Pathophysiology and natural history of chronic mitral regurgitation

INTRODUCTION — Chronic mitral regurgitation (MR) is a relatively common valvular disorder that can progress to ventricular decompensation and the need for mitral valve surgery. The pathophysiology and phases of chronic MR will be reviewed here. The etiology, clinical features, natural history, and overview of management are discussed separately. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation" and "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet" and "Chronic primary mitral regurgitation: General management".)

PATHOPHYSIOLOGY

Causes and mechanisms — Mitral regurgitation (MR) may be due to a primary abnormality (sometimes referred to as organic MR) of one or more of the four components of the valve apparatus (leaflets, chordae tendineae, papillary muscles, and annulus) or the MR may be secondary (often referred to as functional MR) to left ventricular (LV) dilation and dysfunction (such as coronary heart disease or a cardiomyopathy) (table 1). In the developed world, the most common etiologies of MR are degenerative disease with mitral valve prolapse (a primary cause) and coronary heart disease (a secondary cause).

Primary MR — Several disease processes cause abnormalities of the mitral valve complex leading to primary MR.

●Degenerative mitral valve disease (mitral valve prolapse, partial flail, and flail leaflet) includes a range of disorders 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. (See "Mitral valve prolapse: Clinical manifestations and diagnosis", section on 'Pathophysiology'.)

In mitral valve prolapse, what appears to be excessive mitral leaflet tissue and excessive surface area leads to redundancy, folding, and hooding affecting one or more segments of one or both leaflets. Chordae are elongated and may eventually rupture, and the annulus is typically dilated and frequently disjuncted from its normal myocardial support. The alterations yield inadequate apposition of the rough zones of the mitral leaflets so they no longer support each other during systole and fall into the left atrium. (See "Mitral valve prolapse: Clinical manifestations and diagnosis", section on 'Pathophysiology'.)

●Among patients with acute rheumatic carditis, the intensity and time course of the inflammatory process may impact the course of mitral valve disease. Severe inflammation of the chordal structures and mitral valve leaflets can lead to isolated MR, seen predominantly in children and young adults. Moderate chordal and leaflet inflammation, which may be exacerbated by repeated acute rheumatic carditis, may lead to mixed MR and mitral stenosis. Chronic chordal and leaflet inflammation may be exacerbated by repeated acute rheumatic carditis, which may lead to mitral stenosis (algorithm 1). (See "Clinical manifestations and diagnosis of rheumatic heart disease", section on 'Clinical manifestations'.)

●Infective endocarditis can cause valve deformity, vegetations, and/or chordal rupture that results in MR. In addition, patients with pre-existing valve disease (eg, mitral valve prolapse or rheumatic valve disease) are at increased risk for developing infective endocarditis. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Complications and outcome of infective endocarditis".)

●Congenital causes of MR include cleft mitral valve, which may be isolated or associated with other anomalies. MR is a common complication following atrioventricular canal defect repair, particularly in patients with preoperative MR. (See "Management and outcome of atrioventricular (AV) canal defects", section on 'Mitral valve regurgitation'.)

●Use of certain drugs, such as ergotamine, bromocriptine, pergolide, and cabergoline, as well as some anorectic drugs that are no longer available, such as fenfluramine and benfluorex, has been reported to induce MR, although the evidence for cause-effect relationship between exposure to these drugs and mitral valve disease remains weak [1-3]. (See "Valvular heart disease induced by drugs".)

●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. The prevalence of mitral annular calcification increases with age. Also, there typically are mild calcific changes of the valve leaflets associated with aging [4]. (See "Clinical manifestations and diagnosis of mitral annular calcification".)

Flail leaflet — A subset of patients with primary MR have a flail or partial flail mitral leaflet. In contrast to prolapse, where the leaflet tip remains attached to the papillary muscle with the tip pointing towards the LV apex, flail is defined as the loss of the normal leaflet attachment to the LV myocardium so that the leaflet tip points toward the roof of the left atrium. The leaflet is considered flail when most of the anterior or posterior leaflet is detached from the papillary muscle; a partial flail involves only one scallop or smaller segment of the leaflet. The flail leaflet is generally associated with severe MR. By contrast, a partial flail leaflet may exhibit wide variations in severity.

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. With papillary muscle rupture, the detached papillary muscle head remains attached to the leaflet, moving into the left atrium in systole. Acute flail leaflet can cause acute hemodynamic decompensation while partial flail may cause subacute symptoms or no early symptoms but chronic risk of adverse cardiac events including heart failure and death. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet".)

