198 SECTION IV Pediatric Critical Care Cardiovascular with increased stroke volume provided that there is no concomi tant increase in afterload 147 Usually, infusion of fluid into an animal causes art[.]
198 S E C T I O N I V Pediatric Critical Care: Cardiovascular with increased stroke volume provided that there is no concomitant increase in afterload.147 Usually, infusion of fluid into an animal causes arterial pressure to rise, and the increased afterload tends to inhibit the increase in stroke volume that would otherwise occur.147–149 Immediately after birth, there is a significant increase in total body oxygen consumption and cardiac output to about twice its later values (per unit body size).150 This increase has been related to an increase in adrenergic receptors stimulated by fetal thyroid hormones.151 In addition, because approximately 80% of the infant’s hemoglobin is in the form of fetal hemoglobin at birth, the reduced ability of this hemoglobin to unload oxygen at the tissue level compels the infant to have a higher cardiac output than the infant will have to weeks later.150 Therefore, the neonate has limited cardiac output reserve and the heart has near-maximal contractility.152,153 These features make the neonate unusually susceptible to diseases that impair cardiac function However, the Frank-Starling mechanism is intact at this time.154 Evidence indicates that b-adrenoceptor stimulation helps the neonatal ventricle adapt to volume loads.155 Thus b-adrenoceptor blockade might be expected to be much more harmful in the neonate than in the older person with minimal sympathetic tone Myocardial Metabolism: Normal Myocardial Energy Metabolism Basic Metabolic Processes Basal metabolic processes can be studied by measuring oxygen uptake, production of heat, or utilization of high-energy phosphates Isolated papillary muscle and whole-heart preparations reveal that most oxygen consumed generates force (internal work) Approximately 15% is used for shortening (external work), 20% for basal metabolic processes (protein synthesis, sarcolemmal sodium-potassium transport), and 10% for activity of sodiumpotassium adenosine triphosphatase and calcium-adenosine triphosphatase.156–159 The myocardium consumes approximately to 10 mL oxygen/100 g muscle per minute under basal conditions Potassium-induced cardioplegia reduces myocardial oxygen consumption, but “resting” cardiac muscle still consumes more than five times as much oxygen as does resting skeletal muscle During maximal exercise, the myocardium may consume as much as 60 to 80 mL oxygen/100 g muscle per minute.160 Cardiac energy generated by oxidizing substrates to carbon dioxide and water is both used and stored with most of the stored energy in the form of ATP When needed, ATP breaks down to adenosine diphosphate or adenosine monophosphate and releases energy for contractile or transport processes.161 Substrates for energy production can be glucose, lactate, or fatty acids,162 with the b-oxidation of long-chain fatty acids being the preferred substrate except in the neonatal myocardium l-Carnitine is essential for fatty acid transport across the mitochondrial membrane After fatty acids enter the cell, they are activated to fatty acid (or acyl) coenzyme A (CoA) compounds by palmitoyl-CoA synthetase, then linked by carnitine palmitoyl transferase I to carnitine to form acylcarnitines, thus releasing CoA Acylcarnitines cross the mitochondrial membrane and, at the inner surface of the membrane, carnitine palmitoyl transferase II transfers the fatty acids back to CoA The fatty acids can then undergo b-oxidation to produce ATP Fetuses and neonates have decreased activity of carnitine palmitoyl transferase and palmitoyl-CoA synthetase Thus, glucose, lactate, and short-chain fatty acids are the preferred myocardial energy substrates.3,163 Ischemia of heart or skeletal muscle depletes carnitine, as does chronic congestive heart failure.164,165 Carnitine supplementation in these states may be appropriate Increases in plasma fatty acid concentration in fasting or sympathetic stimulation suppress oxidation of carbohydrates by the heart.64,162 Therefore, lactate consumption or extraction cannot be used as an accurate guide to cardiac metabolism unless the concentration of fatty acids is also evaluated.166 ATP is usually generated by oxidative phosphorylation; however, when oxygen supply is restricted, ATP can be generated by anaerobic glycolysis Accumulation of the byproducts of glycolysis inhibit key enzymes and interfere with further ATP production Therefore, the myocardium is unable to build an oxygen debt without further depressing energy production and contractility More than 30% of the myocardial mass is mitochondria, highlighting the importance of oxidative metabolism to the heart.156 Studies of the fetal heart in ovine models reveal that fetal ventricles and adult left ventricles have similar oxygen consumption Because fetal oxygen content is lower, myocardial