Clinical manifestations and diagnosis of chronic mitral regurgitation

INTRODUCTION — Mitral regurgitation (MR) is a common valvular disorder that can arise from abnormalities of any part of the mitral valve apparatus. These include the valve leaflets, annulus, chordae tendineae, and papillary muscles (table 1 and figure 1). The left atrium and ventricle are also integrally involved with mitral valve function.

The etiology and clinical manifestations of chronic MR will be reviewed here. Issues related to acute MR, pathophysiology of chronic MR and management of chronic MR are discussed separately. (See "Acute mitral regurgitation in adults" and "Pathophysiology and natural history of chronic mitral regurgitation" and "Chronic primary mitral regurgitation: General management" and "Chronic secondary mitral regurgitation: General management and prognosis".)

ETIOLOGY — MR may be due to a primary abnormality (sometimes referred to organic MR) of one or more components of the valve apparatus (leaflets, chordae tendineae, papillary muscles, and/or annulus) or may be secondary (previously referred to as functional MR) to another cardiac disease (such as coronary heart disease or a cardiomyopathy) (table 1) [1]. (See "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Causes and mechanisms'.)

The causes of primary MR include:

●Degenerative mitral valve disease (including mitral valve prolapse) is the most common cause of primary MR in developed countries. It includes a spectrum of disease ranging from myxomatous mitral valve disease (also known as myxomatous degeneration, with redundancy of anterior and posterior mitral leaflets and the chordae), seen primarily in younger populations, and fibroelastic deficiency disease, seen primarily in older populations. It is not clear if these are two distinct disease processes or manifestations of a single disease [2]. (See "Mitral valve prolapse: Clinical manifestations and diagnosis" and "Mitral valve prolapse: Overview of complications and their management".)

●Rheumatic heart disease is uncommon in developed countries but continues to constitute a significant burden in the rest of the world. Rheumatic valve disease often results in MR in the first two decades of life [3], while mitral stenosis and mixed mitral stenosis plus MR are more often seen in adults [4,5]. (See "Clinical manifestations and diagnosis of rheumatic heart disease".)

●Infective endocarditis. (See "Complications and outcome of infective endocarditis", section on 'Cardiac complications'.)

●Trauma, which can cause ruptured chordae and acute MR. (See "Acute mitral regurgitation in adults".)

●Use of certain drugs, such as ergotamine, bromocriptine, pergolide, and cabergoline, as well as anorectic drugs that are no longer available such as fenfluramine and benfluorex have been reported to induce MR, although the evidence for cause-effect relationship between exposure to these drugs and mitral valve disease remains weak [6-8]. (See "Valvular heart disease induced by drugs".)

●Congenital malformations including valve cleft.

●Mitral annular calcification is a common finding in older adults that is often associated with mild to moderate MR and is less commonly associated with severe MR. (See "Clinical manifestations and diagnosis of mitral annular calcification".)

Causes of flail or partial flail mitral leaflet include mitral valve prolapse, infective endocarditis, trauma, and rupture of a papillary muscle in the setting of an acute myocardial infarction. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet".)

The secondary causes of MR include (see "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Secondary MR'):

●Coronary heart disease. MR in patients with coronary disease most often is due to a regional wall motion abnormality distorting the mitral valve apparatus resulting in inadequate leaflet closure. In patients with previous myocardial infarction, chronic MR is seen due to adverse ventricular remodeling. However, MR also can occur with transient myocardial dysfunction so that MR severity (and symptoms) may acutely worsen with ischemia, exercise, or other changes in hemodynamic conditions. (See "Pathophysiology and natural history of chronic mitral regurgitation" and "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Secondary MR'.)

●Dilated cardiomyopathy, with MR due to myocardial dyssynchrony, papillary muscle displacement, and annular dilation [9,10].

●Hypertrophic cardiomyopathy with MR due to abnormal systolic anterior motion of the mitral leaflets. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)

●Right ventricular pacing can cause worsened or de novo secondary MR. (See "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Secondary MR'.)

●Atrial functional MR occurs in the setting of heart failure with preserved ejection fraction and/or atrial fibrillation and is characterized by annular dilation and inadequate leaflet coaptation despite normal LV size and systolic function [11,12].

PREVALENCE — The widespread use of color flow Doppler echocardiography, a sensitive technique for detecting valvular regurgitation, has increased the recognition of this lesion, even in healthy subjects [13].

●A trivial amount of MR is detectable with color flow or continuous wave Doppler on transthoracic echocardiography in up to 70 percent of healthy adults; this is often termed "physiologic" MR.

