Br Heart J 1992;68:16-20

Left ventricular filling characteristics inpulmonary hypertension: a new mode ofventricular interaction

B B Stojnic, S J D Brecker, H B Xiao, S M Helmy, M Mbaissouroum, D G Gibson

Cardiac Department,Royal BromptonNational Heart andLung Hospital, LondonB B StojnicS J D BreckerH B XiaoS M HelmyM MbaissouroumD G GibsonCorrespondence toDr Derek G Gibson, CardiacDepartment, RoyalBrompton National Heartand Lung Hospital, SydneyStreet, London SW3 6NP.

Accepted for publication30 January 1992

AbstractObjective-To examine the effects of

pulmonary hypertension on left ven-tricular diastolic function and to relatethe findings to possible mechanisms ofinterdependence between the right andleft sides of the heart in ventricular dis-ease.

Design-A retrospective and prospec-tive analysis of echocardiographic andDoppler studies.Setting-A tertiary referral centre for

both cardiac and pulmonary disease.Patients-29 patients with pulmonary

hypertension (12 primary pulmonaryhypertension, 10 pulmonary fibrosis, fiveatrial septal defect (ASD), and twoscleroderma) were compared with a con-trol group of 10 patients with an en-larged right ventricle but normalpulmonary artery pressure (six ASD,one after ASD closure, one ASD andpulmonary valvotomy, one tricuspidvalve endocarditis and repair, and onepulmonary fibrosis). None had clinical orechocardiographic evidence of intrinsicleft ventricular disease.Main Outcome measures-M mode

echocardiographic measurements weremade of septal thickness, and left andright ventricular internal cavity dimen-sions. Doppler derived right ventricularto right atrial pressure drop, and timeintervals were measured, as wereisovolumic relaxation time, and Dopplerleft ventricular filling characteristics.Results-The peak right ventricular to

right atrial pressure gradient was (mean(SD)) 60 (16) mm Hg in pulmonaryhypertensive patients, and 18 (5) mm Hgin controls. The time intervals P2 to theend of the tricuspid regurgitation, and P2to the start of tricuspid flow were bothprolonged in patients with pulmonaryhypertension compared with controls(115 (60) and 120 (40) v 40 (15) and 45 (10)ms, p values < 0-001). Pulmonary hyper-tensive patients commonly had a domin-ant A wave on the transmitral Doppler(23/29); however, all the controls had adominant E wave. Isovolumic relaxationtime of the left ventricle was prolongedin pulmonary hypertensive patientscompared with controls, measured asboth A2 to mitral valve opening (80 (25) v

50 (15) ms) and as A2 to the start ofmitral flow (105 (30) v 60 (15) ms, p values

17Left ventricularfilling characteristics in pulmonary hypertension: a new mode ofventricular interaction

Table I Characteristics of the study groups

Pulmonary hypertension Right ventricular dilatation(n = 29) (n= 10)

Age (y) (mean (SD)) 44 (13) 42 (18)Aetiology Primary pulmonary Atrial septal defect (8)

hypertension (12)Pulmonary fibrosis (10) Tricuspid valve endocarditis and

repair (1)Atrial septal defect (5) Pulmonary fibrosis (1)Scleroderma (2)

tension from those of right ventricular dilata-tion, septal shift, or left ventricularcompression.

Patients and methodsSTUDY POPULATIONWe studied 29 patients (age (mean (range)) 44(20-63); 17 women) with pulmonary hyperten-sion (12 primary pulmonary hypertension, 10pulmonary fibrosis, five atrial septal defect(ASD), and two scleroderma), and a controlgroup of 10 patients (age (mean (range)) 42 (17-57); 6 women) with right ventricular dilatation(free wall to septal diameter > 2-6 cm at endsystole) but normal pulmonary artery pressure(peak right ventricular to right atrial pressuredrop < 35 mm Hg). Table 1 shows the com-position of each group. All patients were insinus rhythm and all had holosystolic tricuspidregurgitation detectable on Doppler. The twopatients with scleroderma had no features tosuggest involvement of the left ventricle, andthere was no hypertrophy of the free wall. Noclinical or echocardiographic signs of intrinsicleft ventricular disease were found in any otherpatients. The patients were young and nonehad symptoms suggestive of coronary arterydisease; in the absence of clear clinical indica-tions coronary angiography was not performed.

