318 JhCC Vol. 22. No. 1

July 1993:318-325

DIRK L. BRUTSAERT, MD, PHD, FACC, STANISLAS U. SYS,

Antwerp. Belgium

Primary diastolic dysfunction or failure is a distinct pathophys- iologic entity. It results from increased resistance to ventricular tilling, which leads to an inappropriate upward shift of the diastolic pressure-volume relation, particularly during exercise (exercise intolerance), The cawes of diastolic failure are inappro- priate tachycsrdia, decreased diastolic compliance and impaired systolic relaxation. Impaired (incomplete or slowed) systolic re- laxation must be conceptually distimgu~he~ from com~asatory

Diastolic failure of the heart is a widely recognized clinical entity. Whereas most cases of diastolic failure are secondary to systolic failure and are part of the terminal picture of congestive heart failure, there also exists a primary form of diastolic failure commonly defined as “a condition with classic findings of congestive failure with abnormal diastolic but normal systolic function at rest” (l-9). Because the first symptoms of congestive diastolic failirre oft*:n occur during exercise, exercise intolerance is considered as an early sign of diastolic failure (10). It is observed as an early event in many clinical conditions, such as hypertrophic cardiomyop- athy (including aortic stenosis and hypertensiilz heart dis- ease) and ischemic cardiomyopathy. In this sense, diastolic dysfunction with manifest diastolic failure during exercise is more common than originally thought (that is, approxi- mately 40% of all conditions of congestive heart failure seem to evolve from diastolic failure). Nevertheless, isolated left ventricular diastolic failure or dysfunction has been shown to be associated with a low cardiac mortality rate; at the same time, it is associated with substantial morbidity (11).

Because there is often confusion about the use of the terms dimtole and diastolic firnction or dysfunction, one should first make clear what component or phase of the cardiac cycle is under consideration. We therefore first consider the term dhtole and reexamine the definition of diastolic failure. We then review some of the known causes and discuss some therapeutic implications.

From the Department of Physiology and Medicine and University liospi- tal. Antwcrp University, Antwerp, Belgium.

Manuscript received July 22, 1992; revised manuscript received Novem- ber 2.5. 1992, accepted December I, 1992.

Address: Dirk L. Brutsaert, MD, PhD, University of AntWerp, Groenenborgerlaan 171, 2020 Antwerp, Ee!gium.

CI 1993 by the American Callege of Cdiology

prolonged systolic c~~tra~t~~~ i&z1 Optimal therapy will d

drugs.

The heart is a muscular pump. In the same way as in isolated cardiac muscle, a decrease irh force and relengthen- ing during relaxation of an afterloaded twitch are parts of one activity transient (that is, part of one contraction-~e~axat~o~ cycle [or “systole”]), a decrease in ventricular pressure and an increase in ventricular volume during early rapid filling are closely related to this activity transient and should therefore be considered as part of sirstole (12). On these conceptual grounds, the term dinstole should be restricted to the phase during the cardiac cycle that separates two such consecutive contraction-relaxation transients, that is, to the diastasis and the atria1 contraction phase, or approximately the last 5% to 15% of volume change during cardiac filling on a pressure-volume diagram (Fig. I, points 3 to 4).

The previous definition of diastolic failure should there- fore be restated as follows: “a condition resulting from an increased resistance to filling of one or both ventricles, leading to symptoms of congestion due to an inappropriate upward shift of the diastolic pressure-volume relation (that is, during the terminal phase of the cardiac cycle). Whether this upward shift of the diastolic pressure-volume relation is caused by increased pressure for a given vcalume or by increased pressure inappropriate or disproportionate to the increase in volume or whether the shift is symmetric or asymmetric will not affect the henaodynamic consequences: pulmonary wedge pressure will increase (10). Accordingly, the upward shift of the diastolic pnss:u-e-volume relation may lead to symptoms of congestion, often at rest but particularly during exercise, manifesting as exercise intoler- ance. This shift may ajso lead to subendocardial ischemia and, if chronic, to remodeling and hypertrophy of the ventricle.

