193CHAPTER 23 Structure and Function of the Heart Myocardial Mechanics Integrated Muscle Function Relationship Between Muscle Strips and Intact Ventricles With preload, stretching a muscle strip is eq[.]
CHAPTER 23 Structure and Function of the Heart Myocardial Mechanics: Myocardial Receptors and Responses to Drugs Cardiac myocytes express a- and b-adrenoceptors that mediate the responses to endogenous and exogenous catecholamines and therefore are involved in the rapid regulation of myocardial function They can also be inhibited by adrenergic-blocking agents such as b-blockers and are a target in treating heart failure and arrhythmias a1-Adrenoceptors appear early in gestation and in many species reach their highest density in the neonate.3,4,72 In contrast, b-adrenoceptors increase progressively with age b1, b2, and b3 are present on myocytes, but b1-adrenoceptors are described as the predominant receptor subtype in cardiac myocytes.73,74 In addition, histamine H2, vasoactive intestinal polypeptide (VIP), adenosine A1, acetylcholine M2, and somatostatin receptors have been identified They act on the myocyte’s contractile apparatus through one of two main pathways The major pathway involves membrane-bound receptor–G protein–adenylate cyclase complexes G proteins include the Gs (stimulatory) and Gi (inhibitory) proteins.75 When agonists stimulate b-adrenergic receptors, the G proteins undergo a conformational change The changes induce the Gs protein to exchange its guanosine diphosphate (GDP) for guanine triphosphate (GTP) The Gs-a-GTP complex interacts with adenylate cyclase to convert ATP to cyclic adenine monophosphate (cAMP), which activates a variety of protein kinases to phosphorylate proteins, including voltage-dependent calcium channels, phospholamban, and troponin I Consequently, calcium entry during depolarization and during uptake of calcium into the sarcoplasmic reticulum storage pool is increased, thus increasing contractility The Gs-a-GTP complex has intrinsic GTPase activity that converts GTP to GDP In this way, as long as receptors are occupied by the agonist, the Gs cycle produces increasingly more cAMP, amplifying the stimulatory signal The Gi protein complex undergoes a similar cycle when adenosine or acetylcholine receptors are stimulated However, activating Gi protein reduces cAMP formation and decreases contractility b2-adrenergic receptors also couple to Gi in addition to Gs.76 Gi in this context is thought to oppose the effects of Gs to some degree, including limitation of the acute positive inotropic response to adrenergic stimulation and offering some protection from apoptosis.77–79 In heart failure, the number of b1-adrenergic receptors are downregulated, and b2-adrenergic receptors are uncoupled from G proteins.35,73,74,80,81 These changes make the myocardium less responsive to circulating or locally released catecholamines and play a role in the reduced contractility observed in heart failure Treating heart failure with b-adrenergic blocking agents has been shown to reverse the receptor changes and has also been associated with improved function of muscle strips in adult patients.82–85 b3-adrenoceptors, the minor isoform in the heart, can activate different signaling pathways; their role in heart failure therapy is a recent topic of study.86,87 Milrinone is an agent that stimulates contractility by inhibiting phosphodiesterases and increasing cAMP Although previously thought to be ineffective in the newborn,88 a multicenter randomized trial89 and subsequent widespread use has confirmed its efficacy in the neonatal population.90,91 Because contractile mechanisms are almost fully developed at birth, the majority of mechanisms controlling contractility (except for changes in the source of calcium) are in place at birth 193 Myocardial Mechanics: Integrated Muscle Function Relationship Between Muscle Strips and Intact Ventricles With preload, stretching a muscle strip is equivalent to end-diastolic fiber length of the intact ventricle This length can be measured by various devices in animals; however, in the intact human ventricle, it is best related to end-diastolic diameter or volume Frequently, end-diastolic pressure has been used interchangeably with enddiastolic volume as an index of preload, but this usage can be misleading if the distensibility of the ventricle changes or if pressure outside the heart (pericardial or intrathoracic) rises.92–95 Afterload is more complicated in the intact ventricle, commonly defined as the pressure or load against which the heart contracts to eject blood Often, aortic systolic pressure is equated with afterload However, in the muscle strip, afterload represents the force exerted by the muscle during contraction; in physical terms, force pressure area.71,96–98 Therefore, afterload accounts for the distribution of pressure over the surface to which the force is applied When the force is applied to a thick spherical chamber, it is more accurately described by the Laplace wall stress relationship: Wall Stress ( ) Pr 2h where P is the transmural pressure across the wall of the chamber, r is radius of curvature, and h is wall thickness Because the left ventricle is not a regular sphere, particularly in systole, the Laplace formula is an oversimplification.99 A fairly simple and accurate formula was developed by