- Email: [email protected]
Determinants of coronary flow abnormalities in obstructive type hypertrophic cardiomyopathy: noninvasive assessment by transthoracic Doppler echocardiography
Determinants Of Coronary Flow Abnormalities in Obstructive Type Hypertrophic Cardiomyopathy: Noninvasive Assessment by Transthoracic Doppler Echocardiography Seden Celik, MD, Bahadir Dagdeviren, MD, Aydin Yildirim, MD, Sevket Gorgulu, MD, Nevzat Uslu, MD, Mehmet Eren, MD, Tayfun Gurol, MD, Ersin Ozen, MD, and Tuna Tezel, MD, Istanbul, Turkey
We aimed to visualize the coronary flow velocities (CFV) of patients with hypertrophic obstructive cardiomyopathy by using transthoracic Doppler echocardiography, and to determine the relationship between abnormal CFV patterns and conventional echocardiography indices. Guided by 2-dimensional echocardiography and Doppler color flow mapping, CFV in the distal left anterior descending coronary artery were measured in 21 patients with hypertrophic obstructive cardiomyopathy using a 3.5-MHz transducer. The results were compared with those of 18 control subjects. Abnormal systolic flow patterns were observed in 15 (71%) patients (11 systolicreversal flow and 4 no systolic flow). For patients and control subjects, peak diastolic velocity and velocity-time integral obtained from distal left ante-
Hypertrophic cardiomyopathy (HCM) is a genetic
cardiac disease characterized by left ventricular (LV) hypertrophy in the absence of another cause of increased cardiac mass.1 Patients with HCM commonly have evidence of myocardial ischemia despite angiographically normal coronary arteries.2,3 The alterations of phasic coronary flow characteristics have been reported and proposed as a mechanism for the development of angina pectoris in these patients.4-6 Invasive or semi-invasive techniques assessing coronary flow such as Doppler flow wire and transesophageal echocardiography are not practical for daily use. Recent advancements of Doppler transthoracic echocardiography (TTE) provide noninvasive measurement of coronary flow velocities (CFV) in From the Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center. Reprint requests: Seden Celik, MD, Gardenya 4-1 Ka:2, D:9, Atasehir, Ku¨cu¨kbakkalko¨y, 81120 Istanbul, Turkey (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.03.028
744
rior descending coronary artery were higher (63 ⴞ 21 cm/s and 18.5 ⴞ 4 cm vs 41 ⴞ 11 cm/s and 14.2 ⴞ 5 cm, respectively; P < .01 for both) whereas peak systolic velocity and velocity-time integral were significantly lower (ⴚ17 ⴞ 10 cm/s and 4.5 ⴞ 6 cm vs 24 ⴞ 9 cm/s and 9.5 ⴞ 4 cm, respectively; P < .001 for both). Significant positive and negative correlations between diastolic CFV and septal thickness index (r ⴝ 0.79, P < .0001), and between systolic CFV and septal thickness index (r ⴝ ⴚ0.65, P < .005), have been observed. CFV abnormalities that could easily be recorded by a standard Doppler echocardiographic study seem to be related to septal thickness rather than the degree of obstruction in hypertrophic obstructive cardiomyopathy. (J Am Soc Echocardiogr 2004;17:744-9.)
the distal epicardial coronary arteries. However, studies evaluating coronary flow with a transthoracic approach have mostly been performed by using high-frequency transducers and conducted on limited numbers of patients.7,8 The purposes of this study were: (1) to evaluate the feasibility and accuracy of transthoracic coronary flow imaging by using an ultrasonic system equipped with a standard adult transducer in patients with obstructive HCM (HOCM); (2) to investigate the relationship between the severity of LV outflow tract obstruction and CFV; and (3) to assess whether a relationship exists between abnormal CFV pattern and other conventional echocardiography parameters.
METHODS Patients We studied 21 consecutive patients (mean age: 38 ⫾ 13 years; 8 women) with the clinical and echocardiographic diagnosis of HOCM on the basis of the demonstration of a hypertrophied and nondilated LV in the absence of a second-
Journal of the American Society of Echocardiography Volume 17 Number 7
Celik et al 745
ary cause of LV hypertrophy. Inclusion criteria were: (1) interventricular septum thickness ⬎ 15 mm and septum/ posterior wall ratio ⬎ 1.3; and (2) a basal systolic gradient ⬎ 30 mm Hg in the LV outflow tract. In all study patients, drug treatments were withheld 48 hours before the echocardiographic examination. A control group consisted of 18 healthy age- and sex-matched volunteers. All patients were informed about the investigative nature of the study, and the local ethical committee approved the study protocol. Echocardiographic Examination TTE recordings were obtained from parasternal, apical, and subcostal windows by using ultrasound systems (GEVingmed System V and Vivid 7, GE-Vingmed Ultrasound, Horten, Norway) equipped with 1.5- to 3.7-MHz broadband electronic transducers. Conventional M-mode, 2-dimensional, pulsed wave, and color Doppler images were acquired with simultaneous electrocardiographic tracings. LV systolic and diastolic dimensions, and wall thickness, were measured from the M-mode traces according to the recommendations of The American Society of Echocardiography.9 LV mass was calculated by the formula of Devereux and Reichek.10 LV ejection fraction was calculated with the Teichholz formula. Transmitral inflow velocities were recorded at the level of mitral leaflet tips. The early and late diastolic velocities, deceleration time of early diastolic velocities, and isovolumic relaxation time were also measured with previously described methods.11 Coronary Flow Imaging For the optimal coronary flow imaging, the system presets were adjusted as follows: Nyquist limit was 18 to 20 cm/s; color pulse frequency and pulse Doppler frequency were 3.5 MHz; lateral and radial averaging was lowest; color sample volume was minimum; and Doppler sample volume was 1 to 2 mm. The patients were examined in the left lateral position using a modified left parasternal window. The transducer position was around the left midclavicular line in the fourth and fifth intercostal spaces. After the anterior interventricular sulcus was imaged by angling the ultrasonic beam laterally and superiorly, coronary blood flow of distal left anterior descending coronary artery (LAD) was identified by Doppler color flow mapping. Doppler spectral trace was recorded with a sample volume positioned on the color signal within the artery. The long-axis sections were carefully adjusted to minimize the angle (which was kept ⬍20 degrees) between the Doppler beam and the long axis of the artery. Sample volume was located within the vessel lumen, and was kept there as long as possible during the cardiac cycle to acquire a typically diastolic predominant phasic CFV Doppler pattern (Figure 1). All echocardiographic images were stored in 5.5-in MO (magneto optic) disks, and measurements were made by using the internal analyzing software package of the system. By tracing the coronary blood flow Doppler spectrum, the peak systolic and diastolic velocities, and their velocity-time integrals, were measured. For each of those 4
Figure 1 Distal left anterior descending coronary artery Doppler spectra obtained by transthoracic echocardiography (A) and flow wire (B) methods demonstrate typical systolic reversal flow for patient with hypertrophic obstructive cardiomyopathy.
