Diastolic Heart Failure – part 2 pdf

26 T.C. Gillebert and A.F. Leite-Moreira (Figure 2.3, top). Typical examples are the heart in aortic stenosis, the hypertensive heart, and the remodeled heart of the aged subject. The distinction between distensibility, compliance, and cavity size matters, however, when changes in the descriptors of the diastolic PV relation go in opposite directions. This is illustrated by SHF, for example, the ischemic cardiomyopathy (Figure 2.3, bottom). These hearts have an enlarged LV cavity but operate on a steep portion of their PV curve, with small increases in volume leading to sharp increases in diastolic LV pressures. There is an apparent increase in distensibility, 14 which could be explained solely by an increase in the constant A instead of an increase in the intercept P 0 : this actually means an increase in LV size but no increase in LV distensibility. The ventricle operates on a steep portion of the curve because of a combination of overfi lling and decreased compliance of the ventricle. These severely diseased hearts are no more able to work at smaller volumes and respond to exercise, elevated cardiac output, and increased cardiovascular volumes by pulmonary congestion and symptoms. William Little recently referred to this situation as “diastolic dysfunction beyond distensibility,” pointing out that, in addition to distensibility and compliance issues, these hearts developed less elastic recoil and disturbed diastolic acceleration of blood fl ow from the mitral infl ow to the LV apex. 14 For practical purposes, the concept of distensibility/compliance may be simplifi ed to two or slightly more PV combinations allowing calculat- ing a linear slope, ∆P/∆V (operational stiffness) or ∆V/∆P (operational compliance) without assumptions regarding the entire diastolic PV relation. This simplifi ed representation focuses on the clinical relevance of the end-diastolic LV properties. According to Little, the only thing that really matters is the slope of the curve at operating conditions. When this slope is steep, the patients are in a labile balance. Slightly decreased LV volumes will result in decreased cardiac output and impaired tissue perfusion. Slightly increased LV volumes will restore cardiac output but at the expense of elevated fi lling pressures and pulmonary edema. This remains valid regardless of the mechanism of heart failure (systolic or diastolic) and regardless of the size of the ventricle. This discussion focuses on passive material properties of the ventricle of the cardiac chamber. In addition, it is relevant to derive passive tissue, myocardial properties by normalizing chamber stiffness according to chamber geometry. This latter aspect is covered in other chapters of this textbook. In the normal heart, working under normal load and at a normal heart rate, relaxation is completed by end diastole and should not infl uence end-diastolic properties. When relaxation is delayed, when load is abnormal, when diastole is short, or when a combination of these factors concurs, relaxation may interfere to an important extent with fi lling pressures and with end-diastolic LV properties. Considering that relaxation is completed and neglecting extraventricular Pressure (mm Hg) Volume (ml) Pressure (mm Hg) Volume ( ml ) Diastolic heart failure Systolic heart failure FIGURE 2.3. End-dastolic pressure–volume relations in diastolic and chronic systolic heart failure. (Top) The relation is shifted left- ward and upward and is steeper. This is the manifestation of smaller cavity size and reduced compliance. (Bottom) In chronic systolic heart failure, the relation is shifted rightward and is steeper. Cavity size is increased and compliance is reduced. The hallmark of heart failure in both conditions is the reduced compliance and the steep curve accordingly. 2. Myocardial Relaxation and End-Diastolic Stiffness 27 constraint, compliance of the ventricle is determined by (1) ventricular geometry, (2) mechanical myocardial properties commonly alluded to as myocardial stiffness, and (3) myocardial tone. Myocardial tone is a recently expanded concept referring to dynamic aspects of distensibility and stiffness such as titin phosphorylation and neurohumoral modulation of myocardial distensibility. Myocardial Relaxation and Its Time Course Relaxation is the process whereby the myocardium returns to an unstressed length and force. In the normal heart, it comprises the major part of ventricular ejection, pressure fall, and the initial part of rapid fi lling. Left Ventricular Pressure Fall Left ventricular pressure fall is the hemodynamic manifestation of myocardial relaxation. Its analysis allows adequate description of the course of myocardial relaxation. 