Grossman and colleagues100: Wall Stress ( ) Pr h 2h 2r Note that if the left ventricle dilates acutely, wall stress rises markedly because r gets bigger and h gets smaller The major findings from studies of muscle strips have been confirmed in intact ventricles Increasing preload increases the pressure generated by an isolated ventricle that is not allowed to eject, as observed in the 20th century by Otto Frank If the ventricle is allowed to eject, then increased preload allows the heart to eject the same stroke volume against an increased afterload or to eject a greater stroke volume against a constant afterload This is the Starling component of the Frank-Starling law.101,102 The mechanism of this response is twofold: (1) lengthening the sarcomere places the myosin and actin fibrils closer together for stronger interaction and (2) increased calcium sensitivity is mediated in some way by titin stretching.30 Therefore, stretching the sarcomere to its optimal length (see Fig 23.3C) will increase contractility Beyond that length, further stretching (or preload) can be detrimental as the end-diastolic pressure increases without a significant change in the stroke volume There is evidence that in failing hearts, this relationship between preload and developed tension may be absent.103 The force-frequency relationship is a property of the cardiomyocyte whereby heart rate modifies contractility Heart rates up to an optimal heart rate increase the force of contractility beyond which force decreases The force-frequency relationship can be determined in intact hearts104,105 by examining the response of the S E C T I O N I V Pediatric Critical Care: Cardiovascular Pressure-Volume Loops If LV pressure and volume are measured simultaneously, the resulting pressure-volume loop gives information about ventricular performance and can be used to assess myocardial contractility in the intact heart The modern approach to analyzing these loops is based on the elastance concept of Suga and Sagawa.109–111 Elastance is the ratio of pressure change to volume change (the reciprocal of compliance) Consider an isolated ventricle that can be filled to different volumes At each volume, the ventricle is stimulated to contract and generates a peak systolic pressure (Fig 23.4A) As volumes increase (1 n n 3), so the peak systolic pressures generated, and the relationship is linear (Frank’s law) The line joining the peak pressures intercepts the volume axis at a positive value, termed V0, that indicates the unstressed volume of the ventricle The equation for this line is as follows: Pes E es (Ves V0 ) where Pes is end-systolic pressure, Ees is slope of the line, the endsystolic elastance or the maximum elastance (Emax), Ves is endsystolic volume, and V0 is unstressed volume If contractility increases (more calcium enters the cells), the ventricle can generate greater pressures at any given volume, thereby generating a steeper pressure-volume line (higher value of Ees; purple line I in Fig 23.4A) If contractility decreases, the ventricle generates lower pressures at any given volume, and the pressure-volume line is less steep (lower value of Ees; blue line D in Fig 23.4A) The typical pressure-volume loop shown in Fig 23.4B is characterized by four phases marked by the opening and closing of the AV and arterial valves: diastole starts when the aortic and pulmonary valve close and the ventricular pressures fall owing to muscle relaxation; initially, with the AV valves closed, the isovolumic relaxation phase occurs since both inlet and outlet valves are closed with no change in ventricular volume This phase is followed by opening of the AV valve when atrial pressures are higher than ventricular pressures and initiation of ventricular filling During diastolic filling, volume increases and diastolic pressure rises slightly because of the increase in passive tension At the end of diastole, when the ventricular pressures surpass atrial pressure, AV valves close and isovolumic contraction starts In this phase, ventricular pressure rises with no change in volume When ventricular pressure exceeds aortic pressure, the aortic valve opens, blood is ejected, and ventricular volume decreases Ejection ends, and pressure falls to diastolic levels as isovolumic relaxation occurs and the cardiac cycle restarts The decrease in volume during ejection is the stroke volume, which, divided by the end-diastolic volume, gives the ejection fraction; normally, ejection fraction is greater than 65 If afterload is suddenly increased by raising aortic pressure, the normal heart responds as shown in Fig 23.4B In the first beat after the increase, the ventricle must generate a higher pressure before the aortic valve opens (loop 2; orange line) It then ejects but Pressure I V0 A D Volume I Pressure maximal rate of change of pressure (dP/dt max) in the ventricles after premature beats The results in intact ventricles and muscle strips are similar Subsequently, Seed and colleagues106 applied this technique to humans with normal or abnormal LV function and found an optimal R-R interval of 800 ms This response is mediated by an increase in the intracellular calcium in normal hearts but is limited in the setting of ventricular dysfunction As with preload, the force-frequency relationship may be abnormal in failing hearts.107,108 D EDV V0 B