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Effects of induced asynchrony on left ventricular diastolic function in patients with coronary artery disease
Effects of Induced Asynchrony on Left Ventricular Diastolic Function in Patients With Coronary Artery Disease SANDRO
BETOCCHI,
LEONARDO CARMEN
PACE,
MD, FEDERICO MD, ANDREA
SALVATORE,
PISCIONE,
CIARMIELLO,
BS, MARCO
SALVATORE,
MD, BRUNO MD,*
VILLARI,
PASQUALE
MD,* MASSIMO
MD,
PERRONE-FILARDI, CHIARIELLO,
MD,
MD, FACC
Naples, Imiy
Obimdves. This study was denimed tu incraw asynchrony with &uautial alriuve&icuIar CLV) pacing and tu -study i& e8wt.s un left ventricular iwvolumetric reIaxatIust.rapid filllna and stiPes% Backpmd. L?fl venlriculnr nonuniformity is a major deter. minaut of diastdic fun&n. Methods. Tbttn ustients with cumnm~ artew disease were studied by simultm&s equilibrium mdiiuclid; ongi~aphy mod card&x czdbeladzPtii during atrial aud AV pa&g. EJsctIw fraetlun and pear fillklg rate were mersurcd by radlunucllde pngiwmvhy. Raiunal aaalysb was ubtalued lw aaalyzb~ Ilateacttvlty cwve~ 2 four IeR &Iriadar sectors;-systolic s&i dia. s(olic asyuchruny were evalusted m the cueltiebnt d varlatII uI lime tu end-systrdc and, respwtively, time to peak tilling rate in the four secturs. Cardiac index and I& vmlrkulnr pressure were measured si:h high fidelity ealktws at cardiac adbeterb.mtlun.
The timeconsinn, orlmvdumdrlc rddk!Q was derived rwln kfl vrotrkdsr prasure. Pressure-volume loops were assembled aad coastantsufchambtr stillness were cvmputed. Rcfulu. Alrb~vmlrkulsr path@ kd lo a-dccrea!e ia card&c l&x(3.7 * 0.9tu3.3 * 0.8litem/mln per m’, 9 = 0.01) and peak Rlltng rate (352 t 125 tu 287 f 141 mUs, p = 0.03; 2.4 * 0.8 to 2.0 + 0.8 mddlastdlc cunnfs/s, 9 = 0.02; 4 t I.3 tu 3.2 * 1.0 strole camtrls. p = O..wB). TIK ttw amstan* uI Isuvdum&k relaxatkm lnrmased (57 * IO to 44 * 12 ms, 9 = 0.04) and the #&al dlaslulk lwessurc-wlume relnliun shUted upmrd. Conrlurions. Atriovmtrkulu wiq lndms kIl ventrkular olyafarmy, rhlch la asucl&d with a sknver rate dIsuvdumet. rlc ldaxallm. R lsoveiu~ reIaxatIlm lasts after the Smug phasehas bqun, thereby re4uetnl the rats of r&d Wlq. U An Cdl C&id 1993;21:1I24-21)
Left ventricular diastolic function is an active energydependent phenomenon governed by ths interplay of several factors, such as intrinsic relaxation properties and loading conditions. Brutsaert (1) has drawn attention to the role of spatial and temporal nonuniformity as a modulator of left ventricular mechanics. In many cardiac diseases, asynchrony plays an important role in determining diastolic dysfunction. Crass-sectional studies (2-S) in patients with coronary a:!eIy disz:? !,a-ve shown that an increase in various indexes of left ventricular asynchrony is associated with a decrease in peak filling rata, a clinically useful estimate ofventricular filling properties. In these studies, however, poor left ventricular synchmnicity was often associated with impairment in systolic performance, which is known to affect diastolic function by itself, thus making the interpretation of these data complex.
Swntanews asynchrony, in conlrast, has been shown to imp.& left vent&lar mefhanics in patients with normal svstolic function and left bundle branch block (6) or seamen&l early relaxation (7). Because it is known ihut i&laied diastolic dysfunction is capable of inducing symptoms of congestive heari failure even when systolic performance is preserved (8-10). it is relevant to study the impact of increased left ventricular asynchrony an diastolic mechanics in a setting where asynchrony varies while the other determinants of diastolic- fun&n remain unaEected. Several investigators (II-161 have induced asynchrony in the ewerimenta~anitnal by either right ventric&r or a~riovenlric~lar (AV) pacing ~4 intmcorottary illjeclion of beta-agonist drugs, associated with little or no modifications in hemcdynamics and systolic performance, and have shown that induced asynchrony impairs isovolumetric relaxation. This affect is also present in humans (17.18). The outcome of pacing-induced asynchrony on left ventricular filling has been less extensively investigated. In dogs. peak rates of wall thinning and cavity filling decreased with sequential right AV pacing as compared with sinus rhythm (13). No data are available on the influence of as$chmny on left ventricular filling dynamics and compliance in humans. The present s:udy was designed to assess the effects of
,*cc”OI.z1.NO April IW3-1124.3,
5
“ETocCHl
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*SYNC”RoNY *ND D,AsmL,C FUNCTION
t1.e physiologically sequaced right AV pacing on isovolumetric relaxation and early and late filling properties in patients with coronary artery disease.
Methods Patient selection. We studied I3 p.aents who underwent diagnostic cardiac catheterization and coronary angiagraphy for evahmtion of chest pain. They were enrolled according to the following criteria.: I) no recent or healed myocardial infarction as assessed by history and electrocardiogram (KG); 2) no associated cardiac or pulmonary diseases, hypertension, diabetes mellitus or history of alcohol abuse: 3) chest pain with mild to moderate symptoms, enabling discontinuation of therapy; 4) left ventricular global and regional wall motion normal at screening by two-dimeosional echocardiography or radionuclide angiogmphy. or both; 5) sinus rhythm with normal AV conduction without right or left bundle brooch block. There were and 2 women. ranging in age from 43 to 62 years (mean 50). Seven patients were referred fmm other institutions for cardiac catheterization and coronary tieriography; the remaining six patients bad either abnormal ejection fraction response (
II men
,125
voltage was ineffective. it was increased to s6 V; ii this voltage proved ineffective, catheters were repositioned. The AV pacing delay was set as long as possible and assessedas follows. The interval between &al sod ventricular stimuli was set very short and scanned up until the vcntriculirr spike became ineffective; then the delay was reduced until the right ventricle was again captured. Effectiveness of ventricular stimulatioo was checked by iospection of the KC- (IeR bundle branch block appemance). The mean time interval from P wave to QRS complex (SD, measured on the surface ECG at a paper speed of 250 mm/s) was I62 t 22 ms in atrial and 132 2 25 ms in AV pacing studies (p < 0.001). Both atrial and sequential AV pacing studies ‘were performed at the same heart rate just above the spontaoews sinus rhythm (86 C I5 and 87 2 I6 beatslmin. respectively, p = NS). cardiac ca&et&&n ami hail tMaalemenk. Patients were in the fasting state and sedated with diazepam (IO mg orally). A 7F Swan-Ganz thermodilution catheter (Edwards Laboratories) was percutatteausly introduced through the right groin into the pulmonary artery to measure cardiac output and pulmonary artery and wedge pressures. A 7F pigtail high lid&y transducer-tipped catheter (Sentron) ws also percutaneously advanced into the IeR ventricle for measurement of le% ventricular pressure and. eve”tually. cineventriculography. Systemic arlerial pressure was monitored through the side port of the arterial sheath. LeR ventricular pressure and its 61~1derivative (dP/dt) were recorded al a paper speed of 250 mm/s. LeR ventrieokir pressure was also sent to the gamma camera-computer system 10 construct pressure-vdume cmves. High speed le% ventricular pressure and dP/dt wves were digitized at 4-ms intervals for calculation of the time consfant of isovolumetric relaxation, using the shining asymptote technique (19). starting fiwn mirdmal dP/dt and ending when presswe was I/e of its initial value (20). The equation P = B + Ae”, where P is pressure. B is the pressure asymptote, A and k are filling constants, e is the basis of natural logarithm and t is time, can be diierentiated, yielding the iormula: dP/dt = kP - C. By linear regression analysis, the slope k and the inarcept C of this regression can be calculated; the time constant of isovolumetric relaxatian is then the negative reciprocal of the slope (that is, -I,!& and the pressure asymptote represents the pressure value at dP/dt = 0 (that is. the pressure value at which pressure stops decreasing, calculated as CM. Cineventriculogmphy was performed immediately after the end of the expmimental protocol, duringatrial or sequenlial AV pacing (whichever came last) and in a 3v right anterior oblique view. The first well opacitied sinus beat not following an ectopic beat was analyzed for enddiastdic volume (21). using a graphic tablet interfaced with a corn-puter (Digital PDP 11134).Coronary arteriography in multiple views was then prformed for diagnostic pm-poses.