variables, the average value of the measurements from 3 to 5 cardiac cycles was used for statistical calculations. Doppler Flow Wire Study A total of 10 patients for whom a coronary angiography was planned by their physicians to role out the possibility of coronary artery disease underwent Doppler flow wire study after the procedure was completed. Informed consent was obtained from those patients. Coronary angiography revealed normal findings in all. After the completion of the angiographic study, a 0.014-inch Doppler flow wire (FloWire, Cardiometrics, Mountain View, Calif) was placed in the center of the vessel coaxial to the lumen in the distal portion of the LAD. A high quality of blood flow Doppler spectrum was attempted by carefully manipulating the flow wire (Figure 1). Particular attention was paid to Doppler wire position, located between the last diagonal branch and mustache of LAD, which was approximately the same location viewed by Doppler TTE. The peak values and the velocity-time integrals of systolic and diastolic CFV were measured in these 10 patients to compare corresponding values recorded by Doppler TTE. All studies were continuously recorded on super-VHS videotape.
Journal of the American Society of Echocardiography July 2004
746 Celik et al
Table. Demographic, hemodynamic, and echocardiographic data of patients with hypertrophic obstructive cardiomyopathy and control subjects. Variable
Patients
Age (y) Sex (F/M) BSA (m2) HR (bpm) BP-sys (mm Hg) BP-dias (mm Hg) LV mass index (g/m2) LVOT max-grd (mm Hg) EF (%) E vel (cm/s) A vel (cm/s) IVRT (msec)
38.7 ⫾ 13 8/13 1.78 ⫾ 0.26 72 ⫾ 8 121 ⫾ 29 70 ⫾ 11 257 ⫾ 35 60 ⫾ 33 76 ⫾ 11 87 ⫾ 32 66 ⫾ 20 90 ⫾ 17
Control subjects
P
35 ⫾ 11 7/11 1.80 ⫾ 0.30 68 ⫾ 10 115 ⫾ 25 65 ⫾ 10 112 ⫾ 15
NS NS NS NS NS NS 0.001
67 ⫾ 10 89 ⫾ 24 62 ⫾ 15 78 ⫾ 20
NS NS NS NS
A vel, Atrial filling velocity; BP-dias, diyastolic blood pressure; BP-sys, systolic blood pressure; BSA, body surface area; EF, ejection fraction; E vel, early filling velocity; F, female; HR, heart rate; IVR T, isovolumic relaxation time; LV, left ventricular; LVOT max-grad, LV outflow tract maximal gradient; M, male; NS, not significant.
Reproducibility and Agreement of CFV Measurements by Doppler TTE and Flow Wire To evaluate the effect of interobserver variability on CFV measurements by Doppler TTE, two independent, blinded observers (A. Y. and N. U.) analyzed 21 randomly selected Doppler velocity recordings. To evaluate intraobserver variability, 21 randomly selected Doppler velocities were remeasured by the same operator (S. C.) 1 week apart. To evaluate the agreement of CFV measurements obtained by Doppler TTE and Doppler flow wire methods, 10 patients were analyzed. Interobserver and intraobserver variabilities, and the agreement of coronary flow measurements by two methods, were calculated as the SD of the differences between the two measurements or assessments, expressed as a percentage of the average value.
Figure 2 Mean values of peak diastolic and systolic left anterior descending coronary artery (LAD) velocities for patients with hypertrophic obstructive cardiomyopathy (HOCM) and control subjects.
Statistical Analysis Continuous variables were expressed as mean ⫾ 1 SD. An unpaired 2-tailed t test was used for comparing values between groups. Linear regression analysis was used for the correlations between CFV measurements and the other echocardiographic variables. Significance was set at a P value ⬍ .05. Software (SPSS, Version 10.0, Chicago, Ill) was used for computations.
RESULTS Clinical, hemodynamic, and echocardiographic data of the patients with HOCM and control subjects are given in Table. The groups were comparable in terms of age, sex, body surface area, blood pressure, and heart rate. Patients with HOCM had a significantly thickened interventricular septum and, consequently, a higher LV mass index and ventricular septum/posterior wall ratio than control subjects.
The average level of intraventricular pressure gradient was 60 ⫾ 33 mm Hg in study patients. CFV Analysis Technically adequate Doppler flow velocity tracings of the distal LAD could be obtained from all 21 consecutive study patients, but only from 18 of 24 control subjects (75%). The mean diastolic and systolic CFV of patients with HOCM and control subjects are displayed in Figure 2. The peak diastolic velocity and velocitytime integral were significantly higher in patients with HOCM than in control subjects (63 ⫾ 21 cm/s and 18.5 ⫾ 4 cm vs 41 ⫾ 11 cm/s and 14.2 ⫾ 5, respectively; P ⬍ .01 for both). Because CFV were in normal antegrade form in all control subjects but there was a reversal flow in 11 and no systolic flow in 4 patients with HOCM (P ⬍ .0001), the peak systolic velocity and velocity-time
Journal of the American Society of Echocardiography Volume 17 Number 7
Celik et al 747
Figure 3 Correlation between peak diastolic left anterior descending coronary artery (LAD) velocities and interventricular septum thickness index for patients with hypertrophic obstructive cardiomyopathy (HOCM) (A). Relation between peak systolic LAD velocities with interventricular septum thickness index (B), mitral early filling (E) velocities (C), and isovolumic relaxation time (IVRT) (D) for patients with HOCM.
integral were significantly lower in HOCM group (24 ⫾ 9 cm/s and 9.5 ⫾ 4 cm vs ⫺17 ⫾ 10 cm/s and 4.5 ⫾ 6 cm, respectively; P ⬍ .001 for both). Linear regression revealed that for patients with HOCM, no correlation existed between intraventricular pressure gradient and either systolic or diastolic LAD flow velocities. On the other hand, a significant negative correlation was observed between interventricular septum thickness index (interventricular septum thickness/body surface area) and LAD peak systolic velocity (r ⫽ ⫺0.65; P ⬍ .005) (Figure 2). In the analysis of diastolic CFV, significant positive correlations were observed between peak diastolic LAD velocities and both interventricular septum thickness and its indices (r ⫽ 0.79; P ⬍ .0001). Among the conventional diastolic Doppler parameters, the peak early inflow velocities showed a good negative correlation (r ⫽ ⫺0.79; P ⬍ .005), whereas isovolumic relaxation time showed moderately positive correlation with peak systolic CFV (r ⫽ 0.60; P ⬍ .05) (Figure 3).
Reproducibility Interobserver variability of Doppler velocity measurements was 7.2% for systolic and 4.4% for diastolic velocities. Intraindividual variability was excellent and never exceeded 2 cm/s for both diastolic and systolic peak velocity, which provided a maximal ⫾5.6% difference in relative terms. The agreement of CFV measurements obtained by Doppler TTE and flow wire methods was also in acceptable limits. The mean variability of CFV measurements by two methods was 4.2% and 6.1% for diastolic and systolic velocities, respectively.
DISCUSSION In patients with HOCM, the noninvasive Doppler TTE technique allows acquisition of the flow patterns of distal LAD, measuring the peak velocity and velocity-time integrals, and demonstrating the flow
748 Celik et al
pattern abnormalities involving the systolic phase such as its absence and paradoxical reversal. Furthermore, patients with HOCM showed significantly increased diastolic CFV in distal LAD when compared with control subjects. Both systolic and diastolic CFV were observed to significantly correlate with septal thickness and diastolic function parameters, but not with intraventricular pressure gradient. Coronary Flow Abnormalities in HOCM Some previous studies using invasive and noninvasive methods demonstrated decreased or reversed systolic and augmented diastolic coronary flow in patients with HOCM.5-7,12 Possible mechanisms that have been proposed to explain these alterations are the abnormally increased coronary vascular resistance as a result of systolic compression of large intramural arteries, throttling effect of small intramural coronary arteries, and reduced compliance of epicardial coronary arteries because of maximal vasodilatator state even in resting condition. Consistent with those mechanisms, CFV alterations seem to have a close relationship with the degree of septal thickening, as our study demonstrated. This scenario emphasizes that as the myocardial wall thickens, intramural compression on the coronary artery increases, and both the throttling effect and the reduced compliance because of maximal-basal vasodilatation of LAD become more prominent. In the literature, there are some observations supporting our findings. Tomochika et al5 measured CFV in the proximal LAD of 7 patients with nonobstructive HCM by TEE; systolic flow was reduced and reversal flow occurred in two patients with ventricular septal thickness ⬎ 2 cm, and a significant correlation was found between septum thickness and peak systolic velocities. Memmola et al13 also reported a significantly greater diastolic and lower systolic component of CFV in the proximal LAD of 10 patients with HOCM by TEE. In our study, an entirely noninvasive approach performed to a larger patient group with HOCM demonstrated consistent findings with those observations. In addition, it is interesting that the CFV variables were not related to the degree of obstruction severity in our study patients. Altered coronary flow characteristics—regardless of the severity of systolic pressure increase in LV—in relation with the degree of thickening of surrounding myocardium, could suggest the mechanisms involving the local functional and structural changes regulating coronary flow that might probably contribute to the generation of abnormal CFV patterns in patients with HOCM. The findings of a previous study by Kyriakidis et al6 suggested regional difference of coronary flow between the coronary arteries responsible
Journal of the American Society of Echocardiography July 2004
