2ND SEMINAR OF MY UNDERGRADUATE CARREER

1. Dr ChirantanMandalDr KajareeGiriDr Shuvam RoyDr AvikBasu Medical College &Hospital Bengal88 college street, KolkataWest BengalIndia

2. HEART FAILURE NORMAL CARDIAC PHYSIOLOGY KAJAREE GIRI Medical College &Hospital Bengal 88 college street, Kolkata West Bengal India Presented by:

4. Afterload

5. Heart Rate

7. PRELOAD IN THE WHOLE HEART PRELOAD SHOULD CONSTITUTE THE TENSION IN THE WALL AT THE END OF DIASTOLE ( WHICH DETERMINES THE RESTING FIBER LENGTH). FOR PRACTICAL PURPOSES THE VENTRICULAR EDV/EDP IS USED TO INDICATE PRELOAD. IT AFFECTS HEART PERFORMANCE BY “STARLING’S LAW OF THE HEART”.

8. AFTERLOAD

10. IONOTROPIC STATE INFLUENCE OF IONOTROPIC STATE ON LENGTH— TENSION RELATIONSHIP OF CARDIAC MUSCLE.

11. IONOTROPIC STATE INFLUENCE OF CHANGE IN IONOTROPIC STATE ON FRANK STARLING CURVES.

15. THE LOAD AND SHORTENING VELOCITY (RELATED TO AFTERLOAD).

17. SERIES ELASTIC ELEMENTS CONTRACTILE COMPONENT (ACTIVE TENSION) PARALLEL ELASTIC ELEMENTS (PASSIVE TENSION) TOTAL TENSION

18. THE L-T RELATIONSHIP OF FROG SKELETAL MUSCLE(IN BLACK) THE L-T RELATIONSHIP OF CAT CARDIAC MUSCLE FOR THE RANGE OF PHYSIOLOGICAL SARCOMERE LENGTH(IN RED).

20. INCREASING PRELOAD INCREASES MAXIMAL ISOMETRIC FORCE AND INCREASES SHORTENING VELOCITY AT A GIVEN AFTERLOAD,DOESNOT ALTER Vmax.

22. PRESSURE-VOLUME LOOP Pes SBP DBP CO = SV x HR EF = SV / EDV

23. PRESSURE-VOLUME LOOP SYSTOLIC PRESSURE CURVE Isotonic (Ejection) Phase After-load Isovolumetric Phase PRESSURE Stroke Volume DIASTOLIC PRESSURE CURVE Pre-load End Systolic Volume End Diastolic Volume

24. INDEPENDENT EFFECTS OF PRELOAD

25. INDEPENDENT EFFECTS OF AFTERLOAD

26. INDEPENDENT EFFECTS OF IONOTROPISM

27. MANIPULATING CARDIAC FUNCTION PRELOAD AFTERLOADCONTRACTILITY

28. INTERDEPENDANT ACTIONS OF PRELOAD AND AFTERLOAD AT CONSTANT IONOTROPY.

29. TO SUM IT UP

30. WHAT IS HEART FAILURE?? HEART FAILURE OCCURS WHEN THE HEART IS UNABLE TO PUMP BLOOD AT A RATE SUFFICIENT TO MEET THE METABOLIC DEMANDS OF THE BODY OF AN INDIVIDUAL.

32. OBSTRUCTION TO FLOW.

33. REGURGITANT FLOW.

34. SHUNTED FLOW THROUGH DEFECTS CONGENITAL OR ACQUIRED.

35. DISORDER OF CARDIAC CONDUCTION.

37. DIURETICS.

39. THANK YOU..

40. Cardiac Compensation and Decompensation in Heart Failure Shuvam Roy 4th semester student Medical College &Hospital Bengal 88 college street, Kolkata West Bengal India

41. Heart failure Definition: failure of heart to pump enough blood to satisfy the needs of body Types: I) Acute or chronic II) Unilateral (Left/Right) or Bilateral

42. Cardiac compensation Compensatory mechanisms maintain adequate CO & tissue perfusion Mechanisms: sympathetic stimulation fluid retention of kidney varying degrees of recovery of the heart itself

43. Sympathetic stimulation Occurs within 30s of acute heart failure CVS reflexes stimulate sympathetic NS and inhibit parasympathetic NS Effects: Increased strength of heart Increased mean systemic filling pressure Maintains pressure for perfusion of vital organs