Rstinuclide angicgraphy. Equilibrium radionoclide angiography was performed with the patient lying in the supine position on the cardiac catheterization cradle. Red blood cells were labeled in vivo with 20 to 2S mCi of technetium 99-m and counts were collected by a small field of view Angercamera(Siemens LEM ZLC), equipped with ageneral powxe, parallel hole collimator oriented in a 45” or “best septal” left anterior oblique view with a If caudal tilt. Images were acquired with a 2X digital .zmo in frame mode by ECG gating at a framing rate of 50 f?ames/s (that is, 20 ms/frame). At least ISO,OOO counts/frame were collected in the fust study; as the second study was acquired for the same period of time as the first one so that the two studies would consist of the ssme number of cxdiac cycles (heart rate was kept constant). The use of yielded extremely similar durations of the cardiac cycles that were averaged to build a representative cardiac beat: hence no “fall” in late diastole occurred in time-activity curves. This allowed reliable measurement of late diastolic events. The time-activity carve recorded in the second study was expressed in ml by normalizing its end-diastolic number of counts to end-diastolic volume measured by contrast angiography. The first time-activity corw was then corrected for isotope decay and expressed in ml as follows: the eoddiastolic volume in the second study was multiplied by the ratio of end-diastolic number of coonts in the first and second x&s. Ejection fraction was calculated on the “raw” timeactivity carve, whereas peak filling rate was computed after filtering using a Fourier expansion with Rve harmonics as the maximum of the first derivative of time-activity cwves. It was measured in ml/s and further normalized by enddiastolic as well as stroke volume to acwnnt for changes in both enddiastolic volume and systolic function. Time to peak filling rate was defined as the interval from the R wave on the ECG to peak filling rate. Left ventricular regional analysis was performed with the use of a computer algorithm that identified the center of gravity of the left ventricular region of interest and divided it into five sectors of equal anele (72’) slartinr! at the 3 o’clock position and proceeding co&xclockwisey The second region, which includes the area ofmitral and aortic valves, was not used in the analysis. Time-activity curves from the four remaining sectors were filtered after background suhtraction, using a Fourier expansion with three harmonics to minimize errors resulting from both fitting and counting stalistics. We measured time to end-systole (as the time from the R wave to minimal counts) ineach oftbefour sectorsand evaluated systolic asynchrony of the left venlricle by mea. wring the coefficient of variation of the four values of time to end-systole. Likewise, we calculated diastolic asynchrony by computing the coefficient of variatirr, of sector time to peak filling rate. Further details on radionuclide angioAraphic methods as well as the accuracy and reproducibility of these measure-
pacing
mews in our laboratory have been previously reported Cz23). Loft ventricular pressore-volume analysis. Left ventricular pressure measurements were sent to a cuslom-designed interface (Medie s.r.1.) connected to the gamma cameracomputer system (Digital PDP Such interface wrote the pressure values into an assigned line oo the 64 x 64 scintigraphic matrix. In this way, left ventricular pressure carves have the same gating point and framing rate and represent an average of the same cardiac cycles as those for the lime-activity curves, with which they were combined to create high temporal resolution pressure-volume loops. Endsystolic pressure-volume ratios were calculated. The let? ventticolar constaa! of chamber stilTness (kl was measured by using the simple elastic model with shifting asymptote method on the part of pressure-volume loops from minimal pressure lo enddiitole, according to the formula P = B + A?‘, where P is presswe, V is volume, A and k are fitting constants and B is the pressort asymptote (20). Fitting was achieved by a computer program that allowed nonlinear fitting iterations (24). A further estimate of I& venlricular compliance was accomplished by measuring pressures and volumes at three discrete diastolic points: lowest left ventricular pressure, enddiastole and the midwint between these two landmarks (19). Data for all the ‘patients were pooled together to constract “average” diastolic pressure-vdume curves for both pacing modes. No attempt was made at fitting regional pressure-volume carves to measure a regional umstaot of chamber stitTness. Instead. a I-point average approach was used as for global analysis. Absolute sector volumes were not measured. After background subtraction and correction for th isotope decay, end-diastolic counts in the atrial pacing studies were considered equal to IO0 aad end-diastolic couus in the AV pazing studies were accordingly nonaalized. StalisUcal methods. Data are expressed as mean value f SD everywhere but in Figures 3 and 4. where bars represent SEM for the sake of clarity. Paired t test and linear regres sion analysis were used when appropriate. Comparison of the three measures ofpressure and volume between the two studies was accomplished by two-way analysis of variance for repeated measures and poslhw paired I test with Bonferroni’s correction (24).
1l/34).
Results Baseline tidings. Two patients had nonsignificant (<75%) stenosis in one and two major coronary vessels. respectively. Three patients had one-vessel, five had twe vessel and three had three-vessel coronary artery disease. No patients had reduced (~2.5 liter&in per m’) cardiac index; two patients had elevated mean pulmonary wedge presscre (>I5 mm Hg) and left ve&-icular cod-diastolic pressure (>I2 nun Hg) at baseline.
EXfectsuu asyuchmuy. As expected, both systolic and diastolic estimates of left ventricular asynchrony exhibited a large and significant increase (Tables and 2). In particular. the coefiicient of variation of time IO end-systole increased in 10 ofthe 13 patients and the coefficient of variation of time to peak tilling rate increased in II.