from the perfusion of hypertrophic and normal LV segments; they reported an increased coronary flow in LAD compared with left circumflex coronary artery by using flow wire method in 18 patients with HOCM. Thus, one might argue that the regional distribution of hypertrophy closely relates with the regional impairment of coronary flow, and the local regulatory mechanisms largely influence the coronary flow dynamics rather than increased intraventricular pressure. Furthermore, previous observations, which reported similar CFV abnormalities, also for patients with nonobstructive HCM,5,14 may let us think that the intraventricular pressure gradient is not the predominant factor responsible from the CFV alterations for patients with HOCM. In contrast to our findings, transvalvular pressure gradient has been shown to correlate with the degree of systolic reversal coronary flow in patients with valvular aortic stenosis, which may be considered as another form of LV outflow tract obstruction.15,16 In our opinion, these controversial results might be related to the difference between hemodynamic effects of fix-valvular stenosis in which peak gradient was measured at midsystole and dynamic obstruction of HCM, which has a less effective gradient at end-systole. This study also demonstrates that the alterations in CFV significantly relate to the degree of LV diastolic functional impairment. The correlation of abnormally decreased systolic coronary flows with higher early diastolic velocities and shorter isovolumic relaxation time may be caused by an interaction between more advanced form of diastolic dysfunction or high LV filling pressures with coronary flow dynamics. Clinical Implications Noninvasive imaging of distal LAD flow velocities by Doppler TTE without requiring a high-frequency transducer would stimulate further research to explore the prognostic implication of coronary flow abnormalities, and to assess whether the abnormal coronary flow pattern, when established, could guide patient selection for different medical and interventional treatment strategies. Study Limitations Although our comparative Doppler flow wire study demonstrated a satisfactory correlation of the results in 10 patients with HOCM, the study fails to validate the Doppler echocardiography method of assessing distal LAD flow in a larger group of individuals because such a study of an invasive nature could not have been justified because of ethical reasons. In contrast to patients with hypertrophied ventricles, echocardiographic assessment of LAD flow was not possible in all control subjects. This difficulty to obtain CFV in control subjects in our study may be
Journal of the American Society of Echocardiography Volume 17 Number 7
related to the use of an ultrasonic system equipped with a standard adult transducer, which is probably suboptimal for control subjects without hypertrophied ventricles. Conclusion In conclusion, CFV measurements of distal LAD by Doppler TTE revealed a significant increase in diastolic velocities whereas a significant reduction of systolic velocities was shown for patients with HOCM compared with control subjects. These abnormalities of CFV closely correlate with septal thickness and severity of diastolic dysfunction rather than the degree of intraventricular pressure gradient REFERENCES 1. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy: a discussion of nomenclature. Am J Cardiol 1979;43:1242-4. 2. O’Gara PT, Bonow RO, Maron BJ, Damske BA, van Lingen A, Bachrach SL. Myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy: assessment with thallium-201 emission-computed tomography. Circulation 1987;6:1214-23. 3. Cannon RO, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, et al. Myocardial ischemia in hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures. Circulation 1985;71:234-43. 4. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol 1986;8:545-57. 5. Tomochika Y, Tanaka N, Wasaki Y, Shimizu H, Hiro J, Takahashi T, et al. Assessment of flow profile of left anterior descending coronary artery in hypertrophic cardiomyopathy by transesophageal pulsed Doppler echocardiography. Am J Cardiol 1993;72:1425-30. 6. Kyriakidis MK, Dernellis JM, Androulakis AE, Kelepeshis GA, Barbetseas J, Anastasakis AN, et al. Changes in phasic coronary blood flow velocity profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy. Circulation 1997;96:834-41.
Celik et al 749
7. Crowley JJ, Dardas PS, Harcombe AA, Shapiro LM. Transthoracic Doppler echocardiographic analysis of phasic coronary blood flow velocity in hypertrophic cardiomyopathy. Heart 1997;77:558-63. 8. Dimitrow PP, Krzanowski M, Nizankowski R, Szczeklik A, Dubiel JS. Effect of verapamil on systolic and diastolic coronary blood flow velocity in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy. Heart 2000;83:262-6. 9. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography committee on standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989;2:358-67. 10. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circulation 1977;55:613-8. 11. Oh JK, Appleton CP, Hatle LK, Nisgimura RA, Seward JB, Tajik AJ. The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246-70. 12. Akasaka T, Yoshikawa J, Yoshida K, Maeda K, Takagi T, Miyake S. Phasic coronary flow characteristics in patients with hypertrophic cardiomyopathy: a study by coronary Doppler catheter. J Am Soc Echocardiogr 1994;7:9-19. 13. Memmola C, Iliceto S, Venanzio F, Napoli V, Cavallari D, Santoro G, et al. Coronary flow dynamics and reserve assessed by transesophageal echocardiography in obstructive hypertrophic cardiomyopathy. Am J Cardiol 1994;74:1147-51. 14. Petkow Dimitrow P, Krzanowski M, Nizankowski R, Szczeklik A, Dubiel JS. Effect of verapamil on systolic and diastolic coronary blood flow velocity in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy. Heart 2000;83:262-6. 15. Petropoulakis PN, Kyriakidis MK, Tentolouris CA, Kourouclis CV, Toutouzas PK. Changes in phasic coronary blood flow velocity profile in relation to changes in hemodynamic parameters during stress in patients with aortic valve stenosis. Circulation 1995;92:1437-47. 16. Tamborini G, Barbier P, Doria E, Galli C, Maltagliati A, Ossoli D, et al. Influences of aortic pressure gradient and ventricular septal thickness with systolic coronary flow in aortic valve stenosis. Am J Cardiol 1996;78:1303-6.
We aimed to visualize the coronary flow velocities (CFV) of patients with hypertrophic obstructive cardiomyopathy by using transthoracic Doppler echocardiography, and to determine the relationship between abnormal CFV patterns and conventional echocardiography indices. Guided by 2-dimensional echocardiography and Doppler color flow mapping, CFV in the distal left anterior descending coronary artery were measured in 21 patients with hypertrophic obstructive cardiomyopathy using a 3.5-MHz transducer. The results were compared with those of 18 control subjects. Abnormal systolic flow patterns were observed in 15 (71%) patients (11 systolicreversal flow and 4 no systolic flow). For patients and control subjects, peak diastolic velocity and velocity-time integral obtained from distal left ante-
Hypertrophic cardiomyopathy (HCM) is a genetic
cardiac disease characterized by left ventricular (LV) hypertrophy in the absence of another cause of increased cardiac mass.1 Patients with HCM commonly have evidence of myocardial ischemia despite angiographically normal coronary arteries.2,3 The alterations of phasic coronary flow characteristics have been reported and proposed as a mechanism for the development of angina pectoris in these patients.4-6 Invasive or semi-invasive techniques assessing coronary flow such as Doppler flow wire and transesophageal echocardiography are not practical for daily use. Recent advancements of Doppler transthoracic echocardiography (TTE) provide noninvasive measurement of coronary flow velocities (CFV) in From the Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center. Reprint requests: Seden Celik, MD, Gardenya 4-1 Ka:2, D:9, Atasehir, Ku¨cu¨kbakkalko¨y, 81120 Istanbul, Turkey (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.03.028
744
rior descending coronary artery were higher (63 ⴞ 21 cm/s and 18.5 ⴞ 4 cm vs 41 ⴞ 11 cm/s and 14.2 ⴞ 5 cm, respectively; P < .01 for both) whereas peak systolic velocity and velocity-time integral were significantly lower (ⴚ17 ⴞ 10 cm/s and 4.5 ⴞ 6 cm vs 24 ⴞ 9 cm/s and 9.5 ⴞ 4 cm, respectively; P < .001 for both). Significant positive and negative correlations between diastolic CFV and septal thickness index (r ⴝ 0.79, P < .0001), and between systolic CFV and septal thickness index (r ⴝ ⴚ0.65, P < .005), have been observed. CFV abnormalities that could easily be recorded by a standard Doppler echocardiographic study seem to be related to septal thickness rather than the degree of obstruction in hypertrophic obstructive cardiomyopathy. (J Am Soc Echocardiogr 2004;17:744-9.)
the distal epicardial coronary arteries. However, studies evaluating coronary flow with a transthoracic approach have mostly been performed by using high-frequency transducers and conducted on limited numbers of patients.7,8 The purposes of this study were: (1) to evaluate the feasibility and accuracy of transthoracic coronary flow imaging by using an ultrasonic system equipped with a standard adult transducer in patients with obstructive HCM (HOCM); (2) to investigate the relationship between the severity of LV outflow tract obstruction and CFV; and (3) to assess whether a relationship exists between abnormal CFV pattern and other conventional echocardiography parameters.
METHODS Patients We studied 21 consecutive patients (mean age: 38 ⫾ 13 years; 8 women) with the clinical and echocardiographic diagnosis of HOCM on the basis of the demonstration of a hypertrophied and nondilated LV in the absence of a second-
Journal of the American Society of Echocardiography Volume 17 Number 7
Celik et al 745
ary cause of LV hypertrophy. Inclusion criteria were: (1) interventricular septum thickness ⬎ 15 mm and septum/ posterior wall ratio ⬎ 1.3; and (2) a basal systolic gradient ⬎ 30 mm Hg in the LV outflow tract. In all study patients, drug treatments were withheld 48 hours before the echocardiographic examination. A control group consisted of 18 healthy age- and sex-matched volunteers. All patients were informed about the investigative nature of the study, and the local ethical committee approved the study protocol. Echocardiographic Examination TTE recordings were obtained from parasternal, apical, and subcostal windows by using ultrasound systems (GEVingmed System V and Vivid 7, GE-Vingmed Ultrasound, Horten, Norway) equipped with 1.5- to 3.7-MHz broadband electronic transducers. Conventional M-mode, 2-dimensional, pulsed wave, and color Doppler images were acquired with simultaneous electrocardiographic tracings. LV systolic and diastolic dimensions, and wall thickness, were measured from the M-mode traces according to the recommendations of The American Society of Echocardiography.9 LV mass was calculated by the formula of Devereux and Reichek.10 LV ejection fraction was calculated with the Teichholz formula. Transmitral inflow velocities were recorded at the level of mitral leaflet tips. The early and late diastolic velocities, deceleration time of early diastolic velocities, and isovolumic relaxation time were also measured with previously described methods.11 Coronary Flow Imaging For the optimal coronary flow imaging, the system presets were adjusted as follows: Nyquist limit was 18 to 20 cm/s; color pulse frequency and pulse Doppler frequency were 3.5 MHz; lateral and radial averaging was lowest; color sample volume was minimum; and Doppler sample volume was 1 to 2 mm. The patients were examined in the left lateral position using a modified left parasternal window. The transducer position was around the left midclavicular line in the fourth and fifth intercostal spaces. After the anterior interventricular sulcus was imaged by angling the ultrasonic beam laterally and superiorly, coronary blood flow of distal left anterior descending coronary artery (LAD) was identified by Doppler color flow mapping. Doppler spectral trace was recorded with a sample volume positioned on the color signal within the artery. The long-axis sections were carefully adjusted to minimize the angle (which was kept ⬍20 degrees) between the Doppler beam and the long axis of the artery. Sample volume was located within the vessel lumen, and was kept there as long as possible during the cardiac cycle to acquire a typically diastolic predominant phasic CFV Doppler pattern (Figure 1). All echocardiographic images were stored in 5.5-in MO (magneto optic) disks, and measurements were made by using the internal analyzing software package of the system. By tracing the coronary blood flow Doppler spectrum, the peak systolic and diastolic velocities, and their velocity-time integrals, were measured. For each of those 4
Figure 1 Distal left anterior descending coronary artery Doppler spectra obtained by transthoracic echocardiography (A) and flow wire (B) methods demonstrate typical systolic reversal flow for patient with hypertrophic obstructive cardiomyopathy.