7 It has a nonuniform course that encompasses two consecutive phases, an initial acceleration and a subsequent deceleration, that are subjected to a distinct regulation by afterload. 3,4 The initial phase starts at peak LV pressure, before aortic valve closure, and ends close to peak rate of LV pressure fall (dP/dt min ). The subsequent phase begins at dP/dt min and can be further subdivided into intermediate and terminal phases by mitral valve opening. The intermediate phase corresponds to the isovolumetric relaxation, whereas the terminal phase occurs during early LV diastolic fi lling. Analysis of LV pressure fall commonly includes indices that evaluate either time of onset or rate of the intermediate phase of pressure decline. 7 Time of onset is measured by ejection duration and by time from end diastole to aortic valve closure or to peak rate of LV pressure fall (dP/dt min ). Among the indices that evaluate rate of pressure decline, dP/dt min , isovolumetric relaxation time and time constant tau are the most commonly used. Note that the later two indices mainly evaluate the rate of intermediate LV pressure fall and provide no informa- tion on the rate of initial pressure fall. The time constant tau uses data from dP/dt min until mitral valve opening and a logarithmic, exponential, or logistic formula. 21,26–28 Decreases in right ventricular (RV) and LV pressures follow distinct time courses, with the initial acceleration phase being relatively longer in the RV and the subsequent deceleration phase being relatively longer in the LV. As afterload increases, the course of RV pressure decrease becomes progressively more similar with that of LV pressure decrease. We must, therefore, be aware that with normal pulmonary systolic pressures, RV tau . only evaluates a minor portion of RV pressure decrease. 29 Determinants of Myocardial Relaxation Myocardial relaxation is modulated by load, inactivation, and nonuniformity. 30 Modulation of Relaxation by Load Load changes infl uence calcium regulatory mechanisms and myofi lament properties. Effects of load on relaxation depend on its type (preload vs. afterload), magnitude, duration, and time in the cardiac cycle at which it occurs. 7 Afterload elevations have a biphasic effect on relaxation rate and end-diastolic PV relation. 3,4 When they occur early in the cardiac cycle, a mild to moderate afterload elevation will, in the normal heart, delay the onset and accelerate the rate of pressure fall without affecting the end-diastolic PV relation (Figure 2.4). This refl ects a compensatory response and the presence of diastolic tolerance to afterload. On the contrary, a severe afterload elevation or an afterload elevation that occurs later in ejection will induce a premature onset and a pronounced slowing of pressure fall, even in a healthy heart. Such slowing might lead to incomplete relaxation and therefore to elevation of fi lling pressures, a phenomenon that is exacerbated when preload is elevated (Figure 2.5). 20 This refl ects a decompensatory response and the presence of diastolic intolerance to afterload. As marked hypertension represents a heavy afterload to the LV, this mechanism might contribute to exacerbation of diastolic dysfunction and pulmonary congestion in hypertensive crisis. 11,12 28 T.C. Gillebert and A.F. Leite-Moreira The level of afterload above which a decompensatory response occurs may be shifted by pharma- cologic agents, 31,32 varies among animal species, 4,33 is distinct in the two ventricles, 34 and is lower in the failing heart. 15 Potential underlying mechanisms for these differences in the diastolic tolerance to afterload include changes in the activity of the sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) or the Na + /Ca 2+ exchanger, in troponin I phosphorylation or in myosin heavy chain isoforms. 