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Use of Angiotensin II Stress Pulsed Tissue Doppler Imaging to Evaluate Regional Left Ventricular Contractility in Patients with Hypertrophic Cardiomyopathy
Use of Angiotensin II Stress Pulsed Tissue Doppler Imaging to Evaluate Regional Left Ventricular Contractility in Patients with Hypertrophic Cardiomyopathy Yuichiro Mishiro, MD, Takashi Oki, MD, Hirotsugu Yamada, MD, Yukiko Onose, MD, Masako Matsuoka, MD, Tomotsugu Tabata, MD, Tetsuzo Wakatsuki, MD, and Susumu Ito, MD, Tokushima, Japan
There is controversy concerning whether contractility in the nonhypertrophied region of the left ventricular (LV) wall is impaired or normal in patients with hypertrophic cardiomyopathy (HCM). Global LV systolic function decreases with increases in afterload in this disease. This study was performed to identify abnormalities in regional LV contractility along the long and short axes in the setting of HCM with the use of angiotensin II (AT-II) stress pulsed tissue Doppler imaging (PTDI). Angiotensin II was administered intravenously to patients with asymmetric septal hypertrophy (HCM group, n = 21) and age-matched normal volunteers (N group, n = 12). We then measured the percent LV fractional shortening (%FS) and end-systolic circumferential LV wall stress by M-mode echocardiography, LV ejection fraction (LVEF) by 2dimensional echocardiography, and time-velocity integral (TVI) of LV outflow velocity by pulsed Doppler echocardiography. The peak first and second systolic LV wall motion velocities along the long (L-Sw1 and L-Sw2) and short (S-Sw1 and S-Sw2) axes were measured in the LV posterior wall and
Hypertrophic cardiomyopathy (HCM) is characterized by impaired left ventricular (LV) diastolic function caused by nonuniform LV hypertrophy.1,2 However, LV pump function is usually normal in patients with asymmetric septal hypertrophy because the nonhypertrophied posterior wall increases motion to compensate for the decrease in wall motion of the hypertrophied ventricular sepFrom The Second Department of Internal Medicine, School of Medicine, The University of Tokushima. Reprint requests: Takashi Oki, MD, The Second Department of Internal Medicine, School of Medicine, The University of Tokushima, 2-50 Kuramoto-cho, Tokushima 770-8503, Japan. Copyright © 2000 by the American Society of Echocardiography. 0894-7317/2000/$12.00 + 0 27/1/111010 doi:10.1067/mje.2000.111010
ventricular septum with the use of PTDI. The endsystolic circumferential LV wall stress at baseline was significantly lower in the HCM group. The L-Sw1 and L-Sw2 for the posterior wall were significantly lower in the HCM group, but the S-Sw1 and S-Sw2 for the posterior wall and ventricular septum were similar in the two groups. The %FS, LVEF, TVI, and systolic PTDI variables along both axes for the posterior wall decreased significantly, and endsystolic circumferential LV wall stress increased significantly at AT-II doses of 0.005 or 0.010 µg/kg per minute in the HCM group. No significant changes were found in either group in the systolic PTDI variables (except for L-Sw1) for the ventricular septum with AT-II infusion. Contractility along the long and short axes of the nonhypertrophied LV wall is easily impaired with increases in afterload in patients with HCM, resulting in a decrease in global LV systolic function. We found AT-II stress PTDI to be a safe and useful technique for evaluating the regional LV systolic function in this disease. (J Am Soc Echocardiogr 2000;13:1065-73.)
tum.3,4 Furthermore, although it has been thought that in the setting of this disease systolic LV performance is preserved for a long period of time, a dilated cardiomyopathy has been found to develop in some patients who exhibit a dilated phase of HCM.5,6 Consequently, there is controversy concerning whether contractility in the nonhypertrophied region is impaired because some studies3,4 have reported that contractility is normal, and other studies7,8 have reported decreased contractility. We hypothesized that myocardial contractility in patients with asymmetric septal hypertrophy is impaired even in the nonhypertrophied regions, and its abnormality can be detected by an increase in afterload.Angiotensin II (AT-II) causes contraction of the vascular smooth muscles, resulting in an increase 1065
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Figure 1 Sample recordings of the circumferentially and longitudinally directed left ventricular wall motion velocity patterns in the parasternal (left) and apical (center) long-axis views of the left ventricle (LV), respectively, by pulsed tissue Doppler imaging, and measurement of variables obtained from the longitudinally directed left ventricular posterior wall motion velocity pattern in the apical long-axis view (right). T, Transducer; RV, right ventricle; LA, left atrium; Ao, ascending aorta; Sw1, peak first systolic wall motion velocity; Sw2, peak second systolic wall motion velocity; Ew, peak early diastolic wall motion velocity; Aw, peak atrial systolic wall motion velocity; ECG, electrocardiogram; PCG, phonocardiogram; I, first heart sound; II, second heart sound.
in peripheral vascular resistance or afterload. The goal of our study was to identify abnormalities in regional LV contractility along the long and short axes in patients with HCM by using AT-II stress pulsed tissue Doppler imaging (PTDI).
METHODS
Angiotensin II Administration Angiotensin II was administered intravenously to all subjects (0.005, 0.010, 0.015 µg/kg of Delivert per minute over 10-minute intervals). Heart rate, blood pressure, echocardiographic, and PTDI variables were measured at each dose of AT-II. The end point of the study was the completion of the infusion of the dose of 0.015 µg/kg per minute of AT-II or a 30% increase in mean arterial blood pressure.
