dynamic mitral regurgitation · 306 dynamicmitral regurgitation animportant determinant ofthe...

306

Dynamic Mitral RegurgitationAn Important Determinant of the Hemodynamic Response

to Load Alterations and Inotropic Therapyin Severe Heart Failure

Gad Keren, MD, Stuart Katz, MD, Joel Strom, MD,

Edmund H. Sonnenblick, MD, and Thierry H. LeJemtel, MD

Cardiac performance and mitral regurgitation were measured by Doppler echocardiographyand right heart catheterization in 12 patients with severe congestive heart failure whoperformed isometric exercise during control and intravenous administration of dobutamine andnitroglycerin. During control isometric exercise, mitral regurgitant volume increased from18±13 to 31±17 ml (p<0.01), while forward stroke volume, by both thermodilution andDoppler echocardiography, substantially decreased. At rest, dobutamine decreased mitralregurgitant volume from 18± 13 to 11± 10 ml (p<0.05), while forward stroke volume increasedfrom 46±13 to 55±15 ml (p <0.05). During isometric exercise, dobutamine tended to decreasemitral regurgitant volume (24±12 vs. 31±17 ml; NS) when compared with control exercise. Atrest, nitroglycerin decreased mitral regurgitant volume from 18±13 to 11±11 ml (p<0.05),while forward stroke volume, by both thermodilution and Doppler echocardiography, substan-tially increased. Similarly, during isometric exercise, nitroglycerin decreased mitral regurgitantvolume from 31±17 to 20±14 ml (p<0.05), while significantly increasing forward strokevolume. At control rest, the median mitral regurgitant fraction was 24% for the 12 patients.Neither dobutamine nor nitroglycerin changed significantly forward stroke and mitral regur-gitant volumes at rest and during isometric exercise in the six patients with resting mitralregurgitant fraction below the median. In contrast, dobutamine and nitroglycerin significantlydecreased mitral regurgitant volume and increased forward stroke volume both at rest andduring isometric exercise in the six patients with mitral regurgitant fraction greater than themedian. Thus, aggravation of mitral regurgitation contributes substantially to the fall inforward stroke volume noted during isometric exercise in patients with severe congestive heartfailure. The presence and severity of functional mitral regurgitation appears to be an importantdeterminant of the hemodynamic response to acute therapy with dobutamine and nitroglycerinin these patients. (Circulation 1989;80:306-313)

D uring isometric exercise in normal subjects,the rise in systemic arterial pressure isaccompanied by an increase in cardiac

output, but in patients with severe congestive heartfailure, a fall in cardiac output may occur.1-8 Thislatter abnormal hemodynamic response to isometricexercise has been explained by a lack of myocardialcontractile reserve or the descending limb of theFrank-Starling curve.6,7,9 More recently, worseningof functional mitral regurgitation, which is fre-quently observed in patients with dilated cardiomy-

From the Division of Cardiology, Department of Medicine,The Albert Einstein College of Medicine, Bronx, New York.G.K. supported in part by the G. Harold and Leila Y. Mathers

Foundation.Address for reprints: Thierry H. LeJemtel, MD, Albert Einstein

College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.Received April 11, 1988; revision accepted April 4, 1989.

opathy, has been shown to contribute to the fall incardiac output during isometric exercise.10'11Whether changes in the amount of mitral regur-

gitation contribute substantially to the hemody-namic response to increased afterload and vasodi-lator or inotropic therapy is unclear in patients withsevere heart failure.12-1'Accordingly, the presentstudy was undertaken to evaluate the hemodynamicresponse to isometric exercise in patients withsevere congestive heart failure and to compare itwith that of patients successively treated with dobu-tamine and intravenous nitroglycerin. The amountof functional mitral regurgitation during isometricexercise was determined from left ventricular vol-umes measured by two-dimensional echocardiogra-phy and forward stroke volume obtained by Dopp-ler echocardiography and by thermodilution.

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Keren et al Mitral Regurgitation in Cardiomyopathy 307

MethodsPatient PopulationWe studied nine men and three women with

dilated cardiomyopathy and severe chronic conges-tive heart failure who were in New York HeartAssociation functional Class III or IV despite ther-apy with diuretics, digitalis, and nitrates. Theiraverage age was 64 years (range, 52-78 years). Allpatients were in sinus rhythm except one, who wasin atrial fibrillation. Left ventricular ejection frac-tion averaged 24% (range, 20-35%). In six patients,the etiology of dilated cardiomyopathy was coro-nary artery disease, which was documented byprevious myocardial infarction(s), abnormal coro-nary angiograms, or both. Patients with coronaryartery disease had no clinical or electrocardio-graphic evidence of myocardial ischemia duringmaximal stress test. No patient had sustained myo-cardial infarction within 6 months before the study.The dilated cardiomyopathy was of unknown etiol-ogy in the remaining six patients. All patients wereevaluated carefully by Doppler echocardiography.None had primary valvular disease, flail mitralleaflet, or aortic regurgitation. Five patients hadmild tricuspid regurgitation. Left ventricular end-diastolic volume, which was substantially increasedin all patients, averaged 238 ml (range, 175-297 ml).The six patients with coronary artery disease didnot have significant left ventricular asynergy.

Patients who had not been previously treatedwith captopril, hydralazine, or prazosin were admit-ted to the coronary care unit for monitoring thehemodynamic response to investigational inotro-pic or vasodilator agents. Long-acting nitrateswere discontinued 72 hours before admission tothe coronary care unit.

HemodynamicsThe patients underwent right heart catheteriza-

tion with a flow-directed, balloon-tipped, thermodi-lution catheter (Edwards Labs). Mean pulmonaryarterial, pulmonary capillary wedge, and right atrialpressures were monitored and recorded (Elec-tronics for Medicine). Cardiac output was deter-mined by thermodilution technique using iced 5%dextrose in water and obtained in triplicate with lessthan 10% variation. Cardiac output was calculatedwith a bedside computer (Model 9520A, EdwardsLabs). In five patients with mild tricuspid regurgi-tation, cardiac output measured by thermodilutionwas closely correlated with that derived from theFick principle, with determination of oxygen uptakeand systemic arteriovenous oxygen difference.Systemic arterial pressure was measured by eitherintra-arterial in-dwelling catheters or standard cufftechniques. Derived hemodynamic indices werecalculated by standard formulae. An electrocar-diographic lead was monitored continuously

Noninvasive StudiesA Hewlett-Packard ultrasound imaging system

(77020AC) was used for both imaging and Dopplerflow studies. The system has a phased-array sectorscanner and a movable Doppler cursor that allowssampling directed by two-dimensional echocardio-graphic imaging in the pulsed Doppler mode.The echocardiography-Doppler operator trained

carefully with each patient so that while obtainingthe noninvasive studies, he was well acquaintedwith the optimal windows and necessary adjust-ments. Of note, the operator was kept unaware ofthe hemodynamic parameters.

Total stroke volume by two-dimensional echocar-diography. The apical four-chamber view was usedfor volume estimation, as previously described bySchnittger et al15 and Gordon et al16 and later usedin our studies.1217 The patient was positioned in theleft lateral decubitus position. Every effort wasmade to obtain the maximal length and width ofboth right and left ventricles. Optimal and repro-ducible transducer angulation was ensured by anglingthe imaging plane dorsally and ventrally to visualizethe mitral and tricuspid valve leaflets and left atrium.Internal and external landmarks were noted on thebaseline study so that similar landmarks would beused for guidance during intervention. Because theintervention was short term and the delay betweenthe end of baseline study at each stage and obtain-ing an intervention study was only a few minutes, itwas easy to maintain similar position, transducerlocation, and steady gain setting for each patient forthe whole study. Moreover, the transducer positionwas marked on the chest wall at the apical regionand was steady during the intervention, except forsmall rotations performed from the four-chamberview to obtain cardiac volumes and from the apicallong-axis view to obtain aortic flow velocity tracings.Images were accepted for analysis according to

the guidelines proposed by Gordon et al16 when atleast 80% of the endocardium was seen. Echocar-diographic studies were interpreted by the sameinvestigator (G.K.), who did not have knowledge ofthe hemodynamic data. The endocardial echocar-diograms were traced with an integrated Echo-Doppler Analyzer (Microsonics Datavue, Indianap-olis, Indiana) programmed for single plane area,length, and volume computation by Simpson'srule.1217 Left ventricular volumes were measured atend diastole (i.e., largest dimension or onset of theQRS complex) and at end systole (i.e., smallestdimension or one frame before opening of the mitralvalve). Total stroke volume was the differencebetween end-diastolic and end-systolic volumes.Three cardiac cycles were analyzed when patientswere in sinus rhythm (<5% variation per cycle) and10 cycles were analyzed in the patient with atrialfibrillation. Analysis of the baseline and peak iso-metric exercise echocardiographic studies wasrepeated in seven patients. The reproducibility ofthroughout the study.



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308 Circulation Vol 80, No 2, August 1989

the echocardiographic volume determination wasexcellent, with a correlation coefficient of 0.96(p<0.OOl).Forward stroke volume by pulsed Doppler cardi-

ography. Left ventricular outflow was recordedfrom the apical position at the level of the aorticannulus. The sample volume was placed in themiddle of the left ventricular outflow tract, imme-diately proximal to the leaflets of the aortic valve.Slight adjustments were required to optimize theorientation between the sample volume and flow.Forward aortic flow volume was determined as

the product of the time velocity integral of aorticoutflow and the cross-sectional area of the aorticannulus. Curves exhibiting the highest peak veloc-ities were selected. The average of the time velocityintegral was obtained by tracing the contour of thedarkest portion of the curve. The cross-sectionalarea of the aortic annulus was calculated as rrr'where r is half of the maximal annular diametermeasured in the parasternal long-axis view, imme-diately proximal to the points of insertion of theaortic leaflets during systole.Mitral flow study. Every effort was made to

detect the presence of mitral insufficiency by scan-ning the atrium near the mitral valve for regurgita-tion flow. Mitral regurgitation was detected bypulsed Doppler in all patients at the beginning of thestudy.

Left ventricular outflow velocities were recordedon videotape (Model AG6300, Panasonic) and on ablack-and-white paper hardcopy recorder (Model77500B, Hewlett-Packard) at a paper speed of 100mm/sec. Three Doppler flow tracings were analyzedin the patients with sinus rhythm and seven tracingswere analyzed in the patient in atrial fibrillation.The regurgitant volume was derived as the differ-

ence between total stroke volume obtained by two-dimensional echocardiography and forward strokevolume by thermodilution or Doppler echocardiog-raphy. Regurgitant fraction was calculated as theregurgitant volume divided by the total stroke vol-ume. This methodology has been previously reportedand validated.12,17-21The ratio of peak systolic pressure and end-systolic

volume was calculated from peak systolic blood pres-sure and end-systolic volume by two-dimensionalechocardiography, as previously reported.22-24

Study ProtocolPatients remained supine for at least 1 hour before

the study. Hemodynamic measurements and echo-cardiographic determinations were obtained at restand during handgrip exercise. Sixty minutes afterreturn of the resting hemodynamic parameters tobaseline values, the same protocol was repeatedduring administration of dobutamine and, thereafter,during intravenous administration of nitroglycerin.

Isometric exercise was performed using a com-mercially available calibrated hand dynamometer

familiarized and had practiced the handgrip exer-cise, they were asked to compress the dynamome-ter once to the maximum extent possible with theirdominant arm. They were then asked to maintain30% of their previously determined maximal com-pression pressures while breathing normally andavoiding performance of the Valsalva maneuver.

Patients were able to maintain this level of isometricexercise for a total of 5-7 minutes.

Drug AdministrationAdministration of dobutamine was begun at 3

4tg/kg/min, and the dose was titrated at 10-minuteintervals in increments of 2 ,gg/kg/min. Titration ofdobutamine was continued to a maximum dose of13 ,gtg/kg/min until a plateau in cardiac output was

reached or undesirable side effects were elicited.Adverse effects were defined as a 15% increase inheart rate, a 15% decrease in mean systemic arterialpressure, or the development of complex ventricu-lar arrhythmias. After all hemodynamic parametersreturned to baseline and steady hemodynamic statewas established for at least 60 minutes, intravenousnitroglycerin was administered at a starting dose of10 ,tg/min. The dose of intravenous nitroglycerinwas titrated by successive increments of 10, 15, 25,and 35 ,ug/min, given at intervals of 15 minutes, tolower capillary wedge pressure to less than 12mm Hg without aborting the increase in cardiacoutput, decreasing systemic arterial pressure, orincreasing heart rate by more than 15%.

Statistical AnalysisValues are given as mean+SD. Hemodynamic

and Doppler echocardiographic measurements wereassessed with a two-factor within-subject analysisof variance model. Each patient was assessed atrest and during isometric exercise, both before andafter administration of dobutamine and intravenousnitroglycerin, for a total of six observations. Hemo-dynamic and echocardiographic parameters wereanalyzed as a function of the effect of exercise (restvs. isometric exercise), the effect of the drug (con-trol vs. dobutamine or nitroglycerin administra-tion), and the interaction of the two factors. In thepresence of exercise drug interactions, F tests forthe single effects of drugs during isometric exercisewere performed with orthogonal contrasts.

ResultsLeft ventricular performance was reduced at rest

in all 12 patients, as evidenced by a reduced cardiacindex of 2.08+±0.54 1/min/M2 and an elevated pulmo-nary capillary wedge pressure of 18±9 mm Hg(Table 2). During isometric exercise, forward strokevolume decreased from 46+ 13 to 39+13 ml (p<0.05)when calculated from thermodilution and from 45 + 12to 40+13 ml when calculated from Doppler, whilepulmonary capillary wedge pressure increased from18±9 to 31±10 mm Hg (p<0.01; Figure 1). During

(Stoelting Company). Once the patients had been resting conditions (control), stroke volume by ther-



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TABLE 1. Hemodynamic Effects of Isometric Exercise Performed During the Control Period and During Administration of Dobutamine andIntravenous Nitroglycerin

Control period Dobutamine Intravenous nitroglycerin

Rest IEx p Rest IEx p Rest IEx p

HR (beats/min) 80+12 90+16 0.01 88±8* 100±9t 0.01 82±10 90±13 0.01SAP (mm Hg) 87±12 104± 14 0.001 91±11* 105±11 0.01 81±11* 92± 11* 0.01CI (1/minlM2) 2.08±0.54 1.92±0.53 0.05 2.97±0.83* 2.78±0.9* NS 2.45±0.62* 2.37±0.47* NSFSV (ml) 46±13 39±13 0.05 55±15* 47±12* 0.05 51±13* 44±8% 0.05RAP (mm Hg) 7±7 13±7 0.01 3±4* 8±7* 0.01 3+4* 6±5* 0.01PCWP (mm Hg) 18±9 31±10 0.01 12±8* 24±11* 0.01 11±7t 17±7* 0.05SVR (dyn.sec/cm-5) 1,912+629 2,385±882 0.01 1,503+568* 1,802±716* 0.01 1,565+485* 1,774+479* 0.05LVSW (g/m) 43±16 39±16 NS 60±18* 54±21* NS 50±16* 46±13* NS

1Ex, isometric exercise; p, statistical significance of IEx vs. rest; HR, heart rate; SAP, mean systemic arterial pressure; CI, cardiacindex; FSV, forward stroke volume (thermodilution); RAP, mean right atrial pressure; PCWVP, mean pulmonary capillary wedgepressure; SVR, systemic vascular resistance; LVSW, left ventricular stroke work index.

*Statistical significance less than 0.05 vs. control at rest or 1Ex; tstatistical significance less than 0.01 vs. control at rest or 1Ex.

modilution correlated well to Doppler (r=0.8). Heartrate increased from 80±12 to 90±16 beats/min(p<0.01), and mean systemic arterial pressure andvascular resistance rose from 87±12 to 104±14mm Hg (p<0.001) and 1,912+629 to 2,385±882dyn sec/cm-5 (p<0.01), respectively (Table 1).Although the increase in left ventricular end-diastolic volume (Table 3) from 238±39 to 241±34ml and the decrease in end-systolic volume from175+38 to 168+36 ml did not reach statistical sig-nificance, their difference (i.e., total stroke volume)increased significantly from 64±14 to 70±13 ml(p<0.05). The decrease in forward stroke volumeduring isometric exercise was due to a decrease inaortic flow velocity from 47±10 to 43±10 cm/secand shortening of systolic ejection period from267±40 to 248±50 msec and occurred concomitantwith a significant increase in mitral regurgitantvolume from 18±13 to 31±17 ml (p<0.01; Figure 2,Table 3). Thus, mitral regurgitant fraction increasedfrom 28±14% to 43±18% (p<0.01). The results formitral regurgitant volume, as calculated from Dopp-ler (i.e., TSV-ASV; Table 3), were similar. Theratio of peak systolic pressure to ventricular end-

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10 15 20 25 30 35 40PULMONARY CAPILLARY WEDGE PRESSURE (mmHg)

FIGURE 1. Plot offorward stroke volume andpulmonarycapillary wedge pressure at rest (R) and during isometricexercise (IEx) perfformed during the controlperiod (C, )

and during administration of dobutamine (DOB, --

and intravenous nitroglycerin (NTG, -.-).

systolic volume increased during isometric exercisefrom 0.71+0.27 to 0.84+0.32 mm Hg/ml (p<0.05).At rest, dobutamine at an average dose of 7.4

,ug/kg/min (range, 3-12 ,ug/kg/min) increased for-ward stroke volume from 46±13 to 55+15 ml(p<0.05) and reduced pulmonary capillary wedgepressure from 18+9 to 12+8 mm Hg (p<0.05;Figure 1, Tables 2 and 3). Heart rate increased from80±12 to 88±8 beats/min, and mean systemic arte-rial pressure rose from 87± 12 to 91+11 mm Hg

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-80 85 90 95 100 105 110MEAN SYSTEMIC ARTERIAL PRESSURE

(mmHg)

FIGURE 2. Relation between stroke volume (forwardand total) and mean systemic arterialpressure at rest (R)and during isometric exercise (IEx) performed during thecontrol period (C) and during administration of dobu-tamine (D, dotted area) and intravenous nitroglycertin (N,striped area). During the control period, mitral regur-gitant volume (MRV; total stroke volume minus forwardstroke volume) increased while mean systemic arterialpressure rose. Dobutamine significantly decreased MRVat rest, while mean systemic arterialpressure was signif-icantly increased. During isometric exercise, dobutaminetended to decrease MRV when compared with controlexercise. Intravenous nitroglycerin significantly decreasedMRV at rest and during isometric exercise, while meansystemic arterial pressure was significantly decreased atrest and during isometric exercise when compared to thecontrolperiod. *p<0.05 versus mitral regurgitant volumeat rest control; **p<0.05 versus mitral regurgitant vol-ume during control isometric exercise.



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TABLE 2. Ventricular Volumes and Doppler-Derived Parameters at Rest and During Isometric Exercise Performed During the ControlPeriod and During Administration of Dobutamine and Intravenous Nitroglycerin

Control period Dobutamine Intravenous nitroglycerin

Rest IEx p Rest IEx p Rest IEx p

LVEDV (ml) 238+39 241+34 NS 222±26* 233±23 0.05 225+28* 233±31 0.05LVESV (ml) 175+38 168±36 NS 156+24t 162+23 NS 164+28t 168+29 NSASV (ml) 45±12 40+13 0.05 55+8t 45+8t 0.01 50±7t 44+9t 0.05TSV (ml) 64+14 70±13 0.05 67+11 72+10 0.01 61+11 64+13 NSMRVT (ml) 18±13 31+17 0.01 11+10t 24+12 0.01 11+11t 20±14t 0.05MRVD (ml) 18+11 29+16 0.01 11+8t 26+10 0.01 11±9t 19±6t 0.01PSP/ESV (mm Hg/mi) 0.71+0.27 0.84±0.32 0.05 0.82±0.21* 0.92+0.2* 0.01 0.63±0.15t 0.71±0.18t 0.01

1Ex, isometric exercise; p, statistical significance of IEx vs. rest; LVEDV, left ventricular end-diastolic volume; LVESV, leftventricular end-systolic volume; ASV, aortic stroke volume by Doppler; TSV, total stroke volume; MRVT, mitral regurgitant volume asthe difference between TSV and FSV by thermodilution; MRVD, mitral regurgitant volume as the difference between TSV and ASV byDoppler; PSP/ESV, peak systolic pressure/end-systolic volume.

*Statistical significance less than 0.01 vs. control at rest or 1Ex; tstatistical significance less than 0.05 vs. control at rest or 1Ex.

(p<0.05; Figure 2, Table 2). Both left ventricularend-diastolic and end-systolic volumes decreasedfrom 238+39 to 222±26 ml (p<0.01) and 175+±38 to156±24 ml (p<0.05; Table 3), respectively. Totalstroke volume did not change (i.e., 67±11 vs.64±14 ml; NS). Consequently, mitral regurgitantvolume was substantially reduced from 18±13 to11±10 ml (p<0.05; Figure 2). The increase inforward stroke volume and decrease in mitral regur-gitation were documented when calculations weremade by both thermodilution and Doppler (Tables 2and 3). Dobutamine caused an increase in aorticflow velocity from 47±10 to 62±12 cm/sec andshortening of systolic ejection period from 267±40to 245 ± 19 msec. The ratio of peak systolic pressureto ventricular end-systolic volume was increased atrest by dobutamine from 0.71±0.27 to 0.82±0.21mm Hg/ml (p<0.001).

During isometric exercise, intravenous dobu-tamine improved left ventricular performance rela-tive to control. Forward stroke volume was higher(47±12 vs. 39±13 ml; p <0.05) and pulmonary cap-illary wedge pressure was lower (24± 11 vs. 31 ± 10mm Hg; p<0.05; Table 2). Heart rate during iso-metric exercise was higher than during the controlperiod of exercise (100±9 vs. 90±16 beats/min;p<0.01), while systemic arterial pressures weresimilar (105_±11 vs. 104±14 mm Hg; Table 2).Although left ventricular end-diastolic volumeincreased during isometric exercise performed ondobutamine (from 222±26 to 233 ±23 ml;p<0.05), itremained less than that observed during the controlperiod of exercise (233±33 vs. 241±34 ml; NS).Similarly, left ventricular end-systolic volume tendedto be lower during isometric exercise performed ondobutamine than that noted during the control periodof exercise (162± 23 vs. 168 +36 ml; NS), while totalstroke volume during isometric exercise performedon dobutamine was similar to that noted during thecontrol period of exercise (72±10 vs. 70+13 ml;NS). Mitral regurgitant volume tended to be lowerduring isometric exercise performed on dobutaminethan during the control period of exercise (24±12

vs. 31+± 17 ml; NS). Similar results were obtainedwhen calculations were performed fromechocardiography-Doppler (Table 3). The drop inforward stroke volume was due to a decrease inaortic flow velocity (62+12 to 54±10 cm/sec) andshortening of systole (245-+±19 to 232+21 msec;Table 3). The ratio of peak systolic pressure toventricular end-systolic volume increased signifi-cantly during isometric exercise performed on dobu-tamine (from 0.82±0.21 to 0.92±0.20 mm Hg/mi;p<0.01) and was more than the ratio (0.84±0.32mm Hg/ml) noted during the control period of exer-cise (p<0.01).At rest, intravenous nitroglycerin at a mean dose

of 32 ,ug/min (range, 10-105 ,ug/min) decreasedpulmonary capillary wedge pressure (from 18±9 to11±7 mm Hg;p<0.001), while forward stroke vol-ume increased (from 46±13 to 51±13 ml; p<0.05;Figure 1, Table 2). Systemic arterial pressuredecreased (from 87±12 to 81±11 mm Hg;p<0.01),while heart rate was not significantly altered. Rest-ing left ventricular end-diastolic and end-systolicvolumes were significantly decreased by intrave-nous nitroglycerin (from 238+±39 to 225 +28 ml;p<0.01, and from 175±38 to 164±28 ml; p<0.05,respectively) (Table 3). Resting total stroke volumedecreased slightly (from 64±14 to 61+11 ml; NS).Consequently, resting mitral regurgitant volumewas lowered substantially by nitroglycerin (from18±13 to 11±11 ml; p<0.05; Figure 2, Table 3).Similar mean values were obtained when calcula-tions were performed only from noninvasive data(ASV, MRV, Table 3), with a similar general trendof change. The ratio of peak systolic pressure toventricular end-systolic volume was reduced signif-icantly at rest by intravenous nitroglycerin (from0.71±0.27 to 0.63±0.15 mm Hg/ml).

Intravenous nitroglycerin during isometric exer-cise improved left ventricular performance com-pared with that noted during control exercise. For-ward stroke volume was higher (44±8 vs. 39±13ml; p<0.05; Figure 1, Table 2), while pulmonarycapillary wedge pressure was significantly lower



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(17±7 vs. 31±10 mm Hg;p<0.01). Left ventricularperformance during isometric exercise while onnitroglycerin was similar to that observed at rest inthe control state (Figure 1). Systemic arterial pres-sure reached during isometric exercise performedon intravenous nitroglycerin was significantly lowerthan during control isometric exercise (92±11 vs.104±14 mm Hg; p<0.01; Figure 2, Table 2), whileheart rates were similar (90±13 vs. 90±16 beats/min). Left ventricular end-diastolic volume increasedsignificantly during isometric exercise performed onnitroglycerin (from 225 ±28 to 233+31 ml;p<0.05;Table 3) but tended to be less than that reachedduring the control period of exercise (233±31 vs.241±34 ml; NS). Left ventricular end-systolic vol-ume did not change significantly during isometricexercise performed on nitroglycerin. Total strokevolume tended to be lower than that observedduring the control period of exercise (64±13 vs.70±13 ml; NS). Mitral regurgitant volume wassignificantly lower during isometric exercise per-formed on nitroglycerin than during the controlperiod of exercise (20±14 vs. 31+17 ml; p<0.05).The changes, calculated from echocardiography-Doppler data, were similar. The decrease in for-ward stroke volume was mainly due to a decrease inaortic flow velocity (Figure 2, Table 3). The ratio ofpeak systolic pressure to ventricular end-systolicvolume increased significantly during isometric exer-cise performed on intravenous nitroglycerin (from0.63±0.15 to 0.71±0.18 mm Hg/ml; p<0.01) butwas significantly lower than the ratio (0.84±0.32mm Hg/ml) noted during the control period of exer-cise (p<0.05; Table 3).The resting mitral regurgitant fraction ranged

