You are here

Article Text

Article menu

Download PDFPDF

Valvular heart disease
Original article
Renin–angiotensin system inhibitors in patients with myocardial infarction and secondary mitral regurgitation
  1. Hiroyuki Okura1,
  2. Toru Kataoka2,
  3. Kiyoshi Yoshida3
  1. 1First Department of Internal Medicine, Nara Medical University, Kashihara, Japan
  2. 2Division of Cardiology, Bell Land General Hospital, Sakai, Japan
  3. 3Division of Cardiology, The Sakakibara Heart Institute of Okayama, Okayama, Japan
  1. Correspondence to Dr Hiroyuki Okura, First Department of Internal Medicine, Nara Medical University, 840 Shijo, Kashihara, Nara 634-8522, Japan; hokura{at}fides.dti.ne.jp

Abstract

Objectives Secondary mitral regurgitation (MR) is negatively related to the prognosis of patients with myocardial infarction (MI). Renin–angiotensin system inhibitors (RASI) may favourably affect left ventricular remodelling and reduce afterload and thereby improve prognosis of secondary MR. The aim of this study was to investigate if use of RASI improves prognosis of patients with MI with secondary MR.

Methods A total of 953 patients with MI were enrolled in this study. Long-term prognosis was compared between patients with MI with no/mild MR (n=657), moderate MR (n=196) and severe MR (n=100). Patients with MI with significant (≥moderate) secondary MR were further divided into those treated with and without RASI. Survival and cardiac-event (all-cause death and congestive heart failure)-free survival were compared.

Results Long-term survival was significantly associated with severity of MR (log-rank, p<0.0001). In patients with significant MR (n=296), RASI was used in 130 patients (44%) and not used in 166 patients (56%). Ejection fraction (47.3±12.2 vs 46.6±13.4%, p=NS) and E/e′ (18.4±8.1 vs 16.5±7.0, p=NS) were similar between the two groups. Kaplan–Meier curves for cardiac-event-free survival demonstrated that use of RASI was associated with better survival (p=0.006) as well as event-free survival (p=0.02). By univariable and multivariable Cox proportional hazard analysis, age (HR 1.046, 95% CI 1.002 to 1.091, p=0.039) and RASI (HR 0.480, 95% CI 0.231 to 0.995), p=0.048) were independent predictors of cardiac events.

Conclusions Secondary MR affects prognosis in patients with MI. Use of RASI may be associated with better long-term prognosis in patients with MI with significant MR.

http://dx.doi.org/10.1136/heartjnl-2015-308536

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Secondary mitral regurgitation (MR) develops as a result of the tethering of the mitral leaflet due to left ventricular (LV) dilatation, displacement of the papillary muscle and mitral annular dilatation.1–4 Previous studies have consistently demonstrated that secondary MR in patients with ischaemic or non-ischaemic cardiomyopathy is associated with poor prognosis.5–7 According to the recent guidelines, surgical correction of the MR is indicated in patients who undergo coronary artery bypass surgery or aortic valve replacement.8 ,9 On the other hand, surgical indication for secondary MR without concomitant bypass surgery or aortic valve surgery is still controversial and thus is not strongly recommended as the first line therapy for secondary MR.

    Evidence-based optimal medical therapies including β blockers and renin–angiotensin system inhibitors (RASI) are recommended as the first line therapy for patients with myocardial infarction (MI) with poor LV systolic function. On the other hand, impact of these medications on secondary MR is poorly understood.10 We hypothesised that the use of RASI may improve clinical outcome in patients with MI with secondary MR. Accordingly, the aim of this study was to investigate prognostic impact of the RASI in patients with MI with secondary MR.

    Methods

    Patient population

    Between August 2002 and July 2007, 953 consecutive patients after MI (>2 weeks after the onset) (669 men, 284 women) who underwent echocardiographic examination at Bell Land General Hospital were enrolled as the Bell Land General Hospital Myocardial Infarction (BELAMI) Registry. Study patients were stratified by the severity of secondary MR, and long-term prognosis was compared. Patients with significant (≥moderate) secondary MR were then selected to investigate impact of RASI on prognosis. Patients were diagnosed as MI if they have a known previous history of ST elevation or non-ST elevation MI or if they have ECG and echocardiography evidence of MI.

