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Ann Thorac Surg 2009;87:715-719. doi:10.1016/j.athoracsur.2008.11.078
© 2009 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Coronary Microcirculatory Dysfunction in Aortic Stenosis: Myocardial Contrast Echocardiography Study

Shigeru Miyagawa, MDa,*, Takafumi Masai, MDa, Hirotsugu Fukuda, MDa, Takashi Yamauchi, MDa, Katsuomi Iwakura, MDb, Hiroshi Itoh, MDb, Yoshiki Sawa, MDc

a Department of Cardiovascular Surgery, Sakurabashi Watanabe Hospital, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
b Department of Cardiology, Sakurabashi Watanabe Hospital, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
c Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Accepted for publication November 24, 2008.

* Address correspondence to Dr Miyagawa, Umeda 2-4-32 Kitaku, Osaka, 530-0001, Japan (Email: miyagawa{at}surg1.med.osaka-u.ac.jp).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The aims of this study were to quantify the microcirculatory dysfunction in aortic stenosis (AS) and to measure the changes in transmural perfusion after aortic valve replacement (AVR), using quantitative myocardial contrast echocardiography.

Methods: Myocardial contrast echocardiography was used to quantify the myocardial blood flow in both the subendocardium and subepicardium in 22 patients with AS (A group), before, 2 weeks after, and 1 year after AVR. Healthy volunteers (C group, n = 10) and patients with mitral regurgitation (M group, n = 10) were included as controls. Triggered myocardial contrast echocardiography was performed, and the endosystolic 1.5 harmonic images were recorded.

Results: The myocardial contrast echocardiography study showed that, before AVR, the myocardial blood flow in the subendocardium was significantly lower in the A group than in the other groups (CI = –18.6 ± 3.0 dB, –11.8 ± 4.1 dB, and –12.7 ± 4.1 dB, respectively, in A, M, and C groups; p < 0.05), whereas there was no significant difference in blood flow in the subepicardium. In the A group, the myocardial blood flow in the subendocardium was significantly improved 2 weeks after AVR (–13.1 ± 3.5 dB after AVR), and this improvement was preserved 1 year after AVR.

Conclusions: In patients with AS, the myocardial blood flow in the subendocardium declined preoperatively, and the coronary microcirculatory function was recovered after AVR in both the short and long term.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
In patients with aortic valve stenosis (AS), left ventricular hypertrophy (LVH) can develop and lead to microcirculatory dysfunction, even when the coronary arteries are normal [1], by reducing the coronary vasodilator reserve [2, 3]. The reduced coronary vasodilator reserve in LVH might be caused by perimyocytic fibrosis [4], by a decreased number of resistance vessels per unit weight [5], or by reduced diastolic perfusion mainly owing to a decrease in maximal myocardial blood flow [3].

Aortic valve replacement (AVR) causes LVH to regress in most AS patients [6], and several reports suggest that this regression may lead to improved coronary blood flow. One group reported that the coronary blood flow measured by positron emission tomography remained improved 1 year after AVR [7]. Another group demonstrated, using the coronary sinus thermodilution technique, a distinct improvement in coronary flow reserve by 12 to 52 months after AVR [8]. Another study, which used echocardiography, showed an increased coronary flow reserve 6 months after AVR [9]. Although all these reports revealed a long-term improvement in coronary blood flow after AVR, it has remained unclear whether the coronary blood flow improves in the short term after AVR.

A new calibration technique was developed to quantify microvascular integrity using myocardial contrast echocardiography (MCE), and it has been used to measure the transmural extent of microvascular damage in myocardial infarction patients [10]. However, there is no clinical report in which MCE was used to measure the extent of abnormal myocardial blood flow in AS patients or its improvement after AVR; moreover, there is no report at all on the change in myocardial blood flow within the first few weeks after AVR.

Therefore, in this study, we addressed the following specific questions: (1) Can we use MCE to determine abnormal subendocardial or subepicardial myocardial blood flow in patients with AS? (2) Does the abnormal myocardial blood flow improve in the short or long term after AVR?


