Cardiac_Vascular Physiology Review 2023 PDF

Cardiac Physiology Background 12/11/2023 BPS 337 Richard T Clements Outline: Cardiac Physiology Refresher Cardiac Cycle Determinants of CO Pressure Volume Loops Mechanism of cardiac contraction/b-AR modulation Cardiac function and HF Coronary Circulati...

Cardiac Physiology Background 12/11/2023 BPS 337 Richard T Clements Outline: Cardiac Physiology Refresher Cardiac Cycle Determinants of CO Pressure Volume Loops Mechanism of cardiac contraction/b-AR modulation Cardiac function and HF Coronary Circulation and O2 Supply/Demand Cardiac action potential / b-AR modulation Cardiac Cycle Pressure Volume Loops  Multiple PV loops over time LVP LVV  Cardiac Physiology: Cardiac Output CO = HR * SV SV determined by preload, afterload, and contractility Determinants of Cardiac Output: Afterload Preload Contractility Heart Rate  Preload Frank-Starling Mechanism Pressure that fills the ventricle. Increases in preload increase SV and CO Increases End-diastolic pressure and volume Why does the amount of blood filling the heart increase the SV? Frank-Starling mechanism More force is produced the more the ventricle wall is stretched Intrinsic properties of the cardiac sarcomeres (stretch, tension) and Ca++ release machinery Preload = EDV, EDP = SV and CO  Frank-Starling Curve: Summary 1. The heart automatically matches cardiac output during systole (blood out) to variations in ventricular filling pressure during diastole (blood in). 2. An increase in diastolic ventricular volume (venous return) is matched by a rapid increase in cardiac output. A decrease in venous return is matched by a rapid decrease in cardiac output. 3. A failing heart produces a depressed Frank-Starling curve, with diminished cardiac output even at elevated diastolic pressures.  Factors that will affect preload Increase preload: Increased Venous Return Increased Venous Blood Volume Increased Venous Pressure Decreased Venous Compliance Atrial Inotropy Increased Afterload Increased Ventricular Compliance What happens to a PV loop with increased preload? Afterload Afterload is the pressure and/or resistance that the heart has to actively work against Increases in afterload decrease SV and CO Blood pressure Vascular resistance Stiffness of the aorta and peripheral circulation High blood pressure = high afterload Intrinsic Factors of Ventricular Wall: remodeled LV/RV wall can increase afterload Afterload = ESV, ESP = SV and CO Factors that will affect afterload Increased vascular resistance: Hypertension Increased vasoconstriction Vascular anatomical remodeling/constriction Valve Disease (stenosis, regurgitation) Blood viscosity Pulmonary Hypertension (RV Afterload) What happens to the PV loop?  Contractility Contractility is the force generated for a given sarcomere/fiber length Can be modified by Catecholamines * Sympathetic and Parasympathetic Activity * Inotropes * Preload Afterload (Anrep Effect) HR (Bowditch Effect)  ESPVR (Ees) and contractility Ees- end systolic Elastance ESPVR – End Systolic Pressure Volume Relation Preload, Afterload and Contractility are interdependent.  Heart Rate Heart rate increases cause an increase in CO CO = HR * SV However at too high a heart rate, filling is impaired so preload decreases and SV drops effecting HR. A high heart rate can also adversely increase myocardial O2 demand and impair contractility  Summary: CO and SV 4 determinants of cardiac output Preload, Afterload, Contractility and HR Frank-Starling Mechanism: Heart responds to increased preload with increased ejection and CO Heart is tuned to increase ejection with increased stretch ESPVR slope is contractility (Ees). Increased contractility increases CO Increased afterload decreases CO Pressure Volume loops are useful to determine many parameters regarding cardiac physiology – changes dependent on afterload, preload, and contractility. Cardiac Contraction is all about Ca+ + Cardiac Troponin- Tropomyosin complex inhibits binding of myosin to actin Increases in cytosolic Ca++ bind to cTnC allowing myosin and actin to interact and contraction to take place. When Ca++ levels fall every beat of the heart, relaxation occurs.  Excitation-Contraction (E-C) Coupling Action Potential – causes Ca+ influx due to depolarization Ca++ releases more Ca+ + from SR Ca++ binds cTnC – allows actin/myosin interaction Ca++ removed by SERCA –sarcoendoplasmic reticulum Ca++ ATPase Other Ca++ removed by NCX (Na/Ca++ exchange) Na/K ATPase resets membrane potential (voltage) Bers 2002 Most of these steps require large amounts of ATP  B1-AR PKA activation promotes Ca++ release PKA can increase Ca++ release through direct modulation of Ca+ + release through RyR, and external Ca++ channels. However, Ca++ stores need to be replenished and increased so PKA phosphorylates and inhibits PLB PLB normally inhibits SERCA. pPLB no longer inhibits SERCA and SR Ca++ stores increase Subsequent Ca++ release from SR is increased. b-blockers inhibit this and thus limit contractility and CO  Summary Cardiac Contraction 1. Action potential depolarizes cell and activates PM Ca++ channels 2. Increased Ca++ causes Ca++ release from the SR 3. Released Ca++ binds TnC to allow myosin:actin interaction and contraction 4. SERCA activates to restore Ca++ to SR and NCX expels Ca++ from the plasma membrane 5. Cell repolarizes and cycle continues. 6. B-AR activation causes PKA to increase activity of RyR and SERCA among other proteins (ion channels/exchangers etc) Increases in Ca++ within the cell will cause an increase in cardiac contractility.  Ejection Fraction and HF The amount of blood ejected from the heart (stroke volume) divided by the amount of blood in the heart at diastole (EDV) expressed as % EF = SV/EDV *100 IF SV is down CO is down given = HR  Normal HFrEF HFpEF HFrEF: Heart Failure with reduced Ejection Fraction (systolic dysfunction) – reduced contractility causing reduced SV and EF. EDV is increased. HFpEF – Heart Failure with preserved Ejection Fraction (diastolic dysfunction) although SV is lower leading to lower CO. EF is normal due to reduced EDV. EF=SV/EDV*100 Causes of HFrEF Major causes of HF with reduced EF Structural abnormalities Previous MI – infarct/damaged myocardium Coronary Artery Disease Diabetes Metabolic Syndrome Lipids Inflammation O2 disruptions Hypertension Genetic cardiomyopathies Myocardial damage - Toxicity  Causes of HFpEF Not entirely clear disease mechanism Factors Obesity Hypertension CAD Diabetes Metabolic syndrome Kidney disease COPD Sleep Apnea Anemia Fibrosis and Cardiac Remodeling and HF Fibrosis and ECM deposition is a major component of cardiac remodeling in addition to hypertrophy Deposition of ECM molecules promote fibrosis. Fibrotic hearts are stiffer, less elastic Contractile function is impaired depending on severity. Cardiac Fibroblasts drive Myocardial Fibrosis Cardiac Tissue: Green: Myocytes Red : Fibroblasts Blue: Nuclei HFrEF and HFpEF both have less CO.  HFpEF and increased diastolic pressure. HFpEF – associated with stiffer ventricles and/or impaired relaxation signaling function Increased LVEDP for a given volume. Decreased LVEDV and SV To right Frank Starling curve in HFpEF  Preload and Afterload effects on cardiac output with LV dysfunction HFrEF PV loops in Heart Failure Summary of pressure – volume changes in HF Although may have elements of diastolic dysfunction in HFrEF and vice versa. Spectrum Especially as disease progresses/end stage. Summary Heart Failure is divided into two main categories: HFrEF : characterized by impaired contraction and reduced CO. Low EF, high EDV, low SV, low CO HFpEF: characterized by increased diastolic stiffness and/or hypertrophy Normal EF, low EDV, low SV, low CO. Cardiac fibroblasts and fibrosis as well as cardiomyocyte hypertrophy contribute to both HFrEF and HFpEF  Coronary circulation and blood flow. The heart has the highest oxygen demand in the body. Coronary A-VO2 difference is the highest of any circulation (10-13 ml/100ml vs systemic ~5ml. ~75%) -coronary venous blood is VERY dark Flow can dramatically change in the coronary circulation due to changes in metabolic demand: autoregulation and reactive hyperemia.  Coronary circulation and blood flow. Flow in the coronary circulation is different than other vascular beds. During systole flow is greatly reduced due to contraction of the heart muscle and increased coronary resistance. The majority of flow through the heart takes place during diastole. Myocardial Energy Demand  Oxygen consumption/demand: Its all electron transport in mitochondria. Most of these steps require large amounts of ATP  O2 Supply: dictated by coronary flow Coronary circulation is subject to many of the same vasoconstriction and vasodilation signaling cascades as peripheral circulation Vasodilation should enhance coronary flow and O2 supply Vasoconstriction will decrease coronary flow and O2 supply Atherosclerosis will decrease coronary flow and impair normal vasoregulation. Coronary flow = DP/R Coronary pressure in beginning of circuit is ~ MAP  Molecular Basis of Contraction – Smooth Muscle Agonists activate receptors which turn on plasma membrane Ca++ channels Depolarization of smooth muscle and/or signaling causes release of Ca+ + in intracellular stores through IP3 receptor on SR. IP3 generated via PLC cleavage of PIP2 Ca++ activates MLCK to phosphorylate MLC. Rho Kinase is activated in parallel to MLCK to shut off MLC dephosphorylation MLC phosphorylation causes activation of myosin and subsequent vessel contraction Molecular Basis of VSMC Dilation In endothelial cells: Receptor activated signaling cascades activate nitric oxide synthase (eNOS) NO diffuses to VSMC eNOS activated by both receptor and mechanical signal cascades (shear stress, pressure) In VSMC KCa NO activates soluble guanylate cyclase (sGC) K + sGC makes cyclic-GMP cGMP activates PKG PKG has a coordinated response to limit VSMC contraction: Decrease Ca++ influx/release MYP Decrease MLC phosphorylation via active MYPT ML T Increase K+ efflux C  PKA and smooth muscle dilation In smooth muscle: Vasodilators can activate adenylate cyclase Makes cAMP cAMP activates PKA PKA has negative effects on MLCK as well as activates MLCP to reduce contraction This is the complete opposite effect from PKA in the heart  Summary of VSMC signaling Vessel dilation/contraction can cause huge changes in flow (radius4) Signaling mechanism of vessel contraction and dilation 1 Signal (smooth muscle receptor) 2 Plasma membrane Ca++ channels / PLC activation 3 Intracellular Ca store release via IP3 and IP3 receptor 4 MLCK activation / inhibition of MYPT 5 MLC phosphorylation Signaling mechanisms of vessel dilation: 1 Signal (endothelial/VSMC receptor etc..) 2 activation of Nitric Oxide 3 Diffusion of NO to VSMC guanylate cyclase 4 generation of cGMP 5 Activation of PKG 6 activation of myosin phosphatase (limits MLC-phosphorylation) and K+ channels PKA promotes dilation through inhibition of contractile pathways and some PKg like pathways. Summary Coronary Circulation Coronary circulation provides O2 to the energetically demanding cardiac muscle. Factors that increase cardiac output will increase cardiac O2 demand Factors that cause the hear to work harder (afterload) will increase O2 demand O2 supply in the coronary circulation can be modified by increased vasodilation and impaired contraction Lowering O2 demand in the heart and increase supply is the goal of pharmacological interventions in Stable ischemic heart disease  Arrythmia: Propagation of the Action Potential Propagation of the action potential SA nodal cells in atria initiate contraction Impulse travels through atria (P- wave) Impulse travels from atria to ventricle via AV node (PR interval) Conduction through Purkinjie system to majority of ventricle Ventricular cardiomyocytes then spread AP (QRS) Cardiomyocytes repolarize (T wave) AP necessary to initiate contraction and Ca++ cycling Membrane potential and ionic gradients Resting membrane potential Determined by different concentrations of ions inside and outside the cell Interior of the cell more – (~-70 mV) Large amounts or Na+ outside the cell Opening of Na+ channels causes rapid influx High concentration and electrical gradients Large amounts of K+ inside the cell Opening of K+ channels causes K+ efflux High concentration and low electrical gradient (changes in action potential)  SA/AV node action potentials Cation channels allow Na+ influx (If: funny current) (Phase 4) Depolarization opens Ca++ channels (Ca++ influx) (phase 0) K+ channels open causing efflux and repolarization. (Phase 3) No phase 1,2  Sympathetic stimulation of heart rate Activation of b1 receptors Increased Na current through “funny channels” Increased + charge allows Ca++ channels to open HR is increased Parasympathetic PKA stimulation decreases funny currents  ANS effects heart rate Increasing sympathetic stimulation or activation of B-AR: Increases Na current (phase 4) SA nodal cells reach threshold and Ca++ channels open earlier to increase HR. Vagal stimulation and Beta blockers do the opposite of SNS. Cardiomyocyte Action Potential Na channels open due to depolarization of neighboring cells (gap junction). Rapidly depolarize the cell, Na+ influx (phase 0) K+ channels open (efflux) to repolarize the cell and counteract Na+. Ca++ channels(influx) also open to support contraction. Na+ channels closed (phase 2) Ca++ channels close and K+ channels remain open to completely repolarize cell (phase 3) Phase 4: channels closed and at resting membrane potential SA/AV node and ventricular action potentials are VERY different Action Potential and ion currents Na+ channels initiate depolarization – phase 0 Many different proteins/channels give rise to extracellular K+ currents in phase 1,2,3 L-type Ca++ channels for phase 2 Disturbances/mutations of these channels can lead to arrhythmia. ECG signal is a sum of action potentials in the heart. ECG refresher of intervals and waves  Action Potential/ECG Summary Na+ high outside, K+ high inside Na channels open when cell is negative – Na+ in. Cell is more positive K+ and Ca++ channels open when cell is +, K+ goes out, Ca++ enters Ca++ channels close and K+ still open. Cell becomes negative again Na+ , K+ and Ca+ normalized by Na/K-ATPase and Na+/Ca++ exchange Many different K+ channels that open to repolarize cell SA and AV node propagation different from cardiomyocytes. SA node: Small Na+ influx followed by large Ca++ influx, followed by K+ efflux Cardiomyocyte: Large Na+ influx, followed by K+ efflux and Ca++ influx, then K+ efflux Propagating action potential sets up a charge difference measured by EKG Know the adrenergic signaling cascades that determine HR in the SA node. Summary : things to know this lecture Know and draw: Cardiac contraction mechanism Mechanism of B-AR modulation of contractility Vascular contraction mechanism How A1-AR and other contractile agonists modulate contraction Vascular dilation mechanism. How Beta adrenergics increase HR. SA/AV node modulation of cardiac action potential PKA dependent modification of Na channels. Determinants of cardiac output. Do not worry about HF, PV loops, and O2 supply/demand for the test.