determinants and functional significance of myocardial...

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Determinants and Functional Significanceof Myocardial Perfusion Reserve inSevere Aortic Stenosis

Christopher D. Steadman, MB, CHB,*† Michael Jerosch-Herold, PHD,‡Benjamin Grundy, BSC,* Suzanne Rafelt, MSC,† Leong L. Ng, MD,† Iain B. Squire, MD,†Nilesh J. Samani, MD,*† Gerry P. McCann, MD*†

Leicester, United Kingdom; and Boston, Massachusetts

O B J E C T I V E S The purpose of this study was to assess the functional significance of cardiac

magnetic resonance (CMR) measures of left ventricular (LV) remodeling and myocardial perfusion

reserve (MPR) in patients with severe aortic stenosis (AS), without obstructive coronary artery disease.

B A C K G R O U N D Measures of stenosis severity do not correlate well with exercise intolerance in AS.

LV remodeling in AS is associated with myocardial fibrosis and impaired MPR. The functional significance

and determinants of MPR in AS are unclear.

M E T H O D S Forty-six patients with isolated severe AS were prospectively studied before aortic valve

replacement. The following investigations were undertaken: cardiopulmonary exercise testing to

measure aerobic exercise capacity (peak VO2); CMR to assess left ventricular mass index (LVMI),

myocardial fibrosis with late gadolinium enhancement (LGE), myocardial blood flow (MBF), and MPR; and

transthoracic echocardiography to assess stenosis severity and diastolic function.

R E S U L T S Peak VO2 was associated with sex (� � �0.41), age (� � �0.32), MPR (� � 0.45), resting

MBF (� � �0.53), and septal transmitral flow velocity to annular velocity ratio (E/E=) (� � �0.34), but

not with LVMI, LGE, or echocardiographic measures of AS severity. On stepwise regression analysis, only

MPR was independently associated with age- and sex-corrected peak VO2 (� � 0.46, p � 0.001). MPR

was also inversely related to New York Heart Association functional class (p � 0.001). Univariate

associations with MPR were sex (� � 0.38, p � 0.02), septal E/E= (� � �0.30, p � 0.03), peak aortic valve

velocity (� � �0.34, p � 0.02), LVMI (� � �0.51, p � 0.001), and LGE category (� � �0.46, p � 0.002).

On multivariate analysis, LVMI and LGE were independently associated with MPR.

C O N C L U S I O N S CMR-quantified MPR is independently associated with aerobic exercise capacity

in severe AS. LV remodeling appears to be a more important determinant of impaired MPR than stenosis

severity per se. Further work is required to determine how CMR assessment of MPR can aid clinical

management of patients with AS. (J Am Coll Cardiol Img 2012;5:182–9) © 2012 by the American

College of Cardiology Foundation

From the *National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester,United Kingdom; †Department of Cardiovascular Sciences, University Hospitals of Leicester, Leicester, United Kingdom; andthe ‡Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Thiswork was supported by the British Heart Foundation (PG/07/068/2334), the NIHR Comprehensive Local Research Network,and the NIHR Leicester Cardiovascular Biomedical Research Unit. All authors have reported they have no relationshipsrelevant to the contents of this paper to disclose.

Manuscript received June 30, 2011; revised manuscript received August 31, 2011, accepted September 1, 2011.

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The development of left ventricular hyper-

trophy (LVH) in aortic stenosis (AS) hasbeen regarded as a necessary physiologicaladaptation to maintain wall stress and pre-

erve cardiac function. Left ventricular (LV) re-odeling in AS is associated with a number of

etrimental pathophysiological sequelae: intersti-ial fibrosis (1,2), diastolic dysfunction (3), andeduced myocardial perfusion reserve (MPR) (4).here is marked variation in the extent of LVH

See page 190

in patients with severe AS (4,5). Experimentalmodels of pressure overload have shown that ani-mals that do not have LVH are better able tomaintain ejection fraction (6). Furthermore, pa-tients with critical AS, but without LVH, are lesslikely to have heart failure than patients with LVH (5).

