impairment of diastolic function by shortened filling period in … · brheartj1989;62:246-52...

Br Heart J 1989;62:246-52

Impairment of diastolic function by shortened fillingperiod in severe left ventricular disease

KELVIN S K NG, DEREK G GIBSON

From the Cardiac Department, Brompton Hospital, London

SUMMARY A dilated left ventricle with reduced ejection fraction is usually attributed to impaired

systolic function. To investigate the possibility that ventricular filling might also be disturbed, Mmode echocardiograms, phonocardiograms, and Doppler cardiograms were recorded in 30 patientswith ventricular disease ofvarying cause. All but four had functional mitral regurgitation. The size

of the left ventricular cavity was increased in all and peak velocity of circumferential fibreshortening was reduced. Diastolic abnormalities included a short isovolumic relaxation time, and,on digitisedM mode, a reduced rate ofdimension increase and ofposterior wall thinning. Althoughthe timing ofaortic valve closure was normal, mitral regurgitation persisted beyond it by 95 (35) msand beyond mitral valve opening by 60 (40) ms. This reduced the effective filling time (the intervalwhen the mitral valve was open and mitral regurgitation was absent) to < 200 ms in seven patients.The effective filling time correlated closely with the RR interval, the regression equation indicatinga reduction of 80 ms for each 100 ms fall in RR interval. It was also independently shortened by2 ms a year with increasing age. The effective left ventricular filling time may thus be very short inpatients with left ventricular cavity dilatation and functional mitral regurgitation.

It is suggested that when diastolic function is also abnormal, this short filling time may

physically limit ventricular inflow. Its close relation to heart rate might contribute to thetherapeutic effect of # blockade in such patients.

A dilated left ventricular cavity with reduced ejectionfraction is common in the late stages ofheart disease,and is usually held to be caused by depressed systolicfunction.' Such patients are often said to be in "heartfailure" and are treated with digitalis, diuretics, andvasodilators. A minority, however, respond favour-ably to ,B adrenoceptor blocking drugs2 and thiswould be surprising if systolic disease were the onlyreason why function was impaired. It is possible,therefore, that other pathogenic mechanisms areinvolved, and we have attempted to identify them byinvestigating how filling, rather than ejection, can bedisturbed in these patients.

Patients and methods

The records of 30 unselected patients (aged from 12to 75, 22 men) with dilatation of the left ventricular

Requests for reprints to Dr Derek G Gibson, Brompton Hospital,Fulham Road, London SW3 6HP.

Accepted for publication 18 April 1989

cavity and reduced shortening fraction wereexamined retrospectively. The underlying diagnosiswas coronary artery disease in 11, dilated cardio-myopathy in three, presumed myocarditis in two,and there were single cases associated with poly-arteritis nodosa, Churg-Strauss syndrome, sar-coidosis, irradiation, and alcoholic cirrhosis. Coro-nary artery disease was diagnosed by coronaryarteriography or directly at necropsy or at the timeof cardiac transplantation. In the remaining ninepatients, three ofwhom had long standing hyperten-sion, we cannot say whether or not coronary arterydisease was present, because there was no clinicalindication for coronary arteriography. All thepatients were in sinus rhythm and five had leftbundle branch block. All were taking diuretics, eitherfrusemide or bumetanide, along with amiloride innine or metolazone in one. Twenty were takingcaptopril, three a theophylline preparation, two

isosorbide, and one nifedipine, while five were

treated with a digitalis preparation.Cross sectional echocardiography in multiple cuts

