1. Heart failure Laszlo L. Tornoci Inst. Pathophysiology Semmelweis University

2. Definition A clinical syndrome characterized by progressive weakening of the heart as a pump, causing complex changes in processes at systemic, organ and cellular levels, finally leading to premature myocardial cell death.

3. Demography Prevalence of symptomatic HF 0.4-2.0%, 6-10% in people over 65 years Disease of the elderly (mean age > 70 years) Prevalence is rising Bad prognosis: 5-year survival rate < 50% Mortality (even if age adjusted) is increasing

4. Classification Acute/chronic HF Forward/backward failure Systolic/diastolic dysfunction Left/right sided HF

5. Complaints Left heart, backward failure –dyspnea –orthopnea –paroxysmal nocturnal dyspnea Left heart, forward failure –weakness, fatigue –nycturia

6. Physical findings –Right heart, backward failure edema, hydrothorax congestive hepatomegaly distension of neck veins –Left heart, backward failure pulmonary rales –Miscellaneous cyanosis S3 gallop

7. Causes of heart failure Underlying (true) causes Precipitating causes (which make the clinical condition worse, ‘decompensate’ the patient)

8. Underlying causes Ischemic heart disease Hypertension Valvular heart disease Cardiomyopathies Other

9. Precipitating causes 1. Increased cardiac output –metabolic need (fever, infection, hyperthyroidism) –volume overload (renal failure, high sodium intake) Pressure overload –high BP –pulmonary embolism Increased workload

10. Precipitating causes 2. Cardiac ischemia Decreased efficiency (arrhythmias) Drug effect Endocarditis, myocarditis Same workload, but weaker heart

11. Terms Inotropy (contractility) Lusitropy (capability to relax or be filled) Preload Afterload

12. Frank-Starling law isometric contractions

13. Contractility (inotropy)

14. Pressure-volume (PV) loop

15. Increasing inotropy

16. Decreasing inotropy (systolic dysfunction)

17. Decreasing lusitropy (diastolic dysfunction)

18. Cardiac output vs. right atrial pressure

19. Effect of contractility on cardiac output

20. Some of the factors affecting contractility sympathetic stimulation hypertrophy ischemia, AMI valvular heart disease high BP parasympathetic stimulation sympathetic inhibition myocarditis increasedecrease

21. Venous return curve

22. Venous return curves

23. Determinants of MCFP

24. Cardiac output – venous return

25. Effect of sympathetic stimulation

26. Fluid retention in chronic HF

27. Neurohormonal response to HF Hemodynamic defense reaction –Salt and water retention –Vasoconstriction –Cardiac stimulation Inflammatory reaction Hypertrophic response Overview

28. Neurohormonal response Systemic Organ Cellular Effects by levels Fluid retention, fatigue, cachexia Hypertrophy, remodeling Change of myosin isoforms, Ca ++  torlasz: more examples are needed torlasz: more examples are needed

29. Neurohormonal response to HF Hemodynamic defense reaction –Salt and water retention –Vasoconstriction –Cardiac stimulation Inflammatory reaction Hypertrophic response Overview

30. Hemodynamic defense reaction ExerciseShockHF Duration minutes to hours hourslifetime Challenge need more cardiac output  blood volume pump failure Response fluid retention vasoconstriction cardiac stimulation ++++ ++++++ ++++++

31. Hemodynamic defense reaction –Salt and water retention –Vasoconstriction –Cardiac stimulation: contractility , faster relaxation, HR  –Cell growth and proliferation Effects: Stimulatory catecholamines (per. eff.) angiotensin II ADH endothelin Inhibitory ANP NO bradykinin dopamine cathecolamines (central eff.) Mediators:

32. Hemodynamic defense reaction Adaptive (beneficial), short term responses salt and water retention preload  cardiac output  vasoconstriction afterload  BP  cardiac stimulation contractility  relaxation  HR  cardiac output 

33. Hemodynamic defense reaction Maladaptive (not beneficial), long term responses salt and water retention preload  edema pulmonary edema vasoconstriction afterload  cardiac output  energy demand  cardiac stimulation contractility  relaxation  HR  energy demand  arrhythmias sudden death

34. Neurohormonal response to HF Hemodynamic defense reaction –Salt and water retention –Vasoconstriction –Cardiac stimulation Inflammatory reaction Hypertrophic response Overview

35. Inflammatory reaction Adaptive (beneficial), short term results –not known (heat shock proteins?) Maladaptive (not beneficial), long term results –cardiac cachexia –apoptosis –necrosis

36. Neurohormonal response to HF Hemodynamic defense reaction –Salt and water retention –Vasoconstriction –Cardiac stimulation Inflammatory reaction Hypertrophic response Overview

37. Hypertrophic response Gene expression in myocardial cells will change as a result of: cell stress hemodynamic defense reaction inflammatory reaction adaptive hypertrophymaladaptive hypertrophy sarcomere number  cardiac output  remodeling energy demand  cell death  Changes of growth factor expressions: TGF-  , IGF-1 , FGF 

38. Concentric hypertrophy

39. Eccentric hypertrophy

40. Therapy Emergency setting –keep the patient alive! Usual setting –alleviate symptoms (improve QOL) –prolong survival contradiction is possible! Goals of therapy in general

41. Classical approaches in drug therapy Circulation –decrease fluid retention (diuretics) –decrease afterload, preload (vasodilators) Heart –positive inotropic agents (digitalis)

42. Diuretic therapy

43. Maladaptive features of the vasoconstrictor response vasoconstriction afterload cardiac output myocardial energy expenditure myocardial cell death arrhythmias, sudden death survival  worse symptoms   

44. Expected response to vasodilators vasoconstriction  afterload  cardiac output  myocardial energy expenditure  myocardial cell death  arrhythmias, sudden death  survival  better symptoms 

45. Actual response to vasodilators vasoconstriction  afterload  cardiac output  myocardial energy expenditure  myocardial cell death  arrhythmias, sudden death  survival  better symptoms   BP  hemodynamic defense reaction hypertrophy

46. Renin-angiotensin system angiotensinogen (1-14) angiotensin I (1-10) angiotensin II (1-8) angiotensin III (2-8) angiotensin IV (3-8) renin ACE, chymase kallikrein, cathepsin G peptidase ACE: angiotensin converting enzyme

47. Actions of ACE Converts angiotensin I to angiotensin II Breaks down kinins (bradykinin) So ACE inhibitors not only decrease angiotensin II levels, but increase bradykinin concentration. This is beneficial, but may cause coughing as a side effect.

48. Summary of drug therapy drug control fluid retention alleviate symptoms prolong survival diuretic+++? ACE inhibitor ++++  -blocker *  (0)  (+) ++ digitalis+++0 * : long term effects are in parentheses

49. Availability http://xenia.sote.hu/depts/pathophysiology The heart failure lectures (in.ppt file format) can be downloaded from inside the university local area network (e.g. Students’ Center) at this address: