SIHD Background 2024 PDF

SIHD: Background Richard Clements Assistant Professor Biomedical and Pharmaceutical Sciences 1/26 and 1/29/2024  Outline Background: Pathophysiology Coronary blood flow and regulation Ischemia: Oxygen demand and...

SIHD: Background Richard Clements Assistant Professor Biomedical and Pharmaceutical Sciences 1/26 and 1/29/2024  Outline Background: Pathophysiology Coronary blood flow and regulation Ischemia: Oxygen demand and supply Coronary artery disease Blood vessel regulation Drugs Ca channel blockers Nitrates β-Blockers Ranolazine Lipid lowering/statins, Antiplatelets/Aspirin, ACEi/ARB Cardiac Cycle  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 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 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)  Summary 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 Increased preload increases CO Increased contractility increases CO Increased afterload decreases CO  Stable Ischemic Heart Disease : SIHD Ischemic heart disease is caused by oxygen consumption (demand) exceeding oxygen delivery (supply) Most often caused by atherosclerotic Coronary Artery Disease (CAD) which results in physical blockages that reduce flow through the coronary circulation Can also be caused by overactive vasomotor activity and coronary contraction known as vasospasm (less common than CAD) Acute coronary syndromes (acute ischemia or myocardial infarction) is ischemia caused by drastic reductions in flow or oxygen supply due to rupture of a plaque or clot: are treated differently and acutely and often result in significant myocyte death and scarring in the myocardium.  Symptoms of CAD/SIHD Symptoms of ischemic Heart Disease: Chest pain/pressure (angina) (main symptom) Usually transient with exertion/exercise and dissipates at rest/treatment with nitrates Can have pain radiate to other parts of body : arm, neck, back (more common in women) Shortness of breath Indigestion  Types of angina Stable Angina: Transient and relieved with rest and/or treatment with nitroglycerin. Indicative of stable atherosclerotic lesion Unstable Angina: Is not transient or resolved with rest/nitroglycerin treatment. Indicative of complex atherosclerosis and/or ACS involving clots. Variant Angina (Prinzmetal’s Angina) : Vasospasm of the coronary artery. Hypercontraction of the vessel to impede blood flow and O2 supply. Myocardial Energy Demand  Coronary Artery Disease A narrowing of the coronary arteries due to plaque formation. Coronary blood flow is reduced. Leading to increased O2 extraction from the blood and tissue hypoxia. Large occlusions ~>70% are generally needed to impair O2 delivery. Three categories of coronary ischemia Plaques  CAD and plaque formation Mechanism of CAD: 1. Initiated through endothelial injury 2. Lipid deposits and inflammation follow 3. Fibroproliferative response of smooth muscle, inflammatory, and other cell types 4. Subsequent occlusion of vessel and/or plaque rupture Lots of current research to therapeutically target inflammatory cascades that contribute to CAD  Risk factors for CAD/ISHD Risk Factors include : Age (>45) Sex (males, post-menopausal women) Family History Smoking High Blood Pressure High cholesterol/LDL Diabetes Sedentary Lifestyle Diet  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: coronary: ~10-13 ml O2 /100ml blood (~25% saturation in veins) systemic: ~5ml O2 / 100 ml blood. (~75% saturation in veins) 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. High HR can reduce total flow. Myocardial Energy Demand  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 = ∆P/R Coronary pressure in beginning of circuit is ~ MAP Coronary pressure at end is same as central venous pressure.  Vascular Resistance and Blood Flow Blood Flow (Q) = ∆P / R R = η * L/ 8 * r4 * π η = blood viscosity L = vessel length r = radius Q α r4 * ∆P / η * L Small changes in radius can have large effects on flow / pressure Q α r4 Vasodilation and constriction can cause large changes in radius  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. 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 In VSMC NO activates soluble guanylate cyclase (sGC) KCa KCa sGC makes cyclic-GMP K+ K+ cGMP activates PKG PKG has a coordinated response to limit VSMC contraction: Decrease Ca++ influx/release Decrease MLC phosphorylation via active MYPT MYPT MLC Increase K+ efflux  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 3 Intracellular Ca store release 4 MLCK activation 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 and/or K+ channels Increases in vessel dilation and/or decreases in vessel contraction will increase flow and thus O2 supply to the heart. Cardiac contractile rate and force are the major determinants of oxygen demand Increased preload and increased afterload: Make the heart work harder to expel blood. Increases in contractility increase O2 demand Increases in HR increase O2 demand Cardiac contraction is driven by Ca++ signaling and subsequent myosin activation (requires large amounts of ATP) Cardiac relaxation is driven by SERCA and plasma membrane channels (also requires very large amounts of ATP) Modifying cardiac contractile pathways can significantly reduce demand.  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  PKA mechanism of modulating 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. Other kinases are involved in this coordinated response: ex CamKII, but PKA is major player.  Summary of Cardiac contractile mechanisms Signaling mechanisms of cardiac contraction: 1 action potential 2 plasma membrane Ca++ channels (L-type) 3 Sarcoplasmic Ca release through ryanodine receptor 4 Ca++ binding troponin C 5 resequestration of Ca++ by SERCA Increases in cardiac contractility and cardiac output caused by β-AR signaling β-AR, g protein coupled receptor Activation of adenylate cyclase AC makes cAMP and activates PKA PKA phosphorylates multiple targets to increase Ca signaling RyR, phospholamban (PLB) and others.  Oxygen consumption/demand: Its all electron transport in mitochondria. These steps require large amounts of ATP https://www.youtube.com/watch?v=LQmTKxI4Wn4 Myocardial Wall Stress and O2 consumption Law of LaPlace LV wall Stress = (LV pressure X radius)/ 2 x LV wall thickness Is a factor in both preload (increased by preload) and afterload (increases afterload)  Summary of SIHD pathopysiology SIHD is a problem of Oxygen Supply vs Oxygen Demand in the most energetically demanding organ. Demand is increased by increases in: heart rate, preload Wall Stress afterload contractility Supply is increased by: vasodilation, coronary flow Lower heart rate O2 content of blood. Summary Coronary Circulation and O2 demand Coronary circulation provides O2 to the energetically demanding cardiac muscle. Factors that increase cardiac output will increase cardiac O2 demand Factors that cause the heart to work harder (afterload, HR, etc) will increase O2 demand O2 supply in the coronary circulation can be modified by increased vasodilation and reduced contraction/HR Lowering O2 demand in the heart and increasing O2 supply is the goal of pharmacological interventions in stable ischemic heart disease