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(Circulation. 2003;107:3170.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Functional Changes in Coronary Microcirculation After Valve Replacement in Patients With Aortic Stenosis

Kim Rajappan, MD; Ornella E. Rimoldi, MD; Paolo G. Camici, MD; Nicholas G. Bellenger, MD; Dudley J. Pennell, MD; Desmond J. Sheridan, MD, PhD

From the Academic Cardiology Unit, St Mary’s Hospital (K.R., D.J.S.); MRC Clinical Sciences Centre, Hammersmith Hospital (K.R., O.E.R., P.G.C.); and Cardiovascular MR Unit, Royal Brompton Hospital, Imperial College School of Medicine and National Heart and Lung Institute (K.R., N.G.B., D.J.P.), London, UK.

Correspondence to Professor Desmond J. Sheridan, Academic Cardiology Unit, St Mary’s Hospital, Division of National Heart and Lung Institute, 10th Floor QEQM Wing, South Wharf Rd, London W2 1NY, UK. E-mail d.sheridan{at}ic.ac.uk

	Abstract

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Background— Increased extravascular compression and reduced diastolic perfusion time (DPT), rather than vascular remodeling, influence coronary microcirculatory dysfunction in aortic stenosis (AS). However, alterations after aortic valve replacement (AVR) remain unclear. The aim of the present study was to quantify changes in transmural perfusion and coronary vasodilator reserve (CVR), a measure of microcirculatory function, after AVR and determine the relative contribution of left ventricular mass (LVM) regression, change in aortic valve area (AVA), and DPT.

Methods and Results— Twenty-two patients with AS were studied before and 1 year after AVR using echocardiography to measure AVA, cardiovascular magnetic resonance to assess LVM, and positron emission tomography to quantify resting and hyperemic myocardial blood flow (MBF) and CVR. Regression of LVM occurred in all patients (from 129±30 to 94±24 g/m²; P<0.0001), and there was a significant reduction in resting MBF and increase in CVR corrected for rate-pressure product after AVR, although these changes displayed marked heterogeneity. Regression of LVM was linearly related to change in resting total LV blood flow but not CVR. Increase in hyperemic MBF and CVR transmurally was directly related to the increase in AVA after AVR. A significant relationship existed between the change in hyperemic DPT (1.0±4.7 s/min [range, 6.8 to 9.6]) and change in transmural CVR (y=0.08x+0.18; r=0.44; P=0.04).

Conclusions— Changes in coronary microcirculatory function in patients with AS after AVR are not directly dependent on regression of LVM. Reduced extravascular compression and increased DPT are proposed as the main mechanisms for improvement in MBF and CVR after AVR.

Key Words: valves • microcirculation • surgery • hypertrophy • regression

	Introduction

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Development of left ventricular hypertrophy (LVH) in patients with aortic valve stenosis (AS) is associated with abnormalities in microcirculatory function, as demonstrated by a reduced coronary vasodilator reserve (CVR),^1,2 and this may explain anginal symptoms despite angiographically normal coronary arteries.³ Perimyocytic fibrosis⁴ and reduction in the number of resistance vessels per unit weight⁵ may contribute to the reduction in CVR in LVH secondary to hypertension and hypertrophic cardiomyopathy. However, recent work suggests that increased systolic impedance to coronary flow as a result of perivascular compression⁶ and, most importantly, a reduction in diastolic perfusion² are the primary contributors to impairment of coronary microcirculatory function in AS, predominantly because of curtailment in maximal myocardial blood flow (MBF).

See p 3121

Aortic valve replacement (AVR) is accompanied by regression of LVH in most AS patients.⁷ This is associated with an improvement in coronary blood flow in patients after AVR measured both invasively⁸ and noninvasively.⁹ However, the effect of AVR on microcirculatory dysfunction and the role that hemodynamic changes and LVH regression play remain unclear. The aim of the present study was to use positron emission tomography (PET), cardiovascular magnetic resonance (CMR), and echocardiography to investigate alterations in coronary microcirculatory function in patients with AS after AVR and to determine the relative contribution of factors that negatively influence the CVR.