from 0% to 48% for the 12 patients, with a medianvalue of 24%. Regurgitant fraction averaged 10% inthe six patients with a fraction lower or equal to themedian (i.e., group A) and averaged 42% in thepatients with a fraction higher than the median (i.e.,group B). Patients in groups A and B receivedsimilar doses of dobutamine (7.2+4 vs. 7.6±3 ,ug/kg/min, respectively) while the doses of intrave-nous nitroglycerin were slightly higher in patients ingroup B (43+ 17 vs. 35±14 jig/min; NS). In patientsin group A, dobutamine tended to increase restingforward stroke volume (from 54±11 to 58+13 ml;NS; Figure 3), but nitroglycerin did not. Duringisometric exercise, both dobutamine and nitroglyc-erin did not change forward stroke volume. At rest,dobutamine slightly increased mitral regurgitant vol-ume (from 8±4 to 12+10 ml; NS) but nitroglycerindid not (Figure 3). During isometric exercise, dobu-tamine did not change mitral regurgitant volume,while nitroglycerin tended to decrease it (from19±12 to 15+10 ml; NS). In patients in group B,both dobutamine and nitroglycerin increased rest-ing forward stroke volume (from 38±10 to 55±15ml;p<0.05, and from 38±10 to 50±13 ml;p<0.05,respectively) (Figure 3). Resting mitral regurgitantvolume decreased (from 29+7 to 11+9 ml;p<0.05)

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A REST ISOMETRICEXERCISE

C DOB NTG C DOB NTG

60

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20

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B *

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FIGURE 3. Bar graphs of changes in forward strokevolume (FSV) and mitral regurgitant volume (MRV) atrest and during isometric exercise during the controlperiod (C) and during administration of intravenousnitroglycerin (NTG) and dobutamine (DOB) in sixpatientswith resting mitral regurgitation fraction lower than tothe median (i.e., 24%; Panel A) and in six patients withresting mitral regurgitantfraction higher than the median(Panel B). *p<0. 05 versus control.

with dobutamine and (from 29±7 to 14±10 ml;p<O.O5) with nitroglycerin. During isometric exer-cise, dobutamine and nitroglycerin increased for-ward stroke volume (from 32±15 to 44±15 ml;p<0.05, and from 32±13 to 44±12 ml; p<0.05,respectively). They both decreased mitral regur-gitantvolume (from41±14 to 27±11 ml;p<0.05, andfrom 41 ± 14 to 25+13 ml;p <0.05, respectively).

DiscussionThe present study demonstrates that in patients

with severe congestive heart failure, the rise incardiac afterload associated with isometric exerciseaugments the amount of mitral regurgitation, which,in turn, results in a fall in forward stroke volumedespite an increase in total stroke volume. More-over, the reduction in mitral regurgitation producedby acute administration of dobutamine or nitroglyc-erin contributes substantially to the augmentation inforward cardiac output produced by these drugs.

Functional mitral regurgitation is frequentlyobserved in patients with congestive heart failure,but the mechanisms that determine the presenceand severity of the functional mitral regurgitationare incompletely understood. Left ventricular size,extent of emptying, mitral annular diameter, papil-lary muscle function, and left atrial size have beenimplicated. In general, the severity of mitral regur-gitation appears to be related to the size of themitral annulus and not the absolute left ventricular

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end-diastolic volume, which led Boltwood et a125 tosuggest that left atrial size may be an importantdeterminant of the size of the mitral annulus andregurgitant orifice. Studies in animal models ofexperimental mitral regurgitation13,14 have shown adynamic change in mitral regurgitant orifice associ-ated with both ventricular volume alterations, aswell as changes in ventricle-atrial pressure gradi-ents. During isometric exercise, mitral regurgitationworsens in patients with severe congestive heartfailure. Because the square root of the pressuregradient between left ventricle and atrium and theduration of systole are minimally affected by iso-metric exercise, an increase in regurgitant area islikely to be responsible for the worsening of mitralregurgitation.Of interest, while the forward stroke volume falls

concomitantly with the increase in mitral regur-gitant volume, the sum of the two volumes (i.e.,total stroke volume) does not decrease but rises, aspreviously demonstrated by Wiggers et a126 in stud-ies of experimental mitral regurgitation. Total leftventricular stroke work is increased. The fall in leftventricular stroke work index, derived from for-ward stroke volume, which has been reported dur-ing isometric exercise in patients with severe con-gestive heart failure, is more apparent than realbecause mitral regurgitant volume was not includedin the calculation of ventricular stroke work index.Tricuspid regurgitant volume may also haveincreased during isometric exercise, particularly inthe five patients with mild tricuspid regurgitationobserved at baseline. Such an increase could lead tooverestimation of forward stroke volume by ther-modilution. However, even if present, this wouldnot vitiate our argument. The similar changes inforward stroke volume obtained by thermodilutionand Doppler echocardiographic techniques arguethat tricuspid regurgitation did not worsen signifi-cantly during isometric exercise in these patients.