I
pacing significanily decreased maximal dP/dt &I cardiac index. Left ventricular systolic pressure, end-systolic pressurelvolume ratio and pulmonary artery wedge pressure were unaltered. whereas end-diastolic pressure showed a nonsignificant trend toward au increase. End-diastolic volume showed a nonsignificant trend toward a reduction and decreasedwith AV pacing in 9 of the 13 patients. whereas end-systolic volume and eiection fraction remained UL-
changed. E&bun dixtulic fnnc&m. Earlv diastolic function was impaired by sequential AV pacing compared with function during atrial pacing. The time constant of isovolumetric relaxation lengthened and all three estimates of peak tilling rate (in m!Is and normalized by enddiastolic and stroke counts/s) were reduced (Table 2. Fig. I). Furthermore, peak filling rate decreased in IO of the patients in whom sequential AV pacing led to au increase in diastolic
tt
Tab* 2. Meets of Scqwntial Alrioventricular (AV) Pacingon LeR Ventricular Diastolic Function
asynchrony: the only patient in whom peak filling rate increased despite an increase in diastolic asynchrony had an elevation in pulmonary wedge pressure by >SG% (from 7 to I I mm Hg), accounting for the increased rate of filling. Figure 2 shows an example of changes ih volume. pressure and pressure-volume curves in a representative patient. The upward shii in the diastolic portion of the pressurevolume loop is evident. The constant of chamber stiffness showed a puor fit (p > 0.01 on the aoaduess of fit F test) in two atriel vacinp.studies and seven ~equeutial AV pacing studies (that is, 6ve additional patients). In the remaining six patients, the constant of chamber stitTness did not change (fmm 0.019 ? O.CQ5to 0.021 f 0.006 mm Hglml~. Interestingly, its asymptote increased in five of the six patients. almust reaching the significance level despite the small subgroup size (fmm -3.5t 5.2tuo.1 ~3.7mmHg,p=0.07). To overcume the inadequacy of fitting in sequential AV pacmg studies. the diastolic pressure-volume relation was further studied using the 3-point discrete approach already described. No differences were seen as for volume; diastolic pressures. however, were signiticuntly higher by two-way analysis of variance in the sequential AV pacing study (Fig. 3). When differences in pressure were analyzed at each landmark, a signi%autt increase was seen at the lowest pressure (from 0.6 ? 3.2 to 2.9 + 3.6 mm Hg, p = 0.019) and mid-diastole (from 4.6 + 4.2 to 6.9 f 3.9 mm Hg, p = 0.03). whereas changes at enddiastole did not reach the significance level (from 10.6 t 5.4 to 12.2 + 5 mm Hg, P = 0.06). The same discrete 3-point approach was used in the analysis of the regional diastolic pressure-volume relation. There were no changes in area in the septet and apical sectors, whereas we observed u significant increase in relative area in the porterolateral sector and a nondgniticant trend toward an increasein the lateral sector (Fig. 4).
Iigurv 1. individual values or the time eenstam of isevolumeoic relaxation tit @en ktt penett end peak tilling rate narmalized tu end-diastolic ceunts (EtXYs (ton right naeet). stroke ceunts (S% th+ttme ten pan&) and expressed in mtIs (hettan right ganel) during atrinl pacing and sequential atrioventricular (AV) pacing. Open rquares vi* “ermet haIn represent mean values f SD.
Wrid Pacing
AViel Pa&g
AV Pacing
Discussion Etlicacy of sequential AV pacing in inducing asynchrony. Sequential AV pacing led to a substantial elevation in both indexes of systolic and diastolic asynchrony (‘fables and 2) in the vast majority of our patients. In an animal Etttdy (11) performed with a pacing protocol (right atrial appendage and right ventricle at the apex) and an analysis technique similar to ours, a comparable degree of asynchrony was obtained. Etkcts of asynchmny on syr&?lk ftmetlun. Sequential AV pacing exerted-a modest negative inotropic e&t, as peak wsitive dPidt decreased stkhtlv but sianigcantlv. whereas the end-syrtolic pressure/v&te ratio was not a&ted (Table I). In previous studies (13-15,18,25.26). evidence for a negative inotropic effecl associated with asynchrony was supplied by a decrease in peak positive dP/dt; right ventrkular pacing, however, was associated with the greatest impairment in systolic function, whereas this latter was minimal with sequential AV pacing (13,27). In our patients, asynchrony induced by AV pacing led to
I
Volume +
a reduction in cardiac index, which can be interpreted as being the consequence of both a negative inotropic etiect and an impairment of the tilling properties. The reduction in cardiic index was due to a trend toward a decrease in enddiastolic volume and consequently in stroke volume (because end-systolic volume did not change); hence, a decreased rate and extent of filling could lower end-diastolic volume and reduce cardiac index. These results are consistent with thweofananimal study by GroverandGlantz(28). In their study pacing at the right atrial. left ventrkular septal, left ventricular apical and rigftt ventricular apical level was associated with progressively decreasing left ventrkular end-diastolic volumes, whereas end-systolic volumes were the same: thus, the observed decrease in cardiac output was rotely the consequewe of a reduced amount of filling because systoli-, performance did sot change (28). ES~NY d aynchrmty nn dlmldie functimt. In our study and all other studies that have addressed this issue in experimental unimals (I I-16) and in patients (17.18). the
Ftgare 2. Vokme.time tten kftt. pressure-time (top rkhtt. pressure-volume (W left) and ~ressuresolutne at cx. tieded y nab scak Wttem rtghtt during avial pacing tdwd dtunends) and senuential atrioventticular (Au, pwing (ep _: dhnwntst in e representative ptient. Asytchrony induces en evident reduction in the velooity .d volume increase (that is, the rete of tillingt and a discernible though small delay in the left venuicular pressure decay. Pressure-volume curves show a reduction in streke volume as the width of the AV pacing curve is diminished (hdtem kg) and an upward shit of the diastolic pardon of the leep @dtem @to.
[mg
Atrial
AV Pnoirtg
Pacing
e
AV Paci”g_l
increase in asynchrony was associated with a prolongation in the lime constant of isovolumettic relaxation (Fig. I). In a study in humans using AV pacing, Bedotto et al. (18) observed a prolongation in the time cotxant ofisovolumettic relaxation in patients with let7 ventricular dysfunction, whereas they did not find any changes in 10 patients with coronary artery disease. no previous myocardial infarction and normal ejection fraction at rest. Our study group is very similar to lhe subgroup of Bedotto et al. (18) with nom~al left venbictdar performance: however, the discrepancy between these two studies is more apparent than real. In their study. the time constant of isovolumetric relaxation increased in 6 of 10 patients, but the increase did not reach the significance level; in our study, it was pmlonged in 9 of 13 patients, yet the diierence was significant. The time constant of isovolumetric relaxation is slowed by a reduction in the inotropic stale (29). In our patienrs. evidence for a modest nerative inotropic effect induced by AV pacing could be d&ted; th&the prolooggation in isovolometric relaxation can be interpreted as being lhe conoepuence of increased temporal asynchrony, in itself or mediated by a reduction in inotropic state. or both. Becsuse changes in systolic function are minor and isovolumetric relaxation showed a marked deterioration with osynchrony. we consider it unlikely that a decrease in contractility is whollv responsible for the prolongation in isovolumetric
‘&K&O”. If isovobtmetric relaxation is prolonged. the Iefi ventricle is not yet folly relaxed when the mitral valve opens and tilling begins. Thus, rapid filling slows down, a mechanism suggested by Stoddard et al. (30). In the present study. asynchrony induced an upward shift of the 3.point average diastolic pressore-volume curve, which suggests :hat at a given pressure, a smaller volume is achieved (Fig. 3) ad. hence. left ventricular filling is rednced. We wed pezk !.!I; r& rate as a reliable estimate of rapid filling properties (31) and noticed a decrease with AV coapared with atrial pacing
Relative
volume
Figere4. Schelsaticrepresentationofthe sectwsinto which the let7 ventricle was dwided for regional analysis:A refersto the septum. B to the accx. C to the lateral retion and D 10 the wsterotaterat region. Th; areabeA ad D&,,!&kd~ represe& the sector that was not used in the analvsis (see text for details). The ccmyonding graphsrepresent16 meanvaluesof pressureptoned asa function ofmeanvaluesofvolume and havethe sameformat ar tht in Figure 3. All curves show rn upward shift, which was associatedwith a rightward shill in the postemlateralregion. IIcA zonW and vet&d tks represat SEM.