●In the Framingham Heart Study population-based cohort, at least mild MR was detected on transthoracic color flow Doppler echocardiography in 19 percent of participants [14].

●In a review of 3486 subjects in the Strong Heart Study, transthoracic echocardiography found moderate or severe MR in 1.9 and 0.2 percent, respectively [13].

In the developed world, the most common etiologies of MR are degenerative mitral valve disease with mitral valve prolapse (MVP, a primary cause) and coronary heart disease (a secondary cause), which causes ischemic MR (largely post myocardial infarction). (See "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Secondary MR'.)

The prevalence of degenerative mitral valve disease with MVP was approximately 2 to 3 percent in two North American studies [15,16]. The majority of patients with MVP have MR (approximately 70 percent in one cross-sectional population-based study), but most patients with MVP and MR have mild or trace MR [17]. Severe MR is uncommon, identified in 4 percent of patients with MVP.

A high prevalence of MR is seen following myocardial infarction (MI). The reported prevalence of MR detected at cardiac catheterization in the setting of acute MI has ranged from 9 to 13 percent; the MR was moderate to severe in 3 to 4 percent [18-21]. Higher rates of MR are seen with transthoracic echocardiographic evaluation performed days to weeks after MI [22-24] as illustrated by a community-based study of 773 patients who were evaluated within 30 days after an ST elevation or non-ST elevation MI [22]. MR was present in 50 percent (mild in 38 percent and moderate or severe in 12 percent). Similar findings were noted in a study of 300 patients who underwent transthoracic echocardiography within one week of a non-ST elevation acute coronary syndrome [23]. MR was detected with color flow Doppler echocardiography in 42 percent; the MR was mild in 63 percent, mild to moderate in 20 percent, and moderate or severe in 17 percent. MR at the time of or during the first month after MI is seen with increased frequency in older patients and in females, and it is associated with higher Killip class and lower left ventricular ejection fraction [21,22].

Some degree of secondary MR is almost always present in patients with severe dilated cardiomyopathy, regardless of etiology [25-28]. In a study of 470 patients with idiopathic dilated cardiomyopathy, 62 percent had absent or mild MR and 38 percent of patients has moderate to severe secondary MR [28].

Secondary MR is also a common problem in patients with end-stage kidney disease on maintenance dialysis. In this setting, volume expansion rather than intrinsic cardiac disease is primarily responsible for the cardiac enlargement. One study of 21 hemodialysis patients with both MR and tricuspid regurgitation assessed whether valvular regurgitation disappeared with aggressive ultrafiltration [29]. After intensified sessions resulting in a decrease in body weight of approximately 5.4 kg, MR and tricuspid regurgitation was no longer present in 62 percent and 66 percent of patients, respectively. Among those with persistent abnormalities, the degree of regurgitation was much less severe.

CLINICAL MANIFESTATIONS

Symptoms — The nature and severity of the symptoms associated with chronic MR are related to the severity of MR, its rate of progression, the pulmonary artery pressure, arrhythmias (eg, atrial fibrillation), and associated cardiac disease. Because of the importance of identifying the transition from asymptomatic to symptomatic MR in determining the timing of mitral valve surgery, a careful history is important to establish a good estimate of baseline exercise tolerance [30]. Since symptoms occur late in patients with primary MR, serial monitoring of asymptomatic patients is required. (See 'Serial monitoring' below.)

Patients with isolated mild to moderate primary MR are asymptomatic, since there is little volume overload of the ventricle and cardiac hemodynamics, and forward cardiac output remains normal. Most remain asymptomatic until there is left ventricular (LV) cavity enlargement with systolic dysfunction, pulmonary hypertension, or the onset of atrial fibrillation. The most common symptoms are exertional dyspnea and fatigue due to the combination of a decreased forward (ie, effective) cardiac output, an increase in left atrial pressure due to backflow across the mitral valve, and pulmonary artery hypertension. Another common clinical presentation is paroxysmal or persistent atrial fibrillation. Patients with severe MR and LV enlargement eventually progress to symptomatic heart failure with pulmonary congestion and edema. At this stage of LV dilatation, the myocardial dysfunction is often irreversible due to the long-standing MR. In some cases, irreversible LV systolic dysfunction occurs in the absence of symptoms. (See "Pathophysiology and natural history of chronic mitral regurgitation".)

