CRT and exercise capacity in heart failure: the impact of mitral valve regurgitation

Abstract

Cardiac resynchronization therapy (CRT) has emerged as an established therapy for patients with end-stage heart failure (HF) and symptoms refractory to optimal medication. Resynchronization of the ventricles leads to reduced functional mitral regurgitation (MR) both acutely and chronically and to a better haemodynamic and energetic profile. In addition, large clinical trials have confirmed its beneficial effect on exercise performance and quality of life. The link between the pathophysiological mechanisms of CRT and its positive effect on clinical status has not been fully elucidated. Therefore, this review will focus on the effect of CRT on the haemodynamic role of functional MR and its impact on exercise performance in patients with chronic HF.

Introduction

Cardiac resynchronization therapy (CRT) is an established therapy for patients with end-stage heart failure (HF) refractory to the traditional treatment options. According to the latest guidelines, CRT is recommended for patients with HF who remain symptomatic in NYHA class III and IV despite optimal medication, with left ventricular (LV) ejection fraction (LVEF) <35%, LV dilatation, normal sinus rhythm, and a wide QRS complex (>120 ms) (Class I, Level of evidence A). ¹

The clinical benefits of CRT have been confirmed by the data gathered from large randomized clinical trials ( Table  1 ) that demonstrate alleviation of symptoms and improvement of both functional capacity and exercise tolerance. Such changes were exemplified by an increase in 6 min walk distance and peak oxygen consumption on cardiopulmonary exercise testing that already became apparent by the first month after device implantation. ^2–8

Exercise compromise in HF is multifactorial. In part it depends on the maximal pumping capacity of the heart—meaning the maximal forward stroke volume that guarantees oxygen transport to the periphery—and in part it is due to skeletal muscle dysfunction, atrophy, and exercise-induced metabolic abnormalities. ^8–10

The observed improvement in functional status after CRT has been attributed mainly to the improved haemodynamic profile, followed by the inter- and intraventricular synchronization leading to increased cardiac output and reduced LV filling pressures. There are also reports of a sympathoinhibitory effect of CRT, both acutely and chronically, leading to a reversal of skeletal myopathy and consequently to better exercise performance and quality of life. ¹⁰

Dynamic mitral regurgitation (MR) represents one major factor that compromises the normal increase in forward stroke volume during exercise, thus reducing the maximal cardiac output, and correlates well with exercise-induced increases in systolic pulmonary artery pressure that contribute to dyspnoea and exercise intolerance. ¹¹ The response to CRT largely depends on the extent of LV dyssynchrony, but also on the severity of functional MR. ⁹

In this review, we will focus on the acute and chronic haemodynamic improvements due to CRT, at rest and on exercise. More specifically, the effect of CRT on the extent of dynamic MR will be examined.

Heart failure and mitral regurgitation

Functional MR is commonly found in patients with dilated and poorly contracting left ventricles and is associated with poor functional status and prognosis. ¹²

It is attributed to an imbalance between the closing and tethering forces that act on the mitral valve leaflets and negative chamber remodelling. Mitral annulus dilatation, tethering of the leaflets secondary to papillary muscle dislocation caused by increased chamber sphericity, and poor ventricular contraction, leading to a low transmitral pressure gradient (TMP), result in a decreased closing force of the mitral leaflets at rest. Furthermore, these factors vary throughout the cardiac cycle, leading to dynamic changes with exacerbation of the MR during exercise. A biphasic pattern of MR, with early and late systolic peaks and mid-systolic decrease in regurgitation, has been reported. ¹³

Furthermore, Ennezat et al . ¹⁴ showed that myocardial asynchrony at rest substantially contributes to worsening of functional MR during exercise. Kanzaki et al.¹⁵ and Ypenburg et al.^{16 , 17} proposed that the unco-ordinated regional mechanical activation of the LV segments supporting the papillary muscles contributes to the local distortion of the mitral valve geometry and the severity of MR.

