Does balloon mitral valvuloplasty improve cardiac function? A mechanistic investigation into impact on exercise capacity

International Journal of Cardiology 91 (2003) 81–91 www.elsevier.com / locate / ijcard

Does balloon mitral valvuloplasty improve cardiac function? A mechanistic investigation into impact on exercise capacity D.J. Wright, S.G. Williams, B.-H. Tzeng, P. Marshall, A.F. Mackintosh, L.B. Tan* Molecular Vascular Medicine, Martin Wing, Leeds General Infirmary, Leeds, UK Received 14 March 2002; received in revised form 12 November 2002; accepted 3 December 2002

Abstract Procedural technical success of balloon mitral valvuloplasty (BMV) is indicated by an increase in valve area and a reduction in transvalvar gradient, but there are conflicting results regarding whether these indicators correlate with subsequent improvements in exercise capacity. We conducted a study to explore the effects of valvuloplasty on cardiac function to gain insight into the mechanisms responsible for the impact on exercise ability. Sixteen patients with mitral stenosis participated in the study and the five who did not proceed to valvuloplasty served as the control group. All patients performed maximal cardiopulmonary exercise tests before and 6 weeks after valvuloplasty (without valvuloplasty in controls). Central haemodynamics including cardiac output were measured non-invasively at rest and peak exercise. At baseline, the cardiopulmonary exercise test results were similar in the two groups. Following valvuloplasty, cardiac output did not alter at rest, but increased significantly at peak exercise (8.761.7 to 10.562.1 l min 21 , P,0.01), as did peak cardiac power output (1.8860.55 to 2.2860.74, P,0.05) and cardiac reserve (1.0760.33 to 1.4560.55 watts, P,0.05). Aerobic exercise capacity improved (13.964.2 to 16.464.3 ml kg 21 min 21 , P,0.01) as did exercise duration (3546270 to 5006266 s, P,0.01). There were no significant changes in the controls. There was a significant correlation between the changes in peak VO 2 and changes in cardiac reserve (r50.62, P,0.01) but not with changes in resting haemodynamics. These changes did not correlate with changes in peri-procedural mitral valve haemodynamics, despite increases in mitral valve area from 1.0560.16 to 1.7460.4 cm 2 (P,0.0001), accompanied by falls in the transvalvar gradient and pulmonary artery pressure (12.464.7 to 4.563 mmHg, and 26.868.4 to 17.465.2 mmHg, respectively, all P,0.0001). In conclusion, we found that successful mitral valvuloplasty in our patient cohort led to improved cardiac and physical functional capacity but not resting haemodynamics. Neither indicators of technical success nor resting haemodynamics were very reliable in predicting functional improvement.  2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Mitral valvuloplasty; Cardiac function; Oxygen consumption; Cardiac power output; Exercise capacity

1. Introduction Percutaneous balloon mitral valvuloplasty (BMV), is now an acceptable alternative to surgical mitral commissurotomy in appropriately selected patients with mitral stenosis [1]. The initial objectives of the procedure are to increase the cross-sectional valve *Corresponding author. Molecular Vascular Medicine, G Floor, Martin Wing, Leeds General Infirmary, Leeds LS1 3EX, UK. Tel.: 144-113392-5401; fax: 144-113-392-5395.

area, and simultaneously reduce the trans-mitral pressure gradient, left atrial pressure and mean pulmonary artery pressure [2], and the ultimate objectives are to improve the overall cardiac pump function, the exercise ability, quality of life and prognosis. According to previous multivariate analyses, patients whose mitral valve areas and intra-cardiac pressures were improved towards normal values were associated with improved survival [3–5]. Some in-