Most patients with chronic secondary MR (ischemic or non-ischemic) have mild MR, and the clinical presentation (including symptoms and signs of heart failure) generally reflects the state of ventricular dysfunction more than the state of the mitral valve. However, patients with only mild secondary MR at rest may develop severe MR with exercise, leading to acute pulmonary edema [31,32]. Among patients with chronic secondary MR who develop symptoms, the most common complaints reflect decreased forward or effective cardiac output and include weakness, fatigue, and exercise intolerance. Patients with more severe disease or with exercise-induced worsening of MR may present with symptomatic heart failure or pulmonary edema. However, it may be difficult to separate symptoms due to primary LV systolic dysfunction from those due to the added burden of secondary MR. (See 'Clinical manifestations' above.)

Other symptoms such as thromboembolism, hemoptysis, and right-sided heart failure do occur, but are less common than with mitral stenosis. However, there is an increased risk of infective endocarditis in patients with an abnormal mitral valve and moderate to severe MR. (See "Native valve endocarditis: Epidemiology, risk factors, and microbiology".)

Physical examination — In chronic primary MR, the arterial pulse is normal until very late in disease progression because LV ejection time and forward stroke volume remain normal. With acute MR or with end-stage chronic severe MR, there is a rapid reduction in the volume of forward flow late in systole along with a decrease in ejection time, so that the arterial pulse falls off rapidly, which may give the impression of a bounding pulse, similar to that seen with aortic regurgitation. However, the pulse pressure is normal with MR. (See "Examination of the arterial pulse".)

Enlargement of the LV results in a leftward displacement of the apical impulse; it is usually brisk or hyperdynamic. When the MR is severe or when there has been an acute exacerbation of the regurgitation as a result of chordal rupture, an S3 and a palpable thrill may be present. Crackles (rales) may be detected but are absent in many patients with symptomatic disease [33]. Signs of right-sided congestive heart failure are typically absent unless there is associated mitral stenosis or the MR is of long standing and is very severe. (See "Examination of the precordial pulsation".)

Physical examination cannot reliably distinguish chronic severe MR due to primary valve disease from secondary MR due to ischemic heart disease or dilated cardiomyopathy. (See "Examination of the precordial pulsation".)

Heart sounds — In addition to a murmur, chronic MR can produce changes in the heart sounds (see "Auscultation of heart sounds"):

●S1 is diminished, reflecting inadequate apposition of the mitral leaflets as LV pressure exceeds left atrial pressure.

●In chronic MR, the reduced LV forward stroke volume contributes to an early A2, which contributes to a wider splitting of S2. The effect of concomitant pulmonary hypertension on the timing of P2 varies with right ventricular function. If right ventricular function is preserved, P2 is earlier than usual, which tends to narrow splitting of S2. If right ventricular function is depressed, P2 is delayed, which tends to widen splitting of S2.

●The augmented early diastolic flow rate across the mitral valve orifice into a dilated LV produces an S3 filling sound, generally referred to as an S3 gallop; this becomes particularly prominent if LV failure develops.

The murmur of MR is systolic but its timing, duration, quality, intensity, location, and radiation are variable and depend upon the etiology and component of the mitral apparatus that is diseased. In most cases, the murmur is holosystolic, commencing immediately after S1 and continuing up to (and sometime beyond) and obscuring A2, a result of the persistent pressure gradient between the left ventricle and atrium after aortic valve closure.

The murmur is heard best over the apex. When the MR jet is directed posterolaterally, the murmur radiates to the axilla and when very loud, may radiate to the posterior left thorax. The murmur radiates toward the base and the neck if the MR jet is directed anteromedially. It is most often blowing and high pitched in quality. (See "Auscultation of cardiac murmurs in adults".)

Unfortunately, cardiac auscultation poorly predicts the presence or severity of MR [34]. The potential role of point-of-care ultrasound in improving diagnostic accuracy is being studied [35].

There is some correlation between the MR murmur grade and regurgitant severity with primary mitral valve disease. A loud murmur associated with a thrill (grade 4 or greater) has a specificity of 91 percent for severe MR, but a sensitivity of only 24 percent [36]. Conversely, severe MR is rarely present with a grade 1 to 2 murmur. However, there is a wide range of MR severity with a grade 3 murmur (which is common) [36].

The loudness of the murmur correlates even less well with severity in secondary (functional) MR. Up to half of patients with chronic ischemic MR lack an audible murmur [22].

In addition to the classic holosystolic murmur, other types of murmurs can be heard in chronic MR:

●When the posterior leaflet is predominantly involved (due to prolapse or chordal rupture), the murmur may radiate anteriorly toward the sternum and is heard well at the base. This type of murmur is often confused with aortic stenosis but does not radiate to the carotid arteries.

