gives an idea about the basics of heart failure, various management options and recent advances in the field of heart failure development

1. PHARMACOTHERAPY OF
HEART FAILURE
Presenter- Dr. Shivesh
Gupta
PG Guide- Dr. Shyamal
Sinha

2. OUTLINE OF TODAY’S SEMINAR
Introduction
Epidemiology
Classification
Pathophysiology
Management
Recent advances
Summary

4. INTRODUCTION
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
The current American College of Cardiology
Foundation (ACCF)/American Heart Association
(AHA) guidelines define HF:-
Complex clinical syndrome that results from
structural or functional impairment of ventricular
filling or ejection of blood, which in turn leads to
the cardinal clinical symptoms of dyspnea and
fatigue and signs of HF, namely edema and rales

5. EPIDEMIOLOGY
Prevalance- 2% in developed countries and in India- 1.87 %
Its prevalence is increasing worldwide, likely due to improved
survival because of early diagnosis and better treatement
More than 20 million people affected worldwide
HF prevalence follows an exponential pattern, rising with age,
and affects 6–10% of people over age 65
Approx 10% of patients with HF die each year

6. 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
BY OUTPUT:-
 High output failure-Thyrotoxicosis, Paget's dis, Anemia,
Pregnancy, A-V fistula
 Low output failure- 95% of HF is this type

7. NYHA classification

8. Image Source:- Yancy CW, et al. 2016 ACCF/AHA/HFSA focused update on new pharmcological therapy for heart failure: an update of the 2013
guideline for the management of heart failure. Circulation, 2016, 135:e282–e293.

9. ETIOLOGY

10. PATHOPHYSIOLOGY
The pathophysiology of heart failure is complex and involves
four major interrelated systems:-
 the heart itself
 the vasculature
 the kidney
 neurohumoral regulatory circuits

11. COMPENSATORY MECHANISMS

12. SIGNS AND SYMPTOMS

13. MANAGEMENT
Aims:-
1. Relief of signs and symptoms
2. Stabilization of haemodynamics
3. Prevention of disease progress
4. Treatment of risk factors
5. Improvement in Quality of Life and reduction
in Mortality

14. CLINICAL TRIALS

15. NON-PHARMACOLOGICAL
Activity
 Routine modest exercise for class I-III, Graded over a period of time
depending on the improvement
 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)
 Cessation of Smoking and alcohol consumption
 Caloric supplementation- with advanced HF and unintentional weight loss
or muscle wasting (cardiac cachexia)
 Stop any drug contributing to HF

16. PHARMACOLOGICAL THERAPY
Drugs with positive inotropic effects:-
 Cardiac Glycosides:- Digoxin, Digitoxin
 Phosphodiesterase Inhibitors:- Milrinone, Enoximone,
Levosimendan
 Beta- Agonists:- Dopamine, Dobutamine, Nor-adrenaline
Drugs without positive inotropic effects:-
 ACEIs:- Enalapril, Lisinopril, Captopril, Ramipril
 ARBs:- Losartan, Candesartan, Irbesartan
 Beta-Blockers:- Bisoprolol, Carvedilol, Metoprolol
 Vasodilators:- Hydralazine, Isosorbide Dinitrate,
Nitroprusside

17. TREATMENT PRINCIPLES
I. Neurohumoral modulation
II. Preload reduction
III. Afterload reduction
IV. Increasing Cardiac contractility
V. Heart rate reduction

18. NEUROHUMORAL MODULATION
Therapy consists of:-
1. Angiotensin Converting Enzyme Inhibitors
2. Angiotensin Receptor Blockers
3. β blockers
4. Mineralocorticoids Receptor Antagonists

19. ANGIOTENSIN-CONVERTING
ENZYME INHIBITORS
In the 1960s, Ferreira and colleagues:- Certain factors in venom
extract from the Brazilian pit viper (Bothrops jararaca) intensify
vasodilator responses to bradykinin
Erdos and coworkers established that these factors inhibit ACE
and kininase II
This led to the synthesis of a series of carboxy alkanoyl and
mercapto alkanoyl derivatives that are potent competitive
inhibitors of ACE

20. Inhibits enzyme responsible for formation of Angiotensin II
from Angiotensin I
These are the drugs which reduce circulating levels of
Angiotensin II
Antagonises AT1 receptor effects of Angiotensin II:-
1. vasoconstriction
2. stimulation of aldosterone release from the adrenal glands
3. direct hypertrophic and proliferative effects on
cardiomyocytes and fibroblasts, respectively
4. stimulation of NE release from sympathetic nerve endings
and the adrenal medulla

