
symptoms do not improve 44
 CAUTION
• In pts with a current or recent history of fluid retention,
beta blockers should not be prescribed without diuretics
• Beta blockers may be considered in patients who have
reactive airway disease or asymptomatic bradycardia but
should be used cautiously in patients with persistent
symptoms of either condition
• Abrupt withdrawal of treatment with a beta blocker
can lead to clinical deterioration and should be
avoided

45
 RISKS OF BETA BLOCKERS

1) Fluid retention and worsening HF

2) Bradycardia or heart block
3) Hypotension
4) Fatigue

46
 AF AND HF

• FOR PTS WHO DEVELOP HF AS A RESULT OF AF, A

RHYTHM CONTROL STRATEGY SHOULD BE PURSUED
• IN PTS WITH HF WHO DEVELOP AF, A RHYTHM-
CONTROL STRATEGY HAS NOT BEEN SHOWN TO BE
SUPERIOR TO A RATE-CONTROL STRATEGY
• Β-BLOCKERS ARE THE PREFERRED AGENTS FOR
ACHIEVING RATE CONTROL

47
MAJOR CLINICAL TRIALS OF THERAPEUTIC INTERVENTIONS
IN PTS WITH HFREF

48
 DOSES OF BETA BLOCKERS
COMMONLY USED FOR HFREF

Mean Doses Achieved in

Drug Initial Daily Dose(s) Maximum Doses(s)
Clinical Trials

Beta Blockers

Bisoprolol 1.25 mg once 10 mg once 8.6 mg/d (118)

Carvedilol 3.125 mg twice 50 mg twice 37 mg/d (446)

Carvedilol CR 10 mg once 80 mg once ---------

Metoprolol succinate
extended release 12.5 to 25 mg once 200 mg once 159 mg/d (447)
(metoprolol CR/XL)

49
• β-B are currently the cornerstone in HF therapy
• Bisoprolol,Carvedilol and SR metoprolol succinate –
currently approved β-B for HF
• Uptitrating to max dose achieved in clinical trials
necessary to achieve max benefit
• Withholding β-B not necessary in HF
hospitalisation

50
 DIURETICS AND MRA.
(FUROSEMIDE,BUMETANIDE,TORASEMIDE, HTZ, SPIRONOLACTONE,
EPLERENONE)

• Loop diuretics choice of drug for all HFrEF and congestion, should be
started first . S/E- E.I.
• ACE-I reduces the aldosterone secretion but it’s transient and with chronic
therapy with ACE-I, aldosterone level rapidly return to normal.
• MRA is indicated in HFrEF < 35%, NYHA- II-IV and patient is on other
standard Rx ( Diuretic, ACE-I & BB).
• MRA is C/I in CKD with S. Creatinine >2.5 mg/dl, CCR < 30 ml/mint.
• Check S. K+ after 3 days.
• Painful gynecomastia- 10-15%, Eplerenone is an option.
• MRA- diuretic , K sparer, ↓myocardial fibrosis.

51
 ACE-I & ARB

• Overwhelming evidences of benefits of ACE-I in reducing mortality ,

increase the longevity, improve symptoms, HF hospitalization.
• Indicated in all patients with symptoms and asymptomatic patients with LVEF <40%.
• ACE-I inhibits Kininase , thereby reduce breakdown of bradykinin, that has
addition benefits in vasodilatation, over ARB.
• Should be started with low dose, preferable after with diuretics because if
diuretics are not used, fluid retentions from kidneys will attenuates the
effects of ACE-I and ARB.
• Dose should be increased gradually every 24-48 hrly ( c.f. to BB- 5-7 days
interval) till higher/recommended dose is not achieved.
• However before giving the highest dose of ACE-I, better to start BB, so that
BB can be used in adequate dose to reduce the HR without producing
hypotension.
• Higher the dose of ACE-I (BB), better the benefit. But it’s better to treat
with low/modest dose of both ACE-I & BB, than highest dose of any one of
these.

52
 ACE-I AND ARB.

• Abrupt withdrawal may deteriorate the symptoms, so should be avoided

except in life-threatening condition e.g. angioedema and hyperkaelemia.
• Blood pressure, renal function and S. K+ -monitoring after 1-2 wks.
specially if there in preexisting CKD.
• ARB are indicated only when ACE-I are not tolerated due to cough,
angioedema, skin rash.
• Losartan, valsartan(widely studied) and candesartan.
• Aliskiren-direct renin inhibitor- major trials fails to prove it’s benefit and there
not recommended as an alternative to ACE-I or ARB.
• Hydralazine and NO3- alternative if ACE-I & ARB both are not tolerated,
specially in African American black people.