Patient Population
M-Mode Echocardiography
The study included 21 untreated patients with asymmetric septal hypertrophy (HCM group, mean age 62 ± 15 years) in whom the end-diastolic ventricular septal thickness and the posterior wall thicknesses were ≥15 mm and ≤11 mm, respectively, and in whom the ratio of the two wall thicknesses was ≥1.3 by M-mode echocardiography.All the patients were in sinus rhythm without bundle branch blocks. Patients had to meet the following inclusion criteria: (1) no symptoms and no radiographic findings of pulmonary congestion, (2) no evidence of moderate to severe valvular heart disease based on color Doppler echocardiography, (3) LV outflow obstruction <20 mm Hg determined by continuous wave Doppler echocardiography, and (4) blood pressure <140/90 mm Hg. The control group consisted of 12 age-matched healthy volunteers (N group; mean age: 59 ± 14 years). The purpose of this study was fully explained, and informed consent was obtained from all persons. The protocol was approved by the hospital human investigations committee.
Transthoracic echocardiography was performed with a Toshiba SSH-380A (Tokyo, Japan) ultrasound diagnostic system equipped with a 2.5-MHz probe.Left ventricular end-diastolic dimension (LVDd), LV end-systolic dimension (LVDs), maximum left atrial dimension (LAD), end-diastolic ventricular septal thickness (VSth), and end-diastolic LV posterior wall thickness (PWth) were measured by M-mode echocardiography. The percent fractional shortening of the left ventricle (%FS) and the end-systolic circumferential LV wall stress (WS) were calculated with the following equations:9 %FS = [(LVDd – LVDs) / LVDd] × 100 WS (g/cm2) = 0.59 × SBP × LVDs / Ths, where Ths = (VSth + PWth)/2 and SBP = systolic blood pressure. Two-Dimensional and Pulsed Doppler Echocardiography The LV ejection fraction (LVEF) was calculated with use of the modified Simpson’s method10 on the basis of measurements obtained by 2-dimensional echocardiography. Left
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ventricular outflow tract diameter (LVOT-d) was measured from the parasternal LV long-axis view, and its area (LVOTa) was calculated by using the following equation: LVOT-a = 3.14 × (LVOT-d / 2)2 The sample volume was placed in the LV outflow tract on the apical LV long-axis view, and the LV outflow velocity pattern and its time-velocity integral (TVI) were obtained by pulsed Doppler echocardiography.11 Pulsed Tissue Doppler Imaging Parasternal and apical long-axis LV echocardiograms were recorded with the use of transthoracic echocardiography. The sample volumes were placed in the midwall portions in the middle of the ventricular septum and the LV posterior wall in the parasternal long-axis view (Figure 1, left). Sample volumes then were placed in the subendocardial portions in the middle of the ventricular septum and the LV posterior wall in the apical long-axis view (Figure 1, center).The acoustic power and filter frequencies were set to the lowest possible values, and sample volumes (approximately 8 mm wide) were set in the target walls. The wall motion velocity pattern at each site was recorded by the pulsed Doppler method with a commercially available ultrasound diagnostic system with a 3.75-MHz probe (Toshiba SSA-380A). On the basis of the wall motion velocity patterns, we determined the peak first (Sw1) and second (Sw2) systolic wall motion velocities12 (Figure 1, right). This study was performed and reviewed by the different investigators, and they all knew and understood the study protocol. Interobserver variability of the tissue Doppler measurements (3% to 8%) was calculated as the difference in 2 measurements in the same patient by 2 different observers divided by the mean value. Intraobserver variability (2% to 7%) was calculated as the difference between 2 measurements in the same patient by 1 observer divided by the mean value. Statistical Analysis Values are expressed as the mean ± SD.Values between the HCM and N groups were compared by using the unpaired Student t test. Values before and after AT-II administration were compared with a 2-factor analysis of variance for repeated measurements. A P value < .05 was considered statistically significant.
RESULTS Baseline The maximum left atrial dimension and end-diastolic ventricular septal thickness were significantly greater
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Table 1 Clinical, M-mode, and 2-dimensional echocardiography and pulsed tissue Doppler data at baseline N (n = 12)
Age (y) Heart rate (bpm) LVDd (cm) LVDs (cm) %FS (%) VSth (cm) PWth (cm) WS (g/cm2) LAD (cm) LVEF (%) TVI (m) LVOT-a (cm2) PW S-Sw1 (cm/s) S-Sw2 (cm/s) L-Sw1 (cm/s) L-Sw2 (cm/s) VS S-Sw1 (cm/s) S-Sw2 (cm/s) L-Sw1 (cm/s) L-Sw2 (cm/s)
HCM (n = 21)
P value
59 69 4.3 2.5 41 0.8 0.9 8.5 3.3 64 0.20 3.3
± ± ± ± ± ± ± ± ± ± ± ±
14 10 0.6 0.4 9 0.2 0.2 1.9 0.6 4 0.03 0.6
62 66 4.2 2.5 41 2.2 1.1 5.1 4.0 69 0.21 3.0
± ± ± ± ± ± ± ± ± ± ± ±
15 8 0.5 0.4 4 0.7 0.3 1.8 0.8 6 0.04 0.7
NS NS NS NS NS <.001 NS <.001 <.01 NS NS NS
6.7 7.3 9.8 6.9
± ± ± ±
1.4 1.3 2.5 1.2
5.9 7.5 7.0 4.6
± ± ± ±
1.1 1.5 1.4 0.6
NS NS <.01 <.01
6.0 5.6 6.7 5.5
± ± ± ±
1.5 1.3 1.6 2.0
5.3 5.5 5.5 4.6
± ± ± ±
2.0 1.5 1.5 1.6
NS NS <.05 NS
N, Normal control; HCM, patients with hypertrophic cardiomyopathy; NS, not significant; LVDd and LVDs, end-diastolic and end-systolic left ventricular dimension, respectively; %FS, percent fractional shortening of left ventricle; VSth, end-diastolic ventricular septal thickness; PWth, end-diastolic left ventricular posterior wall thickness; WS, end-systolic circumferential left ventricular wall stress; LAD, maximum left atrial dimension; LVEF, left ventricular ejection fraction; TVI, time-velocity integral of left ventricular outflow velocity; LVOT-a, left ventricular outflow tract area; PW, left ventricular posterior wall; VS, ventricular septum; L-Sw1 and S-Sw1, peak first systolic wall motion velocities along the long and short axes, respectively; LSw2 and S-Sw2, peak second systolic wall motion velocities along the long and short axes, respectively.
in the HCM group than in the N group (Table 1).The end-systolic circumferential LV wall stress was significantly lower in the HCM group than in the N group. There were no significant differences in heart rate and other M-mode, 2-dimensional, and pulsed Doppler echocardiography variables between the 2 groups. There were no significant differences in either S-Sw1 or S-Sw2 in the LV posterior wall between the 2 groups. In contrast, L-Sw1 and L-Sw2 were significantly lower in the HCM group than in the N group. L-Sw1 in the ventricular septum was significantly lower in the HCM group than in the N group,though there were no significant differences in the other systolic PTDI variables between the 2 groups. Clinical and M-Mode Echocardiography Variables No significant differences were found in the heart rate before or after AT-II administration between the HCM and N groups (Figure 2). The systolic blood pressure was significantly higher during AT-II admin-
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Figure 2 Clinical and M-mode echocardiography variables. HR, Heart rate; SBP, systolic blood pressure; LVD, left ventricular dimension; %FS, percent fractional shortening of left ventricle; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); *P < .05 versus baseline, **P < .01 versus baseline, ***P < .001 versus baseline, ****P < .0001 versus baseline, #P < .05 versus N group, ##P < .01 versus N group, ###P < .001 versus N group, ####P < .0001 versus N group.
istration in both groups, though there was no significant dose-dependent effect of AT-II on blood pressure between the 2 groups. No significant difference was found in LV end-diastolic dimension during AT-II administration between the 2 groups. In contrast, the LV end-systolic dimension was significantly greater during AT-II administration in both groups, particularly in the HCM group.The percent LV fractional shortening decreased significantly at all doses of AT-II in the HCM group, but decreased only at an AT-II dose of 0.015 µg/kg per minute in the N group.The maximal left atrial dimension did not change during AT-II administration in either group (Figure 3).The end-systolic circumferential LV wall stress was significantly greater for all doses of AT-II in the HCM group, and at AT-II doses of 0.010 and 0.015 µg/kg per minute in the N group. Two-Dimensional and Pulsed Doppler Echocardiography Variables The LVEF and TVI of the LV outflow velocity decreased significantly at all AT-II doses in the HCM group, and decreased significantly at an AT-II dose of 0.015 µg/kg per minute in the N group (Figure 3).
PTDI Variables in the LV Posterior Wall The L-Sw1 and S-Sw2 were significantly lower at all AT-II doses in the HCM group, whereas the L-Sw2 and S-Sw1 decreased significantly at an AT-II dose of 0.010 µg/kg per minute in the HCM group (Figure 4). In the N group, L-Sw1, S-Sw1 and S-Sw2 were significantly lower at an AT-II dose of 0.015 µg/kg per minute, whereas L-Sw2 did not change significantly during AT-II administration. PTDI Variables in the Ventricular Septum The L-Sw1 was significantly lower in the HCM group than in the N group for all doses of AT-II, and significantly decreased at an AT-II dose of 0.015 µg/kg per minute in the HCM group (Figure 5). However, the LSw2, S-Sw1 and S-Sw2 did not change significantly during AT-II administration in either group.
DISCUSSION There is controversy concerning whether contractility in the nonhypertrophied region of the LV wall is
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Figure 3 M-mode, 2-dimensional, and pulsed Doppler echocardiography variables. LAD, Maximum left atrial dimension; LVEF, left ventricular ejection fraction; WS, end-systolic circumferential left ventricular wall stress; TVI, time-velocity integral of left ventricular outflow velocity; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); *P < .05 versus baseline, **P < .01 versus baseline, ***P < .001 versus baseline, ****P < .0001 versus baseline, #P < .05 versus N group, ##P < .01 versus N group, ###P < .001 versus N group, ####P < .0001 versus N group.
impaired or normal in patients with HCM. Global LV systolic function decreases with increases in afterload in this disease. Therefore we attempted to detect abnormalities in regional LV contractility along the long and short axes in patients with HCM with the use of AT-II stress PTDI. In general,systolic LV wall stress is lower in patients with HCM than in healthy persons because of the marked hypertrophy of the LV wall compared with the normal systolic LV pressure.1,13,14 Hirota et al13 reported that a normal LVEF in the setting of HCM is due to decreased afterload because the Frank-Starling relation is shifted downward.Moreover,Pouleur et al14 demonstrated that several parameters reflecting LV contractility decreased easily with an increase in afterload in patients with HCM because of decreased contractility. Therefore, to assess global LV systolic function in patients with HCM, it is important to evaluate regional LV contractility during increases in afterload. Color-coded tissue Doppler imaging15-18 and PTDI19-22 have been applied clinically to evaluate LV function in the setting of various heart diseases.
Pulsed tissue Doppler imaging offers the advantages of providing an easy and noninvasive examination and assessing regional LV myocardial function along the long and short axes.12,27 In the present study, we used low-dose AT-II, which causes an increase in peripheral vascular resistance—and therefore afterload—without affecting heart rate, to evaluate regional LV contractility along the long and short axes in patients with HCM during an increase in afterload. The changes in systolic blood pressure, LV enddiastolic dimension, and LVEF after AT-II administration in our study were similar to those previously reported,23 confirming the increase in afterload mediated by AT-II. However, these systolic parameters did not decrease significantly at doses of 0.005 and 0.010 µg/kg per minute in the N group, despite significant decreases at the same doses in the HCM group. These results suggest that global LV systolic function decreases easily with only a slight increase in afterload in patients with HCM. It is usually difficult to evaluate LV systolic function in detail in patients with HCM because of the
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Figure 4 Systolic pulsed tissue Doppler imaging variables at the left ventricular posterior wall. L-Sw1 and S-Sw1, Peak first systolic wall motion velocities along the long and short axes, respectively; L-Sw2 and S-Sw2 , peak second systolic wall motion velocities along the long and short axes, respectively; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); *P < .05 versus baseline, **P < .01 versus baseline, ***P < .001 versus baseline, ****P < .0001 versus baseline, #P < .05 versus N group, ##P < .01 versus N group, ###P < .001 versus N group, ####P < .0001 versus N group.
changes in LV morphology. Previous reports have shown decreased LV contractility in the hypertrophied region with use of magnetic resonance imaging.24,25 Hattori et al26 have reported that LV contractility along the long axis decreases more than that along the short axis in patients with HCM on the basis of M-mode echocardiography measurements of midwall fractional shortening. It has been reported that the systolic wave of the LV wall motion velocity recorded by PTDI exhibits 2 peaks (Sw1 and Sw2), and Sw1 along the long axis and Sw2 along the short axis reflect LV myocardial contractility during the isovolumic systole and ejection phase, respectively, in healthy subjects.12 In the present study, no significant baseline differences were found in the systolic PTDI variables along the short axis in the posterior wall or the ventricular septum between the two groups. In contrast, the variables measured along the long axis were significantly lower in the HCM group than in the N group.These results demonstrate that LV contractility along the long axis is impaired compared with the contractility along the short axis in
patients with HCM. Specifically, Sw1 along the long axis is a useful parameter for detecting the impaired LV systolic performance in the setting of HCM.27-29 All systolic PTDI variables, particularly Sw1 along the long axis and Sw2 along the short axis, in the nonhypertrophied posterior wall decreased significantly during AT-II administration. In addition, the LVEF and TVI of LV outflow velocity decreased with AT-II administration in patients with HCM. However, aside from Sw1 along the long axis, no significant changes were found in systolic PTDI variables in the hypertrophied ventricular septum during AT-II administration. Oki et al28 have reported that systolic PTDI variables decrease even in healthy subjects during increases in afterload caused by comparatively high doses (0.050 µg/kg per minute) of AT-II. Because we used low-dose ATII (0.005 to 0.015 µg/kg per minute) in the present study, the increase in blood pressure mediated by an increase in afterload was less than that reported in their study. Furthermore, the systolic PTDI variables in the N group did not change significantly at
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Figure 5 Systolic pulsed tissue Doppler imaging variables at the ventricular septum. L-Sw1 and S-Sw1, Peak first systolic wall motion velocities along the long and short axes, respectively; L-Sw2 and S-Sw2 , peak second systolic wall motion velocities along the long and short axes, respectively; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); **P < .01 versus baseline, #P < .05 versus N group, ##P < .01 versus N group.
doses of 0.005 and 0.010 µg/kg per minute. In contrast, the systolic PTDI variables in the HCM group were significantly lower along both the long and short axes, even at low doses (0.005 and 0.010 µg/kg per minute) of AT-II. These results suggest that LV pump function is preserved because of a decrease in afterload in patients with HCM. However, systolic LV function is easily impaired by slight increases in afterload as a result of dysfunction of the nonhypertrophied posterior wall. It has been shown that LV contractility in the setting of HCM decreases along both the long and short axes.24-26 However, in the ventricular septum, systolic PTDI variables along the short axis did not change after AT-II administration. This result can be explained by the following factor: systolic velocities along the short axis in the ventricular septum measured by PTDI are lower than those in the posterior wall because of whole heart motion and right ventricular hemodynamics.22 As an additional possibility, it is considered that the hypertrophied ventricu-
lar septum may not be affected by increases in systolic wall stress compared with the nonhypertrophied posterior wall. In summary, the above findings lend support to our hypothesis that both the abnormal function and the increased sensitivity to afterload in the nonhypertrophied posterior wall could contribute to the LV dysfunction and to a natural history of declining global LV function in patients with HCM. Low-dose AT-II stress PTDI is a safe and easy method to assess wall motion velocities because low-dose AT-II administration does not cause adverse effects. In the future, this method may be useful for evaluating both the regional LV contractility along the long and short axes and the effect of increased afterload in patients with other heart diseases. Study Limitations First, this study was performed with a very select group of patients with HCM to exclude the effect of medication or LV outflow obstruction from our
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results. Therefore further investigation is needed to apply this result to all patients with HCM. Second, we evaluated these wall motion velocities only at the middle portion of the ventricular septum and posterior wall along both the short and long axes.Therefore assessment of global LV wall motion may not be accurately reflected by data obtained from this wall alone, and wall motion velocity patterns of the ventricular septum, particularly along the short axis, may be influenced by motion of the entire heart during the cardiac cycle or the right heart hemodynamics.17,18 In our study, wall motion velocities decreased significantly—not only along the short axis but also along the long axis, which is rarely influenced by whole heart motion. Moreover, the systolic LV wall motion velocities changed almost in parallel with the parameters reflecting global LV systolic function, including the LVEF and TVI of the LV outflow velocity.Therefore, the use of PTDI in this study had no clinical impact. With respect to the pharmacologic effects of AT-II on myocardial cells,positive inotropic effects,30,31 negative inotropic effects,32,33 and biphasic effects34,35 have been reported previously. However, no reports have described direct negative inotropic effects of ATII on myocardial cells in patients with HCM.This pharmacologic effect of AT-II cannot be excluded entirely.