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Profile
Patients with isolated moderate or severe AS were enrolled. We selected patients who had no more than minimal aortic regurgitation, and for whom angiography revealed no significant coronary stenoses in the region targeted by the MCE. Twenty-two suitable patients were identified. Three patients have symptoms of angina and others suffered from dyspnea on effort. The Research and Ethics Committees of all of the participating hospitals approved the study, and the subjects gave informed written consent before any participation. Ten normal volunteers (all male; mean age 35 ± 8 years) and patients with mitral regurgitation (more than grade 3) without LVH (male n = 5, female n = 5; mean age 60 ± 12 years) were also examined to obtain control contrast intensity (CI) values.

Surgical Procedure
Twenty-two valves were implanted in a standard manner (19 bioprostheses and 3 mechanical valves). The valve size ranged from 17 to 25 mm (20.5 ± 1.8 mm). The patients were examined about 1 week before the operation (preoperative period, 6 ± 3 days), 2 weeks after the operation (15 ± 4 days), and 1 year after the operation (340 ± 70 days). Thus, we observed the effect of load reduction in the short and long term after AVR.

Contrast Ultrasonography
The MCE examination was performed with Levovist (Schering Japan, Osaka, Japan) as the contrast agent (300 mg/mL). Two-dimensional echocardiography was performed in the preoperative period, 2 weeks after AVR, and 1 year after AVR, using the SONOS 5500 ultrasound system (Philips Medical Systems, Andover, MA) with an S3 probe, as described previously [10]. Briefly, apical four-chamber views were obtained. The mechanical index and dynamic range were adjusted to the maximum values. The gain was adjusted to minimize artifacts on the baseline study. Levovist solution (3 mL) was injected at a rate of 0.5 mL/s with a volumetric pump (PULSAR; Medrad, Indianapolis, IN). We obtained end-systolic images every four heartbeats. We adjusted the triggering time and reduced the motion artifact as much as possible. The patients were examined in a shallow left lateral decubitus position. The heart was first imaged in the two-dimensional mode in long-axis views. This view was used to position the M-mode cursor perpendicular to the left ventricle (LV) anterior and posterior wall. The LV dimension at end-diastole (LVDd) and LV dimension at end-systole (LVDs) were determined. The ejection fraction (EF) of the LV was calculated as follows:



Formula 1

(1)

Quantitative Evaluation of Myocardial Blood Flow
The MCE was performed as described previously [10], and the images were analyzed off-line using the Volu-Map-445 image analyzing system (YD, Ikoma, Japan). This method generates a quantitative, color-coded representation of the blood flow in the subendocardial layer with 2-dB resolution. Briefly, the CI was determined in a region of interest (ROI [2- to 3-mm width]) in each target region (subendocardial and subepicardial layer) of the LV mid lateral-apical lateral wall and in each adjacent LV cavity. We measured CI both in the ROI and LV cavity 5 times at the same time and within same patients (Fig 1). We calculated the calibrated CI (dB) in the target region as the difference between the mean myocardial CI and the LV cavity CI as follows:


Figure 1
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  		Fig 1. Measurement of contrast intensity in subendocardium and subepicardium of left ventricle (LV) and adjacent LV cavity on myocardial contrast echocardiography image. Circles indicate region of interest (ROI) in targeted region. (Black circle = ROI in LV cavity; red circle = ROI in subendocardial target region; green circle = ROI in subepicardial target region.)

 


Formula 2

(2)

Because the measurements are made in decibels, we subtracted cavity value from myocardial value to derive a relative blood volume fraction.

Statistical Analysis
Data are expressed as the mean ± SD and were subjected to multiple analysis of variance using the StatView 5.0 program (Abacus Concepts, Berkeley, CA). We used a paired t test to analyze the changes in myocardial blood flow, aortic valve gradient (AVG), aortic valve area (AVA), ejection fraction, and LV mass after AVR. The other numerical data were analyzed by one-way analysis of variance with the Tukey-Kramer post-hoc test. Statistical significance was defined as a p value of less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Population Characteristics
The age of the patients was 56 to 81 years (72.3 ± 8.2). All the subjects had at least moderate AS preoperatively (peak AVG, 71.7 ± 24.5 mm Hg [31 to 108]; AVA, 0.74 ± 0.33 cm2 [0.2 to 1.49]). Two weeks after the operation, the peak AVG fell (to 24.3 ± 8.5 mm Hg [9 to 31]; p < 0.05), and the AVA increased (to 1.47 ± 0.30 cm2 [0.98 to 2.01]; p < 0.05). One year after the operation, the peak AVG was 31.3 ± 13.6 mm Hg [14 to 55], and the AVA was 1.31 ± 0.32 cm2 [0.8 to 1.9]. The ejection fraction was unchanged 2 weeks after AVR, but had significantly improved 1 year after AVR (preoperative versus 1 year: 62.5 ± 10.6 versus 69.4 ± 6.9%; p < 0.05; Fig 2a).


