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Effects of a single dose of isosorbide-5-mononitrate on the left ventricular diastolic function in systemic hypertension
Effects of a Single Dose of Isosorbide-5 IViononitrate on the Left Ventricular Diastolic Function in Systemic Hypertension Alon Marmor, MD, Jesse Krakauer, MD, and Adam Schneeweiss, MD
The effect of a single dose of isosorbide-S-mononitrate on left ventricular (LV) diastolic function was assessed by radionuclide ventriculography in 18 hypertensive patients. The effect of the mononitrate on atrial filling also was assessed. As expected, there was a significant decrease in mean blood pressure (120 f 17 to 102 f 18 mm Hg, p
From the Cardiology Department, Rebecca Sieff Hospital, Safed, and the Geriatric Cardiology Research Foundation, Tel Aviv, Israel. Manuscript received December 20, 1988; revised manuscript received and accepted February 21, 1989. Address for reprints: Alon Marmor, MD, Cardiology Department, Rebecca Sieff Hospital, Safed 13 100, Israel.
I
n the past few years, a remarkable surge of interest has been shown in the diastolic properties of the left ventricle in patients with systolic hypertension. The most common abnormality reported has been reduction in peak filling rate in early diastole and time to peak filling as an index of left ventricular (LV) relaxation in early diastole.‘-3 Recently, several studies have dealt with the effect of antihypertensive drugs on diastolic function, showing a general improvement in the diastolic relaxation parameters measured noninvasively.4J In these studies, however, no attempt has been made to assess the simultaneous changes occurring in preload and afterload and their influence on the diastolic relaxation parameters. Nitrates are well known for their ability to reduce mainly preload, and as such they may serve as the means for the assessment of the relation between changes in preload and diastolic function in hypertension. Furthermore, nitrates are used in combination with antihypertensive drugs in many patients with hypertension associated with ischemic heart disease. Therefore, it would be useful to know the effect of nitrates alone on diastolic function in hypertensives and the interrelation of changes in preload and diastolic function. The present study assessed the effect of nitrates on diastolic function in hypertensive patients and the effect of the changes in preload on the diastolic function. METHODS Patient population: Twenty patients with essential hypertension were included in the study. Two patients were excluded after the initial radioventriculography because of the poor quality of the radionuclide study as a result of frequent ventricular extrasystoles. Thirteen men and 5 women, mean age 62 f 10 years, remained in the study and constituted the study population. All patients had mild to moderate systemic hypertension with a duration of 5 to 40 years (mean 11). Active coronary artery disease was excluded in all patients by history, physical examination, rest and exercise electrocardiography, and stress myocardial scintigraphy with thallium-201. The pertinent clinical data of all patients are listed in Table I. All patients were treated with p blockers and diuretics. The mean blood pressure was 94 f 6 mm Hg during treatment. Beta blockers and diuretics were tapered off gradually, and 1 week before the beginning of the study all previous medications were stopped. During this tapering off period, none of the patients experienced withdrawal effects consistent with THE AMERICAN JOURNAL OF CARDIOLOGY MAY 15, 1989
1235
RADIONUCLIDE
ASSESSMENT
OF DIASTOLIC
TABLE
I Patient Data
Pt
Age (yrs), Sex
Weight (kg)
Height Cm)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean SD
66, 47, 60, 70, 59, 56, 63, 60. 69, 61, 67, 67, 67, 60, 41, 79, 49, 59, 62 11
65 80 87 68 82 86 63 74 85 62 75 83 79 65 95 75 80 60 77 10
1.65 1.76 1.74 1.73 1.72 1.82 1.7 1.68 1.62 1.68 1.78 1.85 1.6 1.65 1.69 1.62 1.6 1.55 1.69 0.08
M M M M M M F M M F M M F M M M F F
BSA . (m*) 1.73 1.98 2.05 1.81 1.98 2.09 1.72 1.86 1.96 1.7 1.93 2.07 1.87 1.73 2.11 1.84 1.89 1.61 1.88 0.14
EARLY FILLING
SH (yrs) 6 7 7 20 7 16 7 15 40 15 5 10 5 6 5 6 10 11 9
IHD 0 0
+W* +(4)* + + -I0 0 0 0 0 0 0 0 0 0 0
* Number within parentheses indicates years since myocardial infarction. BSA = body surface area: IHD = ischemic heart disease; SD * standard deviation; SH = systemic hypertension.
