- Email: [email protected]
Functional Mitral Regurgitation: Current Understanding and Approach to Management
Accepted Manuscript Functional Mitral Regurgitation: Current Understanding And Approach To Management Robin A. Ducas, MD Christopher W. White, MD Anthony W. Wassef, MD Ashraf Farag, MD Kapil M. Bhagirath, MD Darren H. Freed, MD James W. Tam, MD PII:
S0828-282X(13)01683-8
DOI:
10.1016/j.cjca.2013.11.022
Reference:
CJCA 1048
To appear in:
Canadian Journal of Cardiology
Received Date: 5 June 2013 Revised Date:
21 November 2013
Accepted Date: 21 November 2013
Please cite this article as: Ducas RA, White CW, Wassef AW, Farag A, Bhagirath KM, Freed DH, Tam JW, Functional Mitral Regurgitation: Current Understanding And Approach To Management, Canadian Journal of Cardiology (2013), doi: 10.1016/j.cjca.2013.11.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
FUNCTIONAL
MITRAL
REGURGITATION:
CURRENT
UNDERSTANDING
RI PT
APPROACH TO MANAGEMENT
Authors: Robin A. Ducas, MD. University of Manitoba Christopher W. White, MD. University of Manitoba
Ashraf Farag, MD. University of Manitoba
Darren H. Freed, MD. University of Manitoba James W. Tam, MD. University of Manitoba’
Dr. Robin A. Ducas
TE D
Corresponding Author:
M AN U
Kapil M. Bhagirath, MD. University of British Columbia
SC
Anthony W. Wassef, MD. University of Manitoba
Room Y3021 Bergen Cardiac Care Centre St. Boniface General Hospital 409 Tache Avenue
EP
Winnipeg, Manitoba R2H 2A6
E-mail: [email protected]
AC C
Phone: (204) 258-1290 Fax: (204) 233-9162
Source of Funding: None
AND
ACCEPTED MANUSCRIPT
Brief Summary:
Functional
mitral
regurgitation
(FMR)
frequently
complicates
ischemic
and
non-ischemic
RI PT
cardiomyopathy, and is associated with increased morbidity and mortality. The pathophysiology of FMR is due primarily to ventricular and sub-valvular apparatus dysfunction causing failure of leaflet coaptation. Echocardiography is the primary modality used in diagnosis and allows for assessment of valvular and
approach
incorporating
medical
therapy
and
of
AC C
EP
TE D
M AN U
resynchronization therapies.
consideration
SC
ventricular structure, and interaction. The optimal management of FMR involves an individualized
Page 2
surgical,
percutaneous,
and
ACCEPTED MANUSCRIPT
Abstract: Functional mitral regurgitation (FMR) is a challenging clinical entity that frequently complicates both
RI PT
ischemic and non-ischemic cardiomyopathy. The underlying pathophysiology of FMR is due primarily to ventricular and sub-valvular apparatus dysfunction causing failure of proper leaflet coaptation. Echocardiography is the primary modality used in diagnosis and characterization of FMR. Echocardiography allows for assessment of valvular and ventricular structures as well as their interaction.
SC
FMR portends a poor prognosis, as it is frequently associated with increased morbidity and mortality. The optimal management of FMR involves an individualized approach that incorporates medical therapy and
M AN U
consideration of surgical, percutaneous, and resynchronization therapies according to the severity of regurgitation, presence of symptoms, option for revascularization, and the degree of ventricular
TE D
remodeling.
Key Words:
EP
1. Functional Mitral Regurgitation 2. Ischemic Mitral Regurgitation
AC C
3. Mitral Valve Disease
ACCEPTED MANUSCRIPT
Introduction Mitral regurgitation is the retrograde flow of blood from the left ventricle (LV) to the left atrium
RI PT
(LA) during systole. Normal function of the mitral valve is a complex process and is dependent upon an intact valve annulus, leaflets, chordae tendonae, papillary muscles, and LV wall working in harmony. Perturbations in any of the aforementioned structures may precipitate mitral
SC
regurgitation. One of the earliest classification systems for mitral valve disease is that of Carpentier.1 In this classification scheme mitral valve regurgitation can be separated into three
M AN U
types: type I (coaptation of the leaflets at the annular plane) due to annular dilatation or leaflet perforation; type II (coaptation beyond the annular plane) secondary to leaflet prolapse or papillary muscle rupture; or type III (coaptation proximal to annular plane) associated with valvular and sub-valvular sclerosis with restricted leaflet motion during diastole and systole (IIIa)
TE D
or restricted leaflet motion predominantly during systole (IIIb) (Figure 1).
Functional mitral regurgitation (FMR) refers to mitral regurgitation that is primarily due to a pathologically dilated LV and mitral annulus or to regional disruptions of the LV and sub-
EP
valvular apparatus. FMR is also referred to as “secondary mitral regurgitation” owing to the fact that it is secondary to myocardial pathology and not a primary disease of the valvular tissues.2
AC C
With respect to the Carpentier classification system, FMR corresponds with the class I or IIIb types. In the literature, “ischemic mitral regurgitation” is a term that is widely used and refers to mitral regurgitation resulting from LV dysfunction due to previous ischemic insults. This is a confusing term as valvular dysfunction is the result of prior infarction and impaired myocardial function, not active or transient ischemia of the papillary muscles.2,3
Page 4
ACCEPTED MANUSCRIPT
Epidemiology As distortion of LV geometry and function are key components in FMR, it is not surprising that
RI PT
FMR is common in both ischemic and non-ischemic cardiomyopathy. The prevalence of moderate to severe FMR has been reported to be up to 60% in ischemic cardiomyopathy and in 40% of cases of non-ischemic cardiomyopathy.4,5 Interestingly, FMR is now the leading cause of
SC
mitral regurgitation in the United States.5
M AN U
FMR is an independent risk factor for death and admission to hospital. When using the proximal iso-volumetric surface area (PISA) method for calculating regurgitant volume (RV) and effective regurgitant orifice (ERO) on echocardiography, there is a clear biological gradient; higher regurgitation results in lower survival. Specifically, patients with FMR and an ERO >0.2cm2 have
TE D
been shown to have higher mortality.6
Pathophysiology
EP
Traditionally FMR has been described as a structurally normal mitral valve with impaired function due to ventricular dilation and dysfunction. However, new insights in to myocardial
AC C
adaptation have also demonstrated abnormalities in the mitral leaflets. Indeed FMR is not simply a disease of ventricular dysfunction and may be better understood in terms of ventricular, subvalvular and valvular interaction and adaptation. 7-9
Left Ventricle
ACCEPTED MANUSCRIPT
In mitral regurgitation, during isovolemic ventricular contraction blood is ejected through the mitral valve into the LA due to a lower pressure gradient, resulting in decreased ventricular
RI PT
volume at the end of isovolemic contraction.2 In severe cases, up to 50% of the LV end diastolic volume is ejected into the LA prior to the opening of the aortic valve.10 Initially this may be well tolerated as the LA enlarges. However, eventually LA compliance is exceeded, resulting in
SC
increased LA pressure and progressive development of pulmonary hypertension.11 A vicious cycle then develops, as the regurgitated blood in the LA returns to the LV during diastole,
M AN U
resulting in LV volume overload and progressive dilatation. With increasing ventricular dilatation there is increased wall stress and worsening of myocardial function, leading in turn to worsening mitral regurgitation.12 Dilation and dysfunction of the LV chamber has long been considered a key component of FMR. Chamber dilation translates into mitral annular dilation, displacement of the papillary muscles, and resultant perturbations in valve leaflet closure. Ventricular
TE D
dyssynchrony also may play a part in FMR by further impairing sub-valvular function.
Ventricular and annular dilatation
EP
The mitral valve annulus, composed of both muscular and fibrous tissue, is a structural component of the LV. A normal mitral valve has a three-dimensional (3D) saddle shape that
AC C
undergoes dynamic changes in area throughout the cardiac cycle, facilitating LV filling and valve closure.13 With dilatation of the LV cavity there is concomitant enlargement and distortion of the mitral annular shape, resulting in a more circular annular configuration. This distortion of the mitral valve shape causes mal-coaptation of the anterior and posterior leaflets and results in valvular incompetence.10,14 Further to the structural abnormalities of the mitral annulus with ventricular dilation, Yiu et al, have demonstrated that loss of systolic annular contraction is
ACCEPTED MANUSCRIPT
associated with a larger ERO and a greater degree of regurgitation.8 Thus both appropriate annular size and configuration, in addition to systolic function are important components valvular
RI PT
competence.
