Chronic mitral regurgitation caused by anatomic abnormalities of the mitral leaflets can be caused by myxomatous degeneration, rheumatic disease, infective endocarditis, connective tissue diseases, congenital disease, or annular calcification (Table 21.1). Myxomatous degeneration of the mitral valve occurs in the setting of mitral valve prolapse syndrome (also known as Barlow syndrome), in which redundant leaflet tissue and elongation of chordae tendineae are associated with premature valve degeneration and chordal rupture. In mitral valve prolapse syndrome, mitral regurgitation can be caused by complete or partial leaflet flail or by pathologic prolapse without flail. The mitral valve is the most commonly affected valve in rheumatic heart disease, with thickening and sclerosis of leaflet and subvalvular tissue, resulting in stenosis, regurgitation, or both. Mitral regurgitation caused by infective endocarditis can occur because of direct interference of a vegetation with leaflet coaptation or, more commonly, because of tissue destruction with leaflet erosion or perforation, or with chordal rupture and complete or partial leaflet flail.

Connective tissue diseases associated with mitral regurgitation include systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, and scleroderma. Valvular involvement in connective tissue diseases is variable, but about half of patients with systemic lupus erythematosus have some mitral regurgitation, and approximately one fourth have significant regurgitation. Congenitally cleft anterior leaflet usually occurs as part of an endocardial cushion defect, with accompanying primum atrial septal defect, paramembranous ventricular septal defect, and abnormalities of the tricuspid valve. Finally, mitral annular calcification is common among elderly patients as well as among patients with diseases associated with dystrophic calcification, such as end-stage renal insufficiency. Although mitral regurgitation is commonly seen in association with mitral annular calcification, it
is not usually severe. Although mitral regurgitation has been described in association with anorectic drug use, this association is not supported by case-controlled studies.

Functional mitral regurgitation is caused by alteration of left ventricular size or geometry or, less commonly, alteration of mitral annular geometry that results in restriction of mitral leaflet motion and incomplete mitral leaflet coaptation. As such, significant functional mitral regurgitation occurs in the setting of normal or nearly normal leaflet anatomy. Functional mitral regurgitation can occur in the setting of nonischemic or ischemic cardiomyopathy. In addition, alteration of left ventricular geometry caused by relatively small inferior or posterolateral myocardial infarction can result in restrictive mitral leaflet motion with incomplete leaflet coaptation and significant regurgitation.

Ischemic mitral regurgitation is mitral regurgitation that results from underlying coronary artery disease. Ischemic mitral regurgitation can be caused by mechanical disruption of the mitral apparatus, such as papillary muscle rupture complicating acute myocardial infarction. More commonly, ischemic mitral regurgitation is functional mitral regurgitation that occurs in the setting of coronary artery disease. Specifically, most ischemic mitral regurgitation is caused by prior myocardial infarction with unfavorable left ventricular remodeling or left ventricular dilation that causes incomplete mitral leaflet coaptation. Ischemic mitral regurgitation can be dynamic, most often as a function of varying left ventricular loading conditions with dynamic changes in left ventricular size and geometry. In addition, transient ischemia involving a papillary muscle and an adjacent region of the left ventricle also may be able to cause dynamic mitral regurgitation.

Finally, mitral regurgitation can occur as a result of mechanical or bioprosthetic valve dysfunction. Mild transvalvular regurgitation is normal and an anticipated finding with many mechanical prostheses, as well as with some constructed pericardial bioprostheses. In addition, small amounts of paraprosthetic regurgitation are common with any mitral valve prosthesis. Larger paravalvular leaks can cause significant regurgitation, which is of potential clinical importance either because of hemodynamic significance or because of the severity of associated hemolysis. Pathologic transvalvular prosthetic regurgitation can occur in association with either mechanical or tissue prostheses. Significant valvular regurgitation with a mechanical valve is suggestive of entrapment or dysfunction of the occluder; significant regurgitation in association with a bioprosthesis is suggestive of leaflet fracture.