multiple ventricular premature complexes or major increases in heart rate. The mean heart rate increased from 66 f 11 to 70 f 10 beats/min (difference not significant). Thallium-201 scintigraphy was performed in all patients during the washout period to avoid false negative results due to the protective effect of the pblockers. After the l-week washout period all subjects underwent radionuclide ventriculography. Immediately after this first ventriculography, the patient was repositioned and a second radionuclide ventriculography was performed for reproducibility purposes. After the 2 radionuclide studies, a placebo or a 20-mg tablet of isosorbide-5-mononitrate was administered in a random fashion and a third radionuclide ventriculography was performed 1 hour after administration of the drug. The results of the first 2 radionuclide studies served for reproducibility calculations and the placebo study results were used as a reference point for statistical analysis. The procedure was repeated 1 week later with drug crossover. Blood pressure and heart rate were monitored every 10 minutes and electrocardiograms were obtained before and 1 hour after drug administration. Systolic and diastolic indexes of LV performance were calculated from the radionuclide studies, as shown later. Left and right ventricular volume changes were evaluated using changes in total counts in the ventricular area. Right and left atria1 time activity curves were derived according to a technique that we developed.6 kintigraphic technique: All patients underwent gated blood pool scintigraphy at rest using red blood cells labeled in vivo with 20 mCi of technetium-99m pertechnate, a standard field-of-view camera, a low energy medium resolution parallel hole collimator and a digital processor (Elscint Apex). The camera was interfaced with a dedicated minicomputer system and data were collected at 45” left anterior oblique with 15” caudal 1236
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
63
AND ATRIAL
FUNCTION
angulation. The cardiac cycle was divided into 24 equal frames and a total of 5 million counts was collected. Temporal and spatial smoothing of the data along with background substraction were then performed and followed by a time activity curve generation using a commercially available software program.7 The program uses a semiautomatic, second-derivative-based edge detection algorithm with edge tracking of each frame of the cardiac cycle. Each edge is subject to operator modification before the final time activity curve generation. The peak filling rate was calculated as the maximal slope of the time activity curve in the early filling phase using a 5-point derivative algorithm after 3-point smoothing to reduce statistical noise.7 The peak filling rate, representing the maximal slope of the first derivative of the early filling portion (count rate per second), was normalized by dividing it by end-diastolic counts and it is expressed as volumes per second. The time of end-diastole (maximal counts) and of end-systole (minimal counts) served as a reference system for the determination of the duration of the diastole and the time to peak filling rate. Time to peak filling was calculated as the time from minimal counts on the time activity curve to the time of the peak filling rate. This parameter is expressed in absolute value (ms) and as a percentage of diastolic time (time to peak filling/diastolic time X 100). These indexes are considered today as good indicators of LV diastolic function.7,s The absolute right and left ventricular counts in the region of interest obtained by automatic edge detection were calculated and compared in the same patient before and after drug administration. The percent change in the absolute counts was considered to represent a close indicator of the volume changes taking place as all the attenuation parameters and the region of interest remained the same before and after drug administration. The scintigraphic technique used to assessthe atria required phase image analysis to be performed in each study using the fundamental Fourier harmonic coefficients.9 The phase image was then displayed using a 16-color code. The atria were differentiated from the rest of the cardiac structures in all patients. A region of interest surrounding the atria1 structure was drawn with a manual electronic cursor that delineated both atria, and atria1 time activity curves were generated. Although the Fourier analysis cannot eliminate the overlap of various heart structures, it can assist in the resolution of nonoverlapping atria1 structures, thus enabling us to exclude nonatrial structures from the region of interest and obtain a time activity curve reflecting atria1 volume changes. When performing Fourier analysis of the atria, the ventricular phase is considered as 0’ and the atria1 phase as 180°, each phase having its own color. The range between these 2 phases is divided into 16 colors, each of them representing 180/ 16’ (11.25’). The region of interest of the atria was considered only the blue color (180’). All the other colors or shades were effectively eliminated by the manual drawing. The maximal error (overlapping of other structures) could not thus exceed 6% (lOO%/ 16 colors). It is reasonable to assume that even if a small part of the atrium was excluded, changes in relative vol-
TABLE
II Scan Data:
Baseline Blood Pressure
Pt
HR (beats/min)
Systolic (mm W
Diastolic (mm W
Mean (mm W
LVEF (%)
RVEF (%)
PFR (counts/s)
NPFR WV/s)
TPFR (ms)
Percent TPFR W)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean SD
69 71 68 50 68 68 96 75 65 69 51 65 83 75 75 69 66 83 70 10
198 150 150 150 140 190 190 150 160 170 200 140 160 200 150 165 150 140 161 24
90 95 110 90 90 100 105 105 90 100 110 100 90 150 95 95 90 90 91 27
126 113 123 110 107 130 133 120 113 123 140 113 113 167 113 118 110 107 120 17
65 71 64 53 63 68 63 59 81 84 71 74 73 59 54 55 58 52 65 9
47 38 47 32 48 48 45 48 46 44 38 48 44 48 47 44 52 37 45 5
15,954 15,389 10,375 13,955 14,087 16,609 18,084 13,251 18,287 15,299 13,072 13,653 15,304 18,452 19,478 11,726 15,223 12,617 15,045 2,409
2.1 2.6 1.6 1.6 2.6 3 3.2 1.9 2.9 3.8 1.7 1.7 3.2 2 2.9 1.5 2.2 2 2.4 0.7
172 168 264 177 176 132 155 200 184 172 116 230 144 160 160 215 135 216 176 36
44 57 46 33 44 38 62 62 40 40 29 50 44 40 44 50 33 75 46 11
EDV = enddiastolic volume; HR = heart rate; LVEF = left ventricular fraction; SD = standard deviation; TPFR = time to peak filling rate.
TABLE
Ill
ejection fraction;
NPFR = normalized
peak filling rate; PFR = peak filling rate; RVEF = right ventricular
ejection
Scan Data: Placebo Blood Pressure
Pt
HR (beats/min)
Systolic (mm Hg)
Diastolic (mm Hg)
Mean (mm W
LVEF (%)
RVEF (“h)
PFR (counts/s)
NPFR WV/s)
TPFR 0-m)
Percent TPFR W)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean SD
69 69 68 60 68 76 96 75 60 76 49 63 81 73 75 69 66 81 71 10
188 110 150 120 130 170 180 135 140 150 200 120 162 200 130 140 120 120 148 28
90 80 95 80 80 96 110 95 90 95 100 70 80 150 90 80 80 80 91 17
123 90 113 93 97 121 133 108 107 113 133 87 107 167 103 100 93 93 110 19
68 73 66 50 64 62 66 57 71 86 71 80 73 58 53 54 66 55 65 9
48 40 40 34 52 46 45 49 41 54 42 45 46 45 45 46 51 36 45 5
14,842 23,721 11,365 15,968 17,869 18,099 12,828 16,385 18,165 15,580 14,288 14,703 14,671 14,364 23,978 13,145 15,952 11,187 15,951 3,411
2.5 3.1 1.7 1.5 2.8 2.6 3.2 2.2 2.2 2.9 1.7 1.8 3.1 1.7 3.0 1.5 2.7 1.9 2.3 0.6
172 172 220 200 176 156 155 200 150 156 183 188 148 205 120 215 135 148 172 28
44 40 42 36 40 50 62 56 33 36 60 40 44 42 33 50 33 50 44 9
Abbreviations
as in Table II
ume would not be affected because in this respect the atrium is a homogeneous chamber. Right and left atria1 tilling rates were calculated according to a previously published technique. lo,] l These parameters were considered to reflect changes in the venous return to the right and left ventricle and may serve for assessment of changes induced by isosorbide mononitrate in preload. Manual delineation of the left ventricular and atria1 regions of interest were performed by 2 experienced nuclear medicine physicians, totally unaware of the nature of the study. No discrepancy >lO% was found between
the 2 observers, whereas with smaller discrepancies an averaged result was presented. Statistical analysis: The results are presented as mean f standard deviation. Statistical analysis was performed using paired t test. When more than 2 groups were compared, repeated measure analysis of variance was performed. The level of significance was p <0.05. RESULTS
The hemodynamic response to mononitrate administration is listed in Tables II through IV. Heart rate inTHE AMERICAN
JOURNAL
OF CARDIOLOGY
MAY 15, 1989
1237
RADIONUCLIDE
TABLE
ASSESSMENT
OF DIASTOLIC
EARLY FILLING
AND ATRIAL
FUNCTION
IV Scan Data: Nitrate Blood Pressure
Pt
HR (beats/min)
Systolic (mm W
Diastolic (mm W
Mean (mm Hg)
LVEF W)
RVEF (“h)
PFR (counts/s)
NPFR WV/s)
TPFR (ms)
Percent TPFR (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean
85 78 63 55 66 63 96 83 68 71 54 73 83 71 90 90 68 90 75
SD
12
150 115 145 90 108 130 140 120 150 130 140 110 160 208 120 132 105 110 131 26
90 84 106 70 70 80 100 80 90 90 90 65 80 140 80 80 80 90 87 16
110 94 119 77 83 97 113 93 110 103 107 80 107 163 93 97 88 97 102 19
71 75 55 58 69 66 67 64 74 80 72 86 74 68 65 54 66 65 68 8
48 53 45 47 47 46 4.8 49 50 54 44 50 48 50 52 39 47 40 48 4
16,538 17,760 8,718 9,901 13.409 13,477 16,175 12,774 14,236 13,476 11,866 10,525 13,707 13,742 21,544 12,702 11,187 12,515 13,569 2,93 1
2.6 2.8 1.5 1.2 2.4 2.4 3.4 1.9 2.2 2.8 1.4 1.6 2.7 2.0 3.2 2.1 2.5 2.9 2.3 0.6
245 152 235 216 180 188 186 180 220 168 165 205 180 210 132 198 220 231 195 30
78 44 56 44 40 44 75 62 50 36 33 56 56 50 44 54 56 88 54 14
Abbreviations
1 TABLE
as in Table II.
V Changes Induced by the Mononitrate
Baseline SD Placebo SD Mononitrate SD F value* p value+
in Systolic and Diastolic Function
HR (beats/ min)
MBP (mm Hg)
LVEF PFR (%) (counts/s)
NPFR (EDV/s)
TPFR (ms)
Percent TPFR (“h)
RAF (counts/s)
LAF (counts/s)
LVEDC (counts)
SVC (counts)
RVEDC
RVSVC
(counts)
(counts)
70 10 72 10 75 12 NS NS
120 17 113 19 102 19 26.6 0.005
65 9 64 9 68 8 NS NS
2.36 0.6 2.25 0.58 2.31 0.6 NS NS
176 36 176 27 195 30 6.15 0.0001
46 11 46 10 54 14 4.33 0.05
50 12 55 11 52 13 NS NS
45 12 43 11 4.0 13 4.15 0.005
7,150 1,230 7,140 1 ,ocnl 6,287 1,269 NS 0.05
4,554 765 4,520 672 4,288 901 NS 0.056
5,294 711 5,301 690 5,183 1,064 NS NS
2,362 430 2,410 670 2,429 663 NS NS
15,045 2,408 15,328 3,362 13,569 2,931 5.09 0.05
* F values are given for at least p <0.02; t refers to the results of paired t tests between placebo and mononitrate. Analysis of variance (ANOVA) was used when all 3 were compared. LAF = mean left atrial filling, LVEDC = left ventricular end-diastolic counts; MBP = mean blood pressure: NS = not significant; RAF = mean right atrial filling; RVEDC = right ventricular enddiastolic counts; RVSVC = right ventricular stroke counts; SVC = left ventricular stroke counts. Other abbreviations as in Table II.
1 T
M
T 1
Y Y P 3 8
RA.FILLING
RATE
T
LA. FILLING
*
RATE
FIGURE 1. Effeci of isosorbide mononitrate on atrial filling rates. The open ibars represent baseline values, whereas the slashed bars show the mononitrate effect. Note that the mononitrate doss not affect right atrial filling, but it significantly reduces left atrial filling rate. M = atrial filling rate after administration of mononitrate. * = p
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
creased from 70 f 10 to 75 f 12 beats/mm (difference not significant). There was a significant decrease in blood pressure, from 161/91 to 13 l/86 mm Hg (p
One of the most interesting findings in the study was the lack of effect of the nitrates on the right side of the heart. Indeed, in contrast with the reduction of left atrial filling rate, the right atria1 filling rate remained unaffected (Figure 1). Right ventricular end-diastolic counts and stroke counts also were unaffected and contrasted sharply with the reduction found in the left side (Table V). The most plausible explanation for these findings is that the nitrates act primarily on the pulmonary vascular tree, causing vasodilation and reduction in pulmonary artery pressuresand reducing preload to the left ventricle. The reduction in LV stroke volume may follow, and reduction in blood pressurewith reflex tachyDISCUSSION The effect of the mononitrate on systolic and diastol- cardia may ensue. Although this is only a hypothesis,the unilateral reic function in the hypertensive population studied was similar to the previously reported effects of nitrates in duction in venous filling on the left side may be highly healthy subjects.5J2The mononitrate slightly improved suggestiveof a primary vasodilator action of the nitrates LV ejection fraction, slightly reduced and nonsignifi- on the pulmonary bed. Of course, vasodilation of the cantly normalized peak filling rate, and caused signifi- systemic circulation may be present even if undetected cant prolongation of the time to peak filling rate (from by our diagnostic means. 176 f 36 to 195 f 29 ms, p
THE AMERICAN JOURNAL OF CARDIOLOGY MAY 15. 1989
1239
The effect of a single dose of isosorbide-S-mononitrate on left ventricular (LV) diastolic function was assessed by radionuclide ventriculography in 18 hypertensive patients. The effect of the mononitrate on atrial filling also was assessed. As expected, there was a significant decrease in mean blood pressure (120 f 17 to 102 f 18 mm Hg, p
From the Cardiology Department, Rebecca Sieff Hospital, Safed, and the Geriatric Cardiology Research Foundation, Tel Aviv, Israel. Manuscript received December 20, 1988; revised manuscript received and accepted February 21, 1989. Address for reprints: Alon Marmor, MD, Cardiology Department, Rebecca Sieff Hospital, Safed 13 100, Israel.