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vestigators have described an immediate increase in resting cardiac output following successful valvuloplasty [5–9]. It is however, unclear whether such haemodynamic effects can translate into improved cardiac and physical functional capacity of individual patients. Marzo et al. [10], found no significant correlation between changes in mitral valve area and changes in peak oxygen consumption 2 days after valvuloplasty. However, after 3 months significant improvement in peak oxygen consumption was observed, which correlated with increases in mitral valve area (r50.8, P,0.05). They did not report correlations with changes in transmitral pressure gradient or pulmonary arterial pressures. Douard et al. [11] on the other hand, have found that the improvements in exercise capacity or peak oxygen consumption when tested 6 months after valvuloplasty could not be predicted by the extents of improvement in mitral valve area or transmitral gradient, even in the absence of valvular restenosis. They conjectured that the reason might have been the persistence of peripheral abnormalities even after 6 months postintervention. The divergent results were both attributed to peripheral factors, while neither group explored the intermediate and direct impact of valvuloplasty on cardiac function. It would seem logical to investigate the effect of valvuloplasty on cardiac function by assessing the correlation between the improvement in cardiac function and the changes in mitral valve area and resting haemodynamics. It would then be possible to investigate whether the changes in cardiac function were in any way related to changes in exercise capacity. Unfortunately most measures of cardiac function (e.g., Emax , LV dp / dt, Vmax ) are extrapolated from physiological methods of assessing muscle function and are known to correlate poorly with markers of functional capacity [12–14]. To evaluate the impact of changes in valvular function on cardiac function, it is more appropriate to measure directly the overall pump function, not only at rest but also during maximal stress, using variables (e.g., power output) that evaluate both the flow- and pressuregenerating capacity of the heart [13,14]. Peak cardiac power output has been shown to provide accurate prognostic information for patients with left ventricular dysfunction [15–17]. Good correlation between peak cardiac power output and exercise duration or

peak oxygen consumption has been reported in a number of cardiac disorders and under variable conditions [18,19]. We conducted a mechanistic investigation to determine whether successful BMV leads to improvements in cardiac and physical functional capacity of the patients, and whether these changes could be predicted from peri-operative alterations in mitral and intracardiac haemodynamics.

2. Methods

2.1. Study subjects Sixteen consecutive patients from the waiting list for balloon mitral valvuloplasty were recruited into the study, having excluded those with evidence of bronchopulmonary disease, or other disabling medical conditions such as arthritis. Five unselected patients who did not proceed to valvuloplasty during the study period but underwent two exercise tests 6 weeks apart served as the control group. The study protocol was approved by the local ethics committee, and informed written consent was obtained from all patients. Mitral valvuloplasty was performed using standard anterograde transseptal technique with an Inoue balloon [2]. Right and left heart pressures were recorded before and immediately after the procedure.

2.2. Exercise protocol All patients performed a preliminary, familiarising, symptom-limited cardiopulmonary exercise test, with non-invasive measurement of cardiac output at rest and during exertion. This was to exclude any physical limitation other than due to impaired cardiac function. Baseline evaluation was made in the week preceding valvuloplasty and the test was repeated 6 weeks following the procedure. This allowed adequate time for full clinical recovery from the intervention. Control subjects repeated the exercise test 6 weeks after the first test without interim valvuloplasty. All tests were performed at the same time of day (approximately 11 a.m.) and supervised by the same staff who were blinded to the valvuloplasty procedure. Subjects were instructed to fast for 3 h before the test and avoid alcohol and caffeine for the preceding 12 h. Tests were performed in an

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air-conditioned room with the temperature maintained at 20 8C. Cardiopulmonary exercise tests were performed in two stages as previously described [19]. The first stage was an incremental test to establish the subject’s peak VO 2 . Following an adequate recovery period (at least 1 h), cardiac output was measured at rest. The patient then re-exercised to between 95 and 100% of their peak VO 2 and their peak exercise cardiac output was measured. The incremental exercise tests were conducted on a treadmill (Marquette 2000, Marquette Electronics, Milwaukee, WI, USA) using the modified Bruce protocol. Continuous 12-lead ECG was recorded. Blood pressure was measured using a sphygmomanometer before exercise commencement and 2 min into each stage. Expired respiratory gases were recorded breath by breath using a MedGraphics CardiO 2 system (MedGraphics, Minnesota, MN, USA). Ventilatory (anaerobic) threshold was determined using the V-slope method [20]. Test termination was governed by symptomatic status once the patient had been encouraged to exceed their ventilatory threshold. The value for peak VO 2 was averaged over the last 15 s of exercise. The subject then rested until the HR, VO 2 and VCO 2 were within 5% of the initial values and stable for 5 min. Baseline cardiac output measurements were made using the equilibrium CO 2 re-breathing technique, described by Collier [21]. Triplicate values were recorded and an average calculated. Cardiac output was evaluated according to the indirect Fick principle using the equation: Cardiac output 5VCO 2 /(Cv CO 2 2 Ca CO 2 ) where Cv CO 2 and Ca CO 2 represent mixed venous and arterial carbon dioxide concentrations, respectively. Concentrations were calculated from partial pressures using dissociation tables stored in the computer. Arterial partial pressure was extrapolated from end-tidal pCO 2 and mixed venous partial pressure from the equilibrium of respiratory gases during rebreathing. A constant maximum exercise stage was then performed using manual control of the treadmill. At an exercise VO 2 exceeding 95% of the previously recorded peak VO 2 and at a similar RER (ensuring reproducible physiological stress) the exponential