    Medical history was determined according to the chart review. Hypertension was defined as blood pressure >140/90 mm Hg or current medication. Hyperlipidaemia was defined as total cholesterol levels >220 mg/dL, triglyceride levels >150 mg/dL or current medication. Diabetes mellitus was defined as fasting plasma glucose >120 mg/dL, haemoglobin A1c >6.5 mg/dL or current medication.

    Baseline medications were checked by a chart review. RASI included angiotensin-converting enzyme inhibitors and angiotensin I receptor blockers. Direct renin inhibitor was not included because it was not available at the time of the study. Each medication was selected and prescribed based on each primary-care physician's discretion. Informed consent for echocardiographic examination was obtained from all patients before echocardiographic study. Informed consent for this study was not obtained because the ethical committee of the institution did not require either approval by the committee or informed consent from the patients for this retrospective analysis.

    Echocardiography

    Transthoracic two-dimensional and Doppler echocardiographic examinations were performed with patients in the left lateral decubitus position using a commercially available echocardiographic machine (GE medical, Vivid 7, Milwaukee, Wisconsin, USA) using a broadband (1.5–4 MHz) phased array transducer. Echocardiographic equipment was maintained according to the guideline.11 Left atrial dimension (LAD), LV end-diastolic dimension and LV end-systolic dimension were measured from parasternal long-axis view. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LV ejection fraction (LVEF) were calculated based on the biplane modified Simpson's method. LV wall motion index (LVWMSI) was calculated. Transmitral flow velocity signals were recorded from the apical four-chamber view and the early (E) and late (A) transmitral flow velocities were measured. Deceleration time (DT) of the E was also measured. Pulmonary venous flow velocity signal was recorded from apical four-chamber view. Systolic (S) and diastolic (D) pulmonary peak flow velocities were measured. Tissue Doppler imaging of the mitral annulus was obtained from the apical four-chamber view. A sample volume of the pulsed-wave Doppler was positioned at the septal side of the mitral annulus and then the spectral signal of the mitral annular velocity was recorded.12–14 The peak early (e′) and late (a′) mitral annular velocity were measured. E/e′ was calculated as E divided by e′. Colour Doppler imaging was performed to assess MR severity. From the apical four-chamber view and long-axis view, the mitral regurgitant jet signal was recorded. The MR was diagnosed as ‘none or mild’ if the regurgitant jet area was less than 20% of left atrial (LA) area. The MR was diagnosed as ‘severe’ if the regurgitant jet area was more than 40% of the LA area. Otherwise, the MR was diagnosed as ‘moderate’.6 ,15 Secondary MR was defined as the MR without organic mitral valvular changes, such as mitral valve prolapse, flail leaflet and rheumatic mitral valvular changes, responsible for the development of the MR.

    Clinical outcome

    Survival and cardiac-event-free survival were compared. Cardiac event was defined as a composite of all-cause death and hospitalization due to congestive heart failure. Clinical events were documented by a medical record review and/or a telephone contact. Clinical events were corrected blinded to the baseline clinical and echocardiographic characteristics.

    Statistical analysis

    Continuous data are expressed as mean±SD or median with IQR, depending on the distribution of the variable (nominal or non-nominal). The differences between two groups for the continuous normal data were tested by unpaired t test and those for continuous non-nominal data were tested by the Mann–Whitney U test. Categorical variables between two groups were compared using the χ2 test. Survival and cardiac-event-free survival between the groups were compared using Kaplan–Meier method and log-rank test. Cox proportional hazard model was used to identify univariable and multivariable predictors of cardiac events. Univariable predictors (age, female gender, hyperlipidaemia, antiplatelets, RASI, statin, loop diuretics, LAD, LVESV, LVEF, LVWMSI, E, E/A, DT, E/e′, S and severe MR) were selected and entered in multivariable analysis. Patients with missing values for selected variable were excluded from the multivariable analysis. The proportional hazards assumption was tested and confirmed by using R. Significance was set at p<0.05. Statistical analysis was performed using commercially available software Statview (Abacus Concepts, California, USA) or R V.3.2.2 for Windows (The R Foundation for Statistical Computing, Vienna, Austria).