I
n the past few years, a remarkable surge of interest has been shown in the diastolic properties of the left ventricle in patients with systolic hypertension. The most common abnormality reported has been reduction in peak filling rate in early diastole and time to peak filling as an index of left ventricular (LV) relaxation in early diastole.‘-3 Recently, several studies have dealt with the effect of antihypertensive drugs on diastolic function, showing a general improvement in the diastolic relaxation parameters measured noninvasively.4J In these studies, however, no attempt has been made to assess the simultaneous changes occurring in preload and afterload and their influence on the diastolic relaxation parameters. Nitrates are well known for their ability to reduce mainly preload, and as such they may serve as the means for the assessment of the relation between changes in preload and diastolic function in hypertension. Furthermore, nitrates are used in combination with antihypertensive drugs in many patients with hypertension associated with ischemic heart disease. Therefore, it would be useful to know the effect of nitrates alone on diastolic function in hypertensives and the interrelation of changes in preload and diastolic function. The present study assessed the effect of nitrates on diastolic function in hypertensive patients and the effect of the changes in preload on the diastolic function. METHODS Patient population: Twenty patients with essential hypertension were included in the study. Two patients were excluded after the initial radioventriculography because of the poor quality of the radionuclide study as a result of frequent ventricular extrasystoles. Thirteen men and 5 women, mean age 62 f 10 years, remained in the study and constituted the study population. All patients had mild to moderate systemic hypertension with a duration of 5 to 40 years (mean 11). Active coronary artery disease was excluded in all patients by history, physical examination, rest and exercise electrocardiography, and stress myocardial scintigraphy with thallium-201. The pertinent clinical data of all patients are listed in Table I. All patients were treated with p blockers and diuretics. The mean blood pressure was 94 f 6 mm Hg during treatment. Beta blockers and diuretics were tapered off gradually, and 1 week before the beginning of the study all previous medications were stopped. During this tapering off period, none of the patients experienced withdrawal effects consistent with THE AMERICAN JOURNAL OF CARDIOLOGY MAY 15, 1989
1235
RADIONUCLIDE
ASSESSMENT
OF DIASTOLIC
TABLE
I Patient Data
Pt
Age (yrs), Sex
Weight (kg)
Height Cm)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean SD
66, 47, 60, 70, 59, 56, 63, 60. 69, 61, 67, 67, 67, 60, 41, 79, 49, 59, 62 11
65 80 87 68 82 86 63 74 85 62 75 83 79 65 95 75 80 60 77 10
1.65 1.76 1.74 1.73 1.72 1.82 1.7 1.68 1.62 1.68 1.78 1.85 1.6 1.65 1.69 1.62 1.6 1.55 1.69 0.08
M M M M M M F M M F M M F M M M F F
BSA . (m*) 1.73 1.98 2.05 1.81 1.98 2.09 1.72 1.86 1.96 1.7 1.93 2.07 1.87 1.73 2.11 1.84 1.89 1.61 1.88 0.14
EARLY FILLING
SH (yrs) 6 7 7 20 7 16 7 15 40 15 5 10 5 6 5 6 10 11 9
IHD 0 0
+W* +(4)* + + -I0 0 0 0 0 0 0 0 0 0 0
* Number within parentheses indicates years since myocardial infarction. BSA = body surface area: IHD = ischemic heart disease; SD * standard deviation; SH = systemic hypertension.