22. Currently used as First line agents in symptomatic and
asymptomatic
Used as Combination with diuretics to make first line therapy in
HF
Slow : progress of ventricular dilatation
Prolong survival : prevent pathological remodelling : heart &
blood vessels

24. ANGIOTENSIN II RECEPTOR
BLOCKERS
Attempts to develop therapeutically useful AngII receptor
antagonists date to the early 1970s
In 1995, the orally active, potent, and selective nonpeptide AT1
receptor antagonist Losartan was developed and approved for
clinical use in the U.S.
Since then, seven additional AT1 receptor antagonists have
been approved

25. The AngII receptor blockers competitively bind and block the
AT1 receptor with high affinity
More than 10,000-fold selective for the AT1 receptor over the
AT2 receptor
ARBs inhibit most of the biological effects of AngII, which
include AngII-induced
 Contraction of vascular smooth muscle
 Vasopressin release & Aldosterone secretion
 Release of adrenal catecholamines
 Increases in sympathetic tone
 Cellular hypertrophy and hyperplasia

26. They are therapeutic alternatives to ACEIs and second choice in
all stages of heart failure in patients who do not tolerate ACEIs
ARBs show the same pharmacological profile as ACEIs with the
exception of not inducing cough
However, the unopposed activity of AT2 receptor pathways in
the presence of AT1 blockade by an ARB seems to confer no
therapeutic advantage to ARBs over ACEIs

27. BETA BLOCKERS
Heart Failure Raised epinephrine and non-epinephrine
level Cardiac Hypertrophy, Remodelling, Apoptosis,
Peripheral vasoconstriction
The β blockers competitively reduce β receptor–mediated
actions of Catecholamines:-
 Reduce heart rate and force
 Slow relaxation
 Slow AV conduction
 Suppress arrhythmias
 Lower renin levels
 And permit more or less bronchoconstriction, vasoconstriction, and
lowering of hepatic glucose production

28. All patients with symptomatic heart failure (stage C, NYHA II–IV) and all
patients with left ventricular dysfunction (stage B, NYHA I) with LVEF less
than 35 % should be treated with a β blocker
Used in mild-moderate (NYHA II/III) systolic dysfunction with
cardiomyopathy
Clinical improvements are slight rise in ejection fraction, reduction in HR,
reduction in symptoms
Initiate at low doses and up titrate to max dose
2-4 months therapy is required for clinical benefits
Long term effect: maintain hemodynamic benefits and reduction in
morbidity/mortality
Not Indicated in:- HF after acute MI or with normal LVEF, AV block,
Asthma, COPD

29. MINERALOCORTICOID RECEPTOR
ANTAGONISTS
•Drugs with a documented life-prolonging effect in patients with
heart failure
•Given in low doses to all patients in stage C (NYHA class II–IV),
that is, with symptomatic HFrEF
•The safety of a low-dose MRA (25 mg vs. a standard of 100 mg
spironolactone) was demonstrated in a large randomized trial in
a patient cohort with severe heart failure (NYHA III–IV), with the
MRA added to ACEIs, diuretics, and digoxin

30. Antagonists of nuclear receptors of aldosterone
They are K+-sparing diuretics but gained more importance for
their additional efficacy in suppressing the consequences of
neurohumoral activation.
Aldosterone promotes Na+ and fluid retention, loss of K+ and Mg2+,
sympathetic activation, myocardial and vascular fibrosis and vascular
damage
MRAs inhibit all these effects of aldosterone, of which the
reduction in fibrosis is most pronounced in animal models.
E.g. - Spironolactone and Eplerenone

31. Spironolactone:-
 Dose: 12.5-25 mg/day
 Add on with ACEI & others in moderate-severe CHF
 In severe CHF: ACEI+ spironolactone+ digitalis: improves
survival
 Retard disease progression
 Slow response
 The most important ADR of both MRAs is hyperkalemia.
 Spironolactone causes gynecomastia, not with Eplerenone

32. PRELOAD REDUCTION
Fluid overload with increased filling pressures (increased preload)
and dilation of the ventricles in heart failure is the consequence of
decreased kidney perfusion and activation of the RAAS
The drugs used here are Diuretics
They increase Na+ and water excretion by inhibiting transporters in
the kidney and thereby improve symptoms of CHF
Diuretics are an integral part of the combination therapy of
symptomatic forms of heart failure