The worsening of functional MR with exercise was clearly demonstrated by Lapu-Bula et al . ⁹ in a small HF population, and several factors, such as LV size, degree of emptying, mitral annular diameter, papillary muscle dysfunction, and left atrial size, were implicated. This study extended previous observations and emphasized that this phenomenon is not only dependent on mitral annulus dilatation, but also involves the apical displacement of the mitral leaflet coaptation as a result of the more spherical shape of the LV during exercise.

The latter is also connected with the reduced peripheral vasodilation observed in HF, which leads to increased afterload and hence LV systolic wall stress. ⁹ The authors’ data also suggest that the change in the severity of functional MR is the strongest determinant of peak exercise stroke volume and thus of exercise capacity. ⁹

But how does CRT improve both resting and exercise-induced MR in parallel with LV remodelling?

Early improvement of functional mitral regurgitation after cardiac resynchronization therapy

Observations of acute reductions in functional MR after CRT were made by Yiu et al ., ¹⁸ who reported a reduction in the MR jet area 1 week after CRT. However, the use of colour Doppler for the quantification of MR carries major limitations that make it less reliable. First, Breithardt et al . ¹⁹ studied the acute effects of CRT on functional MR at rest, quantified by the volumetric method, in an HF population of 24 patients with dilated, poorly contracting, and desynchronized ventricles in the first week after device implantation. It was clearly demonstrated that CRT acutely decreases the severity of functional MR, irrespective of the potential long-term remodelling effect on LV size and geometry. ¹⁹ There was a reduction of effective regurgitant orifice area (EROA) and regurgitant volume as measured with the proximal isovelocity surface area method of ∼40%, and this reduction was quantitatively related to an increase in LV + d p /d t and TMP, both reflecting a better contractility status. The desynchronized LV with a delayed rate of pressure rise was found to be associated with a low TMP and impaired closing force of the mitral leaflets. CRT caused both an improvement in peak transmitral closing force and an accelerated rise in TMP during isovolumic contraction time, which counterbalanced the tethering forces that impair mitral coaptation and decreased the functional MR acutely ( Figure  1 ). ¹⁹

It seems that CRT reduces both the apical displacement of the mitral valve leaflets’ coaptation point and the mitral annulus diameter 24–48 h after pacemaker implantation, which might lead to decreased MR. ²⁰

Furthermore, not only the geometry alterations but the mechanical asynchrony per se , with heterochronous activation of the medial and lateral segments that support the papillary muscles, contributes independently to the increased tethering forces on the mitral apparatus, worsening the functional MR. Hence CRT, by achieving a mechanistically beneficial effect, could restore the closing force of the mitral leaflets, leading to a reduction in functional MR. ^{15 , 17}

Kanzaki et al . ¹⁵ used the strain mechanical activation mapping method to identify the interpapillary muscle activation delay time as a principal cause of functional MR, in the electrical conduction delay setting of left bundle branch block, which is immediately improved with CRT. It seems that a delay in peak strain at the mid-lateral segment adjacent to the anterolateral papillary muscle results in incomplete closure of the mitral leaflets and diastolic MR. ¹⁵

Similarly, Madaric et al . ²¹ confirmed the above results and were able to show a relation between MR at rest and the extent of exercise-induced LV dyssynchrony and contractile reserve before device implantation.

In addition, newer data provided by Ypenburg et al.^{16 , 17} further support the view that the mechanisms underlying the acute reduction of MR after CRT implicate not only the improvement of mitral deformation indexes and local LV remodelling, but also the elimination of dyssynchrony between the papillary muscles. Of the 68 patients included in the study, 43% demonstrated immediate reduction of MR after biventricular pacing therapy and 20% late improvement at 6-month follow-up. The site of latest activation seems to distinguish between the early and late responders regarding MR. The above investigators’ data suggest that LV dyssynchrony involving the posterior papillary muscle may lead to an early response and acute reduction of functional MR after CRT, whereas that affecting the lateral wall characterizes the late responders.

