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(Circulation. 1997;95:892-898.)
© 1997 American Heart Association, Inc.

Articles

Angina Pectoris in Patients With Aortic Stenosis and Normal Coronary Arteries

Mechanisms and Pathophysiological Concepts

Barbara K. Julius, MD; Martin Spillmann, MD; Giuseppe Vassalli, MD; Bruno Villari, MD; Franz R. Eberli, MD; Otto M. Hess, MD

the Division of Cardiology, University Hospital, Zurich, Switzerland.

Correspondence to Otto M. Hess, MD, Cardiology, University Hospital, 3010 Bern, Switzerland.

	Abstract

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Background The incidence of angina pectoris (AP) in patients with severe aortic stenosis (AS) and normal coronary arteries has been reported to be 30% to 40%. The exact pathophysiological mechanism, however, is not known. The purpose of this work was to evaluate the various hemodynamic and angiographic determinants of myocardial perfusion in 61 patients with severe AS.

Methods and Results In a retrospective analysis, 61 patients with severe AS and without significant coronary artery disease were studied. Thirty-three patients with atypical chest pain and angiographically normal arteries served as control subjects. Patients were divided into two groups: 32 with AP and 29 without AP. Quantitative coronary angiography was performed in 59 patients and 22 control subjects. Coronary flow reserve was determined in 29 patients and 7 control subjects by use of coronary sinus thermodilution technique. Patients with AP had a lower left ventricular (LV) muscle mass, an increased LV peak systolic pressure, and increased wall stress than those without AP. Vessels of the left coronary artery were smaller and coronary flow reserve was lower in patients with AP than in those without. Inadequate LV hypertrophy with an increased wall stress was found in patients with AP but not in patients without AP.

Conclusions Myocardial ischemia in patients with severe AS can occur in the absence of coronary artery disease and appears to be due to inadequate LV hypertrophy with high systolic and diastolic wall stresses and a reduced coronary flow reserve. The cause of inadequate LV hypertrophy, however, remains unclear.

Key Words: hypertrophy • angina • hemodynamics • valves • myocardium

	Introduction

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The incidence of angina pectoris in patients with aortic stenosis has been reported to range between 30% and 40% in the absence of associated coronary artery disease.^{1 2 3 4 5 6} AP is a typical symptom in patients with aortic stenosis.^{1 2 6 7} The pathophysiological mechanism of angina is not clear but seems to be due to unbalanced myocardial oxygen supply and demand. This may be explained in part by a reduction in coronary flow reserve,^{8 9 10} although no correlation between AP and coronary flow reserve has been reported. Since patients with AP and severe aortic stenosis have a worse prognosis than those without symptoms,^{6 11 12 13} hemodynamic factors as well as myocardial perfusion have been evaluated with regard to the pathogenesis of AP in the absence of coronary artery disease.

	Methods

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Study Population
Sixty-one patients (mean age, 59±11 years; range, 35 to 81 years) with severe predominant aortic stenosis and without significant coronary artery disease who underwent diagnostic catheterization at our institution between 1977 and 1994 were included in the present analysis. Patients with moderate or severe mitral valve disease and/or significant coronary artery disease (50% stenosis) were excluded. Of the 61 patients with aortic stenosis, 69% had concomitant aortic regurgitation that was mild (5%) or moderate (25%). Mean regurgitant fraction as determined by the angio-Fick method was 19%. However, patients were selected on the basis of their valve area; ie, only patients with an aortic valve area 1.0 mm² were considered to have predominant aortic stenosis. The following clinical symptoms were evaluated: AP, dizziness, syncope, and heart failure. Functional classification according to the NYHA was assessed in each study subject. Patients were divided into two groups according to the presence or absence of AP. There were 32 patients (24 men, 8 women; age, 59±11 years) with a history of typical AP and 29 patients (24 men, 5 women; age, 60±11 years) without AP. Of the group with AP, 27 patients had no angiographic evidence of coronary atherosclerosis, 3 had irregularities of the arterial wall, and 2 had nonsignificant coronary artery stenosis of <50%. In the group without AP symptoms, 22 patients had no angiographic evidence of atherosclerosis, 5 had irregularities of the arterial wall, and 2 showed nonsignificant coronary artery stenosis. Thirty-three patients (24 men, 9 women; age, 50±9 years) with normal coronary arteries at catheterization and atypical chest pain served as control subjects.

Cardiac Catheterization
Informed consent was obtained from all patients. Premedication consisted of chlordiazepoxide (10 mg PO) 1 hour before the procedure. All vasoactive substances were withheld at least 24 hours before catheterization. LV pressure was measured transseptally with an 8.5F Brockenbrough catheter; aortic pressure was measured with a fluid-filled 8F pigtail catheter introduced retrogradely from the right femoral artery. Pulmonary artery pressure was measured with a conventional 7F Cournand catheter. Mean coronary perfusion pressure was calculated from mean aortic pressure minus mean right atrial pressure. Mean systolic pressure gradient and aortic valve area were calculated according to standard formulas. The degree of aortic regurgitation was assessed by the angio-Fick technique.

LV angiograms were obtained simultaneously in the right and left anterior oblique projections at a filming rate of 50 frames per second. LV volumes and ejection fraction were calculated by use of the area-length method.¹⁴ LVMM was determined according to the method of Rackley et al.¹⁵ Circumferential stress was calculated from the end-systolic and end-diastolic cine frames by use of a simplified version of Mirsky's¹⁶ thick-wall model: Midwall Stress (Kilodynes/Centimeter Squared)=(pxb/h)[1-(h/2b)-(b²/2a²)]x1.332, where p is LV pressure (millimeters of mercury), h is LV wall thickness (centimeters), a is the midwall semimajor axis [(L+h)/2, centimeters], and b is the midwall semiminor axis [(D+h)/2, centimeters].

Selective left and right coronary angiographies were carried out from the right femoral artery (Judkins technique, 8F catheters) with multiple views for optimal visualization of the coronary arteries. Only patients with angiographic evidence of no focal narrowing 50% were included in the present analysis. Coronary artery size was determined by quantitative coronary angiography. A subgroup of patients (n=29) underwent coronary sinus blood flow measurements for determination of coronary flow reserve.

Quantitative Coronary Arteriography
Quantitative evaluation of coronary angiograms was performed in 59 of 61 patients and 22 of 33 control subjects with a semiautomatic computer system.^{17 18 19} The system is based on a 35-mm film projector (Tagarno 35 CX), a slow-scan CCD camera for image digitalization, and a computer workstation (Apollo DN 3000) for image storing and processing. Contour detection was carried out with use of a geometric-densitometric edge-detection algorithm.^{18 20 21} The method of computerized analysis of coronary angiograms was described in detail elsewhere.^{17 20 21 22 23}

The proximal cross-sectional areas of the three major coronary vessels (LAD, LCx, and RCA) were measured from two or three end-diastolic cine frames. The proximal cross-sectional areas of the LAD and LCx were defined as the vessel segment immediately beyond the bifurcation of the left main coronary artery over a length of 1 cm. The computer traced this segment automatically and calculated the mean area over this segment. A circular lumen was assumed because only patients with coronary arteries showing no angiographic evidence of focal coronary narrowing 50% were included. The proximal cross-sectional area of the RCA was defined as the vessel segment 1 to 2 cm distal to the coronary ostium. A vessel segment over a length of 1 cm was analyzed, and the mean cross-sectional area was calculated in the same way as for the LCA. For each vessel segment, measurements in different projections were obtained and averaged to correct for biological variations in coronary artery dimensions.^{19 23 24} Calibration was performed automatically by use of the proximal part of the 8F Judkins catheter as a scaling device.^{17 25} As an index of the enlargement of the coronary arteries with respect to the degree of LV hypertrophy, the cross-sectional area of the LCA (LAD+LCx) per 100 g of LV angiographic mass was calculated.^{17 26}

Coronary Blood Flow Measurements
Measurements of coronary sinus blood flow were performed after diagnostic catheterization in 29 of the 61 patients and 7 of the 33 control subjects. Coronary blood flow was measured by the coronary sinus thermodilution technique.²⁷ A 7F thermodilution catheter (CCS-7 U-90 A or B, Webster Laboratory) was introduced from the right femoral vein into the coronary sinus. Correct positioning was checked by measurement of oxygen saturation and injection of small amounts of contrast medium before and after measurements. The signals of the external (mixing temperature of blood and saline) and internal (temperature of the injected saline) thermistors were recorded on an Electronics for Medicine VR-12 oscillograph at a paper speed of 5 mm/s. Saline at room temperature was infused through the thermodilution catheter at a rate of 50 mL/min, and coronary sinus blood flow (CSBF, mL/min) was calculated according to the formula of Ganz et al.²⁷ Coronary resistance (CR, mm Hgxmin/mL) was calculated according to the following formula: CR=(MAP-CSP)/CSBF, where MAP is mean aortic pressure and CSP is mean coronary sinus pressure (both in millimeters of mercury). Normalization per 100 g LVMM was carried out for coronary sinus blood flow and coronary resistance by use of angiographic mass. Coronary sinus blood flow was determined at rest and after infusion of 0.5 mg/kg body weight dipyridamole over 15 minutes. This duration of infusion of dipyridamole was chosen to minimize the systemic effects of dipyridamole on heart rate and blood pressure.²⁸ In no case were adverse effects of dipyridamole encountered.

Coronary flow reserve was calculated as coronary sinus blood flow after dipyridamole infusion divided by the sinus blood flow at rest, and coronary resistance ratio was calculated as the resistance after dipyridamole infusion divided by resistance at baseline. Coronary venous and arterial oxygen saturation was measured to calculate oxygen content before and after infusion of dipyridamole. Because the contrast medium (ventriculography, coronary angiography) may alter coronary dynamics,²⁹ the baseline value of coronary sinus blood flow was recorded at least 20 minutes after any previous contrast material injection. It has to be realized that not total but flow of the LCA is predominantly measured.

Statistical Analysis
Statistical comparisons of hemodynamic and angiographic data among the patients were carried out by a one-way ANOVA followed by the Newman-Keuls test. A value of P<.05 was considered statistically significant. Linear regression analysis was carried out by the least-squares method; in all figures with linear regressions, the 95% confidence limits are included. Data in all tables and figures are reported as mean±SD unless otherwise indicated.

	Results

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Clinical Data
The two groups did not differ with respect to age, body surface area, hemoglobin (14.8±1.4 versus 14.7±1.2 mg%, P=NS), cholesterol level (5.8±1.3 versus 6.6±3.6 mmol/L, P=NS), and history of hypertension. However, the AP+ group had a higher NYHA class than the AP- patients (2.4±0.6 versus 1.9±0.6, P<.005), whereas AP- patients more often reported episodes of syncope than AP+ patients (37% versus 63%, P<.05). The cardiothoracic ratio was similar in both groups (0.51±0.04 versus 0.51±0.06, P=NS). There was no difference between the two groups with respect to the Sokolow-Lyon index (3.7±0.9 versus 3.9±1.5 mV, P=NS) or the presence of LV strain in the resting ECG. Because of changes in the resting ECG, only 26 of 48 exercise ECGs could be reliably evaluated. However, ST-segment depression was significantly more pronounced in AP+ than in AP- patients (0.20±0.13 versus 0.10±0.12 mV, P<.05).

Hemodynamic Data
Tables 1 through 3 summarize the hemodynamic and angiographic data. Resting heart rate was similar in both groups (73±14 versus 72±11 bpm, P=NS). No significant difference was found between the groups with regard to mean aortic and mean pulmonary artery pressures, LV end-diastolic pressure, cardiac index, arteriovenous oxygen difference, diastolic aortic pressure, and rate-pressure product. However, there was a significant elevation of LV peak systolic pressure in AP+ compared with AP- patients (204±28 versus 187±35 mm Hg, P<.05).

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Data

View this table: [in this window] [in a new window]   Table 2. Angiographic Data

View this table: [in this window] [in a new window]   Table 3. LV Circumferential Wall Stress

Angiographic Data
LVMM ranged from 83 to 619 g in the two patient groups. AP- patients had a larger muscle mass index than AP+ patients (Table 2). No differences were detected with respect to LV ejection fraction, stroke volume index, aortic valve area, or systolic pressure gradient. End-systolic (368±79 versus 325±80 dynes·10³/cm², P<.05), peak systolic (528±90 versus 458±92 dynes·10³/cm², P<.01), and end-diastolic wall stress (53±24 versus 37±18 dynes·10³/cm², P<.01) were significantly elevated in AP+ patients.

