Abstract
Functional mitral regurgitation (MR) is a common finding in patients with heart failure (HF). It results from an imbalance between closing and tethering forces that ensure valve competence as a consequence of systolic dysfunction and altered geometry of the left ventricle (LV). In some patients, mechanical asynchrony in chamber contraction might be present and also contributes to the development of MR, either leading to diastolic MR, systolic MR or both.
Cardiac resynchronization therapy (CRT) has the potential to reverse the vicious cycle resulting in MR worsening, specifically in those patients with abnormal electrical conduction leading to disturbances in mechanical contraction. CRT leads to LV reverse remodeling and reduces morbidity and mortality, in addition to symptoms and exercise capacity improvement. CRT can effectively reduce functional MR by improving mechanical dyssynchrony in cardiac contraction, which leads to improve LV systolic and diastolic function, and also by inducing reverse LV remodeling which in turn restores the abnormal geometry of the mitral valve apparatus. There is growing evidence that CRT can be considered as a first line treatment in patients with HF and severe secondary MR who have mechanical dyssynchrony amenable to be electrically corrected with CRT.
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Keywords
- Functional mitral regurgitation
- Cardiac resynchronization therapy
- Left ventricle remodeling
- Dyssynchrony
- Heart failure
- Pacing
- Cardiomyopathy
- Systolic dysfunction
- Predictors
- Mortality
Principles of Treatment
Pathogenesis of functional mitral regurgitation (MR) involves multiple factors, including increased mitral leaflet tethering due to the outward displacement of the papillary muscles caused by global and regional left ventricular (LV) remodeling, decreased LV closing forces and deformation of the whole mitral apparatus including the annulus [1, 2]. In some patients with heart failure, differences in the timing of cardiac chamber or even between myocardial segments contraction, namely mechanical dyssynchrony, can contribute to the development of more insufficiency of the mitral valve. Dyssynchrony may cause the increase in functional MR in several pathways: the presence of global LV dyssynchrony may decrease the efficiency of LV contraction and thus, decrease the LV closing force acting on the mitral leaflets. Also, dyssynchronous contraction of the papillary muscle insertion sites at the LV free wall may induce geometric distortion of the mitral valve apparatus. Finally, dyssynchronous contraction of the LV basal segments may render a non-simultaneous contraction of the papillary muscles and adjacent LV walls, resulting in uneven timing of leaflet coaptation [3]. Also, the presence of atrioventricular dyssynchrony with abnormal atrioventricular coupling may lead to diastolic MR (Fig. 5.1), as well as the presence of interventricular dyssynchrony, which induces an abnormal motion of the interventricular septum, may provoke the inadequate closure of the mitral leaflets.
Improvement in papillary muscles dyssynchrony [4] together with an increase in the rate of LV pressure increase [5], which counteracts tethering forces and leads to more effective mitral valve closure with the consequent reduction of the MR orifice area, explains the immediate decrease of MR with CRT-activation [6, 7]. It has also been observed an acute beneficial change in MV geometry after CRT in patients who would be responders in the follow-up (defined by echocardiographic criteria as a reduction in end-systolic LV volume >15 %) [5]. This acute effect on the mitral valve is pacing dependent as the interruption of CRT causes an immediate recurrence of MR [4]. Another described acute effect of CRT is the correction of the atrioventricular delay in CRT that eliminates diastolic or pre-systolic MR, when present.
In the mid-long run, the reduction of MR induced by CRT can also extend in relation to a global (LV volumes) and local (mitral valve geometry) resynchronization-related reverse remodeling [7] (Fig. 5.2).
Another factor that has to be considered in the response to CRT, including MR improvement, is the presence of myocardial viability. Traditionally, it has been accepted that patients with ischemic cardiomyopathy, large scar tissue and particularly with severe MR at baseline, present lesser LV reverse remodeling and clinical response at follow-up when treated with CRT [8]. Other studies show that ischemic patients do also respond to CRT but to a lesser extent [9]. This discrepancy between studies suggests that response to CRT is a multifactorial process and that the presence and location of myocardial viability is an important factor together with the presence of a mechanical abnormality that is amenable to be electrically corrected [10]. A direct relationship between the extent of myocardial contractile recruitment during a stress echo and the extent of LV remodeling has been shown. Also, the precise status of the myocardium at the site of the lead placement is important; in this sense some studies have shown that the coincidence of the site of the lead implantation on scar tissue is related to a poorer response to CRT [11].
Indications
According to current Guidelines [12], CRT is indicated in symptomatic HF patients in functional class II-IV despite receiving optimal medical treatment, severe left ventricle systolic dysfunction with a left ventricular ejection fraction (LVEF) ≤ 35 % and presenting with a wide QRS on the ECG (QRS width ≥ 120 ms) preferably with a LBBB pattern.
Use of CRT to treat functional MR without fulfilling the previous conditions is still not contemplated in the guidelines, although growing evidence exists about the benefits of CRT in reducing the severity of mitral regurgitation by at least one degree, and for this reason, the possibility to postpone surgical treatment in the CRT- responder patients. The pooled data from 5 major studies including more than 350 patients treated with biventricular pacing, followed up for more than 6 months, showed a decrease in the amount of MR by 30–40 % [13].