Myocardial function and dyssynchrony
SC
Dyssynchrony of the LV myocardium is proposed to result in dyssynchrony of adjacent papillary muscles, disturbing mitral leaflet closure timing and resulting in FMR. Using tissue Doppler
M AN U
imaging (TDI) in 35 patients with impaired ejection fraction (<45%), Lancellotti et al demonstrated worsening FMR due to dynamic LV dyssynchrony with exercise in the absence of ischemia. This study demonstrated correlation between increasing LV dispersion and ERO.15 Hung et al performed a study using 3D echocardiography following acute anterior myocardial infarctions, which demonstrated both regional and global LV dyssynchrony to be independent
TE D
predictors of FMR, with mid-wall dyssynchrony providing incremental information on severity of regurgitation.16 The notion of LV dyssynchrony contributing to FMR is further supported by evidence that cardiac resynchronization therapy (CRT) improves the amount of FMR both at rest
EP
and with exercise.17-19
AC C
Sub-valvular apparatus
The sub-valvular apparatus, composed of the papillary muscles and attached chordae, plays an integral role in mitral valve function. However, changes in LV geometry and wall motion can affect papillary muscle position and function, placing tension on the cordal apparatus and tethering leaflet motion during systole.20 Echocardiography studies have demonstrated that posterior and apical displacement of the papillary muscles is a key determinant of mitral leaflet
ACCEPTED MANUSCRIPT
tethering and FMR.8 Leaflet tethering limits systolic motion of the mitral valves and counteracts the closing forces produced from ventricular contraction, which in turn displaces the point of
RI PT
leaflet coaptation apically, relative to the annular plane, and results in mitral regurgitation (Figure 2).7,8 Though papillary muscle infarction had originally been suspected to cause FMR, both animal and human studies have refuted this assumption. Messas et al employed an ovine model of
SC
ventricular and papillary muscle infarction to demonstrate that LV geometric changes and apical tethering caused FMR rather then papillary muscle infarction.21 Chinitz et al identified that lateral
M AN U
wall; rather then papillary muscle infarction was an independent predictor of FMR in patients with recent myocardial infarction.22 These findings support the idea that adjacent ventricular myocardium plays a large role in papillary muscle function, through both papillary displacement and myocardial wall contraction.20-22_ENREF_19
TE D
Mitral Leaflets
Insufficient mitral leaflet adaptation
EP
Although LV dilatation and related perturbations of the sub-valvular mitral apparatus are accepted causes of FMR, these conditions alone do not explain why the severity of mitral
AC C
regurgitation varies in patients with similar degrees of leaflet tethering. Recent advances in 3D echocardiography have demonstrated an increase in mitral leaflet tissue as an adaptive response to chronic leaflet tethering and morphologic LV changes in dilated, ischemic and valvular cardiomyopathies. In a study looking at a dilated cardiomyopathy population, Chaput et al demonstrated that patients without mitral regurgitation had mitral leaflet areas significantly larger than patients with moderate or greater mitral regurgitation. In this study the most predictive
ACCEPTED MANUSCRIPT
finding of moderate to severe mitral regurgitation was a leaflet area-to-closure-area ratio <1.7 (OR 23.2; p=0.02).9 Beaudoin et al analyzed patients with chronic aortic regurgitation (AR) with
RI PT
and without FMR; they demonstrated mitral valve area to be 31% larger then normal controls in AR, however the patients with AR and FMR did not have the same magnitude of mitral valve enlargement (15%).23 These studies have demonstrated that FMR is associated with an
Diagnosis
History and Physical Examination
M AN U
SC
insufficient increase in mitral leaflet area relative to LV remodeling.9,23
History and physical examination are insensitive for the diagnosis of FMR. Symptomatology of
TE D
FMR includes dyspnea on exertion, fatigue and reduced exercise capacity. These are nonspecific symptoms; for example, all are also found in LV dysfunction. Furthermore, physical examination may be unreliable for the presence of a mitral regurgitant murmur, since the
AC C
and soft. 24
EP
decreased LV pressures result in lower pressure gradients and a murmur that is often low pitched
Imaging
Echocardiography
ACCEPTED MANUSCRIPT
Echocardiography is the mainstay for diagnosis and quantification of FMR. Echocardiography allows for assessment of valvular, sub-valvular and LV structure and function as well as
RI PT
quantification of regurgitation and assessment of pulmonary pressures.14,25
Color Flow
severity.
SC
Color flow imaging provides a rapid and semi-quantitative assessment of valvular regurgitation The area of the regurgitant jet in the LA corresponds to the severity of mitral
M AN U
regurgitation, with an area of >40% being severe. Furthermore, the area of the vena contracta, defined as the length of the narrowest point of the regurgitant jet, also corresponds with severity (severe being >7mm).26 Both of these methods provide simple assessments of FMR severity; however, these methods are prone to over and underestimation and should be combined with
TE D
quantitative methods.
Quantitative Evaluation of Regurgitation
Classically, severe mitral regurgitation is associated with an ERO >0.4cm2 and RV >60mL.26
EP
However, in FMR, lower values for ERO have been associated with worse outcomes. For example, RV of >30mL and an ERO >0.2cm2, (both classically used to define moderate
AC C
regurgitation), have been associated with a severe reduction in life expectancy at 5 years.6 Though not widely adopted, these findings have lead the European Association of Echocardiography to recommended that these lower values (ERO >0.2cm2, and RV >30mL) be used to define severe FMR (Table 1).14
Mitral Inflow Doppler
ACCEPTED MANUSCRIPT
When a large volume of ventricular blood is regurgitated into the LA, it subsequently returns back to the LV during diastole. Pulse-wave Doppler at the tips of the mitral valve producing a
RI PT
Doppler “E” wave velocity greater than 1.2m/s is consistent with severe regurgitation.27 Systolic flow reversal in any of the pulmonary veins is also associated with severe mitral regurgitation.14
SC
Left ventricular Dimensional Analysis
Structural measurement of the LV and mitral valve is essential in the assessment of FMR.
M AN U
Predictors of poor outcome following restrictive mitral valve annuloplasty include indicators of severe LV remodeling and resultant severe tenting of the mitral apparatus. Findings of LV end diastolic diameter >65mm, LV end systolic diameter >51mm, inter-papillary muscle distance >20mm, tenting area (area between the mitral valve annulus and the leaflets at the beginning of systole) >2.5cm2 (Figure 3), and tenting height (the distance between the mitral plane and the
TE D
point of leaflet coaptation during systole) >10mm (Figure 2) are all associated with recurrent FMR after annuloplasty.14,28_ENREF_31
EP
Tissue Doppler Imaging and Strain Imaging
TDI and strain imaging have been used to demonstrate ventricular and papillary muscle
AC C
dyssynchrony in FMR and subsequent improvement in ERO and RV with CRT therapy.29 Studies using TDI have also shown resting and dynamic ventricular dyssynchrony to be strongly predictive of worsening of FMR with exercise.30,31 Though TDI and strain imaging are not required for FMR diagnosis they may help unmask exercise related symptoms as well as determine response to therapy.
ACCEPTED MANUSCRIPT
Exercise Echocardiography Exercise physiology may alter ventricular loading conditions, geometry and dyssynchrony
RI PT
resulting in worsening of FMR. As such, exercise echocardiography may unmask severe FMR and help to explain patient symptoms.31-34 Worsening FMR with exercise has been found to be an independent predictor of exercise intolerance and lower exercise capacity. In a recent study by
SC
Izumo et al, 30 patients with heart failure underwent symptom limited bicycle stress 2D and 3D echocardiography and cardiopulmonary testing. The 10 patients with increases in ERO of
M AN U
>0.13cm2 were classified as exercised induced FMR and shown to have a significant elevation in pulmonary artery pressures and lower peak oxygen uptake with exercise then patients without exercise FMR. On multivariate analysis ERO was found to be the strongest predictor of peak oxygen uptake.32 Along with reductions in cardiopulmonary testing markers, stress echocardiography has also demonstrated reductions in stroke volume as FMR increases with
TE D
exercise. Such findings may help to explain exercise limitations in patients with FMR.35 In a study by Lancellotti et al, 161 patients with chronic FMR were followed for a mean of 35 months. An ERO difference between exercise and rest >0.13cm2 was associated with increased
EP
mortality compared to those who had an ERO difference <0.13cm2.36 Exercise echocardiography has also been used to demonstrate a reduction in ERO and an improvement in cardiac output
AC C
during exercise with CRT therapy.37
3D Echocardiography
Due to the many structures involved, FMR may result in complex failure of leaflet coaptation and as such the regurgitant orifice may take on an elliptical shape (as opposed to circular) or there may be multiple regurgitant orifices. Traditional 2D echocardiography may underestimate FMR
ACCEPTED MANUSCRIPT
as quantification using PISA assumes a single, circular orifice. 3D echocardiography has been shown to more clearly visualize the proximal flow convergence of the regurgitant jet and multiple
RI PT
regurgitant jets in FMR.38,39 Song et al performed 3D echocardiography on 52 heart failure patients with FMR and demonstrated 56% to have an eccentric PISA with 30% having multiple regurgitant orifices.39 Further research has also been done to characterize valve motion, shape and
SC
area, as well as ventricular sphericity and dimensions; providing greater insight into the pathophysiology, characterization and response to exercise in FMR.9,23,32 Though 3D
M AN U
echocardiography may help clinicians to better visualize the mitral valve structures and their function in multiple planes, the precise role of 3D echocardiography in diagnosis and management of patients with FMR is not well defined.
Treatment
TE D
The management of FMR is both challenging and controversial; there is considerable debate and uncertainly regarding the optimal approach, indications, timing, and effectiveness of interventions.2,10 Treatment options include medical treatment, CRT, as well as surgical and
AC C
Medical treatment:
EP
percutaneous interventions.
Optimal medical management is the foundation of therapy for all patients with FMR. The goal of therapy is to optimize cardiac performance, reduce symptoms and enhance survival by unloading the LV while maintaining euvolemia.2,10 Heart failure symptoms should be treated as per guideline recommendations, and angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), beta-blockers, aldosterone antagonists and diuretics should all be
ACCEPTED MANUSCRIPT
considered.40,41 Both ACEIs and beta-blockers have been shown to reduce the severity of mitral regurgitation by progressive inverse LV remodeling and reducing the tethering force in cases of
RI PT
FMR which has translated into improved symptoms and activity tolerance.42,43 Cardiac resynchronization therapy:
SC
The principle behind CRT is to improve ventricular synchrony, which is translated to the valvular and sub-valvular apparatus. CRT has been shown to decrease the amount of FMR through
muscles,
increased
closing
forces
M AN U
reversal of LV remodeling, improved myocardial contractility, resynchronization of the papillary and
improved
contraction
of
the
mitral
annulus.17,44,45_ENREF_36_ENREF_18 The benefits of reduction in FMR have been shown both soon after CRT implementation and on long-term follow-up. Madaric et al. demonstrated a reduction in resting FMR acutely with CRT implementation. After 3 months follow up, this study
TE D
showed a reduction in severity of FMR both at rest and with exercise, as well as improved cardiopulmonary performance.19 The CARE-HF and MIRACLE trials demonstrated long-term benefits of CRT in FMR with respect to mortality, morbidity and quality of life.44,45 Currently the
EP
presence of FMR in and of itself is not an indication for CRT and further research is required to clarify which patients will derive the most benefit from CRT.