M MODE AND CROSS SECTIONALECHOCARDIOGRAPHYM mode and cross sectional echocardiogramswere taken with the patient in the standard leftlateral position, using an Advanced TechnicalLaboratory Imager Mk 300I with a 3-0 MHzmechanical transducer, or a Toshiba SSH160A imager with a 3-5 MHz transducer.Phonocardiograms were recorded from aLeatham microphone with a low frequencyfilter. M mode echocardiograms were recordedwith simultaneous electrocardiogram andphonocardiogram on a Honeywell (Ecoline 22)strip chart recorder at a paper speed of 10 cm/s.Aortic valve closure (A2) was taken as the startofthe first high frequency vibration ofthe aorticcomponent of the second heart sound recordedon the phonocardiogram, and was checked forvalidity with the aortic echogram and the aorticclosure artefact on the Doppler recordings.Left ventricular internal cavity dimensions,septal and posterior wall thickness weremeasured with leading edge methodology,from the parasternal long axis view at endsystole (at A2) and end diastole (start of theQRS complex on the electrocardiogram). Theright ventricle was measured from end diastolicframes of the apical four chamber view. The

short axis was measured transversely at the tipofthe tricuspid valve leaflets. Isovolumic relax-ation time for the left ventricle was measuredfrom A2 to the initial separation of the mitralcusps on the M mode echogram. Interven-tricular septal motion was analysed from Mmode echocardiograms taken at the level of thetips of the mitral leaflets. All measurementswere made on three cardiac cycles and the meanwas taken.

DOPPLER ECHOCARDIOGRAPHYWe recorded Doppler signals on a DoptekSpectrascan with a 2-0 MHz transducer, and aToshiba SSH 160A with a 3-5 MHz trans-ducer. Peak transmitral and transtricuspid flowvelocities were identified by continuous wavefrom the apex and were recorded in pulsedmode with a 3 mm gate and 250 Hz wall filter.The peak velocities ofearly "E wave" and atrial"A wave" transmitral flow were recorded andthe ratio E/A was derived. Tricuspid regur-gitant flow was identified and recorded incontinuous mode from the apex. The peakinstantaneous systolic pressure drop from rightventricle to right atrium was calculated withthe modified Bernoulli equation from the peakvelocity of the tricuspid regurgitant signal, andthe pressure drop at the instant of mitral cuspseparation was also recorded. The RR intervalwas measured from the electrocardiogram,recorded simultaneously with the phonocar-diogram. A second measurement of isovolumicrelaxation time was obtained for the left ventri-cle from A2 to the start of mitral flow. The firsthigh frequency vibration of the second com-ponent of the second heart sound was taken asP2 and this was checked on the pulmonaryechogram and pulmonary closure artefact onDoppler recordings. The time interval frompulmonary closure (P2) to the start of tricuspidflow was recorded in all cases. Allmeasurements were made on three cardiaccycles and the mean taken. Intracavity flow wasdetected within the left ventricle with pulsedDoppler aligned along the ventricular inflow.Having identified flow in pulsed mode, it wasrecorded in colour Doppler superimposedupon a long axis M mode of the left ventricularcavity from the mitral ring to the apex.

STATISTICAL ANALYSISAll values are given as mean (SD). Differencesbetween mean values were compared byStudent's t test, and those in incidence byFisher's exact probability test.

ResultsTables 2 and 3 show mean values of themeasurements. No significant differences werefound between the ages or heart rates ofpulmonary hypertensive patients and controls.

M MODE AND DOPPLER MEASUREMENTSDimensions and septal motionThe internal cavity dimensions of the leftventricle were equally reduced (by the enlargedright ventricle) in both groups of patients,although the septal thickness was greater in

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Table 2 M mode measurements of dimensions of the left and right ventricles (mean (SD))

Pulmonary hypertension Right ventricularVariable (n = 29) dilatation (n = 10) p Value

Left ventricular end diastolic dimension (cm) 3-5 (0 8) 3-8 (0 4) NSLeft ventricular end systolic dimension (cm) 2-3 (0 5) 2-3 (0 4) NSSeptal thickness at Q wave (cm) 1 2 (0 2) 0-9 (0-1) 0 001Posterior wall thickness (cm) 1-0 (0 5) 0-8 (0-1) NSRight ventricular dimension (short axis) (cm) 2-6 (0 5) 2-9 (0-6) NSPosterior septal displacement after A2 (n) 20 0 0 001

patients with pulmonary hypertension than incontrols (1-24 (0.2) v 0-9 (0-1) cm, p < 0-001).In 20 of 29 (69%) patients with pulmonaryhypertension, early diastolic posterior dis-placement of the septum was evident on Mmode recordings, during isovolumic relaxationof the left ventricle (fig 1). This was not seen,however, in any patients of the control group(20/29 v 0/10, p < 0-0001). There were nosignificant differences in the peak systolic rightventricular to right atrial gradient or left ven-tricular filling pattern between those patientswith and without diastolic posterior dis-placement of the septum.