    Results

    Study patients were divided into three groups based on the echocardiographic results as either no/mild MR (n=657), moderate MR (n=196) or severe MR (n=100). Clinical characteristics and echocardiographic indices were shown in table 1. Figure 1 shows Kaplan–Meier survival curves comparing between no/mild MR, moderate MR and severe MR. Survival was significantly associated with severity of MR.

    View this table:
    Table 1

    Clinical characteristics and echocardiographic indices comparing among no/mild, moderate and severe MR

    Figure 1
    Figure 1

    Kaplan–Meier curves comparing among patients with myocardial infarction with no/mild mitral regurgitation (MR), moderate MR and severe MR. Overall survival was significantly associated with severity of secondary MR (log-rank, p<0.0001).

    In patients with significant secondary MR (n=296), RASI was used in 130 patients (44%: RASI group) and not used in 166 patients (56%: control group). Clinical characteristics of both groups are shown in table 2. RASI group was significantly younger, had significantly higher prevalence of hypertension and hyperlipidaemia. Antiplatelets and β blocker were more frequently prescribed in RASI group than in control. Echocardiographic results are summarised in table 2. LVEDV and LVESV were similar between the two groups. As a result, LVEF was also similar between the groups. LAD was similar between the two groups. By Doppler echo, A was significantly lower and E, E/A, D and S/D tended to be higher in the RASI group. By tissue Doppler, e′ showed a trend toward lower and E/e′ tended to be higher in the RASI group than in control. Kaplan–Meier plot of survival as well as cardiac-event-free survival was significantly higher in RASI group than in control (figure 2A–D). Table 3 summarised cardiac events in both groups. To further assess impact of the LV systolic function on the efficacy of RASI, patients were stratified by the LVEF. Figure 3 shows Kaplan–Meier plot of event-free survival curves in patients with preserved LVEF (EF≥50%: figure 3A,C) and those with reduced LVEF (EF<50%: figure 3B,D). By univariable analysis, age, female gender and hyperlipidaemia were clinical predictors of cardiac events. No use of antiplatelets, RASI and statin and use of loop diuretics were medications that predict cardiac events. On the other hand, LAD, LVESV, LVEF, LVWMSI, E, E/A, DT, E/e′, S and severe MR were univariable echocardiographic predictors of cardiac events. By multivariable Cox proportional hazard model, only age (HR 1.046, 95% CI 1.002 to 1.091, p=0.039) and RASI (HR 0.480, 95% CI 0.231 to 0.995), p=0.048) were independent predictors of cardiac events (table 4).

    View this table:
    Table 2

    Clinical characteristics and echocardiographic indices comparing between patients treated with and without RASI

    View this table:
    Table 3

    Cardiac events during follow-up

    View this table:
    Table 4

    Univariable and multivariable predictors of cardiac events

    Figure 2
    Figure 2

    Kaplan–Meier curves comparing between renin–angiotensin system inhibitors (RASI) group and control. (A) Overall survival was significantly higher in RASI group than control (log-rank, p=0.006). (B) Cardiac-event-free survival was also significantly higher in RASI group than in control (log-rank, p=0.02). After adjustment of the baseline characteristics, overall survival (C) as well as cardiac-event-free survival (D) was still significantly higher in RASI group than control.

    Figure 3
    Figure 3

    Kaplan–Meier curves comparing between renin–angiotensin system inhibitors (RASI) group and control in patients with myocardial infarction (MI) with preserved (A: EF≥50%) or reduced (B: EF<50%) ejection fraction. In both groups, the RASI group showed a trend towards higher event-free survival. After adjustment for the baseline characteristics, similar trend was observed in patients with MI with preserved (C) or reduced (D) ejection fraction.

    Discussion

    The principal findings of this study were that RASI was used in 44% of the patients with MI with significant secondary MR and the use of RASI was associated with better prognosis.