AC C
Surgical treatment:
The surgical treatment of FMR aims to restore mitral valve competency and prevent or reverse ventricular remodeling. Most commonly this is accomplished by performing a restrictive annuloplasty with a complete rigid ring to achieve a leaflet coaptation length of 8 mm. However, in patients with echocardiographic predictors of early FMR recurrence14 a biologic mitral valve
ACCEPTED MANUSCRIPT
replacement or the addition of a procedure to address ventricular remodeling may be required.28 Current European guidelines recommend that for patients with an ejection fraction >30%
RI PT
undergoing coronary artery bypass grafting (CABG), the surgical treatment of severe FMR (ERO>0.2 cm2) is indicated (Class I, Level of Evidence: C), and should be considered in patients with moderate FMR (ERO>0.1-0.19 cm2, Class IIa, Level of Evidence: C).46 Additionally,
SC
patients with severe FMR, an ejection fraction <30%, an option for revascularization and evidence of myocardial viability should be considered for surgical intervention (Class IIa, Level
M AN U
of Evidence: C). Crestanello et al have described an algorithmic approach to the surgical treatment of FMR.28
Indications for the surgical correction of moderate to severe FMR remain controversial owing to conflicting outcome data reported in observational studies. Mihaljevic et al completed a propensity matched analysis of 390 patients with moderate-severe FMR undergoing CABG and
TE D
found that the addition of a mitral valve annuloplasty reduced post-operative FMR and improved early symptoms; however, it was not associated with improved long-term survival. McGee et al47 found that 5-years following surgery more than 50% of patients had recurrent ≥ moderate FMR.
EP
However, these studies must be interpreted with caution since only a minority of patients had an annuloplasty ring, while the majority received an annuloplasty band or a posterior suture
AC C
plication.. The use of flexible rings and incomplete bands has since been associated with FMR recurrence and been abandoned.48,49 Second, it is unknown how many of the patients exhibited preoperative factors known to predict FMR recurrence and may have benefited from mitral valve replacement or an additional ventricular procedure.28 Finally, approximately 40% of patients had severe LV dysfunction at the time of surgery. In contrast, Braun et al50 demonstrated that only 15% of patients receiving a rigid ring annuloplasty develop recurrent ≥ moderate FMR at 4.3
ACCEPTED MANUSCRIPT
years and experience a mean NYHA class of 1.6 ± 0.6. Therefore, proper patient selection coupled with advances in device technology and surgical technique may improve the durability of
RI PT
mitral valve annuloplasty for moderate to severe FMR in patients undergoing CABG.
The first randomized controlled trial investigating the impact of adding mitral valve repair to CABG in patients with moderate (PISA of 5-8 mm) FMR was completed in 2009.51 A restrictive
SC
annuloplasty with a rigid ring improved NYHA functional class, promoted LV reverse remodeling, and reduced pulmonary arterial pressures. Importantly, no patients had a recurrence
M AN U
of ≥ mild FMR at 5 years. Though not powered to detect a difference in mortality, 5-year survival was 93.7±3% and 88.8±3% for patients in the CABG plus mitral valve repair and isolated CABG groups, respectively.
In 2012, the RIME study investigated the impact of adding mitral valve repair to CABG in patients with FMR (ERO>0.2 cm2, RV 30-59 mL/beat, and VC 0.30-0.69 cm) and an ejection
TE D
fraction >30%. Seventy-three patients were randomly assigned to CABG or CABG plus restrictive annuloplasty using a complete ring.
Despite greater perioperative morbidity, the
primary end point of peak oxygen consumption at 1-year was significantly better in the CABG
EP
plus mitral valve repair group. Additionally, these patients exhibited LV reverse remodeling, lower B-type natriuretic peptide levels and NYHA functional class scores. Moderate or greater
AC C
FMR was observed at 1-year in 4% of patients in the CABG plus annuloplasty group compared to 50% in the CABG only group.52 Deja et al53 completed a retrospective propensity matched analysis of patients recruited into the STICH trial with moderate to severe FMR and an ejection fraction <35%. The addition of mitral valve annuloplasty or replacement to CABG resulted in a significantly lower risk of mortality compared to CABG alone (HR, 0.42; 95% CI 0.21-0.88; p=0.02). Therefore, there is growing
ACCEPTED MANUSCRIPT
evidence to suggest that in patients with moderate to severe FMR undergoing CABG, a restrictive mitral valve annuloplasty with a complete rigid ring significantly reduces the severity of FMR,
RI PT
improves objective and subjective assessments of heart failure, and promotes LV reverse remodeling. The results of the ongoing Moderate Mitral Regurgitation in Patients Undergoing CABG trial (NCT00613548) investigating the impact of adding mitral valve repair to CABG on
SC
the combined end point of survival and re-hospitalization for heart failure may add additional evidence for this patient population.
M AN U
There is a paucity of evidence to support isolated mitral valve surgery in patients not requiring myocardial revascularization. Surgery may be considered in patients with an ejection fraction >30% who remain symptomatic despite optimal medical therapy and have low surgical risk (Class IIb, Level of Evidence: C).46 Isolated mitral valve surgery in patients with an ejection fraction <30% may be considered for patients who experience persistent NYHA functional class
TE D
III-IV symptoms despite optimal heart failure therapy including CRT (Class IIb, Level of Evidence: C) (Bonow et al. 2008); however, in many cases application of advanced heart failure therapies (CRT, ventricular assist devices, cardiac transplantation) is the preferred
EP
approach.28,46_ENREF_50 The results of the ongoing Effectiveness of Surgical Mitral Valve Repair Versus Medical Treatment for People With Significant Mitral Regurgitation and Non-
AC C
Ischemic Congestive Heart Failure trial (NCT00608140) may provide evidence to guide therapy in this patient population.
Percutaneous techniques:
ACCEPTED MANUSCRIPT
In patients with high peri-operative risk there is a growing interest in emerging percutaneous
annuloplasty and percutaneous mitral valve repair with clip procedure.
RI PT
techniques. The two most commonly used percutaneous procedures are trans-venous mitral
The percutaneous mitral annuloplasty is based on the proximity of the coronary sinus to the posterior aspect of the mitral annulus and attempts to reduce the antero-posterior diameter of the
SC
mitral annulus. 54-56 Both animal models and initial, temporary human studies have demonstrated reduction in mitral regurgitation with this technique, using devices such as the “Monarc” and the
M AN U
“Carillon” presented in the Evolution I and AMADEUS trials respectively.57,58 Long term efficacy and safety are not well documented and require further evaluation. These devices are not approved by Health Canada for general use.
Percutaneous clipping of the mitral valve is another emerging option to reduce severe
TE D
regurgitation. This technique is based on the surgical Alfieri procedure whereby the anterior and posterior mitral leaflets are sutured together. The percutaneous clip grasps and approximates the edges of the posterior and anterior mitral valve leaflets and attempts to re-establish leaflet
EP
coaptation while reducing the ERO and in turn regurgitant volume.59 Feldman et al. reported their experience with the percutaneous mitral valve clip procedure in a non-randomized study of 279
AC C
patients with a 2:1 ratio of percutaneous procedure to surgical repair or replacement. Percutaneous repair was found to be less effective than surgical repair, but had a superior safety profile with similar improvements in clinical outcomes.59 These devices remain experimental and are not approved by Health Canada. Conclusion:
ACCEPTED MANUSCRIPT
FMR, a common complication of ischemic and non-ischemic cardiomyopathy is associated with increased morbidity and mortality. LV remodeling, apical displacement of the papillary muscles,
RI PT
tethering of mitral leaflets and deformation of the mitral annulus all result in decreased closing forces, leaflet mal-coaptation and regurgitation of blood into the LA. Though medical therapy is the foundation of treatment for FMR it is usually insufficient. Although CRT has shown some
SC
survival benefit, it has a high non-responder rate. More invasive surgical techniques bring with them operative risk and have failed to show long-term survival benefit. With the increasing
M AN U
prevalence of congestive heart failure, FMR will continue to complicate patient care and further research and understanding of this entity will be paramount to safe and effective patient
AC C
EP
TE D
management.
ACCEPTED MANUSCRIPT
Figure Legends:
RI PT
Figure 1: Transthoracic echocardiography of the mitral valve demonstrating the Carpentier Edwards classification of mitral valve disease. Panel A: type I – mitral leaflet coaptation at the annular plane. Panel B: type II – mitral leaflet prolapse, coaptation beyond the annular plane. Panel C: type IIIa - mitral leaflet coaptation proximal to the annular plane associated with valvular sclerosis. Panel D: type IIIb – mitral leaflet coaptation proximal to the annular plane due to tethering and restricted leaflet motion.
M AN U
SC
Figure 2: Apical three chamber view on transthoracic echocardiography demonstrating mitral valve tethering. The dashed line represents the mitral annular plane with the solid white line (A) outlining the distance from the annular plane to the point of leaflet coaptation known as the “tenting height”.
AC C
EP
TE D
Figure 3: Apical three chamber view on transthoracic echocardiography demonstrating mitral valve tethering. The area outline in white represents the “tenting area” which is the space enclosed between the mitral leaflets and the annular plane.
Page 20
ACCEPTED MANUSCRIPT
References:
5.
6.
7.
8.
9.
10. 11.
12.
RI PT
SC
M AN U
4.
TE D
3.
EP
2.
Chaliki HP, Nishimura RA, Enriquez-Sarano M, Reeder GS. A simplified, practical approach to assessment of severity of mitral regurgitation by Doppler color flow imaging with proximal convergence: validation with concomitant cardiac catheterization. Mayo Clinic proceedings. Mayo Clinic. 1998;73:929-35. Pierard LA, Carabello BA. Ischaemic mitral regurgitation: pathophysiology, outcomes and the conundrum of treatment. European heart journal. 2010;31:2996-3005. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. European heart journal. 2007;28:230-68. Perez de Isla L, Zamorano J, Martinez Quesada M, et al. Prognostic significance of ischemic mitral regurgitation after non-Q-wave acute myocardial infarction. The Journal of heart valve disease. 2005;14:742-8. de Marchena E, Badiye A, Robalino G, et al. Respective prevalence of the different carpentier classes of mitral regurgitation: a stepping stone for future therapeutic research and development. Journal of cardiac surgery. 2011;26:38592. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103:1759-64. He S, Fontaine AA, Schwammenthal E, Yoganathan AP, Levine RA. Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies. Circulation. 1997;96:1826-34. Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: A quantitative clinical study. Circulation. 2000;102:1400-6. Chaput M, Handschumacher MD, Tournoux F, et al. Mitral leaflet adaptation to ventricular remodeling: occurrence and adequacy in patients with functional mitral regurgitation. Circulation. 2008;118:845-52. Schmitto JD, Lee LS, Mokashi SA, Bolman RM, 3rd, Cohn LH, Chen FY. Functional mitral regurgitation. Cardiology in review. 2010;18:285-91. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. Journal of the American College of Cardiology. 1997;29:153-9. Gaasch WH, Meyer TE. Left ventricular response to mitral regurgitation: implications for management. Circulation. 2008;118:2298-303.