34. Loop Diuretics:- E.g. Furosemide, Torasemide, Bumetanide
 Inhibit the Na+-K+-2Cl symporter mediated reabsorption in the Ascending limb of
the loop of Henle
Thiazide Diuretics:- E.g.- Hydrochlorothiazide, Chlorthalidone
 Mostly used as a combination therapy with loop
 Inhibits Na+-Cl cotransporter in the distal convoluted tubule
 Associated with a greater degree of K+ wasting per fluid volume reduction
K+-Sparing Diuretics:- Amiloride, Triamterene, Spironolactone and
Eplerenone
 Inhibit apical Na+ channels in distal segments of the tubules directly (ENaC; e.g.,
amiloride, triamterene) or reduce its gene expression (spironolactone and eplerenone)
 Used in the treatment of hypertension in combination with thiazides or loop diuretics
to reduce K+ and Mg2+ wasting

35. Uses:-
 Edema associated with congestive heart failure, liver cirrhosis,
chronic kidney disease, and nephrotic syndrome
 In severe CHF: ACEI+ spironolactone+ digitalis: improves survival
 Hypertension with renal insufficiency
 Nephrogenic diabetes insipidus
 Acute pulmonary edema (intravenous)
 Hyponatremia
 Hypercalcemia

36. AFTERLOAD REDUCTION
The failing heart is exquisitely sensitive to increased arterial
resistance i.e., Afterload
They have beneficial effects on patients with heart failure by
reducing afterload and allowing the heart to expel blood
against lower resistance
Vasodilators:-
 Venous Dilators:- Isosorbide Dinitrate, Nitroglycerin, etc
 Arteriolar dilators:- Hydralazine
 Mixed:- ACEI, ARBs, Nitroprusside

37. Hydralazine:-
One of the first orally active Vasodiltator drugs to be marketed in the
U.S.
Combined with sympatholytic agents and diuretics with greater
therapeutic success
Hydralazine directly relaxes arteriolar smooth muscle with little effect
on venous smooth muscle by reduction in intracellular Ca2+
concentrations thus reducing afterload
The usual oral dosage of hydralazine is 25–100 mg twice daily
Adverse effects:- headache, nausea, flushing, hypotension,
palpitations, tachycardia, dizziness, lupus syndrome, hemolytic
anemia, vasculitis, and rapidly progressive glomerulonephritis

38. Nitrates:- Sources of NO that increases cGMP and decreases cytosolic
Ca2+
Isosorbide dinitrate:-
Orally available organic nitrate, preferentially dilates large blood
vessels (venous capacitance and arterial conductance vessels)
The main effect is “venous pooling” and reduction of diastolic filling
pressure (preload)
The fixed-combination formulation
37.5 mg hydralazine + 20 mg ISDN and is uptitrated to a target
dose of 2 tablets, thrice daily
Particularly useful when ACEI are not tolerated
Frequent adverse effects include dizziness and headache

39. INCREASING CARDIAC
CONTRACTILITY
The failing heart is unable to generate force sufficient to meet
the needs of the body for perfusion of oxygenated blood
Historically, physicians attempted to stimulate force
generation with positive inotropic drugs
The drugs included here are:-
1. Na+/K+ ATPase Inhibitors:- Cardiac Glycosides
2. cAMP-Dependent Inotropes:- Milrinone, Enoximone
3. Myofilament Ca2+ Sensitizers:- Levosimendan

40. CARDIAC GLYCOSIDES (CG)
British botanist William Withering (1741–1799)
•Described the actions of Digitalis purpurea in patients with
heart failure (“dropsy”) and gave exact dosing
recommendations (Skou 1986)
Oswald Schmiedeberg (1833–1921)
•Isolated the first chemical entities from foxglove leaves; one of
these entities was digitoxin

41. Cardiac glycosides:-
Inhibit the plasma membrane Na+/K+ ATPase that actively pumps
Na+ out and K+ into the cell
Inhibition of this enzyme slightly reduces the Na+ gradient across
the myocyte membrane and thus reducing the driving force for Ca2+
extrusion by the NCX
Thus provides more Ca2+ for storage in the SR and subsequent
release to activate contraction
Increase in Ca2+ permeability through voltage sensitive L type Ca2+
channels during plateau phase
Release of more Ca2+ from SR & mitochondria by activating Ryr
(ryanodine) receptors
Inhibits SR- Ca2+ ATPase (reuptake channel)