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CO 2 rebreathing technique of Defares [22] was undertaken to obtain at least two consistent cardiac output readings. Values for peak exercise cardiac output were then calculated according to the indirect Fick principle. Validation and reproducibility of noninvasive cardiac output measurements have previously been described for our laboratory [19].

2.3. Haemodynamic and echocardiographic evaluations The invasive haemodynamic data were collected as per standard clinical practice. The mean pressures were obtained from averaging data during two stable respiratory cycles, and for patients with atrial fibrillation, at least 10 consecutive beats were required. Two-dimensional echocardiography and Doppler studies were performed before, immediately after and within 1 week of valvuloplasty as part of routine clinical practice to detect as early as possible any adverse complications arising from the procedure (such as gross mitral regurgitation, ASD, tamponade).

2.4. Calculations and statistical analysis The cardiac power output was calculated according to the equation: CPO5(CO3MAP)3K, where CPO is the cardiac power output in watts, CO is the mean cardiac output in l min 21 , MAP is the mean arterial pressure in mmHg, calculated from the standard equation MAP5(systolic pressure123diastolic pressure) / 3 and K is the conversion factor (52.223 10 23 ) [15]. The span of cardiac function is depicted by cardiac reserve, which is calculated by subtracting the resting cardiac power output from the peak cardiac power output: cardiac reserve5CPO max 2 CPO rest . All data were expressed as mean6S.D. Comparison of data obtained before and after mitral valvuloplasty was done using a Student’s t test for paired samples. The unpaired Student’s t test was employed to compare the valvuloplasty and control groups at baseline. A value of P,0.05 was considered significant. The relationship between changes in different variables was evaluated by Spearman’s correlation coefficient.

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Table 1 Clinical characteristics of the patients and control group Patient No.

Age (years) / gender

NYHA func. class

Coexistent medical disease

ECG

Coexistent valvular disease

Prior surgery

1 2 3 4 5 6 7 8 9 10 11

78 / F 80 / F 28 / F 76 / F 51 / F 43 / F 61 / F 52 / M 58 / F 67 / M 66 / F

III III II IV II III IV II III III III

Hypothyroidism Hypertension – IDDM TIA (3) – Duodenal ulceration – Hypertension Gout –

AF AF SR AF AF SR SR AF AF AF SR

11 11 – 11 11 – 11 – – – 11

– – – – – – – – – – –

Controls 1 2 3 4 5

72 / M 62 / F 50 / F 57 / F 81 / M

II III III III II

Hypertension Duodenal ulceration CVA Diabetes, Hypertension –

AF AF AF AF AF

11 AR 11 AR – – 11 MR

MR MR MR MR MR

TR, 11 MR, 11 AR

M Valvotomy – – – M Valvotomy

AF5Atrial fibrillation; AR5aortic regurgitation; CVA5cerebrovascular accident; F5female; IDDM5insulin dependent diabetes mellitus; M5male; MR5mitral regurgitation; M Valvotomy5mitral valvotomy; SR5sinus rhythm; TIA5transient ischaemic attack; TR5tricuspid regurgitation.

3. Results The clinical characteristics of the patients participating in the study are summarised in Table 1. There were no significant baseline differences between the valvuloplasty patients and the control group except all patients in the control group were in atrial fibrillation (but this did not influence the exercise heart rates, as shown below). Although one patient in the control group gave a history of a previous stroke, she had made a complete recovery and this did not affect her ability to exercise. In the valvuloplasty group there were nine women and two men with a mean age of 60616 years (range 43–80). Eight patients were in functional classes III or IV, and three were in functional class II before valvuloplasty. Afterwards four were in class III / IV and seven in class II. Before valvuloplasty mild (11) mitral regurgitation (MR) was present in six patients (55%) with the rest showing no MR, and after valvuloplasty,

six had 11 MR and four had 21 MR. Three patients had mild aortic regurgitation, and one had mild tricuspid regurgitation. The patients’ weights or prescribed medications remained unchanged during the study period.

3.1. Effects of mitral valvuloplasty on resting haemodynamics The technical outcome of the valvuloplasty measured during peri-procedural invasive haemodynamic evaluation is shown in Table 2. After valvuloplasty, mitral valve area increased significantly from 1.0560.16 to 1.7660.38 cm (P,0.001). Mitral valve gradient decreased from 12.464.7 to 4.563.0 mmHg (P,0.0001), and mean pulmonary artery pressure decreased from 26.868.4 to 17.465.2 mmHg (P, 0.001). The haemodynamics measured non-invasively at rest prior to cardiopulmonary exercise testing are

Table 2 Haemodynamic changes at the time of mitral valvuloplasty (mean6S.D.)

Valve gradient (mmHg) Valve area (cm 2 ) Mean PAP (mmHg)

Pre PBMV

Post PBMV

P value

Control

12.464.7 1.0560.16 26.868.4

4.563.0 1.7660.38 17.465.2

,0.0001 ,0.0001 ,0.0001

13.865.5 1.0060.10 21.867.4

PAP5Pulmonary artery pressure; PBMV5percutaneous balloon mitral valvuloplasty.

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Table 3 Cardiopulmonary responses to exercise and at rest before and after mitral valvuloplasty and in the control group

Exercise time (s) VO 2 max (ml kg 21 min 21 ) Rest HR (min 21 ) Peak HR (min 21 ) Rest mean AP (mmHg) Peak mean AP (mmHg) Rest CO (l min 21 ) Peak CO (l min 21 ) Rest CPO (watts) Peak CPO (watts) Cardiac reserve (watts) Peak RER Peak VE (l min 21 ) VE / VO 2 VE / VCO 2 VE / VO 2 at 1 l min 21 VO 2

Pre BMV

Post BMV

P value

Control test 1

Control test 2

P value

3546270 13.964.2 87.6620.6 144629 90613 98613 4.061.1 8.761.7 0.8160.31 1.8860.55 1.0760.33 1.0660.1 39.1616 33.166.7 42.9610.4 3367

5006266 16.464.3 81.1618.9 150622 87615 96614 4.260.8 10.562.1 0.8260.24 2.2860.74 1.4560.56 1.0760.09 40.7618.1 30.165.3 38.468.4 3065

0.005 0.01 0.08 0.23 NS NS NS 0.01 NS 0.05 0.05 NS NS NS NS NS

3666102 15.563.0 84.3619.4 147625 100611 113612 3.561.0 8.061.3 0.7260.19 1.9560.37 1.2360.25 1.0460.06 43.668.9 3966 4265 3769

3526103 15.262.7 82.6621.3 146631 95615 105610 3.561.0 7.861.0 0.6660.21 1.7860.29 1.1260.10 1.0260.03 43.768.3 3864 4067 37611

NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

AP5Arterial pressure; BMV5balloon mitral valvuloplasty; CO5cardiac output; CPO5cardiac power output; HR5heart rate; peak5at peak exercise; rest5at rest; VCO 2 5rate of carbon dioxide production; VE 5ventilation rate; VO 2 5rate of oxygen consumption; VO 2 max5oxygen consumption at peak exercise.

shown in Table 3. Despite a general trend towards reduction, there were no statistically significant changes in resting heart rate (P50.08). Similarly, the resting values of systolic, diastolic and mean systemic arterial pressures, stroke volume, and in particular, cardiac output and power output in valvuloplasty patients were not significantly different before and after valvuloplasty. These variables also showed no significant changes in the control group of patients.

significantly, from 8.761.7 to 10.562.1 l min 21 (P, 0.01), and 1.8860.5 to 2.2860.7 watts (P,0.05), respectively. The cardiac reserve also increased from 1.0760.3 to 1.4560.5 watts (P,0.05). After valvuloplasty the VE / VO 2 , VE / VCO 2 and the VE / VO 2 at 1 l VO 2 were not reduced to significant extents. The percentage changes in exercise duration, peak oxygen uptake, peak cardiac output, peak cardiac power output and cardiac reserve are shown in Fig. 1. It is apparent that the physical and cardiac functional