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Conclusions Contractility along the long and short axes of the nonhypertrophied LV wall is easily impaired during slight increases in afterload in patients with HCM, resulting in a decrease in global LV systolic function. Furthermore, AT-II stress PTDI is a safe and useful technique for evaluating regional LV systolic function in the setting of HCM.
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There is controversy concerning whether contractility in the nonhypertrophied region of the left ventricular (LV) wall is impaired or normal in patients with hypertrophic cardiomyopathy (HCM). Global LV systolic function decreases with increases in afterload in this disease. This study was performed to identify abnormalities in regional LV contractility along the long and short axes in the setting of HCM with the use of angiotensin II (AT-II) stress pulsed tissue Doppler imaging (PTDI). Angiotensin II was administered intravenously to patients with asymmetric septal hypertrophy (HCM group, n = 21) and age-matched normal volunteers (N group, n = 12). We then measured the percent LV fractional shortening (%FS) and end-systolic circumferential LV wall stress by M-mode echocardiography, LV ejection fraction (LVEF) by 2dimensional echocardiography, and time-velocity integral (TVI) of LV outflow velocity by pulsed Doppler echocardiography. The peak first and second systolic LV wall motion velocities along the long (L-Sw1 and L-Sw2) and short (S-Sw1 and S-Sw2) axes were measured in the LV posterior wall and
Hypertrophic cardiomyopathy (HCM) is characterized by impaired left ventricular (LV) diastolic function caused by nonuniform LV hypertrophy.1,2 However, LV pump function is usually normal in patients with asymmetric septal hypertrophy because the nonhypertrophied posterior wall increases motion to compensate for the decrease in wall motion of the hypertrophied ventricular sepFrom The Second Department of Internal Medicine, School of Medicine, The University of Tokushima. Reprint requests: Takashi Oki, MD, The Second Department of Internal Medicine, School of Medicine, The University of Tokushima, 2-50 Kuramoto-cho, Tokushima 770-8503, Japan. Copyright © 2000 by the American Society of Echocardiography. 0894-7317/2000/$12.00 + 0 27/1/111010 doi:10.1067/mje.2000.111010
ventricular septum with the use of PTDI. The endsystolic circumferential LV wall stress at baseline was significantly lower in the HCM group. The L-Sw1 and L-Sw2 for the posterior wall were significantly lower in the HCM group, but the S-Sw1 and S-Sw2 for the posterior wall and ventricular septum were similar in the two groups. The %FS, LVEF, TVI, and systolic PTDI variables along both axes for the posterior wall decreased significantly, and endsystolic circumferential LV wall stress increased significantly at AT-II doses of 0.005 or 0.010 µg/kg per minute in the HCM group. No significant changes were found in either group in the systolic PTDI variables (except for L-Sw1) for the ventricular septum with AT-II infusion. Contractility along the long and short axes of the nonhypertrophied LV wall is easily impaired with increases in afterload in patients with HCM, resulting in a decrease in global LV systolic function. We found AT-II stress PTDI to be a safe and useful technique for evaluating the regional LV systolic function in this disease. (J Am Soc Echocardiogr 2000;13:1065-73.)
tum.3,4 Furthermore, although it has been thought that in the setting of this disease systolic LV performance is preserved for a long period of time, a dilated cardiomyopathy has been found to develop in some patients who exhibit a dilated phase of HCM.5,6 Consequently, there is controversy concerning whether contractility in the nonhypertrophied region is impaired because some studies3,4 have reported that contractility is normal, and other studies7,8 have reported decreased contractility. We hypothesized that myocardial contractility in patients with asymmetric septal hypertrophy is impaired even in the nonhypertrophied regions, and its abnormality can be detected by an increase in afterload.Angiotensin II (AT-II) causes contraction of the vascular smooth muscles, resulting in an increase 1065
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Figure 1 Sample recordings of the circumferentially and longitudinally directed left ventricular wall motion velocity patterns in the parasternal (left) and apical (center) long-axis views of the left ventricle (LV), respectively, by pulsed tissue Doppler imaging, and measurement of variables obtained from the longitudinally directed left ventricular posterior wall motion velocity pattern in the apical long-axis view (right). T, Transducer; RV, right ventricle; LA, left atrium; Ao, ascending aorta; Sw1, peak first systolic wall motion velocity; Sw2, peak second systolic wall motion velocity; Ew, peak early diastolic wall motion velocity; Aw, peak atrial systolic wall motion velocity; ECG, electrocardiogram; PCG, phonocardiogram; I, first heart sound; II, second heart sound.
in peripheral vascular resistance or afterload. The goal of our study was to identify abnormalities in regional LV contractility along the long and short axes in patients with HCM by using AT-II stress pulsed tissue Doppler imaging (PTDI).
METHODS
Angiotensin II Administration Angiotensin II was administered intravenously to all subjects (0.005, 0.010, 0.015 µg/kg of Delivert per minute over 10-minute intervals). Heart rate, blood pressure, echocardiographic, and PTDI variables were measured at each dose of AT-II. The end point of the study was the completion of the infusion of the dose of 0.015 µg/kg per minute of AT-II or a 30% increase in mean arterial blood pressure.
Patient Population
M-Mode Echocardiography
The study included 21 untreated patients with asymmetric septal hypertrophy (HCM group, mean age 62 ± 15 years) in whom the end-diastolic ventricular septal thickness and the posterior wall thicknesses were ≥15 mm and ≤11 mm, respectively, and in whom the ratio of the two wall thicknesses was ≥1.3 by M-mode echocardiography.All the patients were in sinus rhythm without bundle branch blocks. Patients had to meet the following inclusion criteria: (1) no symptoms and no radiographic findings of pulmonary congestion, (2) no evidence of moderate to severe valvular heart disease based on color Doppler echocardiography, (3) LV outflow obstruction <20 mm Hg determined by continuous wave Doppler echocardiography, and (4) blood pressure <140/90 mm Hg. The control group consisted of 12 age-matched healthy volunteers (N group; mean age: 59 ± 14 years). The purpose of this study was fully explained, and informed consent was obtained from all persons. The protocol was approved by the hospital human investigations committee.
