Diastolic dysfunction in heart failure

Journal of Cardiac Failure Vol. 3 No. 3 1997

Review Diastolic Dysfunction in Heart Failure DIRK L. BRUTSAERT, MD, PhD, STANISLAS U. SYS, MD, PhD Antwerp, Belgium

Diastolic dysfunction and diastolic failure of the heart have become widely recognized clinical entities. Whereas most conditions related to diastolic dysfunction and failure are the mere consequence of systolic cardiac failure, there also exists a distinct primary form of diastolic failure (1-4). Primary diastolic failure occurs in a large variety of clinical conditions, for example, coronary artery disease, systemic hypertension, diabetes mellitus, aortic stenosis, hypertrophic cardiomyopathy, infiltrative cardiomyopathies, and endocardial fibroelastosis. The underlying pathologic processes include myocardial ischemia, hypertrophy, and fibrosis, all increasing significantly with age. In clinical cardiology, primary diastolic failure has been commonly defined as a condition with classic findings of congestive heart failure with near-normal rest systolic function but with predominantly diastolic dysfunction (5). Diastolic failure of the left ventricle is an early event that occurs more commonly (30% in some series)--at least in the elderly population (6,7)-than previously thought and is often manifest as pulmonary congestion and dyspnea during exercise, that is, exercise intolerance (8). With respect to left ventricular (LV) diastolic cardiac failure, "exercise intolerance" ought to be interpreted in a strict sense, that is, exercise dyspnea caused by pulmonary congestion; it does not incorporate exercise-induced muscular fatigue or physical exhaustion. The latter symptoms of chronic systolic cardiac failure have been ascribed to impaired skeletal muscle metabolism resulting from deconditioning, cytokine activation, deficient endothelial vasodilator response, and loss of anabolic function (9-11).

The criteria that help to identify abnormal LV diastolic function in the presence of normal ventricular systolic performance are, however, insufficiently clear to fully comprehend the above clinical definition (7). As a consequence, the concepts of diastolic dysfunction and failure with normal ventricular systolic function are still not well understood by most clinicians, and the diagnosis, the presumed clinical prevalence of which varies widely from 13 to 74% (7,12), as well as the natural history (13) and prognosis (14), continue to cause major controversies, the main reason being that many--mainly clinical--investigators, on either empirical or historical grounds, persist in using different criteria to define normal systolic and abnormal diastolic function (15). For example, the definition of diastole and diastolic failure differs depending on whether the heart is considered as a pump rather than as a muscular pump or whether cardiac hemodynamics are evaluated as a function of time or as pressure-volume relations. A clear pathophysiologic definition is mandatory, however, as the management of patients with primary diastolic dysfunction or failure is very different from the management of patients with primary systolic failure (5). The physiologic concepts on which the subsequent sections are based have been outlined in detail in an exhaustive review on the subject (16). For the erudite clinical and basic scholar, reading of this text is highly recommended to fully appreciate what follows.

Definition of Diastole: The Heart as a Muscular Pump The heart is a combined muscle and pump system. To evaluate the mechanical performance of this muscular pump, one should take into account the mechanical properties of the myocardium as well as those of the system as a pump. In Figure 1, the force and length traces of an afterloaded isotonic twitch obtained from isolated cardiac muscle have been appropriately synchronized on a time scale with the pressure, volume, and mitral flow curves of

From the Department of Physiology and Medicine, University of Antwerp, Antwerp, Belgium. Reprint requests: Dirk L. Brutsaert, MD, Department of Physiology and Medicine, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium. Manuscript received March 12, 1997; revised manuscript received July 2, 1997; revised manuscript accepted July 3, 1997. © 1997 Churchill Livingstone Inc.

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an ejecting left ventricle. Despite the auxotonic loading conditions in the ventricle, there is a striking resemblance of the time patterns between force and pressure traces and between length and volume traces, the speed of the latter two events during relaxation exceeding by at least three to four times the speed during contraction. Importantly, the decrease in force and relengthening of the muscle during relaxation are part of a single activity transient, that is, a single contraction-relaxation cycle or muscular "systole." To muscle physiologists, the subsequent rest constitutes muscle "diastole." Similarly, fall in pressure during isovolumic relaxation and increase in volume during early rapid filling of the ventricle are closely related to these myocardial events and, hence, to muscle systole. Diastole then encompasses diastasis and the atrial contraction phase. On a time scale, the duration of diastole depends mainly on heart rate and, to some extent, as we will see later, on the duration of systole. Together, these two variables determine the systolic-to-total duration ratio. At normal rest heart rates, diastolic duration usually corresponds to approximately 50% of the total duration of the cardiac cycle. By contrast on a volume scale as in a pressure-volume diagram, diastole represents only the last 5-15% of ventricular filling (points 3 to 4 in Fig. 1).

