1. RECENT ADVANCES IN
MANAGEMENT OF HEART FAILURE
DR. PRIYANKA KUMAWAT
Pharmacology deptt.
PGIMS, Rohtak

2. Heart failure
• A pathophysiologic state in which an abnormality of cardiac function is
responsible for failure of the heart to pump blood at a rate commensurate with
metabolic requirements of the tissues -E Braunwald
• Heart failure (HF) is a clinical syndrome that occurs, because of an inherited or
acquired abnormality of
• Cardiac structure
• Cardiac function
develop a constellation of
• Clinical symptoms - dyspnea and fatigue
• Signs- edema and rales
that lead to frequent hospitalizations, a poor quality of life, and a shortened life
expectancy- Harrison’s princilple of internal medicine 18th ed.

3. Epidemiology
• More than 20 million people affected worldwide
• Affects 10% of people over 65 year
• It is the most common condition for which
patients 65 + require admission to hospital
• ”our country is set to be the heart disease capital
of the world in a few years”
• Prevalance in india- 1.87 %
Prevalance- 2% in developed countries
Affects over 50% of people with 85+ years
Approx 10% of patients with HF die each yr.

4. Why HF is increasing ?
• Almost any disease of heart can cause it
• More of HT, DM, Obesity – CVD
• CAD - which is its commonest cause
• Better tools for diagnosis and availability
• Better detection and treatment of causes
• Better Rx. of RF, CAD, MI - PTCA, CABG
• Increasing longevity of the population

5. Classification
• BY EJECTION FRACTION
• Reduced ejection fraction(<40-50%)- systolic heart failure
• Preserved ejection fraction(>40-50%)- diastolic heart failure
• BY TIME COURSE
• Chronic heart failure(CHF)
• Acute heart failure (Cardiogenic Shock)
• ANATOMICALLY
• Left sided- LHF
• Right sided- RHF(CHF)
• BY OUTPUT
• High output failure-Thyrotoxicosis, Paget's dis, Anemia, Pregnancy,
A-V fistula
• Low output failure – 95% of HF is this

6. McMurray J. N Engl J Med 2010;362:228-238
Clinical Classifications of Heart Failure Severity

7. Etiology
• Reduced ejection fraction(< 50%)
• Condition that leads to an alteration in LV structure or function can
predispose a patient to developing HF.
• Coronary artery dis- MI, Angina (60- 70 %)
• Chronic pressure overload dis- Hypertension( 75%), valvular dis
• Chronic volume overload- intracardiac and extracardiac shunting
• Non ischaemic cardiomyopathy
• Drug induced damage- metabolic disorder
• Disorders of rate and rhythm
• Preserved ejection fraction(> 50%)
• Pathologic hypertrophy
• Restrictive cardiomyopathy
• Fibrosis
• Aging
• Pulmonary heart dis- Cor pulmonale, pulmonary vascular dis
• High output states- metabolic disorders, anemia, systemic AV shunting

8. Risk factors

9. PATHOPHYSIOLOGY OF HF

11. Consequences of Neurohormonal
Activation in HF

12. SIGN AND SYMPTOMS

13. MANAGEMENT OF HF

14. Non Pharmacological
• Activity-
• Routine modest exercise for class I-III
• For euvolemic patients- regular isotonic exercise such as walking
or riding a stationary-bicycle ergometer
• Diet-
• Restriction of sodium (2-3 g daily) is recommended in all patients,
Extra < 2g reduction in moderate to severe cases.
• Fluid restriction (<2 L/day) if hyponatremia (<130 meq/L)
• Caloric supplementation- with advanced HF and unintentional
weight loss or muscle wasting (cardiac cachexia)
Three things for preventing heart diseases are – Eat less fried food,
less butter and ghee. Second, exercise daily for around 45 minutes.
And third, reduce stress in life

15. Pharmacological measures
DRUGS FOR
ACUTE DECOMPENSATED HF
• DIURETICS- Furosemide
/hydrochlorthiazide
• VASODILATORS-
Nitroprusside,
Nitroglycerin, Nesiritide
• INOTROPIC AGENTS-
dobutamine, dopamine,
milrinone, levosimendan
Drug Therapy for Chronic HF
Due to Systolic Dysfunction
 DIURETICS-furosemide /
hydrochlorthiazide
 ACE-INHIBITORS*-captopril
• ARBs*- losartan
• HYDRALAZINE + ISOSORBIDE*-
when ACE-I or ARB
contraindicated or not fully
effective
• BETA BLOCKERS*
• SPIRONOLACTONE*
• DIGOXIN
* = SURVIVAL BENEFIT

