Heart disease is a leading cause of death worldwide. key aspects of heart failure are discussed in this powerpoint presentation.

1. KEY ASPECTS OF
HEART FAILURE
DR. BUSHRA HASAN KHAN
DEPARTMENT OF PHARMACOLOGY
JNMC, AMU, ALIGARH

2. Heart failure is a state in which the heart is unable to pump
blood at a rate commensurate with the requirements of body’s
tissues or can do so only at elevated pressure
Progressive disease  gradual reduction in cardiac performance,
punctuated by episodes of acute decompensation

3. Heart failure
Clinical condition Dysfunction of heart
Systolic dysfunction Diastolic dysfunction
Cardiac output reduced
Blood pressure reduces (BP = CO x TPR)
Activation of compensatory mechanisms to improve blood pressure

4. Pathophysiology
Purpose of compensatory mechanisms to improve BP
1. Activation of SNS 2. Activation of RAAS 3. Non osmotic release of AVP

5. 1. Activation of SNS CHF
BP
Baroreceptor activation (Carotid sinus and aortic sinus)
Baroreceptors send signals to VMC present in medulla oblongata
Medulla oblongata increases the sympathetic outflow
Vasoconstriction
BP

6. 2. Activation of RAAS
CHF
BP
Renal perfusion reduces
GFR reduces
Activation of RAAS
Formation of Angiotensin II vasoconstriction BP
Aldosterone released
Na+ and water retention

7. 3. Non osmotic release of AVP

8. Pathophysiologic mechanisms of systolic heart
failure (HFrEF) and therapeutic interventions

11. Pathophysiological mechanisms of diastolic heart
failure HFpEF and possible therapeutic interventions

12. HF ( FOC and CO)
Sympathetic stimulation Renal perfusion
Central baroreceptors
Beta 1 rec FOC, HR
+
Alpha 1 rec preload
afterload
Initially compensation
occurs to CO
Later CO
RAAS +
Ag II AT1rec VC
Cardiac
remodelling
Na+ and water
reabsorption
Aldosterone
Ventricular size
Vicious cycle
Compensatory responses
that occur during congestive heart

13. Vicious spiral of progression of heart failure

14. HF ( FOC and CO)
Sympathetic stimulation Renal perfusion
Central baroreceptors
Beta 1 rec FOC, HR
+
Alpha 1 rec preload
afterload
Initially compensation
occurs to CO
Later CO
RAAS activation
Ag II AT1rec VC
Cardiac
remodelling
Na+ and water
reabsorption
Aldosterone
Ventricular size
Vicious cycle
RAAS inhibitorsBeta blockers
Alpha blockers
ACEI
ARB
+
Diuretics

15. Hemodynamic responses to pharmacologic
interventions in heart failure

16. Stroke volume versus afterload (outflow resistance):
effects of heart failure

17. Relation of left ventricular (LV) performance
to filling pressure in patients with heart failure

19. RV outflow
Blood stagnant in RV
RA unable to pump blood into RV
RA pressure also
SVC pressure
IVC pressure
Hepatic venous pressure increases
Tender hepatomegaly
Pedal edema
Portal HTN (Portal venous pressure)
Ascites
Splenomegaly (Splenic venous pressure)

20. Intestinal wall edema (SMV pressure)
Absorption of food
Continuous vomiting
Weight gain due to fluid overload
Nocturia

21. • Earliest sign of RHF is JVP
• PCWP remains normal
• PCWP represents LA pressure
• PCWP in LHF
• On auscultation : RV S3

23. LVEDP
LA pressure
PV pressure
PC pressure
Fluid enters lungs
Pulmonary edema
Cough with expectoration (pink, frothy)
On auscultation : LV S3
PCWP
Bilateral lung crepitations

24. Earliest clinical manifestation of LHF : PND
Paroxysmal Nocturnal Dyspnea
Orthopnea
Dyspnea

25. FRAMINGHAM CRITERIA IN CHF
MAJOR MINOR
• Crackles
• CVP
• Cardiomegaly (CXR)
• Dyspnea (PND)
• Edematous lungs (Pulmonary edema)
• Fall in weight of patient in response to
treatment (>4.5 kg)
• Gallop rhythm
• Hepatojugular reflux (RHF)
• Hepatomegaly
• Night cough (due to pulmonary edema)
• Edema (pedal)
• Pleural effusion (due to progression of
pulmonary edema)
• Quantitative pulmonary function test
(vital capacity reduced to 1/3 of max)
• Rapid pulse
• Shortness of breath on exertion