AC C
1.
Page 21
ACCEPTED MANUSCRIPT
17.
18.
19.
20.
21.
22.
23.
RI PT
SC
M AN U
16.
TE D
15.
EP
14.
van Rijk-Zwikker GL, Delemarre BJ, Huysmans HA. Mitral valve anatomy and morphology: relevance to mitral valve replacement and valve reconstruction. Journal of cardiac surgery. 1994;9:255-61. Lancellotti P, Moura L, Pierard LA, et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease). European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology. 2010;11:307-32. Lancellotti P, Stainier PY, Lebois F, Pierard LA. Effect of dynamic left ventricular dyssynchrony on dynamic mitral regurgitation in patients with heart failure due to coronary artery disease. The American journal of cardiology. 2005;96:1304-7. Hung CL, Tien SL, Lo CI, Hung TC, Yeh HI, Wang YS. The incremental value of regional dyssynchrony in determining functional mitral regurgitation beyond left ventricular geometry after narrow QRS anterior myocardial infarction: a real time three-dimensional echocardiography study. Echocardiography. 2011;28:66575. Breithardt OA, Sinha AM, Schwammenthal E, et al. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. Journal of the American College of Cardiology. 2003;41:765-70. van Bommel RJ, Marsan NA, Delgado V, et al. Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation. 2011;124:912-9. Madaric J, Vanderheyden M, Van Laethem C, et al. Early and late effects of cardiac resynchronization therapy on exercise-induced mitral regurgitation: relationship with left ventricular dyssynchrony, remodelling and cardiopulmonary performance. European heart journal. 2007;28:2134-41. Di Mauro M, Gallina S, D'Amico MA, et al. Functional mitral regurgitation: from normal to pathological anatomy of mitral valve. International journal of cardiology. 2013;163:242-8. Messas E, Guerrero JL, Handschumacher MD, et al. Paradoxic decrease in ischemic mitral regurgitation with papillary muscle dysfunction: insights from three-dimensional and contrast echocardiography with strain rate measurement. Circulation. 2001;104:1952-7. Chinitz JS, Chen D, Goyal P, et al. Mitral apparatus assessment by delayed enhancement CMR: relative impact of infarct distribution on mitral regurgitation. JACC. Cardiovascular imaging. 2013;6:220-34. Beaudoin J, Handschumacher MD, Zeng X, et al. Mitral valve enlargement in chronic aortic regurgitation as a compensatory mechanism to prevent functional mitral regurgitation in the dilated left ventricle. Journal of the American College of Cardiology. 2013;61:1809-16.
AC C
13.
ACCEPTED MANUSCRIPT
25.
30.
31.
32.
33.
TE D
29.
EP
28.
AC C
27.
M AN U
SC
26.
Desjardins VA, Enriquez-Sarano M, Tajik AJ, Bailey KR, Seward JB. Intensity of murmurs correlates with severity of valvular regurgitation. The American journal of medicine. 1996;100:149-56. Bouma W, van der Horst IC, Wijdh-den Hamer IJ, et al. Chronic ischaemic mitral regurgitation. Current treatment results and new mechanism-based surgical approaches. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2010;37:170-85. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008;118:e523-661. Thomas L, Foster E, Schiller NB. Peak mitral inflow velocity predicts mitral regurgitation severity. Journal of the American College of Cardiology. 1998;31:174-9. Crestanello JA. Surgical approach to mitral regurgitation in chronic heart failure: when is it an option? Current heart failure reports. 2012;9:40-50. Ypenburg C, Lancellotti P, Tops LF, et al. Acute effects of initiation and withdrawal of cardiac resynchronization therapy on papillary muscle dyssynchrony and mitral regurgitation. Journal of the American College of Cardiology. 2007;50:2071-7. Ennezat PV, Marechaux S, Le Tourneau T, et al. Myocardial asynchronism is a determinant of changes in functional mitral regurgitation severity during dynamic exercise in patients with chronic heart failure due to severe left ventricular systolic dysfunction. European heart journal. 2006;27:679-83. Lafitte S, Bordachar P, Lafitte M, et al. Dynamic ventricular dyssynchrony: an exercise-echocardiography study. Journal of the American College of Cardiology. 2006;47:2253-9. Izumo M, Suzuki K, Moonen M, et al. Changes in mitral regurgitation and left ventricular geometry during exercise affect exercise capacity in patients with systolic heart failure. European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology. 2011;12:54-60. Yamano T, Nakatani S, Kanzaki H, et al. Exercise-induced changes of functional mitral regurgitation in asymptomatic or mildly symptomatic patients with idiopathic dilated cardiomyopathy. The American journal of cardiology. 2008;102:481-5.
RI PT
24.
ACCEPTED MANUSCRIPT
35.
36.
41.
42.
43.
44. 45.
TE D
40.
EP
39.
AC C
38.
M AN U
SC
37.
Pierard LA, Lancellotti P. The role of ischemic mitral regurgitation in the pathogenesis of acute pulmonary edema. The New England journal of medicine. 2004;351:1627-34. Takano H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Functional mitral regurgitation during exercise in patients with heart failure. Circulation journal : official journal of the Japanese Circulation Society. 2006;70:1563-7. Lancellotti P, Gerard PL, Pierard LA. Long-term outcome of patients with heart failure and dynamic functional mitral regurgitation. European heart journal. 2005;26:1528-32. Marechaux S, Pincon C, Gal B, et al. Functional mitral regurgitation at rest determines the acute hemodynamic response to cardiac resynchronization therapy during exercise: an acute exercise echocardiographic study. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2009;22:464-71. Kwan J, Shiota T, Agler DA, et al. Geometric differences of the mitral apparatus between ischemic and dilated cardiomyopathy with significant mitral regurgitation: real-time three-dimensional echocardiography study. Circulation. 2003;107:1135-40. Song JM, Kim MJ, Kim YJ, et al. Three-dimensional characteristics of functional mitral regurgitation in patients with severe left ventricular dysfunction: a real-time three-dimensional colour Doppler echocardiography study. Heart. 2008;94:590-6. Arnold JM, Liu P, Demers C, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. The Canadian journal of cardiology. 2006;22:23-45. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). European journal of heart failure. 2008;10:933-89. Seneviratne B, Moore GA, West PD. Effect of captopril on functional mitral regurgitation in dilated heart failure: a randomised double blind placebo controlled trial. British heart journal. 1994;72:63-8. Capomolla S, Febo O, Gnemmi M, et al. Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol. American heart journal. 2000;139:596-608. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. The New England journal of medicine. 2002;346:1845-53. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. The New England journal of medicine. 2005;352:1539-49.
RI PT
34.
ACCEPTED MANUSCRIPT
51.
52. 53.
54. 55.
56.
57.
58.
59.
RI PT
SC
50.
M AN U
49.
TE D
48.
EP
47.
Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). European heart journal. 2012;33:2451-96. McGee EC, Gillinov AM, Blackstone EH, et al. Recurrent mitral regurgitation after annuloplasty for functional ischemic mitral regurgitation. The Journal of thoracic and cardiovascular surgery. 2004;128:916-24. Anyanwu AC, Adams DH. Why do mitral valve repairs fail? Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2009;22:1265-8. Silberman S, Klutstein MW, Sabag T, et al. Repair of ischemic mitral regurgitation: comparison between flexible and rigid annuloplasty rings. The Annals of thoracic surgery. 2009;87:1721-6; discussion 6-7. Braun J, van de Veire NR, Klautz RJ, et al. Restrictive mitral annuloplasty cures ischemic mitral regurgitation and heart failure. The Annals of thoracic surgery. 2008;85:430-6; discussion 6-7. Fattouch K, Guccione F, Sampognaro R, et al. POINT: Efficacy of adding mitral valve restrictive annuloplasty to coronary artery bypass grafting in patients with moderate ischemic mitral valve regurgitation: a randomized trial. The Journal of thoracic and cardiovascular surgery. 2009;138:278-85. O'Gara PT. Randomized trials in moderate ischemic mitral regurgitation: many questions, limited answers. Circulation. 2012;126:2452-5. Deja MA, Grayburn PA, Sun B, et al. Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial. Circulation. 2012;125:2639-48. Masson JB, Webb JG. Percutaneous mitral annuloplasty. Coronary artery disease. 2009;20:183-8. Feldman T, Cilingiroglu M. Percutaneous leaflet repair and annuloplasty for mitral regurgitation. Journal of the American College of Cardiology. 2011;57:529-37. Dubreuil O, Basmadjian A, Ducharme A, et al. Percutaneous mitral valve annuloplasty for ischemic mitral regurgitation: first in man experience with a temporary implant. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2007;69:105361. Schofer J, Siminiak T, Haude M, et al. Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study. Circulation. 2009;120:326-33. Webb JG, Harnek J, Munt BI, et al. Percutaneous transvenous mitral annuloplasty: initial human experience with device implantation in the coronary sinus. Circulation. 2006;113:851-5. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. The New England journal of medicine. 2011;364:1395-406.
AC C
46.