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Impairment of diastolicfunction by shortenedfilling period in severe left ventricular disease

showed uniform enlargement of the left ventricularcavity and a reduced ejection fraction in all, andexcluded a ventricular aneurysm or other majorabnormality of regional wall motion. M modeechocardiograms were recorded with simultaneousphonocardiograms and electrocardiograms at a paperspeed of 100 mm/s at the level of the tips ofthe mitralleaflets. Clear, continuous echoes were obtainedfrom the endocardial surfaces of the left side of theseptum and the endocardium of the posterior wall.Separate echograms were recorded ofthe mitral valveat the level at which cusp separation at the start offilling and closure at the onset of systole could mostclearly be seen (fig la) and of the aortic echogram,from which the aortic component of the second heartsound (A2) was identified as the onset of the first highfrequency vibration of the component coincidingwith cusp apposition. Continuous wave Dopplerrecordings were made with Doptek equipment, againwith simultaneous phonocardiograms and electro-cardiograms, at a paper speed of 100 mm/s to showthe timing offunctional mitral regurgitation (presentin all but four patients), and separately, of earlydiastolic forward flow across the mitral valve.From the M mode echocardiograms we measured

the dimensions of the left ventricular cavity syn-chronously with the Q wave of the electrocardiogram(end diastolic) and with A2 (end ejection), from theleading edges. We digitised the records3 to give plotsof the left ventricular dimension and posterior wallthickness along with their rates of change. Thetiming of A, was superimposed on all digitisedrecords, and the interval A, to peak rate ofdimensionincrease was measured. We took the isovolumicrelaxation time to be the interval between the onset ofthe first high frequency component of A, on thephonocardiogram and the initial cusp separation onthe mitral echogram.4 We estimated the interval overwhich the mitral valve was open (mitral valve opentime)' as that from the initial cusp separation at theonset of diastole to the final apposition at the start ofthe succeeding systole. The left ventricular ejectiontime was determined from the aortic echograms andthe QA2 interval from the electrocardiogram andphonocardiogram. Values of QA, from patients withleft bundle branch block were not included in theanalysis.On the Doppler recording, we measured the

overall duration of the mitral regurgitant signal (figlb) and also the two intervals from Q to the onset ofthe regurgitant signal and from A, to its end. On thetrace offorward mitral flow we measured the intervalfrom A2 to the time of peak flow velocity.

Preliminary examination of the records showedthat the times ofonset and end ofmitral regurgitationbore no fixed relation to those of mitral opening or

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Fig 1 (a) Mitral echogramfrom a patient withcardiomyopathy. Mitral valve open time is indicated(MVO T). Note that mitral cusp separation at the start ofdiastole is synchronous with aortic valve closure (A2).- (b)Continuous wave Doppler recordingfrom the same patient,showing mitral regurgitation (MR). Its duration and that ofthe interval between pulses of regurgitation (non-MR) areindicated. Note that regurgitation continues forapproximately 70 ms beyond A2.-(Full scale deflection16 kHz).

closure, the regurgitation signal sometimes startingbefore mitral closure at the start of systole and oftenpersisting beyond mitral opening at its end (fig 1).The interval from mitral opening to the end ofregurgitation (interval A) was thus measured as thedifference between the intervals A, to the end of

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regurgitation and A2 to mitral opening. The relationbetween the onset ofregurgitation and mitral closureat the start of systole (interval B) was measured as thedifference between the two intervals-Q to mitralclosure and Q to onset of regurgitation. We definedeffective filling time as the interval during which (a)the mitral valve was open and (b) mitral regurgitationhad ceased, and derived it as mitral valve openingtime less the sum of intervals A and B. In patientswithout functional mitral regurgitation, effectivefilling time was taken to be equal to mitral valve opentime.

STATISTICAL ANALYSISAll values were based on the mean ofthree determin-ations, except those of QA2, which, in line with therecommendations of Lewis et al6 were based on 10.

Where appropriate, values were compared withnormal values and their 95% confidence intervalspreviously reported by us. Differences between meanvalues were examined by calculating 95% confidenceintervals,' and linear correlation was performed bythe method of least squares. Estimates ofreproducibility were based on independent deter-minations of all measurements by each co-author.Reproducibility was expressed as the mean (SD) ofthe differences between individual determinationsand their mean.6 We have recorded values formeasurements underlying our conclusions.