Secondary MR — Secondary (also known as functional) causes of MR include:

●Coronary heart disease – Most studies of ischemic MR have focused on chronic postinfarction MR rather than acute MR in the setting of acute myocardial infarction (MI) or reversible MR caused by acute ischemia. Thus, the term "ischemic MR" is used primarily to indicate chronic postinfarction MR. MR caused by coronary artery disease can be classified by the mechanism of the valve dysfunction [5,6]:

•The vast majority of patients with ischemic MR have secondary MR post-MI. Thus, better terms for this condition might be "postinfarction" MR or MR secondary to coronary heart disease. Regional and/or global LV systolic dysfunction and adverse LV remodeling cause restricted leaflet motion and failure of leaflet coaptation [7].

•MR secondary to papillary muscle rupture is a life-threatening complication of acute MI (picture 1). (See "Acute myocardial infarction: Mechanical complications".)

•The papillary muscle may be infarcted with acute MI, but not uniformly ruptured.

•Reversible ischemic MR can be caused by acute myocardial ischemia (eg, acute coronary syndrome or exercise-induced ischemia) [8-10].

●Dilated (nonischemic) cardiomyopathy.

●Hypertrophic cardiomyopathy. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)

●Right ventricular pacing (particularly apical pacing) creates LV asynchrony, which can cause worsening or de novo secondary MR [11,12].

Secondary MR results from a combination of the following processes [7,13-16]:

●Tethering or tenting of mitral leaflets caused by papillary muscle displacement, regional and/or global LV remodeling, and mitral annular dilation.

●Impaired closing as a result of impaired LV contractility, LV dyssynchrony, papillary muscle dyssynchrony, and/or reduced mitral annular contraction.

●Annular enlargement secondary to LV dilatation and remodeling with papillary muscle displacement.

Thus, in secondary MR, the mechanism is largely ventricular rather than valvular, though some compensatory valve changes such as mitral leaflet enlargement have been described [17]. LV systolic dysfunction can contribute to secondary MR, but the severity of the MR correlates weakly with the LV ejection fraction [16]. This may be because a regurgitant volume that meets criteria for severe MR cannot be attained when the LV ejection fraction and total stroke volume are depressed.

The term "papillary muscle dysfunction" was previously used in the literature to describe patients with ischemic MR, but this is a misnomer since papillary muscle dysfunction does not adequately explain the mechanism of this disorder [7,13,18]. The mechanism for MR in this setting may be better described as "papillary muscle displacement" due to dysfunction of adjacent or underlying LV wall and associated alteration of ventricular geometry, as was illustrated by an animal model of ischemic MR [19]. In an echocardiographic study of 95 patients with a first inferior MI, advanced wall motion abnormality of the posterobasal segment of the LV was the most significant independent variable associated with ischemic MR [20].

Echocardiographic studies of functional MR have shown that regurgitant flow varies throughout systole: There is an early systolic peak, a midsystolic decrease, and a smaller late systolic peak [21,22]. In one series, the respective values for regurgitant flow rate at these three time periods were 144, 13, and 62 mL/sec [22]. These variations occur in association with changes in regurgitant orifice area and are said to be more closely associated with changes in transmitral pressure gradient than with mitral annular area [21]. The ratio of flow at the two peaks also correlates with QRS duration. Cardiac resynchronization therapy shortens the QRS duration and reduces the early but not the late regurgitant peak [22]. (See "Chronic secondary mitral regurgitation: General management and prognosis", section on 'Pacemaker management'.)

Cardiac response to MR — MR burdens the LV with a volume load that leads to a series of compensatory myocardial and circulatory adjustments [23-25]. These adjustments vary over the prolonged course of the disorder, so that the changes that are operative in acute or subacute MR are eventually replaced by other compensatory mechanisms. Eventually, the myocardium fails, a decompensated clinical phase follows, and the patient exhibits signs and symptoms of heart failure.

Acute MR — There are two major hemodynamic changes with acute MR and LV volume overload:

●The ventricle utilizes its preload reserve and the Frank-Starling mechanism, which contributes to an increase in total stroke volume.

●According to the law of Laplace (figure 1), a reduction in early systolic volume may be associated with a decline in early systolic wall stress (ie, afterload).

Thus, in acute severe MR, an increase in LV preload and, potentially, a decrease in early afterload result in increases in ejection fraction and total stroke volume. The major burden and threat is to the pulmonary venous circulation and the lungs, sometimes leading to pulmonary edema. (See "Hemodynamics of valvular disorders as measured by cardiac catheterization" and "Acute mitral regurgitation in adults", section on 'Pathophysiology'.)