●When the anterior leaflet is predominantly involved (due to prolapse or chordal rupture), the murmur is often loud, radiates to the back, and may be heard on the top of the head as a result of the excellent sound transmission along the vertebral column.

●A mid to late systolic murmur, harsh in quality, is often heard when the MR is due to prolapse or papillary muscle displacement (previously known as papillary muscle dysfunction). When the murmur is confined to late systole, the volumetric severity of MR is usually only mild to moderate, even if the murmur is loud. S1 is intact in this setting, since the initial closure of the mitral leaflets is normal. The murmur of papillary muscle displacement is variable and becomes louder and longer when there is an acute ischemic episode.

●Infrequently, the large diastolic volume across the mitral valve with severe MR produces an early diastolic murmur (movie 1).

●When the cause is mitral valve prolapse, a midsystolic click (correlating with the maximal prolapse and tension on the chordae) may be heard and the murmur may start in mid to late systole (movie 2). (See "Mitral valve prolapse: Clinical manifestations and diagnosis", section on 'Physical examination'.)

●Heart failure and the volume and geometry of the LV can affect the timing, intensity, and quality of the MR murmur. In patients with MR due to dilation of the valvular annulus, the murmur often diminishes in intensity or disappears as the heart failure is treated and LV function improves.

Effect of diagnostic maneuvers — Since the murmur of MR may be variable, it is important to distinguish it from the murmurs associated with other valvular lesions. The use of certain maneuvers may be helpful in this regard. However, interpretation of changes in a murmur with maneuvers is often difficult and may not be reproducible. The most accurate and cost-effective method for determining the cause of a systolic murmur is echocardiography. (See "Physiologic and pharmacologic maneuvers in the differential diagnosis of heart murmurs and sounds".)

The murmur of MR has the following characteristics (figure 2 and table 2):

●There is little respiratory variation.

●The murmur may become louder when LV volume increases (heart failure or occasionally with an increase in venous return as occurs with leg raising or lying down) or when arterial pressure increases (squatting or isometric hand grip).

●There is a decrease in intensity when venous return is reduced due to standing or the Valsalva maneuver.

These maneuvers can also produce changes in patients with mitral valve prolapse. Those maneuvers that decrease venous return and reduce the LV volume cause the systolic click to occur earlier (move toward S1) and the murmur to be of longer duration (although it is often fainter). On the other hand, those maneuvers that increase venous return or afterload cause the click to occur later (move toward S2) and the murmur to be abbreviated (table 2). (See "Mitral valve prolapse: Clinical manifestations and diagnosis", section on 'Physical examination'.)

Chest radiograph — A chest radiograph is not indicated to diagnose MR but it may be obtained in patients with dyspnea of uncertain cause. The most common finding on the chest radiograph is cardiomegaly, resulting from enlargement of the LV and the left atrium (image 1). However, LV size does not correlate with the severity of MR, nor does left atrial size correlate with the elevation of left atrial pressure.

LV enlargement causes the cardiac silhouette to be displaced towards the left chest wall and the chamber becomes globular. Enlargement of the left atrium results in a straightening of the left heart border with the appearance of a double density and elevation of the left main stem bronchus.

The right ventricle is usually normal in size unless there is pulmonary hypertension. Similarly, the lung fields are usually clear unless congestive heart failure is present. Calcification of the mitral valve annulus may be seen.

Electrocardiogram — An electrocardiogram is not required for the diagnosis of MR but is routinely obtained to assess for concurrent conditions and to serve as a baseline for future comparison. The electrocardiogram in chronic MR most often reflects the hemodynamic burden placed on the left atrium, which can lead to left atrial enlargement, similar to that seen in mitral stenosis. The P wave broadens (>0.12 sec in lead II), becomes increased in amplitude, has notching, and has a significant negative component in V1 (called "P-mitrale"). Other changes are less specific. Chronic MR is often complicated by the development of atrial fibrillation.

DIAGNOSIS AND EVALUATION

Approach to diagnosis — MR should be suspected in patients with an apical holosystolic or mid to late systolic murmur. Most patients with MR are asymptomatic since symptoms are a late manifestation of disease. Testing to establish a diagnosis of MR also involves evaluating the severity of MR, identifying its cause, and determining its hemodynamic consequences (ie, impact on left atrial size, left ventricular [LV] size and function, and pulmonary artery pressure) (table 3A-B).

The diagnosis in patients with suspected MR is generally confirmed by transthoracic echocardiogram (TTE). TTE is recommended in patients with known or suspected MR to determine the severity, etiology, and hemodynamic consequences of MR [30,37-39]. Left atrial size is usually increased. LV size and systolic function are normal early in the disease course, but progressive ventricular dilation and a decline in ejection fraction occur with chronic severe MR. Pulmonary artery pressures also can be noninvasively estimated using Doppler echocardiography. (See "Echocardiographic evaluation of the mitral valve".)