blood flow per unit mass is about twice as high in the fetus as in the adult.167,168 Oxidative capacity is lower and glycogen stores and glycolytic flux are higher in the fetal heart This may explain why the immature heart is more resistant to hypoxemia, provided that an adequate supply of glucose is available for glycolysis The main substrates used by the fetal heart are glucose, lactate, and pyruvate, although ketones, amino acids, and short- and medium-chain fatty acids also can provide energy.169 For these reasons, prolonged severe hypoglycemia can seriously depress cardiac function in the neonate but is unlikely to so in the older person Determinants of Myocardial Oxygen Consumption In 1958, Sarnoff and Mitchell170 found that the area under the LV pressure curve in systole (termed the tension-time index) correlates with LV oxygen consumption; later work has found peak wall tension (or stress) to be an even better predictor171–174 because of the importance of wall thickness and ventricular dimensions to wall stress Increases in contractility or heart rate increase myocardial oxygen consumption However, because they decrease ventricular size and thus wall stress, effects on oxygen consumption are mitigated.175 Stroke volume is also a predictor of myocardial oxygen consumption.25,176–179 This relationship can be assessed using the area within the pressure-volume loop This approach has been extended by Suga and colleagues111,180–185 to note that inclusion of the area representing end-systolic pressure energy (Fig 23.6) leads to a more accurate model Subtracting contributions of basal myocardial metabolism shows that the oxygen consumption–pressure-volume area (PVA) relationship is independent of contractile state Further studies showed that PVA-independent oxygen consumption is a function of contractility, defined by Emax Certain interventions—for example, acidosis— made the slope of this relation between PVA-independent oxygen consumption to Emax steeper, reflecting decreased efficiency of the system Myocardial Oxygen Demand-Supply Relationship Myocardial oxygen demand is roughly proportional to ventricular systolic pressure and the duration of systole, which can be represented by the area under the real-time pressure curve of the ventricle in systole: the systolic pressure-time index (SPTI).186,187 The SPTI is dramatically influenced by cardiac afterload and the correlation between the SPTI and myocardial oxygen demand is CHAPTER 23 Structure and Function of the Heart PE ED D Volume PVA Control Emax B O2 consumption O2 consumption A V0 PVA Increased Emax E-C coupling E-C coupling Basal Basal E ED ED C Volume Pressure-volume area P VA V0 Volume PVA-independent O2 consumption EW V0 ES Pressure ES Pressure Pressure ES 199 F Emax • Fig 23.6 Relationship of myocardial oxygen consumption to the pressure volume area (PVA) (A) Ven- tricular pressure-volume loop with pressure plotted on the ordinate and volume on the abscissa Arrow shows the direction of inscription of the loop (B) Shaded area to the left of the pressure-volume loop in the pressure-volume diagram represents potential energy (PE) (C) Total area (PVA) is the sum of the external mechanical work area (EW) and the potential energy area (PE) (D) PVA is linearly proportional to oxygen consumption, but some oxygen consumption is independent of PVA The PVA-independent oxygen consumption shown below the upper horizontal line results from excitation-contraction (E-C) coupling and basal oxygen consumption (E) When contractility is increased, as indicated by the increased value for maximum elastance (Emax), the relationship between PVA and oxygen consumption is unchanged, but PVA-independent oxygen consumption increases (F) Relationship between Emax and PVA-independent oxygen consumption is linear With myocardial depression, the slope of this relationship is steeper (dashed line) Thus, for any value of Emax, PVA-independent oxygen consumption is increased so that myocardial efficiency is reduced ED, End-diastolic pressure-volume line; ES, line of end-systolic pressure-volume points (end-systolic elastance); EW, area representing external mechanical work; V0, unstressed ventricular volume imperfect because it does not account for wall stress.188 Because LV myocardial perfusion is restricted to diastole (see Chapter 24), myocardial oxygen supply is proportional to both duration of diastole and myocardial perfusion pressure in diastole In general, diastolic myocardial perfusion pressure can be represented graphically as the difference between superimposed aortic and LV pressure curves The area between these curves, from the instant of aortic valve closure in diastole to reopening of the aortic valve in systole, has been termed the diastolic pressure-time index (DPTI) and is proportional to subendocardial blood flow When multiplied by arterial oxygen content, this index correlates with subendocardial oxygen supply.189 The DPTI arterial oxygen content/SPTI