variables, the average value of the measurements from 3 to 5 cardiac cycles was used for statistical calculations. Doppler Flow Wire Study A total of 10 patients for whom a coronary angiography was planned by their physicians to role out the possibility of coronary artery disease underwent Doppler flow wire study after the procedure was completed. Informed consent was obtained from those patients. Coronary angiography revealed normal findings in all. After the completion of the angiographic study, a 0.014-inch Doppler flow wire (FloWire, Cardiometrics, Mountain View, Calif) was placed in the center of the vessel coaxial to the lumen in the distal portion of the LAD. A high quality of blood flow Doppler spectrum was attempted by carefully manipulating the flow wire (Figure 1). Particular attention was paid to Doppler wire position, located between the last diagonal branch and mustache of LAD, which was approximately the same location viewed by Doppler TTE. The peak values and the velocity-time integrals of systolic and diastolic CFV were measured in these 10 patients to compare corresponding values recorded by Doppler TTE. All studies were continuously recorded on super-VHS videotape.
Journal of the American Society of Echocardiography July 2004
746 Celik et al
Table. Demographic, hemodynamic, and echocardiographic data of patients with hypertrophic obstructive cardiomyopathy and control subjects. Variable
Patients
Age (y) Sex (F/M) BSA (m2) HR (bpm) BP-sys (mm Hg) BP-dias (mm Hg) LV mass index (g/m2) LVOT max-grd (mm Hg) EF (%) E vel (cm/s) A vel (cm/s) IVRT (msec)
38.7 ⫾ 13 8/13 1.78 ⫾ 0.26 72 ⫾ 8 121 ⫾ 29 70 ⫾ 11 257 ⫾ 35 60 ⫾ 33 76 ⫾ 11 87 ⫾ 32 66 ⫾ 20 90 ⫾ 17
Control subjects
P
35 ⫾ 11 7/11 1.80 ⫾ 0.30 68 ⫾ 10 115 ⫾ 25 65 ⫾ 10 112 ⫾ 15
NS NS NS NS NS NS 0.001
67 ⫾ 10 89 ⫾ 24 62 ⫾ 15 78 ⫾ 20
NS NS NS NS
A vel, Atrial filling velocity; BP-dias, diyastolic blood pressure; BP-sys, systolic blood pressure; BSA, body surface area; EF, ejection fraction; E vel, early filling velocity; F, female; HR, heart rate; IVR T, isovolumic relaxation time; LV, left ventricular; LVOT max-grad, LV outflow tract maximal gradient; M, male; NS, not significant.
Reproducibility and Agreement of CFV Measurements by Doppler TTE and Flow Wire To evaluate the effect of interobserver variability on CFV measurements by Doppler TTE, two independent, blinded observers (A. Y. and N. U.) analyzed 21 randomly selected Doppler velocity recordings. To evaluate intraobserver variability, 21 randomly selected Doppler velocities were remeasured by the same operator (S. C.) 1 week apart. To evaluate the agreement of CFV measurements obtained by Doppler TTE and Doppler flow wire methods, 10 patients were analyzed. Interobserver and intraobserver variabilities, and the agreement of coronary flow measurements by two methods, were calculated as the SD of the differences between the two measurements or assessments, expressed as a percentage of the average value.
Figure 2 Mean values of peak diastolic and systolic left anterior descending coronary artery (LAD) velocities for patients with hypertrophic obstructive cardiomyopathy (HOCM) and control subjects.
Statistical Analysis Continuous variables were expressed as mean ⫾ 1 SD. An unpaired 2-tailed t test was used for comparing values between groups. Linear regression analysis was used for the correlations between CFV measurements and the other echocardiographic variables. Significance was set at a P value ⬍ .05. Software (SPSS, Version 10.0, Chicago, Ill) was used for computations.
RESULTS Clinical, hemodynamic, and echocardiographic data of the patients with HOCM and control subjects are given in Table. The groups were comparable in terms of age, sex, body surface area, blood pressure, and heart rate. Patients with HOCM had a significantly thickened interventricular septum and, consequently, a higher LV mass index and ventricular septum/posterior wall ratio than control subjects.
The average level of intraventricular pressure gradient was 60 ⫾ 33 mm Hg in study patients. CFV Analysis Technically adequate Doppler flow velocity tracings of the distal LAD could be obtained from all 21 consecutive study patients, but only from 18 of 24 control subjects (75%). The mean diastolic and systolic CFV of patients with HOCM and control subjects are displayed in Figure 2. The peak diastolic velocity and velocitytime integral were significantly higher in patients with HOCM than in control subjects (63 ⫾ 21 cm/s and 18.5 ⫾ 4 cm vs 41 ⫾ 11 cm/s and 14.2 ⫾ 5, respectively; P ⬍ .01 for both). Because CFV were in normal antegrade form in all control subjects but there was a reversal flow in 11 and no systolic flow in 4 patients with HOCM (P ⬍ .0001), the peak systolic velocity and velocity-time
Journal of the American Society of Echocardiography Volume 17 Number 7
Celik et al 747
Figure 3 Correlation between peak diastolic left anterior descending coronary artery (LAD) velocities and interventricular septum thickness index for patients with hypertrophic obstructive cardiomyopathy (HOCM) (A). Relation between peak systolic LAD velocities with interventricular septum thickness index (B), mitral early filling (E) velocities (C), and isovolumic relaxation time (IVRT) (D) for patients with HOCM.
integral were significantly lower in HOCM group (24 ⫾ 9 cm/s and 9.5 ⫾ 4 cm vs ⫺17 ⫾ 10 cm/s and 4.5 ⫾ 6 cm, respectively; P ⬍ .001 for both). Linear regression revealed that for patients with HOCM, no correlation existed between intraventricular pressure gradient and either systolic or diastolic LAD flow velocities. On the other hand, a significant negative correlation was observed between interventricular septum thickness index (interventricular septum thickness/body surface area) and LAD peak systolic velocity (r ⫽ ⫺0.65; P ⬍ .005) (Figure 2). In the analysis of diastolic CFV, significant positive correlations were observed between peak diastolic LAD velocities and both interventricular septum thickness and its indices (r ⫽ 0.79; P ⬍ .0001). Among the conventional diastolic Doppler parameters, the peak early inflow velocities showed a good negative correlation (r ⫽ ⫺0.79; P ⬍ .005), whereas isovolumic relaxation time showed moderately positive correlation with peak systolic CFV (r ⫽ 0.60; P ⬍ .05) (Figure 3).
Reproducibility Interobserver variability of Doppler velocity measurements was 7.2% for systolic and 4.4% for diastolic velocities. Intraindividual variability was excellent and never exceeded 2 cm/s for both diastolic and systolic peak velocity, which provided a maximal ⫾5.6% difference in relative terms. The agreement of CFV measurements obtained by Doppler TTE and flow wire methods was also in acceptable limits. The mean variability of CFV measurements by two methods was 4.2% and 6.1% for diastolic and systolic velocities, respectively.
DISCUSSION In patients with HOCM, the noninvasive Doppler TTE technique allows acquisition of the flow patterns of distal LAD, measuring the peak velocity and velocity-time integrals, and demonstrating the flow
748 Celik et al
pattern abnormalities involving the systolic phase such as its absence and paradoxical reversal. Furthermore, patients with HOCM showed significantly increased diastolic CFV in distal LAD when compared with control subjects. Both systolic and diastolic CFV were observed to significantly correlate with septal thickness and diastolic function parameters, but not with intraventricular pressure gradient. Coronary Flow Abnormalities in HOCM Some previous studies using invasive and noninvasive methods demonstrated decreased or reversed systolic and augmented diastolic coronary flow in patients with HOCM.5-7,12 Possible mechanisms that have been proposed to explain these alterations are the abnormally increased coronary vascular resistance as a result of systolic compression of large intramural arteries, throttling effect of small intramural coronary arteries, and reduced compliance of epicardial coronary arteries because of maximal vasodilatator state even in resting condition. Consistent with those mechanisms, CFV alterations seem to have a close relationship with the degree of septal thickening, as our study demonstrated. This scenario emphasizes that as the myocardial wall thickens, intramural compression on the coronary artery increases, and both the throttling effect and the reduced compliance because of maximal-basal vasodilatation of LAD become more prominent. In the literature, there are some observations supporting our findings. Tomochika et al5 measured CFV in the proximal LAD of 7 patients with nonobstructive HCM by TEE; systolic flow was reduced and reversal flow occurred in two patients with ventricular septal thickness ⬎ 2 cm, and a significant correlation was found between septum thickness and peak systolic velocities. Memmola et al13 also reported a significantly greater diastolic and lower systolic component of CFV in the proximal LAD of 10 patients with HOCM by TEE. In our study, an entirely noninvasive approach performed to a larger patient group with HOCM demonstrated consistent findings with those observations. In addition, it is interesting that the CFV variables were not related to the degree of obstruction severity in our study patients. Altered coronary flow characteristics—regardless of the severity of systolic pressure increase in LV—in relation with the degree of thickening of surrounding myocardium, could suggest the mechanisms involving the local functional and structural changes regulating coronary flow that might probably contribute to the generation of abnormal CFV patterns in patients with HOCM. The findings of a previous study by Kyriakidis et al6 suggested regional difference of coronary flow between the coronary arteries responsible
Journal of the American Society of Echocardiography July 2004