A common problem in science is the difficula~~ in formu- lating the appropriate questions. In the publisher; reports on

DECREASEO q lASlOLlC

‘COMPLIANCE

d_xlivision of the cardiac cycle into systole IS) illustrating the causes of diastolic faib-e: CONT

, IC .- iso~oiiimerric coaPracPion: IR = isovolumetric relaxation; = pressure; = rapid filling phase; V = volume. 1 = aortic valve closure; 2 = mitml vdvk opening; 3 = end of early rapid filling; 4 = e~d-d~ast~~~. Modified from Brutsaert and Sys (12).

ary diastolic failure, two basic questions have been

efore cohltraction I!? many in-

ventricular relaxation, inc dominantty caused by ab may be di2gncsed by so-ca late relaxation measure- ments, such as a prolongation of tau or a decreased rapid filling rate. If, however, only the ve;-j early time course of relaxati@cl is impaired (for example, because of impaired contractile pro ~nter2ctio~ and detachment), meas ments that into ate this early phase of relaxation, sue stroke aork, ejection fr2ction, end-systolic pressure-volglme relation. ;eak neg2Gve first derivative of Ieft rc I# alar pressure (dP/dt) may be abnormai even in the presence of norm21 Bate rei2xtitios indexes. In most clinical conditions, however, contraction 2nd relaxation abnorm2!ities are

A

IMAPPROPRlAW TACHVCARDIA

e causes are

ab~~rm2l~ties of t result in decreased

all three act in concert.

ure, the eliciting patbo-

,part from direct compression

~e~cardia~ pressure, which will be transmitted to the left ventricle, wherf. it will ftirther increase the diastolic

320 BRUTSAERT ET AL. DIASTOLIC FAILURE

JACCC Vol. 22, No. : July 1993:.318-325

Table 1. Various Conditions of Decreased Diastolic Compliance as Causes of Diastolic Failure

Structural and geometric changes of the ventricular wall

Restrictive csrdiomyopathg (interstitial fibrosis. edematous infiltration,

collagen remodeling, amylddosis, hemosiderosis)

Primary and secondary hypertrophic cardio~lyopathy, asymmetric septal

hypertrophy Postmyocardial infarction scarring, aneurysm

Endo~%yGZXdia! Co&, i%ii&iSi~SiS

Ischemia (rigor bridges?)

Extraventdcular causes ____;_:_; _I Rikiiiizii ~.VIIJLLOIIII @WiCalliiai eu”usion, constriction, venrricuiar

enlargement)

Right-left ventricular cross-talk

Pulmonary diseases

pressure-volume relation, with no direct repercussion on systolic function (17). Equally important and often related to conditions of pericardial constraint is the potential functional importance of right-!eft ventricak interdependence in tori- ditions of acute unilateral right ventricular overload. The resultlag “cross-talk” may have implications with respect to some more specific clinical conditions or to some forms of treatment; for example, pulmonary embolism or drug inter- ventions that act on r.he loading conditions of the right ventricle may indirectI,* also affect measured left ventricular compliance during diaztole.

A common cause of diastolic failure is impaired (or slowed or incomplete) systolic relaxation of the left ventri- cle. Impaired nlaxation must be distinguished from delayed or retarded relaxation. the latter condition should preferably be called prolonged contraction (Fig. 2). Although both conditions are often barely distinguishable in clinical cardi- ology, it is important to make the distinction on conceptual

Figure 2. Impaired sysMic relaxation (right) cos.ipared with condi- tions of prolonged systolic contraction Oefi). Impaired systolic relaxation, but not prolonged contraction, can be a cause of diastolic failure. a, b, c = without (a) or with (b, c) physiologic changes in rate of relaxation; -dP/dt = peak negative first derivative of left ven- tricular pressure; 7 = time constant of isovolumetric relaxation: other abbreviations as in Figure I.

e

‘etayed 1 relaxation retarded _I slowed incomplete relaxalion

grounds and for practical diEgnostic and therap erations. Whereas impaired systolic relaxatio pathophysiologic process that is always delete long run, prolonged contraction is ~~ysi~~~gi

in itself deleterious. systok The primary event

y prolong ion is a delayed onset relaxalisii, regardless of MWMIei ir iS accompaiiied bji pii_ iologic changes ia the rate of relaxation. An upward shift of the pressure-v~~~rne ~elatiQ~ during true diastole is not observed in cQnditio~s of co tion; an exception to tkis rule e seen at i~approp~iate~ high heart rates. The caus

k frogs and k&r by Sta rtrophy, at least d~r~~~ t

nary vascular (20-22) and e~docardial (22-27) (Fig. 3. right) induce similar changes in the systole. Substances such as angi~te~si~ II, ca (alpha,-agonist activity) a vasopressin, whose levels may all be increased tions of heart failure, elicit a similar response in systolic duration (25). As stated before, the mere prol~~gat~Q~ sf

can be accompanied by moderate (that is, phys- nges in the rate of co traction or relaxation.

