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Pathophysiologic determinants of third heart sounds: a prospective clinical and Doppler echocardiographic study
Pathophysiologic Determinants of Third Heart Sounds: A Prospective Clinical and Doppler Echocardiographic Study Christophe M. Tribouilloy, MD, Maurice Enriquez-Sarano, MD, Dania Mohty, MD, Robin A. Horn, MD, Kent R. Bailey, PhD, James B. Seward, MD, Arnold M. Weissler, MD, A. Jamil Tajik, MD PURPOSE: We sought to determine the importance of a third heart sound (S3) and its relation to hemodynamic and valvular dysfunction. SUBJECTS AND METHODS: We prospectively enrolled 580 patients who had isolated valvular regurgitation (mitral, n ⫽ 299; aortic, n ⫽ 121) or primary left ventricular dysfunction with or without functional mitral regurgitation (n ⫽ 160). We analyzed the associations between the clinical finding of an audible S3 (as noted in routine clinical practice by internal medicine physicians) and hemodynamic alterations measured by comprehensive quantitative Doppler echocardiography. RESULTS: S3 was more prevalent in patients with primary left ventricular dysfunction (46%, n ⫽ 73) than in organic mitral (16%, n ⫽ 47) or aortic (12%, n ⫽ 14) regurgitation (P ⬍0.001). Patients with an S3 were more likely to have class III–IV symptoms (55% [74 of 137] vs. 18% [80 of 443] of those without an S3, P ⬍0.001) and had a higher mean [⫾ SD] pul-
monary pressure (55 ⫾ 15 vs. 41 ⫾ 11 mm Hg, P ⬍0.001). An S3 was also related to a higher early filling velocity due to a greater filling volume, restrictive filling, or both. An S3 was a marker of severe regurgitation (regurgitant fraction ⱖ40%) in patients with primary left ventricular dysfunction (odds ratio [OR] ⫽ 2.4; 95% confidence interval [CI]: 1.1 to 5.5), mitral regurgitation (OR ⫽ 17; 95% CI: 5.8 to 52), and aortic regurgitation (OR ⫽ 7.1; 95% CI: 1.8 –28). An S3 was also associated with restrictive filling in primary left ventricular dysfunction (OR ⫽ 3.0; 95% CI, 1.6 to 5.9), marked dilatation in mitral regurgitation (OR ⫽ 20; 95% CI: 6.8 to 58), and an ejection fraction (⬍50%) in aortic regurgitation (OR ⫽ 19; 95% CI: 6.0 to 62). CONCLUSION: An audible S3 is an important clinical finding, indicating severe hemodynamic alterations, and should lead to a comprehensive assessment and consideration of vigorous medical or surgical treatment. Am J Med. 2001;111:96 –102. 䉷2001 by Excerpta Medica, Inc.
A
patients with valvular regurgitation is a major determinant of poor outcome and an indication for surgery (19) and because detection of asymptomatic left ventricular dysfunction is important for early treatment (20). Doppler echocardiography allows reliable, noninvasive quantitation of left ventricular systolic and diastolic function (21,22) and valvular regurgitation (23,24). Therefore, we designed a prospective study to define the specific pathophysiologic determinants of S3 in patients with isolated valvular regurgitation or primary left ventricular dysfunction who underwent Doppler echocardiography.
uscultation of a third heart sound (S3) has been performed for more than a century (1). An S3 is physiologic in normal children and young adults but usually becomes pathologic after age 40 years (2,3). Experimental studies have shown that an S3 is produced by diastolic vibrations of the left ventricular wall (4,5) that accompany rapid ventricular filling (5,6). In adults, an S3 is often considered a sign of heart failure or reduced left ventricular function (7–9), but the clinical meaning and importance of this sign have not been fully defined. In previous studies, an audible S3 has been associated with left ventricular volume overload (2,10 –12), dilatation (10,11), systolic dysfunction (2,10,11), or diastolic dysfunction (13). This lack of consistency hinders the clinical assessment of patients with valvular regurgitation or left ventricular dysfunction, in whom an audible S3 is frequent (1,10,12–18). Detecting an S3 may be particularly important because a decreased ejection fraction in From the Division of Cardiovascular Diseases and Internal Medicine (CMT, ME-S, DM, RAH, JBS, AMW, AJT) and the Section of Biostatistics (KRB), Mayo Clinic, Rochester, Minnesota, USA. Requests for reprints should be addressed to Maurice EnriquezSarano, MD, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. Manuscript submitted April 24, 2000, and accepted in revised form March 22, 2001. 96
䉷2001 by Excerpta Medica, Inc. All rights reserved.