Transthoracic echocardiography was performed with a Toshiba SSH-380A (Tokyo, Japan) ultrasound diagnostic system equipped with a 2.5-MHz probe.Left ventricular end-diastolic dimension (LVDd), LV end-systolic dimension (LVDs), maximum left atrial dimension (LAD), end-diastolic ventricular septal thickness (VSth), and end-diastolic LV posterior wall thickness (PWth) were measured by M-mode echocardiography. The percent fractional shortening of the left ventricle (%FS) and the end-systolic circumferential LV wall stress (WS) were calculated with the following equations:9 %FS = [(LVDd – LVDs) / LVDd] × 100 WS (g/cm2) = 0.59 × SBP × LVDs / Ths, where Ths = (VSth + PWth)/2 and SBP = systolic blood pressure. Two-Dimensional and Pulsed Doppler Echocardiography The LV ejection fraction (LVEF) was calculated with use of the modified Simpson’s method10 on the basis of measurements obtained by 2-dimensional echocardiography. Left
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ventricular outflow tract diameter (LVOT-d) was measured from the parasternal LV long-axis view, and its area (LVOTa) was calculated by using the following equation: LVOT-a = 3.14 × (LVOT-d / 2)2 The sample volume was placed in the LV outflow tract on the apical LV long-axis view, and the LV outflow velocity pattern and its time-velocity integral (TVI) were obtained by pulsed Doppler echocardiography.11 Pulsed Tissue Doppler Imaging Parasternal and apical long-axis LV echocardiograms were recorded with the use of transthoracic echocardiography. The sample volumes were placed in the midwall portions in the middle of the ventricular septum and the LV posterior wall in the parasternal long-axis view (Figure 1, left). Sample volumes then were placed in the subendocardial portions in the middle of the ventricular septum and the LV posterior wall in the apical long-axis view (Figure 1, center).The acoustic power and filter frequencies were set to the lowest possible values, and sample volumes (approximately 8 mm wide) were set in the target walls. The wall motion velocity pattern at each site was recorded by the pulsed Doppler method with a commercially available ultrasound diagnostic system with a 3.75-MHz probe (Toshiba SSA-380A). On the basis of the wall motion velocity patterns, we determined the peak first (Sw1) and second (Sw2) systolic wall motion velocities12 (Figure 1, right). This study was performed and reviewed by the different investigators, and they all knew and understood the study protocol. Interobserver variability of the tissue Doppler measurements (3% to 8%) was calculated as the difference in 2 measurements in the same patient by 2 different observers divided by the mean value. Intraobserver variability (2% to 7%) was calculated as the difference between 2 measurements in the same patient by 1 observer divided by the mean value. Statistical Analysis Values are expressed as the mean ± SD.Values between the HCM and N groups were compared by using the unpaired Student t test. Values before and after AT-II administration were compared with a 2-factor analysis of variance for repeated measurements. A P value < .05 was considered statistically significant.
RESULTS Baseline The maximum left atrial dimension and end-diastolic ventricular septal thickness were significantly greater
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Table 1 Clinical, M-mode, and 2-dimensional echocardiography and pulsed tissue Doppler data at baseline N (n = 12)
Age (y) Heart rate (bpm) LVDd (cm) LVDs (cm) %FS (%) VSth (cm) PWth (cm) WS (g/cm2) LAD (cm) LVEF (%) TVI (m) LVOT-a (cm2) PW S-Sw1 (cm/s) S-Sw2 (cm/s) L-Sw1 (cm/s) L-Sw2 (cm/s) VS S-Sw1 (cm/s) S-Sw2 (cm/s) L-Sw1 (cm/s) L-Sw2 (cm/s)
HCM (n = 21)
P value
59 69 4.3 2.5 41 0.8 0.9 8.5 3.3 64 0.20 3.3
± ± ± ± ± ± ± ± ± ± ± ±
14 10 0.6 0.4 9 0.2 0.2 1.9 0.6 4 0.03 0.6
62 66 4.2 2.5 41 2.2 1.1 5.1 4.0 69 0.21 3.0
± ± ± ± ± ± ± ± ± ± ± ±
15 8 0.5 0.4 4 0.7 0.3 1.8 0.8 6 0.04 0.7
NS NS NS NS NS <.001 NS <.001 <.01 NS NS NS
6.7 7.3 9.8 6.9
± ± ± ±
1.4 1.3 2.5 1.2
5.9 7.5 7.0 4.6
± ± ± ±
1.1 1.5 1.4 0.6
NS NS <.01 <.01
6.0 5.6 6.7 5.5
± ± ± ±
1.5 1.3 1.6 2.0
5.3 5.5 5.5 4.6
± ± ± ±
2.0 1.5 1.5 1.6
NS NS <.05 NS
N, Normal control; HCM, patients with hypertrophic cardiomyopathy; NS, not significant; LVDd and LVDs, end-diastolic and end-systolic left ventricular dimension, respectively; %FS, percent fractional shortening of left ventricle; VSth, end-diastolic ventricular septal thickness; PWth, end-diastolic left ventricular posterior wall thickness; WS, end-systolic circumferential left ventricular wall stress; LAD, maximum left atrial dimension; LVEF, left ventricular ejection fraction; TVI, time-velocity integral of left ventricular outflow velocity; LVOT-a, left ventricular outflow tract area; PW, left ventricular posterior wall; VS, ventricular septum; L-Sw1 and S-Sw1, peak first systolic wall motion velocities along the long and short axes, respectively; LSw2 and S-Sw2, peak second systolic wall motion velocities along the long and short axes, respectively.
