Dynamic Mitral Regurgitation — More Than Meets the Eye
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《新英格兰医药杂志》
Recollections of early medical training conjure up images of the master clinician standing beside the exercising patient, keenly observing the effects of disease. Exercise stress testing is a cornerstone of the evaluation of dynamic coronary insufficiency, providing diagnosis and prognosis. Valvular heart disease, in contrast, has been considered relatively static and has been managed largely on the basis of resting evaluation. Current clinical guidelines indicate that there is conflicting evidence regarding exercise testing in valvular disease and that no efficacy has been established; advocates suggest exploring the dynamics of the ventricle, not the valve.
Ischemic mitral regurgitation consequent to myocardial infarction, however, is characteristically dynamic and sensitive to changes in ventricular size, shape, and loading that restrict closure of the mitral leaflet. In this issue of the Journal, Piérard and Lancellotti1 make that point in a new way by showing that patients who present with acute pulmonary edema subsequently have large exercise-induced increases in mitral regurgitation and related pulmonary pressures. The authors have associated this exercise physiology with an adverse prognosis. Exercise can therefore unmask the true severity of what might otherwise be considered a mild lesion.
Pulmonary edema has three basic causes: increased alveolar-capillary permeability, decreased alveolar pressure, and increased pulmonary-capillary pressure (with or without increased interstitial oncotic pressure). In cardiogenic pulmonary edema, the pulmonary venous vasculature acts like a manometer on the left heart and is subjected to the cumulative load of elevated filling pressures.
Acute cardiogenic pulmonary edema results from acute perturbations superimposed on chronic heart disease or from acute events that overwhelm normal compensatory mechanisms and lead to the transmission of pressure back to the lungs, which then leads to the transudation of fluid into the air spaces. Broadly, the mechanisms of acute pulmonary edema involve limited inflow, limited outflow, and backward flow. The stage may be set by conditions that require increased pressures to fill the left heart, including mitral stenosis and diseases that thicken or stiffen the left ventricle, such as hypertension, aortic stenosis, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Under those circumstances, normal adaptations may not withstand acutely increased filling pressures caused by superimposed volume overload (such as occurs in sepsis, transfusion, and pregnancy), pressure overload, or arrhythmias that limit diastolic filling time.
Hypertensive crises acutely limit cardiac filling and emptying. Global ischemia, fulminant myocarditis, and toxins (e.g., scorpion venom) rapidly reduce global systolic function; segmental infarctions may stiffen the ventricle or cause volume overload due to septal defects. Valvular catastrophes include acute severe aortic insufficiency or mitral regurgitation resulting from chordal or papillary-muscle rupture and dramatic malfunction of prosthetic valves. Recurrent "flash" pulmonary edema reflects intermittent inferior-wall ischemia, with mitral regurgitation transmitted to the lungs by means of a noncompliant left atrium.
We must now consider a new mechanism for acute pulmonary edema: dynamic exacerbation of chronic ischemic mitral regurgitation. Piérard and Lancellotti identified patients with established left ventricular systolic dysfunction who were admitted with acute pulmonary edema without evidence of acute ischemia or arrhythmia. A comparison group matched for baseline function and mitral regurgitant volume did not have this acute presentation. During semisupine bicycle exercise, the mitral regurgitant volume in the patients who had presented with acute pulmonary edema doubled, from mild to moderate-to-severe, with parallel increases in pulmonary pressures and exercise-limiting dyspnea. Evaluation of mitral regurgitation at rest, therefore, did not reveal the full effect of inducible increases that could rapidly congest the lungs. The authors also describe pulmonary edema that developed prospectively in a population that included patients with exercise-increased mitral regurgitation.
The mechanism of ischemic mitral regurgitation explains its dynamics. In systole, the mitral leaflets normally close level with their annular insertions; chordal attachments to the papillary muscles prevent leaflet prolapse (Figure 1). In ischemic mitral regurgitation, the leaflet attachments are displaced. The annulus may dilate, and the inferoposterior wall bulges outward, displacing the attached papillary muscles apically and outward.2 The leaflets, tethered at both ends, cannot close effectively and are restrained within the left ventricle; this effect is compounded by a decrease in the ventricular force available to close the leaflets. Ischemic mitral regurgitation, therefore, depends on a balance of forces and left ventricular geometry and will vary in accordance with loading conditions. It is notoriously elusive in the operating room, where pharmacologically reduced tethering obscures mitral regurgitation just when repair is being considered.
