Mitral regurgitation (MR) is abnormally reversed flow from the left ventricle (LV) to the left atrium (LA). MR may be asymptomatic for years or cause severe hemodynamic instability in an acute setting. The aim of this article is to highlight the main etiologies and mechanisms of MR occurrence and to explain the main principles of diagnostic approach to such patients.
MITRAL VALVE ANATOMY
To understand the principles of mitral regurgitation we need, first of all, to analyze the structure of the mitral valve itself and its apparatus. The mitral valve apparatus involves the mitral leaflets, chordae tendineae, papillary muscles and mitral annulus1 (Figure 1 from Braunwald's Heart Disease, 2018). Mitral leaflets are anterior and posterior. Each leaflet is divided into three segments (A1, A2, A3 and P1, P2, P3) (Figure 2 from ASE guidelines 2017). Normally, the leaflets are thin and soft. Each leaflet has an atrial and ventricular surface. The anterior leaflet is larger and is located along the aortic root. The chordae tendinea are fibrous strings that start from the papillary muscles or direct from the ventricular wall and go to the valve leaflets. The papillary muscles start from the apex and middle third of left ventricle wall. There are anterolateral papillary muscles and posteromedial papillary muscles. The first one is supplied from the left anterior descending artery and\or circumflex artery; the second one is supplied from the right coronary artery. The mitral annulus, a D-shaped fibrous ring where the leaflets are connected, contracts to establish the leaflets’ coaptation during systole2. Abnormalities of any of the structures described above as well as left ventricular or atrial dilatation and dysfunction can cause mitral regurgitation.
Mitral regurgitation can be primary or secondary. Primary regurgitation occurs when the problem is in the mitral valve apparatus (leaflets, chordae, papillary muscles etc.). When the mitral valve apparatus is definitely normal or mildly changed, and a problem occurring in the left ventricle and\or left atrium causes the coaptation defect, the mitral regurgitation is secondary3.
MR can be acute, as in papillary muscle rupture, or chronic, as in rheumatic heart disease. Severe primary hemodynamically significant acute MR, in most cases, requires urgent heart surgery. The treatment algorithm in chronic mitral regurgitation depends on various circumstances, primarily the regurgitation severity and etiology. In the case of severe primary MR mitral valve intervention is often required. On the other hand, secondary mitral regurgitation should be treated conservatively in most cases4.
ETIOLOGY OF PRIMARY MITRAL REGURGITATION
1. Chronic rheumatic heart disease.
The mitral valve leaflets shorten, become rigid, deformed and retracted. The posterior leaflet is typically fixed and the anterior leaflet overrides it on closure. Rheumatic mitral regurgitation is often associated with rheumatic mitral valve stenosis and other heart valve involvement5.
2. Infective endocarditis
Infective endocarditis can cause MR by the formation of vegetations that can destroy the leaflets margins or body (leaflets perforation) or prevent the valve leaflets coaptation. Chordae tendinea rupture can also occur due to infective endocarditis6.
3. Spontaneous idiopathic chordae tendineae rupture
This occurs more often in the chordae to the posterior leaflet and may cause either acute heart failure (pulmonary edema or shock) or mild symptoms of low exercise tolerance. Chordae tendinea rupture may occur due to congenital abnormalities, trauma etc.
4. Myxomatous degeneration
Myxomatous degeneration of mitral valve leaflets or chordae tendinea can be responsible for mitral valve prolapse, Ehlers-Danlos syndrome and Marfan syndrome. This degeneration occurs as one of the components of systemic connective tissue disorder. Due to collagen formation defect the mitral valve leaflets become long and thick7.
5. Papillary muscle rupture
Papillary muscle rupture occurs predominantly as a complication of acute myocardial infarction. The posterior papillary muscle, due to it supply, becomes ischemic and infarcted more frequently than the anterior one. In most cases the situation is acute and requires urgent surgical intervention8. Papillary muscle rupture can also occur due to rare causes such as trauma or tumor.