16. Surgical measures
• Cardiac Resynchronization
• Implantable Cardiac Defibrillators
• Intraaortic balloon counter pulsation
• Percutaneous and surgically implanted LV assist
devices
• Cardiac transplantation

17. Medicines used in the first line management of heart failure
DRUG CLASS DOSE REGIME SIDE EFFECTS
ACEIs
Ramipril
Perindopril
Lisinopril
Enalapril
Captopril
1.25 – 10mg daily (2 divided doses)
2.5 – 5mg daily
2.5 – 35mg daily
2.5mg daily – 10-20mg twice daily
6.25 – 50mg three times daily
Postural hypotension; dry
cough; ↑ plasma K+;
caution with renal
dysfunction. Rarely angio-
oedema.
Not to be used during
pregnancy
β-blockers
Bisoprolol§
Nebivolol§
Carvedilol§§
1.25 – 10mg daily
1.25 – 10mg daily
3.125 – 25mg twice daily
Bradycardia; worsening of
heart failure; hypotension;
fatigue; GI disturbances;
cold extremities
Diuretics:
Furosemide
Bumetanide
Bendroflumethiazide
20 – 40mg once or twice daily
0.5 - 2mg daily
2.5mg daily – 10mg daily
Loop diuretics: ↓ K+ and ↓
Na+ ; hypovolaemia;
hypotension; ↑ creatinine;
↑ risk of gout
Thiazides: ↓ K+ ; ↑ risk of
gout; ↑ risk
of diabetes mellitus.
Rarely ↓ Na+

18. Medicines used in the second-line management of heart failure
DRUG CLASS DOSE REGIME CLASS SIDE EFFECTS
ARBs
Valsartan
Losartan
Candesartan
40-160mg twice daily
12.5 – 150mg daily
4 – 32mg daily
Postural hypotension; ↑
plasma K+; caution with
renal dysfunction.
Not to be used during
pregnancy
Aldosterone
(mineralocorticoid
receptor) Antagonists
Spironolactone
Eplerenone 12.5 – 50mg+ daily
25 – 50mg daily
↑ plasma K+ - discontinue if
K+ levels > 5mmol/L;
caution with
↓ renal function.
Gynaecomastia (with
spironolactone).
Do not use eplerenone with
strong inhibitors of CYP
3A4Other drugs which can be used in HF-
INOTROPIC AGENTS- Cardiac Glycosides, Phosphodiesterase inhibitors, dopamine
receptor agonists
Ivabradin
Anticoagulants
Antiarrhythmic agents

19. PHARMACOTHERAPY OF HEART FAILURE

20. Diagnosis
• Detailed history, clinical examination, ECHO and/or serum natriuretic peptide levels
• Confirm heart failure and Assess the severity of symptoms
Treatm
ent
• Education on lifestyle management and exercise training
Step- 1
• ACE inhibitor (or ARB if ACEI not tolerated) +/- β-blocker**
• Concomitant therapy with β-blocker + ACEI (or ARB if ACEI not tolerated)
• If still symptomatic with optimised triple therapy (ACEI, β-blocker, diuretic)
Step- 2
• ADD mineralocorticoid receptor antagonist (MRA) (ARB may be considered if
MRA not suitable)§
• hydralazine + isosorbide may be useful in black populations / patients not
responding or intolerant of step 2 combinations
Step- 3
• Consider adding in digoxin / ivabradine / use of non-surgical
interventional
therapies (ICD, CRT)

21. NEED FOR NEWER THERAPIES
• Available drugs treat only symptomatically
• Even the available drugs do not control symptoms
effectively
• Associated side effects are more
• Needed life long treatment
• HF is associated with high morbidity and mortality