MATERIAL AND METHODS Study Sample We studied consecutive patients who were referred by their physicians for echocardiography. All patients had isolated mitral regurgitation or aortic regurgitation or primary left ventricular dysfunction; simultaneous quantitation of regurgitation by two methods and assessment of left ventricular systolic and diastolic function using Doppler echocardiography performed by one of the authors; and a cardiac examination within 1 month before echocardiography (without an intervening event) per0002-9343/01/$–see front matter PII S0002-9343(01)00769-0
Pathophysiologic Determinants of Third Heart Sounds/Tribouilloy et al
formed by a staff cardiologist or internist. We excluded patients with previous valve surgery; associated valvular stenosis (mean aortic gradient ⬎25 mm Hg, mean mitral gradient ⬎5 mm Hg); acute myocardial infarction; congenital or pericardial heart disease; or a change in treatment or clinical status between the physical and echocardiographic examinations. Our study includes 580 patients who met these criteria. We also studied normal subjects (n ⫽ 51; mean [⫾ SD] age of 57 ⫾ 15 years; 31 men) for quality control of quantitative Doppler methods.
Clinical Data We recorded clinical variables as noted by the referring senior physician (Mayo consultant), including age, sex, blood pressure, heart rate, atrial fibrillation, and an audible S3 gallop. The initial clinical examination was performed independently before echocardiography by each patient’s staff attending physician (402 patients were examined by a cardiologist, 178 by an internist) who was not aware of the study. A subsequent examination by another physician was performed in 101 patients initially examined by a cardiologist and 102 initially examined by an internist.
Doppler Echocardiographic Data Comprehensive Doppler echocardiography and two-dimensional echocardiography were performed. The primary disease was identified on the basis of the echocardiographic result; mitral and aortic regurgitation were at least of mild degree and due to intrinsic valvular lesions. Primary left ventricular dysfunction was defined as an ejection fraction ⬍50% not due to organic valve disease; some of these patients had functional mitral regurgitation with a dilated annulus and a normal valve. Left ventricular volumes were measured at end-diastole and end-systole (21), allowing the ejection fraction to be calculated. Regurgitation was quantified on the basis of two independent quantitative echocardiographic methods: quantitative Doppler, which uses mitral and aortic stroke volumes (23,24), and quantitative two-dimensional echocardiography, which uses left ventricular and forward stroke volumes (24). The regurgitant fraction was estimated as the average of these two methods. With pulsed-wave Doppler (22), we assessed whether left ventricular diastolic filling demonstrated a restrictive filling pattern (deceleration time ⱕ150 msec) (25), typical of reduced compliance (13,26). Other measures of diastolic filling included heart rate and left ventricular filling volume (difference between end-systolic and end-diastolic volume normalized to body surface area) and velocities. Left atrial volume (27), pulmonary artery systolic pressure (28), and cardiac index were also estimated using Doppler echocardiography.
Statistical Analysis Continuous data are presented as mean ⫾ SD. Comparisons among groups of patients were performed with one- or two-way analyses of variance (ANOVA). Within diseases (aortic regurgitation, mitral regurgitation, left ventricular dysfunction), we used the Student t test to compare continuous variables and the chi-squared test to compare dichotomous variables; if necessary, we adjusted for other baseline characteristics in multiple linear or logistic regressions. To determine which hemodynamic variables were independently associated with an audible S3, multivariate analysis using backward logistic regression was performed, first for each group of hemodynamic variables and then for those variables that were significant in univariate analyses at P ⬍0.10. Univariate odds ratio (OR) and 95% confidence intervals (CIs) were estimated for each independent determinant of S3. Statistical significance was set at P ⬍0.05 (two-sided). The sensitivity, specificity, and positive and negative predictive values of an S3 for various hemodynamic alterations— end-diastolic volume index ⬎100 mL/m2 (29), ejection fraction ⬍50% (30,31), regurgitant fraction ⱖ40%, and restrictive filling (32,33)—were estimated. Agreement between observers was estimated with the kappa statistic.
