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Exercise training with a heart device: a hemodynamic, metabolic, and hormonal study

METTAUER, BERTRAND; GENY, BERNARD; LONSDORFER-WOLF, EVE; CHARLOUX, ANNE; MING ZHAO, QUAN; HEITZ-NAEGELEN, BERNADETTE; EPAILLY, ERIC; LAMPERT, ELIANE; LEVY, FRANÇOIS; LONSDORFER, JEAN

Medicine and Science in Sports and Exercise: January 2001 - Volume 33 - Issue 1 - p 2-8
CLINICAL SCIENCES: Case Study
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BERTRAND METTAUER, BERNARD GENY, EVE LONSDORFER-WOLF, ANNE CHARLOUX, QUAN MING ZHAO, BERNADETTE HEITZ-NAEGELEN, ERIC EPAILLY, ELIANE LAMPERT, FRANÇOIS LEVY, and JEAN LONSDORFER. Exercise training with a heart device: a hemodynamic, metabolic, and hormonal study. Med. Sci. Sports Exerc., Vol. 33, No. 1, 2001, pp. 000–000.

Purpose: The mechanisms of the training-induced improvements in left ventricular assist (LVAD) patients are unknown.

Methods: We measured the hemodynamic, gas exchange, and metabolic and hormonal effects of 6-wk exercise training in a cardiogenic shock patient who was assisted by an LVAD.

Results: After training, the peak power and O2 increased by 166% and 56%, respectively (80 W and 16.1 mL·min-1·kg-1), whereas the ventilatory drive decreased. Although the LVAD output increased little with exercise, the systemic cardiac output rose (adequately for the O2) from 5.91 and 4.90 L·min-1 at rest to 9.75 and 9.47 L·min-1 at peak work rate, before and after training, respectively. Thus, the left ventricle ejected again through the aortic valve. Unloading and/or retraining resulted in a left ventricular filling pressure decrease. Although the right ventricular ejection fraction increased with exercise, it decreased again at the maximal load after training. For a given work rate the arterial lactate, the norepinephrine (NE) and epinephrine (E) concentrations fell after training, but the enhanced maximal work rate elicited higher NE and E concentrations (4396 and 1848 pg·mL-1, respectively). The lack of right ventricular unloading might have kept the atrial natriuretic peptide higher after training, but the blood cyclic GMP and endothelin were lower after training.

Conclusion: In an LVAD patient, retraining returns the exercise capacity to the class III level by peripheral and left ventricular hemodynamic improvements, but the safety of maximal exercise remains to be proven in terms of right ventricular function and orthosympathetic drive.

Jeune Equipe 2105, Faculté de Médecine, Strasbourg, FRANCE; and Service de Physiologie Appliquée and Service de Chirurgie Cardio-vasculaire, Hôpitaux Universitaires de Strasbourg, FRANCE

February 2000

April 2000

espite being an established procedure for the treatment of end stage heart failure, heart transplantation is limited by the scarcity of donor hearts. Left ventricular assist devices (LVAD) have therefore been developed, first as a bridge to transplantation for dying patients (21) but now even as an alternative to transplantation as portable units have become available (7,27). Mild exercise has been shown beneficial to patients with left ventricular mechanical assistance (12,23). Systemic cardiac output (CO) increases during exercise, essentially because the left ventricle starts to eject again through the aortic valve and produces blood output in parallel with the mechanical ventricle (2,6,12). Recently, the exercise capacity has been followed for 6 months or more in mechanically assisted patients (6,19) and has been found to improve as the patients have been submitted to prudent exercise training, which may contribute to the success of the subsequent transplantation or in the quality of life of those patients that are permanently assisted (23). From a physiologic point of view, although residual left ventricular function has been shown to contribute significantly to the exercise increase in cardiac output, data on the hemodynamic, metabolic, and neuro-hormonal effects of exercise training are lacking in these patients. Therefore, we report here the case of a mechanically assisted patient who underwent an extensive hemodynamic, metabolic, and neuro-hormonal assessment during exercise, both before and after exercise training.