22. Novel agents in HF
• Newer Inotropes-
• Cardiac myosin activators- Omecamtive mecarbil
• Na/K-ATPase inhibitors- Istaroxime
• Ryanodine receptor stabilizers- JTV-519(K 201),S107,S44121
• SERCA2a activators- MYDICAR
• Vasodilators- Relaxin
• Neuregulins-
• recombinant human NRG-1β2
• Novel RAAS blockers-
• Direct renin inhibitors- Oral Aliskiren,IV Remikiren, IV Enalkiren
• Angiotensin receptor & neprilysin inhibitors- LCZ696, AHU377
,Candoxatril, Ecadotril
• Aldosterone blockers-
• Non steroidal minrelocorticoid receptor antagonist-PF3882845,BR-4628
• Aldosterone synthase inhibitors- FAD286, LCI699

23. • Dual ACE/NEP Inhibition – Vasopeptidase Inhibitors
• Omapatrilat, sampatrilat, fasidotrilat, MDL 100240, Z13752A, BMS 189921
and mixanpril
• Dual NEP & ECE(endothelin converting enz.) inhibitors
• GGS34043, GGS34226, GGS26303, SLV306
• Triple enzyme inhibitors of ECE/NEP/ACE
• GGS26670
• Dual dopamine D2-α2 agonist
• Nolomirol
• Dopamine β-Hydroxylase inhibitor
• Nepicastat
• Adenosine A1 receptor antagonists
• BG9719,BG9928
• Carnitine palmitoyl transferase-1(CPT-1) inhibitors
• Etoxomir, Oxenicine
• Matrix Metalloproteinase (MMP) Inhibitors
• Batimastat, ilomastat, marimastat and prinomastat
• Immune modulator
• CelacadeTM

24. Cardiac Myosin Activators-
Omecamtive Mecarbil
• MOA:
accelerate transition of actin-myosin complex from a
weakly bound to strongly bound configuration
↓
↑ myosin head interaction with actin
↓ nonproductive ATP hydrolysis
↓
↑duration of systole↑stroke vol -improvement in
myocardial systolic function in absence of
arrythmogenesis & ↑ O2 consumption

26. OMECAMTIVE MECARBIL
• ↑stoke vol & CO
• ↓HR & ↓LV end diastolic pressure.
• No effect on BP
• Do not ↑rate of rise of LV pressure but ↑LV ejection time & do
not change myocardial O2 consumption
• No untoward effect on exercise tolerance
• Disadvantage :As it prolongs systole, shorten diastole-
inadequate coronary flow & ventricular filling so lowers
threshold for myocardial ischemia in patients with CAD
• Currently under phase 2b trial.

27. Istaroxime
• MOA-
• Inhibition of sodium/potassium adenosine triphosphatase (Na+/K+
ATPase).
• Stimulation of the sarcoplasmic reticulum calcium ATPase(SERCA)
isoform 2 (SERCA2) – Lucitropic action(rapid sequestration of
cytosolic calcium into the sarcoplasmic reticulum during diastole)
Enhances the heart’s relaxation phase, protects from
arrhythmogenesis caused by calcium overload
• Significantly reducing PCWP.
• Improves ejection fraction, stroke volume and systolic
blood pressure, while also enhancing ventricular filling.
• Reduces heart rate and ventricular diastolic stiffness
• Wider margin of safety
• Drug is under phase 2 trial.

28. Vasodilators - Serelaxin
• Recombinant human relaxin- 2
• Relaxin- circulating peptide found in pregnant women
• Regulates systemic vasodilation
• The rapid vasodilatory responses of relaxin are mediated
by activation of endothelial NOS. Reduces pulmonary
capillary wedge pressure and systemic vascular
resistance
• Improves dyspnea significantly
• Reduces hospital stay with HF
• Dose 30 μg/kg/day infusion
• Currently under phase 3 trial.

29. SERCA 2a activators
• SERCA2a mediates the reuptake of Ca2+ back into the SR
during the early diastolic phase .
• Adeno-associated virus 1 (AAV1) is used for delivery of
SERCA2a complementary DNA by intracoronary infusion
in trials.
• Improved systolic and diastolic functions, improved
ventricular metabolic reserve, and reducing the likelihood
of ventricular arrhythmias during ischemia-induced
Ca2+ overload
• Drawbacks- inhomogeneous SERCA2 overexpression
may be pro-arrhythmic , implantation of a cardioverter
defibrillator was an inclusion criterion for the trial.
• Currently under phase 3 trial.