Figure 1. Mitral Regurgitation.
A normal mitral valve is shown in Panel A. Ischemic mitral regurgitation, in which the leaflets cannot close effectively, is shown in Panel B. The orientation of the illustration is typical of ultrasound imaging.
Tethering of the mitral leaflets tents the leaflets toward the left ventricular apex. Piérard and Lancellotti show that tenting increases with exercise-induced mitral regurgitation, confirming its mechanism. Exercise-induced mitral regurgitation is also responsible for limiting exercise capacity in patients with chronic heart failure.
The dynamics of tethering also have therapeutic implications. Standard annular reduction alone may not relieve ischemic mitral regurgitation, because it addresses only the annular, not the ventricular, aspect of the tethering problem. The remodeling of the left ventricle also presents a moving target, since mitral regurgitation often recurs as tethering increases. More comprehensive approaches are being explored that reduce tethering through localized left ventricular reshaping, chordal modification, ventricular resynchronization, and medical decompression.3,4
Recent studies of acute pulmonary edema have emphasized diastolic dysfunction as the predominant mechanism in hypertensive patients. Yet in 1991, Stone and colleagues reported moderate-to-severe mitral regurgitation in two thirds of patients with acute pulmonary edema (acute myocardial infarction evolved in 40 percent of their group).5 Clearly, population differences (hypertensive hypertrophy vs. ischemic deformity) affect the mechanism. The study by Piérard and Lancellotti suggests that the pendulum is swinging back toward the recognition that mitral regurgitation, along with diastolic stiffness, determines pulmonary hypertension in left ventricular dysfunction.6
In a broader perspective, this study suggests a greater role for exercise testing in patients with valvular disease. Most valve disease varies dynamically depending on annular size and the volume-dependent compliance of the chambers. Nelson Schiller, Ehud Schwammenthal, Jae-Kwan Song, Jean-Louis Vanoverschelde, Thomas Marwick, Brian Griffin, Jean Dumesnil, Philippe Pibarot, and others have emphasized that exercise provides fuller appreciation of lesions and patient adaptation. The master clinician of the early days of medical training now is able to assess dyspnea and fatigue in the context of forward output, retrograde flow, and pulmonary pressures.
The data presented by Piérard and Lancellotti have two practical messages. Acute pulmonary edema can be caused by acute exacerbations of ischemic mitral regurgitation without obvious coronary insufficiency. More generally, perhaps we can understand why "mild" ischemic mitral regurgitation is consistently associated with an adverse prognosis and why some patients have exertional dyspnea out of proportion to the degree of resting dysfunction or mitral regurgitation. Furthermore, dynamic testing can avert the complacency that may result from the appearance of mild mitral regurgitation at rest.
Dr. Levine reports having received grant support from Guidant. Dr. Levine is one of the inventors of U.S. patents 6,544,181, entitled "Method and apparatus for measuring volume flow and area for a dynamic orifice," held by Massachusetts General Hospital, and 6,695,768, entitled "Adjustable periventricular ring/ring like device/method for control of ischemic mitral regurgitation and congestive heart disease." No commercial products are derived from these patents.
Source Information
From the Division of Cardiology, Massachusetts General Hospital, Boston.
References
Piérard LA, Lancellotti P. The role of ischemic mitral regurgitation in the pathogenesis of acute pulmonary edema. N Engl J Med 2004;351:1627-1634.
Otsuji Y, Handschumacher MD, Schwammenthal E, et al. Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation 1997;96:1999-2008.
Hung J, Guerrero JL, Handschumacher MD, Supple G, Sullivan S, Levine RA. Reverse ventricular remodeling reduces ischemic mitral regurgitation: echo-guided device application in the beating heart. Circulation 2002;106:2594-2600.
Messas E, Guerrero JL, Handschumacher MD, et al. Chordal cutting: a new therapeutic approach for ischemic mitral regurgitation. Circulation 2001;104:1958-1963.
