2023-24CBM103WGS10finalN.pdf

Adaptive Response to Physiologic Stress and Increased Workload Email: [email protected] © Northern Ontario School of Medicine 1  Topics Adaptive Response – Frank-Starling mechanism – Neurohormonal response Increased sympath...

Adaptive Response to Physiologic Stress and Increased Workload Email: [email protected] © Northern Ontario School of Medicine 1  Topics Adaptive Response – Frank-Starling mechanism – Neurohormonal response Increased sympathetic activity Increased activation of the renin angiotensin aldosterone system (RAAS) – Cardiac remodeling Hypertrophy (physiologic & pathologic) – Pathophysiologic steps in the development of adverse cardiac remodeling and heart failure 2  Regulation of cardiac output (CO) CO = HR X SV Factors affecting CO: Heart Rate Sympathetic & Parasympathetic activity Contractility (inotropic state) Sympathetic activity Afterload (arterial pressure/vascular resistance) Preload (venous return/filling pressure) Starling’s law © Northern Ontario School of Medicine 3  LV Pressure Volume Loop ESPVR AB: diastolic ventricular filling (aortic valve closed and the mitral valve open) BC: ventricle begins to contract, closure of the mitral valve and aortic valve is still closed (isovolumetric contraction), the onset of systole EDPVR CD: systole with the opening of the aortic valve and ventricular ejection, ventricular volume ↓. DA: mitral valve and aortic valve are closed. This lasts until pressure in ventricle < atrial pressure, diastole (isovolumetric relaxation) occurs EDPVR: end diastolic pressure volume relationship ESPVR: end systolic pressure volume 4 relationship Guyton and Hall, Textbook of Medical Physiology, 12th ed  Heart Failure Hemodynamic changes Syndrome resulting from any Decreased output (systolic structural or functional cardiac dysfunction) disorders Decreased filling (diastolic dysfunction) impairs the ability of the Neuro-hormonal changes ventricles to fill with or eject blood Sympathetic system activation Renin–angiotensin system activation characterized by: Vasopressin release hemodynamic overload Cytokine release alterations in the Cellular changes neurohormonal system 2+ Inefficient intracellular Ca handling myocardial damage Adrenergic desensitization (cellular changes) Myocyte hypertrophy Re-expression of fetal phenotype proteins Cell death (apoptosis) Fibrosis 5  Causes of heart failure Mechanical damage Myocardial damage Pressure overload: Dilated cardiomyopathy – aortic stenosis, hypertension Hypertrophic cardiomyopathy Volume overload: Myocarditis – mitral regurgitation Coronary heart disease Impaired ventricular filling: – pericardial disease, restrictive cardiomyopathy (cardiac iron overload) 6  HFrEF (eg: MI): Impaired contractile function (reduced ejection fraction) Inadequate CO leading to hypoperfusion LV dilation 7  HFpEF: impaired ability of the ventricles to relax and fill during diastole leading to decrease in SV & CO. EDV reduced with impaired filling LV hypertrophy (concentric) 8  Activation of the Sympathetic Nervous System: Adaptive to Maladaptive Response: Adaptive response: SNS activation in HF: an early adaptive response to maintain cardiac function and adequate CO. ↑ contractility increases stroke volume, ↑ HR increases CO, peripheral vasoconstriction (↑ afterload) to maintain blood pressure, venoconstriction leads to ↑venous return which increases CO (FS mechanism). 9  Activation of the Sympathetic Nervous System: Adaptive to Maladaptive Response: Maladaptive response: Increased HR→ increased metabolic demand, decreased filling time Downregulation of β adrenergic receptors, decreased sensitivity to catecholamines →impaired contractility Excessive vasoconstriction leading to ↑ afterload, ↑O2 consumption),↓ cardiac output, Excess fluid retention (contributing to edema) 10  11 Braunwald’s heart disease  Renin Angiotensin Aldosterone System: adaptive response ↓CO stimulate Renin Angiotensin Aldosterone System (RAAS) Renin cleaves circulating angiotensinogen to form Ang I Ang I is converted to Ang II in the presence of angiotensin converting enzyme (ACE) Ang II →vasoconstriction (↑TPR) to maintain arterial pressure In the kidney, Ang II causes sodium & water retention Ang II stimulates increased aldosterone release→salt and vasoconstriction Sodium & Aldosterone Vasopressin water retention (↑plasma water secretion secretion retention ↓ vol)→preload (venous return) and Salt & water ↑CO ( Frank Starling mechanism) retention Ang II stimulates vasopressin release & causes ↑fluid vol. by promoting water retention → increasing preload and CO. 12 Givertz et al., 2001: Circulation Maladaptive Response: Chronic RAAS activation: Elevated arteriolar resistance (vasoconstriction) further ↑afterload→↓CO Excess fluid retention Increased preload→ ↑cardiac workload Ang II causes myocardial remodeling including hypertrophy, apoptosis, Vasoconstriction Sodium & Cardiac Aldosterone Vasopressin fibrosis & inflammation ↓ water ↑ Afterload retention hypertrophy Myocyte secretion ↓ secretion Chronic heart failure: an ↓ apoptosis Salt & water imbalance of neurohumoral ↓Cardiac Output Cardiac