If the TTE is technically suboptimal, transesophageal echocardiogram (TEE) is recommended. One study of 248 patients found that, when compared with surgical diagnosis, the accuracy of TEE was high: 99 percent for etiology and mechanism, presence of vegetations, and prolapsed or flail segment, and 88 percent for ruptured chordae; diagnostic accuracy was higher for TEE compared with TTE [39]. Three-dimensional TTE and TEE may be particularly helpful. (See "Transesophageal echocardiography in the evaluation of mitral valve disease" and "Three-dimensional echocardiography", section on 'Mitral valve'.)

If MR severity and LV systolic function cannot be adequately assessed by TTE and TEE, cardiovascular magnetic resonance imaging is indicated. Cardiovascular magnetic resonance imaging may be particularly valuable in assessing the severity of MR due to an eccentric jet [40]. If these noninvasive tests are inconclusive or discordant (eg, discrepancy between symptoms and noninvasive testing) with respect to the severity of MR, LV function, and/or the need for surgery, invasive cardiac catheterization is indicated.

Stress testing (combined with Doppler echocardiography or cardiac catheterization) is helpful in selected patients with chronic primary MR to evaluate exercise-induced changes in hemodynamics. Stress testing (myocardial perfusion imaging or stress echocardiography) may be used to identify ischemia in patients with suspected ischemic MR.

Identifying the severity of MR — Echocardiography (mainly transthoracic, with transesophageal only when needed) is the dominant means of identifying MR and determining its severity. MR can also be identified and quantified by cardiovascular magnetic resonance (CMR) or by cardiac catheterization. The severity of MR is most commonly determined using semi-quantitative echocardiographic parameters.

When qualitative measures suggest more than mild MR is present, quantitation with calculation of regurgitant volume and regurgitant orifice area is recommended [41]. Doppler and color flow Doppler can be used to measure the severity of MR (movie 3A-B). The simplest approach is measurement of the narrowest segment of the jet, or vena contracta, on color flow imaging. Mitral regurgitant severity can be measured more precisely, when clinically indicated, by calculation of the regurgitant volume, regurgitant fraction, and effective regurgitant orifice area using Doppler approaches [42,43]. As noted in the 2020 American Heart Association/American College of Cardiology guidelines for management of patients with valvular heart disease and the 2017 American Society of Echocardiography recommendations for quantitation of valvular regurgitation, the following findings are consistent with severe MR (table 3A-B) [41,44]:

●Vena contracta width ≥0.7 cm

●Effective regurgitant orifice area ≥0.40 cm²

●Regurgitant volume ≥60 mL

●Regurgitant fraction ≥50 percent

●Regurgitant jet area >40 percent of left atrial area, or a holosystolic eccentric jet

The diagnosis of severe MR is most secure when more than one of these findings is present. The use of three-dimensional (3D) color Doppler to directly measure regurgitant orifice area may be useful when the shape of the orifice is noncircular, or when there are multiple jets. However, this approach requires TEE imaging by an experienced echocardiographer [45,46]. (See "Echocardiographic evaluation of the mitral valve".)

A major limitation to the use of effective regurgitant orifice (ERO) is that quantitation of ERO is technically difficult and should only be performed in an experienced echocardiography laboratory [47]. Another key issue is that ERO does not account for the duration of regurgitation (mid-late systolic versus holosystolic), which likely explains why regurgitant volume rather than ERO predicted outcomes in one large series [48]. Eccentric MR jets are also more difficult to assess using echocardiographic measures. These issues are discussed in more detail separately. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet", section on 'Clinical outcome'.)

An additional issue complicating quantification of MR is that the severity of MR varies with hemodynamic conditions (loading and inotropic stimulation) [49]. The dynamic nature of MR explains variations in the degree of MR with general anesthesia and in some patients presenting with acute pulmonary edema [49].

Identifying the cause of MR — Identification of the cause and type (primary or secondary) of MR is required for appropriate management of MR as well as any associated conditions. The clinical presentation and imaging are helpful in establishing a cause. If the cause of MR cannot be identified by TTE, the cause can generally be determined by TEE. Three-dimensional echocardiography is recommended for defining valve morphology if valve repair or intervention is being considered. Careful evaluation of the mechanism of MR is required, since patients with primary MR are managed differently from those with secondary MR. As an example, while secondary ischemic MR is common among patients with coronary heart disease and prior myocardial infarction, some patients with primary MR due to degenerative disease have coexisting coronary heart disease.