32,34–36 Modulation of Relaxation by Inactivation Myocardial inactivation relates to the processes underlying calcium extrusion (Figure 2.6) from FIGURE 2.4. Systolic load and diastolic function. Five superimposed heartbeats in rabbits: one baseline and four variably afterloaded heartbeats. Each of the afterloaded beats was the first beat following an aortic clamp. With a moderate afterload (beat 2), tau does not increase (it actually decreases slightly) and end-diastolic left ventricular pressure remains unaltered. With elevated afterload (beats 3 to 5), tau and end-diastolic pressure increase as a function of the magnitude of the load. Ele- vated systolic load induces diastolic dysfunction. From Leite-Moreira et al., 4 with permission of The European Society of Cardiology.) Internal Diameter (mm) Internal Diameter (mm) 13.5 14.0 14.5 15.0 15.5 LVP (mm Hg) 0 10 20 30 40 50 14.5 15.0 15.5 16.0 16.5 15.0 15.5 16.0 16.5 Internal Diameter (mm) Mid High Low Control 90% 100% FIGURE 2.5. Diastolic portion of left ventricular pressure (LVP)– internal left ventricular diameter loops of a control and two afterloaded (90% and isovolumetric) heartbeats at low, mid, and high preload. The diastolic portion of the loops was shifted upward when afterload was elevated. This upward shift was exacerbated at higher preload. (From Leite-Moreira and Correira-Pinto, 20 with permission of The American Physiological Society.) 2. Myocardial Relaxation and End-Diastolic Stiffness 29 the cytosol in order to achieve its diastolic levels and cross-bridge detachment. 37 Determinants of myocardial inactivation, listed in Table 2.3, therefore include mechanisms related to calcium homeostasis and myofi lament regulators of cross- bridge cycling. 38 The four pathways involved in calcium extrusion from the cytosol are phospholamban-modulated uptake of Ca 2+ by SERCA2a, Ca 2+ extrusion via Na + /Ca 2+ exchange, mitochondrial Ca 2+ uniport, and sarcolemmal Ca 2+ -ATPase, with the two latter being responsible for about only 1% of total. 37 Recent evidence suggests that the main role of the sarcolemmal Ca 2+ pump may be related to signal transduction in the cardiovascular system. 39 The quantitative importance of the two fi rst major routes varies among species. 37 Decreased levels or activity of SERCA2a can slow the removal of calcium from the cytosol. Increased levels or activity of phospholamban, a SERCA-inhibitory protein, can also impair relaxation. Increased cyclic adenosine monophosphate, resulting from ß-adrenergic stimulation or inhibi- tion of cardiac phosphodiesterase, phosphory- lates phospholamban to remove its inhibitory effect on SERCA. The net effect is an improve- ment in diastolic relaxation. Pathologic LV hypertrophy secondary to hypertension or aortic stenosis results in decreased SERCA and increased phospholamban, again leading to impaired relaxation. Similar changes are seen in the myocardium of patients with hypertrophic or dilated L-Ca 2+ ATP 2K + NCX Ca 2 + sCa 2 + 3Na + SERCA PLB Ca 2 + Ca 2 + RR Ca 2 + Ca 2 + Ca 2 + Ca 2 + T-tubule Sarcolemma Myofilaments Sarcoplasmic reticulum Mitochondria L-Ca 2+ mCa 2+ Na + /K + 3Na + FIGURE 2.6. Excitation–contraction and inactivation–relaxation coupling in cardiomyocytes. Cardiomyocyte depolarization pro- motes Ca 2+ entry through sarcolemmal L-type Ca 2+ channels (L-Ca 2+ ), leading to Ca 2+ release from the sarcoplasmic reticulum through ryanodine receptors (RR), thereby inducing contraction. During relaxation, the four pathways involved in calcium removal from the cytosol are phospholamban (PLB)–modulated uptake of TABLE 2.3. Determinants of myocardial inactivation. Ca 2+ homeostasis Ca 2+ concentration Sarcolemmal and sarcoplasmic reticulum Ca 2+ transport Modifying proteins (phospholamban, calmodulin, calsequestrin) Myofilaments Troponin C Ca 2+ binding Troponin I phosphorylation Ca 2+ sensitivity α/β-Myosin heavy chain adenosine triphosphatase ratio Energetics Adenosine diphosphate/adenosine triphosphate ratio Adenosine diphosphate and inorganic phosphate concentrations Ca 2+ into the sarcoplasmic reticulum by a Ca 2+ -ATPase (SERCA), Ca 2+ extrusion via the sodium–calcium exchanger (NCX), mitochondrial Ca 2+ uniport, and sarcolemmal Ca 2+ -ATPase, with the latter two being responsible for only about 1% of total. (Adapted from Roncon-Albuquerque R Jr, Leite-Moreira AF. A cinética do cálcio na progressa ~ o da insuficie ˆ ncia cardíaca. Rev Portuguesa Cardiol 2004;24(Suppl II):25–44.) 30 T.C. Gillebert and A.F. Leite-Moreira cardiomyopathy. Interestingly, levels of SERCA decrease with age, coincident with impaired diastolic function. As adenosine triphosphate hydro- lysis is required for myosin detachment from actin, calcium dissociation from troponin C, and active sequestration of calcium by the sarcoplasmic reticulum, energetic factors must also be taken into consideration. Modifi cation of any of these steps, the myofi lament proteins involved in these steps, or the ATPase that catalyzes them can alter diastolic function. 36,40–42 It is therefore not surprising that ischemia leads to impaired relaxation. Modulation of Relaxation by Nonuniformity Pacing-induced asynchrony of contraction and relaxation leads to impaired systolic performance. 