Effects of intravenous verapamil administration on left ventricular diastolic function in systemic hypertension

Effects of IntravenousVerapamilAdministration on left VentricularDiastolicFunction in SystemicHypertension SANDRO BETOCCHI, MD, ALBERT0 CUOCOLO, MD, LEONARDO PACE, MD, MASSIMO CHIARIELLO, MD, BRUNO TRIMARCO, MD, BRUNO ALFANO, MS, BRUNO RICCIARDELLI, MD, MARCO SALVATORE, MD, and MARIO CONDORELLI, MD

The effects of intravenous verapamil administration (0.1 mg/kg as a bolus followed by an infusion of 0.007 mg/kg/min) were studied using high-temporal-resolution radionuclide angiography in 27 patients with hypertension. Verapamil administration increased heart rate from 69 f 11 to 75 f 12 beats/min (p
tively, p <0.05). The isovolumic relaxation period changes were inversely related to the baseline values (r = 0.63, p
1

eft ventricular (LV) relaxation and filling are impaired in patients with hypertension,1-4 and such impairment is more pronounced in patients with LV hypertrophy.z-5 Although most hypertensive persons are asymptomatic, impaired relaxation and filling can be important determinants of cardiac symptoms, as it has been observed that congestive heart failure can occur in some hypertensive patients with normal systolic performance as a consequence of reduced LV diastolic function.6J Whether relaxation and filling alterations can be pharmacologically reversed in hypertensive patients is controversial. Fouad et al* and Inouye et al9 reported that various P-blocking drugs, a calcium channel-blocking agent (diltiazem), and diuretic drugs failed to favorably affect diastolic function. The effects of several drugs on diastolic function have been widely studied in patients with hypertrophic cardiomyopaFrom the Departments of Internal Medicine and Nuclear Medicine, University of Naples 2nd School of Medicine, Naples, Italy. Manuscript received July 15, 1986; revised manuscript received October 14,1986, accepted October 15.1986. Address for reprints: Sandro Betocchi, MD, Clinica Medica 1, 2 Facolta’ di Medicina, Via S. Pansini, 5, 80131 Naples, Italy. 624

thy. In such patients, however, p-blocking drugs have no effect on diastolic function,*0 and no further data are available on efficacy of diuretic drugs and diltiazem. In contrast, verapamil enhances LV relaxation11J2 and filling10J3 in patients with hypertrophic cardiomyopathy. Therefore, this study was designed to assess whether verapamil affects diastolic function also in patients with systemic hypertension.

Methods Patients: We studied 27 patients (18 men, 9 women), aged 18 to 59 years (mean 38 f 131, with systemic hypertension. All had a history of elevated blood pressure (BP) levels for more than 1 year and a diastolic BP greater than 90 mm Hg had been recorded in at least 3 measurements in our institution. No patient had associated cardiac or pulmonary diseases or diabetes mellitus. Only 1 patient had had chest pain for 1 year and showed exercise-induced ST-segment depression; her coronary arteries, however, were normal. All patients had either never taken or had discontinued all medications for at least 2 weeks. Radionuclide angiography: Radionuclide angiography was performed with the patient at rest in the

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TABLE

I

Reproducibility

of Radionuclide

Heart rate (beatslmin) Ejection fraction (%) Time to end systole (ms) Time to end systole coefficient of variation (%) Time to onset of rapid filling (ms) Peak filling rate (EDCls) Time to peak filling rate (ms) lsovolumic relaxation period (ms) EDC = enddiastolic ation; r = correlation

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1

Study

68 f 67f 363 f 30 f

14 11 48 6

499 3.2 173 127

66 1.0 55 45

f f f f

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2

r

Max Diff

67 f 66f 373 f 30 f

14 11 52 6

0.98 0.95 0.91 0.89

7 7 60 5

505 3.1 174 130

64 1.0 47 46

0.84 0.85 0.87 0.84

60 0.8 60 40

f f f f

counts; Max Diff = maximal difference; coefficient; 99% CL = 99% confidence

supine position, Red blood cells were labeled in vivo with 25 mCi of technetium-99m.14 Imaging was performed with a small-field-of-view Anger camera equipped with a low-energy, general-purpose, parallel-hole collimator, oriented in the 45” left anterior oblique position with a 15” caudal tilt. Data were acquired in frame mode by computer-based electrocardiographic gating, with a 2X digital zoom. The imaging rate was 50 frames/s (or 20 ms/frame) with a gate tolerance of f5%, to minimize distortion in the diastolic part of the curve. Care was taken to achieve a similar number of counts per frame in the control and verapamil studies, with a minimum of 150,000 counts/frame. LV and background regions of interest were automatically drawn on both end-diastolic and end-systolic frames and from such areas 4 time-activity curves were achieved. The final curve was obtained by weighted interpolation of end-diastolic and end-systolic curves after subtraction of the corresponding background curve. Ejection fraction (EF) was measured on the raw time-activity curve by standard technique. This method has been validated in our laboratory in 45 other patients undergoing contrast left ventriculography within 1 week of radionuclide angiography. An excellent correlation was found between EF measured with the 2 techniques for values of 18 to 93% (y = 8.5 + 0.9x, r = 0.92, p
Mean Diff lf3 lf4 -11 f Of3 -6

f 0 f -2 f -3 f

99%

21

37 0.5 28 25

Mean Diff = mean difference f 1 standard limit of the modulus of the differences.

CL

3 5 29 4 48 0.6 34 29 devi-

To study LV systolic asynchrony, we measured the scatter of the occurrence of end systole on a pixel by pixel basis. Since time-activity curves obtained from 1 pixel are affected by inherent statistical noise, a 3point temporal smoothing was performed and a time to end systole functional image was built by identifying the time of occurrence of minimal counts for each pixel. On such image, a LV region of interest was superimposed and a histogram of time to end systole distribution was obtained. A coefficient of variation of such distribution was calculated by dividing the standard deviation by the mean and multiplying by 100. Immediately before radionuclide angiography an M-mode echocardiogram was recorded by standard technique and LV mass was calculated according to the method of Devereux and Reichek15 and nonnalized by body surface area (LV mass index]. Verapamil administration: Arterial BP was measured by cuff sphygmomanometer at the end of baseline radionuclide study, and it represents the effect of at least 10 minutes of supine rest. Eventually, verapamil was administered intravenously as a bolus of 0.1 mg/kg over 2 minutes, followed by an infusion of 0.007 mg/kg/min throughout the study. Ten minutes after the end of the bolus injection a second radionuclide study was performed. BP was measured at the beginning, middle and end of radionuclide study and averaged for further analysis. Reproducibility: To assess whether changes in values were related to variability in the measurements, we studied 15 patients twice by radionuclide angiography. The 2 radionuclide studies were performed after a single injection of technetium-99m, a few minutes apart, with the patients lying on the bed in the same position. Statistical methods: Paired and unpaired t tests were used when appropriate.16 The relation between measurements was assessed by regression analysis.16 Differences or correlations were considered to be significant for p <0.05.

Results Reproducibility: In the 15 patients who were studied twice, none of the variables differed significantly between the 2 studies, and all values correlated significantly (p
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VERAPAMIL

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TABLE II Measurements Administration

Before

FUNCTION

and During

Verapamil

B Heart rate (beatslmin) Blood pressure Systolic (mm Hg) Diastolic (mm Hg) Mean (mm Hg) Ejection fraction (%) Time to end systole (ms) Time to end systole coefficient of variation (%) Time to onset of rapid filling (ms) Peak filling rate (EDC/s) Time to peak filling rate (ms) lsovolumic relaxation period (ms) B = baseline: verapamil.

69 f

EDC = end-diastolic

V 11

75 f

12


155 102 119 65 351 26

f f f f f f

21 12 14 10 38 5

142 95 109 60f 359 23

f f

19 12 13 11 41 4

453 3.0 la5 95

f f f f

44 1.0 48 46

453 3.5 174 100

f f f f

33 1.1 49 36

counts;

f f f

P

NS = not significant;

V =

confidence interval of the modulus of the differences (Table I, last column). Hemodynamics: LV mass index ranged in the group from 74 to 159 g/m2, with a average value of 119 f 23 g/m”. Table II lists the differences in heart rate, BP and indexes of LV function between baseline and verapamil studies. Systolic, diastolic and mean BP values decreased and heart rate increased significantly during verapamil administration. EF decreased significantly; its changes exceeded the error of the method in 13 of 27 patients. Moreover, the coefficient of variation calculated on time to end systole functional images decreased significantly. Left ventricular filling: Peak filling rate increased in 20 of 27 patients, and significantly for the group (Table II]. Changes in peak filling rate during verapamil administration were inversely related to the corresponding basal value (r = -0.43, p <0.05), with the

8 1

pr 0.001

lowest values increasing the most. Therefore, patients were separated according to whether peak filling rate was subnormal [less than 2.8 end-diastolic counts/s, that is, the lower value of the 99% confidence interval in a group of 20 age-matched normal subjects in our laboratory) in the control study. Peak filling rate increased significantly in patients in whom it was reduced in the baseline [from 2.2 f 0.4 to 3.0 f 0.6 enddiastolic counts/s, in 8 of 11 more than the methodrelated error), but it was unchanged in the other subgroup, although it did increase remarkably in some patients (in 5 of 16 more than the error) (Fig. 1). In the first subgroup, reduced peak filling rate was associated with higher values of LV mass index (129 & 22 vs 112 f 22 g/m2, respectively, p
I-= .83 n= 20 v= 177- 3s+9.10-3\2 p< 0.001

> 1oa Z c =, = c B

v

B

a

v

FIGURE 1. Effect of verapamll (V) admlnlstratlon on peak filling rate (PFR) In 11 patients with subnormal basal values (B) (less than 2.8 end-dlastollc counts/s [EM/s], horlronfal Ime) and In 18 patients with normal or elevated values In the control study. Open circles with vertical bars lndlcate mean f standard deviation. N.S. = not slgnlflcant.

-lOtI FIGURE 2. Change In lsovolumk olotted as a function of Its value

relaxatlon period (IRP) (ordinate) In the basal studv _ (abscissa). .

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Before and During TABLE III Measurements Whom lsovolumic Relaxation Period Increased Decreased or Did Not Change (Right)

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Verapamil Administration (Left) and in 13 Patients

in Seven in Whom

B Heart rate (beatslmin) Blood pressure Systolic Diastolic Mean Ejection fraction (%) Time to end systole (ms) Time to end-systole coefficient of variation (%) Time to onset of rapid filling (ms) Peak filling rate (EDCls) Time to peak filling rate (ms) lsovolumic relaxation period (ms) ‘p <0.05; Tp <0.005 vs patients 6 = baseline; EDC = end-diastolic

66 f

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V 6

11


70f

171 109 129 71 360 26

f 27 f 15 f 17 f 6 f 31 f 5

156 101 120 67 329 20

f 20 f 10 f 12 f 6 f 30 f 3

NS <0.05 <0.05 NS <0.025 <0.005

150 98 116 64f 351 24

420 3.2 177 60

f f f f

451 3.6 186 123

f f f f

<0.025 NS NS <0.005

471 3.2 191 120

in whom counts;

31 1.0 48 23

34 0.7 28 27

isovolumic relaxation V = verapamil.

period

V 11

f f f

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Patients in It Either

B

P

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76f

P 11


f f

18’ 11’ 13’ 12 45 3

141 95 110 61 365 24

f f f f f f

19 12 14 11 38 4


f f f f

41 1.1 45 367

455 3.7 175 91

f & f f

33 1.4 54 36

NS <0.05 <0.05 <0.005

increased.

.