Volume Pressure 194 EDV EDV V0 C I II III Volume • Fig 23.4 Concept of ventricular elastance (A) Isolated ventricle contracting at volumes 1, 2, and 3, generating corresponding pressures Purple line I indicates results at increased contractility Blue line D indicates results at decreased contractility (B) Ventricular pressure-volume loops achieving end-systolic pressures of 1, 2, and at corresponding volumes Purple line I indicates results at increased contractility, with greater endsystolic pressures at each volume Blue line D indicates results at decreased contractility From a given end-diastolic volume, either the same ejection fraction is delivered at a lower end-systolic pressure (dotted line 1) or the same end-systolic pressure is achieved but at a much smaller stroke volume and ejection fraction (line 4) (C) As a consequence of afterload increase, the ventricular end-diastolic volumes (EDV) increase, then stroke volume can be maintained, even though ejection fraction decreases If contractility is decreased (blue line), then stroke volume can be maintained only with increasing end-diastolic pressures 1, 2, 3, Endsystolic volumes and pressures at normal contractility; I, II, III, end-systolic volumes at decreased contractility; V0, resting (unstressed) volume cannot eject the same stroke volume In fact, the end-systolic volume is that which is appropriate for the higher pressure (compare Fig 23.4B, end-systolic volume at and in the orange line) If different afterloads are used, the end-systolic pressure-volume points define a sloping line that is the same as the line obtained in the isolated heart at those same volumes This is the maximal ventricular elastance (Ees) or end-systolic elastance (Ees) line If ventricular contractility increases, then the ventricle can attain higher ejection pressures at any given volume, and the end-systolic pressure-volume points lie on a steeper line that lies above and to the left of the normal line (purple line I in Fig 23.4B) If ventricular contractility decreases, then the end-systolic pressure-volume line lies below and to the right of the normal line (blue line in Fig 23.4B) Note from Fig 23.4B that, from a given end-diastolic volume, the ventricle with impaired contractility can either eject the original stroke volume at much reduced pressures or eject at a normal pressure only by reducing its stroke volume drastically (loop 4) CHAPTER 23 Structure and Function of the Heart In beats that follow a sudden increase in afterload, the ventricles adjust (Fig 23.4C) Because of the reduced stroke volume in the first beat following afterload increase, the end-systolic volume is larger than normal During diastole, however, a normal stroke volume enters the ventricle so that end-diastolic volume increases (loop in Fig 23.4C) In normal ventricles, the increased enddiastolic fiber length causes little increase in diastolic pressure The pressures during ejection and the end-systolic pressurevolume point are unchanged, but stroke volume and ejection fraction increase After a few more cycles, a new equilibrium is established (loop 3) in which the ventricle ejects a normal stroke volume at the higher afterload However, the ejection fraction is subnormal because, although the stroke volume is normal, the end-diastolic volume is increased The ventricle has adapted to the higher afterload by increasing end-diastolic fiber length, a phenomenon described by Starling and discussed by Ross96,97 under the term preload reserve If the ventricle has decreased contractility (dashed loops, blue line in Fig 23.4C), the same pattern of response occurs but with some important differences With decreased contractility, the ventricle cannot eject a normal stroke volume from a normal end-diastolic volume Compensation results in a larger than normal increase in end-diastolic volume, even at normal afterloads Any increase in afterload causes a further increase in end-diastolic volume; this increase causes diastolic pressures to rise to high values that cause pulmonary congestion The normal preload reserve has been used up in the attempt to eject a reasonable stroke volume against a modestly increased afterload In more depressed hearts, even normal afterloads cannot be handled by the ventricle without a pathologically raised diastolic pressure in the ventricles or a drastic decrease in stroke volume Note that in these hearts, because of the relatively flat slope of the maximal ventricular elastance line, a slight reduction of afterload produces a relatively large increase in stroke volume and a relatively large decrease in ventricular end-diastolic volume and pressure This is one of the mechanisms for cardiac improvement with afterload reduction in the setting of systolic dysfunction The normal RV pressure-volume curve is triangular, unlike the more rectangular LV pressure-volume curve described earlier.112 This difference is accounted for by a relative lack of isovolumic contraction and relaxation times in the right ventricle The normally low afterload of the right ventricle and the high compliance of the outflow portion of the ventricle allow ejection to begin almost instantaneously after the onset of contraction and proceed through pressure decline so that there is near complete emptying of the ventricle by the end of systole and the ejection time of the right