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SUBJECT AND METHODS

Case Report

A 61-yr-old man (blood group B) with hypokinetic nonischemic cardiomyopathy and in mild class III heart failure had been referred for heart transplantation. His weight and height were 80 kg and 169 cm, respectively. Because of his very poor left ventricular ejection fraction (22%) and his highly dilated left ventricle (end diastolic diameter: 78 mm) cardiac transplantation was felt necessary on an nonurgent basis despite his relatively good exercise capacity (peak O2: 16.0 mL·min-1·kg-1, peak power output: 80 W), and he was placed on the national waiting list. Three months later, he suddenly deteriorated despite maximal diuretics, angiotensin-converting enzyme inhibitors, and digoxin therapy. He was placed on IV inotropic therapy but remained in cardiogenic shock, which did not resolve after intra-aortic balloon counterpulsation. Thus, having met the mechanical assistance criteria (12,21), he received a pulsatile left ventricular assistance chamber (Thermo Cardiosystems Heart Mate 1000 IP). This LVAD is a vented pneumatically driven implantable pulsatile pump that comprises a pusher-plate actuated blood chamber equipped with an inflow and an outflow artificial valve. Its inflow conduit is connected to the apex of the left ventricle, and the outflow conduit is connected to the ascending aorta via a Dacron graft. This LVAD functions in the asynchronous fill to empty mode: the chamber can receive 85 mL, and its filling is detected by a hall sensor that increases the pumping rate if the chamber filling is over 75 mL and decreases it if this filling is less than 70 mL. The maximal rate is of 140 cycles·min-1, and the theoretical maximal output is of 11.2 L·min-1 but is generally less than 10 L·min-1 as the device is preload and afterload dependent (12). During exercise, as the venous return increases, the device output increases by elevating its pumping rate (6,12). At present, a battery-driven electrically actuated LVAD, whose mode of functioning is identical, uses the same pusher-plate pump and is available for long-term outpatient use (Thermo Cardiosystems Heart Mate 1205 VE). Despite immediate adequate LVAD function, the patient remained for several days in right ventricular and hepatic failure and required assisted ventilation for 10 d. He finally recovered, was ambulated, and transferred to the ward. Three weeks after LVAD implantation, his recovery was sufficient to start the exercise training program, and he gave his written consent to the retraining study in accordance with the institution’s board for human studies. After having his first set of exercise tests, he followed a 6-wk retraining program and subsequently had his second set of exercise tests. Thereafter, he continued to take his walks and exercises, waiting for transplantation. After 103 d of assistance, he suffered a severe LVAD failure (rupture of the pneumatic drive line connection with the chamber housing, whose design has been afterward modified by the manufacturer) before a suitable donor heart became available and died of intractable bleeding during reoperation for device replacement.

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Exercise Testing

The patient was tested by the same protocol before and after training. The maximal exercise capacity has been assessed by an incremental 10-W/2-min symptom-limited maximal exercise on a bicycle ergometer (CardiO2 Cycle, Medical Graphics, St. Paul, MN), while measuring minute BTPS ventilation (VE), STPD oxygen uptake (O2), and STPD carbon dioxide production (CO2) by means of open circuit spirometry (CPX Medical Graphics). The maximal exercise level was considered to be attained when the patient was unable to sustain the prescribed cycling rate of 60 rpm. The ventilatory threshold (VT) was assessed according to the V-slope method (33). Two days afterward, right heart hemodynamics (Swan-Ganz catheterization), blood pressure (radial artery catheter), and thermodilution CO (by triplicate injection of 10-mL iced isotonic glucose solution) were taken at rest and at the 5th, 7th, and 9th min of 10-min constant rate exercises set at 10 W–30 W–60 W as tolerated. The Swan-Ganz catheter and the thermodilution computer used permitted also the assessment of the right ventricular ejection fraction (Edwards Laboratories). VE and gas exchange have been measured during these constant rate exercises (CPX, Medical Graphics). At least 2 h of rest separated two subsequent sets of constant rate exercises. At rest and at the 6th, 7th, and 10th min of the constant rate exercises, the following hormones were measured on arterial blood: norepinephrine (NE) and epinephrine (E) by high-performance liquid chromatography, atrial natriuretic peptide (ANP), cyclic guanosylmonophosphate (cGMP), and endothelin (ET) by immuno-enzymatic methods. To limit noise, the rest values were pooled, as the three exercise values were averaged for each work rate level, to yield averaged hemodynamic, metabolic, and hormonal rest and exercise values for each rectangular exercise level. The arterial lactate concentration (LA) has also been measured by an immuno-enzymatic method at rest and at the end of each constant rate exercise.

