1. PATHOPHYSIOLOGY OF HEART FAILURE Jianzhong Sheng MD PhD

2. Notes to heart physiology Notes to heart physiology Essential functions of the heart Essential functions of the heart to cover metabolic needs of body tissue to cover metabolic needs of body tissue (oxygen, substrates) by adequate blood supply (oxygen, substrates) by adequate blood supply to receive all blood coming back from the tissue to receive all blood coming back from the tissue to the heart to the heart Essential conditions for fulfilling these functions Essential conditions for fulfilling these functions normal structure and functions of the heart normal structure and functions of the heart adequate filling of the heart by blood adequate filling of the heart by blood

3. Essential functions of the heart are secured Essential functions of the heart are secured by integration of electrical and mechanical by integration of electrical and mechanical functions of the heart functions of the heart Cardiac output (CO) = heart rate (HR) x stroke vol.(SV) - changes of the heart rate - changes of stroke volume Control of HR: Control of HR: - autonomic nervous system - hormonal(humoral) control Control of SV: Control of SV: - preload - contractility - afterload

4. Adaptive mechanisms of the heart to increased load Frank - Starling mechanism Ventricular hypertrophy – increased mass of contractile elements   strength of contraction Increased sympathetic adrenergic activity – increased HR, increased contractility Incresed activity of R–A–A system

5. Causes leading to changes of number and size of cardiomyocytes

6. Preload Stretching the myocardial fibers during diastole by increasing end- diastolic volume   force of contraction during systole = Starling´s law preload = diastolic muscle sarcomere length leading to increased tension in muscle before its contraction (Fig. 2,3) tension in muscle before its contraction (Fig. 2,3) - venous return to the heart is important  end-diastolic volume is influenced - stretching of the sarcomere maximises the number of actin-myosin bridges responsible for development of force of actin-myosin bridges responsible for development of force - optimal sarcomere length  2.2  m

8. Myocardial contractility Contractility of myocardium Changes in ability of myocardium to develop the force Changes in ability of myocardium to develop the force by contraction that occur independently on the by contraction that occur independently on the changes in myocardial fibre length changes in myocardial fibre length Mechanisms involved in changes of contractility Mechanisms involved in changes of contractility  amount of created cross-bridges in the sarcomere  amount of created cross-bridges in the sarcomere by  of  Ca ++  i concentration - catecholamines   Ca ++  i   contractility - catecholamines   Ca ++  i   contractility - inotropic drugs   Ca ++  i   contractility  contractility  shifting the entire ventricular function curve upward and to the left curve upward and to the left  contractility  shiffting the entire ventricular function curve (hypoxia, acidosis) downward and to the right curve (hypoxia, acidosis) downward and to the right

9. The pressure – volume loop It is the relation between ventricular volume and pressure This loop provides a convenient framework for understanding the response of individual left ventricular contractions to alterations in preload, afterload, and contractility It is composed of 4 phases: - filling of the ventricle - isovolumic contraction of ventricle - isotonic contraction of ventricle(ejection of blood) - isovolumic relaxation of ventricle

10. Pressure – volume loops recorded under different conditions

11. It is expressed as tension which must be developed in the wall of ventricles during systole to open the semilunar valves and eject blood to aorta/pulmunary artery Laplace law: intraventricular pressure x radius of ventricle wall tension = -------------------------------------------------------- 2 x ventricular wall thickness 2 x ventricular wall thickness  afterload: due to - elevation of arterial resistance -  ventricular size -  ventricular size - myocardial hypotrophy - myocardial hypotrophy  afterload: due to -  arterial resistance - myocardial hypertrophy - myocardial hypertrophy -  ventricular size -  ventricular size Afterload

12. Heart failure Definition It is the pathophysiological process in which It is the pathophysiological process in which the heart as a pump is unable to meet the heart as a pump is unable to meet the metabolic requirements of the tissue for the metabolic requirements of the tissue for oxygen and substrates despite the venous oxygen and substrates despite the venous return to heart is either normal or increased return to heart is either normal or increased

13. Explanation of the terms Myocardial failure = abnormalities reside in the myocardium and lead Myocardial failure = abnormalities reside in the myocardium and lead to inability of myocardium to fulfilling its function to inability of myocardium to fulfilling its function Circulatory failure= any abnormality of the circulation Circulatory failure = any abnormality of the circulation responsible for the inadequacy in body tissue responsible for the inadequacy in body tissue perfusion, e.g. decreased blood volume, changes perfusion, e.g. decreased blood volume, changes of vascular tone, heart functiones disorders of vascular tone, heart functiones disorders Congestive heart failure= clinical syndrome which is developed Congestive heart failure = clinical syndrome which is developed due to accumulation of the blood in front due to accumulation of the blood in front of the left or right parts of the heart of the left or right parts of the heart

14. General pathomechanisms involved in heart failure development Cardiac mechanical dysfunction can develop as a consequence in preload, contractility and afterload disorders Disorders of preload  preload  length of sarcomere is more than optimal    strength of contraction   strength of contraction  preload  length of sarcomere is well below the optimal    strength of contraction   strength of contraction