31. Ryanodine receptor stabilizers (JTV519 )
• Ca+2 entry in SR triggers further its release via activating
the ryanodine receptor 2 (RyR2)
• Diastolic Ca2+ leak through dysfunctional RyR2, leak may
lead to a reduction in SR Ca2+ content, with less
Ca2+ available for release and consequently weaker
muscle contractions.
• Calstabin proteins increase the probability of the channel
to be in its closed state, RyR channel stabilizers.
• MOA- JTV519 (originally called K201), S107, S44121
enhances RyR-calstabin binding and stabilizes the closed
state of the RyR thus preventing SR Ca2+ leak
• preserve left ventricular systolic and diastolic function
• prevents left ventricular remodeling

33. Neuregulins
• Growth-promoting proteins of the epidermal growth factor family .
• Neuregulin-1 (NRG-1) plays a key role in cardiac chamber differentiation and
trabeculation in the developing embryo and in cardiac function.
• Act through the ErbB family of tyrosine kinase receptors.
• In the later stages of HF, both NRG-1 expression and NRG-1/ErbB signaling
are inhibited, enhanced susceptibility of cardiomyocytes to cell death and
progression of HF.
• Recombinant human NRG-1β2 infusion improve cardiac structure and
function by 90 days
• Increase in cardiac output as well as vasodilator effect
• Drawbacks- potential for acceleration of tumor growth , administered
intravenously over many hours on a daily basis, thus limiting its utility in
chronic HF , Nausea
• Currently under phase 3 trial.

34. Novel blockers of the renin–angiotensin
aldosterone system
Direct renin inhibitors
• Oral Aliskiren,IV Remikiren, IV Enalkiren
• Reduce increased plasma renin activity directly
independent of plasma levels of BNP, background effect
of beta blockers & ACEI.
• MOA- inhibit conversion of Angiotensinogen to
angiotensin-I
• Reduces systemic vascular resistance & PCWP
• Ventricular remodeling significantly attenuated
• Delays cardiovascular death and hospitalization
• Drawback- hyperkalemia, hypotension

35. Angiotensin receptor and neprilysin inhibitors
• Atrial natriuretic peptide, B, C and exogenous D-type, possess
differing degrees of hemodynamic, neurohormonal, renal and
cardiac effects
• Candoxatril, Ecadotril
• LCZ696 (Angiotensin receptor blocker)
• AHU377 moiety (neprilysin inhibitor)
• Preservation of systemic blood pressures while causing
significant reductions in central pressures
• Increases in urine sodium excretion and increased urinary
volume while preserving glomerular filtration
• Currently under phase 2 trial

36. Novel approaches to aldosterone blockade
Non-steroidal mineralocorticoid receptor antagonists
• PF3882845 -greater blood pressure reduction and renal
protection
• BR-4628 -dihydropyridine (DHP) structure
• specific MR antagonist without pronounced L-type
calcium channel activity .
Aldosterone synthase inhibitors
• There is induction of aldosterone synthase (CYP11β2) or
angiotensin II in the failing ventricle
• FAD286 - improved cardiac hemodynamic parameters,
preventing progressive LV remodeling
• LCI699 - reduction in blood pressure

37. Dual ACE/NEP Inhibition –
Vasopeptidase Inhibitors
• Omapatrilat, sampatrilat, fasidotrilat, MDL 100240,
Z13752A, BMS 189921 and mixanpril
• Superior to ACE inhibitors in increasing glomerular
filtration rate and sodium excretion and decreasing PCWP
• Improvement in ventricular function in NYHA class II to IV
heart failure.
• Drawback- Severe angioedema than ACEI

38. Dual Neutral Endopeptidase (NEP) and
Endothelin
Converting Enzyme (ECE) Inhibitors
• Endothelin converting enzyme helps in production of ET-
1- a potent vasoconstrictor
• NEP degrades BNP and ANP- helps in natriuresis
• GGS 34226 and GGS 26303 are dual inhibitors of above
enzymes
• Decreased preload, afterload and LV hypertrophy and
increased cardiac output.
• Reducing right and left cardiac filling pressures