ratio (Fig 23.7) is a fair indicator of myocardial oxygen balance At critical levels, subendocardial ischemia occurs.186,187 This ratio is worsened by tachycardia, which shortens diastole and the duration of myocardial perfusion, by elevation of end-diastolic pressures in the ventricles or by elevation of coronary sinus pressure It is adversely affected by low aortic diastolic pressure (as in shock, aortic valve insufficiency, or other large diastolic runoff lesions) and by elevated ventricular systolic pressure (as in aortic stenosis, systemic hypertension, or pulmonary hypertension) The ratio is favorably affected by balloon aortic counterpulsation, which elevates aortic diastolic pressure and reduces systolic afterload Given the imperfect SPTI • Fig 23.7 The DPTI systolic pressure time index (SPTI) reflects myocardial work and oxygen demand The diastolic pressure time index (DPTI) reflects myocardial blood flow (Modified from Fuhrman BP Regional circulation In: Fuhrman BP, Shoemaker WC, eds Critical Care: State of the Art, vol 10 Fullerton, CA: Society of Critical Care Medicine; 1989.) 200 S E C T I O N I V Pediatric Critical Care: Cardiovascular nature of this ratio, too much emphasis should not be placed on any given value, but two points are clear: (1) a fall in the ratio moves toward a supply-to-demand imbalance, and (2) any ratio less than the 8.9 that typifies normal subjects likely indicates myocardial ischemia.190 Effects of Myocardial Ischemia on Cardiac Function and Metabolism Ischemia indicates inadequate flow to supply the demand for oxygen by an organ or tissue and reduced clearance of metabolites,191,192 which distinguishes ischemia from hypoxemia, in which there is a normal flow with decreased oxygen delivery Because the heart cannot sustain an oxygen debt, inadequate oxygen supply rapidly decreases energy supply to the myocytes, which cease to contract normally If a branch of the left coronary artery is severely narrowed or occluded acutely, within to 15 seconds the myocardium supplied by that branch stops contracting, turns blue, bulges, and thins during each systole In global ischemia, the subendocardial muscle is affected first because it has the lowest coronary flow reserve.193–195 Temporary imbalance of supply and demand leads to two patterns of response depending on the duration of the ischemia If a branch coronary artery is occluded for 15 to 30 minutes and then the occlusion is removed, flow returns to normal rapidly, but the muscle may not contract normally for many hours This phenomenon is known as reperfusion injury or stunning.196–199 It should be distinguished from the “no reflow” phenomenon in which, after a longer occlusion, release of the occlusion is followed by incomplete restoration of flow because of myocardial edema, cell swelling, plugging by neutrophils, and endothelial damage Stunning may occur after prolonged cardiopulmonary bypass surgery with cardioplegia and may account for some of the cardiac depression that is observed in the early postoperative recovery period.200,201 Chronic ischemia of moderate severity causes myocardial hibernation, an adaptive response that leads to metabolic downregulation and reduction of flow without extensive cell death.202–205 Regional function is reduced, but restoration of flow leads to functional recovery This phenomenon is best known from studies of coronary artery disease but can be present in some children with normal coronary arteries and subendocardial ischemia Chronic imbalance of oxygen supply and demand leads to death of the affected muscle cells, producing either a localized infarct or diffuse, perhaps patchy, subendocardial fibrosis as occurs commonly with severe aortic stenosis, cyanotic heart disease, or dilated cardiomyopathy Systemic Vasculature General Anatomy The large arteries are elastic, with the media containing concentric lamellae of perforated elastic tubes crosslinked by transverse collagen (type III) and smooth muscle.57,206 When smooth muscle contracts, the wall becomes stiffer Smaller arteries have fewer lamellae The media are bounded by the external and internal elastic laminae, beyond which are the adventitia with nerves and vasa vasorum and the intima with sparse fibrous tissue and a metabolically active endothelium, respectively Arterioles have no lamellae and only a thin media with circular or spiral smooth muscle; the only elastic tissue is in the inner and outer elastic laminae Capillaries are thin walled and nonmuscular, ideal for transport of materials into and from the tissues However, they contain pericytes that have myosin, actin, and tropomyosin and might have some contractile function Veins have medial muscle but thinner walls relative to lumen diameter than arteries Their endothelium may have different properties The numerous extracellular matrix components are reviewed by Buga and Ignarro.207 The developmental aspects of blood vessels are reviewed by Stenmark and Weiser.208 Physiologic