All the available data seem to agree that the improvements in synchronization and contractility status constitute the pathophysiological background of MR improvement at rest, early after CRT. But what about the early benefit of CRT on exercise?

Early improvement of functional mitral regurgitation and exercise after cardiac resynchronization therapy

Functional MR worsens during dynamic exercise and its pathophysiology is different in synchronized vs. non-synchronized ventricles. In the former case, the exercise-induced functional MR is correlated with the changes in local LV distortion and mitral deformation, as estimated by mitral systolic tenting area (TA), whereas in the latter case, it is associated with the mitral closing force, as determined by dyssynchrony itself, and LV contractility, as already discussed. ²²

Ennezat et al . ²³ assessed the acute effects of CRT on dynamic MR during exercise and found that CRT invariably increased LV contractility two-fold, leading to an improved transmitral closure force and decreased EROA. Exercise-induced changes in MR with CRT on were related to changes in systolic TA, and thus to deformation of the mitral apparatus. ²²

Nevertheless, the authors failed to prove any positive effect on exercise duration or systolic pulmonary pressures, proposing as a major determinant of exercise performance the alterations in the periphery (skeletal myopathy, reduced vasculature, and mass). ²³

Subsequently, Lancellotti et al . ²² showed that CRT reduced the dynamic MR during exercise in all patients. But in contrast with the previous findings, the changes in EROA were related to the percentage of increase in LV + d p /d t with CRT off, but not with CRT on.

Surprisingly, Madaric et al . ²¹ found that early after CRT there was a notable increase in LV dyssynchrony, and this was also associated with a lack of improvement in functional MR during exercise, supporting the observation of their close relationship.

Although the existing studies show contradictory results concerning the degree of MR improvement at peak exercise, they all agree on the importance of LV synchronization and improved contractility as its major determinants. ^{24 , 25}

Late improvement of functional mitral regurgitation after cardiac resynchronization therapy

Various randomized trials show a sustained long-term benefit of CRT on LV remodelling and MR reduction. In the MIRACLE study, a significant reduction of MR at 6 months after CRT initiation was recorded. ⁴

A mid-term follow-up study at 3 months after pacemaker implantation, when a significant part of the reverse remodelling of the LV has taken place, points to mitral valve changes, in terms of improved mid-systolic TA and sphericity index, as the leading cause of MR attenuation at rest. ²¹

In addition, Fukuda et al . ¹³ further showed a change in the biphasic pattern of the functional MR (early and late systolic peaks with mid-systolic decrease) with CRT-induced reduction of the early systolic MR in parallel with a reduction in TA, which might be caused by LV asynchrony and suboptimal coaptation of the mitral leaflets, respectively. That study was able to show a 25% improvement in functional MR at rest in all patients, whereas no change in mitral annulus area was noticed during any phase of functional MR.

Similarly, data by Porciani et al . ²⁶ demonstrated the reduction of MR regardless of the LV reverse remodelling, underlying the contribution of synchronous contraction in the pathophysiology of MR.

Finally, recent studies have further expanded these first observations and propose basal LV dyssynchrony as a strong predictor of MR reduction, both acutely and chronically. ¹⁷ Besides the LV remodelling that leads to improved valve geometry and restoration of closure, the resynchronized ventricle achieves a better haemodynamic status with better systolic function and a more co-ordinated contraction, mechanisms which all contribute to the MR reduction. It is of interest that the segment of latest activation can predict the early or late response, with those patients having the latest activation in the lateral wall being late responders. ¹⁷

Late improvement of functional mitral regurgitation and exercise after cardiac resynchronization therapy