	Methods

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Patient Selection
Patients with isolated moderate or severe AS were enrolled. No patient had more than minimal aortic regurgitation (grade ≤1/4), and all had angiographically normal coronary arteries. Patients were excluded if they had asthma, because this precluded use of dipyridamole as a stressor agent, or if they were taking a ß-blocker, ACE inhibitor, calcium channel blocker, or diuretic therapy. Twenty-two suitable patients were identified. The research and ethics committees of all of the participating hospitals approved the study, and the subjects gave informed written consent before any investigations. All procedures were carried out in accordance with institutional guidelines, and radiation exposure was approved by the UK Administration of Radioactive Substances Advisory Committee.

Echocardiography
Transthoracic echocardiography was performed using an ATL HDI 3000 (ATL Ltd) cardiac ultrasound scanner, according to American Society of Echocardiography guidelines.¹⁰ Continuous wave (CW) Doppler was used to derive the peak transvalvular pressure gradient across the aortic valve (peak AVG).¹¹ Aortic valve area (AVA) was calculated according to the ACC/AHA guidelines to determine severity of aortic stenosis.¹² Left ventricular ejection time (LVET) was measured on the CW Doppler trace, from opening to closure of the aortic valve. The mean of 3 separate readings was used for each parameter.

Cardiovascular Magnetic Resonance
LV mass (LVM) was assessed using a Picker Edge 1.5-T scanner (Picker) with ECG triggering and a standard body coil as described previously.² Contiguous 10-mm SA slices were acquired during a single breath-hold using a segmented gradient-echo Turbo-FLASH sequence, and LVM was calculated.¹³ LVM was divided by body surface area to give LVM index (LVMI). Presence of LVH was determined using criteria described by Lorenz et al¹⁴ (LVMI ≥113 or 95 g/m² in men and women, respectively). Image analysis was performed on a personal computer using dedicated software developed in house (CMRtools Imperial College). In our center, the interstudy percentage variability is 3% for LVM.¹³

Positron Emission Tomography
The studies were performed on an ECAT EXACT 3D positron tomograph (CTI) with an axial field of view of 23.4 cm and transaxial spatial resolution of 6.7±0.1 mm full-width half-maximum.¹⁵ The sinograms obtained were corrected, reconstructed, and rebinned into 2D sinograms, and factor images were generated as described previously.² The factor images were resliced into short-axis images in an orientation perpendicular to the long axis of the left ventricle. Regions of interest were defined on these images corresponding to septal, anterior, lateral, and posterior walls of the left ventricle in the apical, mid, and basal planes. A separate set of regions of interest was defined for the right ventricular cavity and left atrium. Tissue time activity curves were then generated from the dynamic image and fitted to a single tissue compartment tracer kinetic model to give values of MBF (mL/min per g). Previous work in our institution has shown that the values for MBF and CVR are highly reproducible (mean difference of 10% and 2%, respectively).¹⁶ CVR was calculated as the ratio of hyperemic MBF (after dipyridamole, 0.56 mg/kg infused IV over 4 minutes) to resting MBF. Rate-pressure product (RPP) corrected CVR was calculated using resting MBF corrected for RPP (MBF_corr). To calculate total ventricular blood flow (mL/min), the transmural MBF (mL/min per g) measured was multiplied by LVM (g) assessed by CMR.

Diastolic Perfusion Time Calculation
The R-R interval (ms) was measured at rest and during hyperemia on the ECGs obtained during the PET scans. Diastolic perfusion time (DPT) (s/min), determined as [(R-R interval-LVET)xheart rate/1000],¹⁷ was calculated both at rest and at maximal heart rate.

Surgical Technique
Twenty-one valves were inserted in a standard manner (7 bioprostheses and 14 mechanical valves). One prosthesis was inserted as a homograft aortic root replacement with reimplantation of the coronary arteries. Valve size ranged from 19 to 27 mm (23±2 mm). Scans were performed within a 2-week preoperative period (8±6 days) and 1 year postoperatively (360±20 days).