RESULTS Of the 580 patients, 299 (52%) had isolated mitral regurgitation (215 with valve prolapse, 84 with miscellaneous lesions), 121 (21%) had aortic regurgitation (54 with valve sclerosis or thickening, 30 with bicuspid valve, 37 with miscellaneous lesions), and 160 (28%) had primary left ventricular dysfunction (Table 1). An audible S3 was present in nearly half of the patients with primary left ventricular dysfunction, compared with about 15% of patients with valvular regurgitation (P ⬍0.001). The greater prevalence of an S3 in patients with primary left ventricular dysfunction was noted even in patients with severe disease (24% [45 of 186] of those with mitral and 20% [12 of 61] of those with aortic regurgitation whose regurgitant fraction was ⱖ40%, compared with 52% [57 of 110] of those with primary left ventricular dysfunction with an ejection fraction ⱕ35%; P ⬍0.001). The clinical and hemodynamic manifestations of the disease were more severe in patients with an S3 than in those without an S3 (Table 2). None of the 51 normal subjects had an S3; the absolute values of the regurgitant volume (4 ⫾ 3 mL) and fraction (5% ⫾ 3%) were minimal. Left ventricular diastolic volume was 73 ⫾ 16 mL/m2, and systolic volume was 28 ⫾ 13 mL/m2, with an ejection fraction of 62% ⫾ 8%. August 1, 2001
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Table 1. Clinical and Echocardiographic Characteristics of the Patients§
Characteristic
Mitral Regurgitation (n ⫽ 299)
Aortic Regurgitation (n ⫽ 121)
Primary Left Ventricular Dysfunction (n ⫽ 160)
47 (16)* 64 ⫾ 14*‡ 191 (64) 72 ⫾ 13*‡ 1.87 ⫾ 0.22 135 ⫾ 20*‡ 77 ⫾ 10‡ 46 (15)‡ 46 (15)*
14 (12)† 57 ⫾ 18†‡ 80 (66) 68 ⫾ 13†‡ 1.91 ⫾ 0.26 141 ⫾ 21†‡ 72 ⫾ 16†‡ 6 (5)†‡ 15 (12)†
73 (46)*† 68 ⫾ 11*† 107 (67) 80 ⫾ 15*† 1.89 ⫾ 0.22 126 ⫾ 21*† 75 ⫾ 11† 37 (23)† 93 (58)*†
38 ⫾ 15*‡ 112 ⫾ 32* 66 ⫾ 8*‡
47 ⫾ 27†‡ 117 ⫾ 42† 62 ⫾ 10†‡
104 ⫾ 43*† 147 ⫾ 45*† 30 ⫾ 9*†
45 ⫾ 18*‡
38 ⫾ 16†‡
27 ⫾ 14*†
73 ⫾ 23* 24 (8)*
70 ⫾ 21† 8 (7)†
43 ⫾ 11*† 88 (58)*†
S3 Age (years) Male sex Heart rate (beats/min) Body surface area (m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Atrial fibrillation Functional class III–IV Left ventricular size and function End-systolic volume index (mL/m2) End-diastolic volume index (mL/m2) Ejection fraction (%) Regurgitation severity Regurgitant fraction (%) Left ventricular diastolic filling Diastolic filling volume (mL/m2) Restrictive diastolic filling
* P ⬍ 0.05 for comparison between mitral regurgitation and left ventricular dysfunction. † P ⬍ 0.05 for comparison between aortic regurgitation and left ventricular dysfunction. ‡ P ⬍ 0.05 for comparison between mitral and aortic regurgitation. § Values are number (%) or mean ⫾ SD. S3 ⫽ third heart sound.
Diastolic Filling Characteristics Associated with an S3 Among all patients, an S3 was associated with an early filling wave of higher velocity (103 ⫾ 33 vs. 88 ⫾ 32 cm/ sec, P ⬍ 0.001) and a shorter deceleration time (163 ⫾ 50 vs. 206 ⫾ 53 msec, P ⬍0.001). In all three groups of patients, diastolic filling of those with an S3 was characterized by fast, early filling due to greater diastolic filling volume, restrictive diastolic filling with abrupt blood deceleration, or both (Table 3).
Clinical Pathophysiologic Correlates of an S3 An S3 was associated with severe regurgitation and with severe ventricular alterations in all three groups (Table 3). In multivariate analyses (Table 4), an audible S3 was as-
sociated with a lower ejection fraction, a greater regurgitant fraction, and restrictive diastolic filling. In general, an audible S3 had a limited sensitivity but an acceptable specificity for these abnormalities (Table 4). Patients with mitral regurgitation and an audible S3 were more often men and had greater mean left ventricular volume, regurgitant fraction, and diastolic filling volume than those without an S3 (Table 3). An S3 was not associated with a lower mean ejection fraction in these patients. An audible S3 was independently associated with a greater regurgitant fraction and greater end-diastolic volume index (Table 4). Mean pulmonary systolic pressure was higher in patients with an S3 (52 ⫾ 18 vs. 40 ⫾ 11 mm Hg, P ⬍0.001), even after adjustment for regurgitant fraction or for diastolic filling volume (both P ⬍0.001).
Table 2. Left Ventricular Dysfunction by the Presence or Absence of a Third Heart Sound (S3)† P Value Manifestation or Measurement
S3
No S3
Univariate
Adjusted*
Functional class III–IV Atrial fibrillation Left atrial volume (mL) Cardiac index (L/min per m2) Systolic pulmonary artery pressure (mm Hg)
74 (55) 34 (25) 133 ⫾ 52 2.5 ⫾ 0.6 55 ⫾ 15
80 (18) 55 (13) 94 ⫾ 53 2.6 ⫾ 0.5 41 ⫾ 11
0.001 0.015 0.001 0.016 0.001
0.001 0.16 0.001 0.21 0.001
* Adjusted for types of heart disease (mitral regurgitation, aortic regurgitation, primary left ventricular dysfunction). † Values are number (%) or mean ⫾ SD. 98
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Table 3. Clinical and Echocardiographic Characteristics of Patients with and without a Third Heart Sound (S3)* Mitral Regurgitation Variable
Primary Left Ventricular Dysfunction
Aortic Regurgitation
S3 No S3 P S3 No S3 P S3 (n ⫽ 47) (n ⫽ 252) Value (n ⫽ 14) (n ⫽ 107) Value (n ⫽ 73)
Age (years) 65 ⫾ 13 Male sex 37 (79) Heart rate (beats/min) 74 ⫾ 12 Left ventricular size and function End-systolic volume index 50 ⫾ 15 (mL/m2) End-diastolic volume index 137 ⫾ 25 (mL/m2) Ejection fraction (%) 64 ⫾ 8 Regurgitation severity Regurgitant fraction (%) 58 ⫾ 10 Left ventricular diastolic filling Diastolic filling volume (mL/m2) 87 ⫾ 22 Restrictive diastolic filling (%) 7 (15)
63 ⫾ 14 154 (61) 71 ⫾ 13
0.33 0.02 0.18
49 ⫾ 18 11 (79) 77 ⫾ 23
58 ⫾ 17 69 (64) 67 ⫾ 11
0.07 0.30 0.13
37 ⫾ 14
0.001
84 ⫾ 34
42 ⫾ 22
0.001 112 ⫾ 39
0.001 163 ⫾ 50
111 ⫾ 37
107 ⫾ 30
No S3 P (n ⫽ 87) Value
68 ⫾ 12 51 (70) 84 ⫾ 14
67 ⫾ 11 0.92 56 (64) 0.47 77 ⫾ 14 0.001 98 ⫾ 45 0.04
0.001 155 ⫾ 41 141 ⫾ 48 0.05
66 ⫾ 8
0.19
49 ⫾ 12
64 ⫾ 8
0.001
28 ⫾ 8
32 ⫾ 9
42 ⫾ 18
0.001
51 ⫾ 13
36 ⫾ 15
0.001
32 ⫾ 13
23 ⫾ 14 0.001
71 ⫾ 22 17 (7)
0.001 0.07
79 ⫾ 31 3 (20)
69 ⫾ 19 5 (5)
0.37 0.09
43 ⫾ 11 49 (72)
42 ⫾ 11 0.82 39 (46) 0.001
0.01
* Values are number (%) or mean ⫾ SD.