    Theoretically, vasodilator therapy using either ACE inhibitors or angiotensin I receptor blockers reduces systemic vascular resistance and blood pressure. Reduction of the systemic vascular resistance may increase forward flow from the left ventricle and decrease MR. The effect of RASI has been studied in animal experiments as well as clinical studies. Efficacy of RASI in organic or primary MR has been reported previously.16 ,17 Nemoto et al16 assessed effect of lisinopril on haemodynamics and LV contraction in experimental MR created by rupture of the chordae tendineae. Although lisinopril reduced preload significantly, it did not improve LV contraction. Harris et al investigated chronic effect of ramipril in 26 asymptomatic patients with moderate-to-severe MR due to mitral valve prolapse. Although overall MR severity, LV size or functional status did not change during 6 months follow-up, MR reduced in a subset of patients with systolic hypertension.17 A recent meta-analysis investigating effects of ACEI and ARBs on chronic MR in patients with normal LV systolic function showed a modest reduction in regurgitant fraction, regurgitant volume and LV size.18 Therefore, ACEI or ARBs may not be routinely recommended in patients with organic or primary MR with preserved LV function.

    On the other hand, efficacy of ACEI or ARBs on regurgitant fraction, regurgitant volume or LV size in patients with secondary MR has not been studied yet. In addition, chronic use of the RASI may favourably affect LV remodelling and improve LV systolic as well as diastolic function.19 ,20 These favourable effects may be translated into better clinical outcome. Indeed, RASI is strongly recommended in the US guidelines for ST elevation MI.10 However, efficacy of RASI on long-term prognosis in patients with MI with secondary MR has not been studied either prospectively or retrospectively. Therefore, results of our present study have strong clinical implications and support the recommendation described in the guidelines. RASI may have a favourable effect in patients with MI with mild MR. Indeed, both survival and cardiac-event-free survival showed a trend towards better in patients who were treated with RASI, though the difference did not reach statistical significance (data not shown).

    Medications other than RASI may also favourably affect the clinical outcome in patients with MI with secondary MR.21 In particular, β blockers are strongly recommended in patients with MI with reduced LV function.10 Because this study included patients with MI who were sent to our hospital almost a decade ago, both RASI and β blockers were underused compared with current clinical practice.21 Interestingly, β blocker was not a predictor of cardiac events in our study population. This may be explained by the underuse or selective use of β blockers among patients with MI.

    Recently, several studies have suggested that mitral leaflet may potential to compensate for the mitral annular dilatation and or mitral leaflet tethering.22 ,23 Chaput et al22 demonstrated that mitral valve area increased over time as the LV remodels after MI in an experimental animal model. More recently, we have demonstrated similar mitral leaflet adaptation in clinical cases with ischaemic or non-ischaemic cardiomyopathy.23 This adaptive mitral leaflet dilatation is not consistent among the patients with LV dilatation and dysfunction, and therefore predictors of mitral leaflet adaptation have not been elucidated yet. Impact of RASI on LV reverse remodelling and mitral leaflet adaptation or remodelling should also be investigated further.

    Surgical correction of the secondary MR may be another potential treatment of choice in patients with MI. Role of mitral valve plasty for the secondary MR has not been established yet. Therefore, a new surgical approach specifically targeting the mitral apparatus24 may be required to improve outcome in patients with MI with secondary MR. Mitral valve surgery is recommended for symptomatic patients who undergo CABG or aortic valve surgery.9 Otherwise, optimal medical therapy is still the recommended first line therapy.

    There are limitations in our study. First, this is a single-centre, retrospective analysis of the registry data. Use of RASI was not randomised and determined based on the each primary-care physicians’ discretion. Although multivariable analysis revealed that RASI was independently associated with cardiac event, unknown covariates might have affected the results of our study. Therefore, our present results were only hypothesis generating and should be confirmed by prospective randomised study. Because RASI is already recommended as class I indication for patients with MI with LV dysfunction by the currently available guidelines, it may be difficult to test the efficacy of RASI in patients with MI with secondary MR who usually have LV dilatation and dysfunction. Alternatively, impact of RASI in patients with MI with preserved LV systolic function and secondary MR may be prospectively studied. Second, echocardiographic study was not serially performed. Therefore, impact of RASI on LV size, LV function as well as severity of secondary MR is unknown. Third, severity of the MR was determined based only on semiquantitative assessment of the colour Doppler jet area. Finally, we did not compare prognosis of the study patients between different RASIs. Therefore, it is uncertain if prognostic impact of RASI is a class effect or not.