44. CVS reflexes Baroreceptor reflex Chemoreceptor reflex CNS ischaemic response Reflexes originating in the heart

45. Baroreceptor reflex

46. Chemoreceptor reflex Aortic & carotid bodies stimulated by hypoxia,  local concentration of H + & CO2 impulses travel via vagus and Hering’s nervesstimulation of VMC

47. CNS ischaemic response VMC is directly stimulated by increase in local concentration of H+ & CO2 hypoxia

48. Bainbridge reflex Increase in atrial pressure stimulates atrial stretch receptors which causes reflex increase in heart rate and myocardial contractility Afferent pathway: vagus nerve Efferent pathway: sympathetic and vagus nerves

51. Fluid retention by the kidneys Occurs over hours to days Beneficial when pumping ability of heart is not very severely damaged Occurs due to activation of renin- angiotensin-aldosterone system Decrease in renal blood flow causes decrease in GFR Increased aldosterone secretion Increased ADH secretion Effects: Increase in mean systemic filling pressure Decreased venous resistance

52. Recovery of the heart Occurs over weeks to months Includes Development of collateral blood supply Fringe areas outside the infarct zone become functional Hypertrophy of functional areas occur Increased collagen that may reduce dilatation

53. Hypertrophy of myocardium In hemodynamic overload it reduces elevated ventricular wall stress to normal In pressure overload, increased systolic pressureincreased systolic stressparallel addition of new myofibrilswall thickening and consequent concentric hypertrophydecreased systolic stress In volume overload, increased diastolic pressureincreased diastolic stressserial addition of new sarcomeres chamber enlargement and eccentric hypertrophy decreased diastolic pressure

55. If heart recovers sufficiently and if adequate fluid volume has been retained, sympathetic stimulation gradually abates towards normal However, cardiac reserve is reduced.

56. Decompensated heart failure Occurs when compensatory mechanisms can no longer maintain an adequate tissue perfusion The same factors that are responsible for cardiac compensation can exacerbate cardiac decompensation

57. Factors behind cardiac decompensation Salt & water retention: pulmonary congestion, anasarca Vasoconstriction: increases cardiac energy expenditure Sympathetic stimulation: increases cardiac energy expenditure Hypertrophy:deterioration and death of cardiac myocytes Increased collagen: impairs relaxation Cardiac remodelling

58. Progressive oedema Compensatory mechanisms fail to raise CO high enough to make kidneys excrete enough water Detrimental effects of fluid retention- Diagnosed by progressive pulmonary congestion and anasarca, bubbling rales in lung and dyspnoea. Treatment Cardiotonic drugs like digitalis Diuretics Restrict salt and fluid intake ANP and BNP delay decompensation by increasing salt and water excretion by kidneys

61. Right or left heart failure does not lead to immediate peripheral oedema as ,initially , there is a fall in capillary pressure. But peripheral oedema begins after one day or so due to fluid retention by the kidneys

62. Acute pulmonary oedema in heart failure Left heart failure causes pulmonary congestion and oedema Pulmonary oedemadecreased oxygenation of bloodfurther weakening of heart and peripheral vasodilatationincreased venous return due to peripheral vasodilatationmore pulmonary oedema

63. Cardiogenic shock Low output heart failure shockfall in arterial pressuredecrease in coronary blood flowdamage to heart Vicious cycle Treatment Surgical clot removal with coronary bypass graft Fibrinolytics Cardiotonic drugs Increase blood pressure

66. HEART FAILURE PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS Medical College &Hospital Bengal 88 college street, Kolkata West Bengal India Presented by: AVIK BASU

67. ETIOLOGIES OF HEART FAILURE

68. •Depressed Ejection Fraction (<40%) Coronary Artery Disease Chronic Pressure Overload 3. Chronic Volume Overload 4. Non-ischemic Dilated Cardiomyopathy 5. Disorders of Rate and Rhythm

69. •Preserved Ejection Fraction (40-50%) Pathological Hypertrophy Aging 3. Restrictive Cardiomyopathy 4. Fibrosis 5. Endomyocardial Disorders