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Exercise Training

Exercise training consisted of daily 20- to 30-min stationary bicycle constant rate exercises, with the work rate set as to obtain 50% of the maximal heart rate increase, recorded during the first incremental maximal exercise. The patient was also encouraged to walk daily along the hallway with his portable console and, if the weather permitted, within the hospital’s gardens. He was always under supervision of a physical therapist. In addition to these submaximal endurance exercises, he underwent daily respiratory kinesitherapy and light calisthenics. No adverse symptoms, especially arrhythmia, were encountered during these training sessions.

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RESULTS

Maximal Incremental Exercise

The effect of training on the gas exchanges at maximal exercise capacity and at the VT are summarized in Table 1. After training, the power and the peak &OV0312;O2 increased by 166% and 64%, respectively, at maximal exercise and by 300% and 56%, respectively, at the VT. The oxygen pulse was also higher after training at the VT and peak exercise. On the other hand, the respiratory exchange ratio (RER) was similar before and after training at rest, at the VT, and at peak exercise. Despite being lower at rest, the VE was higher after training at the VT and peak exercise due to the higher work rates achieved, but the lower ventilatory drive for a given exercise level after training is depicted by the lower ventilatory equivalent for oxygen or for CO2 at the VT and peak exercise.

Table 1

Table 1

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Constant Rate Exercises

The &OV0312;O2 response to the rectangular exercises is depicted in Figure 1 showing that for 30 W a slow component of &OV0312;O2 increase is obvious before training, whereas a true steady-state was obtained after training. In this figure, the large &OV0312;O2 oscillations often seen in the most severe heart failure patients are prominent before training and are blunted after training. The gas exchange, systemic hemodynamics, and LVAD pumping parameters during the serial rectangular exercises are summarized in Table 2. Before and after training, the resting and the exercise &OV0312;O2 at 10 W and 30 W were similar. After training, however, the exercise &OV0312;CO2 was lower at 30 W than before training and the RER became higher than 1 only at 60 W. Thus, the exercise VE was lower at 10 W and 30 W after training. Interestingly, the 30-W exercise before training and the 60-W exercise after training elicited the same VE. Despite being entirely produced by the device at rest, the systemic CO exceeded the device’s output at all of the exercise levels before and after training, and its relation to &OV0312;O2 compares favorably before and after training with the one previously reported in normal subjects and after cardiac transplantation (14) : Before training CO = 5.9&OV0312;O2 + 3.83 (r = 0.60, P = 0.02); after training CO = 5.5&OV0312;O2 + 2.93 (r = 0.93, P = 0.001); normal subjects CO = 6.0&OV0312;O2 + 3.87 (14), where CO and &OV0312;O2 (STPD) are expressed in L·min-1. Although the LVAD output increased moderately during exercise before training by means of an increase of its stroke rate, it failed to increase significantly with exercise after training. From the hemodynamic point of view, the mean pulmonary artery pressure tended to be lower after training but increased similarly during exercise after training. The right and left ventricular filling pressures are depicted in Figure 2. After training, whereas the right atrial pressure was only minimally lower, the LVAD-induced chronic left ventricular unloading resulted on a largely lower pulmonary capillary wedge pressure for a given work rate. After training, the right ventricular ejection fraction was higher but dramatically decreased toward resting levels at the highest work rate. The arterial lactate increase during the serial rectangular exercises decreased for a given work rate after training as shown in Figure 3.

FIGURE 1

FIGURE 1

Table 2

Table 2

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

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Hormonal Status during the Constant Rate Exercises

Table 3 summarizes the hormone levels observed at rest and during the serial rectangular exercises. The NE levels were similar at rest but were decreased for a given submaximal work rate after training as did the E levels. However, the higher 60-W exercise load after training led to a dramatic increase of NE and E. Although after training the ANP levels were unexpectedly higher for any exercise level despite the rather lower filling pressures, the circulating cGMP were lower at all the serial exercise work rates. Moreover the ET levels failed to increase with exercise and tended to be lower after training.