43 When myocardial relaxation starts at different times in various segments of the LV, one segment still contracts while the other relaxes. This leads to asynchronous early segment reextension 44 and premature closure of the aortic valve. During isovolumetric relaxation, reextension of one ventricular segment is accompanied by postsystolic shortening of another segment (Figure 2.7). The ventricle remains isovolumic but changes its shape and produces intraventricular volume displacement. Asynchronous early segment reextension and regional nonuniformity induce a slower rate of ventricular pressure fall and might contribute to the diastolic disturbances observed in myocardial ischemia and with intraventricular conduction disturbances. 45–47 End-Diastolic Properties of Muscle and Heart End-diastolic properties of the ventricular wall are infl uenced by myocardial stiffness, wall thick- ness, and chamber geometry. Determinants of myocardial stiffness include factors intrinsic to FIGURE 2.7. Effects of isoproterenol-induced asynchrony of segment reextension on the rate of left ventricular (LV) pressure fall (ED, end diastole). In the control situation (A), the segments shorten synchronously, wall movement during pressure fall (between aortic closure [AC] and mitral opening [MO]) is limited, and both segments lengthen after MO. The thick horizontal line represents time from end-diastole to minimum segment length. After isoproterenol (B), the stimulated anterior segment develops premature early segment reextension. This leads to abrupt and early onset of LV pressure fall. Pressure fall is slower. Between AC and MO early reextension of the anterior segement is accompanied by postsystolic shortening of the posterior segment. (From Gille- bert and Lew, 46 with permission of The American Physiological Society.) 2. Myocardial Relaxation and End-Diastolic Stiffness 31 the cardiomyocytes themselves (cytoskeleton) and the extracellular matrix (ECM). The cardiomyocyte cytoskeleton is composed of micro tubules, intermediate fi laments (desmin), microfi laments (actin), and endosarcomeric proteins (titin, α-actinin, myomesin, and M protein). Changes in some of these cytoskeletal proteins have been shown to alter diastolic function. 36,40 Most of the elastic force of the cardiomyocytes is now thought to reside in the macromolecule titin (Figure 2.8), whereas contributions of micro- tubules (tubulin) and intermediate fi laments (desmin) appear <10% at operating sarcomere lengths. 48 Titin is expressed as varying isoforms that impart different mechanical properties, and this likely plays a role in altering passive stiffness in failing hearts. Titin can also be posttranslation- ally modifi ed by Ca 2+ (even in the diastolic range) and by phosphorylation, blurring notions of passive versus active tone. 15,36 Phosphorylation of sarcomeric proteins by protein kinase A was recently shown to normalize increased stiffness of cardiomyocytes from patients with DHF. 49 Changes in the structures within the ECM can also affect diastolic function. Myocardial ECM is composed of (1) fi brillar protein (e.g., collagen types I and III and elastin); (2) proteoglycans; and (3) basement membrane proteins (e.g., collagen type IV, laminin, and fi bronectin). Fibrillar collagen apparently is the most important component within the ECM con- tributing to the development of DHF. 36,40 The role played by other fi brillar proteins (basement membrane proteins and proteoglycans) remains largely unexplored. Extracellular membrane fi brillar collagen, par- ticularly in terms of its amount, geometry, dis- tribution, degree of cross-linking, and ratio of collagen type I/type III are often altered in disease processes that alter diastolic function. The regulatory control of collagen biosynthesis and degradation includes (1) transcriptional regulation by physical (e.g., preload and afterload), neurohumoral (e.g., renin-angiotensin-aldosterone, endothelin-1, and sympathetic nervous systems), and growth factors; (2) posttranslational regulation, including collagen cross-linking; and (3) enzy- matic degradation. Collagen degradation is under the control of matrix metalloproteinases. 36,40 Changes in either synthesis or degradation and their regulatory processes have been shown to alter diastolic function and lead to the development of DHF. In addition, it is now increasingly recognized that quality of collagen (specifi cally cross-linking and glycation) plays a key role in translating quantity into myocardial stiffness. 