However logical and important these concepts may be, many clinical investigators, for historical and empirical reasons, remain somewhat reluctant to incorporate them in their routine vocabulary. Although we understa)ld that nonphysiologists do not wish to take a particular stand on where exactly systole ends or diastole begins, this unfortunate habit continues to foster controversy about diagnosis and therapy of clinical conditions with diastolic 229dysfunction and failure. Regardless of this semantic discussion the one important feature to remember from the above considerations is that both pressure fall and early rapid tilling (ie, about 85% of the volume change on the pressure-volume diagram) are inherent parts of the active relaxation process of the muscular pump. Similarly as for the systolic contraction phase, that is, for pressure rise and ejection, relaxation of the heart as a muscular pump is a reflection of the interaction between loading conditions and myocardial (in)activation processes (contractile proteins and Ca 2+ homeostasis), both modulated by some degree of nonuniformity in space and time. It would therefore be helpful if disease processes causing abnormalities in either pressure fall or early rapid filling be considered separately as dysfunction or failure of ventricular relaxation. As already stated above, the terms

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f i Fig. 1. Cardiac cycle of the heart as a muscular pump. Comparison of muscle (f = force, 1 = length) and pump (P = pressure, V = volume, F = mitral flow). The similarity between the corresponding time (t) traces led to the inclusion of isovolumetric relaxation (1R) and rapid filling phase (RFP) into the relaxation part of systole. As a consequence, diastolic dysfunction or failure can be defined as an inappropriate rise in the diastolic pressurevolume relation during exercise or at rest, respectively. Possible causes of diastolic dysfunction or failure are impaired (systolic) relaxation, decreased diastolic compliance, and inappropriate tachycardia or mismatch of systolic to total duration.

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Diastolic Dysfunction in Heart Failure

diastolic dysfunction and diastolic failure should be restricted to diastasis and the atrial contraction, that is, the very last portion on the pressure-volume diagram (Fig. 1, points 3 to 4).

Definition of Diastolic Failure Taking the above conceptual approach, we suggested that genuine diastole consists of diastasis and atrial contraction (ie, the last 5-15% of ventricular filling). Diastolic dysfunction and diastolic failure then refer to disease processes that shift the end portion of the pressure-volume diagram upward so that LV filling pressures are increased disproportionally to the magnitude of LV dilation. Accordingly, LV diastolic failure should be defined as a condition resulting from an increased resistance to LV filling and leading to symptoms of pup monary congestion caused by an inappropriate upward shift of the diastolic pressure-volume (or pressuredimension) relation first during exercise (diastolic dysfunction) and later at rest (diastolic failure) (Fig. 1, Table 1). This definition embodies both a pathophysiologic aspect (the inappropriate shift in AP/AV), and a clinical aspect (that the shift is manifested through symptoms of pulmonary congestion and exercise-induced dyspnea). Accordingly, based on the above definition the single most reliable and most powerful measurement of LV diastolic dysfunction and diastolic failure is the upward shift of the diastolic portion (Fig. 1, points 3 to 4) of the LV pressure-volume or pressure-dimension relation. This shift may be reflected by an increase in related measurements, for example, pulmonary capillary wedge pressure (17), transmitral Doppler A-to-E ratio, A wave on the apexcardiogram.

Causes of Diastolic Failure Causes of diastolic failure are multiple and can be subdivided into (1) inappropriate tachycardia resulting in inappropriate abbreviation of diastolic duration, (2) a decrease in (passive) myocardial or ventricular diastolic compliance, and (3) impairment in (active) LV (systolic)

Table 1. Definition of Left Ventricular Diastolic Dysfunction and Failure Diastolic dysfunction

Diastolic failure

A condition with increased resistance to filling of the left ventricle, leading to an inappropriate rise in the diastolic (ie, endportion) pressure-volume relation and causing symptoms of pulmonary congestion during exercise. A condition with increased resistance to filling of the left ventricle, leading to an inappropriate rise in the diastolic (ie, endportion) pressure-volume relation and causing symptoms of pulmonary congestion at rest.

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Brutsaert and Sys

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relaxation, that is, impaired isovolumic pressure fall or impaired early rapid filling (2). Importantly, whereas these latter impairments may lead to the upward shift in the diastolic portion on the pressure-volume diagram and, hence, to diastolic dysfunction and failure, impaired ventricular (systolic) relaxation should in the absence of such shifts not be called diastolic dysfunction or diastolic failure. Such late systolic abnormalities during relaxation may well be the early manifestation of imminent systolic dysfunction. Inappropriately high heart rate as a cause of diastolic dysfunction and diastolic failure does not merely follow from the inappropriate abbreviation of diastolic duration (ie, of diastasis and atrial contraction), but refers in addition to conditions where prolongation of ventricular systole becomes critical at a given heart rate, that is, when there is a mismatch in the systolic-to-total duration as, for example, at high pressure or volume loads (see below).

Impaired (Systolic) Relaxation as a Cause of Diastolic Failure On conceptual and experimental grounds, ventricular pressure fall and early rapid filling have been considered part of the (systolic) relaxation process of the heart as a muscular pump. Identifying late systolic measurements or derived indices related to ventricular relaxation with diastole (18), is, therefore, conceptually incorrect. Only in specific circumstances may these late systolic events during ventricular relaxation eventually lead to genuine diastolic dysfunction and failure as defined above. For late systolic events during ventricular relaxation to be identified, however, as abnormal or pathologic, it is essential that one first differentiates between prolonged contraction and impaired relaxation (Fig. 2). This distinction will follow from a close analysis of timing and rate of relaxation indices. Prolonged Contraction. Prolonged contraction is due to a delayed or retarded onset of relaxation. It is the physiologic, often compensatory, response to pressure and volume loading of the ventricle (heterometric autoregulation), to various neurohormones and drugs and heart rate (homeometric autoregulation), and to cardiac endothelial activation (endothelial autoregulation) (Fig. 2, left). Although at very high afterloads, close to peak isovolumetric ventricular pressure, onset of relaxation may either be unaltered or occur slightly earlier, the larger remaining part of the relaxation phase remains shifted in time. Concomitant variations in relaxation rate (dP/dt-, tan, isovolumic relaxation time, dV/dt, Doppler E wave, time to peak filling rate, ' etc), if present, should be viewed as mere epiphenomena and are, in general, quite unpredictable. Figure 3 depicts representative examples of the three types of autoregulation with their effect on systolic dura-