ACCEPTED MANUSCRIPT
Table 1: Echocardiographic Predictors of Clinically Significant/Severe Functional Mitral Regurgitation > 0.2 cm2
Effective regurgitant orifice (ERO)
> 30 ml
RI PT
Regurgitant volume
> 1.2 m/s
"E" wave velocity
> 40% of left atrium
Regurgitant colour flow jet
> 7 mm
AC C
EP
TE D
M AN U
SC
Vena contracta
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0828-282X(13)01683-8
DOI:
10.1016/j.cjca.2013.11.022
Reference:
CJCA 1048
To appear in:
Canadian Journal of Cardiology
Received Date: 5 June 2013 Revised Date:
21 November 2013
Accepted Date: 21 November 2013
Please cite this article as: Ducas RA, White CW, Wassef AW, Farag A, Bhagirath KM, Freed DH, Tam JW, Functional Mitral Regurgitation: Current Understanding And Approach To Management, Canadian Journal of Cardiology (2013), doi: 10.1016/j.cjca.2013.11.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
FUNCTIONAL
MITRAL
REGURGITATION:
CURRENT
UNDERSTANDING
RI PT
APPROACH TO MANAGEMENT
Authors: Robin A. Ducas, MD. University of Manitoba Christopher W. White, MD. University of Manitoba
Ashraf Farag, MD. University of Manitoba
Darren H. Freed, MD. University of Manitoba James W. Tam, MD. University of Manitoba’
Dr. Robin A. Ducas
TE D
Corresponding Author:
M AN U
Kapil M. Bhagirath, MD. University of British Columbia
SC
Anthony W. Wassef, MD. University of Manitoba
Room Y3021 Bergen Cardiac Care Centre St. Boniface General Hospital 409 Tache Avenue
EP
Winnipeg, Manitoba R2H 2A6
E-mail: [email protected]
AC C
Phone: (204) 258-1290 Fax: (204) 233-9162
Source of Funding: None
AND
ACCEPTED MANUSCRIPT
Brief Summary:
Functional
mitral
regurgitation
(FMR)
frequently
complicates
ischemic
and
non-ischemic
RI PT
cardiomyopathy, and is associated with increased morbidity and mortality. The pathophysiology of FMR is due primarily to ventricular and sub-valvular apparatus dysfunction causing failure of leaflet coaptation. Echocardiography is the primary modality used in diagnosis and allows for assessment of valvular and
approach
incorporating
medical
therapy
and
of
AC C
EP
TE D
M AN U
resynchronization therapies.
consideration
SC
ventricular structure, and interaction. The optimal management of FMR involves an individualized
Page 2
surgical,
percutaneous,
and
ACCEPTED MANUSCRIPT
Abstract: Functional mitral regurgitation (FMR) is a challenging clinical entity that frequently complicates both
RI PT
ischemic and non-ischemic cardiomyopathy. The underlying pathophysiology of FMR is due primarily to ventricular and sub-valvular apparatus dysfunction causing failure of proper leaflet coaptation. Echocardiography is the primary modality used in diagnosis and characterization of FMR. Echocardiography allows for assessment of valvular and ventricular structures as well as their interaction.
SC
FMR portends a poor prognosis, as it is frequently associated with increased morbidity and mortality. The optimal management of FMR involves an individualized approach that incorporates medical therapy and
M AN U
consideration of surgical, percutaneous, and resynchronization therapies according to the severity of regurgitation, presence of symptoms, option for revascularization, and the degree of ventricular
TE D
remodeling.
Key Words:
EP
1. Functional Mitral Regurgitation 2. Ischemic Mitral Regurgitation
AC C
3. Mitral Valve Disease
ACCEPTED MANUSCRIPT
Introduction Mitral regurgitation is the retrograde flow of blood from the left ventricle (LV) to the left atrium
RI PT
(LA) during systole. Normal function of the mitral valve is a complex process and is dependent upon an intact valve annulus, leaflets, chordae tendonae, papillary muscles, and LV wall working in harmony. Perturbations in any of the aforementioned structures may precipitate mitral
SC
regurgitation. One of the earliest classification systems for mitral valve disease is that of Carpentier.1 In this classification scheme mitral valve regurgitation can be separated into three
M AN U
types: type I (coaptation of the leaflets at the annular plane) due to annular dilatation or leaflet perforation; type II (coaptation beyond the annular plane) secondary to leaflet prolapse or papillary muscle rupture; or type III (coaptation proximal to annular plane) associated with valvular and sub-valvular sclerosis with restricted leaflet motion during diastole and systole (IIIa)
TE D
or restricted leaflet motion predominantly during systole (IIIb) (Figure 1).
Functional mitral regurgitation (FMR) refers to mitral regurgitation that is primarily due to a pathologically dilated LV and mitral annulus or to regional disruptions of the LV and sub-
EP
valvular apparatus. FMR is also referred to as “secondary mitral regurgitation” owing to the fact that it is secondary to myocardial pathology and not a primary disease of the valvular tissues.2
AC C
With respect to the Carpentier classification system, FMR corresponds with the class I or IIIb types. In the literature, “ischemic mitral regurgitation” is a term that is widely used and refers to mitral regurgitation resulting from LV dysfunction due to previous ischemic insults. This is a confusing term as valvular dysfunction is the result of prior infarction and impaired myocardial function, not active or transient ischemia of the papillary muscles.2,3
Page 4
ACCEPTED MANUSCRIPT
Epidemiology As distortion of LV geometry and function are key components in FMR, it is not surprising that
RI PT
FMR is common in both ischemic and non-ischemic cardiomyopathy. The prevalence of moderate to severe FMR has been reported to be up to 60% in ischemic cardiomyopathy and in 40% of cases of non-ischemic cardiomyopathy.4,5 Interestingly, FMR is now the leading cause of
SC
mitral regurgitation in the United States.5
M AN U
FMR is an independent risk factor for death and admission to hospital. When using the proximal iso-volumetric surface area (PISA) method for calculating regurgitant volume (RV) and effective regurgitant orifice (ERO) on echocardiography, there is a clear biological gradient; higher regurgitation results in lower survival. Specifically, patients with FMR and an ERO >0.2cm2 have
TE D
been shown to have higher mortality.6
Pathophysiology
EP
Traditionally FMR has been described as a structurally normal mitral valve with impaired function due to ventricular dilation and dysfunction. However, new insights in to myocardial
AC C
adaptation have also demonstrated abnormalities in the mitral leaflets. Indeed FMR is not simply a disease of ventricular dysfunction and may be better understood in terms of ventricular, subvalvular and valvular interaction and adaptation. 7-9
Left Ventricle
ACCEPTED MANUSCRIPT
In mitral regurgitation, during isovolemic ventricular contraction blood is ejected through the mitral valve into the LA due to a lower pressure gradient, resulting in decreased ventricular
RI PT
volume at the end of isovolemic contraction.2 In severe cases, up to 50% of the LV end diastolic volume is ejected into the LA prior to the opening of the aortic valve.10 Initially this may be well tolerated as the LA enlarges. However, eventually LA compliance is exceeded, resulting in
SC
increased LA pressure and progressive development of pulmonary hypertension.11 A vicious cycle then develops, as the regurgitated blood in the LA returns to the LV during diastole,
M AN U
resulting in LV volume overload and progressive dilatation. With increasing ventricular dilatation there is increased wall stress and worsening of myocardial function, leading in turn to worsening mitral regurgitation.12 Dilation and dysfunction of the LV chamber has long been considered a key component of FMR. Chamber dilation translates into mitral annular dilation, displacement of the papillary muscles, and resultant perturbations in valve leaflet closure. Ventricular
TE D
dyssynchrony also may play a part in FMR by further impairing sub-valvular function.
Ventricular and annular dilatation
EP
The mitral valve annulus, composed of both muscular and fibrous tissue, is a structural component of the LV. A normal mitral valve has a three-dimensional (3D) saddle shape that
AC C
undergoes dynamic changes in area throughout the cardiac cycle, facilitating LV filling and valve closure.13 With dilatation of the LV cavity there is concomitant enlargement and distortion of the mitral annular shape, resulting in a more circular annular configuration. This distortion of the mitral valve shape causes mal-coaptation of the anterior and posterior leaflets and results in valvular incompetence.10,14 Further to the structural abnormalities of the mitral annulus with ventricular dilation, Yiu et al, have demonstrated that loss of systolic annular contraction is
ACCEPTED MANUSCRIPT
associated with a larger ERO and a greater degree of regurgitation.8 Thus both appropriate annular size and configuration, in addition to systolic function are important components valvular
RI PT
competence.