ventricle thus spans the entire period of systole An important consequence of this relationship is that even small increases in RV afterload begin to make the RV pressure-volume curve resemble the normal LV pressure-volume curve, with isovolumic contraction and relaxation times becoming more prominent.113 Ejection fraction is reduced, although stroke volume may be maintained due to RV dilation,114 and the thin-walled right ventricle may handle this new physiology quite poorly Assessing Myocardial Contractility: Systolic Ventricular Function An index of contractility must reflect the ability of the ventricle to perform work independent of changes in preload and afterload Contractility can be defined as the alterations in cardiac function that occur secondary to changes in cytosolic calcium availability or sarcomere sensitivity to calcium Thus, b-adrenergic agonists or phosphodiesterase inhibitors, which increase cytosolic calcium, 195 are positive inotropic agents However, quantifying contractility in the intact heart is difficult115 because all indices of contractility are indices of overall performance of cardiac function and are not independent of loading conditions and heart rate The relationship between loading conditions and contractility is complex since the handling of calcium within the myocyte is influenced by (1) the myocardial fiber length, which, in turn, depends on the preload (Frank-Starling mechanism)116; and (2) afterload, as it has been demonstrated that contractility increases in response to a rise in the afterload.117 Despite these limitations, the methods we currently have to assess contractility can be divided into those occurring in early systole during isovolumic contraction (isovolumic phase indices) and those that occur later, during ejection (ejection phase indices) Isovolumic Phase Indices The maximal rate of change of ventricular pressure (dP/dt max) is achieved during the isovolumic contraction, before the aortic valve opens, and is relatively unaffected by changes in preload It can be measured by invasive pressure tracing or, indirectly, from a continuous-wave Doppler tracing of a mitral regurgitation jet by echocardiography However, the index is markedly affected by changes in afterload Thus, it must be used with caution when afterloads are very different This method is more useful for measuring acute changes in contractility than for assessing absolute contractility Ejection Phase Indices The index of contractility most commonly used today is the maximal (end-systolic) ventricular elastance of Suga and Sagawa, which is defined by the slope of the end-systolic pressure-volume relationships Measurements must be obtained at several different levels of afterload, and either ventricular volumes must be measured or echocardiographic dimensions must be used as substitutes for volumes.71,98 Several studies have shown that the maximal elastance line often is not linear, as previously stated,118,119 but the values of elastance in the midrange of pressures are accurate enough to use the slope of the end-systolic pressure-volume relationship as a parameter of left ventricular contractility.119 The LV end-systolic wall stress-velocity of fiber shortening relation as a single beat index of contractility has also been used This index is not exempted from limitations, which arise from the need to adjust for changes in afterload,120 and single-point determinations are of little use since the relationship is not linear (Fig 23.5).117 Echocardiographic measurements of ventricular function are most commonly used in clinical situations These are load-dependent measurements of contractility These techniques measure global and regional function They can be subdivided into those that are based on dimensional and volume changes (i.e., shortening and ejection fraction, RV fractional area change) and those that are Doppler based (such as dP/dt max).121 M-mode–generated ejection fraction is a popular method used in children to assess LV function noninvasively Even though it is useful, it is a loaddependent measurement and is less accurate in the setting of mitral regurgitation, dysynchrony, regional wall motion abnormalities, and LV dilation (see Chapter 31 for more details) M-mode–derived tricuspid annular plane systolic excursion (TAPSE) is also an easily derived measurement of RV systolic function Cardiac magnetic resonance imaging can be considered as an additional imaging modality if more accurate ventricular volumes and measurements of systolic function are required 196 S E C T I O N I V Pediatric Critical Care: Cardiovascular 1.6 Vcfc = −0.0044 σes + 1.23 r = −0.84 n = 118 Rate corrected Vcf (circ/s) 1.4 +2SD 1.2 Mean −2SD 1.0 0.8 0.6 20 40 60 80 100 120 LV end-systolic wall stress (g/cm2) A * Low afterload B * End-systolic wall stress 1* * Low afterload Normal afterload High afterload Normal afterload High afterload Mean Vcfc * Mean Vcfc Mean Vcfc End-systolic wall stress * End-systolic wall stress • Fig 23.5 (A) Relationship between rate-corrected mean velocity of fiber shortening (Vcf) and left ventricular (LV) end-systolic wall stress (B) Possibility of misinterpreting the relationship between mean velocity of fiber shortening and end-systolic wall stress Left, Data point is more than two standard deviations (SD) above normal relation (taken from left