    Conclusions

    Use of RASI was associated with better long-term prognosis in patients with MI with significant secondary MR.

    Key message

    What is already known on this subject?

    • Renin–angiotensin system inhibitors are useful in patients with myocardial infarction (MI) with reduced systolic function.

    • Theoretically, renin–angiotensin system inhibitors may favourably affect left ventricular remodelling and reduce afterload and thereby improve prognosis of secondary mitral regurgitation (MR) in patients with MI.

    What might this study add?

    • This study adds clinical evidence to support the concept that renin–angiotensin system inhibitors may be efficacious in MI with secondary MR.

    How might this impact on clinical practice?

    • This will encourage the use of renin–angiotensin system inhibitors in patients with MI.

    References

    1. ↵
      1. Otsuji Y,
      2. Handschumacher MD,
      3. Schwammenthal E, et al
      . Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation 1997;96:1999–2008. doi:10.1161/01.CIR.96.6.1999
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Otsuji Y,
      2. Handschumacher MD,
      3. Liel-Cohen N, et al
      . Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: Three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation. J Am Coll Cardiol 2001;37:641–8. doi:10.1016/S0735-1097(00)01134-7
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Watanabe N,
      2. Ogasawara Y,
      3. Yamaura Y, et al
      . Quantitation of mitral valve tenting in ischemic mitral regurgitation by transthoracic real-time three-dimensional echocardiography. J Am Coll Cardiol 2005;45:763–9. doi:10.1016/j.jacc.2004.11.048
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Yamada R,
      2. Watanabe N,
      3. Kume T, et al
      . Quantitative measurement of mitral valve coaptation in functional mitral regurgitation: In vivo experimental study by real-time three-dimensional echocardiography. J Cardiol 2009;53:94–101. doi:10.1016/j.jjcc.2008.09.005
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Grigioni F,
      2. Detaint D,
      3. Avierinos JF, et al
      . Contribution of ischemic mitral regurgitation to congestive heart failure after myocardial infarction. J Am Coll Cardiol 2005;45:260–7. doi:10.1016/j.jacc.2004.10.030
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Okura H,
      2. Takada Y,
      3. Kubo T, et al
      . Functional mitral regurgitation predicts prognosis independent of left ventricular systolic and diastolic indices in patients with ischemic heart disease. J Am Soc Echocardiogr 2008;21:355–60. doi:10.1016/j.echo.2007.06.002
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Rossi A,
      2. Dini FL,
      3. Faggiano P, et al
      . Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy. Heart 2011;97:1675–80. doi:10.1136/hrt.2011.225789
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Vahanian A,
      2. Alfieri O,
      3. Andreotti F, et al
      . Joint Task Force on the Management of Valvular Heart Disease of the European Society of C, European Association for Cardio-Thoracic S. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96. doi:10.1093/eurheartj/ehs109
      OpenUrlFREE Full Text
    9. ↵
      1. Nishimura RA,
      2. Otto CM,
      3. Bonow RO, et al
      . 2014 aha/acc guideline 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. Circulation 2014;129:e521–643. doi:10.1161/CIR.0000000000000031
      OpenUrlFREE Full Text
    10. ↵
      1. O'Gara PT,
      2. Kushner FG,
      3. Ascheim DD, et al
      . 2013 accf/aha guideline for the management of st-elevation myocardial infarction: a report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation 2013;127:e362–425. doi:10.1161/CIR.0b013e3182742cf6
      OpenUrlFREE Full Text
    11. ↵
      1. Nakatani S,
      2. Akaishi M,
      3. Asanuma T, et al
      . Guidelines from the japanese society of echocardiography: Guidance for the management and maintenance of echocardiography equipment. J Echocardiogr 2015;13:1–5. doi:10.1007/s12574-015-0240-x