multiple ventricular premature complexes or major increases in heart rate. The mean heart rate increased from 66 f 11 to 70 f 10 beats/min (difference not significant). Thallium-201 scintigraphy was performed in all patients during the washout period to avoid false negative results due to the protective effect of the pblockers. After the l-week washout period all subjects underwent radionuclide ventriculography. Immediately after this first ventriculography, the patient was repositioned and a second radionuclide ventriculography was performed for reproducibility purposes. After the 2 radionuclide studies, a placebo or a 20-mg tablet of isosorbide-5-mononitrate was administered in a random fashion and a third radionuclide ventriculography was performed 1 hour after administration of the drug. The results of the first 2 radionuclide studies served for reproducibility calculations and the placebo study results were used as a reference point for statistical analysis. The procedure was repeated 1 week later with drug crossover. Blood pressure and heart rate were monitored every 10 minutes and electrocardiograms were obtained before and 1 hour after drug administration. Systolic and diastolic indexes of LV performance were calculated from the radionuclide studies, as shown later. Left and right ventricular volume changes were evaluated using changes in total counts in the ventricular area. Right and left atria1 time activity curves were derived according to a technique that we developed.6 kintigraphic technique: All patients underwent gated blood pool scintigraphy at rest using red blood cells labeled in vivo with 20 mCi of technetium-99m pertechnate, a standard field-of-view camera, a low energy medium resolution parallel hole collimator and a digital processor (Elscint Apex). The camera was interfaced with a dedicated minicomputer system and data were collected at 45” left anterior oblique with 15” caudal 1236
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
63
AND ATRIAL
FUNCTION
angulation. The cardiac cycle was divided into 24 equal frames and a total of 5 million counts was collected. Temporal and spatial smoothing of the data along with background substraction were then performed and followed by a time activity curve generation using a commercially available software program.7 The program uses a semiautomatic, second-derivative-based edge detection algorithm with edge tracking of each frame of the cardiac cycle. Each edge is subject to operator modification before the final time activity curve generation. The peak filling rate was calculated as the maximal slope of the time activity curve in the early filling phase using a 5-point derivative algorithm after 3-point smoothing to reduce statistical noise.7 The peak filling rate, representing the maximal slope of the first derivative of the early filling portion (count rate per second), was normalized by dividing it by end-diastolic counts and it is expressed as volumes per second. The time of end-diastole (maximal counts) and of end-systole (minimal counts) served as a reference system for the determination of the duration of the diastole and the time to peak filling rate. Time to peak filling was calculated as the time from minimal counts on the time activity curve to the time of the peak filling rate. This parameter is expressed in absolute value (ms) and as a percentage of diastolic time (time to peak filling/diastolic time X 100). These indexes are considered today as good indicators of LV diastolic function.7,s The absolute right and left ventricular counts in the region of interest obtained by automatic edge detection were calculated and compared in the same patient before and after drug administration. The percent change in the absolute counts was considered to represent a close indicator of the volume changes taking place as all the attenuation parameters and the region of interest remained the same before and after drug administration. The scintigraphic technique used to assessthe atria required phase image analysis to be performed in each study using the fundamental Fourier harmonic coefficients.9 The phase image was then displayed using a 16-color code. The atria were differentiated from the rest of the cardiac structures in all patients. A region of interest surrounding the atria1 structure was drawn with a manual electronic cursor that delineated both atria, and atria1 time activity curves were generated. Although the Fourier analysis cannot eliminate the overlap of various heart structures, it can assist in the resolution of nonoverlapping atria1 structures, thus enabling us to exclude nonatrial structures from the region of interest and obtain a time activity curve reflecting atria1 volume changes. When performing Fourier analysis of the atria, the ventricular phase is considered as 0’ and the atria1 phase as 180°, each phase having its own color. The range between these 2 phases is divided into 16 colors, each of them representing 180/ 16’ (11.25’). The region of interest of the atria was considered only the blue color (180’). All the other colors or shades were effectively eliminated by the manual drawing. The maximal error (overlapping of other structures) could not thus exceed 6% (lOO%/ 16 colors). It is reasonable to assume that even if a small part of the atrium was excluded, changes in relative vol-
TABLE
II Scan Data:
Baseline Blood Pressure
Pt
HR (beats/min)
Systolic (mm W
Diastolic (mm W
Mean (mm W
LVEF (%)
RVEF (%)
PFR (counts/s)
NPFR WV/s)
TPFR (ms)
Percent TPFR W)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean SD
69 71 68 50 68 68 96 75 65 69 51 65 83 75 75 69 66 83 70 10
198 150 150 150 140 190 190 150 160 170 200 140 160 200 150 165 150 140 161 24
90 95 110 90 90 100 105 105 90 100 110 100 90 150 95 95 90 90 91 27
126 113 123 110 107 130 133 120 113 123 140 113 113 167 113 118 110 107 120 17
65 71 64 53 63 68 63 59 81 84 71 74 73 59 54 55 58 52 65 9
47 38 47 32 48 48 45 48 46 44 38 48 44 48 47 44 52 37 45 5
15,954 15,389 10,375 13,955 14,087 16,609 18,084 13,251 18,287 15,299 13,072 13,653 15,304 18,452 19,478 11,726 15,223 12,617 15,045 2,409
2.1 2.6 1.6 1.6 2.6 3 3.2 1.9 2.9 3.8 1.7 1.7 3.2 2 2.9 1.5 2.2 2 2.4 0.7
172 168 264 177 176 132 155 200 184 172 116 230 144 160 160 215 135 216 176 36
44 57 46 33 44 38 62 62 40 40 29 50 44 40 44 50 33 75 46 11
EDV = enddiastolic volume; HR = heart rate; LVEF = left ventricular fraction; SD = standard deviation; TPFR = time to peak filling rate.