Physiologic modulation in the rate of contraction or relax- ation will depend on sympathetic drive (28), plasma cate- cholamines (beta-adrenergic agonist activity) (29), instanta- neous changes in load during the cardiac cycle (30) and frequency potentiation induced by changes in heart rate (29),

relaxation. By contrast, the primary event in impaired systolic relaxation is an inappropriately decreased rate or decreased extent of relaxation. As a consequence, relaxation extends into true diastole, with an upward shift of the pressure-volume relation. Ischemia and hypertrophy (at least iin the advanced phase of hypertrophy), as in aortic stenosis or hypertensive heart disease, are common causes of impaired relaxation. Nonuniformity of ventricular performance, which often accompanies these two clinical conditions, may also constitute a cause of impaired reiaxation regardless of the degree and extent of underlying ischemia or hypertrophy (31). In all of these clinical conditions, an inappropriately decreased rate or exient of relaxation may indeed result from disturbances in the so-called triple control of relaxation; that is, 1) from impaired activation-inactivation (calcium homeostasis, sar- coplasmic reticulum pump, contractile proteins); 2) from excessive changes in load; or 3) from inappropriate nonuni- formities of load and activation-inaciiva,tion in time and

cts of the three maj~ ulators of cardiac perfor- mance on systolic duration of press ime curves of canine left ventricle (22). For comparable changes in timing of relaxation, the rate-and pattern of relaxation were influenced d~ffe~e~t~y by the three types of modulation. Left ventricular presjurc (LVP) (top), first derivative of left ventricula PIdt ;‘?I. ;ine, nid91:) and phase-plane (d&‘/d? vs. LVP, *ings are displayed. Ir

after dula- lume

(heterometric autoregnlation or Frank Starling mechanism). Com- pared with baseline (big B, lowering left ventricular volume and pressure (k10w) indwced slightly lower rate bf pressure increase and early onset of decreaw in left v ricular pressure. As evident from the phase-plane tracing (hot panel), initial decrease in left ventricular pressure and peak negative dP/dt were slower at the lower end-diastolic volume, in contrast to the late decrease in left ventricular pressure, which was faster (i.e., projected below control

space. An extensive discussion of the triple control of

ing on a given disease and on the instant during the devel- opment cf tha: disease, these two features can be present separately or in combination. This can be best illustrated by examining the ~atho~hysio~ogic evolution of pressure or volume overloading, or both, of the left ventricle (as in Fig. 4). Of importance is the general pattern trf the pathophysio- logic evolution with time and the pattern of the ~~divid~l pressure e~rves in each cardiac cycle. Zn the evolution of pressure and volume overloading with time, several phases can be distinguished. 7%: initial phase is compensatory, with typical prolonged corztraction and, hence, delayed or re-

duiatk of cardiac pa-for

calcium chloride (0.05 mgkg body weight; of rise of pressure; left ventricular pressure

h pm4s, ~odu~a~i~~ of cardiac perfmnance by e helium (eadotheli~m-mediated autoreg~lati0n) (20

The endocardial endothelium was functionally inactivated by higd power. high frequency intracavitary ultrasound E- ). Compared baseline (+); peak ?eff ventricular pressure and peak positive remained unaltered. The decrease in left ventricular pressure was induced prematurely and revealed a slightly accelerated cciurse, evidenced by a slight increase in peak negative dP/

c in left ve~t~co~ar pressure on wel) slightly belo;w the baseline

; this may result fro tarling mecha~ism~, myocaudral h plasma levels of various component sin), among other factor5. In the

inappropriately decreased rates of relaxation impairment of relaxation may disturb the clinical picture. Along with decreased compliance and increased rt rate, impaired relaxation may result in an upward s of the ress~re-volume relation g diastole (Fig. 2, rig

resulting in exercise lntoler Hn the third phase of Figure 4, conco~~ita~t systoolic failure develo s. Systolic failure results in ioss of systolic com~e~sat~o~ (that is, in decreased co~tract~~~ty during contraction and early

e capacity to piOlOnU& systole; inst 4, the onset of relaxation is often induced ~rerna~~r~~y further complicates the already existing clinical picture of diastolic failure.

322 BRUTSAERT ET AL. !%4STC!L!C FAILURE

JAW Vol. 22, No. I July 1993:318-32.5

systolic compensation with diastolic failure

compensalory,prolonged contraction

(delayedlrelarded relaxation)

compensatory prolonged

and I I

impaired

relaxation

decreased

6ompliance

. ACE.lnhlbllw~

. dlwotko: load 1

Figure 4. Successive phases during the pathophysiologic evolution of pressure or volume overloading, or both, of the left ventricle. Only pressure (P) vs. time curves are shown. The P curve in full is the baseline P curve before overloading. ACE = angiotensin- converting enzyme; ANF = atria1 natriuretic factor; CAMP = cyclic adenosine 5’-monophosphate; cGMP = cyclic guanosine S- monophosphate; NEP = neutral endopeptidase; PDE = phospho- diesterase; TnC = troponin C. In the data at bottom, 2 = increase and I = decrease.