53
ROLE OF ARNI

54
 NEPRILYSIN RAPIDLY DEGRADE NATRIURETIC PEPTIDE
AND TURNS THEM INTO INACTIVE FRAGMENTS

SNS
Epinephrine α1, β1, β2
Norepinephrine receptors
Vasoconstriction
RAAS activity
Vasopressin
NP system HF SYMPTOMS & Heart rate
PROGRESSION Contractility
NPRs NPs
Vasodilation
Blood pressure
Sympathetic tone
Natriuresis/diuresis
RAAS
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis

55
• ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker;
AT1R = angiotensin II type 1 receptor; HF=heart failure; MRA=mineralocorticoid receptor antagonist; • 1. McMurrayet al. Eur J Heart Fail 2013;15:1062–73
NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone
system; SNS=sympatheticnervous system • Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert.
Pharmacotherapy2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–71;
Schrier & Abraham N Engl J Med 2009;341:577–85
 CARDIAC DYSFUNCTION TRIGGERS THE ACTIVATION OF THREE COMPENSATORY
NEUROHORMONAL SYSTEMS

Cardiac structure/function abnormality

Activation of compensatory mechanisms to maintain

cardiac output and organ perfusion1

SNS RAAS NP system

Activated in response to reduced cardiac output1 Release of NPs in

response to cardiac stress2
Short-term effects are beneficial in early HF1
Opposes the actions of the
Long-term activation exerts unfavourable effects1,3 RAAS2 and SNS4,5

56

1. Francis et al. Ann Intern Med 1984;101:370–7; 2. Clerico et al. Am J Physiol Heart Circ Physiol 2011;301:H12–H20;
3. Von Lueder et al. Circ Heart Fail 2013;6:594–605 4. Luchner & Schunkert. Cardiovasc Res 2004;63:443–9;
5. Thysgesen et al. Eur Heart J 2012;33:2001–6
EFFECTS OF THE NATRIURETIC PEPTIDE SYSTEM: NPS MEDIATE A WIDE
RANGE OF PHYSIOLOGICAL EFFECTS VIA NP RECEPTORS

Cardiomyocytes1 Endothelial cells1

ANP and BNP

CNP
NPR-A NPR-B NPR-C

GTP GTP Receptor

cGMP cGMP
Internalization recycling

⚫ Vasodilation1,2
⚫ Antihypertrophy1,2 ⚫ Vasodilation1,2 Degradation
⚫ Antiproliferation2 ⚫ Antihypertrophy1,2 of NPs7
⚫ Vascular regeneration3 ⚫ Antiproliferation2
⚫ Myocardial relaxation4,5 ⚫ Vascular regeneration1
⚫ Diuresis, natriuresis1,2 ⚫ Venodilation1 Natriuretic peptide
⚫ Antiapoptosis6 ⚫ Antifibrosis1 degradation and clearance
⚫ Anti-aldosterone1,2
⚫ Renin secretion inhibition7
⚫ Reduced sympathetic tone8
⚫ Lipolysis7
57
 SACUBITRIL/VALSARTAN: NEPRILYSIN INHIBITION COMBINED WITH
RAAS BLOCKADE IS AN ALTERNATIVE TO AN ACEI OR ARB IN PATIENTS
WITH HFREF

β-blockers
SNS
Epinephrine α1, β1, β2
Norepinephrine receptors
Neprilysin Vasoconstriction
inhibitors RAAS activity
Vasopressin
Heart rate
NP system HF SYMPTOMS &
PROGRESSION Contractility
NPRs NPs
Vasodilation
Blood pressure RAAS inhibitors
Sympathetic tone RAAS
Natriuresis/diuresis (ACEI, ARB, MRA)
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
Aldosterone
Sacubitril/valsartan Hypertrophy
Fibrosis

58
1
59
 NEPRILYSIN INHIBITION MUST BE ACCOMPANIED BY SIMULTANEOUS
RAAS BLOCKADE

Angiotensinogen
Neprilysin
▪ Neprilysin metabolizes Ang I and Ang II via several Renin inhibitor
pathways1,2
Ang I Ang-(1–7)
▪ Inhibition of neprilysin alone is insufficient as it associated Neprilysin

with an increase in Ang II levels, counteracting the Neprilysin

ACE
potential benefits of neprilysin inhibition2 inhibitor
Inactive
▪ Neprilysin inhibition must be accompanied by Ang II Neprilysin
fragments
simultaneous RAAS blockade (e.g. AT1 receptor blockade)2
AT1 receptor