Figure 2
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  		Fig 2. Changes in ejection fraction and left ventricle (LV) mass after aortic valve replacement (AVR). (a) The ejection fraction did not change 2 weeks after AVR, but had significantly improved 1 year after AVR. *p < 0.05 versus preoperative value. (b) The LV mass was not reduced significantly 2 weeks after AVR, but had decreased significantly by 1 year after AVR. *p < 0.05 versus preoperative value.

 
Left Ventricular Mass and Regression of Hypertrophy After AVR
All subjects fulfilled the criteria for LVH (LV mass, 245.7 ± 61.6 g [365 to 165]) preoperatively. Two weeks after the operation, the LV mass did not show a significant change, but 1 year after the operation, a significant reduction was observed (175.1 ± 38.7 g [219 to 128]; p < 0.05; Fig 2b).

Myocardial Blood Flow in Hypertrophic Myocardium
The MCE study showed that the myocardial blood flow in the subendocardium was significantly lower in the A group than in the other groups (–18.46 ± 2.56 dB, –11.80 ± 4.05 dB, and –12.68 ± 4.13 dB in A, M, and C groups, respectively; p < 0.05), whereas there was no significant difference in the subepicardium (–20.03 ± 4.83 dB, –17.49 ± 4.06 dB, and –16.53 ± 1.69 dB in A, M, and C groups, respectively; p = not significant; Fig 3).


Figure 3
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  		Fig 3. Myocardial blood flow in hypertrophic myocardium. Myocardial contrast echocardiography analysis showed that the myocardial blood flow in the subendocardium was significantly lower in the A group than in the control groups, although no significant difference was observed in the subepicardium. *p < 0.05. (A = aortic stenosis group; M = mitral regurgitation group; C = normal control group.)

 
Changes in Myocardial Blood Flow After AVR
In the A group, the myocardial blood flow in the subendocardium was significantly improved 2 weeks after AVR (–18.6 ± 3.0 and –13.1 ± 4.7 dB preoperatively and at 2 weeks, respectively; p < 0.05), and this improvement was preserved 1 year after AVR (–12.7 ± 1.6 dB; Fig 4).


Figure 4
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  		Fig 4. Changes in myocardial blood flow after AVR. In patients with aortic stenosis (squares), the myocardial blood flow in the subendocardium had improved significantly 2 weeks after AVR, and this improvement was preserved 1 year later. There were no significant differences between the aortic stenosis group and the control group (circles) 2 weeks and 1 year after the operation. *p < 0.05 versus preoperative (Pre) value. (n.s. = not significant.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
In this study, we used MCE to quantify the myocardial blood flow in cases of cardiac hypertrophy caused by aortic stenosis. We detected a significant decrease in myocardial blood flow in the subendocardium, compared with the control groups, and an improvement in the myocardial blood flow 2 weeks after AVR. In the mitral regurgitation group (nonhypertrophic valvular disease), there was no difference in myocardial blood flow in either the subendocardium or the subepicardium compared with the normal control group. The myocardial blood flow may be decreased because of the hypertrophy.

Myocardial contrast echocardiography was previously used to quantify the deterioration of myocardial blood flow in ischemic myocardium [11]. This is the first clinical report in which MCE was used to evaluate the deterioration of myocardial blood flow in the hypertrophic myocardium.

A recent report showed a decline in myocardial blood flow in the hypertrophic myocardium using positron emission tomography [7], but there has been no study showing an improvement in myocardial blood flow in the first few weeks after AVR, with any technique. Ours is the first to show this. Myocardial contrast echocardiography is relatively easy to use and is not invasive. We therefore think that MCE is suitable for observing changes in myocardial blood flow over time.

The mechanisms responsible for the recovered myocardial blood flow after AVR are reported to be associated with improvements in the coronary vasodilator reserve in LVH [8, 9] and in diastolic perfusion [7]. We found that the myocardial blood flow was improved 2 weeks after AVR, which suggested that the recovery of the deteriorated diastolic perfusion might be an important mechanism underlying this improvement.