42. Actions of Digoxin:-
Positive Inotropic Effect by raising intracellular [Ca2+] and enhanced
contractility
This Increased cardiac output provides symptomatic relief in patients
with heart failure
Decreases in preload and afterload reduce chamber dilation and
thereby ↓ in oxygen requirement
Increased renal perfusion lowers renin production
and increases diuresis, further decreasing preload
Bradycardia, improved myocardial circulation and sense of well being
but Does not substantially increase the survival
Subside pulmonary
congestion and edema

44. Currently given when ACEI & Diuretics fail to control symptoms
Used in Low output heart failure due to HT, IHD & arrhythmias
Dose:
oOral route is preferred: 0.125-0.5mg/day.
1) Slow loading with 0.125-0.25 mg/day
2) Rapid method with 0.5-0.75 mg every 8hrs for 1 day followed
by 0.125-0.25 mg/day( rare)
oIV 0.5 to 1 mg but is seldom required
No role in acute HF with acute MI, MR and papillary muscle
dysfunction

45. I. Therapeutic efficacy - between 0.5 and 0.8 ng/mL
II. Adverse effects:- Seen above 2 ng/mL
 Cardiac effects like Bradycardia, AV Block, Atrial Fibrillation,
Ventricular extrasystoles, bigeminy, etc
 GI side effects like anorexia, vomiting, diarrhea
 Neurotoxicity like mental confusion, delirium, loss of color
perception, hyperkalemia, gynaecomastia

46. Treatment of toxicity:-
 Cessation of CG medication normally suffices, estimate K levels
 Extreme sinus bradycardia, sinoatrial block, or AV block grade II or
III:- Atropine (0.5–1 mg) IV
 Supraventricular tachyarrhytmias:- Oral Propranolol 10-40 mg every 6
hrs or IV 0.5 to 1 mg
 Tachycardic ventricular arrhythmias and hypokalemia:- Lignocaine 1-2
mg/kg or K+ infusion (40–60 mmol/d)
 Antidigoxin immunotherapy with Digibind as the antidote:- 40 mg
neutralizes 0.6 mg digoxin
ENHNACED digitalis toxicity:- Loop diuretics, steroids, Amiodarone,
quinidine

47. CAMP-DEPENDENT INOTROPES
The cAMP-PDE inhibitors decrease cellular cAMP degradation
leading to elevated levels of cAMP
This results in positive inotropic and chronotropic effects in
the heart
Also causes dilation of resistance and capacitance vessels,
effectively decreasing preload and afterload
The drugs included here are Milrinone and Enoximone

48. Milrinone
Milrinone inhibits human heart PDE3 and PDE4 with similar potency
The loading dose of milrinone is ordinarily 25–75 μg/kg, and the
continuous infusion rate ranges from 0.375 to 0.75 μg/kg/min
S/E:- less thrombocytopenia and liver effect, arrhytmogenic
potential, headache, tremors
Enoximone
Congener of inamrinone, is a relative selective Inhibitor of PDE3
IV in acute heart failure
Better tolerated and improves physical quality of life
Bolus doses of enoximone at 0.5–1.0 mg/kg over 5–10 min are
followed by an infusion of 5–20 μg/kg/min

49. MYOFILAMENT CA2+ SENSITIZERS
In some countries, calcium sensitizers are approved for the short-term
treatment of acutely decompensated heart failure
Increase the sensitivity of contractile myofilaments to Ca2+ by binding
to and inducing a conformational change in troponin C
This causes an increased force for a given cytosolic Ca2+
concentration, theoretically without raising the [Ca2+]cytosol
The drugs included are Levosimendan and Pimobendan
Clinical data provide evidence for symptomatic benefit and reductions
in the length of stay in the hospital
Increased rates of arrhythmia and death are likely related to the PDE3
inhibitor activity of these compounds

50. POSITIVE INOTROPIC DRUGS
These agents stimulate the heart’s force of contraction in a situation
of critically diminished cardiac output
Dobutamine:-
 Dobutamine is the β adrenergic agonist of choice for the management of
patients with acute CHF with systolic dysfunction
 Dobutamine is a racemic mixture of (–) and (+) enantiomers
 The (–) enantiomer - agonist at α1 adrenergic receptors, weak agonist at
β1 and β2 receptors
 The (+) enantiomer - potent β1 and β2 agonist, less activity at α1
adrenergic receptors (β1 - Normally Dominates)
 Continuous infusions initiated at 2–3 μg/kg/ min and uptitrated
 S/E:- tachycardia and supraventricular/ventricular arrhythmias