39. Triple Enzyme Inhibitors of ECE/NEP/ACE
• GGS 26670
• Improved LV function and reduced LV collagen accumulation
better than either ACE alone or ECE-NEP inhibition
Dual Dopamine D2- 2 Adrenoceptor agonist
• Nolomirole
• Inhibits catecholamine release from sympathetic
nerve endings and also inhibits the release of TNF-
from cardiac tissue
• Significantly reduces hypertrophy and attenuates
signs and symptoms

40. Dopamine -Hydroxylase Inhibitor
• DBH catalyses the conversion of dopamine (DA) to
norepinephrine (NE) in sympathetic nerves
• Nepicastat- reduce norepinephrine synthesis.
• Attenuates ventricular remodeling and prevents systolic
dysfunction
• Augments level of DA leading to renal vasodilation.
• Phase 2
Adenosine A1 receptor antagonists
• BG 9928, BG 9719
• Protects renal function and exerts additive natriuretic
effects without excessive potassium loss

41. Carnitine Palmitoyl Transferase-1 (CPT-1) Inhibitors
• CPT-1 enz helps in metabolism of fatty acid which is a source
of energy production in heart
• Etoxomir, Oxfenicine
• Convert energy production of heart from fatty acids to glucose
• Preserves cardiac function and prevents ventricular dilation,
reduced PCWP. prevents ventricular remodeling.
Matrix Metalloproteinase (MMP) Inhibitors
• Enhanced expression of MMP triggers signaling cascade of
cardiac remodeling
• Batimastat, ilomastat, marimastat and prinomastat, PG-53072
• Prevent ventricular dysfunction and delay heart failure
progression

42. Immune modulator
• CelacadeTM
• Prevents chronic inflammation and apoptotic cell death by
activating physiological immune system’s IL -10 mediated anti-
inflammatory process
• Celacade is a device-based outpatient procedure involving ex
vivo exposure of 10ml autologous blood to heat, ultraviolet
irradiation, controlled oxidative ozone therapy and subsequent
intramuscular administration at monthly intervals.
• Improve quality of life in patients of NYHA class III or IV heart
failure.
• Reduce the risk of death and hospitalization due to chronic
heart failure

43. Conclusion
• The newer therapeutics may be potential candidates in
future for heart as increasing in understanding of
pathophysiology of heart failure.
• Agents directly acting on remodeling process may even
reverse current pathological condition of heart failure.
• Newer agents are seems to be beneficial over the older
one in efficacy and safety wise eg: newer inotropes,
RAAS antagonists…
• Gene therapy is also emerging as newer technique for HF
seems to be promising in near future.

44. References
• Harrison’s principles of internal medicine 18th ed.
• Pharmacology & Therapeutics Volume 135, Issue 1, July
2012, Pages 1–17
• Novel Strategies for the Treatment of Heart Failure.
RMMJ|www.rmmj.org.il.1 April 2012.Volume 3(2).0011
• Emerging Drug Therapies for Heart Failure.Ijpt. July 2006
| vol. 5 | no. 2 | 87-94
• Wikipedia

47. HF FORMS
• Systolic ventricle unable to contract
normally
LVEF is <50%
Sx due to inadequate out-
put
• Diastolic ventricle unable to relax and
fill normally
LVEF is preserved >50%
Sx related to increased fill-
ing pressures
Estimated at 20-50% of HF
More in elderly women

48. ACUTE HEART FAILURE
PRECIPITATING CAUSES
Arrhyhthmias Thyrotoxicosis
Pregnancy Myocarditis
Myocardial infarction PE
Infective endocarditis Infection
HTN Anemia
Physical,dietary,fluid,environmental or
emotional excesses

49. PATHOGENESIS of HEART FAILURE

50. ACUTE Acute stress for a chronically
burdened heart
CHRONIC Adaptive changes evolve over
time
Patient adjusts and tolerates
Acute decompensation occurs
with precipitating causes

51. SIGN AND SYMPTOMS

52. DRUGS for CHF THERAPY
Diuretic-furosemide / hydrochlorthiazide
Inotrope-digoxin
ACE-I-captopril
ARB-losartan
Isosorbide- hydralazine when ACE-I or ARB contraindicated
or not fully effective
Aldosterone receptor blocker-spironolactone
Beta-blocker-metoprolol
Sodium nitroprusside