Although, overall, administration of dobutamineto patients with severe congestive heart failureincreases resting cardiac output and lowers pulmo-nary capillary wedge pressure, individual responsesare extremely variable.27'28 Some of our patients, aspreviously reported,29'30 did not experience signifi-cant hemodynamic benefits from dobutamine. Thelack of hemodynamic response to dobutamine hasbeen attributed to a reduced positive inotropicaction of the drug, which may be secondary to adesensitization of myocardial 13-adrenergic recep-tors in patients with severe congestive heart failure.31The degree of attenuation of the positive inotropiceffect of dobutamine appears to be inversely relatedto both the degree of plasma norepinephrine eleva-tion and the reduction in cardiac output.27 Similarly,we have found that the changes in myocardialcontractility produced by dobutamine were variablein patients with congestive heart failure and couldbe somewhat predicted by baseline levels of myo-

dP/dt.29 Nevertheless, despite eliciting a modestincrease in myocardial contractility, dobutamineresulted in substantial improvement in ventricularperformance, which was attributed to reduction inperipheral arterial resistance mediated by with-drawal of sympathetic tone, direct f32-adrenergicstimulation, or both.Our present data indicate that the presence and

severity of functional mitral regurgitation is animportant determinant of the hemodynamic responseto dobutamine in patients with dilated cardiomyop-athy. Although positive inotropic agents increasethe pressure gradient between the left ventricle andatrium, in experimental models of mitral regurgita-tion, they decrease mitral regurgitant volume byreducing substantially the mitral regurgitantorifice.13"14 Similarly, in our patients, dobutaminedecreased mitral regurgitant volume at rest and to alesser extent during isometric exercise, despite mod-erately increasing the pressure gradient between theleft ventricle and atrium. Thus, dobutamine proba-bly reduced mitral regurgitation by decreasing theregurgitant orifice. Whether this results entirelyfrom the positive inotropic effect of dobutamine orfrom its direct and indirect effects on the peripheralcirculation is unknown.The present data demonstrate that in patients

with dilated cardiomyopathy and functional mitralregurgitation, intravenous nitroglycerin reducesmitral regurgitant volume at rest and during isomet-ric exercise, and thereby increases forward cardiacoutput. Intravenous nitroglycerin invariably lowerspulmonary capillary wedge pressure, but cardiacoutput does not always increase in patients withsevere congestive heart failure.32'33 The presenceand severity of functional mitral regurgitationappears to account for the variability in cardiacoutput response to acute administration of nitroglyc-erin in patients with severe congestive heart failure.34This is in agreement with the preliminary findings ofRoth et al,35 who found that during isometric exer-cise, transdermal nitroglycerin increases cardiacindex while lowering pulmonary capillary wedgepressure in patients with chronic heart failure. Nitro-glycerin does not alter significantly the systolicpressure gradient between left ventricle and atriumand thus most probably reduces the mitral regur-gitant orifice.12'34 The relative contributions of adecrease in left ventricular and atrial volumes or animprovement in the anatomical position of the mitralvalve apparatus in decreasing the regurgitant orificecannot be determined by the present study.

In summary, the decrease in forward cardiacoutput observed during isometric exercise in patientswith severe congestive heart failure is secondary toa worsening of the functional mitral regurgitation.In addition, a reduction of functional mitral regur-gitation produced by acute administration of dobu-tamine or nitroglycerin to these patients contributessubstantially to the increase in forward cardiac

cardial contractility, as reflected by left ventricular output. Thus, the presence and severity of func-



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tional mitral regurgitation is an important determi-nant of the acute hemodynamic response to inotro-pic and vasodilator therapy in severe heart failure.

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KEY WORDS * mitral regurgitation * stroke volume * heartfailure, congestive



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G Keren, S Katz, J Strom, E H Sonnenblick and T H LeJemtelto load alterations and inotropic therapy in severe heart failure.

Dynamic mitral regurgitation. An important determinant of the hemodynamic response

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