Acute severe mitral regurgitation is caused by infective endocarditis, myxomatous disease with chordal rupture, acute myocardial infarction with either papillary muscle rupture or infarct expansion and leaflet restriction, or prosthetic valve dysfunction.

Mitral regurgitation results in left ventricular volume overload with ejection of left
ventricular volume into both the highimpedance aorta and the compliant, lowimpedance left atrium. In chronic mitral regurgitation, left atrial dilation maintains low left atrial and pulmonary venous pressures. Compensatory left ventricular dilation results in increases in left ventricular end-diastolic volume, ejection fraction, and stroke volume, thereby maintaining forward cardiac output (2). Patients typically remain asymptomatic during this phase of compensated mitral regurgitation, which may last for years. Prolonged left ventricular volume overload eventually leads to left ventricular systolic dysfunction and pulmonary congestion, with an increase in left ventricular end-systolic volume and decreases in ejection fraction and forward cardiac output. Because left ventricular emptying does not rely on overcoming high aortic pressure, left ventricular stroke volume remains elevated, and ejection fraction remains within the normal range despite progressive left ventricular systolic dysfunction (3,4,5,6). Late in the course of disease, the left ventricular ejection fraction decreases to less than normal. At some time during the course of chronic severe mitral regurgitation, symptoms of fatigue and exertional dyspnea develop, followed by more overt symptoms of congestive heart failure. However, symptoms are typically insidious in onset, and patients often fail to recognize the gradual fatigue and subtle exercise limitations associated with chronic severe mitral regurgitation.

In acute severe mitral regurgitation, limited left atrial distensibility results in an acute increase in left atrial and pulmonary venous pressures with resulting pulmonary edema. Although increased preload associated with acute severe mitral regurgitation results in a modest increase in total left ventricular stroke volume (5), the absence of compensatory left ventricular dilation results in reduced forward stroke volume. Compensatory tachycardia is typically insufficient to maintain forward cardiac output. In this setting, patients with acute severe mitral regurgitation are almost always symptomatic, with fulminant symptoms of pulmonary edema.

Physical examination of patients with chronic severe mitral regurgitation may reveal a hyperactive precordium and lateral displacement of the left ventricular apical impulse because of ventricular enlargement. A late systolic left parasternal lift caused by left atrial expansion may be present; this, in conjunction with an apical heave, results in a rocking motion of the precordium. An apical systolic thrill may be evident. The first heart sound is usually normal, although it may be encompassed by the systolic murmur and difficult to appreciate. An S₃ is often present because of the large regurgitant volume reentering the left ventricle across a fixed mitral orifice, and is not necessarily indicative of ventricular failure. The classic murmur of mitral regurgitation is a loud, blowing holosystolic murmur that may obliterate S₁ and S₂. The murmur is usually loudest at the apex with radiation to the axilla or the back, although it is often audible throughout the precordium. Mitral regurgitation caused by leaflet flail is usually eccentric, and the murmur associated with posterior leaflet flail radiates anteriorly to the left sternal border. Because of the proximity of the ascending aorta immediately anterior to the roof of the left atrium, the murmur of an anteriorly directed mitral regurgitation jet can be transmitted to the carotid arteries. The large volume of blood crossing the mitral valve in diastole causes turbulent flow in patients with severe regurgitation, sometimes causing a diastolic rumble, despite the absence of mitral stenosis. In contrast, the systolic murmur in patients with acute severe mitral regurgitation may be decrescendo rather than holosystolic, because of early equilibration of left atrial and left ventricular pressures. In acute severe mitral regurgitation, the apical left ventricular impulse is not displaced, and an S₃ and S₄ are common.

Mitral valve prolapse syndrome can occur without associated mitral regurgitation, although progression of mitral regurgitation is common over the course of the disease.
Patients with mitral valve prolapse syndrome may have symptoms of palpitations or atypical chest pain (7,8). Physical examination reveals a characteristic midsystolic nonejection click that moves later in systole with maneuvers that increase left ventricular preload, such as squatting. In patients with mitral valve prolapse without leaflet flail, mitral regurgitation, if present, occurs late in systole, and the accompanying murmur occurs only in the portion of systole after the midsystolic click.