70. •Pulmonary heart disease 1. Cor Pulmonale 2. Pulmonary Vascular Disorders

71. •High-output states 1. Metabolic Disorders 2. Excessive Blood-flow Requirements

72. FORMS OF HEART FAILURE

73. •PATHOLOGICAL CLASSIFICATION 1. Systolic Heart Failure 2. Diastolic Heart Failure

74. •CLINICAL CLASSIFICATION 1. RIGHT-SIDED Heart Failure 2. LEFT-SIDED Heart Failure

75. •OTHER CLASSIFICATIONS 1. LOW OUTPUT Heart Failure 2. HIGH OUTPUT Heart Failure

76. PATHOGENESIS OF SYSTOLIC HEART FAILURE

78. Activation of Neuro-hormonal Systems in Heart Failure

79. MOLECULARBASISOF SYSTOLIC FAILURE

80. The molecular basis of systolic failure involves three components: • Contractile proteins • Calcium homeostasis • Signal transduction pathways

81. CHANGES IN CONTRACTILE PROTEINS Slowing of cross-bridge cycling rate Increased expression of fetal isoform of Troponin-T Reduced phosphorylation of Troponin-I

82. FAILING HEART NORMAL HEART

83. CHANGES IN CALCIUM HOMEOSTASIS Prolonged Calcium transient • Increased threshold for Calcium release from sarcoplasmic reticulum • Increased diastolic Calcium concentration • Decreased Calcium reuptake by sarcoplasmic reticulum • Prolonged action potential

84. NORMAL HEART FAILINGHEART

85. CHANGES IN SIGNAL TRANSDUCTION PATHWAYS Decreased number of β-adrenoreceptors Increased expression of β-adrenoreceptor kinase Increased expression of inhibitory G-protein

86. NORMAL HEART FAILING HEART

87. CHARACTERISTIC OF HEART IN SYSTOLIC FAILURE Eccentric left ventricular hypertrophy Progressive left ventricular dilatation Abnormal left ventricular systolic properties

88. PATHOGENESIS OF DIASTOLIC HEART FAILURE

89. FACTORS REGULATING VENTRICULAR RELAXATION Systolic Load Myofibre inactivation Uniformity of the distribution of load and inactivation over space and time Left ventricular relaxation is under the ‘Triple Control’ of:

90. POTENTIAL MECHANISM FOR DIASTOLIC DYSFUNCTION Extramyocardial Whole heart Extracellular matrix Cardiomyocyte Myofilaments

91. CHANGE IN TITIN ISOFORM

92. • Titin protein has two isoforms: (1) N2BA (2) N2B • N2B isoform is stiffer than N2BA isoform. • Predominance of N2B isoform in the heart leads to increased stiffness of the ventricles leading to diastolic dysfunctioning.

93. CHARACTERISTIC OF HEART IN DIASTOLIC FAILURE Concentric left ventricular hypertrophy Normal or reduced left ventricular volume Concentric remodelling Abnormal left ventricular diastolic properties

94. PATHOGENESIS OF LEFT-SIDED HEART FAILURE

95. CAUSES OF LEFT-SIDED HEART FAILURE Ischemic heart disease Hypertension Aortic and Mitral valvular disease Non-ischemic myocardial disease

96. MORPHOLOGICAL CHANGES IN THE HEART Hypertrophied and Dilated heart Myocardial fibrosis Secondary left atrial fibrillation

97. CLINICAL MANIFESTATIONS Paroxysmal Nocturnal Dyspnoea Orthopnoea Pulmonary edema Cheyne-Stokes respiration Pre-renal azotemia Hypoxic Encephalopathy

98. PATHOGENESIS OF RIGHT-SIDED HEART FAILURE

99. CAUSES OF RIGHT-SIDED HEART FAILURE Secondary to Left-sided heart failure Severe Pulmonary Hypertension

100. MORPHOLOGICAL CHANGES IN THE HEART Hypertrophied and Dilated right ventricle Dilated right atrium Bulging of ventricular septum to the left

101. CLINICAL MANIFESTATIONS Raised Jugular Venous Pressure Congestive hepatomegaly Hepato-jugular reflex Congestive splenomegaly Pedal & Pre-tibial edema