Primary MR is diagnosed when imaging demonstrates abnormal mitral valve leaflets or chordae. With mitral valve prolapse, the leaflets are diffusely thickened and redundant, with systolic displacement of some leaflet segments into the left atrium in systole, most often the central scallop of the posterior leaflet (see "Mitral valve prolapse: Clinical manifestations and diagnosis", section on 'Imaging definition of MVP'). Rheumatic disease causes typically thickening at the leaflet tips with chordal shortening, thickening and fusion, often with hemodynamics showing combined regurgitation and stenosis (see "Clinical manifestations and diagnosis of rheumatic heart disease", section on 'Chronic valve disease'). Infective endocarditis causes MR due to leaflet destruction and the presence of a valve vegetation (see "Role of echocardiography in infective endocarditis" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis"). Congenital mitral valve disease often is accompanied by other congenital abnormalities; for example, a cleft anterior mitral leaflet often is associated with a primum atrial septal defect or an atrioventricular canal defect. (See "Clinical manifestations and diagnosis of atrioventricular (AV) canal defects".)

A ruptured mitral chordae tendineae or partial flail leaflet may be seen with mitral valve prolapse, infective endocarditis, trauma, rheumatic heart disease, or spontaneous rupture. Papillary muscle rupture may be caused by acute myocardial infarction or trauma. When a chordal or papillary muscle rupture is present, the movement of the leaflets is markedly exaggerated and the ruptured chord or papillary muscle is seen in the left atrium in systole (movie 4A-C). (See "Acute mitral regurgitation in adults".)

Secondary (functional) MR due to LV dilation and systolic dysfunction is characterized by failure of the mitral leaflets to fully coapt and a dilated mitral valve annulus. Causes include coronary heart disease (which causes "ischemic MR") and cardiomyopathies (eg, dilated or hypertrophic). Ischemic MR is characterized by apical "tenting" or "tethering" of the leaflets, resulting in inadequate apposition of the leaflets, which often do not reach the level of the mitral annulus (movie 5A-C) [50,51]. Segmental (typically basal inferolateral) or global LV dysfunction subjacent to the chordal apparatus is seen. Reliable measures of the leaflet tenting area and tenting height, as well as the effective regurgitant orifice, can be obtained on a TTE in most patients [52]. (See "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Secondary MR'.)

Additional details and examples for the echocardiographic identification of the etiology of MR are provided separately. (See "Echocardiographic evaluation of the mitral valve" and "Echocardiographic evaluation of the mitral valve", section on 'Mitral valve lesions causing mitral regurgitation'.)

Assessing hemodynamic consequences — Assessment of MR should include effects on left atrial size, LV size and function, and pulmonary artery pressure. Left atrial size is usually increased. LV size and systolic function are normal early in the disease course but progressive ventricular dilation and a decline in ejection fraction occur with chronic severe MR. Pulmonary artery pressures also can be noninvasively estimated using Doppler echocardiography. (See "Echocardiographic evaluation of the mitral valve".)

Severe chronic MR generally does not exist without left atrial or ventricular enlargement. If the LV end-diastolic dimension (by echocardiography) is less than 60 mm (approximately 35 mm/m²), the diagnosis of severe chronic MR should be seriously questioned. In addition to LV end-diastolic size, end-systolic dimension and volume should be measured because end-systolic measures are less dependent on loading conditions and are key elements in decision making about timing of intervention. Left atrial size may reflect the "history" (severity and duration) of chronic MR [33]. (See "Chronic primary mitral regurgitation: Indications for intervention" and "Pathophysiology and natural history of chronic mitral regurgitation".)

Pulmonary vein systolic flow reversal is an unreliable sign of severe MR. Systolic flow reversal may not be present in all four pulmonary veins, especially with an eccentric jet of severe MR. Conversely, systolic flow reversal or blunting may be seen even when MR is not severe in patients in a non-sinus rhythm because normal systolic flow in the pulmonary veins is caused by atrial relaxation after atrial contraction [53].

Other diagnostic testing

Cardiovascular magnetic resonance — CMR is not recommended for routine diagnosis or monitoring but CMR at an experienced center is indicated when echocardiographic measures of MR severity or LV function are not adequately assessed by echocardiography or are discrepant. Administration of exogenous contrast (ie, gadolinium) is generally not required for CMR assessment of MR [54,55].