FIGURE 3. Time-activity curves before (leff) and during verapamll admlnlstratlon (right) In a patlent In whom lsovolumic relaxation perlod decreased (fop) and of another patient in whom It increased (bottom). Each polnt represents 20 ms. These patlents had slmllar shortening in cardiac cycle lengths (from 860 to 680 me and from 780 to 600 ms, respectively) and increases in peak filling rate (from 3.5 to 4.5 and from 3.2 to 4.7 end-diastolic counts/s [EDCIS]). Time to end systole, however, did not change In 1 patlent and shortened In 1 (360 In both studies and from 360 to 340 ms, respectively), whereas tlme to onset of rapid filling decreased in the former patlent and increased In the latter patient (from 480 to 400 and from 380 to 480 ms, respectively). Thus, lsovolumlc relaxation period decreased in the first patlent from 120 to 40 ms and increased in the second patient from 20 to 140 ms.

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puted on time to end systole functional images decreasedin patientsin whom the isovolumic relaxation period prolonged(in 6 of 7 patientsmore than the error of the method],but it did not changewhen patients in whom the isovolumic relaxation period decreasedor stayed the same were considered(Fig. 4).

Discussion Hemodynamic effects: Acute verapamil administration led to a small but significant decreasein BP (Table II). The heart rateincreasewe observedmay be a reflex one and overcomesthe negativechronotropic effect of the drugseenwith oral therapy.EF decreased significantly despite the BP decreaseand the consequent adrenergicstimulation, as a result of the known negativeinotropic propertiesof acutely administered verapami1.13J7J8 Effects on filling: In our patients, verapamil increasedpeakfilling rate. It should be emphasizedthat such an increase,although relatively small (0.5enddiastolic counts/s) is more impressive if we keep in mind that EF decreased.Bonow et all9 observedthat peakfilling rate is linearly related to EF; therefore,one would expecta decreasein EF to be accompaniedby a decline in peak filling rate. Furthermore, peak filling rate increasedsignificantly by a larger amount in patients in whom it was impaired in the control study (Fig.11, associatedwith higher degreesof LV hypertrophy, whereasit did not changesignificantly in patients with normal or increasedbasal values,although it did increasemore than the error of the method in 5 such patients.Higher degreesof LV hypertrophyare associated with lower endocardial/epicardial flow ratios and, consequently,subendocardialischemia.20Moreover, Morgan and MorgaS observedan imbalance in intracellular calcium regulation,which relatesto diastolic abnormalities in pressure overloaded and hypertrophied hearts. Verapamil therapy can improve LV filling by reducing myocardial ischemia22or readjusting cytosolic calcium levels or both. However,

pi 0.005

B

N.S.

V

B

V

FIGURE 4. Effect of verepamil on time to end systole (TES) coefflcient of variation in 7 patlents In whom lsovolumlc relaxation period Increased (/eff) and In 13 patlents In whom It did not change or decreased (rlghf). Open circles wlth verflcal bars Indicate mean values f standard deviation. 6 = basellne; N.S. = not dgnlflcant; V = verapamll.

acutely administered verapamil is associatedwith a negative inotropic effect,13-17J8 which may heighten left atria1pressureand,consequently,increasethe rate of early filling. Although a similar negative inotropic effect might besuggestedby the similar decreasein EF in either patients in whom peak filling rate increased or did not change,this mechanism cannotbe ruled out becausethe EF decreasecan be accountedfor by factors other than reduced contractility. Colan et alz3reported no influence of an acute BP increase on filling; we did not find any relation between a BP decreaseand changesin peak filling rate.No influence of heart rate changeson peakfilling rate was found, in keeping with data of other investigators.24 Time to peak filling rate showed a trend toward shortening,but the trend was not significant. This is likely the consequenceof the pattern of change of isovolumic relaxation period. Effects on isovolumic relaxation period: Modifications in isovolumic relaxation period duration during verapamil administration were highly dependent on the corresponding basal value (Fig. 2). Becausethe isovolumic relaxation period is shortenedby acuteafterload reduction (as a consequenceof the increased rate of myocardial relaxation25)and by left atria1pressureincrease,onewould expectthe isovolumic relaxation period to shorten or not changeduring verapamil administration. Therefore, we were intrigued by the prolongationin isovolumic relaxation period that occurred in somepatients,associatedwith an earlier occurrence of end systole, especially since BP and EF decreasedsimilarly in either patientsin whom the isovolumic relaxation period increasedor did not (Table III). Time to end-systolicshorteningcould be the result of reducedsystolic asynchrony,as assessedby the significant reductionof the coefficient of variation calculated on time to end-systolicfunctional images(Fig. 4). Although this variable is dependenton cardiac cycle length,similar changesin heart rate were observedin both subgroups[Table III], making it unlikely that the coefficient of variation decreasein patients in whom isovolumic relaxation period lengthening was determined by increasedheart rate. When somedegreeof asynchronyis present,it is conceivable that the “delayed” regions have more weight in determining the occurrenceof global end systole,as a further decrease in number of countsoccursin thoseareaswhile in the other regionssmall volume changesare taking place. This mechanism could accountfor the very short isovolumic relaxation periodsmeasuredwith this method in somepatients (up to 20ms in 1 patient]. Therefore, improved systolic synchrony should shift end systole leftward on the time-activity curve. This hypothesisis supportedby the findings of Greenet aLz6who useda similar method of assessingasynchrony.However, the shortening in time to end systole alone does not account for the prolongation in isovolumic relaxation period. In fact, in this subgroupof patients,the onsetof rapid filling was significantly delayed by the drug, contributing to the prolongation in isovolumic relaxation period. Hori et a127showed that a shortenedtime

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to end systole was associated with a slowed relaxation. Although these data were obtained in isolated hearts and can hardly be applied to our patients, this mechanism might have participated in prolongation in isovolumic relaxation period. The reasons underlying the different isovolumic relaxation period responses to verapamil are not clear: the 2 subgroups were different in the baseline study only for higher BP and shorter isovolumic relaxation period in patients in whom this latter increased. One could speculate that higher pressures would impair systolic function and be associated with an increase in LV asynchrony, thus delaying the occurrence of end systole and making the isovolumic relaxation period shorter. However, time to end systole and its coefficient of variation were similar in the 2 subgroups and EF was higher, although not significantly, in patients in whom isovolumic relaxation period increased. Regardless of the mechanism, verapamil apparently prolongs the isovolumic relaxation period in some patients, but this effect is not associated with LV filling impairment, as shown by the similar increases in peak filling rate in both subgroups of patients (Table III). Limitations of the study: The protocol of this study has limitations. The lack of hemodynamic data makes uncertain whether the peak filling rate increase reflects a true improvement in LV compliance or is the effect of increased LV filling pressure: analysis of the diastolic pressure-volume relation would clarify this point. Likewise, isovolumic relaxation period is an indirect estimate of relaxation, which is more accurately evaluated by LV pressure decay rate. However, cardiac catheterization was not clinically indicated and was therefore considered unethical. In addition, our patients were relatively young and had mild LV hypertrophy; in older patients some extent of LV fibrosis can develop and reduce or abolish the effects of verapamil on filling. Moreover, the efficacy of intravenous verapamil administration does not imply that the same effects on diastolic function would be observed after long-term oral therapy, at the therapeutic dosage range suggested to reduce BP. 28 In patients with hypertrophic cardiomyopathy, however, verapamil did improve diastolic function after either intravenous administration13 or oral midterm1°J2 and long-term therapy.2g Acknowledgment: We thank Robert 0. Bonow, MD, for his useful suggestions and criticisms.

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ventricular function in hypertensive patients with left ventricular hypertrophy [abstr). JACC 1985;5:414. 6. Dougherty AH, Naccarelli GV, Gray EL. Hicks C. Goldstein RA. Congestive heart failure with normal systolic function. Am r Cardiol 1984;54:778-782. 7. Soufer R. Wohlgelernter D. Vita NA, Amuchestegui M, Sostman D, Berger HJ, Zaret BL. Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985;55:1032-1036. 8. Fouad FM, Slominski JM, Tarazi RC, Gallagher JH. Alterations in left ventricular filling with beta-adrenergic blockade. Am r Cardiol 1983:51:161164.

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