Mechanisms General Features Although large arteries are regarded as conduits and capillaries as vessels allowing transport of substances to and from the tissues, many substances can move across arterial walls Oxygen and carbon dioxide can diffuse across arteriolar walls, and lipoproteins can penetrate the walls of large arteries Whether atheromatous deposits form in arteries depends on the balance of lipoprotein that enters and leaves the arterial wall This balance depends on the concentration and chemical nature of lipoproteins and the action of components of the wall, such as glycosaminoglycans, in binding altered lipoprotein molecules and preventing their transit through the wall Arteriolar tone controls peripheral resistance and, with cardiac output, determines blood pressure and regional flow Regions of the circulation may differ markedly in their patterns of vascular regulation A potent stimulus for increased vascular resistance in one region of the circulation may have a different effect in another For example, during hemorrhagic shock, flow is maintained to the heart and brain but is reduced to muscle, kidneys, and the gut Venous and venular tone, together with diuretic and antidiuretic factors, determine blood volume and venous pressure The two active components of the systemic circulation are the medial smooth muscle and the endothelium They both have receptors for innumerable agonists and antagonists that diffuse from autonomic nerve endings, circulate from remote regions, or are produced locally The smooth muscle is responsible for vasoconstriction or vasodilation The vascular endothelium is one of the metabolic powerhouses of the body Endothelial cells have several major functions: They play important roles in the response to injury by causing leukocyte adhesion and extravasation.209,210 They are intimately bound up with coagulation208,210 by virtue of the production of procoagulant (e.g., platelet-activating factor [PAF], von Willebrand factor, fibronectin, and factors V and X) and anticoagulant factors (e.g., heparin, dermatan sulfate, thrombomodulin, ectonucleotidase) and by the production of nitric oxide and PGI2, which inhibit platelet aggregation and degranulation They regulate capillary permeability by producing ET-1 (increase) or PGE1 (decrease) and respond with increased plasma leakage to substances such as bradykinin, histamine, thrombin, oxygen radicals, and PAF.211 They regulate smooth muscle contraction in response to shear stress in keeping with an overriding principle that shear rate must be kept constant within narrow limits to prevent endothelial damage.212 Control of Vascular Tone In general, regional circulations regulate their flow to obtain the required amounts of oxygen and nutrients Vasomotor tone is strongly influenced by several mechanisms: (1) innervation and neural processes, (2) circulating endocrine and neuroendocrine mediators, (3) blood gas composition, (4) local metabolic products, (5) endothelial-derived factors, and (6) myogenic processes CHAPTER 23 Structure and Function of the Heart Receptors responsive to neural products (norepinephrine, acetylcholine, neuropeptides) are found throughout the circulation Nevertheless, innervation and receptor distributions are organ specific, which allows rapid, patterned, coordinated redistribution of blood flow and an orchestrated response to hypoxia, postural changes, and hemorrhage Although these receptors respond to circulating agonists (including angiotensin II and adrenal epinephrine) and to those liberated locally, they are generally associated with innervation by autonomic nerves In general, presynaptic a-adrenergic stimulation causes norepinephrine release and vasoconstriction b-Adrenergic stimulation generally causes vasodilation Cholinergic stimulation generally causes vasodilation In all organs, sensory and efferent nerve endings contain nonadrenergic, noncholinergic peptides, for example, neuropeptide Y, VIP, calcitonin gene-related peptide, and substance P.213–225 Neuropeptide Y is co-localized and released with norepinephrine,226 and VIP is co-localized with acetylcholine and released upon stimulation of vagal nerve endings Most of these peptides, except neuropeptide Y, are vasodilatory and they help modulate blood pressure and regional flows Humoral regulators of vascular tone and blood volume include angiotensin, adrenomedullin, aldosterone, arginine vasopressin (AVP), bradykinin, histamine, serotonin, thyroxine, natriuretic peptides, and various reproductive hormones Most of these regulators have both direct effects and secondary effects, which tend to be organ specific or regional They often have altered concentrations in hypertension, congestive heart failure, or shock, and their antagonists are used in therapy Some agents—such as histamine, serotonin, and thyroxine—probably affect peripheral resistance only in abnormal states and are not physiologic regulators Angiotensin plays a special role in the homeostasis of blood pressure Its concentration increases in hemorrhagic or hypovolemic shock, following increased renal production of renin that produces angiotensin I from angiotensinogen Angiotensin I is converted to active angiotensin II by angiotensin-converting enzyme (ACE) in the endothelium, especially in the pulmonary vessels However, angiotensin II is also produced locally in the heart and vessel walls by renin that enters from the blood and perhaps by other local proteases.227,228 It causes generalized vasoconstriction in both systemic and pulmonary circulations, but locally it stimulates the release of vasodilating prostaglandins in the lung and kidney Angiotensin II, via angiotensin I receptors, plays a role in cardiac and smooth muscle cell hypertrophy In excess, it results in cardiac inflammation, fibrosis, and apoptosis.229–232 Adrenomedullin, originally found in pheochromocytomas, is produced in many normal cell types, including endothelium Among its many actions are long-lasting vasodilation and diuresis.233,234 Its release may be stimulated by ET-1 It may play a role in treating heart failure.235 Aldosterone, known primarily for its effect on sodium absorption and potassium excretion, has indirect central effects on blood pressure.236–238 Its concentration increases when renin release is stimulated In patients with congestive heart failure, its decreased breakdown in the liver accounts for high blood concentrations, which are harmful to the heart and blood vessels Inhibition of aldosterone by spironolactone may have great clinical value.237,239,240 AVP, which is released from the axonal terminals of magnocellular neurons in the hypothalamus, causes vasoconstriction by stimulating VP1 receptors However, at low concentrations, AVP 201 dilates coronary, cerebral, and pulmonary vessels It is an antidiuretic hormone that acts on VP2 receptors in the renal collecting ducts.241 Its concentration is low in septic shock, with ventricular arrhythmias, and after cardiac surgery242 but is increased in myocardial and hemorrhagic shock, congestive heart failure, and liver cirrhosis.102,241,243 Selective AVP antagonists promote free water excretion without concomitant electrolyte excretion.243–246 Bradykinin is a potent pulmonary and systemic vasodilator released locally by the action of proteolytic enzymes on kallikrein after tissue injury.247–250 Bradykinin is metabolized by kininase II, which is the same as ACE Thus, ACE inhibitors not only reduce angiotensin II production but also increase bradykinin concentrations Bradykinin also causes endothelial cell release of tissue-type plasminogen activator.251 The natriuretic peptides are released from the heart when it is distended in congestive heart failure They cause vasodilation and increased diuresis A-natriopeptide (mainly from atria) and Bnatriopeptide (from ventricles) are released from myocardial cells, and C-natriopeptide is released from cardiac endothelium.252–256 These natriopeptides and the kinins are broken down by neutral endopeptidase Inhibition of this breakdown combined with inhibition of ACE by vasopeptidase inhibitors (e.g., omapatrilat) greatly augments vasodilation.257–262 Tissue levels of oxygen and carbon dioxide reflect adequacy of perfusion and oxygen delivery These blood gases are potent determinants of regional blood flow and have effects that differ among regions of the circulation They also have a more general effect mediated by carotid chemoreceptors Local metabolic regulation of vasomotor tone provides an ideal homeostatic mechanism whereby metabolic demand can directly influence perfusion For instance, adenosine, which accumulates locally when tissue metabolism is high and tissue oxygenation is marginal, causes pronounced vasodilation in the coronary, striated muscle, splanchnic, and cerebral circulations Cerebral autoregulation has been suggested to take advantage of local metabolite production as an indicator of adequacy of blood flow The perivascular concentration of these metabolites is restored to normal as flow rises, washing out the metabolites Potassium is released from muscle in response to increased work, ischemia, and hypoxia.262 Hypokalemia causes vasoconstriction.263,264 Hyperkalemia, within the physiologic range, causes vasodilation by stimulating Kir channels.265–267 Many of the agents previously discussed are produced locally and are effective as circulating hormones The endothelial lining of blood vessels plays a prominent role in the regulation of vascular tone.268 Endothelium-derived relaxing factor (EDRF) has been identified as nitric oxide.269 Nitric oxide is a potent vasodilator released from endothelium after stimulation and accounts for some or all of the activity generally ascribed to other agonists Nitric oxide is released from endothelium when flow increases, an example of positive feedback Nitric oxide increases smooth muscle soluble guanylate cyclase activity, raises muscle cyclic GMP, and thereby