16. Important: failing ventricle requires higher end-diastolic volume to achieve the same improvement of CO that normal to achieve the same improvement of CO that normal ventricle achieves with lower ventricular volumes ventricle achieves with lower ventricular volumes Disorders of contractility In the most forms of heart failure the contractility of myocardium is decreased (ischemia, hypoxia, acidosis, inflammation, toxins, metabolic disorders... ) Disorders of afterload due to: fluid retention in the body fluid retention in the body  arterial resistance  arterial resistance valvular heart diseases ( stenosis) valvular heart diseases ( stenosis )

18. Characteristic features of systolic dysfunction (systolic failure) ventricular dilatation reducing ventricular contractility (either generalized or localized) diminished ejection fraction (i.e., that fraction of end-diastolic blood volume ejected from the ventricle during each systolic contraction – les then 45%) in failing hearts, the LV end-diastolic volume (or pressure) may increse as the stroke volume (or CO) decreases

19. Characteristic features of diastolic dysfunctions (diastolic failure) ventricular cavity size is normal or small myocardial contractility is normal or hyperdynamic ejection fraction is normal (>50%) or supranormal ventricle is usually hypertrophied ventricle is filling slowly in early diastole (during the period of passive filling)  end-diastolic ventricular pressure is increased

20. Causes of heart pump failure A. MECHANICAL ABNORMALITIES 1. Increased pressure load – central (aortic stenosis, aortic coarctation...) – peripheral (systemic hypertension) 2. Increased volume load – valvular regurgitation – hypervolemia 3. Obstruction to ventricular filling – valvular stenosis – valvular stenosis – pericardial restriction

21. B. MYOCARDIAL DAMAGE 1. Primary a) cardiomyopathy b) myocarditis c) toxicity (e.g. alcohol) d) metabolic abnormalities (e.g. hyperthyroidism) 2. Secondary a) oxygen deprivation (e.g. coronary heart disease) b) inflammation (e.g. increased metabolic demands) c) chronic obstructive lung disease

22. C. ALTERED CARDIAC RHYTHM 1. ventricular flutter and fibrilation 1. ventricular flutter and fibrilation 2. extreme tachycardias 3. extreme bradycardias 3. extreme bradycardias

23. Pathomechanisms involved in heart failure A. Pathomechanisms involved in myocardial failure 1.Damage of cardiomyocytes   contractility,  compliance  compliance Consequences:  defect in ATP production and utilisation  changes in contractile proteins  uncoupling of excitation – contraction process   number of cardiomyocytes  impairment of relaxation of cardiomyocytes with decrease compliance of myocardium compliance of myocardium  impaired of sympato-adrenal system (SAS)   number of  1 -adrenergic receptors on the surface of cardiomycytes  1 -adrenergic receptors on the surface of cardiomycytes

25. 2. Changes of neurohumoral control of the heart function function Physiology: SNS   contractility Physiology: SNS   contractility  HR  HR  activity of physiologic pacemakers  activity of physiologic pacemakers Mechanism:   sympathetic activity  cAMP   Ca ++  i   contractility  Ca ++  i   contractility   sympathetic activity   influence   sympathetic activity   influence of parasympathetic system on the heart of parasympathetic system on the heart Pathophysiology: normal neurohumoral control is Pathophysiology: normal neurohumoral control is changed and creation of pathologic changed and creation of pathologic neurohumoral mechanisms are present neurohumoral mechanisms are present

27. Chronic heart failure (CHF) is characterized by an imbalance of neurohumoral adaptive mechanisms with a net results of excessive vasoconstriction and salt and water retention Catecholamines : - concentration in blood : - norepinephrin – 2-3x higher at the rest than in healthy subjects - circulating norepinephrin is increased much more during equal load in patients suffering from CHF than during equal load in patients suffering from CHF than in healthy subject in healthy subject -  number of beta 1 – adrenergic receptors   sensitivity of cardiomyocytes to catecholamines   sensitivity of cardiomyocytes to catecholamines    contractility   contractility System rennin – angiotensin – aldosteron heart failure  CO  kidney perfusion  stim. Of RAA system

28. Important: Catecholamines and system RAA = compensatory mechanisms  heart function and arterial BP The role of angiotensin II in development of heart failure  vasoconstriction ( in resistant vesels)  retention of Na  blood volume   releasing of arginin – vasopresin peptide (AVP ) from neurohypophysis from neurohypophysis

29.   sensitivity of vessel wall to norepinephrine  mitogenic effect on smooth muscles in vessels and on cardiomyocytes  hypertrophy on cardiomyocytes  hypertrophy  constriction of vas efferens ( in glomerulus )   sensation of thirst   secretion of aldosteron from adrenal gland  mesangial conctraction   glomerular filtration rate  facilitation of norepinephrine releasing from sympathetic nerve endings sympathetic nerve endings

31. Pathophysiology of diastolic heart failure  systolic heart failure = failure of ejecting function of the heart  diastolic heart failure = failure of filling the ventricles,  resistance to filling of ventricles  resistance to filling of ventricles But, which of the cardiac cycle is real diastole ? Diastolic failure is a widely recognized clinical entity

