Pathophysiology

1. Pathophysiology Department of Pathophysiology Shanghai Jiao-Tong University School of Medicine

2. Chapter 13Cardiac Dysfunction

3. Content • Introduction • Causes and Triggers of Cardiac Dysfunction • Classification of Cardiac Dysfunction • System Compensation to Cardiac Dysfunction • Mechanisms and Pathogenesis of Heart Disease • Clinical Manifestation and Patho-physiology of Cardiac Dysfunction • Pathophysiological basis for the Prevention and Treatment of Cardiac Dysfunction

4. Vagus Nerve Synpathatic Nerve – + Sinus-Atrial Node Excitation-Contraction Coupling Atrial Contraction Septum Bundle of His Excitation-Contraction Coupling Ventricular Contraction Intra-ventricular Conduction

5. Definition of Heart Failure

6. Definition of Heart Failure • Loss of cardiac pump activity due to systolic or diastolic dysfunction, leading to insufficient cardiac output and mis-matched tissue perfusion to meet the metabolic demand. The pathogenic process and the resulting syndrome are defined as heart failure.

7. Myocardial failure • Congestive heart failure • Cardiac dysfunction

8. Congestive Heart Failure (CHF) CHF represents a late stage of chronic heart failure. Loss of cardiac output and venous return mismatch cause increased plasma sodium level, systemic water retention and increased blood volume, leading to peripheral tissue swelling and cardiac chamber dilation as its main symptoms.

9. Causes of HF I. Congenital Heart Disease 1．Defects in Cardiac Myofilament 2．Defects in Cardiac Bioenergenic Metabolism II. Chronic Cardiac Overload 1．Pressure overload 2．Volume Overload III. Ventricular Insufficient Filling

10. Pressure OverloadVolume Overload Blocking of Aortic Outflow： Aortic Valve Stenosis Aortic Valve Insufficiency Left Ventricle Aortic StenosisMitral Insufficiency Asymmetric Ventricular HypertrophyAneurysm Hypertension Pulmonary HypertensionAtrialSeptal Defects Right Ventricle Pulmonary aneurysmVentricle septal defects Pulmonary artery stenosisTricupsid InsufficiencyChronic Pulmonary Congestion Pulmonary aortic valve insufficiency Bi-VentricularHigh Blood viscosity Arteriovenous fistula 、Anemia, Fever, Hyperthyroidism

11. Increased cardiac load due to enhanced metabolism during fever； Increased heart rate leading to higher oxygen consumption and reduced coronal perfusion in diastolic phase leading to reduced blood and oxygen supply. Endotoxin direct injury to cardiomyocytes Lung infection further reduces oxygen supply to heart Triggers and Risk Factors I. Infection

12. II. Acid/Base Imbalance and Eletrolyte Metabolism Acidosis ① H+ binding to Tropon ② Inhibition of SR calcium Release Hyperkalemia

13. III. Arrhythmia Loss of atrial/ventricular coordination, insufficeint ventricular filling and ejection Reduced diastolic phase, coronary perfusion decrease and myocardial ischemia Tachycardia increases oxygen consumption and aggravates ischemia Blood volume overload IV. Pregnancy V. Others Physical and emotional stress, infusion too much/too fast, anemia, Digitalis poisoning

14. Classifications of HF Acute versus chronic heart failure High-outputversus low-output heart failure Right-sided versus left-sided heart failure Contractive versus diastolic heart failure

15. High output heart failure The cardiac output tends to be elevated in patients with heart failure secondary to hyperthyroidism, anemia, arteriovenous fistulas, beriberi. Due to high metabolic demand, the mismatch remains.