26. Diagnostic criteria
2 major criteria OR 1 major + 2 minor

27. CCF
RHF LHF+
• MCC of RHF = LHF
• MCC of Acute RHF = Acute pulmonary embolism
Acute cor pulmonale RV dilatation with or without RHF secondary
to pulmonary or pulmonary vascular pathology
• MCC of Chronic cor pulmonale = COPD

28. Etiology of LHF
Based on Ejection Fraction (N=55-70%)
HFpEF (>50%) HFrEF (<40%)
Diastolic heart failure Systolic heart failure

29. Etiologies of HFrEF (Systolic HF)
Chronic pressure
overload
DCMPCADs Chronic volume
overload
Chaga’s Disease
(Parasitic infection)
MI
• HTN
• AS
• MR
• AR

30. Etiologies of HFpEF (Diastolic HF)
RCMP Fibrosis
of heart
HCM • Cor pulmonale
• Pulm vascular
disease
Endomyocardial
disorders

31. Chest X-ray (signs of pulmonary venous HTN)
Vascular
redistribution
Interstitial edema Alveolar edema
Upper lobe
vein distension
Kerley B lines
Air space opacities
Pleural effusion
(if severity increases)

32. Cardiac biomarkers which are increased in HF
ANP Pro-BNP
(Released
from ventricle)
Adremedullin Endothelin
Released
from Atria
Released
from Endothelium
Released
from myocardium
BNP NT-Pro BNP
Most sensitive
Prognostic
marker of CHF
NT Pro-BNP normal value is <300pg/ml

33. Other important investigations
BUN
S. Creatinine
ECG 2D-Echo
As a part of
Pre Renal failure
• Ejection fraction
• Valve lesions
• Chamber enlargement
• Ischemia/ Infarction
• Arrhythmia

34. Treatment of CHF depends on presentation

35. Acute decompensated (Congestive HF)
If cardiogenic
shock present
Loop diuretics
(Furosemide)
For flushing out fluids
Diuretics Oxygen
(Ventilatory support)
Morphine Vasodilators
Reduce
anxiety
Reduce
sympathetic
outflow

36. Acute decompensated (Congestive HF)
If cardiogenic
shock present
Diuretics Oxygen
(Ventilatory support)
Morphine Vasodilators
Reduce
anxiety
Reduce
sympathetic
outflow
Activation of SNS increases
precipitation of HF because it
increases cardiac work
Afterload with Morphine

37. Acute decompensated (Congestive HF)
If cardiogenic
shock present
Loop diuretics
(Furosemide)
For flushing out fluids
Diuretics Oxygen
(Ventilatory support)
Morphine Vasodilators
Nitrates
Nesiritide
Preload
Afterload
Give
inotropic
agents
Dobutamine/
Dopamine/
Epinephrine/
NE
Do not give Digoxin in Acute decompensated heart failure

38. Congestive HF that is not decompensated
Drugs for relieving
congestion
Drugs for reversing
cardiac remodelling
Drugs which will
improve progression
OR
• ACEI
• ARB
• Beta blockers
• Aldosterone
antagonists
VasodilatorsDiuretics Inotropes Vasoconstrictors
Furosemide
Thiazides
Edema
Nitrates
Nesiritide
Nitroprusside
Preload
Afterload
Digoxin
Dopamine
Minrinone
Levosimendan
Improve
forward flow
Improve
congestion

39. Thiazide Diuretics
Chlorothiazide
HCZ 25 mg  100 mg
Chlorthalidone 50 mg  100 mg
Indapamide
Metolazone
Symptomatic treatment of milder forms of heart failure
Looses efficacy at GFR <30-40 ml/min (except indapamide
and metolazone)
Potentiate effect of loop diuretics in severe heart failure
(sequential tubal blockade)

40. Loop Diuretics
Bumetanide 0.5 mg  5 mg
Furosemide 20 mg  240 mg
Torasemide 5 mg  20 mg
Symptomatic treatment of severe heart failure and acute
decompensation
A/E: hypokalemia, hyponatremia, hypomagnesemia,
hyperuricemia, hypocalcemia, glucose intolerance

41. Vasodilators
ISDN/ Hydralazine
A/E: headache, nausea, flushing, hypotension, palpitations,
tachycardia, dizziness, lupus syndrome

42. Intravenous Vasodilators
Nitroglycerine
Sodium nitroprusside
May cardiac output in acute congestion via preload and afterload
NO released, stimulates soluble guanylyl cyclase
Avoid if systolic BP <110 mmhg

43. Nesiritide
Recombinant human BNP
Stimulates membrane bound GC
May cardiac output via preload and afterload
T1/2 18-23 mins
IV infusion  Vasodilator and Diuretic effect

44. Intravenous positive inotropes
Dobutamine
Dopamine
Epinephrine
Norepinephrine
Beta1 mediated stimulation of cardiac output
Last option in patients with SBP <85 mmHg
Cardiac energy consumption and risk of arrhythmia
Use lowest possible doses for shortest possible time
Dobutamine causes less tachycardia than EPI and less afterload increase
than NE

45. Enoximone
Milrinone
PDE3/4 inhibitors, cellular cAMP
Cardiac output and dilated blood vessels (“inodilator”)

46. Levosimendan
Combined Calcium sensitizer (troponin C binding) and PDE3 inhibitor
CO and vascular resistance (“inodilator”)

47. Cardiac glycosides
• Digoxin used : (contraindicated in renal failure)
• Digitoxin  hepatotoxic  not used
• Not first choice in treating heart failure
• May exert benefits in heart failure and atrial fibrillation
• Half life 1.5 d (digoxin) or 7 days (digitoxin)

48. Cardiac excitation-contraction coupling
and
its regulation by positive inotropic

49. Most common Side effects of digoxin
Extracardiac: Anorexia, Nausea, Vomiting
(Digoxin chemosensors are present in Area Postrema)
Cardiac: Ventricular Bigeminy
Most specific Side effects of digoxin
Extracardiac: Xanthopsia
Cardiac: NPAT

50. Therapeutic range of digoxin : 0.5 – 0.8 ng/ml
Digoxin > 1.2 ng/ml UNSAFE
Hypokalemia risk of toxicity
Injectable K+ : used for treatment of Digoxin toxicity
Digoxin toxicity : Ventricular arrhythmia Lignocaine
Extreme sinus bradycardia : Atropine IV 0.5 mg to 1 mg
Severe Digoxin toxicity : Digibind

51. Contraindications of Digoxin
• Hypokalemia ( binding affinity of Digoxin to Na+-K+ ATPase)
• Hypomagnesemia
• Hypercalcemia
• Myocardial infarction
• WPW syndrome
• Heart block
• Thyrotoxicosis
Favor Sarcoplasmic Ca overload and
spontaneous Ca release events

52. Drugs which increase toxicity of Digoxin
• Diuretics (Hypokalemia)
• Erythromycin
• Verapamil
• Amiodarone
• Corticosteroids
• Tetracycline
• Quinidine

53. • ACEI : most preferred
• ARB
• Beta blockers
• Aldosterone antagonists
Mortality benefit

54. ACEIs
Benazepril
Captopril
Enalapril
Lisinopril
Quinapril
Ramipril
First choice in t/t of heart failure
Start low (1/10 target dose); go slow (2 to 4 weekly doubling)
A/E: cough, angioedema, hypotension, hyperkalemia, skin,
rash, neutropenia, anemia, fetopathic syndrome
C/I: B/L renal artery stenosis
Fosinopril
Trandalopril
Perindopril
Caution in patients
with renal or
hepatic impairment

55. Captopril TDS 6.25 mg  50 mg
Enalapril BD 2.5 mg  20 mg
Lisinopril 2.5 mg  35 mg
Ramipril 2.5 mg  10 mg
Trandalopril 0.5 mg  4 mg

56. ARBs
Candesartan 4 mg  32 mg
Losartan 50 mg  150 mg
Valsartan BD 40 mg  160 mg
Olmesartan
Telmisartan
Irbesartan
Only in cases of intolerance to intolerance to ACEI
Unwanted effects as ACEI, but no cough or angioedema
No evidence for superiority over ACEI
In combination with ACEI more harm than benefit