In patients with ischemic cardiomyopathy, these three phases may, at a myocardial level and at any given time during the pathogenesis, develop simultaneously and inter- act with one another at the ventricular level. This may explain, at least in part, why diastolic dysfunction in differ- ent types of experimental and clinical myocardial ischemia, such as coronary occlusion, rapid pacing in the presence ol” coronary stenosis, multivessel coronary heart disease, reperfusion and stunning, may be rather complex and not easily predictable.

Accordingly, a!though it is clear from the latter two examples of hypertrophic and ischemic cardiomyopathy that the causes of diastolic dysfunction and failure are multifac- torial in most cardiac diseases (that is, based on a combina- tion of the three major causes described [Fig. I]), these pathophysiologic concepts should be kept in mind when developing a diagnostic and therapeutic strategy.

Implicatioas for the evaluation of relaxation. Figures 3 and 4 illustrate that a full evaluation of systolic relaxation (that is, of isovolumetric pressure decline and early rapid filling), should encompass 1) measurements or indexes of i de of pressure decline and early rapid filling (peak negative

urnetric relaxation t rate); 2) measurements of th rate) of the latter rate indexe patterns, including early,

ltaneous measurem

longed contraction and of impaired relaxation. The need to examine rate patterns during the entire course of relaxation has been emphasized by us before (12). This point is also obvious from phase-plane dP/dt versus pressure analysis (Fig. 3). where the rate of early pressure decrease, peak negative dP/dt and rate of late pressure decrease are re- vealed as three distinct aspects of relaxation. In most cases, peak negative dP/dt results from the transition from early to late rate of relaxation and may therefore not be representa- tive for the entire process of relaxation. Moreover, early and late relaxation rates may be affected differently and may oiren change in opposite directions (30).

By extension, these measurements of systolic perfor- mance during relaxation should, in many clinical conditions or after various pharmacologic interventions (32), not nec- essarily be expected to correlate with measurements of diastolic function, such as diastolic pressure-volume rela- tions.

r treating patients w to improve exercise tolerance by dimin upward shifts in the diastolic pressure-volume relation (Fig. 5). Although various drug regimens have been tested,

JACC Vol. 22, MO. I July 1993:318-325

dependsupon

/\

type phase of during

cardiac diastolic disease failure

:atl ion of drug therapy for the treatment of diastolic

ina ropriate Pachycardia

failure. Abbreviations as in Figures I and 4.

no specific therapy is available. on the basis of the preceding classification of three cause5.

ould similarly conceive three classes of potential drugs. hen inappropriate heart rate is the

rugs are the treatment of g agents, calcium channel conditions (such as atriai

fi.br:!!ation). digitalis IL.. _ .._ a\‘p 311 beer! sncressfti? in imprr?ving

exercise tolerance due to primary diastolic failure. There have been several recent developments in such drugs. Some new molecules are potentially interesting with specific bradycarlic properties but, unlike the other drugs of this type, are devoid of direct inotropic actions on time m;‘ocar- dium (33). Ideally, these drugs should preferentially sup- press inappropriate increases in heart rate during exercise, with little or no effect on heart rate at rest.

Little attention has been directed tow ’ the treatment of fundamental changes in myocardiai co the recent introduction of the concept 0 particular in the prevention 3f cardi brosis and regression of hypertrophy, has emphasized potential use of so- called remodeling drugs (35,361. For example. various angiotensin-converting enzyme inhibitors and, more re-

Treatment with bib-0

ate a relation to reiaxairvn a

ing in three successive

ng on the relative contribu- tion of each one bases on ve~tr~c~~a~ perfor- mance at any given mo

action on drugs. Diuretic drugs consistently improve exercise toier- ante with little change in systolic ~e~orma~ce~ probably directly through their effects on both right and left ventric-

iastolic loading conditions as ;Nell as indirectly by reducing pericardial constraint on the left ventricle and on ventricular cross-talk (10,38). Calcium channel blockers

