Abstract
Purpose
To determine the impact of prolapsed volume on regurgitant volume (RegV), regurgitant fraction (RF), and left ventricular ejection fraction (LVEF) in patients with mitral valve prolapse (MVP) using cardiac MRI.
Materials and Methods
Patients with MVP and mitral regurgitation who underwent cardiac MRI from 2005 to 2020 were identified retrospectively from the electronic record. RegV is the difference between left ventricular stroke volume (LVSV) and aortic flow. Left ventricular end-systolic volume (LVESV) and LVSV were obtained from volumetric cine images, with prolapsed volume inclusion (LVESVp, LVSVp) and exclusion (LVESVa, LVSVa) providing two estimates of RegV (RegVp, RegVa), RF (RFp, RFa), and LVEF (LVEFa, LVEFp). Interobserver agreement for LVESVp was assessed using intraclass correlation coefficient (ICC). RegV was also calculated independently using measurements from mitral inflow and aortic net flow phase-contrast imaging as the reference standard (RegVg).
Results
The study included 19 patients (mean age, 28 years ± 16 [SD]; 10 male patients). Interobserver agreement for LVESVp was high (ICC, 0.98; 95% CI: 0.96, 0.99). Prolapsed volume inclusion resulted in higher LVESV (LVESVp: 95.4 mL ± 34.7 vs LVESVa: 82.4 mL ± 33.8; P < .001), lower LVSV (LVSVp: 100.5 mL ± 33.8 vs LVSVa: 113.5 mL ± 35.9; P < .001), and lower LVEF (LVEFp: 51.7% ± 5.7 vs LVEFa: 58.6% ± 6.3; P < .001). RegV was larger in magnitude when prolapsed volume was excluded (RegVa: 39.4 mL ± 21.0 vs RegVg: 25.8 mL ± 22.8; P = .02), with no evidence of a difference when including prolapsed volume (RegVp: 26.4 mL ± 16.4 vs RegVg: 25.8 mL ± 22.8; P > .99).
Conclusion
Measurements that included prolapsed volume most closely reflected mitral regurgitation severity, but inclusion of this volume resulted in a lower LVEF.
Keywords: Cardiac, MRI
© RSNA, 2023
See also commentary by Lee and Markl in this issue.
Keywords: Cardiac, MRI
Summary
Inclusion of prolapsed volume when calculating left ventricular end-systolic volume using cardiac MRI in patients with mitral valve prolapse better reflected mitral regurgitation severity but resulted in a lower left ventricular ejection fraction.
Key Points
■ Compared with the reference standard (which did not rely on calculation of left ventricular (LV) stroke volume to determine the degree of mitral regurgitation), regurgitant volume (RegV) was best reflected when including the prolapsed volume in the LV end-systolic volume (LVESV) calculation (RegVp: 26.4 mL ± 16.4 vs reference standard: 25.8 mL ± 22.8; P > .99) and was larger in magnitude when excluding the prolapsed volume (RegVa: 39.4 mL ± 21.0 vs reference standard: 25.8 mL ± 22.8; P = .02).
■ Inclusion of the prolapsed volume when calculating LVESV resulted in a lower LV ejection fraction (LVEF) than exclusion of the prolapsed volume (LVEFp: 51.7% ± 5.7 vs LVEFa: 58.6% ± 6.3; P < .001).
■ Interobserver agreement was high (intraclass correlation coefficient, 0.98; 95% CI: 0.96, 0.99) when prolapsed volume was included within the LVESV using cross-referencing with long-axis planes.
Introduction
Mitral regurgitation commonly accompanies mitral valve prolapse (MVP) and is observed in approximately 62% of patients diagnosed with MVP (1). MVP is defined as the protrusion of one or both mitral valve leaflets beyond the annular plane by at least 2 mm during systole (2,3). The prevalence of MVP in the general population is 2.4% (2), with approximately 3 million people expected to have mitral regurgitation as a result of MVP in the United States (3).
Most patients with MVP have an excellent prognosis (2,4), although some develop severe regurgitation necessitating mitral valve intervention (5). Risk factors associated with an increased risk of mortality include moderate or severe mitral regurgitation and a left ventricular ejection fraction (LVEF) less than 50% (5,6). The current American Heart Association/American College of Cardiology guidelines recommend mitral valve surgery for symptomatic severe mitral regurgitation (severe defined as a regurgitant fraction [RF] greater than 50%) or for asymptomatic severe mitral regurgitation with LVEF less than 60% or left ventricular (LV) dilatation (7). Early surgery is a reasonable option in asymptomatic patients with severe mitral regurgitation when successful repair without residual regurgitation is likely and the expected risk of mortality is low (7). Therefore, accurately quantifying the amount of mitral regurgitation and LVEF is paramount (8).
Cardiac MRI can be used to quantify regurgitant volume (RegV) and RF while also providing information on the mitral valve and LV volume and function (9). Mitral regurgitation can be estimated with cardiac MRI by various methods. One method estimates RegV as the difference between LV stroke volume (LVSV) and aortic forward flow (AoFF) (10,11). Comparing the stroke volumes of both ventricles is another strategy for estimating mitral regurgitation, although this method is only valid in the absence of other valvular regurgitation and/or a shunt. Notably, both methods use LVSV in their estimations, which can be variable in the setting of MVP given the prolapsed volume. The inclusion or exclusion of the prolapsed volume can substantially affect the LV end-systolic volume (LVESV) and LVSV, and by extension, the RegV, RF, and LVEF.
This study aimed to determine how inclusion of the prolapsed volume in patients with MVP affects quantification of mitral regurgitation and LVEF by cardiac MRI. Additionally, we aimed to validate the results by comparison to an independent reference standard, obtained using mitral valve phase-contrast imaging that does not rely on volumetric measurements.
Materials and Methods
Patients
This institutional review board–exempt retrospective study included patients with known diagnosis of MVP and mitral regurgitation who underwent cardiac MRI at the University of Michigan Medical Center. A flowchart summarizing patient selection is depicted in Figure 1. Using our departmental congenital heart disease database and the Electronic Medical Record Search Engine (12), records between January 1, 2005, and December 31, 2020, were searched for the term “mitral valve prolapse.” Our initial search resulted in 82 patients, of which 50 were excluded for no documented mitral regurgitation (based on prior recent echocardiography or cardiac MRI). Patients with ventricular septal defect, lack of premitral valve intervention study, and lack of phase-contrast MRI data were excluded (n = 13). Hence, a total of 19 patients formed the study group. This Health Insurance Portability and Accountability Act–compliant study was approved by the University of Michigan’s institutional review board, and the requirement of written informed consent was waived.
Figure 1:
Flowchart summarizes patient selection criteria. MVP = mitral valve prolapse, VSD = ventricular septal defect.
Image Acquisition
Cardiac MRI was performed using a commercially available 1.5-T scanner (Philips Achieva or Philips Ingenia). Cine imaging was performed using a breath-hold, electrocardiographically gated, segmented k-space, steady-state free precession sequence with 30 reconstructed phases per cardiac cycle (temporal resolution of 38–50 msec depending on heart rate). A stack of short-axis sections in end expiration covering both ventricles was obtained along with long-axis images in four-chamber, three-chamber, and two-chamber LV views. Phase-contrast imaging was performed using a free-breathing, electrocardiographically gated, velocity-encoded sequence with 40 phases per cardiac cycle (temporal resolution of 19–25 msec depending on heart rate), ensuring orthogonal orientation to the target sites of the ascending aorta and mitral valve. For the mitral inflow, velocity encoding was set at 120 cm/sec and the plane for imaging placed just toward the ventricular aspect of the mitral annulus in systole, adjusted as needed by the imager onsite monitoring the examination. For aortic phase-contrast imaging, velocity encoding was set at 200 cm/sec and adjusted as needed by the onsite imager.
Image Postprocessing
The short-axis cine images were postprocessed using commercially available software (Medis) on a dedicated workstation to obtain LV end-diastolic volume, LVESV, LVSV, and LVEF. The endocardium was contoured in both end systole and end diastole for the LV from base to apex, and volumes were obtained according to the Simpson method. Papillary muscles were included in the ventricular volumes in both systole and diastole.
Basal sections were contoured for LV end-diastolic volume and LVESV excluding prolapsed volume (LVESVa) by cross-referencing with long-axis cine imaging to determine the plane of mitral annulus as described in the guidelines (9). Apart from LVESVa, we also obtained another set of end-systolic contours that extended to the prolapsing mitral leaflets, thereby including the prolapsed volume above the mitral annulus (LVESVp) (Fig 2). The plane of prolapsing leaflets was also determined by cross-referencing with long-axis views (Fig 3). This provided two sets of stroke volume and ejection fraction measurements in each patient, one which included the prolapsed volume (LVSVp, LVEFp) and the other which did not (LVSVa, LVEFa).
Figure 2:
Images in a 38-year-old male patient with mitral valve prolapse. Systolic frame from cine steady-state free precession MRI in (A, B) two-chamber and (C, D) four-chamber planes in a patient with bileaflet mitral valve prolapse. The shaded blue area (B, D) shows the prolapsed volume between the annulus and prolapsing leaflets.
Figure 3:
Images in a 20-year-old female patient with mitral valve prolapse undergoing cardiac MRI for quantification of mitral regurgitation. End-systolic frame on (A) four-chamber, (B) three-chamber, and (C) short-axis basal sections are shown. The technique for contouring the short-axis basal sections (red, C) used cross-referencing with long-axis cine imaging (A, B). The basal short-axis image corresponds to a section above the annulus plane and would be excluded using the standard guidelines (left ventricular end-systolic volume excluding prolapsed volume, LVESVa). However, when cross-referenced with long-axis planes, this section is below the level of prolapsing leaflets and hence included in the contour for estimating LVESV including prolapsed volume (LVESVp).
All ventricular volume and mitral inflow measurements were made independently by a cardiothoracic radiologist with 15 years of cardiac MRI experience (P.A.). To assess interobserver variability, LVESVp contours and mitral inflow were also performed independently by a cardiologist with 5 years of experience (C.M.), with both observers blinded to each other’s results. The extent of prolapse (in millimeters) was obtained using the three-chamber view measuring from the mitral annular plane to the greatest distance of prolapse. The presence or absence of mitral annular disjunction was also noted.
Postprocessing of phase-contrast images was performed using Medis software without employing corrections for phase offset errors. Aortic flow imaging provided systolic antegrade or AoFF and net flow (AoNF). For mitral phase-contrast imaging, contours were drawn during diastole to obtain mitral inflow (Minflow).
Estimation of Mitral Regurgitation
The volume of mitral regurgitation either without prolapsed volume (RegVa), or with prolapsed volume (RegVp), was determined by the difference between the LVSV (LVSVp or LVSVa) and AoFF, that is RegVa = LVSVa – AoFF and RegVp = LVSVp – AoFF.
This was compared with the reference standard mitral regurgitation (RegVg) estimate obtained from Minflow and aortic flow measurements (Minflow – AoNF), which does not rely on LV contouring. The formulas used to determine the RF using the three techniques are summarized below:
  
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Statistical Analysis
Values are presented as numbers and percentages for categorical variables and means ± SDs for continuous variables. The Wilcoxon signed rank test was used to compare RegV, RF ratio, LVESV, LVSV, and LVEF with inclusion versus exclusion of the prolapsed volume due to the underlying nonnormal distribution assumption. The Bonferroni correction was applied to adjust for multiple comparisons. P values less than .05 were considered statistically significant. Interobserver agreement of LVESVp was examined by intraclass correlation coefficient (ICC) with 95% CI and visualized by the Bland-Altman plot. All analyses were performed using SAS software (13), version 9.4 (SAS Institute) and R software, version 3.6.2 (The R Project for Statistical Computing) (14).
Results
Patient Characteristics
Demographic data of the 19 patients (mean age, 28 years ± 16 [SD]; 10 male patients) included in the study are detailed in Table 1.
Table 1:
Patient Demographics
Interobserver Agreement
There was a high degree of agreement for the LVESVp obtained from volumetry between the two readers (ICC, 0.98; 95% CI: 0.96, 0.99) as well as for Minflow (ICC, 0.98; 95% CI: 0.96, 0.99). The Bland-Altman plot for LVESVp is shown in Figure 4.