36 Recent demonstration that 16 weeks of treatment with a glucose cross-link breaker decreased LV mass and improved diastolic fi lling and quality of FIGURE 2.8. Sarcomere passive length–tension relation between cardiac myocytes that predominately express N2B titin and those that predominately express N2BA titin. Coexpression of titin isoforms at variable ratios allows intermediate passive tensions (double-headed arrow) as a long-term passive stiffness adjust- ment mechanism. It has been postulated that short-term adjust- ment mechanisms differentially impact the isoforms, decreasing stiffness of N2B titin and increasing stiffness of N2BA titin. (From Granzier and Labeit. 48 © 2004 American Heart Association, Inc. All rights reserved. Reprinted with permission.) 32 T.C. Gillebert and A.F. Leite-Moreira life in patients with DHF further reinforces this view. 15,36,50 In addition to posttranslational modifi cations of titin, other evidence suggests that diastolic stiffness is actively modulated. Cross-bridge interaction occurs even at low diastolic calcium producing resting muscle tone. Modifi cations of myofi lament calcium sensitivity by heart failure might also alter active tone. 50 This includes changes associated with protein kinase A (or guanosine monophosphate–dependent protein kinase) phosphorylation of myosin light chain 2 and troponin I (Figure 2.9). In this setting, nitric oxide and cyclic guanosine monophosphate increase resting diastolic cell length as a result of guanosine monophosphate–dependent protein kinase– mediated phosphorylation of myofi laments, and in patients with dilated cardiomyopathy adminis- tration of intracoronary substance P (a nitric oxide stimulator) decreases LV stiffness. 51 Fur- thermore, myocardial stiffness is acutely modulated by load, endothelin-1, 52 β-adrenoceptor stimulation, 53 and angiotensin II. 54 With regard to load, as outlined above, a severe afterload elevation or an afterload elevation that occurs later in ejection will induce a pronounced slowing of pressure fall that might lead to incomplete relaxation and therefore to elevation of fi lling pressures. 4 This phenomenon is exacerbated when preload is elevated. 2,20 With regard to β-adrenergic receptor stimulation, it decreases myocardial stiffness through protein kinase A– induced phosphorylation of titin. 53 This posttranslational modifi cation of titin was shown to acutely shift the diastolic length–tension relation downward (i.e., decrease stiffness) both in animal models 53 and in healthy and diseased human myocardium. 49 It is widely accepted that when chronically elevated in pathologic conditions, endothelin-1 and angiotensin II might increase diastolic stiffness by inducing myocardial hypertrophy and altering ECM, leading to fi brosis. 55–58 However, recent studies convincingly demonstrated that both agents acutely decreased myocardial stiffness. 52,54 The acute direct myocardial effects of endothelin- 1 and angiotensin II on myocardial stiffness were overlooked until recently, possibly because the few studies looking at this issue analyzed the effects of exogenously administered supraphysi- ologic doses. In these circumstances, coronary and/or systemic vasoconstriction could potentially have masked any effect on the intrinsic properties of the myocardium. In fact, both myocardial ischemia and severe afterload elevations potentially shift the end-diastolic PV relation upward, refl ecting an decrease in myocardial distensibility. 4,20,23,59 With regard to endothelin-1, the above-men- tioned study 52 showed that this agent increases diastolic distensibility of acutely loaded cardiac muscles by binding to endothelin A receptors and activating the Na + /H + exchanger (Figure 2.10). Although angiotensin II also acutely decreases myocardial stiffness, 54 its effect is observed even in the nonoverloaded myocardium (Figure 2.11). This effect is mediated by angiotensin II type 1 receptors and is dependent on the activation of FIGURE 2.9. (A) Protein kinase A (PKA) treatment reduces passive force (F passive ) in cardiomyocytes from diastolic heart failure (DHF) patients to values observed in a control group at baseline and after PKA treatment. (B) Correlation between PKA-induced fall in F passive and baseline value of F passive . (From Borbely et al. 49 © 2005 Ameri- can Heart Association, Inc. All rights reserved. Reprinted with permission.) 