Stone GW, Griffin B, Shah PK, et al. Prevalence of unsuspected mitral regurgitation and left ventricular diastolic dysfunction in patients with coronary artery disease and acute pulmonary edema associated with normal or depressed left ventricular systolic function. Am J Cardiol 1991;67:37-41.
Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol 1997;29:153-159.(Robert A. Levine, M.D.)
Ischemic mitral regurgitation consequent to myocardial infarction, however, is characteristically dynamic and sensitive to changes in ventricular size, shape, and loading that restrict closure of the mitral leaflet. In this issue of the Journal, Piérard and Lancellotti1 make that point in a new way by showing that patients who present with acute pulmonary edema subsequently have large exercise-induced increases in mitral regurgitation and related pulmonary pressures. The authors have associated this exercise physiology with an adverse prognosis. Exercise can therefore unmask the true severity of what might otherwise be considered a mild lesion.
Pulmonary edema has three basic causes: increased alveolar-capillary permeability, decreased alveolar pressure, and increased pulmonary-capillary pressure (with or without increased interstitial oncotic pressure). In cardiogenic pulmonary edema, the pulmonary venous vasculature acts like a manometer on the left heart and is subjected to the cumulative load of elevated filling pressures.
Acute cardiogenic pulmonary edema results from acute perturbations superimposed on chronic heart disease or from acute events that overwhelm normal compensatory mechanisms and lead to the transmission of pressure back to the lungs, which then leads to the transudation of fluid into the air spaces. Broadly, the mechanisms of acute pulmonary edema involve limited inflow, limited outflow, and backward flow. The stage may be set by conditions that require increased pressures to fill the left heart, including mitral stenosis and diseases that thicken or stiffen the left ventricle, such as hypertension, aortic stenosis, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Under those circumstances, normal adaptations may not withstand acutely increased filling pressures caused by superimposed volume overload (such as occurs in sepsis, transfusion, and pregnancy), pressure overload, or arrhythmias that limit diastolic filling time.
Hypertensive crises acutely limit cardiac filling and emptying. Global ischemia, fulminant myocarditis, and toxins (e.g., scorpion venom) rapidly reduce global systolic function; segmental infarctions may stiffen the ventricle or cause volume overload due to septal defects. Valvular catastrophes include acute severe aortic insufficiency or mitral regurgitation resulting from chordal or papillary-muscle rupture and dramatic malfunction of prosthetic valves. Recurrent "flash" pulmonary edema reflects intermittent inferior-wall ischemia, with mitral regurgitation transmitted to the lungs by means of a noncompliant left atrium.
We must now consider a new mechanism for acute pulmonary edema: dynamic exacerbation of chronic ischemic mitral regurgitation. Piérard and Lancellotti identified patients with established left ventricular systolic dysfunction who were admitted with acute pulmonary edema without evidence of acute ischemia or arrhythmia. A comparison group matched for baseline function and mitral regurgitant volume did not have this acute presentation. During semisupine bicycle exercise, the mitral regurgitant volume in the patients who had presented with acute pulmonary edema doubled, from mild to moderate-to-severe, with parallel increases in pulmonary pressures and exercise-limiting dyspnea. Evaluation of mitral regurgitation at rest, therefore, did not reveal the full effect of inducible increases that could rapidly congest the lungs. The authors also describe pulmonary edema that developed prospectively in a population that included patients with exercise-increased mitral regurgitation.
The mechanism of ischemic mitral regurgitation explains its dynamics. In systole, the mitral leaflets normally close level with their annular insertions; chordal attachments to the papillary muscles prevent leaflet prolapse (Figure 1). In ischemic mitral regurgitation, the leaflet attachments are displaced. The annulus may dilate, and the inferoposterior wall bulges outward, displacing the attached papillary muscles apically and outward.2 The leaflets, tethered at both ends, cannot close effectively and are restrained within the left ventricle; this effect is compounded by a decrease in the ventricular force available to close the leaflets. Ischemic mitral regurgitation, therefore, depends on a balance of forces and left ventricular geometry and will vary in accordance with loading conditions. It is notoriously elusive in the operating room, where pharmacologically reduced tethering obscures mitral regurgitation just when repair is being considered.
Figure 1. Mitral Regurgitation.