53. Epidemiology of Heart Failure
Clinical criteria – Prevalence 1-2 %
Males > Females; in 65+ Prevalence
7%
50% of LVSD is asymptomatic
NEF HF varies from 15 to 50%
Incidence 0.2 to 0.3 %; with age

54. Metabolic Modulators
• MOA: Shift in energy utilisation from FFA glucose
• FFA require larger O2 for oxidation ,myocardial efficiency is
low
• FFA derivative may inhibit PDH & glucose oxidation↑
conversion of pyruvate to lactatelactic acidosisimpaired
myocyte contractility
PERHEXILINE:
• Inhibitor of carnitine palmitoyl transferase-1shift of
myocardial substrate to carbohydrate
• Disadv: narrow TI,hepatotoxicity,peripheral neuropathy
• Clinical trial: improvement in peak O2 uptake,quality
oflife,LVEF

55. • RANOLAZINE:
• Acts through inhibition of late sod channel current prevent
intracellular Ca++ overload during myocardial ischemia
• Also inhibits FFA oxidation
• Beneficial effects on LV diastolic function,LV remodelling &
myocardial fibrosis.
• TRIMETAZIDINE:
• Improvement in NYHA functional class
• ↓ LV end diastolic vol & ↑LVEF
• Improved exercise tolerance
• ↓FFA oxidation & unchanged myocardial oxidative rate↑ glucose
utilisation

56. TREATMENTALGORYTHM

57. Signs and symptoms
Acute heart failure
• Fluid overload-
• Weight gain
• Dyspnea on exertion
• Paroxysmal nocturnal
• dyspnea (PND)
• Orthopnea
• Rales
• Peripheral edema
• Jugular venous
• distension
• Ascites
• Hepato-/splenomegaly
• Low Cardiac Output
• Fatigue
• Nausea and vomiting
• Early satiety
• Weight loss
• Increased serum
• creatinine
Chronic heart failure
• breathing difficulties during the
night or when lying down
• coughing and wheezing
• fatigue and weakness
• shortness of breath
• swollen ankles.
• abdominal pain, bloating, or loss
of appetite
• accumulation of fluid in the
abdomen
• bluish skin around the mouth
• constipation
• pale skin and cold hands or feet
• urination at night

58. Systolic Heart Failure
• LVSD – Left Ventricular Systolic Dysfunction
• Most common type of Heart Failure; 60-70%
• LV is usually dilated & enlarged.
• Fails to contract normally due to WMA, Ischemia
• Cannot pump sufficient blood to meet needs
• In LVSD heart failure the EF is <40 -45%
• This carries a 10% mortality per annum

59. Diastolic Heart Failure
• Accounts for 20-40% of patients
• Ventricles are normal-sized with normal emptying
• But there is an impairment in the ability of the ventricles to
fill with blood during diastole.
• Because of stiff myocardium due to hypertrophy
• The heart fails to relax normally (relaxation poor)
• Generally older women
• Hypertension is the commonest cause
• This carries a 5-8% mortality per annum

60. Important Points
• Chronic Heart Failure (CHF) can be caused by any type of
cardiac dysfunction
• Most commonly attributable to LV Dysfunction
• Rarely HF is due to isolated RV dysfunction
• Most common and best studied cause of CHF is LV Systolic
Dysfunction (LVSD)
• Normal Ejection Fraction Heart Failure (NEFHF) is due to LV
Diastolic Dysfunction – (HFPSF)
• It is difficult to diagnose and quantify.
• 30- 40% of patients die within 1 year of diagnosis and 60-70%
die within 5 years, mainly from worsening HF or as a sudden
event (probably because of a ventricular arrhythmia)

61. NYHA classification
I. No visible sign and symptom
II. Sign and symptom on high level of exercise
III. Sign and symptom on low level of exercise
IV. No physical exercise possible, bed rest necessary

63. Novel agents with inotropic effects
• Cardiac myosin activators- Omecamtive mecarbil
• Agents acting on SERCA2a- MYDICAR
• Na/K-ATPase inhibitors- Istaroxime
• Ryanodine receptor stabilizers- JTV-519(K
201),S107,S44121
• Metabolic modulators-Perhexiline,
Trimetazidine, Ranolazine