Cardiac magnetic resonance (CMR) is the idealnoninvasive technique to study LV remodeling.Left ventricular mass (LVM) and volumes, lategadolinium enhancement (LGE) for the detectionof focal myocardial fibrosis, and MPR can bequantified accurately in a single examination. Myo-cardial fibrosis in AS is detected on LGE images in27% to 62% of patients (1,7,8). The extent of LGEcorrelates with, although underestimates the extentof, interstitial fibrosis on myocardial biopsy (1,2)and increases with LVM (1,7,8).

Peak oxygen consumption (VO2) is an objectiveeasure of exercise capacity and an independent

redictor of prognosis in chronic heart failure (9).here is a paucity of studies in AS, although patientsith moderate to severe asymptomatic AS who are

imited by symptoms on exercise testing do have lowereak VO2 and cardiac index than those who are

limited by fatigue (10). Resting echocardiographicmeasures of stenosis severity and ejection fraction donot predict exercise capacity, although LVH anddiastolic dysfunction may be important (3,11). Theaim of the current study was to assess the importance ofCMR measured LVM, LGE, and MPR in relation topeak VO2 in patients with isolated, severe AS.

M E T H O D S

Patient selection. Patients with severe AS listed foraortic valve replacement (AVR) were prospectivelyenrolled from a single tertiary center between Oc-tober 2008 and April 2010. Inclusion criteria wereages 18 to 85 years and isolated severe AS; defined
as one of the following: aortic valve area (AVA) �1 a
cm2, peak aortic velocity �4 m/s, or mean pressuregradient �40 mm Hg. Exclusion criteria weresyncope; moderate/severe valve disease other thanAS, previous valve surgery, obstructive coronaryartery disease (�50% luminal stenosis on angiogra-phy), chronic obstructive pulmonary disease, atrialfibrillation, inability to exercise, a CMR contrain-dication, and estimated glomerular filtration rate�30 ml/min. The local research and ethics com-mittee approved the study. All subjects gave writteninformed consent before investigations, which wereperformed on the same day, 48 h after discontinu-ing �-blockers.Echocardiography. Transthoracic echocardiography

as performed using a Vivid 7 (GE Healthcare,aukesha, Wisconsin) according to

merican Society of Echocardiographyuidelines (12). Tissue Doppler imagingllowed calculation of the transmitral flowelocity to annular velocity ratio (E/E=), aeasure of LV filling pressure (13). Anal-

sis was performed offline blinded to pa-ient details using EchoPAC softwareGE Healthcare). The mean of 3 readingsas used for each parameter.

Diastolic perfusion time and LV rate pressureproduct. Resting diastolic perfusion timeDPT) was calculated as before (14). Myocar-ial work was estimated by calculating theesting left ventricular rate pressure productLVRPP): (peak aortic pressure gradient �ystolic blood pressure) � heart rate (HR).Cardiopulmonary exercise testing. Symptom-limited exercise testing was performed on abicycle ergometer using a 1-min ramp pro-tocol with age- and sex-specific workloads.A 12-lead electrocardiogram was monitoredcontinuously and blood pressure recordedevery 2 min. Expired ventilatory gases wereanalyzed using an ErgoCard CPEX Test Station(Medisoft, Dinant, Belgium) to determine peak VO2.

ll exercise tests were physician supervised with indi-ations for termination, as previously published (15).Cardiac magnetic resonance. CMR was performedusing a 1.5-T scanner (Siemens, Avanto, Erlangen,Germany) with retrospective electrocardiographictriggering and a 6-channel phased array cardiac coil.Steady-state free precession cine images were ac-quired in 4-, 3-, and 2-chamber views. Perfusionimages were acquired after pharmacological vasodila-tion with adenosine, 140 �g/kg/min, for 3 min anduring data acquisition. A gadolinium-based contrast