A normal mitral valve is shown in Panel A. Ischemic mitral regurgitation, in which the leaflets cannot close effectively, is shown in Panel B. The orientation of the illustration is typical of ultrasound imaging.
Tethering of the mitral leaflets tents the leaflets toward the left ventricular apex. Piérard and Lancellotti show that tenting increases with exercise-induced mitral regurgitation, confirming its mechanism. Exercise-induced mitral regurgitation is also responsible for limiting exercise capacity in patients with chronic heart failure.
The dynamics of tethering also have therapeutic implications. Standard annular reduction alone may not relieve ischemic mitral regurgitation, because it addresses only the annular, not the ventricular, aspect of the tethering problem. The remodeling of the left ventricle also presents a moving target, since mitral regurgitation often recurs as tethering increases. More comprehensive approaches are being explored that reduce tethering through localized left ventricular reshaping, chordal modification, ventricular resynchronization, and medical decompression.3,4
Recent studies of acute pulmonary edema have emphasized diastolic dysfunction as the predominant mechanism in hypertensive patients. Yet in 1991, Stone and colleagues reported moderate-to-severe mitral regurgitation in two thirds of patients with acute pulmonary edema (acute myocardial infarction evolved in 40 percent of their group).5 Clearly, population differences (hypertensive hypertrophy vs. ischemic deformity) affect the mechanism. The study by Piérard and Lancellotti suggests that the pendulum is swinging back toward the recognition that mitral regurgitation, along with diastolic stiffness, determines pulmonary hypertension in left ventricular dysfunction.6
In a broader perspective, this study suggests a greater role for exercise testing in patients with valvular disease. Most valve disease varies dynamically depending on annular size and the volume-dependent compliance of the chambers. Nelson Schiller, Ehud Schwammenthal, Jae-Kwan Song, Jean-Louis Vanoverschelde, Thomas Marwick, Brian Griffin, Jean Dumesnil, Philippe Pibarot, and others have emphasized that exercise provides fuller appreciation of lesions and patient adaptation. The master clinician of the early days of medical training now is able to assess dyspnea and fatigue in the context of forward output, retrograde flow, and pulmonary pressures.
The data presented by Piérard and Lancellotti have two practical messages. Acute pulmonary edema can be caused by acute exacerbations of ischemic mitral regurgitation without obvious coronary insufficiency. More generally, perhaps we can understand why "mild" ischemic mitral regurgitation is consistently associated with an adverse prognosis and why some patients have exertional dyspnea out of proportion to the degree of resting dysfunction or mitral regurgitation. Furthermore, dynamic testing can avert the complacency that may result from the appearance of mild mitral regurgitation at rest.
Dr. Levine reports having received grant support from Guidant. Dr. Levine is one of the inventors of U.S. patents 6,544,181, entitled "Method and apparatus for measuring volume flow and area for a dynamic orifice," held by Massachusetts General Hospital, and 6,695,768, entitled "Adjustable periventricular ring/ring like device/method for control of ischemic mitral regurgitation and congestive heart disease." No commercial products are derived from these patents.
Source Information
From the Division of Cardiology, Massachusetts General Hospital, Boston.
References
Piérard LA, Lancellotti P. The role of ischemic mitral regurgitation in the pathogenesis of acute pulmonary edema. N Engl J Med 2004;351:1627-1634.
Otsuji Y, Handschumacher MD, Schwammenthal E, et al. Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation 1997;96:1999-2008.
Hung J, Guerrero JL, Handschumacher MD, Supple G, Sullivan S, Levine RA. Reverse ventricular remodeling reduces ischemic mitral regurgitation: echo-guided device application in the beating heart. Circulation 2002;106:2594-2600.
Messas E, Guerrero JL, Handschumacher MD, et al. Chordal cutting: a new therapeutic approach for ischemic mitral regurgitation. Circulation 2001;104:1958-1963.
Stone GW, Griffin B, Shah PK, et al. Prevalence of unsuspected mitral regurgitation and left ventricular diastolic dysfunction in patients with coronary artery disease and acute pulmonary edema associated with normal or depressed left ventricular systolic function. Am J Cardiol 1991;67:37-41.
Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol 1997;29:153-159.(Robert A. Levine, M.D.)