Table 3

Table 3

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DISCUSSION

Although being obtained in one single LVAD case, our data confirms previous observations in long term assisted patients: by an ejecting left ventricle the exercise CO exceeds the device output, contributing to yield an exercise capacity similar to moderately severe stable heart failure subjects (2,6,19). Additionally, because we performed an extensive hemodynamic and neuro-hormonal evaluation, we were able to observe after training further left ventricular unloading, and an increased right ventricular (the nonassisted chamber) load at peak exercise leading to a decrease in this chamber’s ejection fraction. After training, we observed a decreased neuro-hormonal drive for a given work rate, although the orthosympathetic stimulation may be higher at the enhanced maximal power. Moreover, the exercise blood lactate and ventilatory drive are lessened after training, whereas the oxygen pulse is increased for a given work rate.

Our data fit with the several previous studies on the postrehabilitation exercise capacity of LVAD supported patients (2,6,11,12,15,17,19). These studies have reported peak &OV0312;O2 in the range 14.1–17 mL·min-1·kg-1 (Table 4), all measured after the patient’s rehabilitation. Conversely, our report describes the improvements gained by exercise training in a previously moribund mechanically assisted patient. The peak work rate increased by 167% and the peak &OV0312;O2 increased by 56% during the 6 wk of training, but the peak exercise cardiac output remained unchanged (Table 3). This is consistent with the muscle hypothesis of exercise intolerance during heart failure (3,20). Indeed, the beneficial effects of exercise training resulted essentially from muscle metabolism and peripheral blood output redistribution changes, without improvements in central hemodynamic function in heart failure patients (13,22,32). We and others have shown in heart transplant, or heart failure patients, that retraining provokes an increase in the muscular mitochondrial density (5,16). Interestingly, after LVAD assistance and retraining, our patient reached the peak &OV0312;O2 that he had when in stable NYHA class III heart failure, at the time of initial evaluation for transplantation. In the recent report by Mancini et al. (19), the LVAD group had a significantly better peak &OV0312;O2 than the severe heart failure group, and the LVAD patients’ VT was equivalent to peak exercise in their heart failure patients. These improvements in gas exchange elicited by retraining are also prominent in Figure 1 where a slow &OV0312;O2 component exists even at 30W before training, whereas it occurs only at 60 W after training. As this slow component results from the type II muscle fiber recruitment (1), a lower percentage of such fibers are probably recruited for a given submaximal work rate after training. As previously stated the measured systemic CO was adequately related to &OV0312;O2(14) in our patient suggesting that there was no obvious deficit in central oxygen transport. Jaski et al. (12) were the first to observe in LVAD patients that the exercise CO exceeds the device output because the left ventricle starts to eject part of its stroke volume through the aortic valve, in parallel with the LVAD, an observation consistently found thereafter (2,11,19) ourselves included. Because the difference between the exercise systemic and device output is larger after training, the chronic left ventricular unloading, together with retraining, might have improved the left ventricular reserve (Table 2). This is also suggested by the benefits we observed on the filling pressures (Fig. 2). Therefore, both LVAD unloading and exercise training are likely to interact to yield a decreased left ventricular preload for any given level of exercise. Accordingly, the left ventricular pressure-volume relation, myocyte hypertrophy, and plasma volume are normalized by LVAD unloading (10,18,34), with beneficial effects on left ventricular morphometry and on histological signs of myocyte injury (26). Training might also participate in the decreased ventricular load because it diminishes the excess neuro-hormonal stimulation for any given submaximal work rate (3,4). This deserves further study. The effects of exercise and training on the right ventricle deserves also further attention: Jaski et al. (11) suggested that the exercise cardiac output is not limited by the unassisted right ventricle in the short-term assisted patient. Our patient’s right ventricular ejection fraction increased with exercise at time of initial assessment, but it decreased toward resting levels during heavy exercise after training, when the muscular improvements induced by retraining allow the exercise to reach a sufficiently high work rate.