2. Myocardial Relaxation and End-Diastolic Stiffness 33 protein kinase C and the Na + /H + exchanger in both the isolated papillary muscle and the in situ intact heart. In the latter, angiotensin II infusion increased LV systolic pressures by 50% while decreasing LV diastolic fi lling pressures. As an elevation of systolic LV pressure of such magnitude signifi cantly increases LV diastolic pressure, it is not surprising that when the effects of angiotensin II on diastolic LV pressures were evaluated at matched systolic LV pressures a larger effect could be detected. In fact, in these circumstances, LV diastolic pressures decreased almost 50%. This means that angiotensin II might allow the ventricle to reach high fi lling volumes at almost half fi lling pressures, which is undoubtedly a quite powerful adaptation mechanism. This compensatory effect of endothelin-1 and angiotensin II on myocardial distensibility in the acute setting might contribute, in the long term, to ventricular dilatation and remodeling. This potentially important pathophysiologic mechanism has not been studied in the failing heart so Endothelin and diastolic function ET-1 (10 nM) Baseline Increase in distensibility Positive lusitropy A B C ET-1 ET-1 + BQ-123 (ET A ) ET-1 + PD-145065 (ET A /ET B ) ET-1 + BQ-788 (ET B ) FIGURE 2.10. Effects of endothelin-1 (ET-1) on diastolic function in rabbits. Endothelin-1 increases the rate of myocardial relaxation (positive lusitropy, (A) and increases myocardial distensibility (B,C). Increased distensibility is apparent as a decrease in resting tension after a heavily loaded (isometric) twitch (lower left). The increases in both relaxation rate and distensibility were inhibited by selective ET A (BQ-123) and nonselective ET A /ET B (PD- 145065) receptor blockers, but not by the selective ET B receptor blocker BQ-788. (From Leite-Moreira et al., 52 with permission of The American Physiological Society.) FIGURE 2.11. Diastolic length–tension relations at baseline and in the presence of angiotensin II (Ang II, 10 −5 M) in rabbits. Angotensin II induced a rightward and downward shift of this relation, indicating a decrease in myocardial stiffness. Data are means ± SE; p < 0.05. *Ang II versus baseline. (Brunner F, Bras-Silva C, Cerdeira AS, Leite-Moreira AF. Cardiovascular endothe- lins: essential regulators of cardiovascular homeostasis. Pharmacol Ther 2006;111: 508–531.) 34 T.C. Gillebert and A.F. Leite-Moreira far and represents an interesting area for future investigations. Ventricular Arterial Coupling and Diastolic Heart Failure In order to understand DHF, we have to integrate loading conditions of the myocardium, myocardial relaxation disturbances, and passive stiffness of ventricle and myocardium. The heart is con- tinuously interacting with the vessels, and this complex interaction determines cardiac load, hence the way the heart contracts and relaxes, ejects and fi lls. Ventricular arterial coupling 60 can be described by the ratio of two parameters: effective arterial elastance (Ea = P es /SV, where P es is end-systolic pressure and SV is stroke volume) and systolic ventricular elastance or (slope of the ventricular end-systolic PV relation), or arterial contribution divided by ventricular contribution. From an energetic point of view, cardiac effi ciency is maximal when Ea/Ees (end-systolic elastance) = 0.5. This is the situation in normal middle-aged healthy subjects 61 and corresponds to an EF = 0.65. The maximal external work is achieved when Ea/Ees = 1.0 and corresponds to an EF = 0.50. Arterial elastance is a simplifi ed, lumped param- eter of arterial stiffness. Both arterial elastance and end-systolic elastance can be approximately evaluated noninvasively. 62 Such a noninvasive FIGURE 2.12. Some of the processes that lead to diastolic dysfunction and heart failure. (From Massie. 65 ) approach may be used to characterize patient populations 63 or normal subjects, 61,64 keeping in mind the limitations of the method. Diastolic heart failure or heart failure with pre- served systolic function is a disease of both heart and vessels and can be more easily understood when considering alterations of heart and vessels as a global process 65 or as a coupling disorder. 10 Figure 2.12 schematically illustrates some of the processes that lead to diastolic dysfunction and failure. The LV undergoes structural and func- tional changes as a result of the increased vascular load presented by hypertension and loss of vascular compliance and elasticity due to arteriosclero- sis, aging, and endothelial dysfunction. In addition, cardiac aging and, in some patients, episodic ischemia have direct effects on myocardial structure and function. These processes result in myocardial hypertrophy and fi brosis, with loss of myocardial compliance and, in some cases, impaired relaxation. 