Chronic compensated MR — The major change that occurs during the evolution from acute to chronic MR is an enlargement of the LV (image 1 and movie 1A-G). As this new steady state develops, the relatively small hyperkinetic chamber of acute MR is converted into a large compliant chamber that is well suited to deliver a large total stroke volume. This comes about through a rearrangement of myocardial fibers, with the addition of new sarcomeres and the development of eccentric LV hypertrophy. The net effect is that the changes in LV loading conditions seen in acute MR tend to be reversed.

●Despite additional LV chamber enlargement, preload at the level of the sarcomere does not show a further increase. At this time, sarcomere length tends to return toward baseline, and preload reserve is reestablished [26].

●The systolic unloading that is characteristic of acute MR is gradually replaced by normal or increased systolic wall stresses (afterload) [27].

Thus, the enhanced total stroke volume seen in chronic compensated mitral regurgitation is "mediated through normal performance of each unit of an enlarged circumference" [28]. In other words, LV contractility, loading conditions (sarcomere length and afterload), and ejection fraction remain within the range of normal with the large end-diastolic volume responsible for an enhanced total stroke volume. An enlarged compliant left atrium contributes to a decline in pulmonary venous pressures.

Chronic decompensated MR — In this late phase of chronic MR, there is substantial LV enlargement, eccentric geometry, depressed contractility, and increased afterload with depressed ejection fraction. The low ejection fraction is a consequence of afterload excess and depressed myocardial contractility [25]. The transition from a compensated to decompensated phase is discussed below.

Afterload and MR — MR provides an alternate pathway for LV emptying, and this has traditionally been thought to produce a decrease in LV afterload. While this may be true in acute severe MR, published data suggest that LV afterload is normal in patients with compensated chronic MR and increased in those with chronic decompensated MR. Indeed, afterload has not been found to be reduced in chronic compensated MR.

Definitions — LV afterload can be considered the load or force developed by the ventricle during systole and is best measured as systolic wall stress. Afterload or wall stress and myocardial fiber shortening are inversely related. As a result, an increase in afterload will be accompanied by a decrease in shortening (or ejection fraction), while a decrease in afterload will be accompanied by an increase in shortening (or ejection fraction).

Stress is defined as the force or load per unit cross-sectional area of a material (eg, grams/cm²). This is an engineering term used to compare loads borne by different-sized elements of a material. In a spherical model of the LV, wall stress is directly proportional to transmural LV pressure (P) divided by relative wall thickness (RWT, which is posterior wall thickness [Th] divided by the LV chamber diastolic internal radius [R]) (figure 1).

As a result, if a given hemodynamic load (pressure) is borne by a smaller amount of a material (myocardium), the stress on that material will be greater.

However, this mathematical definition of LV wall stress is overly simplistic since:

●Geometry in the LV is more complex than that represented by a simple sphere. Ellipsoidal or cylindrical models more accurately represent the ventricle.

●Several components of stress exist within the wall of the ventricle. Meridional stresses are directed from apex to base while circumferential or hoop stresses are usually directed circumferentially at the equator.

●Wall stress varies over time since LV pressure, radius, and wall thickness are continuously changing throughout the cardiac cycle. As a result, afterload can be calculated at the instant of aortic valve opening, at the end of ejection, or at any instant throughout systole. Clinical investigators use peak systolic stress, end-systolic stress, or mean systolic stress as indices of afterload.

Afterload in chronic MR — Noninvasive and invasive data indicate that wall stress is normal or increased with chronic MR.

As an example, noninvasive (echocardiographic) measurements of LV volume, mass, and function in one study of patients with chronic MR showed that meridional wall stresses were not reduced [29]. Indeed, peak-systolic stress tended to be increased. End-systolic stress was normal in compensated MR, but was increased significantly in decompensated MR.

Another report confirmed these observations using invasive (cardiac catheterization) hemodynamic and angiographic measurements [30]. Peak-systolic stress was modestly increased in both compensated and decompensated hearts; end-systolic wall stress was especially high in decompensated MR. Others have noted normal to increased systolic stress levels in chronic MR, but have not analyzed separately the data from compensated or decompensated ventricles.

Impedance in chronic MR — The double-outlet ventricle is often described as a condition exhibiting a "low impedance leak" into the left atrium that facilitates emptying and thereby causes an "unloading effect." As discussed above, afterload is not low and the ventricle is not unloaded. Impedance (and resistance) to regurgitant flow in chronic MR exceeds that of forward flow, except in recent onset severe MR (eg, acute severe MR with a regurgitant fraction above 57 percent). Thus, the MR lesion should not be characterized or described as a "low impedance leak." Nevertheless, the total impedance to LV emptying in MR is low [31]. The enlarged double-outlet ventricle with a low total impedance produces a large total stroke volume, while the afterload and ejection fraction remain normal.

Afterload following corrective surgery — Published data do not support the notion that surgical correction of chronic MR uniformly produces a postoperative increase in systolic wall stress [29,30,32]. Increased afterload may contribute to a decline in ejection fraction in patients with decompensated MR, especially if chordal preservation techniques are not employed. In compensated ventricles, however, afterload is not increased with valve replacement or repair, after a period of recovery.

The functional state of the LV before surgery and the nature of the corrective surgery both influence the LV response to surgical correction of the regurgitant lesion. It is therefore useful to discuss these two issues separately in order to dissect-out those factors responsible for changes in afterload postoperatively.

Functional status of the ventricle — Patients with compensated and decompensated MR differ significantly in LV size and function, and in the ventricular response to valve replacement [24,29]. Such differences in the response to surgery can be illustrated in the form of stress-dimension plots (figure 2) and can be summarized as follows:

●Patients with compensated MR generally develop a salutary decrease in LV chamber volumes after corrective valve surgeries, and, as a result, systolic wall stress remains in the normal range.

●Patients with decompensated MR have persistent postoperative LV enlargement and persistence of high systolic wall stress.

The decrease in fiber shortening and ejection fraction in decompensated MR is related in part to a postoperative change in ventricular geometry and an increase in afterload. In contrast, systolic stress does not increase in compensated MR despite closure of the regurgitant leak. As a result, a postoperative fall in ejection fraction in compensated ventricles cannot be ascribed to excess afterload.

Mitral valve replacement versus repair — Mitral valve replacement or repair generally produce similar reductions in LV end-diastolic volume. In one report, for example, peak systolic stress fell and end-systolic stress were unchanged with both procedures [33]. However, differences were observed in their effects on ejection fraction. Valve replacement caused a significant decline in ejection fraction (60±10 versus 48±10 percent, before and after surgery, respectively) while valve repair was associated with little change (64±5 versus 61±16 percent).

The different effects on ejection fraction from the two procedures can be explained by severance of the chordae tendineae with valve replacement and preservation of the subvalvular apparatus with repair. This is illustrated by a study in which ventricular function in patients undergoing valve replacement with chordal preservation was compared with that in patients undergoing valve replacement with chordal transection [34]. Postoperatively, afterload was lower and the ejection fraction was higher in the patients with chordal preservation.

A second retrospective study of 612 patients undergoing mitral valve repair or replacement also reported that preservation of the subvalvular apparatus improved outcome [35]. Mortality at 30 days was lower in the patients undergoing valve repair or replacement with subvalvular apparatus preservation compared with those with replacement without preservation (1.8 and 1.5 versus 5 percent). Overall survival at seven years was also better in the first two groups compared with the last (71 and 66 versus 63 percent). Subvalvular apparatus preservation was an independent predictor for improved outcome. (See "Surgical procedures for severe chronic mitral regurgitation", section on 'Chordal preservation'.)

NATURAL HISTORY

Factors affecting the natural history — An elusive and poorly understood aspect of the pathophysiology of mitral regurgitation (MR) is the nature of the transition from the chronic compensated phase to a decompensated phase. This evolution generally occurs over many years, even decades, depending upon the severity of the regurgitant lesion and the cardiovascular response to the regurgitant volume. The etiology of MR also plays a role in the natural history of this process. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet".)

Phases of MR — Left ventricular (LV) chamber size and function have been used to define compensated, transitional, and decompensated phases in patients with chronic MR (table 2) [36-42]. These phases combined with the patient’s functional state, valve pathology, and hemodynamic data have been used to define stages for the clinical evaluation of MR (table 3 and table 4) and to guide criteria for mitral valve intervention for chronic primary and secondary MR. (See "Chronic primary mitral regurgitation: General management" and "Chronic secondary mitral regurgitation: General management and prognosis".)

●The compensated phase is defined largely on the basis of natural history and other data that indicate a relatively benign prognosis when the end-diastolic dimension is less than 60 mm and the end-systolic dimension is less than 40 mm (as measured by echocardiography).