Figure 4:
Bland-Altman plot of interobserver agreement for left ventricular end-systolic volume including prolapsed volume for observer 1 (LVESVp, obs1) and for left ventricular end-systolic volume including prolapsed volume for observer 2 (LVESVp, obs2).
Ventricular Volumes and Function
Inclusion of the prolapsed volumes resulted in higher end-systolic volumes (LVESVp: 95.4 mL ± 34.7 vs LVESVa: 82.4 mL ± 33.8; P < .001), lower stroke volumes (LVSVp: 100.5 mL ± 33.8 vs LVSVa: 113.5 mL ± 35.9; P < .001), and lower ejection fractions (LVEFp: 51.7% ± 5.7 vs LVEFa: 58.6% ± 6.3; P < .001) (Table 2). If ejection fractions less than or equal to 60% are used to categorize systolic dysfunction (7), then seven of the 19 patients would be reclassified to the systolic dysfunction group using the LVEFp method when compared with the standard method (LVEFa).
Table 2:
Comparison of LVESV, LVSV, and LVEF with Inclusion versus Exclusion of the Prolapsed Volume
RegV and Fraction
RegV was larger in magnitude when prolapsed volume was excluded from the LVESV (RegVa: 39.4 mL ± 21.0 vs RegVg: 25.8 mL ± 22.8; P = .02), while there was no evidence of a difference when the prolapsed volume was included in the LVESV when compared with our reference standard (RegVp: 26.4 mL ± 16.4 vs RegVg: 25.8 mL ± 22.8; P > .99). Bland-Altman plots demonstrating the degree of agreement between the reference standard and RegVa and RegVp are shown in Figure 5.
Figure 5:
Bland-Altman plots of agreement between (A) regurgitant volume including prolapsed volume (RegVp) and regurgitant volume from reference standard (RegVg) and (B) regurgitant volume excluding prolapsed volume (RegVa) and RegVg.
Similarly, we found no evidence of a difference between mean RF measured from the reference standard versus when the prolapsed volume was included in the LVESV (RFp: 28.3% ± 12.9 vs RFg: 26.4% ± 16.6; P > .99), but the value was larger in magnitude when the prolapsed volume was not included (RFa: 36.9% ± 13.8 vs RFg: 26.4% ± 16.6; P = .002) (Fig 6).
Figure 6:
Box plots of regurgitant fraction with inclusion (RFp) and exclusion (RFa) of the prolapsed volume compared with the reference standard (RFg). P values are adjusted by Bonferroni correction.
If RF values equal to or greater than 50% are used as the cutoff for severe regurgitation (7), three of the 19 patients (16%) would be upgraded to severe regurgitation using RFa.
Discussion
Recent studies have shown that cardiac MRI is a viable method for quantifying mitral regurgitation (11). However, the optimal method of quantification in patients with MVP is unknown as it is unclear whether the prolapsed volume should be included or excluded when calculating LVESV. In this retrospective study of patients with MVP and mitral regurgitation, we evaluated the effect of prolapsed volume inclusion on RegV and LVEF and validated our results with an independent reference standard method based on Minflow phase-contrast imaging rather than volumetry. Our analysis found that RegV was best reflected with prolapsed volume inclusion in LVESV (RegVp: 26.4 mL ± 16.4 vs reference standard: 25.8 mL ± 22.8; P > .99), while calculated RegV was larger in magnitude when the prolapsed volume was excluded (RegVa: 39.4 mL ± 21.0 vs reference standard: 25.8 mL ± 22.8; P = .02). Prolapsed volume inclusion resulted in a lower LVEF when compared with when prolapsed volume was excluded (LVEFp: 51.7% ± 5.7 vs LVEFa: 58.6% ± 6.3; P < .001). Interobserver agreement was high (ICC, 0.98; 95% CI: 0.96, 0.99) when prolapsed volume was included in LVESV using cross-referencing with long-axis planes.
Accurately quantifying the degree of mitral regurgitation is important as the guidelines for mitral valve repair now include the possibility of surgical repair for patients with asymptomatic, severe mitral regurgitation who have a high chance of success and can have their operation performed at a center with low mortality rates. In a retrospective study, Myerson et al (8) found that a RegV more than 55 mL or a RF more than 40% was associated with development of symptoms or other indications for surgery, while Penicka et al (15) showed the optimal cutoff for surgery indication to be a RegV of more than 50 mL. Penicka et al (15) also found a strong correlation between adverse patient outcomes and patients classified as having severe mitral regurgitation at cardiac MRI. The ability to classify patients who might benefit from early surgery (16) further demonstrates the importance of accurate mitral regurgitation quantification.