Quantitative Coronary Angiography
Both proximal LAD and LCx tended to be smaller in AP+ patients (11.0±3.2 versus 12.6±3.5 mm², P<.1, and 10.3±2.6 versus 11.9±4.9 mm², P<.05, respectively) than in AP- patients. There was a significant difference in total cross-sectional area of the LCA between the two groups (20.7±4.8 versus 24.1±6.9 mm², P<.05). Although RCA size was similar in AP+ patients and control subjects (8.9±2.3 versus 9.0±4.7 mm², P=NS), its size was significantly increased in AP- patients (11.7±4.0 mm²; P<.01 versus AP+). Normalization of coronary artery size per 100 g muscle mass was associated with a loss of the significant differences between the groups.

Coronary Flow Measurements
The subgroup of patients in which coronary flow measurements were studied did not differ significantly from the patient population as a whole with regard to the degree of aortic stenosis, LVMM, or LV wall stress. Of the 29 patients, 27 had no angiographic evidence of atherosclerosis, and only 2 showed minor irregularities of the arterial wall in the coronary angiogram, 1 with and 1 without anginal symptoms.

Resting coronary sinus blood flow was significantly higher in patients with aortic stenosis than in control subjects (252±99 versus 170±35 mL/min, P<.05), whereas no difference was observed between the two subgroups (227±75 versus 260±94 mL/min, P=NS). Maximal blood flow, however, was significantly reduced in AP+ compared with AP- patients (341±114 versus 481±215 mL/min, P<.05). There was no significant difference in coronary resistance at rest or after administration of dipyridamole between the two groups or control subjects. Conversely, coronary flow per 100 g LVMM was significantly lower in AP+ patients compared with control subjects (Fig 1) and was significantly lower after infusion of dipyridamole in AP+ patients compared with AP- patients or control subjects. There was no difference in coronary resistance per 100 g LVMM at rest or after infusion of dipyridamole between AP+ and AP- patients or control subjects (Fig 1).

View larger version (43K): [in this window] [in a new window]   Figure 1. Coronary sinus blood flow (CSBF; top) and coronary resistance (CR; bottom) before and after dipyridamole infusion. Resting coronary blood flow per 100 g LVMM is similar in all three groups, whereas maximal flow is significantly lower in AP+ than in AP- patients or control subjects. Conversely, there is no difference in resting or minimal coronary resistance per 100 g LVMM between the three groups.

Coronary flow reserve was significantly reduced in AP+ compared with AP- patients or control subjects (Fig 2). Correspondingly, coronary resistance ratio was increased in AP+ compared with AP- patients or control subjects (Fig 2).

View larger version (37K): [in this window] [in a new window]   Figure 2. Coronary flow reserve (CFR; top) and coronary resistance ratio (CRR; bottom) in AP+ patients and control subjects. Coronary flow reserve is significantly reduced in AP+ patients compared with AP- patients or control subjects. Conversely, coronary resistance ratio is significantly increased in AP+ and AP- patients compared with control subjects.

Correlations
There was a significant correlation between LCA and LVMM for all patients (r=.60, P<.0001; Fig 3), with no difference in slope or intercept between the two groups. Other correlations were found between coronary resistance ratio and arteriovenous oxygen difference (r=.51, P<.005) or pulmonary vascular resistance (r=.60, P<.001).

View larger version (21K): [in this window] [in a new window]   Figure 3. Correlation between LVMM and LCA cross-sectional area (CSA). A linear relation was observed between these two parameters, indicating adequate vessel growth with regard to LVMM. C indicates control subjects. Given are the regression line and the 95% confidence limits.

	Discussion

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The occurrence of AP in patients with severe aortic stenosis is usually associated with an advanced stage of the disease. Ross and Braunwald¹¹ have shown that survival is severely impaired in the presence of angina (mean survival, 5 years), syncope (survival, 3 years), or heart failure (survival, 1.5 years). The pathogenesis of AP in the absence of significant coronary artery narrowing, however, is not yet clear, although it has been assumed that in the presence of severe myocardial hypertrophy with an increased extravascular resistance, a reduction in subendocardial perfusion may occur.^{5 30} Parallel to subendocardial hypoperfusion, a reduction in coronary flow reserve has been reported in severe aortic valve disease^{8 10 31 32} that was restored after successful valve replacement with normalization of LVMM.³¹ However, not all patients with severe aortic stenosis develop AP; eg, 51% of our patients with severe operative aortic stenosis had no anginal pain. Thus, the purpose of the present study was to evaluate the pathophysiological mechanisms involved in the development of AP.

LV Hypertrophy and Myocardial Perfusion
Most of our patients (78%) had severe LV hypertrophy with a mass >200 g,³³ which represents approximately a doubling of the normal LVMM compared with control subjects. Interestingly, our AP+ patients had a smaller LVMM than the AP- patients, suggesting that not the total mass but the appropriateness of LV hypertrophy is essential for the development of anginal symptoms. Inappropriate myocardial hypertrophy seems to be involved in the pathophysiology of AP because LVMM was relatively too small for the high wall stress in our study group (Fig 4). However, ejection fraction is maintained despite an increased wall stress, suggesting an augmentation or at least the maintenance of myocardial contractility.

View larger version (28K): [in this window] [in a new window]   Figure 4. Relationship between LV circumferential peak systolic wall stress (Speak) and LVMM in AP+ and AP- patients. AP+ patients have an increased wall stress with inadequate hypertrophy compared with AP- patients. See text for explanations.

The role of ventricular wall stress in the presence of LV hypertrophy has been widely discussed. Wall stress is an important determinant of myocardial oxygen consumption, myocardial contractile state, and diastolic function.³⁴ A high wall stress has been associated with a less favorable prognosis because of electrical instability and myocardial hypoperfusion.³⁴ According to Gaasch,³⁵ the ratio of LV radius to wall thickness has been used to classify the appropriateness of LV hypertrophy (Fig 4) into inappropriate (low wall stress), appropriate (normal wall stress), or inadequate (high wall stress). Inadequate hypertrophy in association with abnormal stress-shortening relations has been associated with changes in myocardial contractility and thus may predict an impaired postoperative outcome in these patients. Primary and secondary changes in the neurohumoral, molecular, metabolic, and genetic systems have been discussed and are thought to influence cardiac hypertrophy in response to chronic pressure overload.^{36 37} In particular, a decrease in myosin ATPase activity, a transition of myosin heavy chains, and an increase in insulin-like growth factor-I have been described.³⁸ Moreover, an activation of the sympathetic nervous system and renin-angiotensin system as well as a primary genetic disposition have been discussed to influence left ventricular hypertrophy.³⁴

Parallel to the inadequate LV hypertrophy and increased wall stress (Fig 4), smaller coronary arteries with a reduced coronary flow reserve were observed in the present study, supporting the concept that the adaptation of the LV and its coronary size are inadequate in respect to actual loading conditions. This may explain the occurrence of AP.

Other determinants of myocardial oxygen consumption such as heart rate, myocardial contractility, ejection time, and hemoglobin were comparable in the two groups except for systolic and diastolic wall stress, as discussed above. Thus, not only is the oxygen supply reduced (decreased coronary flow reserve), but at the same time oxygen demand is enhanced (increased wall stress). This mismatch between supply and demand could explain the occurrence of subendocardial ischemia with AP.

Myocardial Ischemia in Pressure-Overload Hypertrophy
Metabolic studies of patients with aortic stenosis have shown that coronary sinus lactate is normal at rest. Under conditions of metabolic stress, however, most patients with aortic stenosis and normal coronary arteries elicit either a decrease in lactate extraction or an increase in lactate production as an indicator of myocardial ischemia.^{39 40} In patients with high pressure gradients, coronary blood flow cannot be increased under stress.³⁹ Clinical signs of myocardial ischemia have been gained in aortic stenosis from exercise thallium-201 tomography with perfusion defects in 43% of all patients with normal coronary arteries.⁴¹ Furthermore, ST-segment analysis of 24-hour Holter monitoring showed transient myocardial ischemia in patients with hypertensive LV hypertrophy and normal coronary angiograms.³⁰

Clinical Implications
From a clinical standpoint, inadequate LV hypertrophy with small coronary arteries and reduced coronary flow reserve can explain the occurrence of subendocardial ischemia during high flow situations such as exercise (Fig 5). Activation of the sympathetic system with coronary vasoconstriction and elevation of systolic blood pressure do not seem to be likely because heart rate was similar in the two groups. Thus, other factors such as a lack of growth stimuli or molecular changes may be responsible for the inadequate LV hypertrophy with increased wall stress and reduced coronary flow reserve (Fig 5).

View larger version (17K): [in this window] [in a new window]   Figure 5. Pathophysiology of myocardial ischemia in AP+ patients. LV hypertrophy tends to normalize LV wall stress, but in the presence of inadequate hypertrophy, wall stress is elevated. This leads to an increase in myocardial oxygen consumption and augmentation of extravascular compressive forces. As a result, coronary flow reserve is reduced. Because of LV hypertrophy, diffusion distance is increased and capillary density is decreased. Mechanisms in the presence of inadequate hypertrophy are shown by open arrows.

Study Limitations
In a study subgroup, coronary flow and flow reserve were assessed by coronary sinus thermodilution technique. This method is unable to measure the flow in specific ventricular layers or regions²⁷ and may be inaccurate after interventions leading to coronary sinus reflux.⁴² In the absence of coronary artery disease and no known movement of the catheter, the thermodilution technique, however, is adequate for measuring relatively slow and large changes of coronary blood flow such as that observed in our study.

For the measurement of maximal vasodilator capacity, dipyridamole was used.^{29 43} It is recognized that dipyridamole at the chosen dose (0.5 mg/kg) does not always produce maximal coronary vasodilation.⁴⁴ Dipyridamole infusion lasted 15 minutes to minimize systemic effects on heart rate and blood pressure.^{28 45} A decrease in blood pressure would have been detrimental in patients with aortic stenosis.

Determination of coronary artery size was performed by quantitative coronary angiography. Other determinants of coronary artery size such as age, body surface area, physical working capacity, vessel dominance, and coronary vasomotor tone have been evaluated. First, variable effects of age on LCA size have been reported.^{46 47} In the present study, there was a positive correlation in control subjects (r=.62) but no correlation in either patient group. Thus, no clear statement on the effect of age on coronary artery size can be made from the present data. Second, body size may have a direct effect on coronary dimensions. However, no correlation was found in control subjects or in the two patient groups. Because no differences in body surface area between control subjects and patients with aortic stenosis were found, this factor is unlikely to have influenced the results of our study. Third, physical working capacity has been reported to directly influence coronary artery size.¹⁷ Although all patients had a significantly lower working capacity than control subjects, their coronary artery size was significantly larger. Thus, it is unlikely that the enlargement in coronary artery size was mediated by physical working capacity. However, AP+ patients had a lower working capacity and smaller coronary arteries than AP- patients, probably because symptom-limited exercise testing was performed.

It is well known that a close relation exists between myocardial territory size and proximal coronary diameter.^{48 49} In the present study, however, coronary dominance was the same in control subjects and patients with aortic stenosis. Moreover, after the patients were grouped according to LCA or RCA dominance, the same patterns of variation in the LCA and RCA dimensions were observed.

Conclusions
The present study confirms that 50% of all patients with severe aortic stenosis have AP, which was found to be associated with inadequate LV hypertrophy, increased LV peak systolic wall stress, and small coronary artery dimensions with a reduced coronary flow reserve. This suggests that myocardial ischemia may be due to hypoperfusion of the myocardium under high-flow and high-demand situations such as those seen in severe pressure- and volume-overload hypertrophy.

	Selected Abbreviations and Acronyms

 

AP = angina pectoris AP- = without AP AP+ = with AP LAD = left anterior descending coronary artery LCA = left coronary artery LCx = left circumflex artery LV = left ventricle/left ventricular LVMM = LV muscle mass NYHA = New York Heart Association RCA = right coronary artery

Received May 5, 1996; revision received September 23, 1996; accepted October 7, 1996.

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