3.2. Cardiopulmonary responses to exercise In Table 3, there were no significant differences in the variables between those who underwent valvuloplasty and the control group at baseline. There were no significant changes in the control group between baseline and the 6-week follow-up tests. In the intervention group, the exercise duration was increased from 3546270 to 4646278 s (P,0.005) and the peak VO 2 was increased from 13.964.2 to 16.464.3 ml kg 21 min 21 (P,0.01). Neither exercise duration nor aerobic exercise capacity were significantly correlated with changes in mitral valve area, transmitral valve gradient or changes in pulmonary arterial pressures following valvuloplasty. Peak exercise HR did not increase significantly (P50.23). Peak exercise CO and CPO both increased

Fig. 1. Percentage changes in cardiopulmonary exercise parameters in patients following mitral valvuloplasty and in controls who performed tests but did not undergo mitral valvuloplasty. Ex time5exercise duration; CO max 5cardiac output at peak exercise; CPO max 5cardiac power output at peak exercise; CRes5cardiac reserve; post–pre MVP5values after–values before valvuloplasty; VO 2 max5peak oxygen consumption.

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capacity of patients who underwent mitral valvuloplasty improved significantly, compared to the control group.

3.3. Predictors of improved cardiac function and exercise capacity Fig. 2A showed an absence of any correlation between changes in peak VO 2 and changes in mitral valve area. The correlations between changes in transmitral valve gradient and pulmonary arterial pressures before and after mitral valvuloplasty with changes in peak VO 2 or duration of exercise were similarly poor. The correlations between these direct effects of mitral valvuloplasty with changes in indicators of cardiac functional capacity were also generally poor. Changes in cardiac output measured at rest before and after mitral valvuloplasty did not correlate with aerobic exercise capacity as shown in Fig. 2B. None of the changes in resting values of haemodynamic variables showed any correlation with changes in aerobic exercise capacity, exercise duration, cardiac reserve, peak cardiac power output or peak cardiac output. The changes in cardiac reserve correlated well with the changes in peak VO 2 as shown in Fig. 2C (correlation coefficient50.62, P,0.01). It is important to note that the two variables were not measured simultaneously during the same test, but on separate occasions as described above. Similar correlation was found with peak cardiac power output. The delta changes in peak cardiac power output for patients who had undergone mitral valvuloplasty are plotted against the delta changes in peak VO 2 and shown in Fig. 3, and these were compared to those of controls. The majority of valvuloplasty patients had responses with data points in the right upper quadrant (i.e., increments in both CPO max and VO 2 max), and none of them had data point in the left lower quadrant (decrease in both CPO max and VO 2 max). In contrast, none of the control patients had responses that result in data points in the right upper quadrant. The mean responses of the two patient populations shown by the thick line in the graph lie in polar opposite quadrants relative to the origin.

4. Discussion In individual patients, the effects of mitral valvuloplasty are more complex than initially expected. An indication of technical success during mitral valvuloplasty is not necessarily correlated with an improvement in overall cardiac function and exercise capacity. In this investigation, we found that following percutaneous mitral valvuloplasty, there was an immediate increase in valve area and a reduction in transmitral valve gradient, indicating technical success of the procedure. There was also a reduction in resting pulmonary artery pressure. However, these changes do not appear to be useful in predicting the physical functional capacity of individual patients 6 weeks after valvuloplasty, as there were no significant correlations between these changes and the alterations in exercise capacity measured either as peak VO 2 or as exercise duration. This finding confirmed the observations of Douard et al. [11], who reported similar dissociations. A lack of correlation between mitral valve area and peak VO 2 during exercise in patients with mitral stenosis (who had not undergone valvuloplasty or commisurotomy) has previously been established [23–25]. Our finding that changes in mitral valve area and dynamics are not predictive of subsequent exercise ability after valvuloplasty is consistent with previous reports, and our results suggest that it stemmed from a similar lack of correlation with changes in cardiac functional capacity. Published reports on cardiac output at rest before and after mitral valvuloplasty have revealed conflicting results. Immediately after valvuloplasty, some reported increases in resting cardiac output [6–9,26], whereas others found no significant changes [10,11,27,28]. More than 6 weeks after valvuloplasty, some investigators reported increased resting CO [28], while others reported no increment [6,11]. In this study, we found that the resting values of haemodynamic variables (HR, MAP, CO, CPO) measured before and 6 weeks after valvuloplasty showed no significant changes (Table 3). This finding was similar to the control patients who did not undergo valvuloplasty. If we consider the complex nature of alterations in cardiac dynamics during valvuloplasty, e.g., changes in left ventricular vol-

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Fig. 2. Illustrative graphs showing which haemodynamic parameters can be predictive of the impact of mitral valvuloplasty on aerobic exercise capacity: (A) changes in mitral valve area (DMV area), (B) changes in resting cardiac output (DCO rest ), and (C) changes in cardiac reserve plotted against changes in peak VO 2 (DVO 2 max) following mitral valvuloplasty.