Dynamics of tricuspid regurgitation and timeintervalsBy definition, the peak right ventricular to rightatrial pressure gradient was higher in pulmon-ary hypertensive patients than in controls (60(16) v 18 (5) mm Hg). Tricuspid regurgitationwas prolonged in pulmonary hypertensivepatients, persisting a mean of 75 ms afteropening of the mitral valve, compared withonly 20 ms in controls. Not only did this reducethe time available for forward tricuspid flow(240 (100) ms in pulmonary hypertensivepatients v 360 (1 10) ms in controls, p = 0 012)but, when correlated with events on the leftside of the heart, led to a tricuspid pressuredrop (ventricular to atrial) of 12 (10) mm Hgstill persisting at the time of opening of themitral valve (compared with 0-4 (0-3)mm Hg incontrols, p < 0-001) (figs 1 and 2). Thisoccurred in spite of isovolumic relaxation timeof the left ventricle being longer in pulmonaryhypertensive patients than controls, whethermeasured from A2 to opening of the mitralvalve (80 (25) v 50 (15) ms) or from A2 to thestart of mitral flow on Doppler (105 (30) v 60

(15) ms, p < 0-001). Similarly, the time frompulmonary closure to the start of tricuspid flowon Doppler was prolonged in pulmonaryhypertensive patients compared with controls(120 (40) v 45 (10) ms, p < 0-001). Furthersignificant delay occurred in the start of mitralflow with respect to mitral cusp separation inpulmonary hypertensive patients comparedwith controls (30 (15) v 10 (10) ms, p < 0-001).

Filling patternsOn the transmitral Doppler 23/29 (79%) of thepatients with pulmonary hypertension had adominant "A" wave (23/29 "A fillers"). Thispattern of filling was not found in any of thecontrol group, who were all "E fillers"; thedifference in incidence was highly significant(p < 0-0001). We found no significant dif-ference in heart rate between the two groups ofpatients. Within the group with pulmonaryhypertension, "A fillers" had a longerisovolumic relaxation time than the "E fillers"(100 (25) v 60 (20) ms, p < 0-001).

Intracavity flowIn six patients with pulmonary hypertension,intracavity flow was noted during isovolumicrelaxation. All six patients showed posteriordisplacement of the interventricular septumafter aortic closure. Compared with the groupas a whole, no significant differences occurred induration of isovolumic relaxation, ventricularfilling times, or filling pattern in patients withintracavity flow.

DiscussionIn common with previous studies, we havefound impaired left ventricular diastolic func-tion in our patients with pulmonary hyperten-

Table 3 Doppler and M mode characteristics (mean (SD))

Pulmonary hypertension Right ventricularVariable (n = 29) dilatation (n = 10) p Value

RR Interval (ms) 660 (250) 750 (130) NSRV-RA pressure drop (mm Hg) 60 (16) 18 (5)

Left ventricular filling characteristics in pulmonary hypertension: a new mode of ventricular interaction

Figure 1 M modeechocardiogram of the leftventricular cavity(above), and continuouswave Doppler display oftricuspid regurgitation(below),from a patientwith pulmonaryhypertension. Note theposterior displacement ofthe interventricular septum(arrowed). This septal"dip" occurs duringisovolumic relaxation ofthe left ventricle. Notethat at the instant ofmitral valve opening,tricuspid regurgitationcontinues, with a velocityof 2-25 m/s, correspondingto a right ventricular toright atrial pressuredifference of 20 mm Hg.Electrocardiogram(ECG) andphonocardiogram (PCG)are shown.