Identification of patients who will benefit with CRT treatment is still a matter of controversy, despite recent approaches based on understanding the mechanisms leading to cardiac dyssynchrony amenable to be electrically corrected have been proposed. Some studies [10, 14] have demonstrated that the presence of a correctable mechanical abnormality is almost mandatory to obtain a positive response with CRT. The presence of a septal flash (Fig. 5.3) is the mechanical abnormality that can be most easily corrected with CRT and most related to a clear response. Moreover, patients without any mechanical abnormality are largely non-responders. It is important to use an integral approach when assessing cardiac dyssynchrony, taking into account all kinds of possible subtypes of dyssynchrony, since all of them are potentially correctable with CRT and can lead to a substantial improvement in patient outcome. The presence of these mechanical abnormalities is an independent predictor of echocardiographic response and midterm cardiovascular mortality, along with creatinine level and LV diameters, which reflect severity and evolutive status of the disease. A correctable mechanical abnormality not only detects patients with a higher probability of reverse remodeling, but also has a real impact on survival. However, the extent of response will be variable depending on other baseline parameters such as myocardial substrate (viability), underlying disease (renal insufficiency), and clinical status [10].
Some authors have also tried to identify baseline characteristics that may point to the best candidates for CRT regarding MR reduction after CRT. In this sense a very severe MR with a baseline tenting area of >3.8 cm2 would identify patients in whom CRT would not be effective to reduce MR, suggesting that the more advanced LV remodeling and the more distorted LV geometry, the lower the probability of effective treatment for functional MR [7] (Fig. 5.4). The fact is that response to CRT is modulated by several factors and acute and long-term benefits depend not only on the presence of LV dyssynchrony but also on the extent of residual myocardial viability in ischemic patients and severity of MR.
A less invasive percutaneous approach to treat MR in non-responder patients to CRT using the Mitraclip device has been recently proposed in order to avoid a high-risk surgery in this population of very fragile patients [15].
Results of Treatment
Large prospective studies have demonstrated the additional clinical benefit of CRT in HF patients medically treated with suboptimum response. CRT results in improvement in symptoms, quality of life and survival in patients with advanced heart failure and wide QRS [16, 17], especially if associated to a cardioverter - defibrillator [18, 19]. Echocardiographically, a progressive LV reverse remodelling (with even normalization of LV dimensions) is found with a reduction in LV volumes and dyssynchrony. Moreover, a significant reduction of MR severity of at least one degree is expected in around 30–40 % of the patients [4] independently of the etiology of the underlying cardiomyopathy [7]. These benefits, which are very congruent in all published studies, have helped to expand the indications of CRT, and nowadays, the tendency is to start CRT in less advanced stages of heart failure patients.
The influence of MR severity on CRT response is also conflicting. Some investigators have shown that patients with severe MR have less chance of a positive response to CRT [13, 20, 21]. Others, like from those participating in the CARE-HF study, which was a randomized trial including a large number of patients, conversely showed that patients who did not respond to CRT were likely to have less MR as compared to responders [22]. Nonetheless, the presence of severe MR at baseline is usually associated with lower response to CRT as it usually indicates a more advance stage of the disease (50 % clinical and 40 % echocardiographic response instead of 70 and 50 %) [7].
The reduction in MR severity with CRT typically occurs within the first days after starting CRT [6] and can be expected even until the first 3-months follow-up; however, it is very unlikely to happen after that period [4]. This MR reduction behavior has two important implications: firstly, patients who present MR improvement of at least one degree at 3-months with CRT will probably continue to be CRT responders at mid-long term and no further intervention will be required. Secondly, patients who persist with severe MR at 3-months follow-up, and are candidates for surgery, do not benefit from waiting longer because no positive response is expected anymore at mid-long term and another treatment approach should be proposed, if possible.
Which Patient Should Have This Procedure
According to current Guidelines [12], CRT is indicated for patients with symptomatic heart failure in NYHA class II-IV despite receiving optimum medical treatment, with an LVEF <35 % and a wide QRS in the ECG. All these patients could benefit from CRT therapy, specially if they have not achieved the point of no return in the evolution of the heart failure syndrome: what it seems clear, is that patients presenting with too dilated ventricles, specially of an ischemic origin, too severe MR and a very severe reduction of LVEF [9] have a very low chance of improving with the therapy.
Although some discrepancies exist, the presence of a severe MR reduces the probability of clinical response to CRT, which decreases from 70 % back to 50 %. On the other hand, it is also known that around 30–40 % patients with severe MR respond to the therapy. Complementary information about the presence of dyssynchrony, viability of the LV myocardium, magnitude and transmurality of the scar and the functional etiology of MR can help us to better select the candidate patient for CRT.
Once the device is implanted, an acute benefit on MR reduction is expected. Most patients experience acute improvement confirmed echocardiographically at 3–6 months follow-up. At this point, typically no more improvement is to be expected, and if the patient persists with severe MR, surgery has to be planned. In high risk patients a less invasive approach with Mitraclip can be also proposed (Fig. 5.5).
Abbreviations
- CRT:
-
Cardiac resynchronization therapy
- ECG:
-
Electrocardiogram
- HF:
-
Heart failure
- LBBB:
-
Left bundle branch block
- LV:
-
Left ventricle
- LVEF:
-
Left ventricular ejection fraction
- MR:
-
Mitral regurgitation
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Sitges, M., Vidal, B. (2017). Cardiac Resynchronization Therapy for Functional Ischaemic Mitral Regurgitation. In: Chan, K. (eds) Functional Mitral and Tricuspid Regurgitation. Springer, Cham. https://doi.org/10.1007/978-3-319-43510-7_5
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