(Table 2, Fig. I). The decreae in peak tilling rate seems to depend on increased asyttcir,ony because sequential AV pacing led to att increase in asynchrony in II patients. in 10 of whom a decrease in peak tilling rate occurred. A decrease in peak filling rate associated with no changes in the major determinant of the speed of early filling, (that is, pulmonary wedge pressure [32]) suggeststhat left ventriculx diastolic pressure increases with asynchrony thwughout diastole. thus makine the diastolic AV pressure gradient smaller. We observed a significant ele~otion in ;he IeR ventriular disrtolic pressure at early and middiastole. where-r such elevati~ did not reach the simdticance level (as p = 0.0’5) at end-diastole (Fig. 3). This-tindiog can be interpreted by considering the model of early diastolic pressure decay suggested by Mirsky and Pasipoutarides (29). They reganied left ventricular pressure atIer mi.ial valve opening ar the sum of the decaying relaxation pressure (that is. the extrapotatlon of the pressure decay function after the beginning of filling) and the passive fitting pressure (that is, left ventricular pressure dcp-endeot entirely on liliing, as it would be in a nonbeating ventricle). The dwying relaxation pressure heavily influences measured left ventricular pres-
sure during the early part of diastole, whereas passive filling pressure is almost coincident with measured left ventricular pressure toward end-diastole. In our study, increased aaynchrony slowed isovolumebic relaxation (Fig. I), thereby elevating the decaying relaxation pressure and, hence, augmenting measnred left ventricular pressure during earty diastok. This interpretation is further supported by the increase in the pressure asympIoIe in the six patients in whom the diastolic pressure-volume relation could be adequately fitted: this finding indicates an upward shift of the diastolic pressure-vouune relation. Passive filling proper&es do not need to be altered by asynchrony, which explains why diastolic pressures were widely ditferent during early diastole in buth atria1 and sequential AV pacing studies, whereas such difference decreased al end$iastole (Fig. 3). EffeeIs on regiooal dinstolk preasure.voiu~r~e relaIinn. Examination of the 3-point average pressure-vo!ume curves of the four rectors into which the left ventricle was divided showed an isolated significant upward shitt in the septnl and apical regions. In contrast. the pressure-volume relation was shifted significantly upward and rightward in the gosternlateral region and was inkrmediate in the lateral sector because the volume increase was not sianificant (Fia. 4). These findings suggest that regional op&tive ch%ber’sIilfness was impaired in the septum and apex (that is, the regions closest to the pacing site), whereas it was unatTected by AV pacing in the most remote sectors. This can be interpreted as follows. Nonuniformity is probably greater near the pacing site and lesser far from ir because the depolarization wave front, afIer invading the septum and apex, might recruit specific conduction pathways and, hence, the activation pattern might “normalize” as stimuli travel within the left ventricle. If greater asynchrony in these regions is associated with a myocardial relaxation slower than in more synchronous areas, regions near the depolarization wave front should have reduced filling (that is, lower volumes at any given pressures). In contrast, isovolumotrlc relaxation and filling should be normal in remote regions. Our data seem Ie support this hypothesis (Fig. 4); rnoreovcr, data from a study (28) in the intact dog provide funher evidence. In that study (281, right ventricular pacing induced an end-systolic inward wall motion only along the septum-free wall direction: in other words. regions close tn Ihe pacing site had delayed contraction (that is, more asynchrony). which had the capability of impairing filling. Influence of loading cendilitnts. !sovalumetric relaxation is delayed by afIerload increase and negative inotmpic effeel (331, whereas the effects of preload are probably minimal (34). In our study, we presume that afterload did not increase because left ventricular end-systolic pressure and volume stayed the same. Preload did not increase:in fact, there was a trend toward lower left ventricular end.diastolic volumes. Therefore, we deem it unlikely that the observed changes in diastolic function are the consequence of changes in preload or afterload.
Limitations of the study. This protocol should have been performed in normal subjects to rule out any possible confounding mechanical &ects of chronic (35) or pacinginduced ischemia that ml@ be present in our patients with coronary artery disease. To limit that confounding influence, we chose patients with normnl left ventricular oerforinance at rest 2nd stable angina p-ecioris. Moreover. because we wanted In study patients in Ihe absence of drugs, we selected patients in whom therapy could be discontinued without harm or discomfort (that is, patients with a rclatlvely high ischemic threshold). Both atrial and AV racina were performed at heart rates just above spnntane&s s&s rhythm; therefore, we deem it improbable that pacing-induced ischemia developed.Even lf sntne degree of ischemiadeveloped, however. that would not explain the consistent diaerences seen between atrial and AV oacine studies. We believed Ihat if ischemia developed with pa&g, its eITects would he additive and, hence; greater in second studies; therefore, the Iwo investigations were uerfonued in random order. If ischemia d&eloped and b&ame more severe in the second study, its effects would be evenly distributed among the aoial and AV pacing studies. However, although no patients experienced chest pain during the protecol, 1% possibility cannot be discounted because we had no objective meana of detecting &hernia (the ECG was not helpful during AV pacing because ofthe IeR bundle branch block appearance). Left alrid ~rensure was no1 measured in this study because Iransseptal catheterization was noI clinically indicated. This prevented us from analyzing filling wilh respect to changes in true filling pressure (that is, the AV pressure gradient); instcad, we bad to rely on an estimate such as pulmonary wedge pressure. The left ventricular constant of st&ens showed an inadequate fit in seven patienls in AV pacing studies but in only two of these patients in atrial pacing studies. This
chamber
finding suggeststhat the lelt ventricular diastolic uressurevolume relation is poorly represented by the simile elastic model with shifting asympmte when Iemporal usynchrnny is present because of the asynchmny-induced upward slant in the early pressure-volume relation (Fig. 3). With asyr chrony, viscoelastic forces are probably relevant in early diastole, accounting for the inadequacy of the simple elastic model in describing the diastolic pressure-volume relation. As a consequence. we were unable IO analyze the effects of asynchronyon the constantof chamber stiffness. Clialnl imdkaIlous. Seauenlal AV oacina induces a remarkable degree of temporal asynchrony in &ients with coronary anery disease. This finding is aasoclated with minimal changes in MI ventricular systolic performance, whereas all phases of diastolic function are impaired: the time cnnstnnt of isovnlnmetric relaxation is prnlnnged and isovolumetric relaxation probably extends into the fillinn phase, thus reducing the rate of rapid Iilling. It is conceivable that a similar mechanism occurs in patients with a chroni. tally implanted sequential pacemaker: however, the extent of systolic and diastolic dysfunction is relatively small and is
probably not capable uiiedocing sympknns m the long term. Further studies are needed IO confirm or dispute this asromption. From a physiologic standpoint, sequential AV pacing mimics let? bundle branch block. In a subset of such patients, systolic performance can be normal (6) and asynchrony-induced diastolic dysfunction might be present. In addition, patients with coronary artery disease and isolated asynchmity hsw imptiisd fiKi.i Aaiiics compared with those of similar subjects without asynchrony (7).
BETOCCHI,
LEONARDO CARMEN
PACE,
MD, FEDERICO MD, ANDREA
SALVATORE,
PISCIONE,
CIARMIELLO,
BS, MARCO
SALVATORE,
MD, BRUNO MD,*
VILLARI,
PASQUALE
MD,* MASSIMO
MD,
PERRONE-FILARDI, CHIARIELLO,
MD,
MD, FACC
Naples, Imiy
Obimdves. This study was denimed tu incraw asynchrony with &uautial alriuve&icuIar CLV) pacing and tu -study i& e8wt.s un left ventricular iwvolumetric reIaxatIust.rapid filllna and stiPes% Backpmd. L?fl venlriculnr nonuniformity is a major deter. minaut of diastdic fun&n. Methods. Tbttn ustients with cumnm~ artew disease were studied by simultm&s equilibrium mdiiuclid; ongi~aphy mod card&x czdbeladzPtii during atrial aud AV pa&g. EJsctIw fraetlun and pear fillklg rate were mersurcd by radlunucllde pngiwmvhy. Raiunal aaalysb was ubtalued lw aaalyzb~ Ilateacttvlty cwve~ 2 four IeR &Iriadar sectors;-systolic s&i dia. s(olic asyuchruny were evalusted m the cueltiebnt d varlatII uI lime tu end-systrdc and, respwtively, time to peak tilling rate in the four secturs. Cardiac index and I& vmlrkulnr pressure were measured si:h high fidelity ealktws at cardiac adbeterb.mtlun.
The timeconsinn, orlmvdumdrlc rddk!Q was derived rwln kfl vrotrkdsr prasure. Pressure-volume loops were assembled aad coastantsufchambtr stillness were cvmputed. Rcfulu. Alrb~vmlrkulsr path@ kd lo a-dccrea!e ia card&c l&x(3.7 * 0.9tu3.3 * 0.8litem/mln per m’, 9 = 0.01) and peak Rlltng rate (352 t 125 tu 287 f 141 mUs, p = 0.03; 2.4 * 0.8 to 2.0 + 0.8 mddlastdlc cunnfs/s, 9 = 0.02; 4 t I.3 tu 3.2 * 1.0 strole camtrls. p = O..wB). TIK ttw amstan* uI Isuvdum&k relaxatkm lnrmased (57 * IO to 44 * 12 ms, 9 = 0.04) and the #&al dlaslulk lwessurc-wlume relnliun shUted upmrd. Conrlurions. Atriovmtrkulu wiq lndms kIl ventrkular olyafarmy, rhlch la asucl&d with a sknver rate dIsuvdumet. rlc ldaxallm. R lsoveiu~ reIaxatIlm lasts after the Smug phasehas bqun, thereby re4uetnl the rats of r&d Wlq. U An Cdl C&id 1993;21:1I24-21)
Left ventricular diastolic function is an active energydependent phenomenon governed by ths interplay of several factors, such as intrinsic relaxation properties and loading conditions. Brutsaert (1) has drawn attention to the role of spatial and temporal nonuniformity as a modulator of left ventricular mechanics. In many cardiac diseases, asynchrony plays an important role in determining diastolic dysfunction. Crass-sectional studies (2-S) in patients with coronary a:!eIy disz:? !,a-ve shown that an increase in various indexes of left ventricular asynchrony is associated with a decrease in peak filling rata, a clinically useful estimate ofventricular filling properties. In these studies, however, poor left ventricular synchmnicity was often associated with impairment in systolic performance, which is known to affect diastolic function by itself, thus making the interpretation of these data complex.
Swntanews asynchrony, in conlrast, has been shown to imp.& left vent&lar mefhanics in patients with normal svstolic function and left bundle branch block (6) or seamen&l early relaxation (7). Because it is known ihut i&laied diastolic dysfunction is capable of inducing symptoms of congestive heari failure even when systolic performance is preserved (8-10). it is relevant to study the impact of increased left ventricular asynchrony an diastolic mechanics in a setting where asynchrony varies while the other determinants of diastolic- fun&n remain unaEected. Several investigators (II-161 have induced asynchrony in the ewerimenta~anitnal by either right ventric&r or a~riovenlric~lar (AV) pacing ~4 intmcorottary illjeclion of beta-agonist drugs, associated with little or no modifications in hemcdynamics and systolic performance, and have shown that induced asynchrony impairs isovolumetric relaxation. This affect is also present in humans (17.18). The outcome of pacing-induced asynchrony on left ventricular filling has been less extensively investigated. In dogs. peak rates of wall thinning and cavity filling decreased with sequential right AV pacing as compared with sinus rhythm (13). No data are available on the influence of as$chmny on left ventricular filling dynamics and compliance in humans. The present s:udy was designed to assess the effects of
,*cc”OI.z1.NO April IW3-1124.3,
5
“ETocCHl
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*SYNC”RoNY *ND D,AsmL,C FUNCTION
t1.e physiologically sequaced right AV pacing on isovolumetric relaxation and early and late filling properties in patients with coronary artery disease.
Methods Patient selection. We studied I3 p.aents who underwent diagnostic cardiac catheterization and coronary angiagraphy for evahmtion of chest pain. They were enrolled according to the following criteria.: I) no recent or healed myocardial infarction as assessed by history and electrocardiogram (KG); 2) no associated cardiac or pulmonary diseases, hypertension, diabetes mellitus or history of alcohol abuse: 3) chest pain with mild to moderate symptoms, enabling discontinuation of therapy; 4) left ventricular global and regional wall motion normal at screening by two-dimeosional echocardiography or radionuclide angiogmphy. or both; 5) sinus rhythm with normal AV conduction without right or left bundle brooch block. There were and 2 women. ranging in age from 43 to 62 years (mean 50). Seven patients were referred fmm other institutions for cardiac catheterization and coronary tieriography; the remaining six patients bad either abnormal ejection fraction response (
II men
,125
voltage was ineffective. it was increased to s6 V; ii this voltage proved ineffective, catheters were repositioned. The AV pacing delay was set as long as possible and assessedas follows. The interval between &al sod ventricular stimuli was set very short and scanned up until the vcntriculirr spike became ineffective; then the delay was reduced until the right ventricle was again captured. Effectiveness of ventricular stimulatioo was checked by iospection of the KC- (IeR bundle branch block appemance). The mean time interval from P wave to QRS complex (SD, measured on the surface ECG at a paper speed of 250 mm/s) was I62 t 22 ms in atrial and 132 2 25 ms in AV pacing studies (p < 0.001). Both atrial and sequential AV pacing studies ‘were performed at the same heart rate just above the spontaoews sinus rhythm (86 C I5 and 87 2 I6 beatslmin. respectively, p = NS). cardiac ca&et&&n ami hail tMaalemenk. Patients were in the fasting state and sedated with diazepam (IO mg orally). A 7F Swan-Ganz thermodilution catheter (Edwards Laboratories) was percutatteausly introduced through the right groin into the pulmonary artery to measure cardiac output and pulmonary artery and wedge pressures. A 7F pigtail high lid&y transducer-tipped catheter (Sentron) ws also percutaneously advanced into the IeR ventricle for measurement of le% ventricular pressure and. eve”tually. cineventriculography. Systemic arlerial pressure was monitored through the side port of the arterial sheath. LeR ventricular pressure and its 61~1derivative (dP/dt) were recorded al a paper speed of 250 mm/s. LeR ventrieokir pressure was also sent to the gamma camera-computer system 10 construct pressure-vdume cmves. High speed le% ventricular pressure and dP/dt wves were digitized at 4-ms intervals for calculation of the time consfant of isovolumetric relaxation, using the shining asymptote technique (19). starting fiwn mirdmal dP/dt and ending when presswe was I/e of its initial value (20). The equation P = B + Ae”, where P is pressure. B is the pressure asymptote, A and k are filling constants, e is the basis of natural logarithm and t is time, can be diierentiated, yielding the iormula: dP/dt = kP - C. By linear regression analysis, the slope k and the inarcept C of this regression can be calculated; the time constant of isovolumetric relaxatian is then the negative reciprocal of the slope (that is, -I,!& and the pressure asymptote represents the pressure value at dP/dt = 0 (that is. the pressure value at which pressure stops decreasing, calculated as CM. Cineventriculogmphy was performed immediately after the end of the expmimental protocol, duringatrial or sequenlial AV pacing (whichever came last) and in a 3v right anterior oblique view. The first well opacitied sinus beat not following an ectopic beat was analyzed for enddiastdic volume (21). using a graphic tablet interfaced with a corn-puter (Digital PDP 11134).Coronary arteriography in multiple views was then prformed for diagnostic pm-poses.
Rstinuclide angicgraphy. Equilibrium radionoclide angiography was performed with the patient lying in the supine position on the cardiac catheterization cradle. Red blood cells were labeled in vivo with 20 to 2S mCi of technetium 99-m and counts were collected by a small field of view Angercamera(Siemens LEM ZLC), equipped with ageneral powxe, parallel hole collimator oriented in a 45” or “best septal” left anterior oblique view with a If caudal tilt. Images were acquired with a 2X digital .zmo in frame mode by ECG gating at a framing rate of 50 f?ames/s (that is, 20 ms/frame). At least ISO,OOO counts/frame were collected in the fust study; as the second study was acquired for the same period of time as the first one so that the two studies would consist of the ssme number of cxdiac cycles (heart rate was kept constant). The use of yielded extremely similar durations of the cardiac cycles that were averaged to build a representative cardiac beat: hence no “fall” in late diastole occurred in time-activity curves. This allowed reliable measurement of late diastolic events. The time-activity carve recorded in the second study was expressed in ml by normalizing its end-diastolic number of counts to end-diastolic volume measured by contrast angiography. The first time-activity corw was then corrected for isotope decay and expressed in ml as follows: the eoddiastolic volume in the second study was multiplied by the ratio of end-diastolic number of coonts in the first and second x&s. Ejection fraction was calculated on the “raw” timeactivity carve, whereas peak filling rate was computed after filtering using a Fourier expansion with Rve harmonics as the maximum of the first derivative of time-activity cwves. It was measured in ml/s and further normalized by enddiastolic as well as stroke volume to acwnnt for changes in both enddiastolic volume and systolic function. Time to peak filling rate was defined as the interval from the R wave on the ECG to peak filling rate. Left ventricular regional analysis was performed with the use of a computer algorithm that identified the center of gravity of the left ventricular region of interest and divided it into five sectors of equal anele (72’) slartinr! at the 3 o’clock position and proceeding co&xclockwisey The second region, which includes the area ofmitral and aortic valves, was not used in the analysis. Time-activity curves from the four remaining sectors were filtered after background suhtraction, using a Fourier expansion with three harmonics to minimize errors resulting from both fitting and counting stalistics. We measured time to end-systole (as the time from the R wave to minimal counts) ineach oftbefour sectorsand evaluated systolic asynchrony of the left venlricle by mea. wring the coefficient of variation of the four values of time to end-systole. Likewise, we calculated diastolic asynchrony by computing the coefficient of variatirr, of sector time to peak filling rate. Further details on radionuclide angioAraphic methods as well as the accuracy and reproducibility of these measure-
pacing
mews in our laboratory have been previously reported Cz23). Loft ventricular pressore-volume analysis. Left ventricular pressure measurements were sent to a cuslom-designed interface (Medie s.r.1.) connected to the gamma cameracomputer system (Digital PDP Such interface wrote the pressure values into an assigned line oo the 64 x 64 scintigraphic matrix. In this way, left ventricular pressure carves have the same gating point and framing rate and represent an average of the same cardiac cycles as those for the lime-activity curves, with which they were combined to create high temporal resolution pressure-volume loops. Endsystolic pressure-volume ratios were calculated. The let? ventticolar constaa! of chamber stilTness (kl was measured by using the simple elastic model with shifting asymptote method on the part of pressure-volume loops from minimal pressure lo enddiitole, according to the formula P = B + A?‘, where P is presswe, V is volume, A and k are fitting constants and B is the pressort asymptote (20). Fitting was achieved by a computer program that allowed nonlinear fitting iterations (24). A further estimate of I& venlricular compliance was accomplished by measuring pressures and volumes at three discrete diastolic points: lowest left ventricular pressure, enddiastole and the midwint between these two landmarks (19). Data for all the ‘patients were pooled together to constract “average” diastolic pressure-vdume curves for both pacing modes. No attempt was made at fitting regional pressure-volume carves to measure a regional umstaot of chamber stitTness. Instead. a I-point average approach was used as for global analysis. Absolute sector volumes were not measured. After background subtraction and correction for th isotope decay, end-diastolic counts in the atrial pacing studies were considered equal to IO0 aad end-diastolic couus in the AV pazing studies were accordingly nonaalized. StalisUcal methods. Data are expressed as mean value f SD everywhere but in Figures 3 and 4. where bars represent SEM for the sake of clarity. Paired t test and linear regres sion analysis were used when appropriate. Comparison of the three measures ofpressure and volume between the two studies was accomplished by two-way analysis of variance for repeated measures and poslhw paired I test with Bonferroni’s correction (24).
1l/34).
Results Baseline tidings. Two patients had nonsignificant (<75%) stenosis in one and two major coronary vessels. respectively. Three patients had one-vessel, five had twe vessel and three had three-vessel coronary artery disease. No patients had reduced (~2.5 liter&in per m’) cardiac index; two patients had elevated mean pulmonary wedge presscre (>I5 mm Hg) and left ve&-icular cod-diastolic pressure (>I2 nun Hg) at baseline.
EXfectsuu asyuchmuy. As expected, both systolic and diastolic estimates of left ventricular asynchrony exhibited a large and significant increase (Tables and 2). In particular. the coefiicient of variation of time IO end-systole increased in 10 ofthe 13 patients and the coefficient of variation of time to peak tilling rate increased in II.
I
pacing significanily decreased maximal dP/dt &I cardiac index. Left ventricular systolic pressure, end-systolic pressurelvolume ratio and pulmonary artery wedge pressure were unaltered. whereas end-diastolic pressure showed a nonsignificant trend toward au increase. End-diastolic volume showed a nonsignificant trend toward a reduction and decreasedwith AV pacing in 9 of the 13 patients. whereas end-systolic volume and eiection fraction remained UL-
changed. E&bun dixtulic fnnc&m. Earlv diastolic function was impaired by sequential AV pacing compared with function during atrial pacing. The time constant of isovolumetric relaxation lengthened and all three estimates of peak tilling rate (in m!Is and normalized by enddiastolic and stroke counts/s) were reduced (Table 2. Fig. I). Furthermore, peak filling rate decreased in IO of the patients in whom sequential AV pacing led to au increase in diastolic
tt
Tab* 2. Meets of Scqwntial Alrioventricular (AV) Pacingon LeR Ventricular Diastolic Function
asynchrony: the only patient in whom peak filling rate increased despite an increase in diastolic asynchrony had an elevation in pulmonary wedge pressure by >SG% (from 7 to I I mm Hg), accounting for the increased rate of filling. Figure 2 shows an example of changes ih volume. pressure and pressure-volume curves in a representative patient. The upward shii in the diastolic portion of the pressurevolume loop is evident. The constant of chamber stiffness showed a puor fit (p > 0.01 on the aoaduess of fit F test) in two atriel vacinp.studies and seven ~equeutial AV pacing studies (that is, 6ve additional patients). In the remaining six patients, the constant of chamber stitTness did not change (fmm 0.019 ? O.CQ5to 0.021 f 0.006 mm Hglml~. Interestingly, its asymptote increased in five of the six patients. almust reaching the significance level despite the small subgroup size (fmm -3.5t 5.2tuo.1 ~3.7mmHg,p=0.07). To overcume the inadequacy of fitting in sequential AV pacmg studies. the diastolic pressure-volume relation was further studied using the 3-point discrete approach already described. No differences were seen as for volume; diastolic pressures. however, were signiticuntly higher by two-way analysis of variance in the sequential AV pacing study (Fig. 3). When differences in pressure were analyzed at each landmark, a signi%autt increase was seen at the lowest pressure (from 0.6 ? 3.2 to 2.9 + 3.6 mm Hg, p = 0.019) and mid-diastole (from 4.6 + 4.2 to 6.9 f 3.9 mm Hg, p = 0.03). whereas changes at enddiastole did not reach the significance level (from 10.6 t 5.4 to 12.2 + 5 mm Hg, P = 0.06). The same discrete 3-point approach was used in the analysis of the regional diastolic pressure-volume relation. There were no changes in area in the septet and apical sectors, whereas we observed u significant increase in relative area in the porterolateral sector and a nondgniticant trend toward an increasein the lateral sector (Fig. 4).
Iigurv 1. individual values or the time eenstam of isevolumeoic relaxation tit @en ktt penett end peak tilling rate narmalized tu end-diastolic ceunts (EtXYs (ton right naeet). stroke ceunts (S% th+ttme ten pan&) and expressed in mtIs (hettan right ganel) during atrinl pacing and sequential atrioventricular (AV) pacing. Open rquares vi* “ermet haIn represent mean values f SD.
Wrid Pacing
AViel Pa&g
AV Pacing
Discussion Etlicacy of sequential AV pacing in inducing asynchrony. Sequential AV pacing led to a substantial elevation in both indexes of systolic and diastolic asynchrony (‘fables and 2) in the vast majority of our patients. In an animal Etttdy (11) performed with a pacing protocol (right atrial appendage and right ventricle at the apex) and an analysis technique similar to ours, a comparable degree of asynchrony was obtained. Etkcts of asynchmny on syr&?lk ftmetlun. Sequential AV pacing exerted-a modest negative inotropic e&t, as peak wsitive dPidt decreased stkhtlv but sianigcantlv. whereas the end-syrtolic pressure/v&te ratio was not a&ted (Table I). In previous studies (13-15,18,25.26). evidence for a negative inotropic effecl associated with asynchrony was supplied by a decrease in peak positive dP/dt; right ventrkular pacing, however, was associated with the greatest impairment in systolic function, whereas this latter was minimal with sequential AV pacing (13,27). In our patients, asynchrony induced by AV pacing led to
I
Volume +
a reduction in cardiac index, which can be interpreted as being the consequence of both a negative inotropic etiect and an impairment of the tilling properties. The reduction in cardiic index was due to a trend toward a decrease in enddiastolic volume and consequently in stroke volume (because end-systolic volume did not change); hence, a decreased rate and extent of filling could lower end-diastolic volume and reduce cardiac index. These results are consistent with thweofananimal study by GroverandGlantz(28). In their study pacing at the right atrial. left ventrkular septal, left ventricular apical and rigftt ventricular apical level was associated with progressively decreasing left ventrkular end-diastolic volumes, whereas end-systolic volumes were the same: thus, the observed decrease in cardiac output was rotely the consequewe of a reduced amount of filling because systoli-, performance did sot change (28). ES~NY d aynchrmty nn dlmldie functimt. In our study and all other studies that have addressed this issue in experimental unimals (I I-16) and in patients (17.18). the
Ftgare 2. Vokme.time tten kftt. pressure-time (top rkhtt. pressure-volume (W left) and ~ressuresolutne at cx. tieded y nab scak Wttem rtghtt during avial pacing tdwd dtunends) and senuential atrioventticular (Au, pwing (ep _: dhnwntst in e representative ptient. Asytchrony induces en evident reduction in the velooity .d volume increase (that is, the rete of tillingt and a discernible though small delay in the left venuicular pressure decay. Pressure-volume curves show a reduction in streke volume as the width of the AV pacing curve is diminished (hdtem kg) and an upward shit of the diastolic pardon of the leep @dtem @to.
[mg
Atrial
AV Pnoirtg
Pacing
e
AV Paci”g_l
increase in asynchrony was associated with a prolongation in the lime constant of isovolumettic relaxation (Fig. I). In a study in humans using AV pacing, Bedotto et al. (18) observed a prolongation in the time cotxant ofisovolumettic relaxation in patients with let7 ventricular dysfunction, whereas they did not find any changes in 10 patients with coronary artery disease. no previous myocardial infarction and normal ejection fraction at rest. Our study group is very similar to lhe subgroup of Bedotto et al. (18) with nom~al left venbictdar performance: however, the discrepancy between these two studies is more apparent than real. In their study. the time constant of isovolumetric relaxation increased in 6 of 10 patients, but the increase did not reach the significance level; in our study, it was pmlonged in 9 of 13 patients, yet the diierence was significant. The time constant of isovolumetric relaxation is slowed by a reduction in the inotropic stale (29). In our patienrs. evidence for a modest nerative inotropic effect induced by AV pacing could be d&ted; th&the prolooggation in isovolometric relaxation can be interpreted as being lhe conoepuence of increased temporal asynchrony, in itself or mediated by a reduction in inotropic state. or both. Becsuse changes in systolic function are minor and isovolumetric relaxation showed a marked deterioration with osynchrony. we consider it unlikely that a decrease in contractility is whollv responsible for the prolongation in isovolumetric
‘&K&O”. If isovobtmetric relaxation is prolonged. the Iefi ventricle is not yet folly relaxed when the mitral valve opens and tilling begins. Thus, rapid filling slows down, a mechanism suggested by Stoddard et al. (30). In the present study. asynchrony induced an upward shift of the 3.point average diastolic pressore-volume curve, which suggests :hat at a given pressure, a smaller volume is achieved (Fig. 3) ad. hence. left ventricular filling is rednced. We wed pezk !.!I; r& rate as a reliable estimate of rapid filling properties (31) and noticed a decrease with AV coapared with atrial pacing
Relative
volume
Figere4. Schelsaticrepresentationofthe sectwsinto which the let7 ventricle was dwided for regional analysis:A refersto the septum. B to the accx. C to the lateral retion and D 10 the wsterotaterat region. Th; areabeA ad D&,,!&kd~ represe& the sector that was not used in the analvsis (see text for details). The ccmyonding graphsrepresent16 meanvaluesof pressureptoned asa function ofmeanvaluesofvolume and havethe sameformat ar tht in Figure 3. All curves show rn upward shift, which was associatedwith a rightward shill in the postemlateralregion. IIcA zonW and vet&d tks represat SEM.
(Table 2, Fig. I). The decreae in peak tilling rate seems to depend on increased asyttcir,ony because sequential AV pacing led to att increase in asynchrony in II patients. in 10 of whom a decrease in peak tilling rate occurred. A decrease in peak filling rate associated with no changes in the major determinant of the speed of early filling, (that is, pulmonary wedge pressure [32]) suggeststhat left ventriculx diastolic pressure increases with asynchrony thwughout diastole. thus makine the diastolic AV pressure gradient smaller. We observed a significant ele~otion in ;he IeR ventriular disrtolic pressure at early and middiastole. where-r such elevati~ did not reach the simdticance level (as p = 0.0’5) at end-diastole (Fig. 3). This-tindiog can be interpreted by considering the model of early diastolic pressure decay suggested by Mirsky and Pasipoutarides (29). They reganied left ventricular pressure atIer mi.ial valve opening ar the sum of the decaying relaxation pressure (that is. the extrapotatlon of the pressure decay function after the beginning of filling) and the passive fitting pressure (that is, left ventricular pressure dcp-endeot entirely on liliing, as it would be in a nonbeating ventricle). The dwying relaxation pressure heavily influences measured left ventricular pres-
sure during the early part of diastole, whereas passive filling pressure is almost coincident with measured left ventricular pressure toward end-diastole. In our study, increased aaynchrony slowed isovolumebic relaxation (Fig. I), thereby elevating the decaying relaxation pressure and, hence, augmenting measnred left ventricular pressure during earty diastok. This interpretation is further supported by the increase in the pressure asympIoIe in the six patients in whom the diastolic pressure-volume relation could be adequately fitted: this finding indicates an upward shift of the diastolic pressure-vouune relation. Passive filling proper&es do not need to be altered by asynchrony, which explains why diastolic pressures were widely ditferent during early diastole in buth atria1 and sequential AV pacing studies, whereas such difference decreased al end$iastole (Fig. 3). EffeeIs on regiooal dinstolk preasure.voiu~r~e relaIinn. Examination of the 3-point average pressure-vo!ume curves of the four rectors into which the left ventricle was divided showed an isolated significant upward shitt in the septnl and apical regions. In contrast. the pressure-volume relation was shifted significantly upward and rightward in the gosternlateral region and was inkrmediate in the lateral sector because the volume increase was not sianificant (Fia. 4). These findings suggest that regional op&tive ch%ber’sIilfness was impaired in the septum and apex (that is, the regions closest to the pacing site), whereas it was unatTected by AV pacing in the most remote sectors. This can be interpreted as follows. Nonuniformity is probably greater near the pacing site and lesser far from ir because the depolarization wave front, afIer invading the septum and apex, might recruit specific conduction pathways and, hence, the activation pattern might “normalize” as stimuli travel within the left ventricle. If greater asynchrony in these regions is associated with a myocardial relaxation slower than in more synchronous areas, regions near the depolarization wave front should have reduced filling (that is, lower volumes at any given pressures). In contrast, isovolumotrlc relaxation and filling should be normal in remote regions. Our data seem Ie support this hypothesis (Fig. 4); rnoreovcr, data from a study (28) in the intact dog provide funher evidence. In that study (281, right ventricular pacing induced an end-systolic inward wall motion only along the septum-free wall direction: in other words. regions close tn Ihe pacing site had delayed contraction (that is, more asynchrony). which had the capability of impairing filling. Influence of loading cendilitnts. !sovalumetric relaxation is delayed by afIerload increase and negative inotmpic effeel (331, whereas the effects of preload are probably minimal (34). In our study, we presume that afterload did not increase because left ventricular end-systolic pressure and volume stayed the same. Preload did not increase:in fact, there was a trend toward lower left ventricular end.diastolic volumes. Therefore, we deem it unlikely that the observed changes in diastolic function are the consequence of changes in preload or afterload.
Limitations of the study. This protocol should have been performed in normal subjects to rule out any possible confounding mechanical &ects of chronic (35) or pacinginduced ischemia that ml@ be present in our patients with coronary artery disease. To limit that confounding influence, we chose patients with normnl left ventricular oerforinance at rest 2nd stable angina p-ecioris. Moreover. because we wanted In study patients in Ihe absence of drugs, we selected patients in whom therapy could be discontinued without harm or discomfort (that is, patients with a rclatlvely high ischemic threshold). Both atrial and AV racina were performed at heart rates just above spnntane&s s&s rhythm; therefore, we deem it improbable that pacing-induced ischemia developed.Even lf sntne degree of ischemiadeveloped, however. that would not explain the consistent diaerences seen between atrial and AV oacine studies. We believed Ihat if ischemia developed with pa&g, its eITects would he additive and, hence; greater in second studies; therefore, the Iwo investigations were uerfonued in random order. If ischemia d&eloped and b&ame more severe in the second study, its effects would be evenly distributed among the aoial and AV pacing studies. However, although no patients experienced chest pain during the protecol, 1% possibility cannot be discounted because we had no objective meana of detecting &hernia (the ECG was not helpful during AV pacing because ofthe IeR bundle branch block appearance). Left alrid ~rensure was no1 measured in this study because Iransseptal catheterization was noI clinically indicated. This prevented us from analyzing filling wilh respect to changes in true filling pressure (that is, the AV pressure gradient); instcad, we bad to rely on an estimate such as pulmonary wedge pressure. The left ventricular constant of st&ens showed an inadequate fit in seven patienls in AV pacing studies but in only two of these patients in atrial pacing studies. This
chamber
finding suggeststhat the lelt ventricular diastolic uressurevolume relation is poorly represented by the simile elastic model with shifting asympmte when Iemporal usynchrnny is present because of the asynchmny-induced upward slant in the early pressure-volume relation (Fig. 3). With asyr chrony, viscoelastic forces are probably relevant in early diastole, accounting for the inadequacy of the simple elastic model in describing the diastolic pressure-volume relation. As a consequence. we were unable IO analyze the effects of asynchronyon the constantof chamber stiffness. Clialnl imdkaIlous. Seauenlal AV oacina induces a remarkable degree of temporal asynchrony in &ients with coronary anery disease. This finding is aasoclated with minimal changes in MI ventricular systolic performance, whereas all phases of diastolic function are impaired: the time cnnstnnt of isovnlnmetric relaxation is prnlnnged and isovolumetric relaxation probably extends into the fillinn phase, thus reducing the rate of rapid Iilling. It is conceivable that a similar mechanism occurs in patients with a chroni. tally implanted sequential pacemaker: however, the extent of systolic and diastolic dysfunction is relatively small and is
probably not capable uiiedocing sympknns m the long term. Further studies are needed IO confirm or dispute this asromption. From a physiologic standpoint, sequential AV pacing mimics let? bundle branch block. In a subset of such patients, systolic performance can be normal (6) and asynchrony-induced diastolic dysfunction might be present. In addition, patients with coronary artery disease and isolated asynchmity hsw imptiisd fiKi.i Aaiiics compared with those of similar subjects without asynchrony (7).