      OpenUrlCrossRefPubMed
    12. ↵
      1. Okura H,
      2. Takada Y,
      3. Kubo T, et al
      . Tissue doppler-derived index of left ventricular filling pressure, e/e’, predicts survival of patients with non-valvular atrial fibrillation. Heart 2006;92:1248–52. doi:10.1136/hrt.2005.082594
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Okura H,
      2. Takada Y,
      3. Yamabe A, et al
      . Age- and gender-specific changes in the left ventricular relaxation: A doppler echocardiographic study in healthy individuals. Circ Cardiovasc Imaging 2009;2:41–6. doi:10.1161/CIRCIMAGING.108.809087
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Okura H,
      2. Takada Y,
      3. Yamabe A, et al
      . Prevalence and correlates of physiological valvular regurgitation in healthy subjects. Circ J 2011;75:2699–704. doi:10.1253/circj.CJ-11-0277
      OpenUrlCrossRefPubMed
    15. ↵
      1. Zoghbi WA,
      2. Enriquez-Sarano M,
      3. Foster E, et al
      . Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and doppler echocardiography. J Am Soc Echocardiogr 2003;16:777–802. doi:10.1016/S0894-7317(03)00335-3
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Nemoto S,
      2. Hamawaki M,
      3. De Freitas G, et al
      . Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation. J Am Coll Cardiol 2002;40:149–54. doi:10.1016/S0735-1097(02)01926-5
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      1. Harris KM,
      2. Aeppli DM,
      3. Carey CF
      . Effects of angiotensin-converting enzyme inhibition on mitral regurgitation severity, left ventricular size, and functional capacity. Am Heart J 2005;150:1106. doi:10.1016/j.ahj.2005.07.023
      OpenUrlPubMed
    18. ↵
      1. Strauss CE,
      2. Duval S,
      3. Pastorius D, et al
      . Pharmacotherapy in the treatment of mitral regurgitation: a systematic review. J Heart Valve Dis 2012;21:275–85.
      OpenUrlPubMed
    19. ↵
      1. Greenberg B,
      2. Quinones MA,
      3. Koilpillai C, et al
      . Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the solvd echocardiography substudy. Circulation 1995;91:2573–81. doi:10.1161/01.CIR.91.10.2573
      OpenUrlAbstract/FREE Full Text
    20. ↵
      1. Nicolosi GL,
      2. Golcea S,
      3. Ceconi C, et al
      . Effects of perindopril on cardiac remodelling and prognostic value of pre-discharge quantitative echocardiographic parameters in elderly patients after acute myocardial infarction: the preami echo sub-study. Eur Heart J 2009;30:1656–65. doi:10.1093/eurheartj/ehp139
      OpenUrlAbstract/FREE Full Text
    21. ↵
      1. Fox KA,
      2. Steg PG,
      3. Eagle KA, et al
      . Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006. JAMA 2007;297:1892–900. doi:10.1001/jama.297.17.1892
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Chaput M,
      2. Handschumacher MD,
      3. Guerrero JL, et al
      . Mitral leaflet adaptation to ventricular remodeling: Prospective changes in a model of ischemic mitral regurgitation. Circulation 2009;120:S99–103. doi:10.1161/CIRCULATIONAHA.109.844019
      OpenUrlAbstract/FREE Full Text
    23. ↵
      1. Saito K,
      2. Okura H,
      3. Watanabe N, et al
      . Influence of chronic tethering of the mitral valve on mitral leaflet size and coaptation in functional mitral regurgitation. JACC Cardiovasc Imaging 2012;5:337–45. doi:10.1016/j.jcmg.2011.10.004
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Komeda M,
      2. Koyama Y,
      3. Fukaya S, et al
      . Papillary heads “optimization” in repairing functional mitral regurgitation. J Thorac Cardiovasc Surg 2012;144:1262–4. doi:10.1016/j.jtcvs.2012.06.038
      OpenUrlCrossRefPubMed

    Footnotes

    • Contributors HO: study concept and design, acquisition of data, analysis and interpretation of data and drafting of manuscript. TK: acquisition of data, critical revision. KY: study concept and design, critical revision.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.