Statistical Analysis
All values are reported as mean±SD (range). All data were analyzed using a commercially available computer analysis package (Graphpad PRISM, Graphpad software Inc). Data were tested for equality of variance with F-test. Normal distribution was assessed by the Kolmogorov-Smirnov test. A paired Student’s t test was used to assess differences between continuous variables, and linear regression was used to test the relationship between variables. P<0.05 was considered significant.

	Results

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Population Characteristics
Age ranged from 41 to 80 years (65.5±9.7 years). All subjects had at least moderate AS preoperatively (peak AVG, 90±20 mm Hg [52 to 117]; AVA, 0.73±0.25 cm² [0.32 to 1.29]), and 16 of 22 fulfilled criteria for severe aortic stenosis.¹⁸ Postoperatively, peak AVG fell (to 18.7±7 mm Hg [12 to 36]; P<0.0001) and AVA increased (to 2.34±0.74 cm² [1.06 to 3.67]; P<0.0001). All subjects had normal systolic LV function both preoperatively (ejection fraction, 73±6% [56 to 81]) and postoperatively (ejection fraction, 75±6% [60 to 83]; P=0.16).

Hemodynamic Data
There was no difference between patients’ heart rates preoperatively and postoperatively, either at rest (63±8 versus 68±13 beats/min) or during hyperemia (79±9 versus 82±17 beats/min). Similarly, there was no difference in systolic blood pressure (SBP) at rest (133±25 versus 137±25 mm Hg), diastolic blood pressure (DBP) at rest (73±11 versus 75±9 mm Hg), and DBP during hyperemia (70±11 versus 67±17 mm Hg). There was a significant increase in hyperemic SBP (125±22 versus 134±25 mm Hg; P<0.05) and both resting RPP (8229±1316 versus 9199±1558 beats/min · mm Hg; P<0.05) and hyperemic RPP (9866±2036 versus 10910±2719 beats/min · mm Hg; P<0.05). The different relationship of rest and hyperemic SBP seen postoperatively was similar to that seen in healthy volunteers.¹⁹

Left Ventricular Mass and Regression of Hypertrophy
Fifteen of the 22 subjects fulfilled CMR criteria for LVH (LVMI, 129±30 g/m² [83 to 199]) preoperatively. Postoperatively there was a reduction in LVMI in all patients by 27±9% to 94±24 g/m² [66 to 167] (P<0.0001), and only 5 patients still had LVH (Table 1).

View this table: [in this window] [in a new window]   TABLE 1. Demographic, Echocardiographic, Cardiovascular Magnetic Resonance, and Microcirculatory Function Data

Myocardial Blood Flow and Coronary Microcirculatory Function
There were no significant changes after AVR in resting MBF (from 1.08±0.27 to 1.01±0.39 mL/min per g [6.4±27.6%]; P=0.27), hyperemic MBF (from 2.17±0.82 to 2.27±1.18 mL/min per g [7.8±44.6%]; P=0.61), or CVR (from 2.02±0.60 to 2.28±0.74 [21.5±54.1%]; P=0.17), but resting MBF_corr did decrease (from 1.33±0.31 to 1.05±0.33 mL/min per g [-20.7±19.4%]; P=0.00003), and CVR corrected for RPP (CVR_corr) increased (from 1.62±0.39 to 2.12±0.63 [35.8±42.1%]; P=0.0006) (Tables 1 and 2). Resting total ventricular blood flow decreased by 31.4±22.7% (from 256±82 to 172±71 mL/min) and hyperemic total ventricular blood flow decreased by 22.9±33.1% (from 504±181 to 381±199 mL/min).

View this table: [in this window] [in a new window]   TABLE 2. Changes in Myocardial Blood Flow and Diastolic Perfusion Time After Aortic Valve Replacement

Relationships Between Measured Parameters
There was no relationship between blood pressure values and LVM/LVMI. There was also no difference in LVM/LVMI regression between patients with SBP >140 mm Hg and those with SBP <140 mm Hg. There was a linear relationship between regression of LVH (as defined by absolute change in LVMI) and the absolute change in resting total ventricular blood flow (y=2.5x+3.6; r=0.61; P=0.003) but no relationship between absolute change in LVMI and absolute change in resting MBF, hyperemic MBF, hyperemic total ventricular blood flow, AVA, or CVR (Figure 1). There was no relationship between the absolute change in AVA after AVR and the absolute change in resting MBF but a highly significant relationship with the absolute change in hyperemic MBF and CVR (Figure 2).

View larger version (19K): [in this window] [in a new window]   Figure 1. Relationship between absolute change in CVR and absolute change in LVMI after aortic valve replacement. Linear regression lines (solid line), 95% confidence intervals (dashed lines) with equations, and r and P values are shown.

View larger version (18K): [in this window] [in a new window]   Figure 2. Relationship between absolute change in CVR and absolute change in AVA after aortic valve replacement. Linear regression lines (solid line), 95% confidence intervals (dashed lines) with equations, and r and P values are shown.

In a univariate regression analysis model, the absolute change in resting DPT (0.1±4.6 s/min [-9.1 to 8.7]) was linearly related to the absolute change in resting total ventricular blood flow but not to resting MBF. There was, however, a significant relationship between the absolute change in hyperemic DPT (1.0±4.7 s/min [-6.8 to 9.6]) and absolute change in CVR (Figure 3).

View larger version (19K): [in this window] [in a new window]   Figure 3. Relationship between absolute change in CVR and absolute change in hyperemic DPT after aortic valve replacement. Linear regression lines (solid line), 95% confidence intervals (dashed lines) with equations, and r and P values are shown.

	Discussion

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In the present study, there was significant regression of LVM in all patients after AVR and a related reduction in total left ventricular blood flow. In addition, there was a significant reduction in resting MBF_corr and an increase in CVR_corr after AVR. However, changes in coronary microcirculatory function, assessed by measuring CVR after AVR, were not directly related to regression of LVM. The improvement in CVR was more closely related to changes in hemodynamic variables, including AVA and DPT.

Regression of LVH After AVR
In view of the age of our patients, it is reasonable to assume that, independently of whether outflow obstruction was attributable to calcification of a normal tricuspid valve or an initially functional bicuspid valve, the increased afterload was imposed on a LV whose myocyte population was capable of hypertrophy but not of hyperplasia and whose capillaries would no longer replicate. Therefore, macroscopic hypertrophy would represent an increase in myocyte size with a relative decrease in capillary density. Under these circumstances, significant regression of hypertrophy would be associated with a more physiological balance between myocyte mass and capillaries. Using CMR we found significant regression of LVM in all patients 1 year after AVR, comparable with that described previously with other techniques.²⁰ However, there were individual differences in the extent to which this occurred. Because residual LVH has been associated with poor outcome in this group of patients,²¹ the use of techniques such as CMR may be warranted to monitor regression, especially for patients in whom echocardiography is technically difficult.

Changes in Coronary Perfusion and Microcirculatory Function After AVR
Coronary microcirculatory function is impaired for several reasons in patients with pathological LVH. Rarefaction of the myocardial vasculature⁵ and medial hypertrophy with a resultant increase in the wall to lumen ratio in the vessels²² are contributing factors in patients with LVH attributable to hypertrophic cardiomyopathy or arterial hypertension. Intramural coronary vessels of patients with LVH attributable to AS, however, do not show evidence of vascular remodelling.⁴ We have demonstrated that functional vascular compressive forces produced by an increase in LV filling pressure (extravascular resistance) and reduction in hyperemic diastolic perfusion limit MBF in those patients with AS.² It is hypothesized that increased extravascular resistance leads to deformation of vessels in the myocardial microvasculature by the mechanical motion of the beating heart and reduction in diastolic perfusion is responsible for myocardial ischemia in the absence of epicardial coronary artery stenosis, particularly in the subendocardium.