Our study showed that the blood flow in the myocardium 1 year after AVR was slightly improved over that at 2 weeks after AVR, although this change was not significant. We speculate that the improvement in perimyocytic fibrosis and the amelioration of the coronary vasodilator reserve might contribute to the positive change in myocardial blood flow observed 1 year after the operation.

It is interesting that the blood flow recovered significantly even though the LV mass volume had not decreased at the 2-week post-AVR MCE measurement. We believe it will be important to investigate the process and mechanism for the reverse remodeling of the hypertrophic myocardium in AS after AVR in future studies.

We have obtained a finding pertaining to the pathophysiology of AS in this study. It is likely that the early increase in microvascular function is involved in, and could initiate, the long-term process of "positive" remodeling after AVR. Decreased wall stress on endocardium accompanied with lower LV mean pressure and the decreased LV end-diastolic pressure that allows blood to flow into the endocardial layer during diastole after AVR may be one of the mechanisms explaining the early increase in subendocardial blood flow.

This study had some limitations. One was the small number of patients, and another was the incomplete follow-up at 1 year. In addition, we could not compare the MCE results with those of well-established techniques such as positron emission tomography or perform a sensitivity and specificity study. Another was that quantity of epicardial blood flow with MCE may be a little bit inaccurate because of its distance from the blood pool within the LV cavity, and that may represent a limitation in the attempt to compare subendocardial to subepicardial blood flow.

In conclusion, we found that MCE could be used to measure the myocardial blood flow in the hypertrophic myocardium and is applicable for evaluating the distressed myocardial blood flow in AS patients and its improvement after AVR.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We wish to thank Masakazu Ueda, Rie Terai, Kayo Komura, Kazuya Yoshioka, Fumi Torikawa, Maya Nakagawa, and Michiko Matsunoya for their excellent technical assistance.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries N Engl J Med 1982;307:1362-1366.[Medline]
  2. Choudhury L, Rosen SD, Patel D, Nihoyannopoulos P, Camici PG. Coronary vasodilator reserve in primary and secondary left ventricular hypertrophy: a study with positron emission tomography Eur Heart J 1997;18:108-116.[Abstract/Free Full Text]
  3. Rajappan K, Rimoldi OE, Dutka DP, et al. Mechanisms of coronary microcirculatory dysfunction in patients with aortic stenosis and angiographically normal coronary arteries Circulation 2002;105:470-476.[Abstract/Free Full Text]
  4. Schwartzkopff B, Frenzel H, Dieckerhoff J, et al. Morphometric investigation of human myocardium in arterial hypertension and valvular aortic stenosis Eur Heart J 1992;13(Suppl D):17-23.[Abstract/Free Full Text]
  5. Marcus ML, Harrison DG, Chilian WM, et al. Alteration in the coronary circulation in hypertrophied ventricles Circulation 1987;75:119-125.
  6. Monrad ES, Hess OM, Murakami T, Nonogi H, Corin WJ, Krayenbuehl HP. Time course of regression of left ventricular hypertrophy after aortic valve replacement Circulation 1988;77:1345-1355.[Abstract/Free Full Text]
  7. Rajappan K, Rimoldi OE, Camici PG, Bellenger NG, Pennell DJ, Sheridan DJ. Functional changes in coronary microcirculation after valve replacement in patients with aortic stenosis Circulation 2003;107:3170-3175.[Abstract/Free Full Text]
  8. Eberli FR, Ritter M, Schwitter J, et al. Coronary reserve in patients with aortic valve disease before and after successful aortic valve replacement Eur Heart J 1991;12:127-138.[Abstract/Free Full Text]
  9. Hildick-Smith DJ, Shapiro LM. Coronary flow reserve improves after aortic valve replacement for aortic stenosis: an adenosine transthoracic echocardiography study J Am Coll Cardiol 2000;36:1889-1896.[Medline]
  10. Yano A, Ito H, Iwakura K, et al. Myocardial contrast echocardiography with a new calibration method can estimate myocardial viability in patients with myocardial infarction J Am Coll Cardiol 2004;43:1799-1806.[Medline]
  11. Takagi Y, Ohmori K, Yukiiri K, et al. Quantitative assessment of coronary stenosis by harmonic power Doppler with a simple pulsing sequence and vasodilator stress in patients J Am Coll Cardiol 2003;41:2060-2067.[Medline]

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