Signaling
cascade

Biological actions

Hypertrophy Vasoconstriction Na+/H2O retention Norepinephrine release

Fibrosis Hypertrophy Aldosterone release ↑Sympathetic tone
60

ACE=
 LCZ696 SIMULTANEOUSLY INHIBITS NEPRILYSIN (VIA LBQ657) AND BLOCKS
AT1 RECEPTORS (VIA VALSARTAN)

LCZ696
ANP, BNP, CNP, other
vasoactive peptides*
RAAS
Angiotensinogen
(liver secretion)
Sacubitril
(AHU377; pro-drug)
Ang I

Inactive LBQ657 Ang II

fragments Valsartan
(NEP inhibitor)

O O
AT 1 receptor
Enhancing N OH

Vasorelaxation HN
O
Inhibiting
OH N
• Blood pressure O
HO
N
N NH
Vasoconstriction
• Sympathetic tone O • Blood pressure
• Aldosterone levels • Sympathetic tone
• Fibrosis • Aldosterone
• Hypertrophy • Fibrosis
• Natriuresis/diuresis • Hypertrophy
61
*

Levin et al. N Engl J Med 1998;339:321–8

SIMULTANEOUS INHIBITION OF NEPRILYSIN AND SUPPRESSION OF THE RAAS
WITH LCZ696 HAS COMPLEMENTARY EFFECTS

LCZ696

Enhancing cGMP-mediated effects of

Suppressing RAAS-mediated effects
natriuretic peptides
🠙 Vasodilation 🠙 Vasoconstriction
🠙 Natriuretic and diuretic effects 🠙 Sodium and water retention
🠙 Proliferation 🠙 Ventricular hypertrophy/remodeling
🠙 Hypertrophy
🠙 Aldosterone secretion
🠙 SNS outflow/sympathetic tone
🠙 Cardiac fibrosis
🠙 Aldosterone secretion
🠙 Sympathetic tone
🠙 Detrimental effects of
vascular remodeling 🠙 Systemic vascular resistance
62
 OPEN-LABEL EXTENSION OF THE PIONEER-HF TRIAL

Effect of Sacubitril/Valsartan on Clinical Outcomes Over 12 Weeks

DeVore AD, Braunwald E, Morrow DA, et al. Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure Secondary Analysis of
the Open-label Extension of the PIONEER-HF Trial. JAMA Cardiol. doi:10.1001/jamacardio.2019.4665; E1-E6 63

64
Role of SGLT2 receptor
blockers in
management of heart
failure

64
 SGLT 2 INHIBITORS
• CANA-, DAPA-, EMPAGLIFLOZIN, ERTUGLIFLOZIN
• Diabetic patients are at higher risk of HF compared with healthy persons.
• SODIUM GLUCOSE CO-TRANSPORTERT 2 (SGLT2)- Is not included In GDMT. It’s an
beneficial adjunctive to GDMT IN HFREF.
• ANTI-DIABETIC EFFECT, CARDIO PROTECTION, ANTI-FAILURE, RENO-PROTECTION.
• REDUCE HBA1C, DIURESIS, WEIGHT REDUCTION.
• IT PROMOTES HEPATIC KETONES SYNTHESIS ( BETA OH BUTERATE), THAT IS UTILIZED
• BY MYOCARDIUM and kidney and preferentially oxidized with more energy
• Production by less O2 consumption ( FFA oxidation needs more O2
utilization).
• NA+/H EXCHANGER 1 (NHE-1) Produce cardiomyocyte injury and decreases
• MITROCHONDRIAL CA+➔Decrease ATP production.
• DM AND HF PATIENTS HAVE HIGHER NHE-1 LEVEL. SGLT2 INHIBITOR INHIBITS THE
NHE-1 . 65
66

90
 IF-CHANNEL INHIBITOR

• Ivabradine is indicated in HF patients with:

• symptomatic patients with HFrEF
• in sinus rhythm and with a heart rate ≥70 bpm
• who had been hospitalized for HF within the
previous 12 months

67
68
69
70
OTHER TREATMENTS WITH LESS CERTAIN BENEFIT IN SYMPTOMATIC
PATIENTS WITH HFREF

• Digoxin and other digitalis glycosides

• Digoxin may be considered in patients in sinus rhythm to reduce the
risk of hospitalisation in symptomatic patients with HFREF
• It is only recommended for the treatment of patients with HFREF and AF with
rapid ventricular rate when other therapeutic options cannot be pursued
• A resting ventricular rate in the range of 70–90 bpm is recommended,
although a resting
• Ventricular rate of up to 110 bpm might still be acceptable
• Digitalis should always be prescribed under specialist supervision. Caution
should be exerted in females, in the elderly and in patients with reduced
renal function. 71
THANK YOU

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