During this compensated phase of MR, most patients remain asymptomatic, rhythm disturbances are uncommon, and corrective surgery is generally postponed. Although these patients appear to be asymptomatic, some have impaired functional capacity and reduced exercise tolerance. The degree of functional impairment is, however, an unreliable guide to disease severity or LV dysfunction. In some such patients, physical deconditioning contributes to functional impairment.

●The natural history of the transitional period is not precisely defined, but most published data indicate that a good clinical result can be achieved if surgery is performed before the patient enters the decompensated phase.

●The decompensated phase is based upon observational data indicating risk for a poor or suboptimal clinical result after valve intervention. These markers include LV end-diastolic dimension greater than 70 mm, LV end-systolic dimension greater than 45 to 47 mm, or an LV ejection fraction less than 50 percent.

While these considerations do not identify the optimal time for mitral valve replacement or repair, they do enable the clinician to predict a poor LV response to corrective surgery and, in this fashion, provide a picture of the options of surgical or nonsurgical treatment. In principle, corrective surgery should be performed prior to or during the transition from a compensated to decompensated phase of the disease (ie, before the decompensated phase is established). (See "Chronic secondary mitral regurgitation: Intervention", section on 'Concurrent mitral valve surgery and CABG'.)

Early identification of progression avoids the development of irreversible changes in LV structure and function that may preclude an optimal response to corrective surgery. Patients with chronic MR and LV dysfunction are at very high risk of a suboptimal postoperative result. Many of these patients exhibit characteristics of a dilated cardiomyopathy with increased LV afterload and depressed myocardial contractility [25].

The best natural history data that are available come from studies of patients with mitral valve prolapse and flail mitral valve leaflet. It is generally assumed that these findings may be applied to MR of other causes. (See "Natural history of chronic mitral regurgitation caused by mitral valve prolapse and flail mitral leaflet".)

Transition to heart failure — An elusive and poorly understood aspect of the pathophysiology of MR is the nature of the transition from the compensated to a decompensated phase. Such a change may occur as a consequence of progressive increments in the regurgitant volume and/or an increase in LV chamber size. The decompensated phase is characterized by substantial and progressive ventricular enlargement with increased LV diastolic pressures, increased systolic wall stress, and a decline in the ejection fraction; the fall in ejection fraction is a consequence of a depressed contractile state and excessive afterload. These changes in LV size and function are often accompanied by progressive atrial enlargement, atrial arrhythmias, pulmonary hypertension, and eventually the signs and symptoms of heart failure.

Some patients experience fatigue, limited exercise tolerance, or even dyspnea during this transition. In such patients, the decision to proceed with surgery or other intervention is relatively easy, and the results are generally good, but the adverse ventricular remodeling may not be reversible. Other patients, however, may proceed through the transition period and show evidence of LV dysfunction with minimal or no symptoms. Such patients have reached a decompensated phase in which LV and left atrial dysfunction become irreversible and it may be too late to expect an optimal result from corrective surgery.

If an optimal response to surgery is the goal, it is important to identify such a patient before the development of irreversible changes in LV size and function. This can be achieved by considering the markers of a decompensated ventricle and developing guidelines for the identification of patients who are entering the period of transition from compensated to decompensated MR.

Markers of a decompensated ventricle — Echocardiographic and angiographic indices of LV size and function play a critical role in the definition of a decompensated ventricle. (See "Echocardiographic evaluation of the mitral valve" and "Transesophageal echocardiography in the evaluation of mitral valve disease".) The decompensated phase as defined herein, is not based upon semiquantitative estimation of the severity of regurgitation obtained from cine angiography or Doppler echocardiography. Rather, it is described in terms of LV structure, geometry, and function.

Clinical investigators have studied the temporal changes in LV size and function before and after mitral valve replacement in patients with chronic MR [36,37]. Approximately 75 percent of the reported patients exhibited a postoperative decline in LV chamber size and a significant regression of LV hypertrophy; the remaining patients had persistent postoperative LV enlargement and systolic dysfunction.

These two groups had distinctly different preoperative indices of LV size and function. In particular, the patients with a suboptimal ventricular response to valve replacement could be identified by the following preoperative echocardiographic parameters:

●LV end-diastolic dimension exceeding 70 mm

●LV end-systolic dimension exceeding 45 mm

●A depressed LV ejection fraction

The prognostic importance of an end-systolic diameter above 45 to 47 mm has been confirmed in a later study [38]. This echocardiographic dimension translates into an end-systolic volume of approximately 50 mL/m², which is in agreement with the angiographic data in other reports (table 2) [39-41].

