Author + information
- Received December 4, 2018
- Revision received February 17, 2019
- Accepted March 5, 2019
- Published online May 27, 2019.
- Gennaro Giustino, MDa,b,
- Jessica Overbey, MSb,
- Doris Taylor, PhDc,
- Gorav Ailawadi, MDd,
- Katherine Kirkwood, MSb,
- Joseph DeRose, MDe,
- Marc A. Gillinov, MDf,
- François Dagenais, MDg,
- Mary-Lou Mayer, RNh,
- Alan Moskowitz, MDb,
- Emilia Bagiella, PhDb,
- Marissa Miller, DVM, MPHi,
- Paul Grayburn, MDj,
- Peter K. Smith, MDk,
- Annetine Gelijns, PhDb,∗ (, )
- Patrick O'Gara, MDl,
- Michael Acker, MDh,
- Anuradha Lala, MDa,b,∗ and
- Judy Hung, MDm,∗
- aThe Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- bDepartment of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
- cDepartment of Regenerative Medicine Research, Texas Heart Institute, Houston, Texas
- dDivision of Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, Virginia
- eDepartment of Cardiovascular and Thoracic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
- fDepartment of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
- gInstitut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
- hDepartment of Surgery, Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- iNational Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland
- jDivision of Cardiology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas
- kDivision of Cardiothoracic Surgery, Department of Surgery, Duke University, Durham, North Carolina
- lDivision of Cardiology, Brigham and Women’s’ Hospital, Boston, Massachusetts
- mDivision of Cardiology, Massachusetts General Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Annetine C. Gelijns, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1077, New York, New York 10029.
Objectives This study investigated sex-based differences in outcomes after mitral valve (MV) surgery for severe ischemic mitral regurgitation (SIMR).
Background Whether differences in outcomes exist between men and women after surgery for SIMR remains unknown.
Methods Patients enrolled in a randomized trial comparing MV replacement versus MV repair for SIMR were included and followed for 2 years. Endpoints for this analysis included all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE) (defined as the composite of death, stroke, hospitalization for heart failure, worsening New York Heart Association functional class or MV re-operation), quality of life (QOL), functional status, and percentage of change in left ventricular end-systolic volume index (LVESVI) from baseline through 2 years.
Results Of 251 patients enrolled in the trial, 96 (38.2%) were women. Compared with men, women had smaller LV volumes and effective regurgitant orifice areas (EROA) but greater EROA/left ventricular (LV) end-diastolic volume ratios. At 2 years, women had higher rates of all-cause mortality (27.1% vs. 17.4%, respectively; adjusted hazard ratio [adjHR]: 1.85; 95% confidence interval [CI]: 1.05 to 3.26; p = 0.03) and of MACCE (49.0% vs. 38.1%, respectively; adjHR: 1.58; 95% CI: 1.06 to 2.37; p = 0.02). Women also reported worse QOL and functional status at 2 years. There were no significant differences in the percentage of change over 2 years in LVESVI between women and men (adjβ: −10.4; 95% CI: −23.4 to 2.6; p = 0.12).
Conclusions Women with SIMR displayed different echocardiographic features and experienced higher mortality and worse QOL after MV surgery than men. There were no significant differences in the degree of reverse LV remodeling between sexes. (Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation [Severe Ischemic Mitral Regurgitation]; NCT00807040)
Ischemic mitral regurgitation (MR) affects more than 2 million patients in the United States and is associated with significant morbidity and mortality (1–4). Following myocardial infarction, geometric left ventricular (LV) shape changes and distortion of the normal spatial relationships of the components of the mitral valve (MV) apparatus lead to incomplete mitral leaflet coaptation and secondary MR (1–4). Within this setting, ischemic MR exacerbates maladaptive LV remodeling and has been strongly associated with the development of heart failure (HF), decreased quality of life (QOL), and reduced survival (1–3,5,6). Current guidelines recommend consideration of surgical correction of severe ischemic mitral regurgitation (SIMR) in patients with persistent New York Heart Association (NYHA) functional class III and IV symptoms, despite optimal guideline-directed medical therapy, revascularization, and/or cardiac resynchronization therapy if indicated (7). The Cardiothoracic Surgical Trials Network (CTSN) recently completed a randomized controlled trial comparing mitral valve replacement (MVR) with mitral valve repair (MVRep) for patients with SIMR and demonstrated no significant differences in reverse LV remodeling between strategies among survivors at 2 years. However, MVR was associated with significantly lower rates of rehospitalization and recurrent moderate or greater MR (3,4).
Major differences exist between men and women in the prevalence, pathophysiology, response to treatment, and prognosis across multiple cardiovascular conditions (8,9). However, women have been historically underrepresented in cardiovascular trials (8,10), and with respect to primary MR, registry data suggest that women are less likely to undergo MV surgery (11) and will have worse long-term outcomes than men (12,13). The question of whether sex-based differences in outcomes exist after surgery for SIMR has not been adequately studied. Therefore, in the present analysis from the CTSN SIMR (Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation; NCT00807040) trial, we sought to characterize differences in baseline characteristics, clinical outcomes, QOL, and LV remodeling after MV surgery between women and men with SIMR.
The present study is a secondary analysis from the CTSN SIMR trial (3,4), in which we sought to investigate sex-based differences in baseline characteristics, clinical outcomes, QOL, and LV remodeling in patients with SIMR undergoing MV surgery. The overall CTSN SIMR trial design and results have been previously reported (3,4). Briefly, SIMR was a National Institutes of Health (NIH)-sponsored multicenter randomized trial that compared chordal-sparing mitral valve replacement (MVR) with mitral valve repair (MVRep) in patients with SIMR and coronary artery disease who were eligible for either procedure, with or without concomitant coronary artery bypass graft (CABG) surgery. SIMR was assessed by means of transthoracic echocardiography prior to the procedure based on integrative criteria adjudicated by an independent echocardiographic core laboratory. SIMR was defined as an effective regurgitant orifice area of 0.4 cm2 or more. If the effective regurgitant orifice area was <0.4 cm2, the assessment of the severity of MR was guided by associated Doppler/echocardiographic findings, as previously described (3). The trial was conducted at 22 clinical centers and featured a data and clinical coordinating center, an independent committee that adjudicated causes of death and adverse events, and a data and safety monitoring board, appointed by the NIH, that oversaw trial progress. All patients provided written informed consent, and the institutional review board at each study center approved the protocol.
MVR was performed using complete preservation of the subvalvular apparatus. The technique of subvalvular apparatus preservation and type of prosthetic valve was left to the surgeon’s choice. MVRep was performed using an approved downsized rigid or semirigid complete annuloplasty ring, according to operator preference. CABG surgery was performed using standard techniques and was targeted to achieve complete revascularization at the discretion of the surgeon. All patients were treated with guideline-directed medical therapy for heart failure and coronary artery disease, including neurohormonal antagonists, antiplatelet agents, lipid-lowering agents, and cardiac resynchronization and defibrillator therapy as appropriate. Patients were followed for up to 2 years.
Endpoints of interest included 2-year all-cause death, a composite of major adverse cardiac or cerebrovascular events (MACCE) (defined as the composite of death, stroke, MV reoperation, hospitalization for heart failure, or an increase in NYHA functional class ≥I), treatment failure (defined as the composite of death, MV reoperation, or recurrence of moderate or severe MR), rehospitalization, metrics of QOL, and mean percent change in LV end-systolic volume index (LVESVI) at 2 years. QOL was assessed at baseline and then at 1, 6, 12, and 24 months after the procedure by using the European QOL-5 dimensions, Minnesota Living with Heart Failure (MLHF), the Duke Activity Status Index (DASI), the SF-12 physical health score, and the SF-12 mental health score. LVESVI was assessed at 30 days and at 6, 12, and 24 months using transthoracic echocardiography, verified by the echocardiography core laboratory.