51. Dopamine:-
 The pharmacologic and hemodynamic effects of DA vary with concentration
 Low doses (≤2 μg/kg/min):- stimulation of D2 receptors and inhibits NE
release and reduces α adrenergic stimulation of vascular smooth muscle,
particularly in splanchnic and renal arterial beds
 At intermediate infusion rates (2–5 μg/kg/min):-stimulation of cardiac β
receptors to enhance myocardial contractility
 At higher infusion rates (5–15 μg/kg/min):- Stimulation of α adrenergic
receptor leading to peripheral arterial and venous constriction occurs
 Other drugs are Epinephrine, Nor-epinephrine

52. VASOPRESSIN ANTAGONISTS
Vasopressin receptors V1a : vasoconstriction and V2: antidiuretic
Conivaptan (Vaprisol)
V1a & V2 antagonist
APPROVED for hyponatremia (SIADH)
T1/2: 5-12 hrs
Dose: 20 mg loading IV over 30 min followed by 20 mg IV over 24
hrs
Potential use in heart failure: as ↓ afterload and
S/E: infusion site reaction, headache, hypotension, pyrexia
Tolvaptan:- V2 antagonist, Oral: 15-45 mg/day

53. VASOACTIVE PEPTIDES
Released from the cardiac ventricles in response to increased wall
tension
ANP (Atrial Natriuretic Peptide) and BNP (Brain Natriuretic Peptide)
diagnostic and prognostic marker in heart failure
Rapid Measurement BNP →emergency diagnosis of heart failure

54. Nesiritide
Recombinant form of human BNP
Binds to surface4 receptors on vascular smooth muscle cells and
endothelial cells and activates cGMP
MOA:-
o↓ arteriolar and venous tone (↑ cGMP in smooth muscle cells-
smooth muscle relaxation)
oAlso causes Natriuresis (Inhibits Na+ absorption in collecting duct)
APPROVED for acute decompensated HF

55. VASOPEPTIDASE INHIBITORS
Inhibition of neutral endopeptidases like ACE and NEP
↑ANP & ↑BNP
Vasodilatation and Na+ & water excretion
↓Afterload and Preload
E.g.: Omapatrilat, Sampatrilat, Fasidopatrilat
 Omapatrilat:- Clinical status: in phase 3 trials

56. OTHER MEASURES
CARDIAC RESYNCHRONIZATION THERAPY:- With placement of a
pacing lead via the coronary sinus to the lateral wall of the ventricle,
it enables a more synchronous ventricular contraction by aligning the
timing of activation of the opposing walls.
SURGICAL THERAPY IN HEART FAILURE like CABG in ischaemic cause
of HF which can use the hibernating myocardium and improve the
heart function
STEM CELL THERAPY where either bone marrow–derived precursor
cells or autologous cardiac-derived stem cells and programming
them to develop and remodel into cardiac cells and improve the
function of heart
GENE THERAPY

57. Stage A Stage B Stage C
Stage D

58. MANAGEMENT OF ACUTE HF
Aims of therapy:- Reduction of afterload, CO & BP
maintainance
1. Semiupright position and Tourniquet appliaction:-
Raising head end of the bed or by backrest
2. Oxygen:- 6-8 L/min
3. Furosemide:- IV 40-60 mg, every 30 min till
diuresis
4. Morphine:- IV 2-4 mg every 15 mins to a total of
15 mg
5. Aminophylline, in case there is bronchospasm
6. Sublingual NTG:- 0.4 mg, repeated every 5 mins
for 3 doses, Monitor BP
7. ACEI:- Low dose is given to start with

59. MANAGEMENT OF CHRONIC HF

60. RECENT ADVANCES
Medicines in development for heart disease & stroke, 2018. Available from:- http://phrma-
docs.phrma.org/files/dmfile/midreport_heartstroke_2018_final.pdf

65. Recent data indicate that additional benefit may accrue via a drug
combination called Angitensin Receptor- Neprilysin Inhibitor (ARNIs)
In July 2015, the FDA approved a fixed-dose combination:-
ARB (Valsartan) + Neprilysin Inhibitor (Sacubitril) {ENTRESTO}
Sacubitril inhibits the degradation of the natriuretic peptides ANP and
BNP
Recommended dose of 100–400 mg daily, divided into two doses
Approved for
Chronic and stable but symptomatic HF
Left ventricular ejection fraction (LVEF) of less than 40%
Reduces the rates of hospitalization and death