Table 4

Table 4

Consistently, from the work by James et al. (9) left ventricular assistance results in a normalization of baseline NE and E levels. However, E normalized in our patient only after long-term ventricular unloading and retraining. Consistently with current knowledge in normal and heart failure subjects (8,29), NE increased proportionally to the relative exercise level and E as a function of absolute work rate, but both reached a higher peak value after training owing to the largely higher maximal tolerated power. Because of this massive sympathoadrenal response, exercising at the maximal intensity reachable after retraining might be detrimental to the LVAD patient (28). This may also contribute to the decline in right ventricular ejection fraction we observed at near maximal exercise after training. We expected to find higher than normal resting ANP levels (9,10), but the cause for the higher levels we observed after long-term LVAD treatment and/or training remains unclear. James et al. (9,10) already speculated that chronic LVAD treatment might not decrease but may even increase the ANP levels. They advocated that LVAD unloading significantly decreases the left but not the right atrial stretch and that the exercise ventricular distension and geometry changes might contribute to an enhanced ANP secretion. The effector consequences of these ANP levels might be unchanged because the cGMP levels are similar before and after training. Unlike the other hormones observed, the ET levels were unchanged with exercise as previously observed in normals and heart transplants (31), and decreased with chronic unloading and/or retraining. This may be beneficial to the muscular nutritive flow and ultimately to exercise capacity (15). Thus, as a whole, the consequences of retraining on the hormonal response to exercise appears beneficial for a given work rate, except that the highest exercise levels should be avoided.

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Limitation of the Study and Clinical Implications

The main limitation of this case study concerns the fact that we obtained data in one single patient. Therefore, our observations can only serve as guide for subsequent studies. Nevertheless, because our hemodynamic and gas exchange data are closely consistent with data previously reported after rehabilitation in LVAD patients (Table 4), we are convinced that it represent the average LVAD recipient. Another limitation concern the fact that our study does not permit us to separate the improvements due to retraining from those due to left ventricular unloading only. Because peak exercise CO remains similar before and after training, the beneficial muscular metabolic or vasomotor effects are likely to result from retraining, whereas the decrease in filling pressures and beneficial neuro-hormonal effects most likely result mainly from unloading with a contributing effect of retraining (10). Nevertheless, our preliminary data may help to design the necessary further studies on this topic. Because portable electrically actuated devices have become available (7), very prolonged LVAD support up to 794 d (30) have been reported, sometimes with sufficient heart recoveries to allow successful explantations of the LVAD without subsequent cardiac transplantation (30). This supposes that LVAD implantation can be seen as an independent therapeutic option for the dying heart failure patient, either as a permanent mechanical assist or as a bridge to recovery rather than as a bridge to transplantation (24,27,30). In this view, a comprehensive rehabilitation approach of the patient is mandatory, with its necessary exercise retraining program. Such an approach has been shown feasible even at a large scale (23), but the mechanisms that lead to improvements remained to be made precise. On the other hand, the assessment of the physiological response to exercise might reveal essential, especially in terms of right ventricular function and neuro-hormonal responses, to assess the long term safety of the LVAD assistance option without subsequent transplantation.

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CONCLUSION

We conclude that exercise training in the previously moribund patient subject to left ventricular mechanical assistance results in beneficial metabolic muscular effects at submaximal exercise, without deleterious hemodynamic and neuro-hormonal consequences. Nevertheless the safety of exercise at near maximal level, as well as the long term consequences of regular training, remain to be examined.

We are indebted to Prof. Bernard Eisenmann, Prof. Jean-Georges Kretz, and Dr. Jean-Claude Thiranos for their support, the nurses team of our cardiovascular surgery department for their enthusiastic participation, and our patient who gave us lessons of hope.

This work has been supported in part by the INSERM network Activité Physique, Muscle et Handicap.

Address for correspondence: Bertrand Mettauer, M.D., Ph.D., Unité Fonctionnelles des Explorations Cardio-circulatoires à L’Exercice et Service de Chirurgie Cardio-Vasculaire, Pavillon Chirurgical A, Hôpitaux Universitaires de Strasbourg, 1, Place de L’Hôpital, 67091 Strasbourg Cedex, France; E-mail: Bertrand.Mettauer@physio-ulp. u-strasbg.fr.

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    Keywords:

    HEART FAILURE,; ASSISTED CIRCULATION,; EXERCISE TRAINING,; HEMODYNAMICS,; HORMONES

    © 2001 Lippincott Williams & Wilkins, Inc.