Results

LEFT VENTRICULAR SYSTOLIC FUNCTION

The size ofthe left ventricular cavity was increased inall patients (mean (1 SD) 7-1 (0-3) cm) at end diastoleand 6-3 (0 7) cm at end ejection. The mean leftventricular ejection time was 235 (30) ms, and thevalues correlated with the RR interval (table). Themean value ofthe QA2 intervals was 375 (50) ms, witha reproducibility of0 (8) ms, and again this correlatedwith the RR interval (table) but not with age. The

Ng, Gibsoncorresponding regression relation with heart rate

was:

QA2 = 510 - 1-65 (heart rate)ms,

the standard errors of the estimate was 30 ms, andthose of the slope and intercept were 0-36 and 35respectively. The slope and intercept of this equationdid not differ significantly from normal valuespreviously reported by Lewis et al.6 The mean valueof peak velocity of circumferential fibre shortening(VCF) was 0X6 (0.2)/s. In all the patients, it was belowthe normal range of 1.2-2-0/s.

MITRAL VALVE MOTIONThe isovolumic relaxation time was 25 (35) ms(reproducibility 1 (7) ms), significantly less than thenormal value of 60 (10) ms; only 11 patients were

within the normal range, values being abnormallyshort in the remainder. The mean mitral valve opentime was 345 (130) ms (reproducibility -3 (10)) andvalues correlated strongly with heart rate (table).Mitral closure followed the Q wave by 75 (55) ms, aninterval unrelated to heart rate.

DOPPLER MEASUREMENTSMitral regurgitation was detected by continuouswave Doppler in 26 of the 30 patients. It lasted 400(70) ms, reproducibility - 3 (10), with values above500 ms in three patients. It correlated weakly withRR interval and rather more strongly with age

(table). The interval between the pulses of regurgita-tion (non-MR interval) was 290 (120) ms(reproducibility 3 (10) ms) which correlated stronglywith RR interval (table). The mean interval betweenthe Q wave and the onset of mitral regurgitation was65 (20) ms, and between A2 and its end it was 95(35) ms, (reproducibility 0 (7) ms). Neither wasrelated to heart rate, though the time from A2 to theend ofmitral regurgitation increased with age (table).

EFFECTIVE FILLING PERIODIn all but three patients mitral regurgitation persis-ted forup to 160 ms after mitral valve opening (mean

Table Determinants of ventricular function

Standard error

Dependent variable (x) Independent variable (y) r Slope Intercept Slope Intercept Estimate

Duration ofMR Age 0-53 2-0 290 0-68 38 54A2to end ofMR Age 0-68 1-3 18 0 30 17 24Non-MR interval Mitral valve open time 0-87 1-0 69 0-11 36 68Mitral valve open time RR interval 0-78 0-82 -220 0-12 88 90Non-MR interval RR interval 0-87 0-75 -230 009 65 63Effective filling time RR interval 0-80 0-78 -260 0-12 83 84QA2 interval RR interval 0-67 0-23 205 0 05 34 37Ejection time RR interval 050 0-11 160 004 26 28Duration ofMR RR interval 0-43 0-21 250 0 09 66 66

MR, mitral regurgitation.



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600XE~~~~~~~~

's 00- 0

~200-

300 500 700 900 1100RR interval (ms)

Fig 2 Relation between RR interval and effectivefillingperiod. Limits are set at two standard errors of the estimate.Closed synbols represent resultsfrom patients with mitralregurgitation and open symbolsfrom those without.

60 (40) ms). By contrast, the onset of mitral regur-gitation could precede or follow mitral closure, themean interval between the two being 8 (40) ms. Themean value of effective filling period was thus 275(135) ms, reproducibility 6 (17) ms, which againcorrelated strongly with the RR interval (table andfig 2). In seven patients the effective filling periodwas <200 ms. Their average age (45 (15)) was nodifferent from that of the whole group. They all hadfunctional mitral regurgitation. Two of them hadmyocarditis, one each had heart disease caused bycoronary artery disease, irradiation, or polyarteritisnodosa, while a definite diagnosis had not beenestablished in two. Two had left bundle branchblock. In six, the RR interval was in the range 480-590 ms; in the seventh, it was 740 ms, and in thispatient the effective filling period was short becausemitral regurgiation-lasted560 ms, extending 160 msbeyond A2

DIGITISED M MODE ECHOCARDIOGRAMSOn the digitisedM mode echocardiograms, the peakrate of dimension increase was 7-5 (3 8) cm/s. Sevenvalues were within the normal range and the remain-der were below. The rapid filling period was 150(45) ms, with values below the normal range in 11and above it in one. The peak rate of wall thinningwas very low (3 5 (2) cm/s) and values from all butfour patients were below the lower limit of normal.The interval from minimum cavity dimension tomitral opening was 3 (40) ms, which was not sig-nificantly different from normal. There was widevariation between patients, however: mitral openingwas abnonnally delayed in seven, andwas premature,

occurring up to 80 ms before minimum dimension,in six. Finally, phase relations between the peak rateof dimension increase and peak flow were abnormalduring rapid filling, when the normal delay in peakfilling velocity with respect to peak rate ofdimensionincrease (50 (15) ms) was lost in 10 patients.

WITHIN PATIENT COMPARISONSWe recorded at two different heart rates in eightpatients. With a mean fall in RR interval of 155(110) ms, the non-MR interval shortened by 105(130) (95% confidence interval 45 ms) and mitralvalve open time by 105 (90) (95% confidence interval60 ms), while isovolumic relaxation time, and theduration of mitral regurgitation and its persistencebeyond A2 were all unchanged.

Discussion

Although impaired systolic function is usuallyheld to be the main cause of the dilated left ven-tricular cavity and reduced ejection fraction seen inpatients with severe heart disease,' diastolic abnor-malities have also been described. The peak rate ofpressure decline during isovolumic relaxation wasreduced9 and the time constant of pressure fall wasprolonged.'0 Although the peak rate of increase ofventricular volume during early diastole was usuallynormal," the peak rate of dimension increase wasoften low, and in many patients the early rapid fillingperiod was short.9 12 Finally, left ventricular passivestiffness was increased, both when expressed ascavity compliance or as a myocardial stress-strainrelation." These abnormal measurements, however,do not necessarily define independent disturbancesof diastole. When left ventricular filling pressure israised, as it often has been in reported cases,isovolumic relaxation time may be very short or evenzero,4 so that the fundamental assumption underly-ing the use of the time constant of pressure fall as ameasure of relaxation, namely that the ventricle isisovolumic for the period over which the calculationis made, does not necessarily apply. At a constanttransmitral flow rate, the peak rate of dimensionincrease is inversely-proportional to the square ofthedimension, so on simple geometrical grounds it willbe low when the ventricle is enlarged. "Normal-isation" to unit dimension by calculating the velocityof circumferential fibre shortening or lengtheningmerely increases the discrepancy, making the peakrates of dimension increase sensitive to the cube ofthe dimension. Finally passive stiffness can only becalculated when pressure and volume increasetogether. This does not occur until late diastole whenheart rate is low'4 and may not do so at all when it israpid.

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250In our study, therefore, we examined the effective

left ventricular filling period, an aspect of diastolicfunction that is independent of increased cavity size,heart rate, or isovolumic relaxation time. We definedit as the period during which the mitral valve wasopen and retrograde flow had ceased, assuming thatthere is no forward flow from atrium to. ventricle inthe presence of mitral regurgitation. In severalpatients, this effective filling period was very short,and in seven, it was < 200 ms. In healthy individuals,left ventricular filling time varies with heart rate. Itshortens with tachycardia caused by exercise or atrialpacing, reaching a minimum of 100 ms.5 Ventricularfilling may be very rapid, therefore, when diastolicfunction is normal. In patients with left ventricularhypertrophy and associated diastolic disease, fillingtime does not drop below 200 ms, even when heartrate is high; the extra filling time is found within theRR interval by shortening isovolumic relaxationtime. Diastolic abnormalities in our patients differedfrom those seen in patients with hypertrophy. Theisovolumic relaxation time was usually very short oreven zero at rest rather than being increased, and theearly diastolic filling period was either normal orshort, rather than prolonged. Nevertheless, phaserelations between transmitral flow velocity anddimension changes were often abnormal. Rapid wallthinning, intimately related to rapid ventricularfilling under normal conditions,'5 was much lowerthan would have been expected from cavity dilatationalone. Mitral valve opening was often delayed inrelation to minimum cavity dimension, indicatingincoordinate relaxation.'6 Finally, changes in cavityshape, which also form a prominent part of normalventricular adaptation to rapid filling, are likely tohave been absent in our patients.'7 Superimposed onsuch abnormal diastolic function, therefore, a fillingperiod of < 200 ms might be expected to limitventricular inflow directly.A striking feature of the functional mitral regur-