6. Mitral annulus calcification
Calcification of the mitral annulus is often associated with coronary and carotid atherosclerosis. It affects the mitral valve orifice. The calcification may immobilize the basal portion of the mitral leaflets and lead to restricted motion and coaptation defect9.
7. MR associated with drug exposure
Certain drugs can increase the risk of mitral regurgitation. These include dopamine agonists that are used in Parkinson disease treatment, drugs containing ergotamine and similar medicines for migraines and appetite suppressants (fenfluramine and dexfenfluramine)10.
8. Congenital mitral valve abnormalities
Congenital abnormalities of the mitral valve leaflets such as clefts or fenestrations, malposition of the papillary muscles, absence of one papillary muscle (that leads to parachute mitral valve), mitral annulus defects etc. can cause MR.
9. Carcinoid heart disease
Carcinoid heart disease more often affects the right side of the heart. But in some cases the mitral valve can be involved and valve problems occur due to fibrotic tissue formation. This tissue leads to leaflet thickening and degeneration that causes a severe retraction and coaptation defect of the valve11.
10. Radiation of the mediastinum
Mediastinal radiation treatment can lead to progressive valve thickening and calcification leading to valve restriction and dysfunction, with stenosis and\or regurgitation development12.
ETIOLOGY OF SECONDARY MITRAL REGURGITATION
Remodeling of the left ventricle due to ischemic or nonischemic cause leads to papillary muscle displacement, dilation and flattening of the mitral annulus and reduces the leaflets’ coaptation. Secondary MR is very dynamic and depends on preload conditions. The development of significant functional mitral regurgitation is strongly associated with poor prognosis in patients with heart failure.
A rare cause of MR is isolated left atriual enlargement due, for example, to atrial fibrillation. This enlargement in the absence of left ventricle dilatation or mitral valve changes leads to a dilated mitral annulus with leaflets coaptation defect4.
There can be mixed etiologies of MR, i.e. primary +secondary.
MITRAL REGURGITATION MEASUREMENTS
The initial step is the visual assessment of the mitral valve. You can analyze the leaflets' mobility, presence of leaflet defects or additional masses.
The next step is to perform the specific measurements. The valvular measurements in ultrasound evaluation of mitral insufficiency are based on the Doppler effect. The Doppler effect is the change of frequency of sound emitted or reflected by a moving object, named after Christian Doppler13. The sum of real-time 2D images and Doppler flowmetry is the main power of echocardiography, the reason why this method is the gold standard in the evaluation of valvular pathology14,15. How can we evaluate blood flow using echocardiography? Let’s take a closer look.
For MR evaluation we use three main types of Doppler mode16:
1. Pulsed wave Doppler (PW);
2. Continuous wave Doppler (CW);
3. Color Doppler (CD) or color flow imaging (CFI) or color velocity imaging (CVI) or color mode.
PW and CW help us to evaluate velocity, direction of the flow in some point or along the line of the ultrasound beam. PW and CW images look like graphs with velocity and time on the axes (Figures 3,4).
The ultrasound machine registers echo signals and shows as waveforms on a graph with waveforms above the baseline indicating flow towards the probe, and waveform below the baseline representing flow away from the probe (Figures 4,5,6). PW is based on the work of a single piezoelectric element that sends the ultrasound signal to the target, then receives the signal when it is reflected back. The process repeats, one signal at a time, over many pulses. PW thereby estimates the velocity of blood flow in a small space, known as the sample volume. As an example, PW estimates flow velocity in the left ventricular outflow tract a few millimeters before the aortic valve (Figure 5). PW is not intended for high-velocity flows (> 1.7-2.0 m/s).
CW is based on constant activity of two piezoelectric elements: one sends the ultrasound signal and the other receives it. CW estimates velocity of blood flow along the ultrasound beam and is intended for measurement of high velocity flows (> 1.7-2.0 m/s). For example, in Figure 6 we can see the flow of mitral regurgitation. The important point of blood flow measurements using PW or CW Doppler is the parallel alignment of the ultrasound beam to blood flow.
CD helps us to understand presence or absence of flow by letting us visualize the flow and evaluate its direction using color mapping. Instead of graphs CD uses colors for designation of flow directions. CD assigns different colors when blood is moving. Figure 7 illustrates the standard red and blue scale. Red is used to show the flow moving towards the probe (goes to upper part of the picture, figure 8), blue for flow moving away from the probe (goes to lower part of the picture) (Figure 9).
Let’s look at some examples. To obtain the color view you need to activate the color mode box in the 2D image (Figure 8). You can move this box to receive information in the exact area of interest (for example, at mitral valve or outflow tract) (Video 10). Flow in this box may look like a jet (Figure 11) and it is better delineated if flow is narrow and has a high velocity.
In contrast, wide and slow flow is poorly delineated. In CD mode the jet has several typical parts: convergence zone (like “head”), vena contracta (the narrowest part) and the main part of the jet (Figures 12,13). Mitral regurgitation is the pathological flow between left ventricle (LV) and left atrium (LA) during systole. It is a well known fact that the gradient between the LA and LV during LV systole is about 100-120 mm Hg, which is probably high. This is why the MR jet has a high velocity and is well seen (video 14).
Keep it in mind that the best way to correctly measure flow across the valve is to align the ultrasound beam parallel to blood flow! (Figure 15).
The severity of MR defines the treatment strategy17. There is no one gold standard parameter for evaluation of mitral regurgitation. The main, guideline-approved criteria of mitral regurgitation are vena contracta, effective regurgitant orifice area, regurgitation volume, regurgitation fraction etc. (Figure 16).
First, let’s evaluate and measure the components of the jet: flow convergence or proximal isovelocity surface area (PISA) radius, vena contracta (VC) and jet area. All jet measurements and calculations are based on the assumption that the larger valve defect, the greater flow going through it. There is qualitative and quantitative evaluation of regurgitation severity.
SIGNS OF SEVERE MR18,19
Qualitative and semi-quantitative parameters.
1. VC width 7 mm or more with scale aliasing velocity 50-70 cm/s (Figure 17).
VC is the measurement of the narrowest portion of regurgitation jet. It is better to use optimal plane and zoomed view for accurate measurement. Even a small mistake can have a significant impact.
2. Large jet area, more than 50% of the left atrium area with scale aliasing velocity 50-70 cm/s (Figure 18).
3. PISA radius 1,0 cm or more with scale aliasing velocity 30-40 cm/s.
To measure convergence zone radius we need optimal scale settings and an optimal view so it is better to use zoom as well. Perform the measurement accurately from the regurgitant orifice i.e. from the level of the leaflets to the edge of the convergence zone at peak systole (Figure 19).
These measurements are highly dependent on the ultrasound machine settings and the patient’s hemodynamic state. Do not forget to check settings and evaluate heart rate and blood pressure before calculations (Figures 20,21 from ASE guidelines 2017)!
4. Reversed flow in pulmonary veins.
Use CD to find the flow from the pulmonary veins to the atrium. Put the PW sample volume into the pulmonary vein and register the flow (Figure 22). Reversed pulmonary vein systolic flow has high sensitivity for elevated left atrial pressure and severe MR.
Quantitative evaluation methods are more reliable and reproducible. The main disadvantage of these methods is technical difficult and is therefore dependent on the experience of the operator.
Despite the fact that modern ultrasound machines perform all required calculations themselves, it is better to know the fundamental formulas.
1. Effective regurgitant orifice area (EROA) and regurgitation volume (RVol) based on PISA radius.
First, measure the PISA radius (see above) with optimal plane and scale alignment. To calculate the regurgitation flow (RFlow) use the following formula:
RFlow = 2π × r2 × Va
where r- PISA radius, Va- velocity aliasing
Then, find the MR jet and align the CW Doppler plane parallel to this jet (Figure 15). Register the flow with CW Doppler and trace it to calculate velocity and velocity time integral (VTI). The last step is to calculate EROA and RVol using formulas (Figure 23 from ASE guidelines 2017):
EROA = (2π × r2 × Va)/PeakV RegJet
where r- PISA radius, Va- velocity aliasing, Peak V RegJet- peak velocity of regurgitation jet
RVol = EROA × VTI RegJet
where VTI RegJet- velocity time integral of regurgitation jet
The main problem of measurements based on the jet characteristics (VC, EROA, RVol (PISA method)) is the time-dependency of these measurements and variability during cardiac cycle. End-systolic regurgitation in contrast to holosystolic creates the most difficulties (Figures 24, 25). In such a case it is better to use volumetric evaluation, such as regurgitation fraction based on PW Doppler, 3D volume or take several frames and calculate the average PISA radius and EROA.
2. Regurgitation fraction (RF) and regurgitation volume (RVol) based on PW Doppler measurements
Since PW Doppler allows us to measure the flow going across the surface you can use it to calculate the volume. The difference between the volumes that come through MV and LVOT will give us the regurgitation volume (Figure 26).
First, we have to measure LVOT diameter at mid systole and calculate LVOT area, using the formula:
CSA = π × d2/4 =0,785× d2
where CSA-cross-sectional area, d- diameter.
Then, register LVOT systolic flow with PW Doppler and trace it to calculate VTI and calculate the LVOT stroke volume (SV) using formula:
SV = CSA × VTI = 0.785 × d2 × VTI
Next step: repeat these calculations for MV and find MV SV.
Then, find the difference between MV stroke volume and LVOT stroke volume.
RVol= MV SV- LVOT SV
where MV SV- mitral valve stroke volume, LVOT SV- left ventricle outflow tract stroke volume.
Regurgitation fraction can be calculated as regurgitation volume divided by mitral valve stroke volume.
RF = RVol/MV SV
In cases of aortic valve insufficiency it is better to use tricuspid valve stroke volume (EROA and 3D planimetry).
Three-dimensional vena contracta area (3D VC area)
Nowadays, the newer technologies allow us to obtain high quality 3D images. 3D visualization gives us the ability to directly measure the regurgitant orifice. All we need is to obtain a good 3D mitral valve image, turn on the CD and optimize color. Using high quality images, we can measure regurgitant orifice area or 3D VC area by direct planimetry trace (Figure 27 from ASE guidelines 2017). Cut off values for severe MR are similar to EROA cut off values20. The 3D VC area has the same limitations: variability during cardiac cycle.
TRANSESOPHAGEAL ECHOCARDIOGRAPHY (TEE) OR CARDIAC MAGNETIC RESONANCE (CMR)
Transesophageal echocardiography (TEE) or cardiac magnetic resonance (CMR)21 are indicated in patients with poor image quality, inconclusive transthoracic echocardiography (TTE) or before mitral valve surgery or MitraClip procedure22,23 when comprehensive evaluation of valve is needed. TEE allows us to see and precisely evaluate mitral valve details in high resolution 2D or 3D imagery. CMR is the best visualization method for measurement of chamber sizes, volumes, function and for volumetric parameters of MR (RVol, RF).
SECONDARY MR EVALUATION
There are some differences in primary and secondary MR evaluation. Secondary MR occurs due to ventricular problems, where the valve is almost normal. In general, we have to perform measurements the same way as described above, but the cut off values are more ambiguous. For example, ASE 2017 guidelines use the same severity criteria (Figure 28) for secondary and primary MR19, while the ESC/EACTS 2017 guidelines suggest different severity criteria (Figure 29)17. The patient with even moderate secondary MR has an unfavorable prognosis.
Evaluation of MR is a complex process. First of all, you need to obtain a high quality image and accurate measurements. The better the image quality and measurements the better the reproducibility of the results. Sometimes you can obtain controversial parameters of MR in one patient. For example, VC can be small -0.3 cm and EROA- 0.6 cm2. In such cases you need to check these parameters and calculations in different views to establish the clear result. Moreover, you may need additional information received from TEE or CMR. 3D TEE evaluation of a mitral valve, performed by the experienced operator, is a gold standard of mitral valve evaluation.
It is worth saying that in every case of MR you need to look at the whole picture of the patient23: their complaints, hemodynamic status, the way the mitral valve apparatus looks and functions, chambers size, shape and function.
1. D. P. Zipes, P. Libby, R. O. Bonow et al. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 11th edition, 2018.
2. K. P. McCarthy, L. Ring, B. S. Rana. Anatomy of the mitral valve: understanding the mitral valve complex in mitral regurgitation. European Journal of Echocardiography, 2010, 11 (10): i3–i9.
3. J. L. Zamorano, J. M. Monteagudo, D. Mesa et al. Frequency, Mechanism and Severity of Mitral Regurgitation: Are There any Differences Between Primary and Secondary Mitral Regurgitation? J Heart Valve Dis, 2016; 25(6):724-729.
4. A. W. Asgar, M. J. Mack, Gr. W. Stone. Secondary Mitral Regurgitation in Heart Failure
Pathophysiology, Prognosis, and Therapeutic Considerations. J Am Coll Cardiol, 2015; 65(12):1231-1248.
5. J. R. Carapetis, An. Beaton, M. W. Cunningham et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers, 2016; 14 (2):15084
6. Fr. Nappi, Cr. Spadaccio, J. Dreyfus et al. Mitral endocarditis: A new management framework. The Journal of thoracic and cardiovascular surgery; 2018, 156 (4):1486-1495.
7. F. L. Neto, L. C. Marques, V. D. Aiellob. Myxomatous degeneration of the mitral valve. Autops Case Rep. 2018 Oct-Dec; 8(4): e2018058.
8. B. Ibanez, St. James, St. Agewall et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology. European Heart Journal, 2018, 39 (2): 119–177.
9. M. F. Eleid, Th. A. Foley, S. M. Said et al. Severe Mitral Annular Calcification
Multimodality Imaging for Therapeutic Strategies and Interventions. J Am Coll Cardiol Img 2016; 9:1318–37.
10. Ch. S. Elangbam. Drug-induced Valvulopathy: An Update. Toxicologic Pathology, 2010; 38: 837-848.
11. Shi-Min Yuan. Valvular Disorders in Carcinoid Heart Disease. Braz J Cardiovasc Surg, 2016; 31(5): 400–405.
12. D. M. Gujral, G. Lloyd, S. Bhattacharyya. Radiation-Induced Valvular Heart Disease. Heart 2016, 102(4):269-76.
13. G. S. Reeder, P. J. Currie, D. J. Hagler et al. Use of Doppler techniques (continuous-wave, pulsed-wave, and color flow imaging) in the noninvasive hemodynamic assessment of congenital heart disease. Mayo Clin Proc, 1986; 61(9):725-44.
16. R.S. Moorthy. Doppler ultrasound. Med J Armed Forces India, 2002; 58(1): 1–2.
17. H. Baumgartner, V. Falk, J. J. Bax et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. European Heart Journal, 2017, 38: 2739–2791.
19. W.A. Zoghbi, D. Adams, R. O. Bonow et al. Recommendations for Noninvasive Evaluation of Native Valvular Regurgitation. Journal of the American Society of Echocardiography; 2017, 30 (4).
20. Björn Goebel, Roland Heck, Ali Hamadanchi et al. Vena contracta area for severity grading in functional and degenerative mitral regurgitation: a transoesophageal 3D colour Doppler analysis in 500 patients. European Heart Journal - Cardiovascular Imaging, 2018, 19 (6): 639–646.
21. P. Garg, An. J. Swift, L. Zhong et al. Assessment of mitral valve regurgitation by cardiovascular magnetic resonance imaging. Nature Reviews Cardiology, 2019 , 17: 298–312
22. W. E Katz, A. J Conrad Smith, F. W Crock et al. Echocardiographic evaluation and guidance for MitraClip procedure. Cardiovasc Diagn Ther, 2017, 7(6):616-632.
23. R. O. Bonow, P. T. O’Gara, D. H. Adams et al. 2020 Focused Update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation. Journal of the American College of Cardiology, 2020, 75 (17): 2236-2270.