According to the study by Madaric et al . ²¹ in the chronic phase after pacemaker implantation, a progressive decrease in the magnitude of resting MR occurs. During exercise, the magnitude of MR appears to be reduced, with the exercise performance as assessed by exercise duration and peak VO ₂ improving more in those patients with fewer changes in MR severity after exercise. Chronically, the improvement of resting functional MR is also accompanied by near abolition of LV dyssynchrony and attenuation of functional MR during exercise. This is a result of the synergistic role of the improvement in contractility and synchronicity together with the effect of reverse remodelling of the LV, with better TA and sphericity index. ^{21 , 24 , 25}

Exercise capacity following cardiac resynchronization therapy

Among the many factors that appear to contribute to poor exercise performance in HF, patients are the diffused early skeletal myopathy of HF, with distinct histological features; alterations in metabolism and reduced muscle mass; tissue hypoperfusion and poor oxygen transport due to low output state; and chronic sympathetic activation with vasoconstriction and endothelial dysfunction. ¹⁰ Furthermore, an impaired heart rate response to exercise and abnormal ventilatory drive may represent additional mechanisms that lead to compromised exercise tolerance. ²⁷

The peak oxygen consumption during cardiopulmonary exercise testing and the 6 min walking distance have traditionally been used in most clinical trials for the assessment of functional status, since they have been proved to be more robust indicators compared with other haemodynamic parameters. In these studies, 3–6 months after CRT, the peak VO ₂ improvement ranged from 1.1 to 2.5 mL/kg/min, whereas the change in peak VO ₂ for controls was from 0 to 1.2 mL/kg/min. ^{27 , 28}

The randomized, prospective clinical trials ( Table  1 ), with the exception of the Companion study, show a consistent and impressive beneficial effect of CRT on peak VO ₂ at 6, 9, and 12 months after treatment assignment.

In the Companion Trial, CRT did not improve the peak VO ₂ at 6 months, although it did result in an increase in the 6 min walk distance, and the quality of life as measured by QqL score and NYHA functional class symptoms. ⁸

This observation is in accordance with the skeletal myopathy hypothesis. Previous studies ¹⁰ have already elucidated the role of chronic sympathetic overactivation, chronic inflammation, deconditioning, and chronic hypoperfusion in the pathogenesis of down-regulation of skeletal muscle capacity. By correcting the myocardial asynchrony, CRT causes a beneficial improvement in haemodynamic profile, as measured by an increase in LVEF and contractility, and a reduction in functional MR, resulting in increased cardiac output and increased d p /d t . This is followed by a decrease in muscle sympathetic nerve activity through the baroreceptor inhibition and reversal of muscle inflammation, leading to an improvement of skeletal myopathy and exercise capacity.

Finally, Salukhe et al . ²⁹ showed that the acute gain in peak VO ₂ from CRT is similar to that in the long term. Furthermore, based on the knowledge that total isovolumic time (t-IVT) is a major determinant of peak VO ₂ and of peak stress cardiac output, the authors showed that resynchronization of the ventricles causes an acute reduction in t-IVT, both at rest and during exercise, and that the most significant reduction is observed at high heart rates during exercise. A reduction in t-IVT corresponds to increased filling and ejection times and is proposed as the underlying mechanism of acute peak VO ₂ improvement.

Conclusion

Cardiac resynchronization therapy has become an established treatment option that has changed the physical course of end-stage HF in patients with symptoms refractory to conventional therapy and electrical conduction delay in the form of left bundle branch block. By correcting the asynchronous activation of the LV, CRT achieves both haemodynamic and neurohormonal improvement, leading to a better functional status. Many trials show a consistent benefit in terms of LVEF, end-diastolic dimension, and filling pressures, and in the magnitude of resting mitral valve regurgitation. Although early post-CRT reveals non-significant reductions in dynamic MR, later evaluation of exercise-induced MR shows that it is attenuated in parallel with the reversal of cardiac remodelling, thereby contributing to the overall improvement in exercise performance in patients with HF.

Conflict of interest: none declared.

References