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Fig. 3. Graph showing the individual and group mean changes in peak cardiac power output (CPO) against changes in peak oxygen consumption (delta VO 2 max) in patients who underwent mitral valvuloplasty (MVP) and control patients who did not.

ume, end-diastolic pressure and ejection fraction, etc., and the confounding effects of procedural physiological and psychological stress, it is possible that measurement of cardiac output at the time of intervention may be quite variable and therefore unreliable without blinded data collection and analyses. Perhaps blinded measurements more removed from the procedure and carried out non-invasively may provide more representative values and such data in our study suggest that there are no significant changes in resting cardiac output. We also found that the changes in resting cardiac function (CO, CPO) after mitral valvuloplasty did not correlate with the changes in exercise duration or aerobic capacity. It has been known for sometime that indices of cardiac function at rest correlate poorly with exercise capacity [12–14]. Other indicators, such as left ventricular ejection fraction, are similarly not expected to be helpful in evaluating cardiac function in valvular interventions [6]. We may infer from these that changes in cardiac output or other parameters of cardiac performance measured at rest are unreliable predictors of the functional gain derived from mitral valvuloplasty. Several studies have measured central haemodynamic responses and cardiac function during either maximal or submaximal exercise. Rigolin et al. [25] performed right heart catheterisation on patients with

mitral stenosis and normal controls, and found that exercise limitation in the patients was primarily due to inadequate cardiac output reserve. McKay et al. [6] found peak exercise cardiac output increased from 5.961.7 before valvuloplasty to 8.061.5 l min 21 after (P,0.01). Burger et al. [9] showed a rise in submaximal exercise cardiac output from 4.5 to 5.8 l min 21 (P50.003) after mitral valvuloplasty. Tanabe et al. [29] studied patients during supine bicycle exercise testing at the same workload before and 5 days after valvuloplasty and found that exercise cardiac output increased from 6.461.4 to 8.161.9 l min 21 (P,0.001). Although such studies showed increased exercise cardiac output, they all employed invasive methods of measurement. The nature of invasive testing and the accompanying discomfort and psychological stress may affect the patients’ ability to attain maximal exercise. Using non-invasive radionuclide ventriculography, Choy et al. [30] studied 25 patients with mitral stenosis and normal controls during supine exercise. They found that patients only managed 37644% increase in cardiac output from rest to peak exercise compared to 173625% in controls (P,0.001), indicating markedly impaired exercise cardiac reserve in patients with mitral stenosis. Unfortunately, they did not report the absolute values of cardiac output. Employing non-invasive methods in our investiga-

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tion, we found a 117.5% increment in cardiac output from rest to peak exercise before valvuloplasty, and 150% after, and a significant 22% increase in peak cardiac output from 8.761.7 to 10.562.1 l min 21 (P,0.01) during maximal treadmill exercise after valvuloplasty (Fig. 1). Despite our patient population being older, with a mean age of 60616 years, than in the invasive study groups [6,29], the baseline pre-valvuloplasty peak exercise cardiac output of 8.761.7 l min 21 was over 33% greater than the 6.461.4 l min 21 in Tanabe et al.’s group (50610 years) [29] and 5.961.7 l min 21 in McKay et al.’s group (41615 years) [6]. This may suggest that peak exercise cardiac output is underestimated when measured invasively. Moreover, in our study all patients performed a preliminary familiarisation cardiopulmonary exercise test in order to exclude the unreliable effects of first tests [31]. Such crucial familiarisation tests cannot be readily conducted or ethically justified when using invasive methods. Measuring cardiac output merely evaluates the flow generating capacity of the heart. It is well known that maintaining the same cardiac output against a much higher arterial pressure head after an intervention requires a greater cardiac performance than against a lower pressure head. Therefore, for a more comprehensive physiological assessment of cardiac functional status, this should be complemented with an estimate of the pressure-generating capacity [13,14]. The combined flow and pressure generating capacity can be represented by peak exercise cardiac power output. In this study, we found that there was a 25% increase in peak cardiac power output and a 40% increase in cardiac reserve after valvuloplasty (Fig. 1), suggesting that the improvement in cardiac flow-generating capacity following valvuloplasty was not at the expense of its pressure-generating capacity despite greater systemic arterial vasodilatation during exercise. This was consistent with the view that there was a true improvement in the overall cardiac functional capacity after valvuloplasty. Compared to pre-valvuloplasty tests, the results at the 6-week follow-up demonstrated significant improvements in terms of both cardiac function and exercise capacity. The gains in cardiac function varied from 20 to 40%, and this was associated with

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an improvement in aerobic exercise capacity of 20% and in exercise duration of nearly 40%. These improvements were significantly different from those observed in control patients who showed an absence of significant changes (or slight insignificant deterioration) during evaluations within similar time periods. These improvements were comparable to a previous ¨ report by Kolling et al. who reported 19% improvements in treadmill exercise duration and 12% improvement in peak oxygen consumption [27]. Despite the observed wide biological variation of individual responses, the majority of patients (8 out of 11) demonstrated improvements in both peak cardiac power output and aerobic exercise capacity, whereas none the control patients showed this type of improvement (Fig. 3). The finding of a significant correlation between the changes in cardiac reserve and the changes in aerobic exercise capacity lends further support to the notion that cardiac function, measured at peak exercise, improved after successful mitral valvuloplasty and this contributed to subsequent improvements in exercise capacity. Overall, the benefits of successful mitral valvuloplasty can be classified as a sequence of three objective endpoints: (A) improvement in cardiac function, (B) improvement in exercise capacity and quality of life and (C) improvement in longevity. As described above, there are apparent contradictory findings in that technical success of valvuloplasty appears to correlate with (C) prognosis [3–5] but not with (B) exercise capacity [11] (Fig. 2A). Since the aim of cardiac interventions is primarily to improve or preserve cardiac function (A), which can thereby lead to preservation or improvements in B and C, our exploratory study has shown for the first time that successful mitral valvuloplasty does indeed lead to improved overall cardiac function, but this is dependent not only on mitral valvular dynamics but also other cardiac and haemodynamic factors. Further and larger studies are necessary to elucidate what these other factors are. Our results also showed that it was the improvement in cardiac function that was probably responsible for the improved exercise capacity.

4.1. Limitations Because this study was an exploratory investigation into the pathophysiological mechanisms involved

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affecting the cardiac functional changes following mitral valvuloplasty, the number of subjects in our study was necessarily small. In particular, since control patients hardly contributed to our knowledge of the changes, their numbers were even smaller. Previous studies evaluating the exercise physiology of patients with mitral stenosis had also employed similar numbers of subjects [10]. Future trials to answer relevant clinical questions unravelled by this study will require recruitment of larger patient numbers. Nevertheless, several important insights into the pathophysiological processes affecting the cardiovascular system following valvuloplasty could be gleaned. It still remains unclear at what point following valvuloplasty the patient’s cardiac and physical functional status begins to increase, and how long this is maintained for, and whether further improvements can be gained by rigorous exercise training. These unanswered questions deserve further consideration and investigation. Comprehensive evaluation would require sequential exercise tests on a regular basis (e.g., weekly or fortnightly) for an extended period. This was beyond the remit of the present investigation.

4.2. Clinical implications By recruiting an unselected population of consecutive patients awaiting percutaneous balloon mitral valvuloplasty, these results are representative of patients encountered in routine clinical practice in our centre. Our results support the finding that mitral valvuloplasty produces beneficial cardiac and physical functional benefits. However, these benefits could neither be reliably predicted from peri-operative changes in mitral valve area (or related pressures) nor from cardiac function assessed at rest following the procedure. It would appear therefore that functional benefits could not be assumed from successful periprocedural changes in mitral dynamics. We believe that if the objective information is needed, there is no substitute but to assess directly how much cardiac and physical functional gain has been derived from the valvuloplasty. If these are not adequately improved, then alternative therapy and interventions may need to be considered.

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