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Assessment of Coronary Blood Flow in Hypertrophic Cardiomyopathy Using Thrombolysis in Myocardial Infarction Frame Count Method
February 2005
Hypertrophic cardiomyopathy (HCM) is a genetically transmitted disease of the sarcomeres, characterized phenotypically by an inappropriate thickness of the interventricular septum and less frequently, of the free left ventricular wall of a nondilated ventricle.1,2 Anginal symptoms and signs of ischemia occur frequently in patients with HCM without detectable lesions of the major epicardial coronary arteries,3–6 suggesting that the presence of ischemia is the result of abnormalities of the coronary microcirculation. Furthermore, coronary flow reserve has been reported to be decreased in patients with hypertrophic cardiomyopathy without evidence of structural and/or functional stenoses of the epicardial vessels.3–6 Thrombolysis In Myocardial Infarction (TIMI) frame count is a simple clinical tool for assessing quantitative indexes of coronary blood flow. This technique counts the number of cineangiographic frames from initial contrast opacification of the proximal coronary artery to opacification of distal arterial landmarks.7 This measurement has been significantly correlated with flow velocity measured with the Flowire by several investigators during baseline conditions or hyperemia.8,9 It has been suggested that a higher TIMI frame count may reflect disordered resistance vessel function.7 The purpose of the present study was to investigate coronary blood flow in patients with HCM by way of the TIMI frame count method.
Method
Study population. Thirty-two patients with HCM (22 male, 10 female; mean age = 48 ± 7 years), who underwent coronary angiography due to the presence of typical angina pectoris and detected as having angiographically normal epicardial coronary arteries, were included in the study as patient group. All patients had an asymmetrically hypertrophic nondilated left ventricle and a basal intraventricular pressure gradient > 30 mmHg recorded in the left ventricular outflow tract. Control group comprised 36 consecutive subjects (23 male, 13 female; mean age = 49 ± 7 years) with atypical chest pain admitted to the hospital for elective coronary angiography and subsequently found to have angiographically normal coronary arteries. All patients and control subjects were in sinus rhythm. Patients with coronary artery disease, left ventricular dysfunction, valvular heart disease, systemic or cardiac diseases that cause left ventricular hypertrophy, diabetes mellitus, hypertension and atrial fibrillation were not included in this study.
Transthoracic echocardiography. A complete transthoracic echocardiographic examination, including two-dimensional, M-mode, pulse and continuous Doppler was performed in all patients and control subjects. M-mode measurements in end-diastole of both the anterior interventricular septum and posterior wall thickness, and their ratio, were obtained from a parasternal long-axis view. Left ventricular end-diastolic and end-systolic diameters, left ventricular ejection fraction and fractional shortening were also measured in M-mode. The intraventricular pressure gradient was calculated by continuous Doppler wave sampling of blood flow velocity in the left ventricular outflow tract using the Bernoulli simplified formula.
Evaluation of coronary blood flow. Coronary flow was quantified objectively by two observers independently blinded to the clinical details of the individual case using the TIMI frame count method. The TIMI frame count method is a simple, reproducible, objective and quantitative index of coronary flow velocity.7 The TIMI frame count was determined for each major coronary artery in each patient and control subject according to the method first described by Gibson et al.7 Briefly, the number of cineangiographic frames, recorded at 25 frames per second, that are required for the leading edge of the column of radiographic contrast to reach a pre-selected landmark is determined and corrected to a frame acquisition rate of 30 frames per second. The first frame is defined as that in which concentrated dye occupies the full width of the proximal coronary artery lumen, touching both borders of the lumen, and then flows forward down the artery.
The final frame is designated when the leading edge of the contrast column initially arrives at the distal landmark. In the left anterior descending (LAD) coronary artery, the landmark used is the most distal branch nearest the apex of the left ventricle, commonly referred as the “pitchfork” or “whale’s tail.” The LAD coronary artery is usually longer than the other major coronary arteries,10 and the TIMI frame count for this vessel is often higher. To obtain a corrected TIMI frame count for the LAD coronary artery, the TIMI frame count was divided by 1.7.7 The right coronary artery (RCA) distal landmark is the first branch of the posterolateral RCA after the origin of the posterior descending artery, regardless of the size of this branch. The branch of the left circumflex (LCx) artery that encompassed the greatest total distance traveled by contrast was used to define the distal landmark of the LCx artery. The TIMI frame counts in the LAD and LCx arteries were assessed in a right anterior oblique projection with caudal angulation, and the RCA TIMI frame count was assessed in a left anterior oblique projection with cranial angulation.