in the HCM group than in the N group (Table 1).The end-systolic circumferential LV wall stress was significantly lower in the HCM group than in the N group. There were no significant differences in heart rate and other M-mode, 2-dimensional, and pulsed Doppler echocardiography variables between the 2 groups. There were no significant differences in either S-Sw1 or S-Sw2 in the LV posterior wall between the 2 groups. In contrast, L-Sw1 and L-Sw2 were significantly lower in the HCM group than in the N group. L-Sw1 in the ventricular septum was significantly lower in the HCM group than in the N group,though there were no significant differences in the other systolic PTDI variables between the 2 groups. Clinical and M-Mode Echocardiography Variables No significant differences were found in the heart rate before or after AT-II administration between the HCM and N groups (Figure 2). The systolic blood pressure was significantly higher during AT-II admin-
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Figure 2 Clinical and M-mode echocardiography variables. HR, Heart rate; SBP, systolic blood pressure; LVD, left ventricular dimension; %FS, percent fractional shortening of left ventricle; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); *P < .05 versus baseline, **P < .01 versus baseline, ***P < .001 versus baseline, ****P < .0001 versus baseline, #P < .05 versus N group, ##P < .01 versus N group, ###P < .001 versus N group, ####P < .0001 versus N group.
istration in both groups, though there was no significant dose-dependent effect of AT-II on blood pressure between the 2 groups. No significant difference was found in LV end-diastolic dimension during AT-II administration between the 2 groups. In contrast, the LV end-systolic dimension was significantly greater during AT-II administration in both groups, particularly in the HCM group.The percent LV fractional shortening decreased significantly at all doses of AT-II in the HCM group, but decreased only at an AT-II dose of 0.015 µg/kg per minute in the N group.The maximal left atrial dimension did not change during AT-II administration in either group (Figure 3).The end-systolic circumferential LV wall stress was significantly greater for all doses of AT-II in the HCM group, and at AT-II doses of 0.010 and 0.015 µg/kg per minute in the N group. Two-Dimensional and Pulsed Doppler Echocardiography Variables The LVEF and TVI of the LV outflow velocity decreased significantly at all AT-II doses in the HCM group, and decreased significantly at an AT-II dose of 0.015 µg/kg per minute in the N group (Figure 3).
PTDI Variables in the LV Posterior Wall The L-Sw1 and S-Sw2 were significantly lower at all AT-II doses in the HCM group, whereas the L-Sw2 and S-Sw1 decreased significantly at an AT-II dose of 0.010 µg/kg per minute in the HCM group (Figure 4). In the N group, L-Sw1, S-Sw1 and S-Sw2 were significantly lower at an AT-II dose of 0.015 µg/kg per minute, whereas L-Sw2 did not change significantly during AT-II administration. PTDI Variables in the Ventricular Septum The L-Sw1 was significantly lower in the HCM group than in the N group for all doses of AT-II, and significantly decreased at an AT-II dose of 0.015 µg/kg per minute in the HCM group (Figure 5). However, the LSw2, S-Sw1 and S-Sw2 did not change significantly during AT-II administration in either group.
DISCUSSION There is controversy concerning whether contractility in the nonhypertrophied region of the LV wall is
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Figure 3 M-mode, 2-dimensional, and pulsed Doppler echocardiography variables. LAD, Maximum left atrial dimension; LVEF, left ventricular ejection fraction; WS, end-systolic circumferential left ventricular wall stress; TVI, time-velocity integral of left ventricular outflow velocity; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); *P < .05 versus baseline, **P < .01 versus baseline, ***P < .001 versus baseline, ****P < .0001 versus baseline, #P < .05 versus N group, ##P < .01 versus N group, ###P < .001 versus N group, ####P < .0001 versus N group.
impaired or normal in patients with HCM. Global LV systolic function decreases with increases in afterload in this disease. Therefore we attempted to detect abnormalities in regional LV contractility along the long and short axes in patients with HCM with the use of AT-II stress PTDI. In general,systolic LV wall stress is lower in patients with HCM than in healthy persons because of the marked hypertrophy of the LV wall compared with the normal systolic LV pressure.1,13,14 Hirota et al13 reported that a normal LVEF in the setting of HCM is due to decreased afterload because the Frank-Starling relation is shifted downward.Moreover,Pouleur et al14 demonstrated that several parameters reflecting LV contractility decreased easily with an increase in afterload in patients with HCM because of decreased contractility. Therefore, to assess global LV systolic function in patients with HCM, it is important to evaluate regional LV contractility during increases in afterload. Color-coded tissue Doppler imaging15-18 and PTDI19-22 have been applied clinically to evaluate LV function in the setting of various heart diseases.
Pulsed tissue Doppler imaging offers the advantages of providing an easy and noninvasive examination and assessing regional LV myocardial function along the long and short axes.12,27 In the present study, we used low-dose AT-II, which causes an increase in peripheral vascular resistance—and therefore afterload—without affecting heart rate, to evaluate regional LV contractility along the long and short axes in patients with HCM during an increase in afterload. The changes in systolic blood pressure, LV enddiastolic dimension, and LVEF after AT-II administration in our study were similar to those previously reported,23 confirming the increase in afterload mediated by AT-II. However, these systolic parameters did not decrease significantly at doses of 0.005 and 0.010 µg/kg per minute in the N group, despite significant decreases at the same doses in the HCM group. These results suggest that global LV systolic function decreases easily with only a slight increase in afterload in patients with HCM. It is usually difficult to evaluate LV systolic function in detail in patients with HCM because of the
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Figure 4 Systolic pulsed tissue Doppler imaging variables at the left ventricular posterior wall. L-Sw1 and S-Sw1, Peak first systolic wall motion velocities along the long and short axes, respectively; L-Sw2 and S-Sw2 , peak second systolic wall motion velocities along the long and short axes, respectively; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); *P < .05 versus baseline, **P < .01 versus baseline, ***P < .001 versus baseline, ****P < .0001 versus baseline, #P < .05 versus N group, ##P < .01 versus N group, ###P < .001 versus N group, ####P < .0001 versus N group.