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-ECG

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O .Oc-/d DA= O DF= 8 DG= 7 PRF=25

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sion.89 As well as confirming well recogniseddisturbances of ventricular filling with reducedearly diastolic and increased atrial velocities,we also found that isovolumic relaxation wasabnormal. The interval from aortic closure tomitral cusp separation was significantlyincreased, and a further abnormal delayoccurred between cusp separation and the

Figure 2 M modeechocardiogram of the leftventricular cavity(above), and continuouswave Doppler display oftricuspid regurgitation(below),from a controlpatient with dilatation ofthe right ventricle andnormal pulmonary arterypressure. Note that at theinstant of opening of themitral valve, tricuspidregurgitation has ceased,by contrast with theprolonged tricuspidregurgitation shown infig1.

earliest start of detectable transmitral flow bypulsed Doppler. Also, ventricular dimensioncharacteristically fell during isovolumic relaxa-tion, indicating a change in cavity shape, and insix patients, intracavity flow was detected.

Several mechanisms have been proposed toexplain how right sided abnormalities candisturb left ventricular diastolic function in theabsence of left ventricular diastolic disease.Distension or hypertrophy of the right ven-tricle may compress the left, thus alteringchamber stiffness. Raised diastolic pressuresfrom the right may directly affect those of theleft, possibly by moving the septum, or theinteraction may be indirect and involve thepericardium. In our study we aimed to inves-tigate these possibilities in more detail.The characteristic disturbances of

isovolumic relaxation that we saw in ourpatients suggest that whatever the mode ofinteraction between the two ventricles it wasalready operating before mitral valve opening.This makes it unlikely that the primary distur-bance was simply one of passive ventricularpressure and volume relations. Neither didpericardial restraint appear to be important asthis is also a late diastolic phenomenon and it isdifficult to see how such restraint could possiblyaffect isovolumic relaxation. Our patients allshowed the characteristic anatomical findings ofright ventricular dilatation with correspondingcompression of the left ventricle, often withreversed septal motion. To investigate thispossible mechanism we used a control group ofpatients with identical anatomical abnor-malities, but in whom right ventricular systolicpressures were normal. Left ventricular dias-tolic function was effectively normal in thisgroup. We concluded, therefore, that disturbedleft ventricular diastolic function in ourpatients with pulmonary hypertension couldnot be attributed to reduced right ventriculardiastolic compliance, pericardial interaction,left ventricular compression, or any otherdirect result of right ventricular dilatation, butseemed to be much more closely related to thepresence of the pulmonary hypertension itself.Not only is peak pressure in the pulmonary

artery raised in patients with pulmonary hyper-tension, but the rate of fall is reduced," so thepressure pulse lasts longer. This may showitself in several ways. The interval from pul-monary valve closure to tricuspid opening isincreased'2 '3 and the duration of the Dopplersignal of functional tricuspid regurgitation isstrikingly prolonged so that it may persist100 ms or more after P2. These findings are soconsistent that they can be used to estimatepeak pressure in the right ventricle inindividual patients."'5 Effectively, therefore,pulmonary hypertension causes decline of rightventricular tension to be prolonged; withtricuspid regurgitation as a marker, thisprolongation beyond pulmonary closure isconsiderable, being on average 3 ms for every1 mm Hg rise in pressure in the right vent-ricle.'5 In our present study we were par-ticularly concerned to examine the effects on leftsided events. We found that tricuspid regur-gitation consistently continued beyond open-

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ing of the mitral valve, and that at the time ofmitral cusp separation a mean gradient of12 mm Hg from right ventricle to right atriumstill existed. Thus tension in the right ventriclecontinues to decline throughout, and beyondisovolumic relaxation of the left ventricle. It islikely that tension within the interventricularseptum is equally prolonged. This wouldexplain the displacement of the posterior sep-tum and associated fall in the dimension of theleft ventricle seen in the patients with pulmon-ary hypertension but not in the controls. Thisseptal shift will have contributed to the inco-ordinate wall motion seen during isovolumicrelaxation, and thus to delaying the opening ofthe mitral valve and the start of filling as well asto the abnormal intracavity flow.The period of isovolumic relaxation is

critical to normal filling. Prolonged or dis-organised isovolumic relaxation has importantconsequences on function later in diastole,reducing early velocity diastolic filling andcausing a corresponding increase in velocityduring atrial systole. This effect has been shownin hypertrophic cardiomyopathy,'6 coronaryartery disease,'7 and left ventricular hyper-trophy due to aortic stenosis.'8 We suggest thatour findings represent yet another example ofthe interaction between isovolumic relaxationand ventricular filling, and as the disturbancesin filling of the left ventricle were so typical ofthose previously described, we think that noother explanation for them need be sought.Even within our group of patients with pul-monary hypertension, "A fillers" had a sig-nificantly longer isovolumic relaxation timethan "E fillers". The effects of a diastolicpressure gradient across the septum on ven-tricular septal motion have been recognised forsome time, both in whole animals,2 and humanswith pulmonary hypertension,6 but suchgradients have been associated with raised rightventricular diastolic pressure due to disturbedcompliance and thus occur during ventricularfilling; hence they are different in their mechan-ism and timing to those we have described.Similarly, left ventricular asynchrony has beenrecognised in pulmonary hypertension,'0 butagain this was only apparent during filling andevents during isovolumic periods werespecifically excluded from this study. That apressure gradient across the septum may dis-organise isovolumic relaxation and thus disturbfilling does not appear to have been previouslyproposed.This study highlights a potential problem of

nomenclature that will become increasinglyimportant once it is recognised that systole anddiastole need not be synchronous on the twosides of the heart. In our patients decline ofright ventricular tension during late systole

corresponded to early left ventricular diastoleand this asynchrony had important practicalconsequences. It, in fact, represents a novelmode of ventricular interaction that hasreceived little attention, and it also providesfurther evidence of the importance ofisovolumic relaxation of the left ventricle indetermining events for the remainder ofdiastole.

S J D B is supported by a British Heart Foundation juniorresearch fellowship and H B X by the Brompton HospitalSpecial Cardiac Fund.

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2 Kingma IK, Tyberg JV, Smith ER. Effects of diastolictransseptal pressure gradient on ventricular septalposition and motion. Circulation 1983;68:1304-14.

3 Visner MS, Arentzen CE, Crumbley III AJ, Larson EV,O'Connor MJ, Anderson RW. The effects of pressure-induced right ventricular hypertrophy on left ventriculardiastolic properties and dynamic geometry in the cons-cious dog. Circulation 1986;74:410-9.

4 Goldstein JA, Harada A, Yagi Y, Barzilai B, Cox JL.Hemodynamic importance of systolic ventricular inter-action, augmented right atrial contractility and atrio-ventricular synchrony in acute right ventriculardysfunction. JAm Coll Cardiol 1990;16:181-9.

5 Jessup M, St John Sutton M, Weber KT, Janicki JS. Theeffect of chronic pulmonary hypertension on left ven-tricular size, function and interventricular septal motion.Am Heart J 1987;113:1114-22.

6 Tanaka H, Tei C, Nakao S, Tahara M, Sakurai S, KashimaT, Kanehisa T. Diastolic bulging of the interventricularseptum toward the left ventricle: An echocardiographicmanifestation of negative interventricular pressuregradient between left and right ventricles during diastole.Circulation 1980;62:558-63.

7 Ryan T, Petrovic 0, Dillon JC, Feigenbaum H, Conley MJ,Armstrong WF. An echocardiographic index for separa-tion of right ventricular volume and pressure overload. JAm Coil Cardiol 1985;5:918-24.

8 Louie EK, Rich S, Brundage BH. Doppler echocardio-graphic assessment of impaired left ventricular filling inpatients with right ventricular pressure overload due toprimary pulmonary hypertension. J Am Coll Cardiol1986;6:1298-306.

9 Dittrich HC, Chow LC, Nicod PH. Early improvement inleft ventricular diastolic function after relief of chronicright ventricular pressure overload. Circulation 1989;80:823-30.

10 Bhargava V, Sunnerhagen KS. Left ventricular asynchronyin patients with pulmonary hypertension. J Appl Physiol1990;69:517-22.

11 Triffon D, Groves BM, Reeves JT, Ditchey RV. Determin-ants ofthe relation between systolic pressure and durationof isovolumic relaxation in the right ventricle. J Am CollCardiol 1988;11:322-9.

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15 Brecker SJD, Xiao HB, Stoinic BB, Mbaissouroum M,Gibson DG. Assessment of the peak tricuspid regurgitantvelocity from the dynamics of retrograde flow. Int JCardiol 1992;34:267-71.

16 Sanderson JE, Gibson DG, Brown DJ, Goodwin JF. Leftventricular filling in hypertrophic cardiomyopathy. Anangiographic study. Br Heart J 1977;39:661-70.

17 Fioretti P, Brower RW, Meester GT, Serruys PW. Inter-action of left ventricular relaxation and filling during earlydiastole in human subjects. Am J Cardiol 1980;46:197-203.

18 Lee CH, Hogan JC, Gibson DG. Diastolic disease in leftventricular hypertrophy: comparison of M mode andDoppler echocardiography for the assessment of rapidventricular filling. Br Heart J 1991;65:194-200.

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