CMR enables quantitation of the severity of MR based on calculating the regurgitant volume as the difference between LV stroke volume and ascending aortic forward flow or as the difference between left and right ventricular stroke volumes [56]. Alternatively, MR may be quantified by CMR planimetry of the anatomic regurgitant orifice [57]. CMR also enables highly detailed and accurate quantitation of LV volumes and ejection fraction when these data are needed for clinical decision making [55,58]. While CMR has generally been restricted to patients with inconclusive or discordant findings between echocardiography and symptoms, a prospective study of 103 patients undergoing transthoracic echocardiography and CMR demonstrated that CMR was more accurate for the quantification of MR and potentially for guiding surgical interventions [40].

Cardiac catheterization — Invasive cardiac catheterization for measurement of intracardiac pressures and/or left ventriculography is not recommended for evaluation of chronic MR unless noninvasive tests are inconclusive or discordant (eg, discrepancy between symptoms and noninvasive testing) with respect to the severity of MR, LV function, and/or the need for surgery [30].

Evaluation of coronary anatomy by computed tomography (CT) or invasive angiography is indicated before valve intervention in patients with suspected coronary artery disease (including symptoms of angina or objective evidence of ischemia), decreased LV systolic function, or coronary risk factors (including males >40 years old and postmenopausal women) [30]. Since coronary artery disease is a cause of chronic secondary MR, coronary angiography is suggested in patients with chronic severe functional/secondary MR [30]. (See "Chronic secondary mitral regurgitation: General management and prognosis".)

In patients in the intensive care unit with a right heart catheter in place, the balloon occlusion pressure in the pulmonary artery (or pulmonary capillary wedge pressure), which is used as a surrogate for left atrial pressure, may demonstrate a significant "cv" wave from the regurgitant blood flow into the left atrium (waveform 1A-B). (See "Hemodynamics of valvular disorders as measured by cardiac catheterization".)

In patients undergoing cardiac catheterization for other indications, left ventriculography may establish the presence and severity of MR. The diagnostic finding is opacification of the left atrium during systole. The rapidity and density of opacification of the left atrium provides a semiquantitative index of MR severity (severe MR associated with angiographic grade 3 to 4+) (table 3A-B) [30]. The angiogram can also provide a measure of left atrial and ventricular dimensions and LV function.

In contrast to its occasional utility in chronic MR, contrast left ventriculography is generally avoided at the time of catheterization in patients with acute MR because of the additional iodinated contrast load in an already compromised patient. (See "Acute mitral regurgitation in adults", section on 'Cardiac catheterization'.)

Stress testing — In patients with chronic MR with symptoms that seem out of proportion to severity of MR at rest, measurement of supine bicycle, exercise-induced changes with either Doppler echocardiography (to assess changes of MR and pulmonary artery pressure) or cardiac catheterization (to assess pulmonary capillary wedge pressure and LV diastolic pressure) may be helpful in selected cases but is not routinely recommended [30].

In some patients with severe chronic primary MR who do not report symptoms, exercise treadmill testing can be useful to evaluate symptom status and exercise tolerance [30].

Among patients with ischemic MR, exercise echocardiography may be helpful in patients with mild MR at rest. Some of these patients have a marked increase in MR severity and pulmonary artery pressure with exercise, particularly those with recent acute pulmonary edema [31,59]. Such patients have a worse prognosis [60]. In patients with ischemic MR, worsening with exercise may be related to myocardial ischemia so that evaluation of regional ventricular function and coronary anatomy may be needed.

The magnitude of ischemic MR with exercise cannot be predicted from the severity of MR when the patient is at rest. In addition, an increase in MR can occur with exercise in the absence of exercise-induced ischemia [31,59]. This phenomenon was illustrated by a report of 70 patients with ischemic MR in which Doppler echocardiography was used to determine the ERO at rest and during semi-supine bicycle exercise [59]. The ERO decreased in 13 patients, increased slightly in 38 patients, and increased markedly in 19 patients.

The potential utility of exercise echocardiography in investigating the cause of acute pulmonary edema was evaluated in a study of 28 patients with ischemic heart disease, LV systolic dysfunction, and at least mild MR who had previously presented with acute pulmonary edema without apparent cause [31]. The comparison group included 46 patients with ischemic heart disease and at least mild MR who had not presented with pulmonary edema. With semi-supine bicycle exercise echocardiography, there was a greater likelihood of the test being stopped because of dyspnea among patients with recent acute pulmonary edema (61 versus 17 percent). On multivariate analysis, exercise-induced changes in ERO, in tricuspid regurgitation pressure gradient, and in the LV ejection fraction were independent predictors of recent pulmonary edema. None of the patients had evidence of acute ischemia as manifested by chest pain or electrocardiographic or echocardiographic changes, suggesting that the increase in MR resulted from the hemodynamic and anatomic changes with exercise.