33. Definition of diastolic heart failure It is pathophysiological process characterized by symptoms and signs of congestive heart failure, which is caused by increased filling resistance of ventricles and increased intraventricular diastolic pressure Primary diastolic heart failure - no signs and symptoms of systolic dysfunction is present - ! up to 40% of patients suffering from heart failure! Secondary diastolic heart failure - diastolic dysfunction is the consequence of primary systolic dysfunction systolic dysfunction

34. Main causes and pathomechanisms of diastolic Main causes and pathomechanisms of diastolic heart failure heart failure 1. structural disorders  passive chamber stiffness a)intramyocardial – e.g. myocardial fibrosis, amyloidosis, hypertrophy, – e.g. myocardial fibrosis, amyloidosis, hypertrophy, myocardial ischemia... myocardial ischemia... b) extramyocardial – e.g. constrictive pericarditis 2. functional disorders   relaxation of chambers e. g. myocardial ischemia, advanced hypertrophy of ventricles, ischemia, advanced hypertrophy of ventricles, failing myocardium, asynchrony in heart failing myocardium, asynchrony in heart functions functions

35. Causes and mechanism participating on impaired Causes and mechanism participating on impaired ventricular relaxation ventricular relaxation a) physiological changesin chamber relaxation due to: a) physiological changes in chamber relaxation due to: – prolonged ventricular contraction – prolonged ventricular contraction Relaxation of ventricles is not impaired Relaxation of ventricles is not impaired ! b) pathological changesin chamber relaxation due to: b) pathological changes in chamber relaxation due to: Impaired relaxation process Impaired relaxation process  delayed relaxation (retarded)  incomplete (slowed) relaxation

38.  Consequences of impaired ventricular relaxation - filling of ventricles is more dependent on diastasis and on the systole of atrias than in healthy subjects and on the systole of atrias than in healthy subjects Symptoms and signs:  exercise intolerance = early sign of diastolic failure   coronary blood flow during diastole  Causes and mechanisms involved in development of ventricular stiffness of ventricular stiffness  ventricular compliance = passive property of ventricle Source of compliance: cardiomyocytes and other heart tissue to stretching tissue to stretching

39.  Ventricular compliance is caused by structural abnormalities  Ventricular compliance is caused by structural abnormalities localized in myocardium and in extramyocardial tissue localized in myocardium and in extramyocardial tissue a) Intramyocardial causes : myocardial fibrosis, hypertrophy of ventricular wall, restrictive cardiomyopathy ventricular wall, restrictive cardiomyopathy b. Extramyocardial causes: constrictive pericarditis b. Extramyocardial causes : constrictive pericarditis The role of myocardial remodelling in genesis of heart failure heart failure  adaptive remodelling of the heart  pathologic remodelling of the heart

40. Main causes and mechanisms involved in pathological remodelation of the heart pathological remodelation of the heart 1. Increased amount and sizeof myocytes = hypertrophy 1. Increased amount and size of myocytes = hypertrophy Due to: -  volume and/or pressure load (excentric, concentric hypertrophy) (excentric, concentric hypertrophy) - hormonal stimulation of cardiomyocytes by norepinephrine, angiotenzine II norepinephrine, angiotenzine II 2. Increased % of non-myocytic cells in myocardium and their influence on structure and function of heart and their influence on structure and function of heart a. endothelial cells – endothelins : mitogenic ability   stimulation growth of smooth muscle cells of vessels, fibroblasts  stimulation growth of smooth muscle cells of vessels, fibroblasts b. fibroblasts -  production of kolagens

42. Symptoms and signs of heart failure 1.forward failure: symptoms result from inability of the heart to pump enough symptoms result from inability of the heart to pump enough blood to the periphery (from left heart), or to the lungs (from blood to the periphery (from left heart), or to the lungs (from the right heart) the right heart) a) forward failure of left heart:-muscle weakness, fatigue, a) forward failure of left heart:- muscle weakness, fatigue, dyspepsia, oliguria.... dyspepsia, oliguria....  general mechanism: tissue hypoperfusion b) forward failure of right heart:- hypoperfusion of the b) forward failure of right heart: - hypoperfusion of the lungs  disorders of gas lungs  disorders of gas exchange exchange - decreased blood supply to the left heart to the left heart

43. 2. backward failure: symptoms result from inability of the heart to accept – symptoms result from inability of the heart to accept the blood comming from periphery and from lungs the blood comming from periphery and from lungs a.backward failure of left heart: – increased pulmonary capillary pressure  dyspnoea – increased pulmonary capillary pressure  dyspnoea and tachypnoea, pulmonary edema (cardiac asthma)  and tachypnoea, pulmonary edema (cardiac asthma)   arterial hypoxemia and hypercapnia....  arterial hypoxemia and hypercapnia.... b. backward failure of right heart: increased pressure in systemic venous system  – increased pressure in systemic venous system   peripheral edemas, hepatomegaly, ascites  nocturnal diuresis....  peripheral edemas, hepatomegaly, ascites  nocturnal diuresis....

44. Thanks