All analyses were performed in the intention-to-treat population, which included all patients according to the group to which they were randomly assigned, regardless of the treatment received. Baseline and operative characteristics were compared by sex using the chi-square and Fisher exact tests for categorical variables and Student’s t-tests or Wilcoxon tests for continuous measurements as appropriate. Distributions of time to first event were estimated using the Kaplan-Meier method. Multivariate Cox regression models were used to evaluate the adjusted association between sex and time-to-first-event outcomes. Multivariate logistic regression models were used to evaluate the adjusted association between sex and binary outcomes without a time component. Multivariate linear regression models were used to evaluate the association between sex and QOL scores and percentage changes in LVESVI from baseline through 2 years. MLHF scores at 2 years had a skewed distribution; therefore, they were log-transformed prior to modeling. Candidate covariates for all multivariate models were selected based on a p value of <0.25 in univariate models. Final covariates were selected using backward selection retaining only covariates with a p value of <0.10 (the full list of covariates retained in each model is reported in the Online Appendix). Sex and randomization assignment were included in all models. All multivariate models for QOL scores and LVESVI also included their respective baseline values alongside the candidate covariates. A 2-sided p value of <0.05 indicated statistical significance. All statistical analyses were performed with the use of SAS version 9.4 software (SAS Institute, Cary, North Carolina).
Of 251 patients enrolled in the trial, 96 were women (38.2%) and 155 were men (61.8%) (Online Figure 1). Baseline clinical characteristics of women and men are reported in Table 1. Although there were no significant differences in age between the groups, when men and women were compared, women were more likely to have diabetes mellitus, hypertension, chronic kidney disease, and thyroid disease. Conversely, men were more likely to have a history of smoking and ventricular arrhythmia. At baseline, women had worse MLHF, whereas no significant differences were observed between NYHA functional classes or other QOL scores. Procedural characteristics by sex are reported in Table 1. The proportions of concomitant procedures (including CABG surgery, tricuspid valve repair, and atrial maze) and duration of cross-clamping or total cardiopulmonary bypass times were similar between groups. Baseline echocardiographic parameters in women and men are shown in Table 2. Compared with men, women had smaller LV volumes, LV diameters, and LV mass. Also, women had smaller MV effective regurgitant orifice areas (EROA), MV annulus areas, MV tethering areas, and shorter interpapillary muscle distances. However, the EROA-to-LV end-diastolic volume (LVEDV) ratios were greater in women than in men (0.24 ± 0.09 vs. 0.20 ± 0.09, respectively; p = 0.002) (14). Left atrial volume was lower in women than in men, whereas the MR jet-to-left atrial area ratios were greater in women. There were no significant differences in guideline-directed medical therapy used at baseline between the groups (Online Table 1).
Clinical outcomes at 2 years for men and women are reported in Table 3. At 2 years, women had significantly higher risk of mortality than men (Figure 1A) (27.1% vs. 17.4%, respectively; absolute risk difference [ARD]: +9.7%; adjusted hazard ratio [HR]: 1.85; 95% confidence interval [CI]: 1.05 to 3.26; p = 0.03), and MACCE (49.0% vs. 38.1%, respectively; ARD: +10.9%; adjusted HR: 1.58; 95% CI: 1.06 to 2.37; p = 0.02) (Figure 1B). There were no significant differences in rates of rehospitalization between the groups. Rehospitalizations due to heart failure accounted for 26.4% of all rehospitalizations among women and for 28.2% of all rehospitalizations among men (Online Table 2). The proportions of patients for whom treatment failed over 2 years are illustrated in Figure 2. There was a trend toward higher risk of treatment failure in women (49 of 86 patients [57.0%] vs. 57 of 132 patients [43.2%]; ARD: +13.8%; adjusted odds ratio [OR]: 1.72; 95% CI: 0.93 to 3.19; p = 0.08), and of MR recurrence (31 of 68 patients [45.6%] vs. 36 of 111 patients [32.4%]; ARD: +13.2%; p = 0.08). Rates of death, treatment failure, and MR recurrence by sex and randomized assignment to MVR or MVRep are reported in Online Table 3. Compared with MVR, MVRep was associated with higher absolute rates of MR recurrence in both women and men.
Quality of life
After MV surgery, QOL scores improved in both men and women over 2 years (Online Tables 4 and 5). However, at 2 years, women had higher (i.e., worse) mean MLHF scores than men (30.0 ± 25.2 vs. 18.5 ± 19.8, respectively; adjusted exp [β] [ratio of means]: 1.54; 95% CI: 1.05 to 2.27; p = 0.03) and lower (i.e., worse) mean European QOL-5 dimensions score (69.9 ± 18.9 vs. 74.6 ± 17.2, respectively; adjusted β: −6.7; 95% CI: −12.8 to −0.7; p = 0.03) compared with men. Also, women had lower DASI scores than men at 2 years (14.4 ± 9.6 vs. 23.5 ± 16.1, respectively; adjusted β: −7.33; 95% CI: −11.90 to −2.76; p = 0.002). The SF-12 physical health score and the SF-12 mental health scores at 2 years were similar between the groups (respectively, 41.7 ± 8.2 vs. 43.4 ± 8.2; adjusted β: −1.41; 95% CI: −3.94 to 1.12; p = 0.27; and 48.9 ± 7.2 vs. 48.5 ± 6.6; adjusted β: 0.73; 95% CI: −1.46 to 2.92; p = 0.51). After MV surgery, NYHA functional class improved in both women and men over 2 years (Figure 3). However, there was a trend toward higher prevalence of NYHA functional class III or IV in women at 2 years (10 of 60 patients [16.7%] vs. 9 of 109 patients [8.3%]; ARD: 8.4%; adjusted OR: 2.37; 95% CI: 0.87 to 6.41; p = 0.09).
Left ventricular reverse remodeling
At 2 years after MV surgery, LVESVI improved in both women and men (Online Table 6, Online Figure 2). Mean percent changes in LVESVI from baseline to 2 years by sex are reported in Central Illustration. There were no significant differences in the percentage of changes in LVESVI between women and men at 2 years (−12.4 ± 34.6% vs. −5.4 ± 37.3%, respectively; adjusted β: −10.4; 95% CI: −23.4 to 2.6; p = 0.12). Smaller EROA/LVEDV ratio was associated with more reverse remodeling (Online Figure 3).
In this secondary analysis from the CTSN SIMR trial, sex-based differences in baseline characteristics and outcomes were compared between men and women undergoing MV surgery for SIMR. To the best of our knowledge this is the first report from a prospective randomized trial to investigate differences in outcomes by sex in an SIMR cohort undergoing MV surgery. The major findings of the present study include (Central Illustration): 1) after adjusting for key covariates associated with each outcome of interest, women remained at increased risk of mortality and MACCE over 2 years compared with men; whereas there was a trend toward higher risk of treatment failure in women; the rates of recurrent MR were higher with MVRep than with MVR, regardless of sex; 2) although both functional status and QOL improved in both groups after MV surgery, at 2 years, women had worse health-related and HF-related QOL scores at baseline and post-operatively than men; 3) compared with men, women had smaller LV volumes and EROAs but greater EROA/LVEDV ratios, indicating more disproportionate SIMR; and 4) change in LVESVI, a surrogate for LV reverse remodeling, improved similarly in both sexes at 2 years after MV surgery.
Women with cardiovascular diseases constitute an underdiagnosed, undertreated, and underinvestigated patient population (8,15). Sex has been previously shown to influence the prevalence, response to treatment, and prognosis of multiple cardiovascular disease states (6,16–19). Unfortunately, women are usually underrepresented in randomized controlled trials investigating cardiovascular devices and pharmacotherapies (6,10,19). Although the differences between anatomical profiles and outcomes of women and those of men have been previously explored in the setting of primary MR, to date, very limited data exist for sex-based differences in baseline characteristics and outcomes in patients with SIMR undergoing MV surgery (9).
Sex-based differences in baseline characteristics in patients with SIMR
In the current analysis from the CTSN SIMR trial, despite similar age at time of surgery, women displayed a greater prevalence for comorbidities (e.g., diabetes, hypertension or chronic kidney disease) and worse HF-related QOL scores (i.e., MLHF score) than men. In addition, there were marked echocardiographic differences between sexes. For example, women had smaller LV volumes (accounting for body surface area), as well as smaller EROAs and tethering areas. However, the EROA/LVEDV ratio, which has been recently proposed to better characterize the hemodynamic severity of SIMR (14), was greater in women, suggesting more disproportionate MR in relation to the LV volumes. Interestingly, the smaller EROA/LVEDV ratio (reflecting larger LV volumes at baseline) was associated with greater reverse remodeling over 2 years. Whether the severity of SIMR characterized with the EROA/LVEDV ratio influences outcomes in patients undergoing MV surgery warrants further evaluation.
Sex-based differences in outcomes after MV surgery for SIMR
Following adjustment for baseline confounders, female sex was independently associated with higher risk of mortality and MACCE at 2 years after MV surgery. Reasons for the worse outcomes in women after MV surgery for SIMR remain unclear and are likely not entirely attributable to differences in LV remodeling (measured with changes in LVESVI) or differential response to MVR or MVRep and warrant further exploration. First, women had smaller ventricles (indexed for body surface area [LVESVI]) than men, and changes in LVESVI over time have been strongly associated with outcomes in patients with HF (20). However, LVESVI improved in both sexes over 2 years, and differences between the percentage of changes in LVESVI in women and those in men were not statistically significant. Second, in the main CTSN SIMR trial, recurrence of MR was demonstrated to influence the degree of LVESVI improvement over 2 years (3,4). However, in the present analysis, the absolute differences between treatment failure, recurrent MR, and death with MVR and MVRep appeared to be similar by sex. Third, although absolute values of EROA were smaller in women (suggesting less severe MR), the EROA/LVEDV ratio was greater in women than in men, suggesting more disproportionate MR in relation to LV volumes. Interestingly, in the present analysis, smaller EROA/LVEDV ratios were associated with more reverse LV remodeling, possibly explaining the worse outcomes in women than in men.
Sex-based differences in quality of life
Although the EuroQOL and the MLHF scores improved in both sexes over 2 years after MV surgery, female sex was independently associated with worse QOL scores at 2 years, adjusting for both baseline confounders and baseline differences in QOL scores. Quality of life is increasingly recognized as a critical patient-oriented outcome, but to date, these outcomes have received less attention in cardiovascular intervention studies. Although the reasons for differences in QOL scores between sexes remain unclear, it was previously stated that women undergoing CABG reported worse QOL scores than those reported by men (21). Reasons for these disparities require further investigation.
Comparison among primary MR cohorts
In the setting of primary MR, women display different anatomical characteristics, clinical risk profiles, and long-term outcomes (9,11–13). Particularly, registry data suggest that women with primary MR are referred later than men for MV surgery, and among patients with primary severe MR, women have worse long-term outcomes than men (9,11). Our study extends these previous observations to an SIMR cohort demonstrating a greater prevalence of chronic comorbidities in women at the time of MV surgery. In line with the findings from primary MR cohorts (9,11–13), and even other cardiac surgery cohorts (22–24), the higher measured and unmeasured, comorbid burden at the time of surgery offers a plausible explanation for the observed excess risk of mortality and adverse events after MV surgery for SIMR in women than in men.
The present study underscores the importance of timely and appropriate correction of SIMR in both men and women alongside guideline-directed medical therapy, revascularization, or cardiac resynchronization therapy as appropriate. Similarly, in the recently completed COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation; NCT01626079) trial, correction of secondary severe MR with transcatheter MVRep compared with no correction reduced the risk of death or HF re-hospitalizations in both men and women (25). Drawing insights from these findings, the current analysis support the need to pay more attention to the earlier diagnosis of SIMR in women, timelier referral to MV surgery or transcatheter therapies, and more aggressive treatment of comorbidities prior to surgery to reduce the observed outcome disparities between sexes.
First, this is a post hoc secondary analysis from a prospective, multicenter randomized controlled trial and, as such, the findings should only be considered hypothesis-generating. Second, the primary endpoint of the CTSN SIMR trial was an echocardiographic measurement of LV remodeling and not a clinical outcome, such as survival or MACCE. Third, the small sample size precluded a more precise characterization of the association between biological sex and outcomes and testing a differential effect of MVR versus MVRep for SIMR by sex. Fourth, residual confounding bias may explain the observed differences between clinical outcomes and QOL scores in women and those in men that were not accounted for by multivariate models. Fifth, natriuretic peptides levels at baseline and at follow-up were not collected in the SIMR trial. Sixth, a survivor analysis is used for QOL and other longitudinal data.
In this study, MV surgery for SIMR resulted in improved QOL, functional status, and LV remodeling in both women and men. However, compared with men, women had different clinical and anatomical profiles at baseline and were at significantly higher risk of mortality, MACCE, and worse QOL over 2 years after MV surgery. Such differences did not seem to be explained by differential degrees of reverse LV remodeling between sexes or by greater risk of MR recurrence with MVRep in women. Our study underscores the prognostic importance of SIMR in women and the need to further investigate reasons for sex-based differences in outcomes as well as strategies to address these disparities.
COMPETENCY IN MEDICAL KNOWLEDGE: SIMR is a highly disabling condition associated with increased morbidity and mortality. In this study, mitral valve surgery for SIMR improved functional status, QOL, and left ventricular remodeling in both women and men. However, compared with men, women displayed features of more disproportionate SIMR, despite smaller left ventricular volumes and effective regurgitant orifice area. Women were at significantly higher risk of mortality, MACCE, and worse QOL over 2 years after MV surgery. Such differences did not seem to be explained by a differential LV reverse remodeling between sexes.
TRANSLATIONAL OUTLOOK: This study underscores the prognostic importance of SIMR in women and the need to further investigate reasons for sex-based differences in outcomes as well as strategies to address these disparities.
↵∗ Drs. Lala and Hung contributed equally to this work and are joint senior authors.
The Severe Ischemic Mitral Regurgitation trial was supported by a cooperative agreement among National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Neurological Disorders and Stroke (NINDS), and Canadian Institutes of Health Research (grant U01 HL088942). The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, the NIH, or the U.S. Department of Health and Human Services. Dr. Ailawadi is a member of the advisory board for Abbott. Dr. Gillinov is a consultant for Abbott, Medtronic, Edwards Lifesciences, CryoLife, and Atricure. Dr. Grayburn has received grant support from Abbott Vascular, Boston Scientific, Edwards Lifesciences, Medtronic, and Neochord; has served as a consultant for Abbott Vascular, Edwards Lifesciences, Medtronic, and Neochord; and has received core laboratory support from Edwards Lifesciences and Neochord. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery bypass graft
- effective regurgitant orifice area
- heart failure
- left ventricular end-diastolic volume
- left ventricular end-systolic volume index
- mitral regurgitation
- mitral valve
- mitral valve replacement
- mitral valve repair
- New York Heart Association
- quality of life
- severe ischemic mitral regurgitation
- Received December 4, 2018.
- Revision received February 17, 2019.
- Accepted March 5, 2019.
- 2019 American College of Cardiology Foundation
- Sannino A.,
- Smith R.L. II.,
- Schiattarella G.G.,
- Trimarco B.,
- Esposito G.,
- Grayburn P.A.
- Goliasch G.,
- Bartko P.E.,
- Pavo N.,
- et al.
- Nishimura R.A.,
- Otto C.M.,
- Bonow R.O.,
- et al.
- McNeely C.,
- Vassileva C.
- Scott P.E.,
- Unger E.F.,
- Jenkins M.R.,
- et al.
- Mantovani F.,
- Clavel M.A.,
- Michelena H.I.,
- Suri R.M.,
- Schaff H.V.,
- Enriquez-Sarano M.
- Grayburn P.A.
- Grayburn P.A.,
- Sannino A.,
- Packer M.
- Mikhail G.W.
- Zusterzeel R.,
- Spatz E.S.,
- Curtis J.P.,
- et al.
- Saad M.,
- Nairooz R.,
- Pothineni N.V.K.,
- et al.
- Giustino G.,
- Dangas G.D.
- Giustino G.,
- Harari R.,
- Baber U.,
- et al.
- Konstam M.A.,
- Kramer D.G.,
- Patel A.R.,
- Maron M.S.,
- Udelson J.E.
- Vaccarino V.,
- Lin Z.Q.,
- Kasl S.V.,
- et al.
- Hsich E.M.,
- Naftel D.C.,
- Myers S.L.,
- et al.
- Stone G.W.,
- Lindenfeld J.,
- Abraham W.T.,
- et al.