Exercise echocardiography has been used to predict LV function after mitral valve repair [43]. Patients with a postoperative ejection fraction below 50 percent were compared with those with higher values. The patients with a postoperative ejection fraction below 50 percent had significantly lower preoperative ejection fractions (57 versus 73 percent, p<0.0005), larger exercise end-systolic volume index (32 versus 18 cm³/m², p<0.0005), and a smaller change in ejection fraction with exercise (-4 versus 9 percent). An exercise end-systolic volume index above 25 cm³/m² was the best predictor of postoperative LV dysfunction (sensitivity and specificity of 83 percent).

Patients who exhibit one or more of these markers of a decompensated ventricle are at high risk of persistent postoperative LV enlargement, depressed postoperative ventricular function, and a poor or suboptimal clinical result. While these considerations do not identify the optimal time for mitral valve replacement or repair, they do enable the clinician to predict a poor LV response to corrective surgery and, in this fashion, provide a picture of the options of surgical or nonsurgical treatment [44]. The compensated phase of chronic MR is defined largely on the basis of natural history and other data that indicate a benign prognosis when the end-diastolic dimension is less than 60 mm and the end-systolic dimension is less than 40 mm [45].

Recognizing that these phases of LV structure and function and their prognostic implications have not been statistically validated in a prospective fashion, they should be used only as general guidelines in a decision analysis that includes other clinical data, including patient preferences (table 2).

SUMMARY

●Mitral regurgitation (MR) is caused by either a primary abnormality of one or more components of the valve apparatus (leaflets, chordae tendineae, papillary muscles, and/or annulus) or is secondary (often referred to as functional MR) to left ventricular (LV) dysfunction (such as coronary heart disease or a cardiomyopathy) (table 1). In the developed world, the most common etiologies of MR are degenerative mitral valve disease (a primary cause) and coronary heart disease (a secondary cause). (See 'Causes and mechanisms' above.)

●MR burdens the LV with an excessive volume load that leads to a series of compensatory myocardial and circulatory adjustments. These compensatory adjustments vary over the prolonged course of the disorder. In severe MR, the myocardium eventually fails, the ventricle decompensates, and the patient exhibits signs of heart failure. (See 'Cardiac response to MR' above.)

●Normal LV systolic wall stress occurs in chronic MR because of opposing effects of LV dilation and hypertrophy (with maintenance of a normal ratio of thickness to radius). Increased wall stress is seen when LV dilation is not accompanied by adequate hypertrophy (with decreased ratio of wall thickness to radius). (See 'Afterload in chronic MR' above.)

●After corrective surgery or other intervention, increased afterload may contribute to a decline in ejection fraction in patients with decompensated MR, especially if chordal preservation techniques are not employed. In compensated ventricles, however, afterload does not increase postoperatively with valve repair or replacement with chordal preservation. (See 'Afterload following corrective surgery' above.)

●LV chamber size and function have been used to define compensated, transitional, and decompensated phases in patients with chronic MR (table 2) [36-42]. These concepts have been incorporated in the stages that are used for the clinical description of MR (table 3 and table 4) and to guide management of patients with chronic primary and secondary MR. (See 'Phases of MR' above and "Chronic primary mitral regurgitation: General management" and "Chronic secondary mitral regurgitation: General management and prognosis".)

●The major change that occurs during the evolution from acute to chronic MR is an enlargement of the LV. In chronic compensated MR, LV contractility, loading conditions, and ejection fraction remain within the normal range with the large end-diastolic volume being responsible for the enhanced total stroke volume. An enlarged compliant left atrium contributes to the prevention of severe pulmonary venous hypertension. During this compensated phase of chronic MR, most patients remain asymptomatic. (See 'Chronic compensated MR' above.)

●Since patients may or may not experience symptoms during the transition from compensated to decompensated chronic MR, monitoring for evidence of decompensation, including periodic measurement of LV size and systolic function by echocardiography, is required. (See 'Transition to heart failure' above and "Chronic primary mitral regurgitation: General management", section on 'Monitoring' and "Chronic secondary mitral regurgitation: General management and prognosis", section on 'Evaluation and monitoring'.)

●Patients who exhibit one or more markers of a decompensated ventricle are at high risk of persistent postoperative LV enlargement, depressed postoperative ventricular function, and a poor or suboptimal clinical result. (See 'Markers of a decompensated ventricle' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William H Gaasch, MD (deceased), who contributed to an earlier version of this topic review.