fibrosis retention ↓ mechanisms → impaired Cytokines Plasma volume ↓ contractility, adverse cardiac Preload remodeling, excessive ↓ ↑ Cardiac vasoconstriction and excess workload fluid buildup 13 Givertz et al., 2001: Circulation  Preload Preload increases with: – ↑Fluid volume An ↑ in preload: – leads to↑ in SV and CO and results in↑ width of the PV loop. – Increasing preload will increase initial muscle length, which increases the extent of fibre shortening(Frank Starling mechanism) 14 Costanzo CV Physiology 2018  Afterload Afterload: (↑ in aortic pressure): The Left ventricular pressure ventricle must eject blood ESPVR against a high pressure, resulting in ↓in SV (higher ESV) which results in ↓ width of PV loop Linear relationship between afterload and end systolic pressure volume relationship, ESPVR) 15 Costanzo CV Physiology 2018  Contractility ↑contractility shifting the PV loop upward and to the left ventricles develop greater tension than usual causing an ↑in stroke volume ¯ contractility shifting the end diastolic pressure volume relationship) PV loop to the right. SV is ¯ and ESV is ↑ 16 CV Physiology concepts Diastolic dysfunction: Impaired relaxation, diastolic PV curve is shifter upward & to the left, increase in LVEDP (reduced compliance) Reduced SV 17 A) Systolic dysfunction PV curve shifted to the right ESPVR shifted downward SV reduced Compensatory response B) Increase LV volume/elasticity C) Increase contractility D) Increase preload 18 Hemodynamic changes Decreased output (systolic dysfunction) Decreased filling (diastolic dysfunction) Neuro-hormonal changes Sympathetic system activation Renin–angiotensin system activation Vasopressin release Cytokine release Cellular changes 2+ Inefficient intracellular Ca handling Adrenergic desensitization Myocyte hypertrophy Re-expression of fetal phenotype proteins Cell death (apoptosis) Fibrosis 19  Cardiac remodeling Alterations in myocyte: – Excitation-Contraction coupling and crossbridge interaction – Hypertrophy – Beta adrenergic receptor desensitization Myocyte loss – Necrosis – Apoptosis Alterations in Extracellular Matrix – Fibrosis (collagen) Alteration in ventricular geometry – LV dilation – LV wall thinning 20  Cardiac remodeling Hypertrophy (provides initial compensation to mechanical strain) Elongation as well as myocyte slippage Robbins and cotran. Ventricular wall thinning Scar formation Infarct expansion Alibhai et al,, 2014), Martino et al., 2011  22 Robbin & Cotran: Pathologic basis of disease Cardiac remodeling Robbin & Cotran: Pathologic basis of disease 23 Physiologic Hypertrophy Pathologic Hypertrophy Chronic exercise training Pressure and Volume overload Increased myocyte size. Formation Increased myocyte size. Formation of new sarcomeres of new sarcomeres. Cardiac function: normal or Cardiac function depressed over hyperfunctional time Adequate vasculature Inadequate vasculature Absence of excess collagen Cardiac fibrosis, myocyte necrosis deposition or cell death and apoptosis Hypertrophy regresses upon Transitions from adaptive response termination of the stimuli to heart failure 24  Concentric Hypertrophy Pressure overload hypertrophy (eg Aortic stenosis, hypertension) Increased systolic wall stress leads to addition of sarcomeres in parallel Increased LV thickening WALL THICKENING CHAMBER ENLARGEMENT Concentric hypertrophy Helps to reduce systolic wall stress & maintain contractile function 25 BraunwaldsHeart Disease  Eccentric Hypertrophy Increase in diastolic wall stress leads to the addition of sarcomeres in series Lengthening of cardiac myocytes Increase in chamber size CHAMBER ENLARGEMENT and cardiac mass LV dilation Eccentric hypertrophy 26 CV Pathology: Ed; Buja & Butany27  Hypertrophy: adaptive to maladaptive Hypertrophy (initially adaptive) can progress to cardiac dysfunction Inadequate vasculature Increased metabolic demands (oxygen consumption) due to increase in muscle mass, heart rate and contractility Fibrosis 28 Robbins & Cotran, Pathologic basis of disease, 10th ed Altered calcium handling, impaired excitation-contraction (EC) coupling Decreased function of sarcoplasmic reticulum (SR) Ca-pump – decreased calcium reuptake into SR Upregulation of the sarcolemmal Na-Ca exchanger activity – (leading to low intracellular calcium levels for EC coupling, – low affinity of troponin for calcium (leading to reduced cross bridge formation and contractile ability) – Impaired ability of myocyte to contract (systolic dysfunction) Impaired activation of ryanodine receptors – calcium leakage during diastole leading to diastolic dysfunction 29 Heart Failure, A companion to Braunwald’s Heart Disease. 4th Ed.  Acute Effects of Cardiac Failure 3 stages: Immediate effect of cardiac damage Initial compensatory mechanism Chronic compensation (resulting from partial recovery) 30 Guyton and Hall, Textbook of Medical Physiology, 12th ed Summary  Resources Guyton & Hall: Textbook of Medical Physiology, 14th ed, chapters 21, 22 Cecil: Essentials of Medicine, 7th ed, chapter 6 Berne and Levy Physiology, 7th ed, chapter 19 L S. Lilly: Pathophysiology of Heart Disease, 3rd ed, chapter 9 32