6 mm Hg, P ⬍0.001), even after adjustment for ejection fraction, regurgitant fraction, or diastolic filling volume (all Ps ⬍0.001). Among patients with primary left ventricular dysfunction, those with an audible S3 had more restrictive diastolic filling, a lower mean ejection fraction, a greater mean mitral regurgitant fraction, and a faster heart rate
Patients with aortic regurgitation and an audible S3 had a lower mean ejection fraction and greater mean left ventricular volume and regurgitant fraction than those without an S3 (Table 3). An audible S3 was independently associated with greater regurgitant fraction and lower ejection fraction (Table 4). Mean pulmonary systolic pressure was higher in those with an S3 (49 ⫾ 16 vs. 36 ⫾
Table 4. Independent Determinants and Diagnostic Value of an Audible Third Heart Sound
Group, Hemodynamic Alteration Overall (n ⫽ 580) Systolic left ventricular dysfunction‡ Severe regurgitation§ Restrictive diastolic filling (deceleration time ⱕ150 msec) Mitral regurgitation (n ⫽ 299) Left ventricular enlargement (end-diastolic volume index ⬎100 mL/m2) Severe regurgitation§ Aortic regurgitation (n ⫽ 121) Systolic left ventricular dysfunction‡ Severe regurgitation§ Primary left ventricular dysfunction (n ⫽ 160) Restrictive diastolic filling (deceleration time ⱕ150 msec) Severe regurgitation§
Odds Ratio (95% Confidence Interval)*
P Value†
Specificity
Positive Predictive Value
Negative Predictive Value
Sensitivity
5.6 (3.6–7.8) 1.6 (1.1–2.3) 5.6 (3.6–8.6)
0.001 0.001 0.02
45 27 50
87 81 85
60 57 49
78 55 85
20 (6.8–58)
0.02
25
98
96
47
17 (5.8–52)
0.007
24
98
96
44
19 (6.0–62) 7.1 (1.8–28)
0.001 0.03
60 20
93 97
43 86
96 54
3.0 (1.6–5.9)
0.001
56
70
72
54
2.4 (1.1–5.5)
0.04
63
58
26
87
* Indicates the univariate odds of a particular hemodynamic alteration in those with an S3 compared with the odds in those without an S3. † P value as determined in multivariate logistic regression models. ‡ Left ventricular ejection fraction ⬍50%. § Regurgitant fraction ⱖ40%. August 1, 2001
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than those without an S3 (Table 3). An S3 was independently associated with greater functional mitral regurgitation and restrictive left ventricular filling (Table 4). Mean pulmonary systolic pressure was greater in those with an S3 than in those without an S3 (59 ⫾ 13 vs. 46 ⫾ 13 mm Hg, P ⬍0.001), despite similar diastolic filling volumes (Table 3). Ejection fraction was not independently associated with an S3. In patients with no restrictive filling and a regurgitant fraction ⬍40%, an S3 was heard in 37% (11 of 30) of those with an ejection fraction ⬍35% and 24% (8 of 34) of those with an ejection fraction of 35% to 49% (P ⫽ 0.25).
Interobserver Agreement about the Presence of an S3 Among the 102 patients who were initially examined by an internist and who had more than one clinical examination, the agreement between observers about the presence or absence of an audible S3 was 88% (kappa, 0.56 ⫾ 0.11). Among the 101 patients initially examined by a cardiologist and who had more than one clinical examination, the agreement between observers about the presence or absence of an audible S3 was 91% (kappa, 0.75 ⫾ 0.08).