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Germany) was administered intravenously (0.05mmol/kg) at 5 ml/s, followed by a 20-ml saline flush.First-pass perfusion was assessed for 3 slices (basal,mid, and apical) acquiring every heartbeat using asaturation recovery gradient echo sequence. Rest im-aging was performed approximately 10 min after stressimaging with a further 0.05 mmol/kg of contrast. Inthe intervening time, a stack of short-axis slices wereobtained using cine imaging covering the entire leftventricle. A further 0.1 mmol/kg of contrast was givento bring the total dose to 0.2 mmol/kg. At least 10min after this, LGE images were obtained with theuse of an inversion-recovery prepared, segmentedgradient echo sequence, as previously described (16).CMR analysis. Analysis was performed offline blindedo patient details using QMass software, version 7.1Medis, Leiden, the Netherlands). The LV contoursere drawn manually and left ventricular end-diastolicolume (LVEDV), LV end-systolic volume, strokeolume, left ventricular ejection fraction (LVEF), andnd-diastolic LVM were calculated. Values were in-exed by body surface area, denoted by the suffix ‘I,’or example, LVMI. Interobserver and intraobserverariability was calculated on 10 random datasets by 2xperienced observers (C.D.S., G.P.M.). The epicar-ium and endocardium were contoured on the perfusionmages, along with a region of interest in the LV bloodool, to generate signal intensity curves. The measuredrterial input, measured in arbitrary signal intensity units,as converted to a curve of percent enhancement, byividing by the baseline signal-intensity, namely, theignal intensity in the blood pool before any contrastnhancement. A calibration curve of effective contrast

Recruitment Data

er of patients approached, excluded, and recruited. AR � aorticon; CMR � cardiac magnetic resonance; COPD � chronic obstruc-nary disease; EF � ejection fraction; LGE � late gadolinium

Tent.

nhancement versus the contrast enhancement extrapo-ated from the low R1 (contrast concentration) range wasalculated by numerical simulation, using the sequencearameters, and a mean pre-contrast T1 value for bloodf 1,450 ms. This calibration curve was then inverted,nd used for correction of the observed percent contrastnhancement in the blood pool. Saturation correctionesulted, on average, in a 20% to 30% increase of the peakontrast enhancement of the arterial input function. Therterial input function corrected for signal saturation wassed for myocardial blood flow (MBF) quantification byodel-independent deconvolution (17). TransmuralPR was calculated by dividing hyperemic MBF by

esting MBF. All MPR results refer to uncorrectedalues, although resting MBF results are also displayedorrected for LVRPP. Two experienced observersC.D.S., G.P.M.) qualitatively assessed the perfusionmages for subendocardial perfusion defects (a visibleefect for �5 heartbeats) and the LGE images for focalbrosis, categorized as present or absent. Additionally,omputer-assisted planimetry was used to determine theass and percentage of enhanced myocardium �5 SD

bove the mean signal intensity of remote normalyocardium.

Statistical analysis. The distributions of continuousvariables were assessed using graphical displays andthe Shapiro-Wilk test for normality. Values arereported as mean � SD or median (interquartilerange) if the distribution was not normal. SeptalE/E=, lateral E/E=, and LGE (%LV mass) wereskewed and logarithmically transformed before re-gression analysis. Statistical analysis was undertakenusing SPSS, version 16.0 (SPSS, Chicago, Illinois)and SAS (SAS Institute, Cary, North Carolina).Comparison of means of 2 groups was done with at test and �2 groups with 1-way analysis of vari-ance. Linear regression investigated possible asso-ciations of continuous outcome measures. Stepwiseselection methods were used to determine the mostimportant associations. Hyperemic MBF was ad-justed for resting MBF (thereby assessing MPR) byforcing resting MBF into the model before selec-tion methods were applied. The same method wasused when adjusting peak VO2 for age and sex. All

values �0.05 were considered significant.

R E S U L T S

Population characteristics. Details of recruitment areutlined in Figure 1. Demographic data for the 46atients included in this report are presented in

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Cardiopulmonary exercise data. One exercise test wasmedically terminated because of angina associatedwith a �20 mm Hg drop in systolic blood pressure.

here were no complications. Twenty-two patients48%) were symptom limited, and the remainder wereimited by fatigue, including all 9 patients in Nework Heart Association (NYHA) functional class I.xercise data are presented in Table 2.

Cardiac magnetic resonance. Volumetric data andGE images were available for all patients. Results areisplayed in Table 2. Interobserver and intraobserverariability were as follows: LVM 5.2% and 4.9%,VEDV 3.1% and 3%, LVEF 6.6% and 4.7%.hirty-four patients had global subendocardial perfu-

ion defects. There was a wide range of LVMI andPR, but all patients had normal or near normal

ystolic function (n � 5, LVEF 45% to 50%; n � 1,LVEF 40% to 45%). LGE was present in 26 (56%)patients, and except in the patient excluded, therewere no clear myocardial infarctions. Examples ofpatients with variable LVM, LGE, and MPR areshown in Figure 2.Associations with exercise capacity. Univariate analyses

Table 1. Patient Characteristics

Age, yrs 66.2 � 9.3

Male/female 34/12

Body surface area, m2 1.92 � 0.21

Systolic blood pressure, mm Hg 131 � 20

Diastolic blood pressure, mm Hg 74 � 10

Resting heart rate, beats/min 69 � 12

ACEI/ARB 15 (33%)

Beta-blocker 18 (39%)

Statin 28 (61%)

Diabetes mellitus 10 (22%)

Hypertension 27 (59%)

Smoking

Former 29 (63%)

Current 3 (6%)

NYHA functional class, (n) I (9); II (32); III (5)

Echocardiography

Peak AV velocity, m/s 4.4 � 0.6

Mean PG, mm Hg 48.5 � 14.1

AVA/I, (cm2)/(cm2/m2) 0.86 � 0.22/0.45 � 0.13

LVRPP, mm Hg·beats/min·10�4 1.46 � 0.29

Resting DPT, s/min 37.9 � 3.1

Septal E/E= 13.7 (11.1–18.6)

Lateral E/E= 10.2 (7.2–14.0)

Values are mean � SD, n, or n(%).ACEI � angiotensin-converting enzyme inhibitor; ARB � angiotensin-

receptor blocker; AV � aortic valve; AVA/I � aortic valve area/index; DPT �diastolic perfusion time; E/E= � transmitral flow velocity to annular velocityratio; LVRPP � left ventricular rate pressure product; NYHA � New York HeartAssociation; PG � pressure gradient.

and results from the stepwise model selection for peak

VO2 are summarized in Table 3. Peak VO2 was highern men compared with women: 16.2 � 4.1 ml/kg/minersus 12.3 � 3.1 ml/kg/min, respectively (p � 0.005),

and decreased with age (Fig. 3A). Peak VO2 wasnversely related to septal E/E= and resting MBF, andorrelated with MPR (� � 0.45, r2 � 0.2) (Fig. 3B), butot with resting MBF/LVRPP or hyperemic MBF.nly MPR was independently associated with age- and

ex-corrected peak VO2 on stepwise analysis. Correctionfor �-blocker usage did not affect the significance of themodels.Symptomatic status. NYHA functional class was asso-iated with peak VO2, even after adjustment for age andex (� � �0.4, p � 0.002). Patients with higher NYHA

functional class had lower MPR (p � 0.001) (Fig. 4),despite no significant differences in AS severity betweengroups. Adding NYHA functional class to the stepwiseregression for associations with peak VO2 had no effecton the significance of MPR as the only independentvariable.Associations with resting MBF and perfusion reserve.Resting and hyperemic MBF were higher in womenthan men (resting, 1.07 � 0.24 vs. 0.84 � 0.15, p �0.001; hyperemic, 2.16 � 0.53 vs. 1.64 � 0.38, p �

Table 2. Cardiac Magnetic Resonance andCardiopulmonary Exercise Data

Cardiac magnetic resonance

LVMI, g/m2 69.6 � 17.7

LVEDVI, ml/m2 96.9 � 14.6

LVESVI, ml/m2 42.5 � 10.6

LVM/LVEDV, g/ml 0.72 � 0.15

LVEF, % 56.5 � 6.5

Stroke volume index, ml/m2 53.6 � 7.7

Maximum wall thickness, mm 13.2 � 2.5

Resting MBF, ml/min/g 0.90 � 0.20

Resting MBF/LVRPP, (ml/min/g)/(mm Hg.beats/min.10�4)

0.60 � 0.14

Hyperemic MBF, ml/min/g 1.77 � 0.47

Hyperemic heart rate, beats/min 88 � 12

MPR (n � 41) 2.03 � 0.55

LGE positive 26 (56%)

LGE, % (�5 SD above remote) 1 (0–28)

LGE mass, g (�5 SD above remote) 1.8 (0.8–4.8)

Cardiopulmonary exercise testing

Peak heart rate, % predicted 85 � 12

Rise in systolic blood pressure, mm Hg 39 � 23

Respiratory exchange ratio 1.09 � 0.1

Peak VO2, ml/kg/min 15.2 � 4.2

Values are mean � SD, n (%), or median interquartile range.LGE � late gadolinium enhancement; LVEDV � left ventricular end-

diastolic volume; LVEDVI � left ventricular end-diastolic volume index; LVEF � leftventricular ejection fraction; LVESVI � left ventricular end-systolic volumeindex; LVM � left ventricular mass; LVMI � left ventricular mass index; MBF �myocardial blood flow; MPR � myocardial perfusion reserve, VO2 � volume
oxygen consumption; other abbreviation as in Table 1.

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0.002). Resting MBF correlated with resting LVRPP(� � 0.47, p � 0.02) and was inversely related to DPT(� � �0.35, p � 0.025). Sex and resting LVRPP werendependent associations with resting MBF.

MPR was inversely related to peak aortic valveelocity, mean pressure gradient, CMR measures ofVH, LGE category, and septal E/E=. Results are

ummarized in Table 4. MPR was not related toistory of smoking, diabetes, or hypertension. Withll univariable associations, the best stepwise mul-ivariate regression model contained LVMI andGE category as independent associations. MPRas reduced in patients with LGE (1.87 � 0.47 vs..24 � 0.58, p � 0.031), and there was also an

inverse correlation between MPR and LGE scarmass at 5 SD (� � �0.4, p � 0.008).

D I S C U S S I O N

Determinants of resting MBF and MPR. Resting andyperemic MBF were higher in women, as has beenound previously (18). As reported by Rajappan et al.4), we did not find that measures of AS severity or

Figure 2. Examples of Patients With Varying LV Remodeling

Cardiac magnetic resonance images: (i) short-axis cine end-diastoleenhancement (LGE) at same level as “i” (LGE marked with white arrhyperemia; and (iv) during rest perfusion. Four male patients displapoint LGE, and reduced myocardial perfusion reserve (MPR [age 63(AVA) 0.92 cm2, MPR 1.07, peak volume oxygen consumption (VO2)LGE (age 65 years, LVMI 76 g/m2, AVA 0.79 cm2, MPR 1.59, peak VO55 g/m2, AVA 0.99 cm2, MPR 2.30, peak VO2 18.5 ml/kg/min). (D) NLGE (age 63 years, LVMI 66 g/m2, AVA 0.73 cm2, MPR 2.4, peak VO2

VMI were related to resting MBF. Contrary to that f

tudy, there was an association between resting MBFnd estimated myocardial work (LVRPP), as has alsoeen shown in hypertrophic cardiomyopathy (18).he results of MPR in this study are remarkably

onsistent with those from Rajappan’s similar cohortf patients with severe AS before AVR (2.03 � 0.55s. 1.90 � 0.60, respectively), considering that posi-ron emission tomography was used in that report (4).

e have shown that aortic valve velocities/pressureradients, measures of LVM, and, for the first time,emale sex, LV filling pressure (septal E/E=), andyocardial fibrosis (LGE), have univariate associa-

ions with MPR. Of these, LVMI and LGE appearo be the most important. These findings are some-hat different from those of Rajappan et al. (4), whose

esults suggested that AS severity and DPT were moremportant determinants of MPR in severe AS. Theiscrepancies are likely due to the smaller numbers (20s. 41), that positron emission tomography was used,hat no LGE for fibrosis was performed, and that theajority of patients in the Rajappan study were

symptomatic (4). Given the modest correlations

iddle level (A, B, and C) and basal level (D); (ii) late gadolinium); (iii) perfusion imaging in middle left ventricular (LV) slice during: (A) Significantly raised left ventricular mass (LVM), clear insertionrs, left ventricular mass index (LVMI) 126 g/m2, aortic valve area7 ml/kg/min). (B) Mildly elevated LVM with mild insertion point.4 ml/kg/min). (C) Normal LVM with no LGE (age 65 years, LVMIal LVM with mild insertion point LGE but more significant remote6 ml/kg/min).

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findings may be spurious; however, they are physio-logically plausible. The lack of association betweensmoking, hypertension, and diabetes (19) and MPR inthis study is almost certainly due to the smaller samplesize and the large effect of LV remodeling in thesepatients with AS.

This is the first study to demonstrate the impor-tance of myocardial fibrosis (LGE) in relation toMPR in AS. This association may be explained byreduced arteriolar and capillary density seen withLV remodeling and fibrosis (20) and loss of the“suction” wave seen in patients with LVH (21). It isimportant to emphasize that diffuse myocardialfibrosis (22) was not assessed (as newer T1-mapping techniques were not available to us at thetime), and this may be an important determinant ofMPR. However, the extent of LGE does correlatewith diffuse fibrosis on myocardial biopsy (1).Associations with exercise capacity. We hypothesizedhat CMR measures of LV remodeling would bendependently associated with aerobic exercise capac-ty. As previously demonstrated, measures of ASeverity did not predict exercise capacity (15). Septal/E=, resting MBF and MPR, but not measures ofVH, had univariate associations with peak VO2.

Table 3. Associations With Peak VO2

Univariate Associations

� p Value

Sex �0.41 0.005

Age �0.32 0.03

Peak AV velocity �0.18 0.24

Mean PG �0.18 0.24

AVAI 0.04 0.79

Septal E/E= �0.34 0.02

Lateral E/E= �0.23 0.13

LVMI 0.02 0.89

LVM/LVEDV ratio �0.04 0.79

LV maximum wall thickness �0.2 0.90

LVEF 0.01 0.97

LGE 0.05 0.73

Resting MBF �0.53 0.001

Resting MBF/LVRPP �0.28 0.08

Hyperemic MBF �0.01 0.94

MPR 0.45 0.004

Final Model (Stepwise Selection)

� p Value R2

Sex �0.44 0.002 0.42

Age �0.15 0.25

MPR 0.46 0.001

LV � left ventricular; other abbreviations as in Tables 1 and 2.

nly MPR was independently associated with age-

nd sex-corrected exercise capacity. This clinical studyas identified imaging and clinical parameters thatave a clear and independent association with exerciseapacity in AS. Previous studies have suggested aange of parameters that include aortic valve compli-nce (23–24), reduced longitudinal strain (25), LVlling pressure (13) and diastolic dysfunction (3, 11).owever, those studies have looked at exercise-

nduced symptoms, which may be subjective, as in ourtudy, where 50% of symptomatic patients were lim-ted by fatigue, and they have not accounted for agend sex as determinants of exercise capacity. Manyther factors may influence peak VO2, including

genetics, physical activity, and skeletal musclechanges, which may be particularly important inpatients with cardiac dysfunction.Mechanisms linking reduced myocardial perfusionreserve and peak VO2. With exercise, cardiac outputises incrementally with workload. Increased cardiac

Figure 3. Associations With Exercise Capacity

Relationship between peak volume oxygen consumption (VO2)
and (A) age and (B) myocardial perfusion reserve.

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output in severe AS is largely dependent on increasedheart rate (26), which is associated with the develop-ment of impaired MPR in both patients (27) andexperimental models of AS (28). The inability toincrease blood flow to the myocardium is limitedbecause vasodilation may already be near maximal(29), DPT will be limited further with increased heartrate, and there is a rapid increase in LV end-diastolicpressure (26), which further reduces the effective

Figure 4. Perfusion Reserve and Symptomatic Status

Myocardial perfusion reserve and New York Heart Association(NYHA) functional class. CI � confidence interval.

Table 4. Associations With Perfusion Reserve

Univariate Associations

� p Value

Sex 0.38 0.02

Age �0.09 0.54

Hyperemic heart rate 0.2 0.19

Beta-blockers 0.008 0.96

LVRPP �0.1 0.58

Resting DPT �0.28 0.08

Peak AV velocity �0.34 0.02

Mean PG �0.30 0.04

AVAI 0.21 0.17

LVMI �0.51 �0.001

LVM/LVEDV �0.43 0.003

LV maximum wall thickness �0.41 0.005

LVEF 0.28 0.07

LGE �0.46 0.002

Septal E/E= �0.33 0.03

Lateral E/E= �0.19 0.20

Final Model (Stepwise Selection)

� p Value R2

LVMI �0.40 0.004 0.43

LGE �0.31 0.02

Abbreviations as in Tables 1, 2, and 3.

pressure gradient for perfusion. Patients unable toincrease blood flow to the myocardium on exercise willlikely develop subendocardial myocardial dysfunction(25,28), which will limit cardiac output and contributeto exercise intolerance.Clinical implications. MPR is an important prognostic

arker in hypertrophic cardiomyopathy, predicting ad-erse ventricular remodeling and clinical outcomes (30).mpaired MPR could be a therapeutic target in ASatients unable to have aortic valve intervention and inatients with persistent symptoms after AVR. Tradi-ional therapies targeting LV remodeling such as inhib-tors of the renin-angiotensin-aldosterone system andrugs with novel mechanisms of action, for example,erhexilene, may be useful in this context. The impor-ance of impaired MPR to the development of symp-oms and outcome in asymptomatic patients with ASarrants further investigation.

Study limitations. The results of this mechanistictudy may not be applicable to the wider AS popula-ion. Although we have touched on symptomatictatus in this paper, the number of asymptomaticatients is small and, therefore, limited conclusionsan be drawn about this group. The cross-sectionalature of our data does not allow one to drawonclusions as to whether myocardial fibrosis leads toreduction in MPR or if the reduced MPR causesyocardial fibrosis. Longitudinal studies in patientsith less severe AS with assessment of diffuse fibrosisay be able to answer this question. The reproduc-

bility of MPR measurements in AS is unknown.inally, because of the relatively small numbers, theumber of variables that can be appropriately used inhe multivariate regression analysis is necessarily lim-ted. Therefore, we limited the number of univariatessociations entered into the multivariate model to 5nd used the strongest univariate associations, avoid-ng overlapping variables.

C O N C L U S I O N S

We have shown for the first time that MPR isindependently associated with objectively measuredexercise capacity in severe AS. Impaired MPR isdetermined by a combination of factors includingAS severity, LV remodeling, and filling pressure.Further work is required to determine how CMRassessment of MPR can aid the clinical manage-ment of patients with AS.

Reprint requests and correspondence: Dr. Gerry P. Mc-Cann, Department of Cardiovascular Sciences, GlenfieldHospital, Groby Road, Leicester LE3 9QP, United
Kingdom. E-mail: [email protected].
mailto:[email protected]

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Key Words: aortic stenosis ycardiac magnetic resonance ycardiopulmonary exercise testing
y myocardial perfusion reserve.

determinants and functional significance of myocardial...

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