Statistical analysis. Continuous variables were expressed as mean ± SD, and categorical variables were expressed as percentage. Comparison of categorical and continuous variables between the two groups was performed using the chi-square test and the unpaired t-test, respectively. The correlation between echocardiographic variables, left ventricular outflow gradient and TIMI frame count was assessed by the Pearson correlation test. A p-value of Echocardiographic characteristics. The interventricular and posterior wall thicknesses and the interventricular septum-to-posterior wall thickness ratio were found to be significantly higher in patients with HCM compared to control subjects (Table 1). The left ventricular outflow gradient was 66 ± 13 mmHg. No significant difference were detected between the two groups regarding left ventricular end-diastolic and end-systolic diameters, left ventricular ejection fraction and fractional shortening (Table 1).
TIMI frame counts. The TIMI frame count for the LAD coronary artery was found to be significantly higher in patients with HCM compared to the control subjects (Table 1, Figure 1). However, we found no significant difference between the two groups regarding TIMI frame counts for the LCx coronary artery and the RCA (Table 1, Figure 1). Furthermore, the TIMI frame count for the LAD coronary artery was found to be significantly correlated with interventricular septal wall thickness (r = 0.546, p = 0.001; Figure 2) and the interventricular septum/posterior wall thickness ratio (r = 0.490, p = 0.004, Figure 3). However, no significant correlation was detected between the TIMI frame count for the LCx coronary artery and RCA and interventricular septal wall thickness (r = 0.250, p = 0.167 and r = 0.130, p = 0.944, respectively) and the interventricular septum/posterior wall thickness ratio (r = 0.256, p = 0.096 and r = 0.176, p = 0.334, respectively). In addition, the left ventricular outflow gradient had no significant correlation with the TIMI frame count for the LAD coronary artery (r = 0.278, p = 0.123). None of the other echocardiographic parameters such as posterior wall thickness, left ventricular end-diastolic and end-systolic diameters, left ventricular ejection fraction, and fractional shortening had any significant correlation with the TIMI frame counts for either major epicardial coronary arteries.
Discussion
The main finding of the present study is that patients with HCM had a higher TIMI frame count for the LAD coronary artery compared to the control subjects, indicating impaired coronary blood flow for this vessel. We also found no significant difference between patients with HCM and the control subjects regarding TIMI frame counts for the LCx coronary artery and the RCA. Furthermore, we found a significant positive correlation between the TIMI frame count for the LAD coronary artery and interventricular septal wall thickness and the interventricular septum/posterior wall thickness ratio. Previously, abnormalities in coronary blood flow for the LAD coronary artery have been repeatedly demonstrated in HCM by means of transthoracic or transesophageal Doppler echocardiography.11–14 Because of their directions, it is impossible to obtain Doppler velocity signals for the LCx coronary artery and the RCA. Thus, transthoracic or transesophageal echocardiography allow us to explore coronary flow velocity dynamics only in the LAD coronary artery. To our knowledge, this is the first study evaluating coronary blood flow for all three major epicardial coronary arteries in patients with HCM using the TIMI frame count method.
The normal coronary system consists of large epicardial vessels that normally offers little intrinsic resistance to coronary blood flow and small intramyocardial vessels (microcirculation) which, because of their small diameters and well developed media, are the major source of coronary vascular resistance.15 Because of their well developed media, they have the capacity to profoundly alter the resistance to coronary blood flow. Apart from the striking pathologic and molecular findings of the myocardium, recent reports indicate that the coronary microcirculation is disturbed in HCM. Maron et al16 qualitatively reported this from autopsy studies where they found abnormal intramural coronary arteries in 40 of 48 patients with HCM. Abnormal arteries were characterized by a thickening of the vessel wall and a decrease in luminal size, which were more frequently found in the interventricular septum than in the anterior and posterior left ventricular free wall. Similarly, Schwartzkopff et al17 showed medial hypertrophy with a lumen-to-wall ratio reduction of the preterminal arteriolar wall, indicating vascular remodeling in patients with HCM. Tanaka et al18 also reported an autopsy study showing a reduced percentage of arteriole lumens with diameters 12,19,20 as well as by positron emission tomography studies6 to a larger extent in the hypertrophied interventricular septum. In the present study, we detected an increased TIMI frame count for the LAD coronary artery supplying the hypertrophied interventricular septum.
Furthermore, we found a significant positive correlation between the TIMI frame count for the LAD coronary artery and the interventricular septal thickness. However, TIMI frame counts for the LCx coronary artery and the RCA in patients with HCM were found to be similar to the control subject values. Nienabar et al6 reported that baseline myocardial blood flow was lower in the hypertrophied septum in patients with HCM. In addition, Tomochika et al21 showed that the peak systolic flow velocity of the LAD was significantly lower in patients with HCM than in the control subjects, and that there was a significant inverse correlation with interventricular septal thickness in all patients. Compared to the control subjects, the acceleration time of the diastolic LAD flow velocity in HCM has been reported to be significantly prolonged and the acceleration rate significantly reduced.21 Therefore, it is reasonable to suggest that within the hypertrophied left ventricle, there were regions perfused by the LCx coronary artery and the RCA that were not involved in the impaired coronary blood flow effect of hypertrophied myocardium — at least not to the extent that it occurred in the LAD coronary artery.
In conclusion, we have shown that patients with HCM had a significantly higher TIMI frame count for the LAD coronary artery which supplies the hypertrophied interventricular septum, indicating impaired coronary blood flow. In addition, we found a significant positive correlation between the TIMI frame count for the LAD coronary artery and interventricular septal thichness and the interventricular septum/posterior wall thickness ratio, suggesting a relationship between the extent of myocardial pathology and the impairment of coronary blood flow. However, there was no significant difference between the patients and the control groups regarding TIMI frame counts for the LCx coronary artery and the RCA, suggesting that the presence of regional (interventricular septal), rather than global impairment of coronary blood flow in patients with asymmetric HCM.
1. Wigle ED, Rakowski H, Kimball BZ, Williams WG. Hypertrophic cardiomyopathy: Clinical spectrum and treatment. Circulation 1995;92:1680–1692.
2. Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation 1995;91:532–540.
3. O'Cannon RO, Schenke WH, Maron BJ, et al. Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with non-obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:53–62.
4. Camici P, Chiriatti G, Lorenzoni R, et al. Coronary vasodilatation is impaired in both hypertrophied and non-hypertrophied myocardium of patients with hypertrophic cardiomyopathy: A study with nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol 1991;17:879–886.
5. Pasternac A, Noble J, Streulens Y, et al. Pathophysiology of chest pain in patients with cardiomyopathies and normal coronary arteries. Circulation 1982;65:778–788.
6. Nienaber CA, Gambhir SS, Vaghaiwalla F, et al. Regional myocardial blood flow and glucose utilization in symptomatic patients with hypertrophic cardiomyopathy. Circulation 1993;87:1580–1590.
7. Gibson CM, Cannon CP, Daley WL, et al. for the TIMI 4 Study Group. TIMI frame count: A quantitative method of assessing coronary artery flow. Circulation 1996;93:879–888.
8. Kern MJ, Moore JA, Aguerre FV, et al. Determination of angiographic (TIMI grade) blood flow by intracoronary Doppler flow velocity during acute myocardial infarction. Circulation 1996;94:1545–1552.
9. Manginas A, Gatzov P, Chasikidis C, et al. Estimation of coronary flow reserve using the Thrombolysis In Myocardial Infarction (TIMI) frame count method. Am J Cardiol 1999;83:1562–1565.
10. Dodge JT, Brown BG, Bolson EL, Dodge HT. Intrathrocic spatial location of specified coronary segments on the normal human heart: application in quantitative arteriography, assessment of regional risk and contraction, and anotomic display. Circulation 1988;78:1167–1180.
11. O’Gara PT, Bonow RO, Maron BJ, et al. Myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy: Assessment with thallium-201 emission computed tomography. Circulation 1987;76:1214–1223.
12. von Dohlen TW, Prisant LM, Frank MJ. Significance of positive or negative thallium-201 scintigtaphy in hypertrophic cardiomyopathy. Am J Cardiol 1989;64:498–503.
13. Koga Y, Yamaguchi R, Ogata M, et al. Decreased coronary vasodilatory capacity in hypertrophic cardiomyopathy determined by split dose thallium-dipyridamole myocardial scintigraphy. Am J Cardiol 1990;65:1134–1139.
14. Takata J, Counihan PJ, Gane JN, et al. Regional thallium-201 washout and myocardial hypertrophy in hypertrophic cardiomyopathy and its relation to exertional chest pain. Am J Cardiol 1993;72:211–218.
15. Epstein SE, Cannon O, Talbot TL. Hemodynamic principles in the control of coronary blood flow. Am J Cardiol 1985;56:4E–10E.
16. Maron BJ, Wolfson JK, Epstein SE, Robert WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol 1986;8:545–557.
17. Schwartzkopff B, Mundhenke M, Strauer BE. Alterations of the architecture of subendocardial arterioles in patients with hypertrophic cardiomyopathy and impaired coronary vasodilator reserve: A possible cause for myocardial ischemia. J Am Coll Cardiol 1998;31:1089–1096.
18. Tanaka M, Fuijiwara H, Onodera T, et al. Quantitative analysis of narrowing of intramyocardial small arteries in normal heart, hypertensive hearts, and hearts with hypertrophic cardiomyopathy. Circulation 1987;75:1130–1139.
19. Pitcher D, Wainwright R, Maisey M, et al. Assessment of chest pain in hypertrophic cardiomyopathy using exercise thallium-201 myocardial scintigraphy. Br Heart J 1980;44:650–656.
20. Cannon RO, Dilsizian V, O’Gara PT, et al. Myocardial metabolic, hemodynamic and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy. Circulation 1991;83:1660–1667.
21. Tomochika Y, Tanaka N, Wasaki Y, et al. Assessment of flow profile of left anterior descending coronary artery in hypertrophic cardiomyopathy by transesophageal pulsed Doppler echocardiography. Am J Cardiol 1993;72:1425–1430.