DISCUSSION We found that an audible S3 was present in nearly half of patients with left ventricular dysfunction and in about 15% of those with organic valve regurgitation and was associated with severe clinical and hemodynamic manifestations of the underlying disease. Previous studies have reported that 26% to 69% of patients with left ventricular dysfunction have an S3 (13,18,34 –36), as well as 28% to 67% of those with valvular regurgitation (10,11). Patients with an S3 had higher left ventricular filling pressures and altered left ventricular filling that was characterized by restrictive filling (abrupt deceleration), an increased volume, or both. An S3 does not necessarily imply a decreased ejection fraction, however. In patients with valvular regurgitation, an S3 is a marker of severe regurgitation. It is also an indicator of marked left ventricular enlargement in patients with mitral regurgitation and a decreased ejection fraction in patients with aortic regurgitation. In patients with primary left ventricular dysfunction, an S3 indicates marked functional mitral regurgitation and advanced diastolic dysfunction (excess ventricular stiffness), rather than profound systolic dysfunction. An S3 is generated by the vibration of the ventricular wall in early diastole (4 – 6), due to increased early inflow followed by abrupt deceleration of blood (5) as a result of reversed intraventricular gradients (37). This mechanism is valid whether an S3 is physiologic or pathologic 100
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(2,5,38). These mechanisms of sound generation (39) provide insight into the alterations of diastolic filling that led to audible S3 in our study. We observed that S3 was associated with increased early filling velocity, reflecting an increased inflow volume, restrictive left ventricular physiology, or both. Restrictive left ventricular filling, diagnosed by an abrupt deceleration of ventricular inflow, is due to excess cavity (ventricular and atrial) stiffness (26), which causes increased filling pressures. Increased diastolic stiffness of the left ventricle is common (5,37) among patients with primary left ventricular dysfunction and presumably explains why about half of these patients had an S3. Previous studies in this area were limited by small (10) or selected (11) samples, by examiners aware of the study (2,10,12) or with little experience (11), by limited analysis (2,10,12), or by grouping different diseases (11,39). In addition, methods for quantifying regurgitation and for measuring systolic and diastolic ventricular function are relatively recent. This is most important among patients with mitral regurgitation because left ventricular dysfunction can cause functional mitral regurgitation (27) or be a consequence of advanced mitral regurgitation (31). This may explain why there is disagreement about the association of an S3 with the degree of mitral regurgitation (11), with decreased ejection fraction in aortic regurgitation (10,11), as well as with severe systolic (18,32) or diastolic (13,32,38) dysfunction, or with functional mitral regurgitation (13,32) among patients with primary left ventricular dysfunction. In primary left ventricular dysfunction, we found that an audible S3 was associated with the degree of diastolic, rather than systolic, dysfunction, reflecting restrictive diastolic filling and high filling pressures secondary to reduced ventricular compliance. Functional mitral regurgitation also contributes to an audible S3 and to marked hemodynamic alterations in these patients (27). The combination of restrictive filling and functional mitral regurgitation may explain the poor outcome associated with an audible S3 (9,33,40). In mitral regurgitation due to primary valvular disease, we found that an S3 is directly related to the severity of regurgitation, as others have shown (14). This association was suggested by indirect evidence (2,12), but discordant data were obtained with catheterization (11). An S3 was also associated with marked left ventricular dilatation (2), which has prognostic implications in organic mitral regurgitation (29). In aortic regurgitation, an audible S3 was also a marker of severe regurgitation and left ventricular dysfunction (decreased ejection fraction). This association with a low ejection fraction, which had been controversial (10,11), has important prognostic implications (30). In the present study, the presence of an S3 was ascertained in routine practice by experienced clinicians (41).
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We found that the clinical diagnosis of an audible S3 had acceptable reproducibility. Phonocardiography may have improved the diagnostic accuracy, but the test is rarely used in clinical practice. We did not use resident physicians, whose diagnostic acumen is less certain (42). Our results have several clinical implications. Among patients with primary left ventricular dysfunction, an audible S3 reflects severe diastolic dysfunction (restrictive filling) and greater functional mitral regurgitation, implying a higher risk of hemodynamic complications (13,27) and a poor prognosis (9,33,40). Therefore, in patients with an audible S3, a comprehensive hemodynamic assessment and vigorous therapeutic approaches are warranted (20). In patients with valvular regurgitations, S3 carries a high probability of severe regurgitation, as well as adverse hemodynamic characteristics. Because qualitative assessment may underestimate the degree of regurgitation (43), an audible S3 should lead to quantitative assessment of regurgitation (24), with consideration of valve replacement surgery.
12. 13.
14. 15.
16. 17. 18.
19. 20. 21.
ACKNOWLEDGMENT Dr. C. M. Tribouilloy was supported by a grant from the Federation Franc¸aise de Cardiologie.
22.
23.