Myocardial function and dyssynchrony
SC
Dyssynchrony of the LV myocardium is proposed to result in dyssynchrony of adjacent papillary muscles, disturbing mitral leaflet closure timing and resulting in FMR. Using tissue Doppler
M AN U
imaging (TDI) in 35 patients with impaired ejection fraction (<45%), Lancellotti et al demonstrated worsening FMR due to dynamic LV dyssynchrony with exercise in the absence of ischemia. This study demonstrated correlation between increasing LV dispersion and ERO.15 Hung et al performed a study using 3D echocardiography following acute anterior myocardial infarctions, which demonstrated both regional and global LV dyssynchrony to be independent
TE D
predictors of FMR, with mid-wall dyssynchrony providing incremental information on severity of regurgitation.16 The notion of LV dyssynchrony contributing to FMR is further supported by evidence that cardiac resynchronization therapy (CRT) improves the amount of FMR both at rest
EP
and with exercise.17-19
AC C
Sub-valvular apparatus
The sub-valvular apparatus, composed of the papillary muscles and attached chordae, plays an integral role in mitral valve function. However, changes in LV geometry and wall motion can affect papillary muscle position and function, placing tension on the cordal apparatus and tethering leaflet motion during systole.20 Echocardiography studies have demonstrated that posterior and apical displacement of the papillary muscles is a key determinant of mitral leaflet
ACCEPTED MANUSCRIPT
tethering and FMR.8 Leaflet tethering limits systolic motion of the mitral valves and counteracts the closing forces produced from ventricular contraction, which in turn displaces the point of
RI PT
leaflet coaptation apically, relative to the annular plane, and results in mitral regurgitation (Figure 2).7,8 Though papillary muscle infarction had originally been suspected to cause FMR, both animal and human studies have refuted this assumption. Messas et al employed an ovine model of
SC
ventricular and papillary muscle infarction to demonstrate that LV geometric changes and apical tethering caused FMR rather then papillary muscle infarction.21 Chinitz et al identified that lateral
M AN U
wall; rather then papillary muscle infarction was an independent predictor of FMR in patients with recent myocardial infarction.22 These findings support the idea that adjacent ventricular myocardium plays a large role in papillary muscle function, through both papillary displacement and myocardial wall contraction.20-22_ENREF_19
TE D
Mitral Leaflets
Insufficient mitral leaflet adaptation
EP
Although LV dilatation and related perturbations of the sub-valvular mitral apparatus are accepted causes of FMR, these conditions alone do not explain why the severity of mitral
AC C
regurgitation varies in patients with similar degrees of leaflet tethering. Recent advances in 3D echocardiography have demonstrated an increase in mitral leaflet tissue as an adaptive response to chronic leaflet tethering and morphologic LV changes in dilated, ischemic and valvular cardiomyopathies. In a study looking at a dilated cardiomyopathy population, Chaput et al demonstrated that patients without mitral regurgitation had mitral leaflet areas significantly larger than patients with moderate or greater mitral regurgitation. In this study the most predictive
ACCEPTED MANUSCRIPT
finding of moderate to severe mitral regurgitation was a leaflet area-to-closure-area ratio <1.7 (OR 23.2; p=0.02).9 Beaudoin et al analyzed patients with chronic aortic regurgitation (AR) with
RI PT
and without FMR; they demonstrated mitral valve area to be 31% larger then normal controls in AR, however the patients with AR and FMR did not have the same magnitude of mitral valve enlargement (15%).23 These studies have demonstrated that FMR is associated with an
Diagnosis
History and Physical Examination
M AN U
SC
insufficient increase in mitral leaflet area relative to LV remodeling.9,23
History and physical examination are insensitive for the diagnosis of FMR. Symptomatology of
TE D
FMR includes dyspnea on exertion, fatigue and reduced exercise capacity. These are nonspecific symptoms; for example, all are also found in LV dysfunction. Furthermore, physical examination may be unreliable for the presence of a mitral regurgitant murmur, since the
AC C
and soft. 24
EP
decreased LV pressures result in lower pressure gradients and a murmur that is often low pitched
Imaging
Echocardiography
ACCEPTED MANUSCRIPT
Echocardiography is the mainstay for diagnosis and quantification of FMR. Echocardiography allows for assessment of valvular, sub-valvular and LV structure and function as well as
RI PT
quantification of regurgitation and assessment of pulmonary pressures.14,25
Color Flow
severity.
SC
Color flow imaging provides a rapid and semi-quantitative assessment of valvular regurgitation The area of the regurgitant jet in the LA corresponds to the severity of mitral
M AN U
regurgitation, with an area of >40% being severe. Furthermore, the area of the vena contracta, defined as the length of the narrowest point of the regurgitant jet, also corresponds with severity (severe being >7mm).26 Both of these methods provide simple assessments of FMR severity; however, these methods are prone to over and underestimation and should be combined with
TE D
quantitative methods.
Quantitative Evaluation of Regurgitation
Classically, severe mitral regurgitation is associated with an ERO >0.4cm2 and RV >60mL.26
EP
However, in FMR, lower values for ERO have been associated with worse outcomes. For example, RV of >30mL and an ERO >0.2cm2, (both classically used to define moderate
AC C
regurgitation), have been associated with a severe reduction in life expectancy at 5 years.6 Though not widely adopted, these findings have lead the European Association of Echocardiography to recommended that these lower values (ERO >0.2cm2, and RV >30mL) be used to define severe FMR (Table 1).14
Mitral Inflow Doppler
ACCEPTED MANUSCRIPT
When a large volume of ventricular blood is regurgitated into the LA, it subsequently returns back to the LV during diastole. Pulse-wave Doppler at the tips of the mitral valve producing a
RI PT
Doppler “E” wave velocity greater than 1.2m/s is consistent with severe regurgitation.27 Systolic flow reversal in any of the pulmonary veins is also associated with severe mitral regurgitation.14
SC
Left ventricular Dimensional Analysis
Structural measurement of the LV and mitral valve is essential in the assessment of FMR.
M AN U
Predictors of poor outcome following restrictive mitral valve annuloplasty include indicators of severe LV remodeling and resultant severe tenting of the mitral apparatus. Findings of LV end diastolic diameter >65mm, LV end systolic diameter >51mm, inter-papillary muscle distance >20mm, tenting area (area between the mitral valve annulus and the leaflets at the beginning of systole) >2.5cm2 (Figure 3), and tenting height (the distance between the mitral plane and the
TE D
point of leaflet coaptation during systole) >10mm (Figure 2) are all associated with recurrent FMR after annuloplasty.14,28_ENREF_31
EP
Tissue Doppler Imaging and Strain Imaging
TDI and strain imaging have been used to demonstrate ventricular and papillary muscle
AC C
dyssynchrony in FMR and subsequent improvement in ERO and RV with CRT therapy.29 Studies using TDI have also shown resting and dynamic ventricular dyssynchrony to be strongly predictive of worsening of FMR with exercise.30,31 Though TDI and strain imaging are not required for FMR diagnosis they may help unmask exercise related symptoms as well as determine response to therapy.
ACCEPTED MANUSCRIPT
Exercise Echocardiography Exercise physiology may alter ventricular loading conditions, geometry and dyssynchrony
RI PT
resulting in worsening of FMR. As such, exercise echocardiography may unmask severe FMR and help to explain patient symptoms.31-34 Worsening FMR with exercise has been found to be an independent predictor of exercise intolerance and lower exercise capacity. In a recent study by
SC
Izumo et al, 30 patients with heart failure underwent symptom limited bicycle stress 2D and 3D echocardiography and cardiopulmonary testing. The 10 patients with increases in ERO of
M AN U
>0.13cm2 were classified as exercised induced FMR and shown to have a significant elevation in pulmonary artery pressures and lower peak oxygen uptake with exercise then patients without exercise FMR. On multivariate analysis ERO was found to be the strongest predictor of peak oxygen uptake.32 Along with reductions in cardiopulmonary testing markers, stress echocardiography has also demonstrated reductions in stroke volume as FMR increases with
TE D
exercise. Such findings may help to explain exercise limitations in patients with FMR.35 In a study by Lancellotti et al, 161 patients with chronic FMR were followed for a mean of 35 months. An ERO difference between exercise and rest >0.13cm2 was associated with increased
EP
mortality compared to those who had an ERO difference <0.13cm2.36 Exercise echocardiography has also been used to demonstrate a reduction in ERO and an improvement in cardiac output
AC C
during exercise with CRT therapy.37
3D Echocardiography
Due to the many structures involved, FMR may result in complex failure of leaflet coaptation and as such the regurgitant orifice may take on an elliptical shape (as opposed to circular) or there may be multiple regurgitant orifices. Traditional 2D echocardiography may underestimate FMR
ACCEPTED MANUSCRIPT
as quantification using PISA assumes a single, circular orifice. 3D echocardiography has been shown to more clearly visualize the proximal flow convergence of the regurgitant jet and multiple
RI PT
regurgitant jets in FMR.38,39 Song et al performed 3D echocardiography on 52 heart failure patients with FMR and demonstrated 56% to have an eccentric PISA with 30% having multiple regurgitant orifices.39 Further research has also been done to characterize valve motion, shape and
SC
area, as well as ventricular sphericity and dimensions; providing greater insight into the pathophysiology, characterization and response to exercise in FMR.9,23,32 Though 3D
M AN U
echocardiography may help clinicians to better visualize the mitral valve structures and their function in multiple planes, the precise role of 3D echocardiography in diagnosis and management of patients with FMR is not well defined.
Treatment
TE D
The management of FMR is both challenging and controversial; there is considerable debate and uncertainly regarding the optimal approach, indications, timing, and effectiveness of interventions.2,10 Treatment options include medical treatment, CRT, as well as surgical and
AC C
Medical treatment:
EP
percutaneous interventions.
Optimal medical management is the foundation of therapy for all patients with FMR. The goal of therapy is to optimize cardiac performance, reduce symptoms and enhance survival by unloading the LV while maintaining euvolemia.2,10 Heart failure symptoms should be treated as per guideline recommendations, and angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), beta-blockers, aldosterone antagonists and diuretics should all be
ACCEPTED MANUSCRIPT
considered.40,41 Both ACEIs and beta-blockers have been shown to reduce the severity of mitral regurgitation by progressive inverse LV remodeling and reducing the tethering force in cases of
RI PT
FMR which has translated into improved symptoms and activity tolerance.42,43 Cardiac resynchronization therapy:
SC
The principle behind CRT is to improve ventricular synchrony, which is translated to the valvular and sub-valvular apparatus. CRT has been shown to decrease the amount of FMR through
muscles,
increased
closing
forces
M AN U
reversal of LV remodeling, improved myocardial contractility, resynchronization of the papillary and
improved
contraction
of
the
mitral
annulus.17,44,45_ENREF_36_ENREF_18 The benefits of reduction in FMR have been shown both soon after CRT implementation and on long-term follow-up. Madaric et al. demonstrated a reduction in resting FMR acutely with CRT implementation. After 3 months follow up, this study
TE D
showed a reduction in severity of FMR both at rest and with exercise, as well as improved cardiopulmonary performance.19 The CARE-HF and MIRACLE trials demonstrated long-term benefits of CRT in FMR with respect to mortality, morbidity and quality of life.44,45 Currently the
EP
presence of FMR in and of itself is not an indication for CRT and further research is required to clarify which patients will derive the most benefit from CRT.