TABLE
Ill
ejection fraction;
NPFR = normalized
peak filling rate; PFR = peak filling rate; RVEF = right ventricular
ejection
Scan Data: Placebo Blood Pressure
Pt
HR (beats/min)
Systolic (mm Hg)
Diastolic (mm Hg)
Mean (mm W
LVEF (%)
RVEF (“h)
PFR (counts/s)
NPFR WV/s)
TPFR 0-m)
Percent TPFR W)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean SD
69 69 68 60 68 76 96 75 60 76 49 63 81 73 75 69 66 81 71 10
188 110 150 120 130 170 180 135 140 150 200 120 162 200 130 140 120 120 148 28
90 80 95 80 80 96 110 95 90 95 100 70 80 150 90 80 80 80 91 17
123 90 113 93 97 121 133 108 107 113 133 87 107 167 103 100 93 93 110 19
68 73 66 50 64 62 66 57 71 86 71 80 73 58 53 54 66 55 65 9
48 40 40 34 52 46 45 49 41 54 42 45 46 45 45 46 51 36 45 5
14,842 23,721 11,365 15,968 17,869 18,099 12,828 16,385 18,165 15,580 14,288 14,703 14,671 14,364 23,978 13,145 15,952 11,187 15,951 3,411
2.5 3.1 1.7 1.5 2.8 2.6 3.2 2.2 2.2 2.9 1.7 1.8 3.1 1.7 3.0 1.5 2.7 1.9 2.3 0.6
172 172 220 200 176 156 155 200 150 156 183 188 148 205 120 215 135 148 172 28
44 40 42 36 40 50 62 56 33 36 60 40 44 42 33 50 33 50 44 9
Abbreviations
as in Table II
ume would not be affected because in this respect the atrium is a homogeneous chamber. Right and left atria1 tilling rates were calculated according to a previously published technique. lo,] l These parameters were considered to reflect changes in the venous return to the right and left ventricle and may serve for assessment of changes induced by isosorbide mononitrate in preload. Manual delineation of the left ventricular and atria1 regions of interest were performed by 2 experienced nuclear medicine physicians, totally unaware of the nature of the study. No discrepancy >lO% was found between
the 2 observers, whereas with smaller discrepancies an averaged result was presented. Statistical analysis: The results are presented as mean f standard deviation. Statistical analysis was performed using paired t test. When more than 2 groups were compared, repeated measure analysis of variance was performed. The level of significance was p <0.05. RESULTS
The hemodynamic response to mononitrate administration is listed in Tables II through IV. Heart rate inTHE AMERICAN
JOURNAL
OF CARDIOLOGY
MAY 15, 1989
1237
RADIONUCLIDE
TABLE
ASSESSMENT
OF DIASTOLIC
EARLY FILLING
AND ATRIAL
FUNCTION
IV Scan Data: Nitrate Blood Pressure
Pt
HR (beats/min)
Systolic (mm W
Diastolic (mm W
Mean (mm Hg)
LVEF W)
RVEF (“h)
PFR (counts/s)
NPFR WV/s)
TPFR (ms)
Percent TPFR (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Mean
85 78 63 55 66 63 96 83 68 71 54 73 83 71 90 90 68 90 75
SD
12
150 115 145 90 108 130 140 120 150 130 140 110 160 208 120 132 105 110 131 26
90 84 106 70 70 80 100 80 90 90 90 65 80 140 80 80 80 90 87 16
110 94 119 77 83 97 113 93 110 103 107 80 107 163 93 97 88 97 102 19
71 75 55 58 69 66 67 64 74 80 72 86 74 68 65 54 66 65 68 8
48 53 45 47 47 46 4.8 49 50 54 44 50 48 50 52 39 47 40 48 4
16,538 17,760 8,718 9,901 13.409 13,477 16,175 12,774 14,236 13,476 11,866 10,525 13,707 13,742 21,544 12,702 11,187 12,515 13,569 2,93 1
2.6 2.8 1.5 1.2 2.4 2.4 3.4 1.9 2.2 2.8 1.4 1.6 2.7 2.0 3.2 2.1 2.5 2.9 2.3 0.6
245 152 235 216 180 188 186 180 220 168 165 205 180 210 132 198 220 231 195 30
78 44 56 44 40 44 75 62 50 36 33 56 56 50 44 54 56 88 54 14
Abbreviations
1 TABLE
as in Table II.