In addition to determining the severity of mitral regurgitation and assessing LV function, recent studies have also shown the ability of cardiac MRI findings to illustrate other pathophysiologic aspects of MVP. For example, cardiac MRI has been used to evaluate morphologic changes of the posterior annulus and basal myocardium and the pattern of late gadolinium enhancement in patients with MVP (17–19), features that have been associated with an increased risk of arrhythmia and sudden death (19). Further work is also being done to elucidate the role of T1 mapping and extracellular volume analysis in the evaluation of patients with MVP, with some studies suggesting increased T1 and extracellular volumes in these patients, suggestive of myocardial alteration (20–22). These features may permit evaluation of early pathologic changes in the myocardium, although these aspects are outside the scope of this work.
The most accepted and commonly used method for quantifying mitral regurgitation at cardiac MRI relies on the difference between LVSV and AoFF (10). However, in context of MVP, inclusion or exclusion of the prolapsed volume in the calculation of LVESV can have substantial effects on LVSV and mitral regurgitation quantification, as shown in our study. This is similar to the results of Vincenti et al (23), who showed differences in mitral regurgitation quantification when accounting for prolapsed volumes. They estimated the prolapsed volume by averaging the heights of the prolapsed mitral valves in three different planes and multiplying this by the area of the basal end-systolic section (23), while we directly measured prolapsed volume to improve accuracy. We propose extrapolating the cross-referencing principle to determine the plane of prolapsing leaflets. This way, prolapsed volume can be included within the LVESV measurements while avoiding geometric assumptions. Cross-referencing is a commonly used technique in deciphering the annular plane for standard volumetric measurements that cardiac MRI readers are very familiar with. We found this technique to have high interobserver reliability, highlighting a well-established strength of cardiac MRI.
Furthermore, our study used a method to determine RegV which is independent of stroke volumes (phase-contrast imaging of aorta and mitral inflow) to determine the optimal technique for mitral regurgitation quantification. This method of quantification was found to be consistent and reproducible in a recent study by Fidock et al (24). Comparison with the reference standard reinforced the need to include prolapsed volumes in LVESV to accurately quantify mitral regurgitation. While more accurate for RegV, inclusion of prolapsed volumes led to lower ejection fractions and stroke volumes than the standard method. This observation is similar to the findings of Vincenti et al (23) and Wolff and Uretsky (16). The LV can be conceptualized as having a muscular chamber (main LV cavity) and a prolapsing chamber (prolapsed volume demarcated by the prolapsing leaflets and annulus). It is the volume of the prolapsing chamber that increases the measured LVESV and therefore reduces the estimated LVEF. However, it is not clear if this lower LVEF is the more accurate measure of LV contractility. Indeed, the LV is agnostic to the direction of blood flow when it contracts; contractility of the muscular chamber is likely the same whether blood is displaced into the prolapsed volume or through the mitral valve into the left atrium via regurgitation. From a functional standpoint, this blood volume has been ejected from the LV cylinder. Based on this and clinical experience, it is likely that LVEFa better matches the historical data on ventricular function used for clinical decision-making. In the absence of clinical outcomes data, the lower ejection fraction generated by including the prolapsed volume in the LVESV should not be used as an indication for earlier mitral valve surgery. The optimal method for measurement of LVEF is not clear, which must be considered when interpreting values in this patient population. Also, the precise method of obtaining the LVEF should be discussed in the report for clear communication. Strain analysis may play an important role and can be assessed in future studies.