65 In DHF, heart and vessels interact differently. An example of this different interaction is how myocardial relaxation responds to alterations of the systolic pressure pattern. If waves, refl ected by the peripheral arterial tree, are delayed until after the aortic valve closure, such as in young subjects, the systolic pressure pattern is horizontal (control beat) or with an early peak similar to an early load clamp (Figure 2.13). These patterns do not signifi - cantly affect myocardial relaxation. 66 If refl ected waves reach the heart before aortic closure, such as in elderly subjects, subjects with hypertension, 2. Myocardial Relaxation and End-Diastolic Stiffness 35 or in general in subjects with a stiffening arterial tree, refl ected waves will result in higher systolic pressures and in a systolic pressure pattern with a late peak, similar to a late-systolic load clamp. 67 This pressure waveform will delay myocardial relaxation 3,66 and will contribute to altered LV fi lling and elevated fi lling pressures. 4 A related issue is increased pulse pressure, characteristic for elderly subjects. Increased pulse pressure is a consequence of aortic stiffening and a loss of the windkessel capacity. During ventricular systole, the stroke volume ejected by the ventricle results in some forward blood fl ow to the organ beds, but part of the ejected volume is stored, buffered in the elastic arteries. This process represents the healthy pressure-equalizing or buffering function of the aorta. During ventricular diastole, the elastic recoil of the arterial wall maintains blood fl ow for the remaining part of the cardiac cycle. With aging, the stiffened aorta increases the systolic blood pressure, while the loss of elasticity decreases diastolic recoil so that the diastolic blood pressure falls. 68 The heart is overloaded during systole, whereas diastolic organ perfusion is at the lower limit or beyond. Large cross-sectional studies have established age-dependent increases in vascular stiffening. 64,69,70 This vascular stiffening is accompanied by changes in the LV that increase end-systolic stiffness. 10,64 These changes can already be observed at an early stage of the disease in a sub- group of a normal middle-aged population (35–55 years old). 61 This combined ventricular arterial stiffening alters the way in which the cardiovascular system can respond to changes in pressures and volumes, hence to stress and physical exercise. Figure 2.14 depicts the concept of age-dependent adaptations in two situations. 10 The left illustrates ventricular arterial coupling in a young and healthy subject. The right illustrates an elderly healthy subject. The left is the reference with bal- anced end-systolic elastance (Ees) and arterial elastance (Ea), normal ventricular and arterial Time (ms) 0 100 200 300 400 0 50 100 150 LVP (mmHg) 0 50 100 150 Early Late Control Test Contraction Relaxation - Diastole FIGURE 2.13. (Top) Early left ventricular pressure (LVP) elevation. The control heartbeat is displayed as a solid line. The solid vertical gray line indicates transition from contraction to relaxation. An elevation of systolic LVP (12 mm Hg) initiated during contraction and maintained throughout ejection (dashed line) delays the onset of LVP fall. Rate of LVP fall slightly accelerates. (Bottom) Late LVP elevation. An elevation of systolic LVP with a similar magnitude (12 mm Hg) but timed at mid ejection (dashed line) and is initiated during relaxation induces an early onset of LVP fall. The course of LVP fall is slower. (From Leite-Moreira and Gillebert. 3 © 1994 American Heart Association, Inc. All rights reserved. Reprinted with permission.) Normal subject Aged subject P V V P Ees Ea Ees Ea FIGURE 2.14. With increasing age, ventricular end-systolic elastance (Ees) and arterial elastance (Ea) both increase. Pressure (P)– volume (V) loops from young (left) and aged (right) subjects show increases in Ees that match increases in arterial loading indexed by arterial elastance (Ea). The coupling Ea/Ees remains close to optimal efficiency, somewhat higher than 0.5. The pressure–volume loop of the aged subject is distorted, trapezoidal. See text for further discussion. [...]... Engl J Med 20 01;344:1 7 2 2 12 Leite-Moreira AF, Correia-Pinto J, Gillebert TC Diastolic dysfunction and hypertension N Engl J Med 20 01;344:1401 13 Little WC Enhanced load dependence of relaxation in heart- failure — clinical implications Circulation 19 92; 85 :23 2 6 2 328 14 Little WC Diastolic dysfunction beyond distensibility: adverse effects of ventricular dilatation Circulation 20 05;1 12: 288 8 2 890 15 Gillebert... 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