relaxes vascular smooth muscle In addition to EDRF, endothelial-derived hyperpolarizing factors, which are probably epoxyeicosatrienoic acids and hydrogen peroxide, are now thought to play major roles The hydrogen peroxide is produced by the action of superoxide dismutase on superoxide anions that are generated by the metabolism of ATP.270 The vascular endothelium elaborates the endothelins (ET-1, ET-2, ET-3), a family of compounds that are vasoactive, structurally related peptides ET-1 is the most potent vasoconstrictor known It also promotes mitogenesis and stimulates the renin-angiotensin-aldosterone 202 S E C T I O N I V Pediatric Critical Care: Cardiovascular system and the release of vasopressin and atrial natriuretic peptide.237,271–276 Endothelin antagonists, such as bosentan, are being used, specifically in the setting of pulmonary arterial hypertension.277,278 Myogenic responses of vessels are changes in smooth muscle tone in response to stretch or increased transmural pressure An increase in inflow pressure causes a rise in vessel wall tension and transmural pressure279 that causes localized vasoconstriction The reverse occurs when inflow pressure falls The mechanisms of this response are complex As expected, a complex interplay exists among myogenic, flowmediated, and metabolic regulation of vessel tone.280 The relative importance of these mechanisms likely varies in different vascular beds Autoregulation In all organs, when inflow pressure is suddenly raised or lowered while oxygen consumption remains constant, flow rises or falls transiently but then returns to the earlier value The phenomenon is termed autoregulation Myogenic tonic response is partly responsible for this phenomenon, but it is not the only mechanism Some investigators believe that tissues have oxygen sensors that respond to transient increases or decreases in oxygen supply.281–283 Others believe that the process is mediated by greater or lesser release of nitric oxide carried to the tissues by hemoglobin in the form of S-nitrosohemoglobin or by ATP release by red blood cells.283–288 Carbon monoxide produced by the action of hemoxygenase in endothelium and smooth muscle may play a regulatory role.289–296 Key References Anderson PAW Immature myocardium In: Moller JH, Neal WA, eds Fetal, Neonatal, and Infant Cardiac Disease Norwalk, CT: Appleton & Lange; 1992 Buga GM, Ignarro LJ Vascular endothelium and smooth muscle function In: Gluckman PD, Heymann MA, eds Pediatrics and Perinatology The Scientific Basis London: Edward Arnold; 1996 Colan SD, Borow KM, Neumann A Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load-independent index of myocardial contractility J Am Coll Cardiol 1984;4:715-724 Friedberg MK, Redington AN Right versus left ventricular failure: differences, similarities, and interactions Circulation 2014;129:1033-1044 Hoffinan JI, Buckberg GD The myocardial supply: demand ratio—a critical review Am J Cardiol 1978;41:327 Hoffman TM, Wernovsky G, Atz AM, et al Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease Circulation 2003;107:996-1002 Katz AM Contractile proteins in normal and failing myocardium In: Braunwald E, ed The Myocardium: Failure and Infarction New York: HP Publishing; 1974 Ross Jr J Mechanisms of cardiac contraction What roles for preload, afterload and inotropic state in heart failure? Eur Heart J 1983;4(suppl A):19 Sagawa K The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use Circulation 1981;63:1223 Santamore WP, Dell’Italia LJ Ventricular interdependence: significant left ventricular contributions to right ventricular systolic function Prog Cardiovasc Dis 1998;40:289-308 Smith VE, Zile MR Relaxation and diastolic properties of the heart In: Fozzard HA, et al., eds The Heart and Cardiovascular System: Scientific Foundations New York: Raven Press; 1991 Strauer BE Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve Am J Cardiol 1979;44:730-740 Suga H Ventricular energetics Physiol Rev 1990;70:247 Tyberg JV, Grant DA, Kingma I, et al Effects of positive intrathoracic pressure on pulmonary and systemic hemodynamics Respir Physiol 2000;119:171-179 Tynan MJ, Becker AE, Macartney FJ, Jiménez MQ, Shinebourne EA, Anderson RH Nomenclature and classification of congenital heart disease Br Heart J 1979;41:544-553 The full reference list for this chapter is available at ExpertConsult.com ... artery is severely narrowed or occluded acutely, within to 15 seconds the myocardium supplied by that branch stops contracting, turns blue, bulges, and thins during each systole In global ischemia,... Arterioles have no lamellae and only a thin media with circular or spiral smooth muscle; the only elastic tissue is in the inner and outer elastic laminae Capillaries are thin walled and nonmuscular, ideal... indicator of myocardial oxygen balance At critical levels, subendocardial ischemia occurs.186,187 This ratio is worsened by tachycardia, which shortens diastole and the duration of myocardial perfusion,