This study had some limitations. Although we had a small sample size, our results show a significant difference between the RegV and ejection fraction obtained with and without including the prolapsed volumes, and these results have been borne out in other studies (23). While the present study was retrospective in nature, the investigators involved in the collection and analysis of the data were blinded to the results, therefore limiting any potential bias during handling of the data. Finally, the lack of a true reference standard for measuring mitral regurgitation volumes is a challenge, but in the absence of such a standard, we have internally validated our data by comparing our findings to a method that does not rely on LVSVs. A potential limitation with phrase-contrast imaging of the Minflow relates to through-plane motion of the valve plane, which can cause errors in the measurement of flow. For this reason, there is ongoing work in developing prospective section tracking flow cardiac MRI sequences (25). Future directions include larger prospective studies using four-dimensional flow data to help make various comparisons with a time efficient imaging algorithm. Additionally, in patients with variable heart rates, readers should consider heart rate differences between various phase-contrast and cine acquisitions which can impact estimates of regurgitation. A four-dimensional flow acquisition eliminates the issue of differences in heart rates between various two-dimensional phase-contrast acquisitions. A recently published study using four-dimensional flow in MVP showed four-dimensional flow to be feasible and comparable to standard cardiac MRI, but with a lower RegV estimate when compared with transthoracic echocardiography (26). More studies are needed to validate these preliminary observations.
In summary, including prolapsed volume in the LVESV for calculation of mitral regurgitation in patients with MVP provides a closer estimation of the severity of mitral regurgitation when compared with methods that do not rely on volumetry. However, using the prolapsed volume also results in a lower calculated LVEF, which might not be an accurate portrayal of LV function for prognostic purposes. When calculating the severity of mitral regurgitation and LVEF, the technique used (inclusion vs exclusion of the prolapsed volume) should be part of the imaging report so that the ordering clinician understands how to interpret the values provided. This is also important when making comparisons regarding severity of regurgitation at follow-up examinations.
Authors declared no funding for this work.
Data sharing: Data generated or analyzed during the study are available from the corresponding author by request.
Disclosures of conflicts of interest: B.T.O. No relevant relationships. E.M.L. No relevant relationships. E.S. No relevant relationships. C.M. No relevant relationships. S.B. Royalties from UpToDate Inc for chapter authorship; travel and accommodation expenses to the Cardiology 2022: The New Normal — Transformation in Pediatric and Congenital Heart Care meeting in August 2022; member of SCMR Steering Committee, ASE Public Relations Subcommittee, and the NASCI Research Committee. T.M. No relevant relationships. A.J. No relevant relationships. J.C.L. Member of the American Society of Echocardiography Pediatric and Congenital Heart Disease Steering Committee and the Society for Cardiovascular Magnetic Resonance Pediatric and Congenital Heart Disease Steering Committee. A.L.D. Grants from Additional Ventures FORCE (Fontan Outcomes Research using CMR Examinations) through consortium with Boston Children’s Hospital and the NIH (NIH-DHHS-US 5 U01 HL135842-04) for Image-based Multi-scale Modeling Framework of the Cardiopulmonary System: Longitudinal Calibration and Assessment of Therapies in Pediatric Pulmonary Hypertension; legal consultation compensation for defense attorney of malpractice case in 2021. P.A. Grants from SPIROMICS and the American College of Radiology Fund; payments as Seminars in Roentgenology editor-in-chief; support from the Radiological Society of North America for travel to RSNA Global Learning Centers; travel funding from the American Board of Radiology for committee meetings; treasurer for the North American Society for Cardiovascular Imaging.
Abbreviations:
- AoFF
- aortic forward flow
- AoNF
- aortic net flow
- ICC
- interclass correlation coefficient
- LV
- left ventricle
- LVEF
- LV ejection fraction
- LVEFa
- LV ejection fraction excluding prolapsed volume
- LVEFp
- LF ejection fraction including prolapsed volume
- LVESV
- LV end-systolic volume
- LVESVa
- LV end-systolic volume excluding prolapsed volume
- LVESVp
- LV end-systolic volume including prolapsed volume
- LVSV
- LV stroke volume
- LVSVa
- LV stroke volume excluding prolapsed volume
- LVSVp
- LV stroke volume including prolapsed volume
- Minflow
- mitral inflow
- MVP
- mitral valve prolapse
- RegV
- regurgitant volume
- RegVa
- RegV excluding prolapsed volume
- RegVg
- reference standard RegV
- RegVp
- RegV including prolapsed volume
- RF
- regurgitant fraction
- RFa
- RF excluding prolapsed volume
- RFg
- reference standard RF
- RFp
- RF including prolapsed volume
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