228 Journalof Cardiac FailureVol. 3 No. 3 September 1997

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Fig. 2. Prolonged contraction is not impaired relaxation. Prolongedcontraction--or delayed onset of relaxation--causes an increase in the duration of systole as indicated by the dotted lines in the pressure (P) and volume (V) traces on the left. This compensatory and physiologic modulation of systolic duration can result from a number of different heterometric, homeometric (O, prolongation; Q abbreviation), and cardiac endothelial types of autoregulation. These may be accompanied by substantial but often divergent changes in the relaxation rate (b and c versus a). Impaired relaxation, illustrated by slower (inappropriately decreased rate) and incomplete (inappropriately decreased extent) relaxation (dotted lines on the right), is pathologic and leads to diastolic dysfunction or failure. Causes of impaired relaxation can be interpreted in terms an impaired triple control of relaxation (16,19), that is, inappropriateness of loading, inactivation, or nonuniformity. CL, contraction load; RL, relaxation load.

tion and on relaxation rate, both in isolated cardiac muscle (Fig. 3, top) and in the intact left ventricle (Fig. 3, bottom). All three types of autoregulation are characterized by consistent changes in systolic duration. Less consistent are the alterations in relaxation rate. For example, for identical systolic prolongation with increased loading (Fig. 3, left) and with cardiac endothe-

lial activation (Fig. 3, right) the two changes in peak relaxation rate are unpredictable and opposite. These features are illustrated further in Figures 4 (20-23), 5 (23), 6 (24,25), and 7 for changes in early loading (heterometric autoregulation), that is, in afterload, preload, and (contraction) load clamp. With all these load manipulations, systolic duration consistently

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I Fig. 3. Left ventricular systolic duration and left ventricular relaxation rate: effects of heterometric, homeometric, and cardiac endothelial autoregulation. Effects of the three major types of autoregulation on the time course of force and left ventricular pressure (LVP) and time derivatives (dF/dt and dP/dt) during an isometric twitch in isolated cardiac muscle (top) or during systole in in vivo canine heart (bottom). Note that heterometric autoregulation (left) and endothelium-mediated autoregulation (right) consistently modulate systolic duration; that is, a higher end-diastolic length (EDL) or volume (EDV) and the presence of an intact endocardial endothelium (+EE) increase systolic duration. Yet, they do not affect peak relaxation rate in the muscle but induce divergent changes in peak relaxation rate in the pump, that is, an increase and a decrease, respectively. These changes in peak rates are hardly predictable and may vary from one animal or from one experiment to the other. By contrast, increased contractility as, for example, by extracellular calcium (middle, homeometric autoregulation), consistently increases peak relaxation rate, but with relatively minor effects on systolic duration. Homeometric autoregulation, in general (see also Fig. 2, left), can induce either abbreviation of systolic duration, or prolongation, or little changes as in the present example.

varies by more than 30% due to shifts in time of the relaxation phase (Fig. 4). In contrast to the consistent and reproducible changes in systolic duration, concomitant changes in relaxation rate are in all the above examples unpredictable, often divergent, and provide, in general, little further information. Moreover, during the load manipulations in Figure 5, systolic duration varied by more than 30% when early and late aortic occlusions were compared, but neither dP/dt- nor tau were affected. The marked prolongation of pressure generation during the second half of ejection (24,25) in Figure 6, to far beyond the timing of the pressure decline as anticipated from the superimposed isovolumic beat at the smaller

peak systolic volume, is the mere consequence of the combined effects of (1) maintained myocardial force generation due to sustained high cooperative activity at a crossbridge level and (2) the late-ejection reversal of the pressure gradient caused by the momentum of the blood column in the outflow tract (26,27). This causes the (relaxation) loading faced by the ejecting ventricle to transiently decrease to below the force generated by the ventricular wall, thereby unloading the ventricle during late ejection. The ensuing prolongation of systole contrasts with the abbreviation of systole when the (relaxation) loading was augmented during this late phase of ejection (Fig. 5, bottom).

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Fig. 4. Effects of heterometric autoregulation on left ventricular systolic duration and left ventricular relaxation rate. Increases in loading during the contraction phase, caused either by changing afterload or preload or by a load clamp (by abrupt occlusion of the ascending aorta), induce compensatory increases in systolic duration. Time courses of left ventricular pressure (LVP) in these physiologic conditions consistently show a substantially delayed onset of the relaxation phase, that is, by more than 30% of total systolic duration. [Afterload from Slinker et al. (20) and preload from Gillebert and Brutsaert (21), with permission. Load clamp modified from Brutsaert and Sys (23), with permission.]