Among patients with ischemic MR, exercise-induced increases in the severity of MR and tricuspid regurgitation pressure gradient have been identified in patients with history of acute pulmonary edema [31].

DIFFERENTIAL DIAGNOSIS — The apical holosystolic murmur of MR is distinguished from similar murmurs by its location, radiation, timing, and character. When the holosystolic murmur of MR radiates toward the base and root of the neck (rather than to the axilla), it may be confused with the ejection murmur of aortic stenosis or hypertrophic obstructive cardiomyopathy with left ventricular obstruction. Tricuspid regurgitation causes a holosystolic murmur that is located at the left lower sternal border and increases with inspiration. A ventricular septal defect causes a harsh holosystolic murmur (often with a thrill) at the left sternal border; however, with elevated pulmonary artery pressures, the murmur becomes shorter.

A careful physical exam is helpful in distinguishing the above murmurs. A transthoracic echocardiogram is diagnostic for each of these lesions. In an echocardiogram, care should be taken to distinguish the spectral signal from aortic outflow from that of MR. Distinguishing characteristics of MR signal include holosystolic duration and presence of mitral inflow signal during diastole. (See "Echocardiographic evaluation of the mitral valve", section on 'Pulsed and continuous wave Doppler of mitral inflow'.)

SERIAL MONITORING — Following initial evaluation, patients with chronic MR should receive periodic monitoring. The goals of monitoring are to assess changes in clinical status by history and physical examination and to assess (generally by transthoracic echocardiography) changes in severity of MR, left atrial size, left ventricular cavity size, systolic function, and pulmonary artery systolic pressure that can occur in the absence of symptoms.

The recommendations for serial monitoring, which vary with the severity of MR, are presented separately. (See "Chronic primary mitral regurgitation: General management", section on 'Monitoring'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Mitral regurgitation (The Basics)")

●Beyond the Basics topic (see "Patient education: Mitral regurgitation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Etiology

•Primary mitral regurgitation – Causes of primary (organic) mitral regurgitation (MR) include degenerative mitral valve prolapse, rheumatic heart disease, infective endocarditis, trauma, certain drugs, cleft mitral valve, and mitral annular calcification. (See 'Etiology' above.)

•Secondary mitral regurgitation – Causes of secondary (functional) MR include coronary heart disease and cardiomyopathies (eg, dilated or hypertrophic cardiomyopathy). Ischemic MR primarily occurs in patients with a prior myocardial infarction. The MR may become more severe with adverse ventricular remodeling and may acutely worsen with ischemia or changes in hemodynamic conditions. (See 'Etiology' above.)

●Symptoms – Many patients with severe MR are initially asymptomatic. When symptoms develop, they include exertional dyspnea and fatigue. Another common clinical presentation is paroxysmal or persistent atrial fibrillation. (See 'Clinical manifestations' above.)

●Physical examination – In patients with chronic MR, the arterial pulse is usually brisk and the apical impulse is usually hyperdynamic. The murmur of MR is usually holosystolic and blowing in quality.

●Diagnosis – Echocardiography is essential for diagnosing MR and establishing its severity, etiology, and hemodynamic consequences. (See 'Approach to diagnosis' above.)

●Identifying severe MR – Echocardiographic criteria for severe MR include a regurgitant fraction ≥50 percent, an effective regurgitant orifice (ERO) area ≥0.40 cm² and a regurgitant volume ≥60 mL (table 3A and table 3B). (See 'Identifying the severity of MR' above.)

●Identifying the cause – If the cause of MR cannot be identified by transthoracic echocardiography, the cause can generally be determined by transesophageal echocardiography. Three-dimensional echocardiography may be particularly beneficial for defining valve morphology. (See 'Identifying the cause of MR' above.)

●Other diagnostic testing

•CMR – Cardiovascular magnetic resonance (CMR) is not recommended for routine diagnosis of MR. When echocardiographic measures of MR severity or left ventricular function are inadequate, or when there is a discrepancy between clinical findings and echocardiography, CMR assessment of MR severity may be helpful, especially in situations in which the echocardiographic findings and patient symptoms are discordant. (See 'Cardiovascular magnetic resonance' above.)

•Cardiac catheterization – The major indications for cardiac catheterization in a patient with MR are to assess hemodynamics and severity of MR when noninvasive tests are inconclusive or discordant and for definition of coronary anatomy when patients are being considered for an intervention. (See 'Cardiac catheterization' above.)