‘hitropic is derived From the Greek words AM&i, meaning lOOSk

releasing. ransoming, means of letting. deliverance from guilt. redemption of mortgage or pledge, emptying. evacuation, emission of semen. unraveling, softening or divorce, and ~pono(,ir. meaning turn, direction. way. manner or fashion. The tetm hitropic was coined by Phyllis B. Katz to mean predom- inantly acting (positively or negatively) on the relaxation of the keart both as muscle and as pump. The major advantage of the term /~siii’nPif. (that is. its potential usefulness as a general term to describe interventions that preferen- tially act on relaxation) unfortunately has the same limitations as the term hotropic for the contraction phase. In particular. it lacks SUffiCient SPeCifiCitY

for the different phases to which the term is meant to relate during relaxation. Moreover. does it refer to changes in onset. in speed. in extent. or to changes jn the time pattern of relaxation with little changes in onset. in peak speed or extent. or a:\ ofthese? Does it refer tc kactivation. or does it also incotpot3te effects medi,,,ted through changes in loading? (11).

324 BRUTSAERT ET AL. DlASTOLIC FAILURE

have been shown to improve exercise intolerance in phase? I and II shown in Figure 4 for still largely unknown reasons (including relief of ischemia, decrease in intracelhdar Cd-

cium ioR overload and improvement of inappropriate non- uniformities [39-421) but are in our opinion expected to be deleterious in phase III. Nitrates, nitroprusside and related molecules have been shown to consistentiy decrease the diastolic pressure-volume relation (43,44) and therefore to improve exercise tolerance (10). A diminished diastolic load of both the ieft and the righ; ventricle and decreased peri- cardial constraint have been invoked to explain this benefi- cial effect. Equally important but largely overlooked in all previous studies, however, is the direct Sect cf nitrates+ nitroprusside and related molecules in abbreviating systolic duration, with no effect on contraction dynamics, by increas- ing myocardial intracellular cyclic guanosine Y-monophos- phate level (45). Such an effect could be particularly benefi- cial during phase II of the example shown in Figure 4. Similar to nitrates and nitroprusside. atrial natriuretic factor (45,46) and neutral endopeptidase inhibitors, which inhibit the breakdown of atria1 natriuretic factor, would at least theoretically also be expected to be beneficiai in the treat- ment of diastolic failure. Partial beta-agonists may slightly shorten the duration of contraction, with little change in heart rate owing to the concomitant beta-blocking proper- ties. Such treatment could be advantageous in phase II, where it would suppress excessive systolic compensatory prolongation while simultaneously accelerating the rate of relaxation. The latter drug actions would be deleterious, however, during monotherapy in the terminal phase of combined systolic and diasto!ic failure (47). For similar reasons, as well as for their vasodila,tor properties, phos- phodiesterase inhibitors may also decrease the diastolic pressure-volume relations, thus improving exercise toler- ance in patients with diastolic fnilure ‘during phase II, but should be given with caution in phase III.

As explained b&ire, in many diseases (for example, ischemic cardiomyopathy and, more conclusively, when in combination with pressure-overload hypertrophy [13]), the somewhat arbitrary but conceptualiy useful subdivision into the successive phases shown in Figure 4 is not always easily appreciated because various segments of the ventricular wall

may undergo successive phases at different moments and at different speeds. Here, the efficacy of a drug will depend on the relative contribution of any one of these phases present in the various segments of the ventricular wall at any moment during pathogenesis,

Of interest, drugs with a positive or a negative Iusitropic action in a given clinical setting will, in other conditions, not

necessarily act as positive or negative lusitropic “drugs.”

VENOUS calcium-sensitizing drugs (48) as well as sodium

channel openers (49), have often, but erroneously, been referred to as negative lusitropic because of their contrac- tion-prolonging effect. These cardiotonic drugs might indeed be less desirable in phase KI of the example shown in Figure

4. During phase III, however, and in combination with

JACC Vol. 22, No. I July 1993:318-325

a~giote~si~-converting enzyme cium or sodium sensitization m and, hence, be positive lusitropic. agonists and calcium channel blockers might, stated, be useful in phase HI but not in phase words, there is no single standar treatment of diastolic failure.

compensatory prolonged contraction (delay relaxation). Treatment of diastolic failure

feasible but necessitates a clear understanding of the etiol- ogy, pathogenesis and pathophysiology of the ~~deriyi cardiac disease. Optimal therapy will depend on the type disease, on the phase during the pathophysiologic evolution of the disease and on the coexiste ative contribu- tion of various CQrn~e~sato~y or satory mecha- nisms. This often requires a comprehensive analysis of hemodynamics ifor example, with combined, echocardio- graphic and Doppler studies), completed, whenever neces- sary, by catheterization, both at rest and during exercise.

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