16. Compensatory mechanism in Heart Failure HR HF Contractility  SV =CO  Compensation Tissue oxygen and blood supply Heart HR Volume Force relation Remodeling Contractility  CO Relaxation SV  Effective Blood Circulation Peripheral Blood Volume Redistribution RBC, Hemoglobin ODC right shift Mitochondria，ETC Supply Cardiac Blood Supply Oxygen Utilization

17. Heart Rate Quick response, heart rate leading to increased output within certain limit Limitation Higher HR（＞180bpm）increases oxygen consumption Reduced diastolic phase decreases crononary flow and impairs cardaic perfusion

18. Pathogenesis of Heart Failure Myocyte depolarization Cytosolic Ca2+increases from 10-7至10-5mol/L Excitation contraction coupling Ca2+binds to TnC，conformational change TnI removed ，TnT triggers myosin rotation Expose myosin activity and forming cross-bridge, Ca2+ activates myosin ATPase, hydrolysis of ATP to produce energy Myosin head rotation, myofilament sliding. Contraction of heart muscle

19. Myofilament sliding Model

20. Key factors to maintain normal systolic and diastolic function • Thick/thin myofilament structure • Ca2+cycling and homeostasis • Energy supply and utilization

21. I. Systolic Dysfunction 1. Injured myocyte 2. Metabolic defects 3. EC coupling defects 4. Decompensate remodeling

22. II. Ventricular Diastolic Defects 1. Prolonged Calcium Reuptake 2. Cross-bridge Cycling 3. Diastolic Potential 4. Ventricular Compliance reduced III. Asynchronized Relaxation

23. Causes and mechanism of HF in late stage hypertrophy • Ischemia/hypoxia due to insufficient coronary supply； • Sympathatic stimulation and Catecholamine signaling defects • Myosin isoform switch from  to ，ATPase activity is reduced • Ion channels, receptors, ion pumps and mitochondrial defects； • Interstitial fibrosis and compliance defects • Reduced volume vs. surface ratio. • Sustained oxygen consumption。

24. Functional & metabolic alterations in Heart Failure • Heart failure causes organ metabolic changes due to defective cardiac pump. Three major clinical features: • Cardiac output reduction • Tissue blood supply reducdtion • Venous (peripheral and pulmonary) congestion

25. Blood pressure change • Venous hypertension and congestion • Increased blood volume and decreased blood flow

26. Remodeling in Heart Reduced Cardiac Reserve Parameters for Cardiac function： CO，CI Parameters for contractility： EF，Vmax，+dp/dtmax Parameters for relaxation and compliance： –dp/dtmax，T value，ventricular filling volume，ventricular filling rate Parameters for end-diastolic function： PAWP/PCWP，CVP

27. Pulmonary congestion • Compliance • V/Q ratio • Cap sensor • Bronchial congestion and edema • Short of Breath • Causes：Congestion, Congestion • and Edema • symptoms • short of breath after labor • Sleep apnea • orthopnea • Pulmonary edema

28. Pulmonary Edema 1、Pulmonary capillary pressure 2、pulmonary capillary permeability

29. Mild heart failure. Symptomatic after physical activity and return to normal after rest Short of Breath Orthopnea Severe heart failure, symptomatic at rest and short of beath even laying down. Have to take sitting position Sleep apnea LV failure, short of breath in sleep leading to coughing

30. Short of breath after physical activities • Under physical activity, cardiac return increases, aggravate pulmonary congestion. Pulmonary compliance reduced, leading to higher work load of breathing. • increased heart rate, reduced diastolic phase and LV return is shortened, leading to more severe pulmonary congestion. • Peripheral ischemia and CO2 retention leading to central stimulation and harder breathing.

31. IN sitting straight, blood pool to lower part of body due to gravity, reduces cardiac return and alleviate pulmonary congestion and edema. • Diaphram is lower, increases chest cavity volume, support lung expansion. • Reduced tissue fluid entry into blood stream and reduced total blood volume Orthopnea

32. Systemic Congestion • Jugular Veins expansion • hepatic expansion, pain, dysfunction • Edema

33. Reduced Cardiac Output • Aortic Pressure reduction • Urine volume reduction • Brain function • Lethargy and pale

34. Other organ defecdts • Liver function defects • Abnormal digestive function Water, electrolyte, Acid/base • Water/sodium homeostasis • Hpokalemia • Hypomagnesemia • Metabolic acidosis

35. Treatment principles of Heart Failure • Remove causal and triggering factors • Improve relaxation • Reduce afterload and preload, increase output • Adjust humeral regulation • Control edema and reduce blood volume • Correct homeostasis of water, electrolytes and acid/base. • Other, heart transplant

36. Thank You