102. LOW-OUTPUT HEART FAILURE

103. STAGES OF CARDIOGENIC SHOCK Non-progressive/Compensatory phase Progressive phase Irreversible phase

105. HIGH-OUTPUT HEART FAILURE

106. CONDITIONS LEADING TO HIGH-OUTPUT HEART FAILURE Arterio-venous fistula • Beriberi

107. ARTERIO-VENOUS FISTULA

108. OXYGEN LACK THEORY

109. BERIBERI

110. Treatment of Heart Failure CHIRANTAN MANDAL 4thsemester student Medical College &Hospital Bengal 88 college street, Kolkata West Bengal India

111. Therapeutic Overview Problems ↓force of contraction ↑total peripheral resistance organ hypoperfusion Ventricular remodelling Worsening renal function ↑ venous pressure with ↓cardiac output edema ↓exercise tolerance

114. Diurese

115. Reverse hemodynamic abnormalities

116. Decreased renal perfusionRapid relieve of symptoms Prevent Sudden Cardiac Arrest & ventricular remodeling

117. Diet and Activity Salt restricted diet Fluid restriction weight loss Control Hypertension Reduce cardiac work Rest

118. Diuretic Therapy fluid volumes overload ↓ ECF volume ↓ venous return ↓ The most effective symptomatic relief Four Flavours: Loop diuretics Thiazide diuretics K+-sparing Carbonic anhydrase inhibitors

120. Thiazide ADH Inhibitors

121. Carbonic Anhydrase Inhibitors Loop Diuretic

122. Aldosterone Inhibitors (K+ Sparing Agents )

123. For More severe heart failure -> loop diuretics Furosemide, Bumetanide , Torsemide Mechanism ofaction: Inhibit chloride reabsortion in ascending limb of loop of Henle results in natriuresis, kaliuresis and metabolic alkalosis Adverse reaction: pre-renal azotemia Hypokalemia Skin rash ototoxicity

124. K+ Sparing Agents Potassium sparing diuretics help in reducing the hypokalemia due to otherdiuretics. Triamterene & amiloride – acts on distal tubules to ↓ K secretion Spironolactone (Aldosterone antagonist) it improve survival in CHF patients due to the effect on renin-angiotensin-aldosterone system with subsequent effect on myocardial remodeling and fibrosis Aldosterone inhibition minimize potassium loss, prevent sodium and water retention, endothelial dysfunction and myocardial fibrosis.

126. Reninangiotensin system Baroreceptor mediated activation of the SNS leads to an increase in renin release and formation of angiotensin II AngiotensinII acts through AT1 and AT2 receptors (most of its actions occur through AT1 receptors) This causes vasoconstriction and stimulates aldosteroneproduction aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction

128. Inhibitors of renin-angiotensin- aldosterone system Angiotensinconverting enzyme inhibitors Angiotensin receptors blockers Spironolactone(Aldosterone antagonist)

129. Angiotensin Converting Enzyme (ACE) Inhibitors ACE inhibitors improve mortality, morbidity, exercise tolerance, left ventricular ejection fraction. Captopril, Lisinopril, Enalapril, Ramipril, Quinapril. Advantages Improves symptoms significantly Improves exercise tolerance Slows disease progression ↓ cardiac remodeling Prolong survival

130. Scope for ACE Inhibitors…..

132. Angiotensin Converting Enzyme Inhibitors MOA They block the R-A-A system by inhibiting the conversion of angiotensin I to angiotensin II -> vasodilation and ↓ Na retention ↓ Bradykinin degradation ↑ its level -> ↑ PG secretion & nitric oxide

133. Angiotensin Receptor AT-1 blockers (ARB) Losartan, Irbesartan, Candesartan Competitive antagonists of Angiotensin II (AT-1). Has comparable effect to ACE I Can be used in certain conditions when ACE I are contraindicated (angioneurotic edema, cough)

134. ACE-Inhibitors and ARB effects Vasodilation Decreased fluid retention (afterload & preload) Reduction in aldosterone secretion Inhibition of cardiac and vascular remodeling

135. Animation

136. Inotropes Increase force of contraction All increase intracellular cardiac Ca++ concentration Eg: Digitalis (cardiac glycoside) Dobutamine (β-adrenergic recepter agonist) Amrinone (PDE inhibitor)

138. Digoxin MOA

139. Cardiac glycosides : Digoxin (Digitalis) inhibit Na +,K +ATPase, the membrane-bound transporter increase of intracellular sodium concentration a relative reduction of calcium expulsion from the cell by the sodium-calcium Exchanger due to ↑ Na distinctive increase in Cardiac contractility during systole increased cytoplasmic calcium is sequestered by SERCA in the SR for later release

140. early, brief prolongation of the action potential, followed by shortening (especially the plateau phase) The decrease in action potential duration is probably the result of increased potassium conductance that is caused by increased intracellular calcium Effects of Digoxin on Electrical Properties of Cardiac Tissues

141. inhibition of the Na+ pump and reduced intracellular K+ resting membrane potential is reduced oscillatory delayed depolarizing afterpotentials appear following normally evoked action potentials At higher concentrations…….. overloading of the intracellular calcium stores and oscillations in the free intracellular calcium ion concentration

143. β 1 Agonist Eg: Dobutamine Effects:- ↑ cardiac output ↓ intraventricular filling pressure direct stimulation of the SA node to↑heart rate ↓peripheral resistance by activating alpha2 receptors vasodilation Conduction velocity in the AVnode is ↑ refractory period is ↓ Intrinsic contractility is ↑ ejection time is ↓

144. β 1 Agonist MoA

145. Bipyridinesphosphodiesterase 3 inhibitor Targets PDE -3 (found in cardiac and smooth muscle) Inamrinone, milrinone increasing inward calcium flux in the heart during the action potential alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum increase myocardial contractility

146. Inhibition of PDE3 Increase in cAMP the conversion of inactive protein kinase to active form Protein kinases are responsible for phosphorylation of Ca channels increased Ca entry into the cell increase in contractility vasodilation ↑ Vascular Permeability leads to ↓ in intravascular fluid Volume

147. β Blockers bisoprolol, carvedilol , metoprolol MOA Acts primarily by inhibiting the sympathetic nervous system (attenuation of the adverse effects of high concentrations of catecholamines) reduced remodeling (inhibition of the mitogenic activity of catecholamines.) Increases beta receptor sensitivity

149. β blockers

150. Anti-arrhythmic & Anti-oxidant properties. shows substantial improvement in LV function & improved survival The only contraindication is severe decompensated CHF

151. Vasodilators Reduction of afterloadby arteriolar vasodilatation (hydralazin) reduce LVEDP, O2 consumption,improve myocardial perfusion,  stroke volume and COP Reduction of preload Byvenous dilation ( Nitrate)↓ the venous return ↓ the load on both ventricles. Usually the maximum benefit is achieved by using agents with both action.

153. Vasodilators Isosorbidedinitrate and hydralazine also used specially in patients who cannot tolerate ACE inhibitors. Amlodipine and prazosin are other vasodilators can be used in CCF.

155. Calcium Channel Blockers for VasodialationNisoldipine, Isradipine bind more effectively to open channels and inactivated channels (inner side of the membrane) reduces the frequency of opening in response to depolarization marked decrease in transmembrane calcium current activation of myosin light chain kinase Vascular smooth muscle (the most sensitive long-lasting relaxation

157. Nitrates & Nitrites Nitroglycerin is denitrated by glutathione S -transferase in smooth muscle Free nitrite ion is released, which is then converted to nitric oxide activation of guanylylcyclase increase in cGMP dephosphorylation of myosin light chains, preventing the interaction of myosin with actin

159. Venous dilators Reduce preload Direct smooth muscle relaxants Eg: sodium nitropruside

160. (BNP)-Niseritide Brain (B-type) natriuretic peptide (BNP) is secreted constitutively by ventricular myocytes in response to stretch Niseritide = recombinant human BNP Naturally occurring atrialnatriuretic peptide may vascular permeability may reduce intravascular volume) Main Side Effect:- hypotension

161. Human BNP binds to the particulate guanylatecyclase receptor of vascular smooth muscle and endothelial intracellular concentrations (cGMP) ↑ smooth muscle cell relaxation dilate veins and arteries systemic and pulmonary vascular resistances ↑ Indirect ↑ in cardiac output and diuresis. Effective in HF because preload and afterload↓

163. β blockers are used in selected patients (mild/moderate failure)

165. Heart Failure Treatment Algorithm

166. ThankU !