Figure 7 summarizes changes in systolic duration and in relaxation rate, as published by various authors over the past two decades (15,16,20,24,25,28-51), for increases either in contraction loadings (CL), that is, preload or afterload, or in various relaxation loadings (RL). Depending on the experimental (Fig. 7) or clinical (52) condition or on the change in systolic duration, either an increase in relaxation rate or a decrease or no change at all may be observed. For these reasons, measurements of relaxation rates are, in general, quite unreliable for evaluating late systolic cardiac performance unless normalized for changes in systolic duration. Although such normalized relaxation rates have, in our opinion, as yet not been published, we anticipate that interpretation of relaxation rates will remain difficult as these depend in a very complex fashion on the interaction of 1. the instantaneous force in the ventricular myocardium and the loading handled by the ventricle; 2. the load distribution and pattern during early and late ejection, in particular, the relative contribution of CL versus RL (Figs. 5, 6) (6,32); 3. the substantial shifts in time, as described above (up to 30% of systolic duration) (Figs. 4-6) of the instant during systole at which these rates are measured; 4. the degree of nonuniformity in space and time of loading and inactivation, being generally more pro-

nounced during ventricular systolic relaxation than during contraction (16,53--60); and 5. the auxotonic loading conditions during pressure fall and early rapid filling. Surprisingly, variations in systolic duration are quite consistent despite anxotonic loading and despite often important nonuniformities during ventricular relaxation. By contrast in these same conditions of auxotonic loading and substantial nonuniformities, relaxation rates can no longer be interpreted in terms of simple mechanics of a muscular pump and are, therefore, of doubtful diagnostic value. As most clinicians persist in measuring rates (dP/dt-, tau, isovolumic relaxation time, dV/dt, Doppler E wave, time to peak filling rate) to evaluate pressure decline and early rapid filling during ventricular relaxation, the above considerations must be taken into account as major obstacles in the area. Within an appropriate range of relaxation rates, prolonged contraction normally does not shift diastolic pressure-volume relations upward (Fig. 2, left, inset) and, therefore, does not normally lead to diastolic cardiac dysfunction and failure. It may, however, do so at high heart rates when, despite the heart rate-induced systolic abbreviation, a compensatory prolonged systole becomes the limiting factor for filling (mismatch of the systolicto-total duration at any given heart rate), even when no intrinsic relaxation abnormalities are present. Either

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Fig. 5. Contraction versus relaxation load clamps on left ventricular systolic duration and left ventricular relaxation rate. Left ventricular pressure (LVP) and dP/dt-versus-time and phase plane loops of dP/dt versus LVP were obtained from in vivo ejecting dog heart. Control beats (solid lines) are compared with ascending aortic occlusion beats (dotted lines). Despite negligible effects on relaxation rate (measured by dP/dt- or tau) in this experiment, aortic occlusion before ejection (CL, contraction load) and during the second half of ejection (RL, relaxation load) markedly affected overall (from CL to RL) systolic duration by 25 to 30%, by inducing either delayed (for CL) or premature (for RL) onset of relaxation, respectively. This experiment also illustrates that evaluation of LV relaxation necessitates measurement of at least three variables (Table 2): timing (systolic duration), relaxation rate, and relaxation rate pattern (eg, phase plane). [Modified from Brutsaert and Sys (23); with permission.]

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bradycardic therapy or procedures that shorten systolic duration, such as pressure or volume unloading of the ventricle, are then the obvious treatments of choice. I m p a i r e d Relaxation. In contrast to prolonged contraction (or delayed or retarded relaxation), the primary event of impaired relaxation (or slowed or incomplete relaxation) is an inappropriate reduction in rate or in the extent of relaxation during pressure decline or early rapid filling (Fig. 2, right). As a consequence, the relaxation process extends late into diastole, resulting in an upward shift of the diastolic pressure-volume relation, thus leading to diastolic failure. Given the numerous limitations of relaxation rate measurements as outlined above, one could, however, wonder what transforms a given appropriate change in rate into an inappropriate one. An additional problem is that impaired relaxation can be observed in conditions where systolic duration is prolonged as, for example, in phase II of pressure-volume overloading (Fig. 8, middle), as well

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i/Vm as in conditions where it is abbreviated such as ischemic heart disease (61) or in the presence of systolic failure (Fig. 8, right). Theoretically, only when for any given systolic duration and heart rate relaxation rate has been reduced to such a degree that it leads to an upward shift of the diastolic pressure-volume relation, can it be considered as a manifestation of impaired relaxation. For rate measurements to be of practical use in the diagnosis of diastolic dysfunction or pending diastolic failure, one should first know the normal range of relaxation rate measurements after normalization for systolic duration and heart rate. This inventory must still be made. Causes of impaired systolic relaxation include (1) diminished myocardial load dependence due to impaired inactivation (Ca z÷ handling, detachment of cross bridges, affinity of the contractile proteins, etc) (62); (2) excessive increases in load; and (3) inappropriately increased nonuniformity of load and inactivation in time and space (2,16).

232

Journal of Cardiac Failure Vol. 3 No. 3 September 1997

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Fig. 6. Prolongation of pressure-generating capacity during ejection: a combination of cooperative activity and late ejection unloading. Isovolumic left ventricular pressure (P) waveforms (dotted lines), from first beats after isovolumic clamps at different times during filling, illustrate volume dependence of systolic duration; corresponding volume (V) traces are in the lower panel. Full lines represent the steady-state ejecting beat, which starts (isovolumic contraction) and ends (end-diastole) at the highest volume of the clamped beats. On the one hand, pressure generation of the ejecting beat is prolonged when referred to the isovolumic beat at the smaller volume. This may result from the interaction of two simultaneously occurring events: contraction load is higher through higher initial pressure and volume, hence promoting cooperative activity at the crossbridge level, and relaxation load is decreasing during late ejection as a result of the pressure reversal at this instant created by the momentum. On the other hand, pressure generation of the ejecting beat is abbreviated when referred to the higher volume isovolumic beat: contraction load is progressively decreased through unloading during early ejection, hence gradually diminishing the effect of cooperative activity of the crossbridges. As a result, the timing of relaxation in the ejecting beat is intermediate between relaxations in the smaller- and the higher-volume isovolumic beats. The auxotonic nature of the filling period is illustrated by the initial pressure decline and later pressure rise during the volume increase in the ejecting beat. [Pressure traces modified from Burkhoff et al. (25) with permission; volume traces schematically reconstructed.]

A decrease in myocardial or ventricular diastolic comp l i a n c e - o r an increase in diastolic stiffness--may lead to an inappropriate upward shift of the diastolic portion of the ventricular pressure-volume relation and, hence, to diastolic dysfunction and failure. As a convenient way to measure ventricular compliance/stiffness, many investigators display pressure-volume (or pressure-dimension) loops obtained from single cardiac beats. In the ventricular filling portion of these single-beat loops one cannot possibly distinguish, however, between early rapid filling (usually about 80-85% of the volume change) and true diastole, that is, diastasis and the atrial contraction phase. Hence in such an approach, late systolic abnormalities during ventricular relaxation cannot possibly be differentiated from decreased diastolic compliance as a cause of diastolic heart failure. This is one example, among numerous others, emphasizing the need for a more rigorous definition of diastole as discussed above. In a most elegant experimental study, Pak et al. raised some serious concern regarding the traditional analysis of chamber stiffness based on single steady-state beats (63). Figure 9A, B illustrates pressure-volume loops obtained from patients with hypertrophic cardiomyopathy (A) and from normal control patients (B) (63). For comparison, two different methods to estimate LV pressure-volume relations were superimposed: (1) pressure-volume relations obtained from single steady-state beats and (2) pressure-volume relations obtained from multiple beats during a transient preload reduction by caval occlusion. In the former viscoelastic single-beat loops, stiffness data were derived in a dynamic fashion during the entire filling (hence, erroneously, including early rapid filling during ventricular relaxation), whereas in the latter multiple-beat method a monoexponential fit was constructed from genuine diastolic data points. With the latter method, a pressure-volume relation was reconstituted devoid of possible interference from impaired systolic relaxation during early rapid ventricular filling. Here, diastole has obviously been considered more correctly in the stricter conceptual sense of the heart as a muscular pump as defined by us (Fig. 1). The disparity between the two estimates was striking. When derived from (end-)diastolic pressure-volume data points from multiple beats, diastolic chamber stiffness in the hypertrophic cardiomyopathy was more concordant with data from the control patient: the single-beat analysis erroneously makes the diastolic pressure-volume relation appear much more compliant than the multiple-beat method. Although the authors claim that the reason for this disparity is still unclear, it raises at least some serious concern regarding measurements of chamber stiff-

Diastolic Dysfunction in Heart Failure •

ltCLIJ IIRLJJ® Fig. 7. Summary of published effects of increased contraction and relaxation loadings on left ventricular systolic duration and left ventricular relaxation rates. Pressure (P)-, volume (V)-, and mitral flow (F)-versus-time (t) traces (top) illustrate the approximate time sequence of impact of various contraction (CL) and relaxation (RL) loadings. The effects on systolic duration are consistent prolongation (O) for increased CL and abbreviation (O) for increased relaxation loading (bottom). For increased impedance as a RL, see also Fig. 5 (bottom). For increased momentum as a relaxation unloading, see also Fig. 6. The effects of increased loading on measurements of relaxation rate (dP/dt-, tau, dV/dt, E) are variable (+, increased rate; -, decreased rate; 0, unchanged rate) and depend not only on the change in systolic duration but also on the experimental condition. With changes in loading, measurements of systolic duration seem to be more reliable than relaxation rates to evaluate late systolic cardiac performance. RT or Rt, right; LT or Lt, left.

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ness based on a viscoelastic model using single beats and which includes the entire early rapid filling phase of (systolic) ventricular relaxation. Accounting for a mismatch in the systolic-to-total duration could perhaps help to clarify this enigma. Indeed, systolic duration is usually significantly prolonged in nonfailing hypertrophic cardiomyopathy at baseline, independently of the concomitant impaired relaxation, and would be substantially abbreviated by preload reduction. As emphasized by the authors, even in the normal control heart (Fig. 9B), there was a slight disparity between the two models. Similar

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observations were made after vena caval occlusion in conscious dogs with tachycardia-induced dilated cardiomyopathy (65). Another example of the erroneous pitfall introduced by the traditional use of single-beat pressure-volume loops is also illustrated in Figure 9 C, D (64). Here, pressure-volume loops were displayed at increasing heart rates during cardiac pacing in patients with coronary artery disease (C) and normal control patients (D). The downward shift in the dynamic viscoelastic loop in the normal control patients at the higher rates suggested

234

Journal of Cardiac Failure Vol. 3 No. 3 September 1997

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• mismatched systolic-to-total duration • mismatched systolic-to-total duration • impaired relaxation • impaired relaxation • decreased diastolic compliance • decreased diastolic compliance

[Aims for Treatment] • bradycardic agents e.g. beta-blockade • abbreviation of systole by gentle preload/aftedoad reduction e.g, . nitrc-derivatives • diuretics • ACE-Inhibitors • Ca~-channel blockers • acceleration of relaxation e.g. beta-agonists

[Aims for Treatment] • treatment of systolic failure e.g, ACE-Inhibitors = bradycardic agents e.g. • low dosage beta-blockade • (digitalis) • prolongation of systole and acceleration of relaxation e.g. , Ca'-sensitizers (?) • cardiac endothelial protection (?)

Fig. 8. Pathophysiologic evolution of pressure and/or volume overloading. The successive phases of the pathophysiologic evolution of pressure and/or volume overloading of the left ventricle are illustrated by pressure (P)-versus-time (t) curves (dotted lines), in comparison with the baseline pressure curve (full lines) prior to overloading. Phase I is characterized by systolic compensatory prolongation. Phase II, systolic compensation with diastolic failure, is reached when a mismatch of systolic-to-total duration results from impaired relaxation, decreased compliance, or inappropriately high heart rate: the diastolic pressure-volume relation will shift upward and result in exercise intolerance. Finally, phase III is characterized by the simultaneous failure of both systolic and diastolic performance. The aims of treatment in the different phases are a logical consequence of the analysis. ACE, angiotensin-converting enzyme. [Modified from Brutsaert et al. (2), with permission.]

decreased ventricular stiffness, whereas a (more appropriate) monoexponential fit of the (end-)diastolic data points (solid dots) did not reveal such changes. Incorporation of variations in the systolic-to-total duration could perhaps again help to clarify the disparity. By contrast in patients with coronary artery disease, there was a clear upward shift of the (end-)diastolic data points at higher heart rates, reflecting, as expected, increased diastolic stiffness. Figure 10 (66-69,119) illustrates that similarly, in various physiologic conditions as, for example, during interventions that act either through homeometric (70) (Fig. 10A) or through cardiac endothelial (Fig. 10B) autoregulation, care needs to be exercised in the interpretation of single-beat diastolic pressure-volume relations. The disparity of single- versus multiple-beat diastolic pressure-volume relations in all these conditions may again result from alterations in the systolic-to-total duration in the presence of unaltered genuine diastolic pressure-volume relations.

Measurements and Indices of LV Diastolic Dysfunction and Failure As discussed above, the diagnosis of diastolic dysfunction or failure relies on the observation of an inappropriate upward shift of the (end-)diastolic pressurevolume relation or inappropriate increase of any directly related measurement, such as pulmonary capillary wedge pressure and A wave on the apex cardiogram and, more indirectly, transmitrai Doppler A-to-E wave ratio, during exercise (diastolic dysfunction) or at rest (diastolic failure). As will be outlined below, correct management, however, relies on a precise knowledge of the exact cause of such shifts, that is, inappropriate tachycardia, or decreased compliance, or impaired relaxation, or a combination. Evaluation of these causes consists of assessment of (1) systolic relaxation during LV pressure fall and early rapid filling, that is, measurement of systolic duration, of peak relaxation rates normalized for systolic duration, of

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relaxation rate patterns, etc. (Table 2), and (2) multiplebeat diastolic pressure-volume and stress-strain relations of the myocardium (Figs. 9, 10). These can be performed from high-fidelity LV pressure recordings and simultaneous high-speed LV angiograms. In addition, through the wide application of powerful noninvasive techniques there has been increasing understanding of abnormal LV filling patterns and transmitral flow profiles during systolic LV relaxation. From these noninvasive techniques, in particular, echo-Doppler and radionuclide imaging, numerous indices have been derived (71-83). Since the worldwide application of Doppler echocardiography and radionuclide imaging, LV relaxation rate and interval measurements have become easily accessible. It has been tantalizing to speculate (15) that a single abnormal index can be used to identify patients with relaxation abnormalities. It is often forgotten, however, that these, mainly rate, measurements are only indirect measures of

LV function providing no direct assessment of systolic LV relaxation or of diastolic compliance. Moreover, noninvasive measurements of LV systolic relaxation rates during pressure fall and early filling (isovolumic relaxation time, Doppler E wave, dV/dt, time to peak filling rate, etc) without considerations of overall systolic duration have contributed significantly to the many diagnostic misinterpretations of systolic-versus-diastolic dysfunction and failure. In the absence of a disproportionally increased ventricular diastolic pressure at (end-)diastolic volume or of derived indices, these noninvasive rate measurements should be interpreted with caution (50,84-87). Several excellent reviews have been published recently warning against uncritical application of these techniques as the sole basis for diagnosis and therapy (50,52,59,71,84). An approach frequently used by clinicians is the attempt to resolve scientific questions by searching for

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Fig. 10. (A) Homeometric and (B) cardiac endothelial control of diastolic pressure-volume relation. (A) Left ventricular (LV) pressure-volume loops at rest and during exercise, in control and after dobutamine, and at rest and during exercise under beta blockade were obtained from averaged data during a 15-second recording. Changes in ventricular stiffness, or the absence of such changes, should be derived from the true end-diastolic data points (filled circles). The present examples illustrate that such changes cannot correctly be derived from the single-beat viscoelastic approach, because it takes the pressure-volume relation during the entire filling period into account. (B) In the pressure-volume loops (left) obtained before (control) and at the end of a bicoronary infusion of substance P in a healthy subject, single- and multiple-beat methods are concordant in suggesting an increased compliance of the ventricle under substance R Nitroprusside (open symbols in middle and right) consistently decreases the pressure at similar volumes or dimensions in the smaller volume range during the filling period. Yet, one could imagine one and the same pressure-volume or -dimension curve for each patient to fit the true end-diastolic pressure-volume or -dimension points for the control data (closed symbols) and the nitroprusside data together, hence unchanged diastolic chamber stiffness. SV, stroke volume; HR, heart rate. [A Modified from Cheng et al. (66), B (left) from Paulus (119), B [middle] modified from Smith et al. (68), and B (right) modified from Carroll et al. (69), with permission.]

correlations between often widely unrelated parameters. Apart from considerations about the doubtful scientific basis for deriving concepts from such correlations, it can be anticipated that, when applied to medicine, the more advanced a disease state the higher such correlations will be. One example of such circular reasoning is the recent introduction of tan versus ventricular afterload (end- or peak systolic pressure or force) for the evaluation of ventricular performance (32,33,65). This approach was derived from the excellent work of Gaasch and co-workers on the various determinants of myocardial relaxation in vivo (88,89). In a most elegant editorial, Little criticized this approach when uncritically applied as a diagnostic tool, emphasizing that it is fraught with numerous technical

problems and theoretical limitations (90). In addition and apart from the inherent circular argument hidden in this approach, this relationship lacks a conceptual basis and it overlooks the substantial shifts in the instant at which peak systolic pressure and tan are measured when the amplitude of peak systolic pressure is experimentally altered to obtain this relationship. Normalization of tau or of peak pressure for baseline or for peak isovolumic pressure, respectively (42), eclipses these manipulations of data even more. Moreover, experimental data have disproved that it would constitute a load independent assessment of cardiac performance (51). In this regard, we remind the reader that since the early 1970s, there has been general agreement that in the evaluation of systolic ventricular performance during the

Diastolic Dysfunction in Heart Failure Table 2. Indices of Left Ventricular (LV) Systolic Relaxation

as Derived From LV Pressure Measurements, Doppler Echocardiography, and Radionuclide Angiography* Measurements of LV systolic duration (systolic time intervals)

Time from onset (R wave on electrocardiogram)(ms) To opening of aortic valve (PEP or ICT) To closing of aortic valve (PEP + LVET) To peak dP/dt(-) To 10% LVP decline To 90% LVP decline To onset dV/dt(+) To peak dV/dt(+) To onset doppler E-wave To peak doppler E-wave LV systolic-to-total(R-R interval) duration LV filling period-to-total(R-R interval) duration Measurements of LV systolic relaxation rate

LVP fall: Peak dP/dt(-) (mmHg/s) Peak dS/dt(-) (g/cm2/s)(LVwall stress) Isovolumicrelaxation time (interval between aortic valve closure and mitral valve opening, IVRT) (ms) Time constant (tau) of LV isovolumicP fall (ms) Phase plane dP/dt(-) vs LVP (mmHg/s vs mmHg) LV filling (early rapid): Peak dV/dt(+) Time from OnsetdV/dt(+) to peak dV/dt(+) (ms) Peak Doppler E wave (cm/s) E-wave deceleration time (DT) (ms) Time from onset E wave to peak E wave (ms) Peak filling rate (E wave x mitral valve area) Normalized peak filling rate (peak filling rate/LV end-diastolic volume ratio) Duration of E wave (ms) E-wave velocity-time integral (VTI) (cm) * Note that all systolic time intervals should be measured from the onset of the cardiac cycle (R wave on electrocardiogram). LVE left ventricular pressure; ICT, isovolumic contraction time; LVET, left ventricular ejection time; PEP, preejection period.

contraction phase, considerations of time could for pract i c a l - t h o u g h thermodynamically incorrect--reasons be discarded, the argument being that myocardial activation (activating Ca 2+, affinity of the contractile proteins, number of crossbridges, cooperative activity) is sufficiently high during the larger portion of this phase. Eliminating time did allow for evaluation of myocardial contractility or of ventricular performance during contraction based on an analysis of the time-independent force-velocitylength interrelation (91) or of corresponding measurements or derived indices at the ventricular level; during the contraction phase, this approach is still valid up to the present. Hence, in combination with pressure and volume, rate measurements continue to be of practical use in the evaluation of ventricular performance during the contraction phase, that is, during LV pressure rise and ejection. By contrast, investigations during the past two decades on ventricular relaxation during isovolumic pressure fall and rapid filling have revealed that considerations of time and loading are inherent to the process of inactivation

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during relaxation. Decline in activating Ca 2+, detachment of crossbridges, changes in the affinity in the contractile proteins, reversed cooperative activity, and so on are all dynamic processes returning to a state of minimal entropy in diastole (16). During this vulnerable and thermodynamically highly unstable transient toward a state of nonequilibrium with reduced entropy, both time and loading (load dependence of relaxation) are critical determinants of these processes. Given, moreover, the substantial variations in the systolic-to-total duration ratio resulting from shifts in time of relaxation as shown above with changes in load, drugs, and cardiac endothelium, timing and normalization for these time shifts are essential in any analysis of ventricular relaxation. Hence, searching for a load- and/or time-independent measure during this phase is like "noyer le poisson."

Implications for Therapy There is general consensus that diastolic dysfunction and diastolic failure can be treated (1,5,92,93). First, causes or aggravating conditions, such as coronary artery disease and pressure and/or volume overloading, should be corrected if possible. Hence, myocardial ischemia and/or hypertrophy should be prevented or reduced by appropriate therapeutic interventions (94-98); however, apart from this causal therapeutic strategy and apart from some general recommendations common to both diastolic and systolic failure, there are important differences in the pharmacologic management of diastolic versus systolic dysfunction and failure. Although there is no specific therapy for diastolic dysfunction and failure, the goal should be to normalize diastolic pressure-volume relations and to relieve symptoms of pulmonary congestion and exercise intolerance, that is, exercise-induced dyspnea. On theoretical grounds, one should take into account the above three major subgroups of pathophysiologic causes. From these, at least three subclasses of medication can be derived. First, when an inappropriate increase in heart rate participates in causing symptoms of pulmonary congestion or exercise intolerance (ie, exercise-induced dyspnea), low dosage of a beta blocking agent is the treatment of choice (99). Drugs with selective bradycardic properties and devoid of (positive or negative) inotropic properties have been commercialized, but compared with lowdosage beta blockade, with very little success. Apart from a reduction in heart rate and stabilization of rhythm, beta blockade has the additional beneficial effects of protecting the myocardium against the harmful effects of sympathetic overactivity and, possibly, improving myocardial energetics and remodeling the left ventricle. Second, increasing attention has been given to developing drugs aimed at improving the passive properties of the myocardium, for example, either by suppressing inappropriate growth of noncontractile tissue c o m p o -

