Effects of acute alterations in left ventricular loading conditions on peak filling rate in the denervated (transplanted) ventricle

MISCELLANEOUS

Effects of Acute Alterations in Left Ventricular Loading Conditions on Peak Filling Rate in the Denervated (Transplanted) Ventricle Douglas S. Schulman, MD, Brian A. Herman, MD, Galal Ziady, MD, Todd Edwards, MD, Robert Kormos, MD, P.S. Reddy, MD, William P. Follansbee, MD, and Barry F. Uretsky, MD

Peak filling rate is an indicator of left ventricular (LV) diastolll function. It is in6uenced by heart rate, kmding conditions, sympathetic nervous system activity, ejectlw fraction and other factors. To detemtlne the effect of altered loading conditions on peak filling rate, independent of heart rate and sympathetic nervous system activity, 12 patients were studied 3 weeks after orthotopic heart transplantation. Plasma catecholamine level, heart rate and ejection fraction were not changed by any maneuver. Nitroglycerin caused a decrease in pulmonary artery wedge pressure (9 f 2 to 6 f 1 mm Hg, p
relation to pulmonary artery wedge pressme as loading conditions are altered. Nonnrwwd peak filling rate is less iMuenced bypul--w wedge pressure. (Am J Cardiol1991;67:1103-1109)

eak filling rate measuredwith a variety of techniques is a marker of left ventricular (LV) diastolic function. It is abnormal in patients with coronary artery disease,l hypertrophic cardiomyopathy2 and the syndrome of congestiveheart failure accompanied by normal systolic function.3 It has been suggested that these patients have abnormal intracellular calcium metabolism and LV relaxation.3-7 In experimental preparation+ l l and in humans,i2J3 peak transmitral valve velocity and flow are load-dependent.With radionuclide studies, peak filling rate has been normalized to end-diastolic counts, but this normalized measure may also be influenced by changes in loading conditions.i4 Furthermore, these measurementsalso vary with heart rate15J6and sympathetic nervous system activity. 14,17Becausealterations in loading conditions usually produce changes in these variables, it is difficult to sort out the effects of load alone on peak filling rate in humans. Patients who have undergoneorthotopic heart transplantation offer a unique opportunity to study this problem. They have denervated ventricles and donor atria, so that modest changes in loading cause little change in heart rate and intrinsic cardiac sympathetic nervous system activity. Therefore, the current study determinesthe effect of altered loading conditions alone on radionuclide-derived peak filling rates in patients who have undergoneorthotopic cardiac transplantation.

P

METHODS

The protocol was approved by the Biomedical Institutional Review Board of the University of Pittsburgh. All patients gave informed consent. Twelve patients undergoing orthotopic heart transplantation between March and November 1989 were enrolled. In our instiLOADING CONDITIONS AND PEAK FILLING

1103

tution, such patients routinely undergo serial right-sided cardiac catheterizations and right ventricular endomyocardial biopsies to monitor cardiac rejection. Patients were entered in the study at the time of their predischarge right-sided cardiac catheterization and endomyocardial biopsy study (23 f 3 days after cardiac transplantation). All patients were hemodynamically stable. We excluded patients with a systolic blood pressure 160 mm Hg, a heart rate <60 or >lOO beats/mm or evidence of congestiveheart failure. No patient had any tissue rejection on myocardial biopsy and all patients had normal ejection fractions at rest. All patients were receiving immunosuppressivetherapy, including cyclosporine and prednisone.One patient was on the vasodilator hydralazine for hypertension. The other 11 patients did not require antihypertensive medication. No patient was taking a calcium antagonist or a @blocker. Hemodynamic measurements: Right-sided cardiac catheterization was performed with a standard pulmonary artery flotation catheter through either the femoral or internal jugular vein. Hemodynamic measurements were made of right atrial, pulmonary artery and pulmonary artery wedge pressures.The wedge position was confirmed by fluoroscopy in all cases.Roth phasic and mean pressureswere recorded. Cardiac output was measuredby the thermodilution technique. An average of 3 measurementsnot varying by 10% was obtained. Heart rate was monitored continuously. Systemic artery pressure was measured with either a 5Fr femoral artery catheter ( 10 of 12 patients) or with an automatic timed blood pressure cuff (Dynamapp) (2 of 12 patients). Radionudide angtagraphy: Radionuclide angiography was performed with a standard gamma camera (General Electric Starcam). The patients’ red blood cells were labeled with 25 mCi of technetium-99m pertechnetate by standard in vivo techniques. The camera was positioned over the patient in the best left anterior oblique view and was not moved for the duration of the study. The study was formatted at 32 frames per cardiac cycle, resulting in an averagetime per frame ranging from 17 to 28 ms. Beatsoutside of a 5% variation from the baseline cardiac cycle length were excluded from analysis. For each study, data were acquired for 500 beats. All radionuclide angiogramswere processedby 1 experienced technologist. A semiautomatic program that generatesLV regions of interest in each frame of the cardiac cycle, using combined secondderivative and count threshold algorithm, was used (General Electric Semi-Automatic Gated Equilibrium). From the background-corrected regions of interest, a time activity curve was obtained, and LV ejection fraction was calculated in the standard manner. The time activity curve 1104

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67

was fitted with a Fourier transform seriesusing 4 harmonics, and a point-by-point derivative calculation was performed. The maximal first derivative during diastole was used to establish absolute peak filling rate in kcts/ s. Two methods of normalization were used. Peak filling rates were normalized by dividing the absolute peak filling rates by LV end-diastolic counts and by LV stroke counts. Time to peak filling rate was measured in milliseconds from the end-systolic point to the point at which peak filling rate occurs. The background-corrected end-diastolic counts were corrected for radioactive decay, using a 6-hour half-life for technetium-99m pertechnetate. Catecholamine level: Arterial blood was obtained during hemodynamic measurement at the midpoint of each radionuclide acquisition. Plasma norepmephrine levelswere measuredby a high-pressureliquid chromatography method.l8 Study protocol: We acquired 2 sets of baseline hemodynamic data and a radionuclide angiogram at rest. The secondset of hemodynamic data was acquired at the midpoint of the radionuclide study. Nitroglycerin was infused at 10 pg/min. The dose was increased 10 ,ugevery 3 minutes until pulmonary artery wedge pressure decreasedby approximately 30%. After data acquisition, the patient was allowed to return to his hemodynamic baseline (
TABLE I Hemodynamic and Radionuclide Data at Baseline and After Each Intervention

9

VOL 13

MET 5

Base

11 5 2 3 7

3

TNG

13 4 6 9

14 10 4 7 10

7

VOL

3 10

10 4 5 7

17 9 3 6 9

8

MET

97 10

95 85

90 80 100 90

104 98 110 98 95

122

Base

88* 8

90 74

80 82 90 80

89 90 98 85 90

105

TNG

96 10

105 92

95 82 90 85

85 102 105 100 102

115

VOL

122* 12

125 106

118 118 118 110

119 135 130 105 138

145

MET

69 7

69 68

51 80 70 68

67 78 78 74 67

62

Base

71 7

67 71

57 83 73 70

68 78 78 75 75

60

TNG

71 8

72 65

50 81 76 69

75 77 75 80 67

64

VOL

65 10

70 71

49 80 72 66

53 68 73 73 62

46

MET

5.5 0.8

5.5 5.4

4.5 5.1 5.1 4.6

4.8 5.4 4.3 7.0 7.3

5.7

Base

5.5 1.0

5.3 6.1

4.7 5.3 4.7 4.5

5.1 5.5 4.7 6.7 7.5

5.3

TNG

6.0* 0.8

6.4 5.8

4.4 5.8 6.0 5.4

5.4 5.9 5.5 7.6 7.4

5.2

VOL

5.5 1.0

5.7 6.4

4.2 5.3 5.1 4.7

4.2 5.4 5.0 7.3 7.1

4.9

MET

88 9

85 90

107 75 80 102

89 94 78 91 80

87

89 9

85 90

108 79 81 104

90 94 79 98 81

86

Base TNG

89 10

83 89

107 75 86 102

91 99 76 94 79

86

VOL

87 9

80 89

99 73 81 100

87 97 72 91 80

91

MET

4

g F E $ 0

z TNG

11 8 2 6 9 6 2 2 4 6 10 8 3

HR (beats/min)

3 23 18 16 16 16 9 2 5 7 2 6 8* 2

CO (liters/min)

Base

14 14 14 18 12 10 7 7 11 4 9 4* 2

EF

7 12 7 6 9 7 11 8 9 11 10 17 6 2

BP

1 16 10 9 14 10 5 4 4 7 10 14 13* 3

RAP

2 3 4 5 6 8 6 7 9 4 10 12* 2

PAWP

7 8 9 10 6 14 6’ 1

Base

33.7 18.4 36.4 57.8 46.2 44.3 41.1 50.1 51.1 37.5 49.3 37.3

TNG

36.3 25.3 36.7 65.4 59.4 52.9 45.3 63.1 62.5 51.6 65.8 39.8

VOL

32.5 16.5 30.3 57.1 50.4 48.6 55.7 71.2 50.1 58.0 66.9 49.2

MET

2.52 3.80 5.39 3.92 4.61 3.16 3.99 3.68 3.57 4.77 3.84 5.31

Base

3.28 3.08 5.77 4.51 4.66 3.1 4.01 3.91 3.69 4.34 3.65 5.26

TNG

2.88 4.56 4.92 4.24 5.83 3.54 3.93 4.09 4.62 5.36 4.15 5.08

VOL

3.90 0.91

2.26 2.57 4.34 3.25 4.77 3.17 4.11 4.05 3.67 5.14 3.71 5.82

MET

5.97 1.19

4.06 5.70 6.95 5.01 6.23 4.73 7.78 5.78 5.12 7.02 5.53 7.77

Base

5.86 1.19

5.43 4.56 7.45 5.81 6.22 4.22 7.82 4.71 5.05 6.23 5.42 7.38

TNG

6.27 1.03

4.47 6.06 6.35 5.64 7.33 5.17 7.05 5.76 6.06 7.80 5.79 7.78

VOL

5.89 1.31

4.93 4.82 6.36 4.43 6.53 5.08 8.38 5.06 5.10 6.55 5.29 8.18

MET

165 29

189 160 120 168 140 161 170 216 192 144 198 126

Base

158 26

160 160 114 192 171 161 136 207 184 119 168 120

TNG

145 20

189 133 126 120 152 161 136 150 198 126 132 120

VOL

169 28

220 200 152 175 100 184 160 175 192 152 176 147

MET

i2 E

9

11 12 9 2

Pt. No.

Mean SD

MET 33.3 26.9 38.7 58.4 50.2 46.3 48.7 54.8 51.7 39.9 48.3 42.0

4.52* 0.47

TPF(ms)

VOL 14.4 6.4 7.0 17.6 10.6 15.3 13.5 17.6 13.6 11.3 18.0 8.5

4.10 0.70

PFR(SV/s)

Base TNG 12.6 5.6 7.5 15.4 10.2 14.9 11.5 15.4 13.5 9.6 15.9 7.8

4.04 0.54

PFR (EDV/s)

10.3 6.0 6.3 12.8 9.9 14.3 10.3 12.8 13.9 8.6 13.5 7.1

48.3 6.7

PFR(kcts/s)

13.2 7.1 7.2 14.9 10.9 14.7 12.2 14.9 14.5 8.4 12.6 7.9

51.5* 5.3

EDC (kcts)

1 2 3 4 5 6 7 8 9 10 11 12

42.8* 2.5

PFR = peak

46.0 3.0

wedge pressure;

12.5 2.9

artery

11.6 2.8

PAWP = pulmonary

10.1* 1.9

HR = heart rate; MET = methoxamine;

11.2 2.0

fraction;

Mean SD

* p <0.015. Base = baseline;BP = meansystemicarterialpressure;CO= cardiacoutput;EDC = end-diastolic counts; EDV = enddiastolic volume; EF = ejection tilling rate: RAP = right atrial pressure; SD = standard deviation; SV - stroke volume; TNG = nitroglycerin; TPF = time to peak tilling rate; VOL = volume.

Hg, p
P*

0.04). LV end-diastolic and end-systolic counts increased.Although pulmonary artery wedge pressureincreased,there was no change in the absolute or normalized peak filling rates. Time to peak filling rate also did not change. Patients receiving methoxamine were divided into 2 subsetsbased on the LV ejection fraction responseto increasing blood pressure.Four patients had a decrease in LV ejection fraction of 15% (-5, -10, -14, -16), whereas the remaining 8 patients had a decreaseof <5% (mean -1 f 2%). There were similar degreesof blood pressure elevation in both subsets.The former group had a marked increase in pulmonary artery wedge pressure (9 f 1 to 16 f 2 mm Hg). This was accompanied by a trend for absolute (39.3 to 34.0 kcts/s) and normalized (3.91 to 3.11 end-diastolic volumes/s and 5.43 to 5.14 stroke volumes/s) peak filling rates to decline. In patients who maintained their LV ejection fractions, pulmonary artery wedge pressure also increasedsignificantly (9 f 3 to 12 f 4 mm Hg). However, unlike the patients with systolic dysfunction, the increase in pulmonary artery wedge pressure was associatedwith an increasein absolute peak filling rate (47.7 f 4.9 to 56.3 f 8.6 kcts/s, p
20

t Y E .6 :: 5 6

10

0

-6

-4

-2

0 Change

1106

2 in PAWP

4

6

6

10

(mmHgb

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67

and

peak filling: During preload modification (nitroglycerin and volume infusion) in which LV systolic function was unaffected, there was a highly significant correlation between the changesin pulmonary artery wedge pressure and absolute peak filling rate (r = 0.82, p
MAY 15. 1991

nary artery wedge pressure and peak filling rate normalized to stroke counts (r = 0.21, p = 0.3) (Figure 3). Norepinephrine levels: There were no significant changes in plasma norepinephrine levels. The levels were 283 f 235, 391 f 345, 314 f 302 and 177 f 138 pg/ml at baseline and with nitroglycerin, volume and methoxamine infusions, respectively.

tween pulmonary artery wedge pressure and absolute filling rate as defined with preload modification. With increased afterload (methoxamine), patients with systolic dysfunction are representedas the 4 points outside the 95% confidence interval of the line of relation in the lower right quadrant of Figure 1. For all patients, there was a much weaker relation betweenchangesin pulmonary artery wedge pressure and peak filling rate normalized to end-diastolic counts during preload modification, with nitroglycerin and volume infusion (r = 0.38, p = 0.05) (Figure 2). The points representing patients with systolic dysfunction after methoxamine tended to be below the line of relation. Finally, there was no significant relation between changes in pulmo-

DISCUSSION These data demonstrate that absolute peak filling rate is load-dependent and, when systolic function remains intact, is directly related to changes in pulmonary artery wedge pressure.In this model, normalized

2 -

FIGURE 2. Relation between changes from-h pulmonurarkrywedge prauve(PAWfY=dpsakliRmr~ (PFR)llcmnadtoceuntsperenddlastolic vehme (EDV/s). Symbels as in Figure 1.

-2 -6

I

I

-4

-2

I

I

I

I

I

0

2

4

6

8

10

Change

in PAWP

FIGURE 3. Relation between changes fromb8dineInpdmonmy pressme (PAWP) md peak s:?e (PFR) nomdked to stroke comts (SC/s). Symbob~hlFigun1.

-2 -6

-4

-2

4

2

0 Change

PAWP

LOADING CONDITIONS AND PEAK FILLING

1107

peak filling rates appear lessinfluenced by loading conditions. Current model: The model used in this study is unique. Changes in blood pressure, and in atria1 and ventricular pressures,which would activate the sympathetic and parasympathetic nervous system under ordinary circumstances,l9 have no effect in the cardiac transplant patient.*OAlthough, hypothetically, cardiac transplant recipients may respond to stressby increasing plasma levels of catecholamines,*i~**we measured plasma norepinephrine to ascertain that our interventions did not produce significant changes. Because changes in heart rate*5y16and sympathetic innervation14J7 affect peak filling rates, it would be difficult under ordinary circumstancesin humans to dissect out the effects of loading conditions alone on filling rates, independent of the effects of changing heart rate and sympathetic nervous system activity. Effests of preload: Alterations in left atria1 (pulmonary artery wedge) pressurehad the major influence on absolute peak filling rate. There was an excellent correlation between changes in absolute peak filling rate and pulmonary artery wedge pressureduring nitroglycerin and volume infusions. Therefore, it is likely that changes in pulmonary artery wedge pressure during preload modulation reflected alterations in the gradient between the left atrium and ventricle at the time of mitral valve opening. In experimental preparations, this gradient is a major factor influencing absolute peak lilling rate.s-l1 In humans, nitroglycerin caused peak mitral valve filling velocity to decrease,12J3 whereas augmented preload caused it to increase.‘* Heart rate and ejection fraction, factors known to influence peak lilliig rate,15,23did not change with either maneuver. Blood pressure decreasedwith nitroglycerin, which might be expected to enhance active relaxation of the ventricle’ 1*24and therefore the peak filling rate. Nonetheless, absolute peak filling rate appearedto vary directly with the driving pressurefor filling in early diastole. In contrast to absolute peak filling, there was only a weak correlation between changesin pulmonary artery wedge pressure and peak filling rate when normalized to end-diastolic counts as preload was varied. There was no significant correlation between changesin these variables when peak filling rate was normalized to stroke counts. This finding would be expected because there were similar directional changesin absolute peak filling rate and in both end-diastolic and stroke counts. Therefore, by accounting for changes in LV end-diastolic size and stroke volume as preload was altered, normalized peak tilling rate became much less dependent on tilling pressure. Effects of afterha& Methoxamine had varied effects on LV function. In patients in whom afterload excesscaused systolic dysfunction, both absolute and 1108

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67

normalized peak filling rates tended to decline, despite a large increase in pulmonary artery wedge pressure. Theseresults demonstratethe influence of systolic function on measurementsof diastolic function. It is likely that active relaxation was impaired in this group of patients, which would also impact on peak filling rates.11,24Becauseof the systolic dysfunction and increasedend-systolicvolume, the decreasein peak filling rate could in part be due to a decreasedgradient for flow at the time of mitral valve opening; that is, LV minimal pressureincreasedto a greater degreethan left atria1 pressure.8-11In the group with preservedsystolic function during methoxamine infusion, absolute peak filling rate and pulmonary artery wedge pressure both increased.The relation between changes in pulmonary artery wedge pressureand absolute peak filling rates in these patients was similar to that observedwith preload modification. Becauseboth mean absolute peak filling rate, stroke volume and end-diastolic volume increased in this subgroup, the mean normalized peak filling rates were unchanged. Normalized peak filling rater The effect of changing load on normalized peak tilling rates has been lessstudied than the effect on mitral valve velocity and flow. Converting Doppler peak mitral inflow velocity to normalized peak filling rate involves geometric assumptions that lead to a less than ideal correlation between peak filling rate normalized to end-diastolic volume measuredby Doppler and radionuclide techniques.25*26 Bowman et al*’ suggestednormalizing absolute peak Iilling rate to stroke volume, as LV stroke volume can be calculated from the Doppler time-velocity integral of mitral inflow without geometric assumptions. They found that Doppler and radionuclide peak filling rates normalized to stroke volume correlated highly. Peak filling rate normalized to stroke volume is abnormal in certain diseasestatesthat are associatedwith abnormal diastolic function.28 However, there are no data concerning the effect of altered load on Doppler-derived normalized peak filling rates. Using radionuclide techniques in normal volunteers, Plotnick et all4 showed that peak filling rate normalized to end-diastolic volume varied with changesin posture, and with nitroglycerin and verapamil administration; fluctuations in heart rate and sympathetic nervous system activity as well as in load were thought to influence peak filing rates. Mew Iimitatiow We did not measure left atria1 or LV pressureduring the study. Therefore, we could not measure the time constant of LV pressure decay nor the actual gradient between the left ventricle and atrium at the time of peak filling. Peak filling in absolute terms is influenced by active relaxation of the ventricle.24 In addition, the gradient between the left atrium and ventricle at the time of mitral valve opening will be influenced by characteristics of the pulmonary MAY 15, 1991

veins, the left atrium and ventricle, and the mitral valve.8 Although changes in loading conditions were modest in this study, we specifically attempted to modify load within a physiologic range. We did not want to cause peripheral catecholamine release or significant changes in cardiac output or ejection fraction, because these factors all influence peak filling rate. We did not directly measure LV end-diastolic volume. It is known that radionuclide- and angiographicderived LV volumes correlate we11.29 Becauseeach patient acted as his own control, attenuation coefficients were not calculated. By maintaining the camera position constant, acquiring data for a set number of beats in a setting in which heart rate does not change, and correcting for radioactive decay, we believed that measured end-diastolic counts would compare well with end-diastolic volume. Finally, patterns of LV filling in cardiac transplant patients may be dissimilar from patients with other forms of heart disease.The cardiac transplant patient has recipient and donor atria. These recipient atria are functional and contribute to ventricular fJling.3o Also, the contribution to filling will depend on where in the cardiac cycle these recipient atria contract. Over the 50!3-beat radionuclide acquisition, one would expect that recipient atria1 systole would occur throughout the cardiac cycle and not affect averaged peak filling. Although, recipient atria respondto baroreceptor stimulation during altered load, an increase or decreasein native atria1 activity would not be expected to affect the distribution over the cardiac cycle during a 500-beat acquisition.

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