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athy. Relation to symptoms and prognosis. Circulation. 1994;90: 2772–2779. Xie GY, Berk MR, Smith MD, et al. Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol. 1994;24:132–139. Campana C, Gavazzi A, Berzuini C, et al. Predictors of prognosis in patients awaiting heart transplantation. J Heart Lung Transplant. 1993;12:756 –765. Chakko S, Woska D, Martinez H, et al. Clinical, radiographic, and hemodynamic correlations in chronic congestive heart failure. Conflicting results may lead to inappropriate care. Am J Med. 1991; 90:353–359. Pozzoli M, Capomolla S, Sanarico M, et al. Doppler evaluations of left ventricular diastolic filling and pulmonary wedge pressure provide similar prognostic information in patients with systolic dysfunction after myocardial infarction. Am Heart J. 1995;129:716 – 725. Van de Werf F, Minten J, Carmeliet P, et al. The genesis of the third and fourth heart sounds. A pressure-flow study in dogs. J Clin Invest. 1984;73:1400 –1407.
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38. Pozzoli M, Febo O, Tramarin R, et al. Pulsed Doppler evaluation of left ventricular filling in subjects with pathologic and physiologic third heart sound. Eur Heart J. 1990;11:500 –508. 39. Downes TR, Dunson W, Stewart K, et al. Mechanism of physiologic and pathologic S3 gallop sounds. J Am Soc Echocardiogr. 1992;5: 211–218. 40. Blondheim DS, Jacobs LE, Kotler MN, et al. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J. 1991;122:763– 771. 41. Ishmail AA, Wing S, Ferguson J, et al. Interobserver agreement by auscultation in the presence of a third heart sound in patients with congestive heart failure. Chest. 1987;91:870 – 873. 42. Mangione S, Nieman LZ. Cardiac auscultatory skills of internal medicine and family practice trainees. A comparison of diagnostic proficiency. JAMA. 1997;278:717–722. 43. Enriquez-Sarano M, Tajik AJ, Bailey KR, Seward JB. Color flow imaging compared with quantitative Doppler assessment of severity of mitral regurgitation: influence of eccentricity of jet and mechanism of regurgitation. J Am Coll Cardiol. 1993;21:1211–1219.
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monary pressure (55 ⫾ 15 vs. 41 ⫾ 11 mm Hg, P ⬍0.001). An S3 was also related to a higher early filling velocity due to a greater filling volume, restrictive filling, or both. An S3 was a marker of severe regurgitation (regurgitant fraction ⱖ40%) in patients with primary left ventricular dysfunction (odds ratio [OR] ⫽ 2.4; 95% confidence interval [CI]: 1.1 to 5.5), mitral regurgitation (OR ⫽ 17; 95% CI: 5.8 to 52), and aortic regurgitation (OR ⫽ 7.1; 95% CI: 1.8 –28). An S3 was also associated with restrictive filling in primary left ventricular dysfunction (OR ⫽ 3.0; 95% CI, 1.6 to 5.9), marked dilatation in mitral regurgitation (OR ⫽ 20; 95% CI: 6.8 to 58), and an ejection fraction (⬍50%) in aortic regurgitation (OR ⫽ 19; 95% CI: 6.0 to 62). CONCLUSION: An audible S3 is an important clinical finding, indicating severe hemodynamic alterations, and should lead to a comprehensive assessment and consideration of vigorous medical or surgical treatment. Am J Med. 2001;111:96 –102. 䉷2001 by Excerpta Medica, Inc.
A
patients with valvular regurgitation is a major determinant of poor outcome and an indication for surgery (19) and because detection of asymptomatic left ventricular dysfunction is important for early treatment (20). Doppler echocardiography allows reliable, noninvasive quantitation of left ventricular systolic and diastolic function (21,22) and valvular regurgitation (23,24). Therefore, we designed a prospective study to define the specific pathophysiologic determinants of S3 in patients with isolated valvular regurgitation or primary left ventricular dysfunction who underwent Doppler echocardiography.
uscultation of a third heart sound (S3) has been performed for more than a century (1). An S3 is physiologic in normal children and young adults but usually becomes pathologic after age 40 years (2,3). Experimental studies have shown that an S3 is produced by diastolic vibrations of the left ventricular wall (4,5) that accompany rapid ventricular filling (5,6). In adults, an S3 is often considered a sign of heart failure or reduced left ventricular function (7–9), but the clinical meaning and importance of this sign have not been fully defined. In previous studies, an audible S3 has been associated with left ventricular volume overload (2,10 –12), dilatation (10,11), systolic dysfunction (2,10,11), or diastolic dysfunction (13). This lack of consistency hinders the clinical assessment of patients with valvular regurgitation or left ventricular dysfunction, in whom an audible S3 is frequent (1,10,12–18). Detecting an S3 may be particularly important because a decreased ejection fraction in From the Division of Cardiovascular Diseases and Internal Medicine (CMT, ME-S, DM, RAH, JBS, AMW, AJT) and the Section of Biostatistics (KRB), Mayo Clinic, Rochester, Minnesota, USA. Requests for reprints should be addressed to Maurice EnriquezSarano, MD, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. Manuscript submitted April 24, 2000, and accepted in revised form March 22, 2001. 96
䉷2001 by Excerpta Medica, Inc. All rights reserved.