changes in LV morphology. Previous reports have shown decreased LV contractility in the hypertrophied region with use of magnetic resonance imaging.24,25 Hattori et al26 have reported that LV contractility along the long axis decreases more than that along the short axis in patients with HCM on the basis of M-mode echocardiography measurements of midwall fractional shortening. It has been reported that the systolic wave of the LV wall motion velocity recorded by PTDI exhibits 2 peaks (Sw1 and Sw2), and Sw1 along the long axis and Sw2 along the short axis reflect LV myocardial contractility during the isovolumic systole and ejection phase, respectively, in healthy subjects.12 In the present study, no significant baseline differences were found in the systolic PTDI variables along the short axis in the posterior wall or the ventricular septum between the two groups. In contrast, the variables measured along the long axis were significantly lower in the HCM group than in the N group.These results demonstrate that LV contractility along the long axis is impaired compared with the contractility along the short axis in
patients with HCM. Specifically, Sw1 along the long axis is a useful parameter for detecting the impaired LV systolic performance in the setting of HCM.27-29 All systolic PTDI variables, particularly Sw1 along the long axis and Sw2 along the short axis, in the nonhypertrophied posterior wall decreased significantly during AT-II administration. In addition, the LVEF and TVI of LV outflow velocity decreased with AT-II administration in patients with HCM. However, aside from Sw1 along the long axis, no significant changes were found in systolic PTDI variables in the hypertrophied ventricular septum during AT-II administration. Oki et al28 have reported that systolic PTDI variables decrease even in healthy subjects during increases in afterload caused by comparatively high doses (0.050 µg/kg per minute) of AT-II. Because we used low-dose ATII (0.005 to 0.015 µg/kg per minute) in the present study, the increase in blood pressure mediated by an increase in afterload was less than that reported in their study. Furthermore, the systolic PTDI variables in the N group did not change significantly at
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Figure 5 Systolic pulsed tissue Doppler imaging variables at the ventricular septum. L-Sw1 and S-Sw1, Peak first systolic wall motion velocities along the long and short axes, respectively; L-Sw2 and S-Sw2 , peak second systolic wall motion velocities along the long and short axes, respectively; N, normal control; HCM, hypertrophic cardiomyopathy (mean ± SD); **P < .01 versus baseline, #P < .05 versus N group, ##P < .01 versus N group.
doses of 0.005 and 0.010 µg/kg per minute. In contrast, the systolic PTDI variables in the HCM group were significantly lower along both the long and short axes, even at low doses (0.005 and 0.010 µg/kg per minute) of AT-II. These results suggest that LV pump function is preserved because of a decrease in afterload in patients with HCM. However, systolic LV function is easily impaired by slight increases in afterload as a result of dysfunction of the nonhypertrophied posterior wall. It has been shown that LV contractility in the setting of HCM decreases along both the long and short axes.24-26 However, in the ventricular septum, systolic PTDI variables along the short axis did not change after AT-II administration. This result can be explained by the following factor: systolic velocities along the short axis in the ventricular septum measured by PTDI are lower than those in the posterior wall because of whole heart motion and right ventricular hemodynamics.22 As an additional possibility, it is considered that the hypertrophied ventricu-
lar septum may not be affected by increases in systolic wall stress compared with the nonhypertrophied posterior wall. In summary, the above findings lend support to our hypothesis that both the abnormal function and the increased sensitivity to afterload in the nonhypertrophied posterior wall could contribute to the LV dysfunction and to a natural history of declining global LV function in patients with HCM. Low-dose AT-II stress PTDI is a safe and easy method to assess wall motion velocities because low-dose AT-II administration does not cause adverse effects. In the future, this method may be useful for evaluating both the regional LV contractility along the long and short axes and the effect of increased afterload in patients with other heart diseases. Study Limitations First, this study was performed with a very select group of patients with HCM to exclude the effect of medication or LV outflow obstruction from our
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results. Therefore further investigation is needed to apply this result to all patients with HCM. Second, we evaluated these wall motion velocities only at the middle portion of the ventricular septum and posterior wall along both the short and long axes.Therefore assessment of global LV wall motion may not be accurately reflected by data obtained from this wall alone, and wall motion velocity patterns of the ventricular septum, particularly along the short axis, may be influenced by motion of the entire heart during the cardiac cycle or the right heart hemodynamics.17,18 In our study, wall motion velocities decreased significantly—not only along the short axis but also along the long axis, which is rarely influenced by whole heart motion. Moreover, the systolic LV wall motion velocities changed almost in parallel with the parameters reflecting global LV systolic function, including the LVEF and TVI of the LV outflow velocity.Therefore, the use of PTDI in this study had no clinical impact. With respect to the pharmacologic effects of AT-II on myocardial cells,positive inotropic effects,30,31 negative inotropic effects,32,33 and biphasic effects34,35 have been reported previously. However, no reports have described direct negative inotropic effects of ATII on myocardial cells in patients with HCM.This pharmacologic effect of AT-II cannot be excluded entirely.
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Conclusions Contractility along the long and short axes of the nonhypertrophied LV wall is easily impaired during slight increases in afterload in patients with HCM, resulting in a decrease in global LV systolic function. Furthermore, AT-II stress PTDI is a safe and useful technique for evaluating regional LV systolic function in the setting of HCM.
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