57. Beta blockers
Bisoprolol 1.25 mg  10 mg
Carvedilol 3.125 mg  25 mg
Metoprolol 12.5 mg  200 mg
Nebivolol 1.25 mg  10 mg
First choice in t/t of heart failure
Start low (1/10 target dose); go slow (2 to 4 weekly doubling)
A/E: Bradycardia, AV block, bronchospasm, peripheral
vasoconstriction, worsening of acute heart failure

58. • Acute CHF : Contraindicated
• Chronic CHF : Mortality
• Start low dose : Go slow
• Most commonly used : Carvedilol
Beta blockers

59. Potassium sparing Diuretics
Eplerenone 50 mg  200 mg
Spironolactone 50 mg  200 mg
Amiloride 5 mg  20 mg
Triamterene 50 mg  200 mg
A/E: hyperkalemia, hyponatremia, hypomagnesemia,
hyperuricemia, hypocalcemia, glucose intolerance

60. Aldosterone antagonists
First choice in treating symptomatic heart failure
Low doses (25-50 mg)
S/E: Hyperkalemia
Gynecomastia and impotence in men
Dysmenorrhea in women
Due to
nonselective
binding to sex
hormone receptors
Eplerenone 50 mg  200 mg
Spironolactone 50 mg  200 mg
Amiloride 5 mg  20 mg
Triamterene 50 mg  200 mg

61. Newer drugs

62. NEPI
• Ecadotril
• Sacubitril

63. NEPI + ACEI
Vasopeptidase inhibitors
Omapatrilat
Sampatrilat
Fasidotrilat
S/E
Dry cough
Angioedema

64. NEPI + ARB
Vasopeptidase inhibitors
(Sacubitril + Valsartan)
Superior to the ACEI enalapril
Degradation of natriuretic peptides
S/E Hypotension

65. ANP analogue : Vasodilator
• Carperitide
• Ularitide

66. Cimaglermin
Neuroregulatory protein
Improves cardiac function

67. Liraglutide
GLP-1 Analogue

68. Empagliflozin
SGLT2 inhibitor

69. Istaroxime
Inhibits Na+-K+ ATPase
+
Sequestration of Calcium from SR
Contractility

70. Omecamtive Mecarbil
Activate Myosin
+
Prolong systole without O2 demand

71. Vasopressin Receptor antagonists
Conivaptan
Tolvaptan
V2 receptor antagonist
Increased excretion of water

72. NYHA I No limitation of ordinary physical activity;
only strenuous physical activity produces
discomfort
NYHA II Ordinary physical activity
Shortness of breath
NYHA III Less than ordinary physical activity
Shortness of breath
NYHA IV Shortness of breath at rest
NYHA Heart failure classification

73. STAGE A High risk patient for HF,
But no structural damage of the heart
STAGE B Structural damage of the heart
Without clinical features
STAGE C Structural damage of the heart
With presence of clinical features
STAGE D Decompensated heart failure
Dyspnea at rest
ACC/AHA Stages of Heart failure

74. ACC/AHA NYHA Description Treatment
STAGE A Pre-failure No symptoms but risk factors
present
Treat obesity, HTN, DM,
dyslipidemia
STAGE B I Symptoms with severe exercise ACEI/ ARB,
Beta blocker,
Diuretic
STAGE C II/III Symptoms with marked (class II) or
mild (class III) exercise
Add Spironolactone,
Digoxin, ARNI,
Nitrate/ Hydralazine,
CRT
STAGE D IV Severe symptoms at rest Transplant, LVAD
Classification and treatment of chronic heart failure

75. Interventions in CCF
CRT ICD LVAD
In patients with
medically refractory arrhythmias
Acts as a bridge for
cardiac transplantation
Those patients where medical therapy
fails to bring improvement in symptoms

76. REFERENCES
• National Guideline Centre (UK). Chronic Heart Failure in Adults:
Diagnosis and Management. London: National Institute for Health
and Care Excellence (UK); 2018 Sep. (NICE Guideline, No. 106.) 6,
Treating Heart Failure. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK536070/
• Basic & Clinical Pharmacology, Fourteenth Edition
• The pharmacological basis of therapeutics, Thirteenth edition