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nents or by helping to regress myocardial hypertrophy. Examples of this class of remodeling drugs are angiotensin-converting enzyme (ACE) inhibitors and antialdosterone agents (eg, spironolactone). In contrast to the plethora of studies in animals (100-102), studies demonstrating the effectiveness of such drugs in patients with diastolic dysfunction or failure are, however, limited (92,103-107). In view of the above considerations on single-beat pressure-volume relations (Figs. 9, 10), it may be of interest to note that in some very specific conditions, such as hypertrophic cardiomyopathy (Fig. 9A, B), mere unloading of the heart may lead more efficiently to a drastic reduction of congestion, albeit by allowing the operating position of the single-beat pressure-volume relation during the early major filling portion of the curve to descend along an unaltered passive diastolic pressure-volume curve, hence allowing early rapid filling to occur at lower filling pressures in the presence of unchanged diastolic compliance. Similar observations but in different clinical conditions were made with nitro derivatives (Fig. 10B). To what extent such therapeutic improvements (1,93,107-112) result from normalization of the systolic-to-total duration (Fig. 8, middle) requires further investigation. Third, most efforts have been directed at developing socalled lusitropic* drugs, that is, drugs aimed at improving impaired relaxation. The problem with this category of drugs is that only a few studies have examined their action on diastolic pressure-volume relations. Most of these studies have evaluated drag efficacy by merely analyzing relaxation rate measurements, but in none of these studies have considerations about systolic duration been taken into account. The former approach, measurements of relaxation rates, has been summarized in an excellent review (113) for various classes of drugs and for various categories of disease states that lead to diastolic failure. In view of the above, however, whether and to what extent a drug would be positive lusitropic depend only on the degree to which such a drug can improve the diastolic pressure-volume relations in so far as impaired systolic relaxation had been the cause of the upward shift. In other words, whether a drug is positive lusitropic does not depend on the nature of the molecule but on its action in any given disease and, in particular, on the phase during the pathogenesis of the disease. For example, in a broader context of conditions with pressure or volume overloading (Fig. 8), positive lusitropic drugs would be drugs that either abbreviate systolic duration and/or augment relaxation rate whenever there is a mismatch of the systolic-tototal duration with impaired (ie, slowed or incomplete) relaxation (Fig. 8, left and middle) or, on the other hand, prolong systolic duration but also fasten relaxation whenever diastolic dysfunction or failure is accompanied by systolic failure (Fig. 8, right). Hence, when merely refer-

ring to relaxation rate, the terms positive lusitropy and negative lusitropy should be avoided. Even more cumbersome is the still unresolved question whether treating mere abnormalities in LV systolic relaxation rates during LV pressure fall or early rapid filling, when these do not lead to an inappropriate rise in the diastolic pressure-volume relations and, hence, when these do not cause diastolic dysfunction or failure as defined here, would be beneficial to the patient. The above considerations should also be kept in mind whenever new therapeutic strategies (114-118) such as cardiac endothelial protection, calcium-sensitizing drugs, atrial or brain natriuretic peptides, and potassium channel drugs are developed.

Conclusion Despite the profusion of publications on diastolic dysfunction and diastolic failure in the presence of normal systolic ventricular function, the diagnosis, prevalence, prognosis, and management of these conditions remain largely unknown, the main reason being the lack of appropriate definitions of diastolic function, dysfunction, and failure. This lack of consensus among clinicians has been reinforced by the easy access to powerful noninvasire techniques in cardiology. In this review, we took a conceptual approach. Considering the heart as a muscular pump, we discussed the pathophysiology of ventricular relaxation and filling. In addition, we derived a pathophysiologically unquestionable and at the same time clinically useful definition of diastolic dysfunction and failure. With this definition in mind and taking into account stricter criteria for normal systolic performance, we feel that the previously presumed clinical prevalence, prognosis, and treatment of primary diastolic heart failure should be reconsidered.

*Lusitropic (16): The term lusitropic was coined by Phylis B. Katz (A. M. Katz, personal communication)to mean predominantly acting (positively or negatively) on relaxation of the heart both as muscle and as pump. Lusitropic and lusitropy are from the Greek words lusis meaning loosening, releasing, ransoming, means of letting, deliverance from guilt, redemption of mortgage or pledge, emptying, evacuation, emission of semen, unraveling, softening, or divorce" and tropos meaning "turn, direction, way, manner, or fashion." The major advantage of the term lusitropic is its potential usefulness as a general term to describe interventions that preferentially act on relaxation. Unfortunately,it suffers from the fact that it lacks sufficient specificity as for the different phases to which the term is meant to relate during relaxation. It is also not clear what positive or negative lusitrnpy means. Do these connotations refer to changes in onset, in speed, or in extent, or do they, instead, refer to changes in the time pattern of relaxation with little changes in onset, peak speed, and/or extent? Do they refer to inactivation or do they also incorporate effects mediated through changes in loading. For all these reasons and despite the beauty of the term, it has been suggestedby many that it should not be used any longer.

Diastolic Dysfunction in Heart Failure

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