Normal CVR can be restored in renovascular hypertensive rats by reversal of LVH.²³ Similarly, a study using coronary sinus blood flow measurements in patients with AS showed that AVR was associated with an increase in CVR, predominantly attributable to a reduction in coronary flow at rest.⁸ This was said to be associated with a distinct although not complete regression of LVMI, but direct correlation was not possible because the patients in the preoperative group were different from those in the postoperative group. Hildick-Smith et al⁹ demonstrated echocardiographically that flow reserve increased 6 months after AVR, again possibly related to regression of LVM. In this patient cohort, CVR_corr increased after AVR to values very similar to those of healthy volunteers of comparable age.²⁴ The major determinant of this increase seems to be the decrease in MBF_corr after AVR. These findings are likely to reflect the effect of decreased wall stress and extravascular compressive forces, especially given the fact that increased CVR was demonstrable at a time when regression of LVM was still ongoing.²⁰ Similar findings have been reported in hypertensive patients in whom treatment with verapamil, but not an ACE inhibitor, resulted in an improvement in CVR, independent of LVM.²⁵

Other indicators of altered coronary supply to the myocardium after regression of LVM include the reduction in cross-sectional size of the epicardial coronary arteries after AVR with a trend toward the normal ratio of coronary artery size to LV muscle mass.²⁶ It remains unclear whether regression of epicardial vascular remodeling is accompanied by improvement in microcirculatory function in humans,²⁷ although it has been demonstrated in animal models.²⁸ The effect of intraventricular pressure changes on MBF is also poorly understood, with conflicting evidence from animal models.^29,30 In our study there was a clear relationship between a reduction in hemodynamic workload, as demonstrated by the change in AVA, and increase in CVR, which, in the absence of epicardial stenosis, suggests an improvement in coronary microcirculatory function in these patients after AVR.³¹ Shortened DPT in AS results in blunting of myocardial perfusion,^2,32 particularly during tachycardia. However, after AVR, improvement in coronary microcirculatory function was related to hyperemic DPT, supporting the theory that improvement in transmural myocardial perfusion after AVR is a combination of a reduction in extravascular compressive forces as well as improved diastolic perfusion. The strength of this relationship was increased when only those patients with a systolic blood pressure less than 140 mm Hg postoperatively (r=0.522) or those with greater than 35 g/m² (mean absolute change) of LVMI regression (r=0.633) were included. This suggests that hypertension and persistence of LVH can also affect perfusion indirectly.

It is not possible to directly comment on whether the increase in CVR seen in the present study contributed to an improvement in the symptoms of angina pectoris in these patients. However, Julius et al³³ suggested that a reduction in CVR may be a mechanism for ischemia and angina in AS with normal coronaries. Although inadequate hypertrophy may have been associated with a reduced CVR in their study, DPT rather than LVMI determines vasodilator reserve impairment.² Therefore, improvement in CVR may be predicted to improve symptoms of angina. This may serve to explain the relief of anginal symptoms in these patients immediately after surgery, before regression of LVH has occurred.

	Acknowledgments

 
This work was funded through a project grant (PG 98431) from the British Heart Foundation. K. Rajappan is supported by a grant from the Hariri Foundation. The authors acknowledge the assistance of the staff of the MRC Cyclotron Unit and Royal Brompton Hospital CMR Unit. They particularly express their gratitude to the surgeons who performed the valve replacements: B. Glenville, R.D.L. Stanbridge (St Mary’s Hospital, London); K. Taylor, P. Punjabi, P. Smith, J. Anderson (Hammersmith Hospital, London); N. Moat, J.R. Pepper, A.C. DeSouza (Royal Brompton Hospital, London); and G. Venn (St Thomas’ Hospital).

Received December 17, 2002; revision received April 3, 2003; accepted April 4, 2003.

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