from the perfusion of hypertrophic and normal LV segments; they reported an increased coronary flow in LAD compared with left circumflex coronary artery by using flow wire method in 18 patients with HOCM. Thus, one might argue that the regional distribution of hypertrophy closely relates with the regional impairment of coronary flow, and the local regulatory mechanisms largely influence the coronary flow dynamics rather than increased intraventricular pressure. Furthermore, previous observations, which reported similar CFV abnormalities, also for patients with nonobstructive HCM,5,14 may let us think that the intraventricular pressure gradient is not the predominant factor responsible from the CFV alterations for patients with HOCM. In contrast to our findings, transvalvular pressure gradient has been shown to correlate with the degree of systolic reversal coronary flow in patients with valvular aortic stenosis, which may be considered as another form of LV outflow tract obstruction.15,16 In our opinion, these controversial results might be related to the difference between hemodynamic effects of fix-valvular stenosis in which peak gradient was measured at midsystole and dynamic obstruction of HCM, which has a less effective gradient at end-systole. This study also demonstrates that the alterations in CFV significantly relate to the degree of LV diastolic functional impairment. The correlation of abnormally decreased systolic coronary flows with higher early diastolic velocities and shorter isovolumic relaxation time may be caused by an interaction between more advanced form of diastolic dysfunction or high LV filling pressures with coronary flow dynamics. Clinical Implications Noninvasive imaging of distal LAD flow velocities by Doppler TTE without requiring a high-frequency transducer would stimulate further research to explore the prognostic implication of coronary flow abnormalities, and to assess whether the abnormal coronary flow pattern, when established, could guide patient selection for different medical and interventional treatment strategies. Study Limitations Although our comparative Doppler flow wire study demonstrated a satisfactory correlation of the results in 10 patients with HOCM, the study fails to validate the Doppler echocardiography method of assessing distal LAD flow in a larger group of individuals because such a study of an invasive nature could not have been justified because of ethical reasons. In contrast to patients with hypertrophied ventricles, echocardiographic assessment of LAD flow was not possible in all control subjects. This difficulty to obtain CFV in control subjects in our study may be
Journal of the American Society of Echocardiography Volume 17 Number 7
related to the use of an ultrasonic system equipped with a standard adult transducer, which is probably suboptimal for control subjects without hypertrophied ventricles. Conclusion In conclusion, CFV measurements of distal LAD by Doppler TTE revealed a significant increase in diastolic velocities whereas a significant reduction of systolic velocities was shown for patients with HOCM compared with control subjects. These abnormalities of CFV closely correlate with septal thickness and severity of diastolic dysfunction rather than the degree of intraventricular pressure gradient REFERENCES 1. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy: a discussion of nomenclature. Am J Cardiol 1979;43:1242-4. 2. O’Gara PT, Bonow RO, Maron BJ, Damske BA, van Lingen A, Bachrach SL. Myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy: assessment with thallium-201 emission-computed tomography. Circulation 1987;6:1214-23. 3. Cannon RO, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, et al. Myocardial ischemia in hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures. Circulation 1985;71:234-43. 4. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol 1986;8:545-57. 5. Tomochika Y, Tanaka N, Wasaki Y, Shimizu H, Hiro J, Takahashi T, et al. Assessment of flow profile of left anterior descending coronary artery in hypertrophic cardiomyopathy by transesophageal pulsed Doppler echocardiography. Am J Cardiol 1993;72:1425-30. 6. Kyriakidis MK, Dernellis JM, Androulakis AE, Kelepeshis GA, Barbetseas J, Anastasakis AN, et al. Changes in phasic coronary blood flow velocity profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy. Circulation 1997;96:834-41.
Celik et al 749
7. Crowley JJ, Dardas PS, Harcombe AA, Shapiro LM. Transthoracic Doppler echocardiographic analysis of phasic coronary blood flow velocity in hypertrophic cardiomyopathy. Heart 1997;77:558-63. 8. Dimitrow PP, Krzanowski M, Nizankowski R, Szczeklik A, Dubiel JS. Effect of verapamil on systolic and diastolic coronary blood flow velocity in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy. Heart 2000;83:262-6. 9. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography committee on standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989;2:358-67. 10. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circulation 1977;55:613-8. 11. Oh JK, Appleton CP, Hatle LK, Nisgimura RA, Seward JB, Tajik AJ. The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10:246-70. 12. Akasaka T, Yoshikawa J, Yoshida K, Maeda K, Takagi T, Miyake S. Phasic coronary flow characteristics in patients with hypertrophic cardiomyopathy: a study by coronary Doppler catheter. J Am Soc Echocardiogr 1994;7:9-19. 13. Memmola C, Iliceto S, Venanzio F, Napoli V, Cavallari D, Santoro G, et al. Coronary flow dynamics and reserve assessed by transesophageal echocardiography in obstructive hypertrophic cardiomyopathy. Am J Cardiol 1994;74:1147-51. 14. Petkow Dimitrow P, Krzanowski M, Nizankowski R, Szczeklik A, Dubiel JS. Effect of verapamil on systolic and diastolic coronary blood flow velocity in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy. Heart 2000;83:262-6. 15. Petropoulakis PN, Kyriakidis MK, Tentolouris CA, Kourouclis CV, Toutouzas PK. Changes in phasic coronary blood flow velocity profile in relation to changes in hemodynamic parameters during stress in patients with aortic valve stenosis. Circulation 1995;92:1437-47. 16. Tamborini G, Barbier P, Doria E, Galli C, Maltagliati A, Ossoli D, et al. Influences of aortic pressure gradient and ventricular septal thickness with systolic coronary flow in aortic valve stenosis. Am J Cardiol 1996;78:1303-6.