V Changes Induced by the Mononitrate
Baseline SD Placebo SD Mononitrate SD F value* p value+
in Systolic and Diastolic Function
HR (beats/ min)
MBP (mm Hg)
LVEF PFR (%) (counts/s)
NPFR (EDV/s)
TPFR (ms)
Percent TPFR (“h)
RAF (counts/s)
LAF (counts/s)
LVEDC (counts)
SVC (counts)
RVEDC
RVSVC
(counts)
(counts)
70 10 72 10 75 12 NS NS
120 17 113 19 102 19 26.6 0.005
65 9 64 9 68 8 NS NS
2.36 0.6 2.25 0.58 2.31 0.6 NS NS
176 36 176 27 195 30 6.15 0.0001
46 11 46 10 54 14 4.33 0.05
50 12 55 11 52 13 NS NS
45 12 43 11 4.0 13 4.15 0.005
7,150 1,230 7,140 1 ,ocnl 6,287 1,269 NS 0.05
4,554 765 4,520 672 4,288 901 NS 0.056
5,294 711 5,301 690 5,183 1,064 NS NS
2,362 430 2,410 670 2,429 663 NS NS
15,045 2,408 15,328 3,362 13,569 2,931 5.09 0.05
* F values are given for at least p <0.02; t refers to the results of paired t tests between placebo and mononitrate. Analysis of variance (ANOVA) was used when all 3 were compared. LAF = mean left atrial filling, LVEDC = left ventricular end-diastolic counts; MBP = mean blood pressure: NS = not significant; RAF = mean right atrial filling; RVEDC = right ventricular enddiastolic counts; RVSVC = right ventricular stroke counts; SVC = left ventricular stroke counts. Other abbreviations as in Table II.
1 T
M
T 1
Y Y P 3 8
RA.FILLING
RATE
T
LA. FILLING
*
RATE
FIGURE 1. Effeci of isosorbide mononitrate on atrial filling rates. The open ibars represent baseline values, whereas the slashed bars show the mononitrate effect. Note that the mononitrate doss not affect right atrial filling, but it significantly reduces left atrial filling rate. M = atrial filling rate after administration of mononitrate. * = p
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
creased from 70 f 10 to 75 f 12 beats/mm (difference not significant). There was a significant decrease in blood pressure, from 161/91 to 13 l/86 mm Hg (p
One of the most interesting findings in the study was the lack of effect of the nitrates on the right side of the heart. Indeed, in contrast with the reduction of left atrial filling rate, the right atria1 filling rate remained unaffected (Figure 1). Right ventricular end-diastolic counts and stroke counts also were unaffected and contrasted sharply with the reduction found in the left side (Table V). The most plausible explanation for these findings is that the nitrates act primarily on the pulmonary vascular tree, causing vasodilation and reduction in pulmonary artery pressuresand reducing preload to the left ventricle. The reduction in LV stroke volume may follow, and reduction in blood pressurewith reflex tachyDISCUSSION The effect of the mononitrate on systolic and diastol- cardia may ensue. Although this is only a hypothesis,the unilateral reic function in the hypertensive population studied was similar to the previously reported effects of nitrates in duction in venous filling on the left side may be highly healthy subjects.5J2The mononitrate slightly improved suggestiveof a primary vasodilator action of the nitrates LV ejection fraction, slightly reduced and nonsignifi- on the pulmonary bed. Of course, vasodilation of the cantly normalized peak filling rate, and caused signifi- systemic circulation may be present even if undetected cant prolongation of the time to peak filling rate (from by our diagnostic means. 176 f 36 to 195 f 29 ms, p
THE AMERICAN JOURNAL OF CARDIOLOGY MAY 15. 1989
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