panel), suggesting increased contractility Data point is within the normal range, suggesting normal contractility Middle, Alternative explanation for point is that contractile state is normal, but points obtained at very low afterloads follow a hyperbolic, not a linear, relationship Right, Alternative explanation for point is that contractility is decreased However, because of the hyperbolic relationship and the low afterload, it appears within the “normal” linear range (A, From 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 B, Modified from Banerjee A, et al Nonlinearity of the left ventricular end-systolic wall stress-velocity of fiber shortening relation in young pigs: a potential pitfall in its use as a single-beat index of contractility J Am Coll Cardiol 1994;23:514–524.) Assessing Myocardial Relaxation: Diastolic Ventricular Function Diastolic function refers to the rate and extent of ventricular relaxation.93,122 Many forms of heart disease manifest abnormalities of both systolic and diastolic function, but one or the other form of dysfunction may predominate and impact optimal therapy.123 Diastolic dysfunction results in increased ventricular diastolic pressure at normal or even low ventricular volume122 either from an increase in passive stiffness of the ventricles from chronic infiltrates (e.g., amyloid), myocardial scars, constrictive pericarditis, or diffuse myocardial fibrosis, or from impaired relaxation or AV dyssynchrony Diastolic relaxation of ventricular muscle associated with rapid release of calcium from troponin and its subsequent uptake by the sarcoplasmic reticulum allows actin-myosin cross-bridges to dissociate and the sarcomeres to lengthen, permitting the ventricle to relax Impairment of calcium removal due to abnormalities in major contractile proteins or transport processes decreases the rate and extent of relaxation.69,124 Many heart diseases, including ischemia, impair calcium metabolism and diastolic ventricular function.40,43,105,125 The most common methods to assess diastolic function are invasive measurement of end-diastolic LV pressure in the catheter laboratory or noninvasively by measurements of tissue Doppler indices, ventricular inflow, and systemic and pulmonary venous Doppler profiles Assessing diastolic function noninvasively remains challenging in children.126,127 One can measure diastolic function more accurately using micromanometer-tipped catheters to assess the time constant of diastolic relaxation (Tau), which has been associated with clinically relevant events such as duration of intensive care and hospital stay after the Fontan operation.128 However, this primarily remains a research tool owing to complexity and expense CHAPTER 23 Structure and Function of the Heart Pericardial Function The parietal pericardium is a fibrous membrane that surrounds the heart and is separated from the epicardium by a thin layer of fluid Owing to its nonelastic properties, the pericardium enhances mechanical interactions of the cardiac chambers and limits acute cardiac dilation.129 Thus, if the ventricles enlarge because of sudden volume load or myocardial depression, the pericardium becomes tense and restrains further enlargement of the ventricles.94,95 This is seen with acute myocardial ischemia, where LV diastolic pressure can increase without much change in ventricular volume because of tension from the pericardium In this setting, changes in the diastolic pressure-volume relationship reflect both myocardial stiffness and pericardial constraint.92,93,130–132 Transmural pressure is the difference between intracavitary and extracavitary pressure (intracardiac pressure–pericardial pressure) Pericardial pressure reflects intrapleural pressure during the respiratory cycle,133 which oscillates around –5 cmH2O in a spontaneously breathing patient in the absence of pericardial disease With each inspiration, the pleural pressure becomes more negative and the pericardial pressure drops, which increases cardiac transmural pressure and facilitates filling of the right heart Mechanical ventilation increases pleural and pericardial pressure, reduces transmural pressure and impedes filling of the right heart.134 This reduction in transmural pressure is detrimental for right heart filling but decreases both ventricular and aortic transmural pressure, decreasing wall stress/afterload and therefore improving stroke volume In volume-replete patients, increased intrathoracic pressure will primarily assist the left ventricle However, this benefit may be lost or it may even be detrimental to use positive-pressure ventilation in the volume-depleted patient This afterload reduction and a decrease in metabolic demands due to less respiratory effort are the basis of using positive pressure, either noninvasive or invasive, ventilation in the setting of heart failure.135 Furthermore, in those with significant work of breathing, such as patients with pulmonary edema, the inspiratory pleural pressure is likely to be much more negative than in healthy people This serves to significantly increase LV transmural pleural pressure and potentially make the use of positive-pressure ventilation more beneficial Ventricular Interactions Ventricular interactions independent of humoral, neural, or circulatory effects are called ventricular interdependence and can be divided into diastolic and systolic ventricular interactions.131,136 They occur because of anatomic associations between the ventricles, interventricular septum as a shared septal wall, and enclosure within the pericardium In normal circulation, diastolic ventricular interactions are responsible for changes in the pulse pressure during spontaneous ventilation During inspiration, RV filling and volume increase, and the septum moves slightly toward the left, increasing LV enddiastolic pressure and decreasing LV end-diastolic volume and therefore decreasing stroke volume These effects reverse during exhalation, increasing stroke volume This mechanism is the basis of pulsus paradoxus in conditions that accentuate ventricularventricular interactions such as cardiac tamponade or asthma In the failing right ventricle, dilation of the right ventricle pushes the septum to the left, decreasing LV volume and preload and shifting the LV diastolic pressure-volume relationship upward137 and decreasing cardiac output.94,138,139 Increasing LV afterload by manipulation of systemic vascular resistance can potentially counteract septal displacement, improving ventricular-ventricular 197 interactions and overall cardiac output.140,141 In systole, due to the shared interventricular septum, the left ventricle generates 20% to 40% of RV contractility,142 whereas only 4% to 10% of LV systolic pressure is generated by the right ventricle The decrease in cardiac output that occurs with acute RV failure with an intact pericardium is at least partially attributable to a decrease in systolic LV performance.143 Neural Control of the Heart The autonomic nervous system is the major determinant of heart rate in the normal heart, through the balance of sympathetic and parasympathetic tone.144 Sympathetic fibers innervate the atria, ventricle muscles, and the conduction system Sympathetic activation releases norepinephrine through both the autonomic nervous system and humoral adrenaline from the adrenal glands Catecholamines bind to b1-adrenoceptors activating Gs proteins, which results in increased heart rate (chronotropic effect), more rapid AV conduction (dromotropic effect), enhanced contractility (inotropic effect), and faster relaxation (lusitropic effect).145 The parasympathetic acetylcholine fibers mainly innervate the sinus and AV nodes Vagal effects on the heart are mostly demonstrated by changes in heart rate but minimal direct effect on myocardial contractility Parasympathetic stimulation may have an indirect effect on inotropy by reducing effects of circulating catecholamines or sympathetic nerve stimulation Conversely, blockade of muscarinic receptors can intensify the myocardial contractile response to sympathetic stimulation In conscious animals, resting sympathetic tone is low, and parasympathetic tone is high Therefore, sympathetic blockade has little effect on heart rate and myocardial contractility, whereas parasympathetic blockade causes marked tachycardia On the other hand, many anesthetics depress the sympathetic nervous system, leading to acutely decreased contractility and bradycardia The carotid and aortic baroreceptors respond to changes in arterial blood pressure Since basal sympathetic tone is usually low, inhibiting sympathetic tone by raising aortic pressure has little effect on myocardial contractility, whereas a decrease in arterial pressure causes a reflex increase in sympathetic tone, with increases in heart rate and contractility Carotid and aortic chemoreceptors are stimulated by low partial pressure of arterial oxygen, high partial pressure of arterial carbon dioxide, and low pH, but only when changes are significant, and even then the increase in myocardial contractility is modest The fetus seems to be less sensitive than the adult to chemoreceptor stimulation.146 Innervation is not necessary for cardiac function, as evidenced by those who have undergone cardiac transplantation The response to exercise in the denervated heart is limited and mediated by increases in circulating catecholamines and a rise in body temperature In intact animals and humans, b-adrenoreceptor blockade blunts the heart rate increase with exercise and abolishes inotropic response.144 Cardiac Output Cardiac output (CO) is the volume of blood ejected by the heart over one minute; therefore, CO stroke volume (volume ejected per contraction) heart rate (contractions per minute) Cardiac output in the fetus is determined mainly by heart rate because of a limited capacity to increase stroke volume that results mainly from decreased diastolic distensibility Consequently, fetal bradycardia is detrimental to blood flow and oxygen delivery However, the fetal heart can respond to increased preload (Starling’s law) ... Subsequently, Seed and colleagues106 applied this technique to humans with normal or abnormal LV function and found an optimal R-R interval of 800 ms This response is mediated by an increase in... reduced, although stroke volume may be maintained due to RV dilation,114 and the thin-walled right ventricle may handle this new physiology quite poorly Assessing Myocardial Contractility: Systolic... ventricles.94,95 This is seen with acute myocardial ischemia, where LV diastolic pressure can increase without much change in ventricular volume because of tension from the pericardium In this setting,