AC C
Surgical treatment:
The surgical treatment of FMR aims to restore mitral valve competency and prevent or reverse ventricular remodeling. Most commonly this is accomplished by performing a restrictive annuloplasty with a complete rigid ring to achieve a leaflet coaptation length of 8 mm. However, in patients with echocardiographic predictors of early FMR recurrence14 a biologic mitral valve
ACCEPTED MANUSCRIPT
replacement or the addition of a procedure to address ventricular remodeling may be required.28 Current European guidelines recommend that for patients with an ejection fraction >30%
RI PT
undergoing coronary artery bypass grafting (CABG), the surgical treatment of severe FMR (ERO>0.2 cm2) is indicated (Class I, Level of Evidence: C), and should be considered in patients with moderate FMR (ERO>0.1-0.19 cm2, Class IIa, Level of Evidence: C).46 Additionally,
SC
patients with severe FMR, an ejection fraction <30%, an option for revascularization and evidence of myocardial viability should be considered for surgical intervention (Class IIa, Level
M AN U
of Evidence: C). Crestanello et al have described an algorithmic approach to the surgical treatment of FMR.28
Indications for the surgical correction of moderate to severe FMR remain controversial owing to conflicting outcome data reported in observational studies. Mihaljevic et al completed a propensity matched analysis of 390 patients with moderate-severe FMR undergoing CABG and
TE D
found that the addition of a mitral valve annuloplasty reduced post-operative FMR and improved early symptoms; however, it was not associated with improved long-term survival. McGee et al47 found that 5-years following surgery more than 50% of patients had recurrent ≥ moderate FMR.
EP
However, these studies must be interpreted with caution since only a minority of patients had an annuloplasty ring, while the majority received an annuloplasty band or a posterior suture
AC C
plication.. The use of flexible rings and incomplete bands has since been associated with FMR recurrence and been abandoned.48,49 Second, it is unknown how many of the patients exhibited preoperative factors known to predict FMR recurrence and may have benefited from mitral valve replacement or an additional ventricular procedure.28 Finally, approximately 40% of patients had severe LV dysfunction at the time of surgery. In contrast, Braun et al50 demonstrated that only 15% of patients receiving a rigid ring annuloplasty develop recurrent ≥ moderate FMR at 4.3
ACCEPTED MANUSCRIPT
years and experience a mean NYHA class of 1.6 ± 0.6. Therefore, proper patient selection coupled with advances in device technology and surgical technique may improve the durability of
RI PT
mitral valve annuloplasty for moderate to severe FMR in patients undergoing CABG.
The first randomized controlled trial investigating the impact of adding mitral valve repair to CABG in patients with moderate (PISA of 5-8 mm) FMR was completed in 2009.51 A restrictive
SC
annuloplasty with a rigid ring improved NYHA functional class, promoted LV reverse remodeling, and reduced pulmonary arterial pressures. Importantly, no patients had a recurrence
M AN U
of ≥ mild FMR at 5 years. Though not powered to detect a difference in mortality, 5-year survival was 93.7±3% and 88.8±3% for patients in the CABG plus mitral valve repair and isolated CABG groups, respectively.
In 2012, the RIME study investigated the impact of adding mitral valve repair to CABG in patients with FMR (ERO>0.2 cm2, RV 30-59 mL/beat, and VC 0.30-0.69 cm) and an ejection
TE D
fraction >30%. Seventy-three patients were randomly assigned to CABG or CABG plus restrictive annuloplasty using a complete ring.
Despite greater perioperative morbidity, the
primary end point of peak oxygen consumption at 1-year was significantly better in the CABG
EP
plus mitral valve repair group. Additionally, these patients exhibited LV reverse remodeling, lower B-type natriuretic peptide levels and NYHA functional class scores. Moderate or greater
AC C
FMR was observed at 1-year in 4% of patients in the CABG plus annuloplasty group compared to 50% in the CABG only group.52 Deja et al53 completed a retrospective propensity matched analysis of patients recruited into the STICH trial with moderate to severe FMR and an ejection fraction <35%. The addition of mitral valve annuloplasty or replacement to CABG resulted in a significantly lower risk of mortality compared to CABG alone (HR, 0.42; 95% CI 0.21-0.88; p=0.02). Therefore, there is growing
ACCEPTED MANUSCRIPT
evidence to suggest that in patients with moderate to severe FMR undergoing CABG, a restrictive mitral valve annuloplasty with a complete rigid ring significantly reduces the severity of FMR,
RI PT
improves objective and subjective assessments of heart failure, and promotes LV reverse remodeling. The results of the ongoing Moderate Mitral Regurgitation in Patients Undergoing CABG trial (NCT00613548) investigating the impact of adding mitral valve repair to CABG on
SC
the combined end point of survival and re-hospitalization for heart failure may add additional evidence for this patient population.
M AN U
There is a paucity of evidence to support isolated mitral valve surgery in patients not requiring myocardial revascularization. Surgery may be considered in patients with an ejection fraction >30% who remain symptomatic despite optimal medical therapy and have low surgical risk (Class IIb, Level of Evidence: C).46 Isolated mitral valve surgery in patients with an ejection fraction <30% may be considered for patients who experience persistent NYHA functional class
TE D
III-IV symptoms despite optimal heart failure therapy including CRT (Class IIb, Level of Evidence: C) (Bonow et al. 2008); however, in many cases application of advanced heart failure therapies (CRT, ventricular assist devices, cardiac transplantation) is the preferred
EP
approach.28,46_ENREF_50 The results of the ongoing Effectiveness of Surgical Mitral Valve Repair Versus Medical Treatment for People With Significant Mitral Regurgitation and Non-
AC C
Ischemic Congestive Heart Failure trial (NCT00608140) may provide evidence to guide therapy in this patient population.
Percutaneous techniques:
ACCEPTED MANUSCRIPT
In patients with high peri-operative risk there is a growing interest in emerging percutaneous
annuloplasty and percutaneous mitral valve repair with clip procedure.
RI PT
techniques. The two most commonly used percutaneous procedures are trans-venous mitral
The percutaneous mitral annuloplasty is based on the proximity of the coronary sinus to the posterior aspect of the mitral annulus and attempts to reduce the antero-posterior diameter of the
SC
mitral annulus. 54-56 Both animal models and initial, temporary human studies have demonstrated reduction in mitral regurgitation with this technique, using devices such as the “Monarc” and the
M AN U
“Carillon” presented in the Evolution I and AMADEUS trials respectively.57,58 Long term efficacy and safety are not well documented and require further evaluation. These devices are not approved by Health Canada for general use.
Percutaneous clipping of the mitral valve is another emerging option to reduce severe
TE D
regurgitation. This technique is based on the surgical Alfieri procedure whereby the anterior and posterior mitral leaflets are sutured together. The percutaneous clip grasps and approximates the edges of the posterior and anterior mitral valve leaflets and attempts to re-establish leaflet
EP
coaptation while reducing the ERO and in turn regurgitant volume.59 Feldman et al. reported their experience with the percutaneous mitral valve clip procedure in a non-randomized study of 279
AC C
patients with a 2:1 ratio of percutaneous procedure to surgical repair or replacement. Percutaneous repair was found to be less effective than surgical repair, but had a superior safety profile with similar improvements in clinical outcomes.59 These devices remain experimental and are not approved by Health Canada. Conclusion:
ACCEPTED MANUSCRIPT
FMR, a common complication of ischemic and non-ischemic cardiomyopathy is associated with increased morbidity and mortality. LV remodeling, apical displacement of the papillary muscles,
RI PT
tethering of mitral leaflets and deformation of the mitral annulus all result in decreased closing forces, leaflet mal-coaptation and regurgitation of blood into the LA. Though medical therapy is the foundation of treatment for FMR it is usually insufficient. Although CRT has shown some
SC
survival benefit, it has a high non-responder rate. More invasive surgical techniques bring with them operative risk and have failed to show long-term survival benefit. With the increasing
M AN U
prevalence of congestive heart failure, FMR will continue to complicate patient care and further research and understanding of this entity will be paramount to safe and effective patient
AC C
EP
TE D
management.
ACCEPTED MANUSCRIPT
Figure Legends:
RI PT
Figure 1: Transthoracic echocardiography of the mitral valve demonstrating the Carpentier Edwards classification of mitral valve disease. Panel A: type I – mitral leaflet coaptation at the annular plane. Panel B: type II – mitral leaflet prolapse, coaptation beyond the annular plane. Panel C: type IIIa - mitral leaflet coaptation proximal to the annular plane associated with valvular sclerosis. Panel D: type IIIb – mitral leaflet coaptation proximal to the annular plane due to tethering and restricted leaflet motion.
M AN U
SC
Figure 2: Apical three chamber view on transthoracic echocardiography demonstrating mitral valve tethering. The dashed line represents the mitral annular plane with the solid white line (A) outlining the distance from the annular plane to the point of leaflet coaptation known as the “tenting height”.
AC C
EP
TE D
Figure 3: Apical three chamber view on transthoracic echocardiography demonstrating mitral valve tethering. The area outline in white represents the “tenting area” which is the space enclosed between the mitral leaflets and the annular plane.
Page 20
ACCEPTED MANUSCRIPT
References:
5.
6.
7.
8.
9.
10. 11.
12.
RI PT
SC
M AN U
4.
TE D
3.
EP
2.
Chaliki HP, Nishimura RA, Enriquez-Sarano M, Reeder GS. A simplified, practical approach to assessment of severity of mitral regurgitation by Doppler color flow imaging with proximal convergence: validation with concomitant cardiac catheterization. Mayo Clinic proceedings. Mayo Clinic. 1998;73:929-35. Pierard LA, Carabello BA. Ischaemic mitral regurgitation: pathophysiology, outcomes and the conundrum of treatment. European heart journal. 2010;31:2996-3005. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. European heart journal. 2007;28:230-68. Perez de Isla L, Zamorano J, Martinez Quesada M, et al. Prognostic significance of ischemic mitral regurgitation after non-Q-wave acute myocardial infarction. The Journal of heart valve disease. 2005;14:742-8. de Marchena E, Badiye A, Robalino G, et al. Respective prevalence of the different carpentier classes of mitral regurgitation: a stepping stone for future therapeutic research and development. Journal of cardiac surgery. 2011;26:38592. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103:1759-64. He S, Fontaine AA, Schwammenthal E, Yoganathan AP, Levine RA. Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies. Circulation. 1997;96:1826-34. Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: A quantitative clinical study. Circulation. 2000;102:1400-6. Chaput M, Handschumacher MD, Tournoux F, et al. Mitral leaflet adaptation to ventricular remodeling: occurrence and adequacy in patients with functional mitral regurgitation. Circulation. 2008;118:845-52. Schmitto JD, Lee LS, Mokashi SA, Bolman RM, 3rd, Cohn LH, Chen FY. Functional mitral regurgitation. Cardiology in review. 2010;18:285-91. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. Journal of the American College of Cardiology. 1997;29:153-9. Gaasch WH, Meyer TE. Left ventricular response to mitral regurgitation: implications for management. Circulation. 2008;118:2298-303.