66. IVABRADINE
In April 2015, FDA approved Ivabradine (CORLANOR) from Amgen
Ivabradine acts by reducing the heart rate via specific inhibition of
the pacemaker current
Used in combination with beta blockers in people with:-
 Heart failure with LVEF lower than 35 %
 Inadequately controlled by beta blockers alone
 Heart rate exceeds 70 beats per minute
Combination decreases the risk of hospitalization for heart failure

67. TRV027
A β-arrestin-based AT1 receptor blocker, TRV027 is being developed
It binds AT1 receptor and blocks G protein– coupled signaling while
engaging β-arrestin
In animal models, it Increases myocyte contractility and protects
against apoptosis
In phase II clinical studies, TRV027 decreased mean arterial pressure
and was well tolerated
The safety and efficacy of TRV027 is being tested in the BLAST-HF
study in patients with acute heart failure

68. SERELAXIN
Serelaxin is a recombinant form of the human hormone relaxin
Recent studies have shown that relaxin is also produced by the
vasculature and failing myocardium
Relaxin interacts with a G protein-coupled receptor, leading to
increased cAMP that leads to nitric oxide production and thus
relaxaton
Increases cardiac output, arterial compliance, and renal blood flow,
supporting important physiological changes during pregnancy
Given its potent vasodilator properties as well as its ability to
increase renal perfusion, Relaxin became of interest as a potential
therapy for acute decompensated HF

69. SOLUBLE GUANYL CYCLASE
ACTIVATORS
Oxidative inactivation of sGC is believed to be a common pathology
in cardiovascular disease and a reason for endothelial dysfunction
sGC activators have maintained (or even enhanced) effects at sGC
enzymes inactivated by oxidation
Riociugat is a direct, heme-dependent stimulator of sGC and is
approved for the treatment of pulmonary artery hypertension and
chronic thromboembolic pulmonary hypertension
Cinaciugat is a heme-independent activator of sGC and lowered
pulmonary wedge pressure and increased cardiac output, but also
markedly increased the rate of symptomatic hypotension, hence
stopped

70. OMECAMTIV MECARBIL
New Sarcomere directed drug
Selective cardiac myosin activator
Increases myocardial contractility and stroke volume without O2
consumption
Currently under evaluation for the treatment of CHF caused by LV
dysfunction

71. ADRENOMEDULLIN
Potent vasodilator peptide
Experimental therapeutic intervention in rats showed inhibition of
progression of cardiac hypertrophy and remodeling
Promotes maintenance or improvement in renal function
Counter the activation or actions of vasoconstricting and sodium-
retaining hormone systems
Potential therapeutic agents for Heart failure

72. ISTAROXIME
Investigational steroid derivative
Inhibition of (Na+/K+ ATPase)
Stimulation of the sarcoplasmic reticulum calcium ATPase (SERCA)
isoform 2 (SERCA2)
Enhances the heart’s relaxation phase, protects from
arrhythmogenesis caused by calcium overload
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

73. ULARITIDE
Recombinant peptide mimics activity of urodilatin
Urodilatin was first isolated from human urine in 1988 as a modified
version of pro-ANP produced mainly by distal renal tubule cells
Route of administration- IV
Under evaluation for acute heart failure
Improve Cardiovascular parameter & promote diuresis without ↓
creatinine clearance
In phase 3 clinical trail

74. OTHER MOLECULES
SB207266, a 5HT4 receptor antagonist has been noted to improve
cardiac function in heart failure rats, suggesting a possible beneficial
effect of 5-HT4 receptor antagonist in heart failure
PG-53072, a selective inhibitor of MMP has attenuated left ventricular
dysfunction and cardiac remodeling in experimental heart failure
CelacadeTM is an immune modulator which has prevented chronic
inflammation and apoptotic cell death by activating IL-10 mediated
anti-inflammatory process

75. SUMMARY
oHeart failure is a significant clinical challenge associated with high
morbidity, mortality and economic burden
oThe prevalence of chronic heart failure is continuously increasing
globally
oDespite the fact that major advances in lifesaving treatment have
been made; our ability to recognize and optimally treat heart failure
is limited
oThe short- and long-term morbidity and mortality in acute heart
failure is still unacceptably high
oFurther advances in understanding of pathophysiology of heart
failure will probably help to identify novel therapeutic agents for
patients with poor prognosis of heart failure

76. REFERENCES
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