gitation in our patients was that it lasted > 500 ms.Though the QA, interval was normal, retrogradeflow was prolonged beyond the end of ejection intowhat would normally have been isovolumic relaxa-tion. In our patients, however, isovolumic relaxationwas usually short or even zero. This led to theparadoxical finding in most that the mitral valve wasopen in the face ofcontinuing regurgitation (fig 1). Inaddition, the excessive duration of the regurgitationwas little affected by heart rate. Filling time thusbecame very sensitive to tachycardia, shortening by80 ms for each 100 ms fall in RR interval. As heartrate rises, therefore, the cardiac cycle becomesincreasingly occupied by mitral regurgitation, andfilling time becomes disproportionately shortened(fig 2). This effect ofheart rate was seen whatever the

Ng, Gibsoncause of the ventricular disease, pointing to thedilated cavity itself as a possible cause. The effect ofage on the duration of mitral regurgitation and itscontinuation beyond A, suggests that filling might bemore frequently disturbed in older patients, but wefound no evidence of this. Presumably the durationof mitral regurgitation reflects the period duringwhich myocardial tension develops in the left ven-tricle, though we do not know why this is so strikinglyprolonged. Perhaps the time course of deactivation'8is modified by the abnormal pattern of developmentof systolic stress in a dilated ventricle or by the loss of# adrenoceptive receptors found in "failing" humanhearts removed at the time of transplantation.'9Certainly, our results accord with the disturbedcalcium handling described in vitro in myocardiumfrom patients with severe ventricular disease.'0

In some of our patients, therefore, cardiac outputseemed to have been limited not directly by systolicdisease but by ventricular inflow. When filling timeis short, mean flow rates across the mitral valve mustbe rapid to maintain stroke volume, and this meansthat acceleration and deceleration rates must becorrespondingly high. Such rapid changes in bloodvelocity must, on a simple physical basis, be accom-panied by considerable pressure drops along thedirection of flow. This leads to conditions closelyresembling those seen in rheumatic mitral stenosis,when ventricular filling also depends on a highpressure difference between left atrium and leftventricle. In both conditions cardiac output may below and arterial pressure maintained only by raisedperipheral resistance, effectively increasing ven-tricular afterload. This may explain the reducedejection rates seen in mitral stenosis and the tendencyfor cavity size and filling pressures to fall aftersuccessful operation." Sometimes these changes maybe very striking, with a remarkable increase inejection fraction and fall in end diastolic pressure." Ifventricular function was modified in the same way inour patients, the low observed ejection fractionsmight have been caused in part by this secondaryincrease in resistance to ejection and not exclusivelyby left ventricular disease. These similarities couldbe summarised by suggesting that our patients had"temporal" mitral stenosis to emphasise how muchthey resemble those of the well recognised "spatial"variety.The filling period was not short in all our patients.

The heart rate was low in some and regurgitationnot unduly prolonged in others. It would not havebeen possible to predict these differences inhaemodynamic state from simple measurements ofheart rate or cavity size. Yet they are not purelyof theoretical importance because they suggestapproaches to treatment. If the filling period does



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Fig 3 (a) Continuous wave Doppler trace from a patientwith sinus tachycardia, showing non-MR interval reduced toapproximately 80 ms. (b) Continuous wave Doppler tracefrom the same patient while taking oral metoprolol. Heartrate has slowed and non MR interval has increased to400 ms. (Full scale deflection =16 kHz).