AC C
1.
Page 21
ACCEPTED MANUSCRIPT
17.
18.
19.
20.
21.
22.
23.
RI PT
SC
M AN U
16.
TE D
15.
EP
14.
van Rijk-Zwikker GL, Delemarre BJ, Huysmans HA. Mitral valve anatomy and morphology: relevance to mitral valve replacement and valve reconstruction. Journal of cardiac surgery. 1994;9:255-61. Lancellotti P, Moura L, Pierard LA, et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease). European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology. 2010;11:307-32. Lancellotti P, Stainier PY, Lebois F, Pierard LA. Effect of dynamic left ventricular dyssynchrony on dynamic mitral regurgitation in patients with heart failure due to coronary artery disease. The American journal of cardiology. 2005;96:1304-7. Hung CL, Tien SL, Lo CI, Hung TC, Yeh HI, Wang YS. The incremental value of regional dyssynchrony in determining functional mitral regurgitation beyond left ventricular geometry after narrow QRS anterior myocardial infarction: a real time three-dimensional echocardiography study. Echocardiography. 2011;28:66575. Breithardt OA, Sinha AM, Schwammenthal E, et al. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. Journal of the American College of Cardiology. 2003;41:765-70. van Bommel RJ, Marsan NA, Delgado V, et al. Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation. 2011;124:912-9. Madaric J, Vanderheyden M, Van Laethem C, et al. Early and late effects of cardiac resynchronization therapy on exercise-induced mitral regurgitation: relationship with left ventricular dyssynchrony, remodelling and cardiopulmonary performance. European heart journal. 2007;28:2134-41. Di Mauro M, Gallina S, D'Amico MA, et al. Functional mitral regurgitation: from normal to pathological anatomy of mitral valve. International journal of cardiology. 2013;163:242-8. Messas E, Guerrero JL, Handschumacher MD, et al. Paradoxic decrease in ischemic mitral regurgitation with papillary muscle dysfunction: insights from three-dimensional and contrast echocardiography with strain rate measurement. Circulation. 2001;104:1952-7. Chinitz JS, Chen D, Goyal P, et al. Mitral apparatus assessment by delayed enhancement CMR: relative impact of infarct distribution on mitral regurgitation. JACC. Cardiovascular imaging. 2013;6:220-34. Beaudoin J, Handschumacher MD, Zeng X, et al. Mitral valve enlargement in chronic aortic regurgitation as a compensatory mechanism to prevent functional mitral regurgitation in the dilated left ventricle. Journal of the American College of Cardiology. 2013;61:1809-16.
AC C
13.
ACCEPTED MANUSCRIPT
25.
30.
31.
32.
33.
TE D
29.
EP
28.
AC C
27.
M AN U
SC
26.
Desjardins VA, Enriquez-Sarano M, Tajik AJ, Bailey KR, Seward JB. Intensity of murmurs correlates with severity of valvular regurgitation. The American journal of medicine. 1996;100:149-56. Bouma W, van der Horst IC, Wijdh-den Hamer IJ, et al. Chronic ischaemic mitral regurgitation. Current treatment results and new mechanism-based surgical approaches. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2010;37:170-85. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008;118:e523-661. Thomas L, Foster E, Schiller NB. Peak mitral inflow velocity predicts mitral regurgitation severity. Journal of the American College of Cardiology. 1998;31:174-9. Crestanello JA. Surgical approach to mitral regurgitation in chronic heart failure: when is it an option? Current heart failure reports. 2012;9:40-50. Ypenburg C, Lancellotti P, Tops LF, et al. Acute effects of initiation and withdrawal of cardiac resynchronization therapy on papillary muscle dyssynchrony and mitral regurgitation. Journal of the American College of Cardiology. 2007;50:2071-7. Ennezat PV, Marechaux S, Le Tourneau T, et al. Myocardial asynchronism is a determinant of changes in functional mitral regurgitation severity during dynamic exercise in patients with chronic heart failure due to severe left ventricular systolic dysfunction. European heart journal. 2006;27:679-83. Lafitte S, Bordachar P, Lafitte M, et al. Dynamic ventricular dyssynchrony: an exercise-echocardiography study. Journal of the American College of Cardiology. 2006;47:2253-9. Izumo M, Suzuki K, Moonen M, et al. Changes in mitral regurgitation and left ventricular geometry during exercise affect exercise capacity in patients with systolic heart failure. European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology. 2011;12:54-60. Yamano T, Nakatani S, Kanzaki H, et al. Exercise-induced changes of functional mitral regurgitation in asymptomatic or mildly symptomatic patients with idiopathic dilated cardiomyopathy. The American journal of cardiology. 2008;102:481-5.
RI PT
24.
ACCEPTED MANUSCRIPT
35.
36.
41.
42.
43.
44. 45.
TE D
40.
EP
39.
AC C
38.
M AN U
SC
37.
Pierard LA, Lancellotti P. The role of ischemic mitral regurgitation in the pathogenesis of acute pulmonary edema. The New England journal of medicine. 2004;351:1627-34. Takano H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Functional mitral regurgitation during exercise in patients with heart failure. Circulation journal : official journal of the Japanese Circulation Society. 2006;70:1563-7. Lancellotti P, Gerard PL, Pierard LA. Long-term outcome of patients with heart failure and dynamic functional mitral regurgitation. European heart journal. 2005;26:1528-32. Marechaux S, Pincon C, Gal B, et al. Functional mitral regurgitation at rest determines the acute hemodynamic response to cardiac resynchronization therapy during exercise: an acute exercise echocardiographic study. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2009;22:464-71. Kwan J, Shiota T, Agler DA, et al. Geometric differences of the mitral apparatus between ischemic and dilated cardiomyopathy with significant mitral regurgitation: real-time three-dimensional echocardiography study. Circulation. 2003;107:1135-40. Song JM, Kim MJ, Kim YJ, et al. Three-dimensional characteristics of functional mitral regurgitation in patients with severe left ventricular dysfunction: a real-time three-dimensional colour Doppler echocardiography study. Heart. 2008;94:590-6. Arnold JM, Liu P, Demers C, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. The Canadian journal of cardiology. 2006;22:23-45. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). European journal of heart failure. 2008;10:933-89. Seneviratne B, Moore GA, West PD. Effect of captopril on functional mitral regurgitation in dilated heart failure: a randomised double blind placebo controlled trial. British heart journal. 1994;72:63-8. Capomolla S, Febo O, Gnemmi M, et al. Beta-blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol. American heart journal. 2000;139:596-608. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. The New England journal of medicine. 2002;346:1845-53. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. The New England journal of medicine. 2005;352:1539-49.
RI PT
34.
ACCEPTED MANUSCRIPT
51.
52. 53.
54. 55.
56.
57.
58.
59.
RI PT
SC
50.
M AN U
49.
TE D
48.
EP
47.
Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). European heart journal. 2012;33:2451-96. McGee EC, Gillinov AM, Blackstone EH, et al. Recurrent mitral regurgitation after annuloplasty for functional ischemic mitral regurgitation. The Journal of thoracic and cardiovascular surgery. 2004;128:916-24. Anyanwu AC, Adams DH. Why do mitral valve repairs fail? Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2009;22:1265-8. Silberman S, Klutstein MW, Sabag T, et al. Repair of ischemic mitral regurgitation: comparison between flexible and rigid annuloplasty rings. The Annals of thoracic surgery. 2009;87:1721-6; discussion 6-7. Braun J, van de Veire NR, Klautz RJ, et al. Restrictive mitral annuloplasty cures ischemic mitral regurgitation and heart failure. The Annals of thoracic surgery. 2008;85:430-6; discussion 6-7. Fattouch K, Guccione F, Sampognaro R, et al. POINT: Efficacy of adding mitral valve restrictive annuloplasty to coronary artery bypass grafting in patients with moderate ischemic mitral valve regurgitation: a randomized trial. The Journal of thoracic and cardiovascular surgery. 2009;138:278-85. O'Gara PT. Randomized trials in moderate ischemic mitral regurgitation: many questions, limited answers. Circulation. 2012;126:2452-5. Deja MA, Grayburn PA, Sun B, et al. Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial. Circulation. 2012;125:2639-48. Masson JB, Webb JG. Percutaneous mitral annuloplasty. Coronary artery disease. 2009;20:183-8. Feldman T, Cilingiroglu M. Percutaneous leaflet repair and annuloplasty for mitral regurgitation. Journal of the American College of Cardiology. 2011;57:529-37. Dubreuil O, Basmadjian A, Ducharme A, et al. Percutaneous mitral valve annuloplasty for ischemic mitral regurgitation: first in man experience with a temporary implant. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2007;69:105361. Schofer J, Siminiak T, Haude M, et al. Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study. Circulation. 2009;120:326-33. Webb JG, Harnek J, Munt BI, et al. Percutaneous transvenous mitral annuloplasty: initial human experience with device implantation in the coronary sinus. Circulation. 2006;113:851-5. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. The New England journal of medicine. 2011;364:1395-406.
AC C
46.
ACCEPTED MANUSCRIPT
Table 1: Echocardiographic Predictors of Clinically Significant/Severe Functional Mitral Regurgitation > 0.2 cm2
Effective regurgitant orifice (ERO)
> 30 ml
RI PT
Regurgitant volume
> 1.2 m/s
"E" wave velocity
> 40% of left atrium
Regurgitant colour flow jet
> 7 mm
AC C
EP
TE D
M AN U
SC
Vena contracta
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT