M ultiple mechanisms are held responsiblefor the limited exercise capacity of pa-tients with rheumatic mitral stenosis
(MS). Studies of exercise limitation in MS havepredominantly used exercise tests combined with
m the aDivision of Cardiovascular Diseases and Internal Medicine, Tel Avi
dicine, Tel Aviv University, Tel Aviv, Israel; cDivision of Cardiovascular D
dical Center, Philadelphia, Pennsylvania; dDivision of Radiology, Tel Avi
Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota. The autho
evant to the contents of this paper to disclose.
nuscript received May 9, 2016; revised manuscript received July 11, 2016
catheterization (1) or the equilibrium cardiac output(CO) rebreathing technique (2) to calculate CO and pe-ripheral muscle oxygen extraction. The studies werelimited by: 1) the invasive nature of the catheterizationtechniques, resulting in selection bias in those studies;
v Medical Center, Tel Aviv, Israel; bSackler Faculty of
iseases, Heart and Vascular Institute USA, Einstein
v Medical Center, Tel Aviv, Israel; and the eDivision
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and 2) insufficient anatomic data provided with bothtechniques (3). Therefore, we created a combinedcardiopulmonary exercise (stress) test (CPET) andstress echocardiography (SE) protocol that allowsassessment of cardiac and peripheral responses toexercise at 4 pre-defined levels (rest, unloadedcycling, anaerobic threshold [AT], and peak). Ouraims were to: 1) test whether cardiovascular responseto exercise differs between patients with MS andnormal subjects; 2) look for differences in cardiovas-cular response to exercise between patients with MShaving poor exercise tolerance and those with pre-served exercise tolerance; and 3) assess the indepen-dent factors associated with limited exercise capacityin patients with MS.
SEE PAGE 634RER = respiratory exchange
ratio
SE = stress echocardiography
SPAP = systolic pulmonary
artery pressure
SV = stroke volume
METHODS
STUDY POPULATION. Between January 2013 and July2015, we performed 173 combined CPET and SE ex-aminations. The study included all consecutive pa-tients who had rheumatic MS (N ¼ 20). There were noselection criteria for the MS group, but because car-diopulmonary stress or SE testing is rarely performedin patients with very severe MS (1) (valve area <1 cm2)or in asymptomatic or severely symptomatic (NewYork Heart Association [NYHA] functional class IV)patients, our group consisted mostly of patients inthe moderate-to-severe (1) range (valve area 1.0 to 1.5cm2) with milder symptoms (NYHA functional class IIor III). Control subjects were selected from 37 patientswith no cardiac disease who were referred for evalu-ation of dyspnea; 20 were selected after matching forage, gender, and ejection fraction (EF). Nine of thesepatients were determined to have dyspnea on thebasis of peripheral factors; the other 11 had normalexercise capacity. Subanalysis was performed in theMS group, comparing the 10 patients who hadreduced exercise capacity (<80% of predicted) withthe 10 patients who had preserved exercise capacity(>80% of predicted).
A second CPET was performed in 13 patients withMS without echocardiography and without change inmedical therapy (including b-blocker if present): 6 of7 patients who underwent intervention and 7 otherswho were treated conservatively. The interventiongroup included 6 patients who had mitral valvereplacement (1 of whom refused repeat CPET) and 1who had balloon valvuloplasty.
In a third analysis, 7 patients with MS underwentrepeat CPET combined with SE after withdrawal ofb-blocker therapy.
These data were collected in the course ofroutine clinical care. Observers who per-formed and analyzed the exercise gas ex-change data and the echocardiographicimages were blinded to patient group andother characteristics. This retrospective studywas approved by our Institutional ReviewBoard at Tel Aviv Medical Center.
EXERCISE PROTOCOL. Exercise was per-formed as previously described (4). Asymptom-limited graded ramp bicycle exer-cise test was performed in the semisupineposition on a tilting dedicated micropro-cessor controlled eddy current brake SE cycleergometer (Ergoselect 1000 L, CareFusion,San Diego, California). We estimated the ex-pected peak VO2 on the basis of the patient’sage, height, and weight after considering thepatient’s history. We then calculated thework rate increment necessary to reachthe patient’s estimated peak VO2 in 8 to 12
min. The protocol included 3 min of unloadedpedaling, a symptom-limited ramp graded exercise,and 2 min of recovery. Breath-by-breath minuteventilation, carbon dioxide production (VCO2), andoxygen consumption (VO2) were measured using aMedical Graphics metabolic cart (ZAN, nSpire HealthInc., Oberthulba, Germany). Peak VO2 was the highestaveraged 30-s VO2 during exercise. AT was deter-mined manually using the modified V-slope method.The respiratory exchange ratio (RER) was defined asthe ratio between VCO2 and VO2 obtained fromventilatory expired gas analysis (2). In 7 patientstaking b-blockers during the first exercise test,b-blockers were subsequently withdrawn before asecond examination. In patients on b-blockertherapy, chronotropic incompetence on stress testingwas determined when <62% of heart rate (HR)reserve was used (5).
EXERCISE ECHOCARDIOGRAPHY TESTING. Echo-cardiographic images were obtained concurrentlywith breath-by-breath gas exchange measurements ina continuous manner as previously described (3).Each cycle of imaging included left ventricular (LV)end-diastolic and end-systolic volumes, stroke vol-ume (SV), peak E- and A-wave velocities, decelerationtime, and septal e0 and lasted between 30 and 60 s.LV end-diastolic volume, end-systolic volume, andEF were calculated according to the single planeellipsoid apical 4-chamber area-length method.Left atrial volume was calculated according to thebiplane area-length method. SV was calculated by
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multiplying the LV outflow tract area at rest by the LVoutflow tract velocity–time integral measured bypulsed-wave Doppler during each activity level.All echocardiographic measurements were done us-ing manual tracing (4). We then analyzed the echo-cardiographic data retrospectively at 4 differentstages. Rest stage images were taken before cycling.Unloaded stage images were taken during unloadedexercise. AT and the HR at the AT were determinedmanually and retrospectively using the gas exchangemeasurements and the modified V-slope method. Onthe basis of the HR at the AT echocardiogram, datawere analyzed from the images captured immedi-ately after reaching the HR at the AT. Peak exerciseimages were defined as those captured immediatelyafter reaching RER >1.05 (5). A–VO2 difference wascalculated using the Fick equation as follows: VO2/echocardiography-calculated CO at each activitylevel (5). Mitral valve area at rest and during exer-cise was calculated by applying the continuityequation as the ratio of SV to the mitral valvevelocity–time integral, according to previously pub-lished recommendation (6).
STATISTICAL ANALYSIS. Descriptive results areexpressed as mean � SD for continuous variablesand as percentages for categorical variables. For theanalysis of differences in echocardiographic and ex-ercise variables, paired Student t test was used forcomparisons between MS and matched controlgroups. For comparisons between the reduced andpreserved exercise capacity groups, we used analysisof variance for continuous, normally distributedvariables; Wilcoxon test for other continuous vari-ables; and Fisher exact test or chi-square test forcategorical variables. To analyze the differences inthe various stages of effort, we used the repeatedmeasures linear model analysis to define the within-group effect for each parameter over time, the be-tween group differences over time, and the group bytime interactions. To analyze the associates of ex-ercise tolerance in patients with MS, the primaryendpoint was peak VO2. Univariate analysis to assessthe association of rest and effort (at each stage)parameter and peak VO2 was performed in the firststep. In the second step we used stepwise multi-variate linear regression models (with peak VO2 asthe dependent variable, and the echocardiographicand cardiopulmonary stress variables as indepen-dent variables) for each effort stage individually.The entry criterion was a univariate p value <0.10.To detect colinearity, we used correlation factoranalyses to determine whether any pairs of predictor
variables were correlated (correlation coefficients>0.9). If any such pairs were found, the variablewith the lowest univariate p value was chosen forinclusion in the analysis. The incremental value ofstress parameters (for each effort stage individually)on rest clinical and echocardiographic parameterswas tested by nested models with F tests. All com-putations were performed using JMP statisticalsoftware for Windows version 9.0 (SAS Institute Inc.,Cary, North Carolina).
INTEROBSERVER AND INTRAOBSERVER VARIABILITY.
Interobserver variability for peak velocity, meangradient, and SV at peak exercise was determinedby a second independent blinded observer whomeasured the echocardiographic variables in 10randomly selected patients. Intraobserver variabilitywas determined by having the first observer remeas-ure the same parameters in these same 10 patients atleast 1 month after the initial measurements. Inter-observer and intraobserver variability were assessedusing the Bland-Altman method and the within-subject coefficient of variation. The within-subjectcoefficient of variation (calculated as the ratio ofthe standard deviation of the measurement differ-ence to the mean value of all measurements) providesa scale-free, unit-less estimate of variation expressedas a percentage.
RESULTS
ECHOCARDIOGRAPHIC AND STRESS CORRELATES
OF EXERCISE CAPACITY. Patients with MS had amean valve area of 1.36 � 0.4 cm2 and a meangradient of 5.3 � 3.0 mm Hg. None of our patients hadsignificant (greater than mild) involvement of othervalves. Mitral regurgitation was trivial or none in10 patients, mild in 8, and moderate in 2. Variousclinical and exercise characteristics of the MS andcontrol subjects are given in Table 1. Per patient dataare given in Online Table 1. Echocardiographic andcombined CPET-SE parameters of the MS and controlgroups in each of the exercise phases are given inOnline Table 2 and Figure 1.
Various clinical and exercise characteristics of theMS subgroups (preserved vs. reduced exercise ca-pacity) are given in Table 2. Echocardiographic andcombined CPET-SE parameters of the MS subgroupsin each of the exercise phases are given in Table 3 andFigure 2. Patients with reduced exercise capacity hadattenuated changes in end-diastolic volume, HR, andtidal volume, but no difference in transmitralgradient compared to patients with MS and preserved
Values are mean � SD (range) or n (%) unless otherwise indicated.
AT ¼ anaerobic threshold; A-V difference ¼ arterial–venous difference; FEV ¼ forced expiratory volume;FEV1 ¼ forced expiratory volume first second; FVC ¼ forced vital capacity; HR ¼ heart rate; LAVI ¼ left atrialvolume index; MS ¼ mitral stenosis; NYHA ¼ New York Heart Association; O2 pulse ¼ oxygen consumption percardiac cycle; RA ¼ right atrium; RER ¼ respiratory exchange ratio; VE ¼ minute ventilation; VCO2 ¼ carbondioxide output; VO2 ¼ oxygen consumption; VT ¼ tidal volume.
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function. Systolic pulmonary artery pressure (SPAP)increased during exercise in both MS subgroups.However, in those with preserved exercise capacityit increased steadily throughout exercise, whereasin patients with reduced exercise capacity it starteda bit higher, increased in the first stage of exercise,and then showed little change between AT andpeak exercise (p ¼ 0.03 for the time ∙ groupinteraction).
UNIVARIATE AND MULTIVARIABLE ANALYSIS. Theresults of univariate analysis to test associations be-tween rest and stress parameters and peak VO2 aregiven in Table 2. Stepwise multivariable analyses toexplore the independent determinants of peak VO2 atall exercise stages are given in Table 4. The bestmodel to determine peak VO2 used parametersmeasured at peak exercise (p < 0.005 for nestedmodels compared to rest clinical and echocardio-graphic parameters), but even models based on earlystages of exercise improved the prediction comparedto models using rest parameters (p < 0.05 for both).The independent determinants of exercise capacity atpeak exercise were HR, tidal volume, and A–VO2
difference.
Peripheral oxygen extraction and effort capacity. Therewas no difference between MS subgroups in exerciseresponse of average A–VO2 difference (Table 3 andFigure 2). Nevertheless, low peak A–VO2 differencewas a strong univariate correlate of reduced exercisecapacity and an independent predictor of low peakVO2 (Tables 2 and 4).Chronotropic incompetence. Peak HR and percent ofpredicted HR were decreased in the MS groupcompared to the control group (Table 1). Althoughthe use of b-blockers was more prevalent in the MSgroup (75% vs. 15%; p < 0.0001), we were able toshow that chronotropic incompetence was morecommon in patients with MS (30% vs. 5%; p ¼ 0.03)by using criteria accounting for the presence ofb-blocker therapy (7). Furthermore, chronotropicincompetence was more common in the patientswith MS having reduced exercise capacity (50% vs.10%; p ¼ 0.04) and contributed significantly to poorexercise capacity (p ¼ 0.02). Results of the secondCPET (comparing post-intervention with conserva-tive therapy subgroups), performed 9.5 � 6.9months (range 0.7 to 15.0 months) post-intervention,are given in Table 5. On the initial (baseline)CPET, peak HR, peak O2 pulse, peak O2, and peakRER were similar between patients ultimatelytreated conservatively or with intervention. Onsubsequent CPET, peak O2 pulse (a surrogate for SVand A-VO2 difference) increased significantly only in
the interventional group, with a trend for increasein peak O2 as well. Mitral intervention (compared toconservative treatment) was associated withimproved peak O2 pulse (p ¼ 0.05) and peak O2
(p ¼ 0.055). However, RER and peak HR did not
FIGURE 1 Echocardiographic Parameters at All Activity Stages in the MS and Control Groups
Baseline Unloaded AT Peak
Response
EDV220
180
140
100
60
A
Baseline Unloaded AT Peak
Response
EF90
80
70
60
50
B
Baseline Unloaded AT Peak
Response
S Wave14
12
10
8
6
4
2
C
Baseline Unloaded AT Peak
Response
SV180
160
140
120
100
80
60
40
D
Baseline Unloaded AT Peak
Response
HR200
180
160
140
120
100
80
E
Baseline Unloaded AT Peak
Response
CO30
25
20
15
10
5
0
F
Baseline Unloaded AT Peak
Response
E’ cm/s25
20
15
10
5
0
G
Baseline Unloaded AT Peak
Response
SPAP100
80
60
40
20
0
H
Baseline Unloaded AT Peak
Response
A-VO2 Difference0.18
0.14
0.10
0.06
0.02
I
Baseline Unloaded AT Peak
Response
O2 Pulse20
15
10
5
0
J
Baseline Unloaded AT Peak
Response
VO24
3
2
1
0
K
Baseline Unloaded AT Peak
Response
VT4500
4000
3500
3000
2500
2000
1500
1000
500
L
Baseline, unloaded, anaerobic threshold (AT), and maximal cardiopulmonary exercise (stress) test and stress echocardiography test for (A) EDV, (B) EF, (C) S-wave,
(D) SV, (E) HR, (F) CO, (G) E’, (H) SPAP, (I) A–VO2 difference, (J) O2 pulse, (K) VO2, and (L) VT in the patients with MS (green) and control subjects (pink). CO ¼ cardiac
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change in either group, and there were no signifi-cant associations between mitral intervention andchanges in RER (p ¼ 0.70) or peak HR (p ¼ 0.40).Use of b-blockers in MS. Our data show profoundchronotropic incompetence and abnormal SVreserve, particularly in the reduced exercise capac-ity group. Because b-blockers can impair chrono-tropic response, SV, and CO reserve, we comparedthe CPET-SE results in the 7 patients with MS whoperformed the testing twice, off and on b-blockers.In these patients, peak HR (115 � 20 beats/min vs.93 � 14 beats/min; p ¼ 0.03) and peak exercisemean transmitral gradient (14.0 � 6.0 mm Hg vs.12.0 � 4.0 mm Hg; p ¼ 0.20) were lower with
b-blockers. Peak SV tended to decrease (75.8 � 29.0cc vs. 68.6 � 7.0 cc; p ¼ 0.5). This in combinationwith a reduced HR response resulted in a significantdecrease in peak CO (8.8 � 1.6 vs. 6.3 � 0.88;p ¼ 0.05) and a trend for reduced exercise capacity(0.99 � 0.4 l/min vs. 0.76 � 0.1 l/min; p ¼ 0.20).Surprisingly, the use of b-blockers did not decreasethe peak systolic pulmonary pressure (80.7 � 25.0mm Hg vs. 81.4 � 13.0 mm Hg; p ¼ 0.60).Mitral valve gradient, area, and systolic pulmonarypressure. No correlation was found between peak VO2
and transmitral gradient during exercise. Similarly,there was no correlation between mitral valve areaand peak VO2.
TABLE 2 Characteristics of Patients With MS Stratified by Exercise Capacity and Univariate Analyses to Explore the Contribution of
Different Exercise Parameters on Maximal Exercise Capacity (VO2max)
Values are mean � SD (range) or n (%) unless otherwise indicated.
A-VO2 difference ¼ arterial–venous difference; O2 pulse ¼ oxygen consumption per cardiac cycle; other abbreviations as in Table 1.
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INTEROBSERVER AND INTRAOBSERVER VARIABILITY.
Comparison of intraobserver parameters showedgood agreement between measurements of peakvelocity (mean difference 0.8 � 4.5 cm/s; r ¼ 0.97;
p ¼ 0.86), mean gradient (mean difference –0.5 �0.4 mm Hg; r ¼ 0.97; p ¼ 0.30), and SV (meandifference 0.7 � 1.4 cc; r ¼ 0.96; p ¼ 0.60). TheBland-Altman plot showed a random scatter of
TABLE 3 LV Dimensions, Function, and Hemodynamics Throughout Exercise Stages Among Patients With MS and Preserved or Reduced Exercise Capacity
EF ¼ ejection fraction; LV ¼ left ventricle; other abbreviations as in Tables 1 and 2.
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points around 0, indicating no systematic bias ormeasurement error proportional to the measure-ment value. Measurement variability (within-subjectcoefficient of variation) for intraobserver differenceswas peak velocity 1.8%, mean gradient 2.4%, andSV 2.3%.
Comparison of interobserver parameters showedgood agreement between measurements: peak veloc-ity (mean difference�1.3� 3.1 cm/s; r¼0.98; p¼0.70),mean gradient (mean difference �0.3� 0.5 mmHg; r¼0.93; p ¼ 0.80), and SV (mean difference �1.7 � 3.0 cc;r ¼ 0.88; p ¼ 0.70). The Bland-Altman plot showed arandom scatter of points around 0, indicating nosystematic bias or measurement error proportional tothe measurement value. Measurement variability(within-subject coefficient of variation) for interob-server differences was peak velocity 1.3%, meangradient 3.8%, and SV 4.8%.
DISCUSSION
Our major findings are that: 1) the combined CPET-SEprotocol allows for detailed noninvasive evaluation ofexercise physiology in patients with MS; 2) patients
with MS have reduced exercise systolic reserve,relaxation, SV, HR, and ventilation compared tocontrol subjects; 3) transmitral gradient and mitralvalve area showed absence of any correlation withpeak VO2 during exercise; and 4) chronotropicincompetence, limited SV reserve, peripheral factors(low peak A–VO2 difference), and limited tidal volumeresponse each contribute to the reduced exercisecapacity found in MS. The study provides severalnovel insights. First, patients with MS have abnormalSV reserve. Second, patients with MS have ventilatoryabnormalities similar to those reported in heart fail-ure patients (8). In addition, this study providesstrong confirmation of an important evolvingtheme in heart failure physiology, that is, the contri-bution of chronotropic incompetence and peripheral,presumed skeletal muscle, abnormalities to exerciseintolerance.
DETERMINANTS OF EFFORT INTOLERANCE. Chronotropicincompetence. In patients with MS, peak exercise HRwas reduced, as was percent of HR reserve utilized.These factors likely contributed to the limited exer-cise capacity of these patients. This phenomenon hasalso been observed in patients with heart failure, both
FIGURE 2 Echocardiographic Parameters at All Activity Stages in Patients With MS Having Preserved Exercise Capacity and Those With Reduced
Exercise Capacity
Baseline Unloaded AT Peak
Response
EDV160
140
120
100
80
60
A
Baseline Unloaded AT Peak
Response
EF90
80
70
60
50
B
Baseline Unloaded AT Peak
Response
S Wave8
7
6
5
4
3
2
C
Baseline Unloaded AT Peak
Response
SV120
110
100
90
80
70
60
50
40
D
Baseline Unloaded AT Peak
Response
HR180
160
140
120
100
80
60
E
Baseline Unloaded AT Peak
Response
CO14
12
10
8
6
4
F
Baseline Unloaded AT Peak
Response
E’ cm/s9
8
7
6
5
4
3
2
G
Baseline Unloaded AT Peak
Response
SPAP110
90
70
50
30
10
H
Baseline Unloaded AT Peak
Response
A-VO2 Difference0.18
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
I
Baseline Unloaded AT Peak
Response
Mean Gradient25
20
15
10
5
0
J
Baseline Unloaded AT Peak
Response
MVA Continuity4.5
3.5
1.5
0.5
K
Baseline Unloaded AT Peak
Response
VT1600
1400
1200
1000
800
600
400
L
Baseline, unloaded, anaerobic threshold (AT), and maximal cardiopulmonary exercise (stress) test and stress echocardiography test for (A) EDV, (B) EF, (C) S-wave, (D)
SV, (E) HR, (F) CO, (G) E’, (H) SPAP, (I) A–VO2 difference, (J) mean gradient, (K) MVA, and (L) VT in patients with mitral stenosis (MS) and preserved exercise capacity
(pink) and patients with MS and reduced exercise capacity (green). MVA ¼ mitral valve area; other abbreviations as in Figure 1.
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with preserved EF (9) and reduced EF (10). Eventhough b-blocker therapy was left unchanged, wewere able to show that chronotropic incompetencewas common in patients with MS, even when usingthe criteria used in the presence of b-blocker therapy(7). Importantly, chronotropic incompetence wasmostly seen in patients with MS and reduced exercisecapacity, and it was a strong independent predictor ofpeak VO2. Furthermore, in exploratory analyses usingCPET after mitral intervention, we found thatimproved exercise capacity (peak O2) was relatedto improvement in SV and A-VO2 difference (peakO2 pulse) but not to improved chronotropicresponse (peak HR) or motivation (RER). Thus, chro-notropic incompetence does not merely reflect the
consequences of reduced motivation, or exercisecapacity but seems to play an independent role in thepathogenesis of reduced exercise capacity in patientswith rheumatic MS.Use of b-blockers in patients with rheumatic MS. Ourresults showed that b-blockers decreased peak HRand tended to decrease the transmitral gradient atthe end of exercise as expected. However, they ten-ded to decrease SV, although normally the decreasein HR would be expected to produce supranormal SVby increasing the time for filling. The combined effectwas a significant decrease in CO and a trend towarddecreased peak VO2. These preliminary resultsare similar to those in previous reports (11,12)and suggest that the beneficial effect of decreasing
TABLE 4 Multivariate Analyses to Explore the Contribution of Different Parameters on
Maximal Exercise Capacity (VO2max)
p Value
VO2 by Rest VO2 by Unloaded VO2 by AT VO2 by Max
Age, yrs 0.60 0.50 0.10 0.40
Height 0.30 0.10 0.30 0.40
EDV index, cc/m2 0.10 0.10 0.50 0.50
ESV index, cc/m2 0.30 0.30 0.60 0.60
SPAP 0.30 0.001 0.10 0.30
FEV1 0.0003 0.10 0.10 0.40
S’ 0.70 0.50 0.10 0.30
E’ 0.50 0.50 0.008 0.30
Stroke volume 0.10 0.30 0.50 0.10
Heart rate 0.100 0.30 0.40 0.01
VT 0.20 0.09 0.0008 0.0001
VE 0.60 0.50 0.50 0.50
RVESA 0.10 0.40 0.50 0.60
EF 0.60 0.60 0.60 0.10
Mean mitral gradient 0.50 0.50 0.10 0.30
Mitral valve area 0.10 0.20 0.100 0.30
A-VO2 difference stress 0.30 0.30 0.40 0.03
p value 0.01 0.0001 0.0001 <0.0001
R2 0.61 0.86 0.88 0.95
AT ¼ anaerobic threshold; EDV ¼ end-diastolic volume; ESV ¼ end-systolic volume; R2 ¼ coefficient ofdetermination of the entire model; RVESA ¼ right ventricular end systolic area; other abbreviations as inTables 1, 2, and 3.
TABLE 5
Conservat
Peak HR
Baseline
Post-int
p value
Peak O2 p
Baseline
Post-int
p value
Peak VO2
Baseline
Post-int
p value
Peak RER
Baseline
Post-int
p value
Values are‡Univariatein heart rate
CPET ¼ c
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transmitral gradient may be outweighed by the un-favorable decrease in CO and exercise capacity. Itshould be noted that the effects of b-blockersvaried in individual patients. Some had a significant
CPET Examination Performed After Mitral Intervention or After
ive Therapy
Intervention Conservative p Value
126 � 15 121 � 42 0.80*
ervention 110 � 19 119 � 29 0.60*
paired Student paired t test 0.40† 0.80† 0.40‡
ulse
6.6 � 2.2 8.0 � 1.0 0.20*
ervention 8.2 � 1.9 7.7 � 1.8 0.70*
paired Student paired t test 0.05† 0.60† 0.05‡
0.83 � 0.20 0.99 � 0.30 0.30*
ervention 0.94 � 0.30 0.91 � 0.30 0.80*
paired Student paired t test 0.10† 0.20† 0.06‡
1.08 � 0.10 1.08 � 0.10 0.90*
ervention 1.10 � 0.10 1.10 � 0.10 0.90*
paired Student paired t test 0.40† 0.30† 0.70‡
mean � SD unless otherwise indicated. *Student t test. †Paired Student t test.analysis to assess impact of intervention vs. conservative therapy on changes in time, respiratory exchange ratio, peak O2 pulse, and peak VO2.
ardiopulmonary exercise (stress) test; other abbreviations as in Table 1.
decrease in transmitral gradient with no change (oreven an increase) in exercise capacity, whereasothers had no change in transmitral gradient but asignificant decrease in CO and exercise capacity. Webelieve that our new noninvasive protocol may beuseful in evaluating patients with MS to define thespecific mechanisms limiting exercise capacity.This might improve patient selection for targetedtherapies.Abnormal SV. In the patients with MS and reducedexercise tolerance, no significant change or even adecrease in SV was observed. The reduced SVresponse in these patients may have resulted fromthe inability to utilize the Frank-Starling mecha-nism and a blunted increase in EF. Although our datacannot determine whether this results from subtleabnormalities in valve function or intrinsic LVdysfunction, it may be the result, at least in part, ofconcomitant LV reserve dysfunction.Peripheral factors. Low peak A–VO2 difference was anindependent predictor of reduced exercise capacity inour patients with MS, suggesting an importantcontribution of skeletal muscle abnormalities toexercise intolerance. Several reports have suggestedthat rheumatic MS is associated with systemicinflammation and increased levels of inflammatorycytokines (13). Similar pathophysiology has beenimplicated in inflammatory myopathies and heartfailure associated skeletal muscle disease. Interest-ingly, balloon valvuloplasty was found to reducelevels of inflammatory cytokines (14), suggesting thatsymptomatic improvement after the procedure mayresult, at least in part, from changes in inflammatorymediators and possible improved skeletal muscularperformance.Ventilatory abnormalities. It has long been knownthat MS is associated with changes in pulmonarycirculation and in the composition of lung tissue,including accumulation of water, proteins, andproteoglycans in the interstitium (15). These changesare important contributors to the clinical manifes-tations of MS. We found that baseline respiratoryparameters were decreased in patients with MScompared to control subjects, and in the subgroupof patients with MS and reduced exercise capacitycompared to patients with MS and preserved exer-cise capacity. During exercise, the inability to in-crease tidal volume during exercise was especiallynotable in the patients with MS and decreasedexercise tolerance.Mitral valve gradient and systolic pulmonary pressure. SEis an established tool in the evaluation of patientswith MS, with a discrepancy noted between find-ings on resting echocardiography and symptoms.
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Traditionally SE focuses on the transmitral gradientand pulmonary artery pressure immediately afterpeak exercise because they are considered indica-tors of the overall hemodynamic burden of MS (16).Surprisingly, we found no correlation between exer-cise capacity and transmitral gradient and little cor-relation between exercise capacity and SPAP(significant only in early exercise but not at peak).Brochet et al. (17) recently measured transmitralgradient and SPAP during various stages of exercise(although without measuring gas exchange). Theirresults resemble ours in that symptomatic patientswith MS exhibited a rapid increase in mean trans-mitral gradient and SPAP at low levels of exercisecompared with asymptomatic patients. In our study,as exercise continued, mean transmitral gradientleveled off and SPAP showed a blunted increase in thepatients with MS and reduced exercise capacitycompared to the patients in the preserved exercisecapacity subgroup. Because SV and duration of dias-tole are important drivers of mean transmitralgradient and SPAP, it may be that the attenuated in-crease in SV and HR at later stages of exercise in pa-tients with reduced exercise capacity attenuated theincrease in transmitral gradient and SPAP. These ob-servations suggest that the pattern of transmitralgradient and SPAP progression, rather than just peakvalues, play an important role in the exercise capacityof patients with MS. Our results are somewhatdifferent from previous invasive studies, but this maybe due to our use of semisupine exercise as opposedto the supine exercise used in catheterization-basedstudies (18). Pre-load is already maximized at supineexercise and LA pressures are exaggerated, so there islittle chance to observe a significant Frank-Starlingresponse in supine patients.
We believe that focusing on SPAP measured atpeak exercise, as suggested by previous guidelines(19), may not be as useful as its rate of rise and themeasurements made at a low level of exercise.Combined cardiopulmonary exercise and SE protocol.Most previous studies of the determinants of exercisecapacity in patients with MS measured CO invasively(20) or used the equilibrium carbon oxide rebreathingtechnique (21). Studies using catheterization arelimited by their invasive nature and associated se-lection bias. Furthermore, patients are rarely able toperform maximal exercise during right heart cathe-terization. The carbon oxide rebreathing technique islimited by insufficient anatomic and hemodynamicdata and cannot discriminate different causes oflow CO.
Several studies attempted to assess exercise ca-pacity in patients with MS using SE or dobutamine
echocardiography (22). However, our protocol differsfrom these studies in several important aspects.First, we did not simply compare rest and immediatepost-exercise images. Instead, we calculated thework rate increment necessary to reach the patient’sestimated peak work in 8 to 12 min. This allowedenough time to acquire echocardiographic images,including comprehensive hemodynamic data, atmultiple time points during exercise testing, evenin the sickest patients. Second, we analyzedechocardiographic images at individual stages ofeffort instead of pre-selected power outputs. Third,we used semisupine exercise, which is far morephysiological than the supine exercise performed inmost previous studies.
CLINICAL IMPLICATIONS. Cardiopulmonary stress orSE testing is rarely performed in patients with verysevere MS or in severely symptomatic (NYHA func-tional class IV) patients. Thus, our group consistedmostly of patients with MS in the moderate-to-severerange (1) and milder symptoms (NYHA functionalclass II or III). Our data suggest that the combinedtests are extremely useful in patients with this in-termediate range of MS, particularly when symptomsare out of proportion to resting hemodynamics (1).The most physiological form of exercise is uprighttreadmill, but that test makes continuous echocar-diographic imaging impossible. In contrast, such im-aging is readily performed in the semisupine position.The heterogeneity of the MS population poses a majorchallenge to development of optimal individualizedtherapy. A potential solution is to identify theparticular factors contributing to a reduction in ex-ercise capacity and peak VO2. In our study, combiningCPET with echocardiography and noninvasive he-modynamic measurements permitted us to evaluateeach component of VO2 and to subclassify patients onthe basis of the dominant mechanism limiting exer-cise capacity (mitral, ventilatory, chronotropic, SV,peripheral, or other). This approach may improvepatient selection for targeted therapeutics. Forexample, patients with MS could be classified intothose with primarily impaired peripheral O2 extrac-tion, chronotropic incompetence, extreme anatomicdamage to the mitral valve, or impaired SV responseand be treated accordingly. Importantly, nearly allcardiovascular centers have the equipment neededfor this testing, and the tests are noninvasive andinexpensive.
STUDY LIMITATIONS. The control group was hetero-geneous, combining subjects with normal andabnormal exercise capacity. A–VO2 difference was notmeasured but was calculated (as VO2/CO) using the
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: The
heterogeneity of the rheumatic population poses a
challenge to development of optimal individualized
therapy in patients with MS. This is particularly true
for patients with MS in the moderate-to-severe range,
especially when symptoms are out of proportion to
resting hemodynamics. A potential solution is to
identify subjects in whom the reduction in effort ca-
pacity is attributable to any one of the components of
peak VO2. In this study, combined CPET with echo-
cardiography permitted us to evaluate each compo-
nent of VO2 to classify patients with rheumatic MS on
the basis of the dominant mechanism limiting exercise
capacity. This approach may improve selection for
targeted therapeutics. For example, patients with MS
could be classified into those with primarily impaired
impaired SV response, severe mitral deformation, or
pulmonary restriction and be treated accordingly.
Furthermore, our study highlights the significant role
of impaired peripheral oxygen extraction and chro-
notropic incompetence in contributing to exercise
intolerance in patients with rheumatic MS.
TRANSLATIONAL OUTLOOK: Further studies are
needed to determine the effect of targeting different
aspects of the limits to peak VO2 in patients with MS.
Although individual etiologies for effort intolerance
implied by the combined tests are thought provoking,
they need to be tested in adequately powered,
prospective, randomized, controlled, and blinded
fashion before they can be suggested for use in indi-
vidual rheumatic MS patient management.
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CPET and Echocardiography in MS J U N E 2 0 1 7 : 6 2 2 – 3 3
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Fick equation. However, our results are similar tothose reported previously in studies that measuredA–VO2 difference invasively (23). We cannot excludethat the continued effects of b-blocker may haveinfluenced the blunted HR response. However, theresults were unchanged when adjustments weremade for long-term b-blocker use, with rates of chro-notropic incompetence similar in patients who per-formed the tests with and without b-blockers.Although individual etiologies for effort intoleranceand the effects of b-blockers on exercise capacity inpatients with MS implied by our work are intriguing,they should be considered hypothesis generating.Further investigations via adequately powered pro-spective studies are needed before they can beapplied to patientmanagement. Until then, we cautionagainst the use of the echocardiographic Dopplerexercise findings in individual patient management.
CONCLUSIONS
In patients with rheumatic MS, exercise intolerance ispredominantly due to chronotropic incompetence,limited stroke volume reserve, and peripheral factors,and not simply due to impaired valvular function.Combined testing can be helpful in determiningmechanisms of exercise intolerance in these patients.Most important, the beneficial effect of reducedtransmitral gradient associated with chronotropicincompetence may be outweighed by an unfavorabledecrease in cardiac output and exercise capacity insome patients.
ADDRESS FOR CORRESPONDENCE: Dr. YanTopilsky, Division of Cardiovascular Diseases andInternal Medicine, Tel Aviv Medical Center, 6Weizmann Street, Tel Aviv NA 61000, Israel. E-mail:[email protected].
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KEY WORDS congestive heart failure,echocardiography, exercise testing
APPENDIX For supplemental tables, pleasesee the online version of this article.