indeed limit cardiac output, it would be reasonable totreat it. One way would be to reduce the heart rate;such an action might explain the favourable responseto fi adrenoceptive blocking drugs seen in a minorityof patients with dilated cardiomyopathy. Figure 3shows an example of such a patient who greatlyimproved with metroprolol as the filling timeincreased by a factor of more than three. The actionof positive inotropic drugs in increasing the peakforce of myocardial contraction and its peak rate ofdevelopment is well recognised,3 but their additional

effect of shortening the overall duration of systolemight be particularly valuable when filling time islimited and could perhaps be enhanced by suitabletreatment design. A drug, such as digitalis, with botheffects might thus have special advantages. Finally,the unexpected relation between retrograde mitralflow and motion of the valve cusps needs more studybecause the erosion of filling time by regurgitationthat persists after mitral opening might also bemanipulated by drugs.The patients we have described all had a dilated

cavity and a reduced ejection fraction; all mighttherefore have been diagnosed as having "heartfailure" and a uniform treatment prescribed.However, the position of the rate limiting step in thecirculation varied even in this small group. Webelieve that individual treatment on the basis ofindividual analysis of the underlying disturbance tothe circulation may be a more fruitful approach to themanagement of the common but intractable clinicalproblem of advanced ventricular disease.

References

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2 Swedberg K, Hjalmarson A, Waagstein F,-Wallentin I.Beneficial effects of long term beta-blockade in con-gestive cardiomyopathy. Br Heart J 1980;44:117-33.

3 Gibson DG, Brown D. Measurement of instantaneousleft ventricular dimension and filling rate in man,using echocardiography. Br Heart J 1973;35:1141-9.

4 Mattheos M, Shapiro E, Oldershaw PJ, Sacchetti R,Gibson DG. Non-invasive assessment of changes inleft ventricular relaxation by combined phono-, echo-and mechanography. Br Heart J 1982;47:253-60.

5 Oldershaw PJ, Dawkins KD, Ward DE, Gibson DG.Diastolic mechanisms of impaired exercise tolerancein aortic valve disease. Br Heart J 1983;49:568-73.

6 Lewis RP, Boudalas H, Forester WF, Weissler AM. Acritical review of systolic time intervals. Circulation1977;56:146-58.

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10 Carroll JD, Lang RM, Neumann AL, Borow KM,Rajfer SI. The differential effect of positive inotropicand vasodilator therapy on diastolic properties inpatients with congestive cardiomyopathy. Circulation1986;74:815-25.

11 Rahko PS, Shaver JA, Salemi R, Uretsky BF. Digital



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14 Fioretti P, Brower RW, Meester GT, Serruys PW.Interaction of left ventricular relaxation and fillingduring early diastole in human subjects. Am J Cardiol1980;46:197-203.

15 Hui WKK, Gibson DG. The dynamics of rapid leftventricular filling. Adv Cardiol 1985;32:7-35.

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17 Gibson DG, Brown DJ. Continuous asSessment of leftventricular shape in man. Br Heart J 1975;37:904-10.

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control of relaxation: its role in the ventricularfunction in the mammalian heart. Circ Res1980;47:637-52.

19 Bristow MR, Ginsburg R, Minobe W, et al. Decreasedcatecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N EnglJ Med 1982;307:205-1 1.

20 Gwathmwey JK, Copelas L, MacKinnon R, et al.Abnormal intracellular calcium handling inmyocardium from patients with end-stage heartfailure. Circ Res 1987;61:70-6.

21 Gash AK, Carabello BA, Cepin D, Spann JF. Leftventricular ejection performance and systolic musclefunction in patients with mitral stenosis. Circulation1983;67:148-54.

22 Traill TA, St. John Sutton MG, Gibson DG. Mitralstenosis with high left ventricular diastolic pressure.Br Heart J 1979;41:405-1 1.

23 Sonnenblick EH, Braunwald E, Morrow AG. Thecontractile properties ofhuman heart muscle: studieson myocardial mechanics of surgically excisedpapillary muscles. J Clin Invest 1965;44:966-77.



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