MATERIAL AND METHODS Study Sample We studied consecutive patients who were referred by their physicians for echocardiography. All patients had isolated mitral regurgitation or aortic regurgitation or primary left ventricular dysfunction; simultaneous quantitation of regurgitation by two methods and assessment of left ventricular systolic and diastolic function using Doppler echocardiography performed by one of the authors; and a cardiac examination within 1 month before echocardiography (without an intervening event) per0002-9343/01/$–see front matter PII S0002-9343(01)00769-0
Pathophysiologic Determinants of Third Heart Sounds/Tribouilloy et al
formed by a staff cardiologist or internist. We excluded patients with previous valve surgery; associated valvular stenosis (mean aortic gradient ⬎25 mm Hg, mean mitral gradient ⬎5 mm Hg); acute myocardial infarction; congenital or pericardial heart disease; or a change in treatment or clinical status between the physical and echocardiographic examinations. Our study includes 580 patients who met these criteria. We also studied normal subjects (n ⫽ 51; mean [⫾ SD] age of 57 ⫾ 15 years; 31 men) for quality control of quantitative Doppler methods.
Clinical Data We recorded clinical variables as noted by the referring senior physician (Mayo consultant), including age, sex, blood pressure, heart rate, atrial fibrillation, and an audible S3 gallop. The initial clinical examination was performed independently before echocardiography by each patient’s staff attending physician (402 patients were examined by a cardiologist, 178 by an internist) who was not aware of the study. A subsequent examination by another physician was performed in 101 patients initially examined by a cardiologist and 102 initially examined by an internist.
Doppler Echocardiographic Data Comprehensive Doppler echocardiography and two-dimensional echocardiography were performed. The primary disease was identified on the basis of the echocardiographic result; mitral and aortic regurgitation were at least of mild degree and due to intrinsic valvular lesions. Primary left ventricular dysfunction was defined as an ejection fraction ⬍50% not due to organic valve disease; some of these patients had functional mitral regurgitation with a dilated annulus and a normal valve. Left ventricular volumes were measured at end-diastole and end-systole (21), allowing the ejection fraction to be calculated. Regurgitation was quantified on the basis of two independent quantitative echocardiographic methods: quantitative Doppler, which uses mitral and aortic stroke volumes (23,24), and quantitative two-dimensional echocardiography, which uses left ventricular and forward stroke volumes (24). The regurgitant fraction was estimated as the average of these two methods. With pulsed-wave Doppler (22), we assessed whether left ventricular diastolic filling demonstrated a restrictive filling pattern (deceleration time ⱕ150 msec) (25), typical of reduced compliance (13,26). Other measures of diastolic filling included heart rate and left ventricular filling volume (difference between end-systolic and end-diastolic volume normalized to body surface area) and velocities. Left atrial volume (27), pulmonary artery systolic pressure (28), and cardiac index were also estimated using Doppler echocardiography.
Statistical Analysis Continuous data are presented as mean ⫾ SD. Comparisons among groups of patients were performed with one- or two-way analyses of variance (ANOVA). Within diseases (aortic regurgitation, mitral regurgitation, left ventricular dysfunction), we used the Student t test to compare continuous variables and the chi-squared test to compare dichotomous variables; if necessary, we adjusted for other baseline characteristics in multiple linear or logistic regressions. To determine which hemodynamic variables were independently associated with an audible S3, multivariate analysis using backward logistic regression was performed, first for each group of hemodynamic variables and then for those variables that were significant in univariate analyses at P ⬍0.10. Univariate odds ratio (OR) and 95% confidence intervals (CIs) were estimated for each independent determinant of S3. Statistical significance was set at P ⬍0.05 (two-sided). The sensitivity, specificity, and positive and negative predictive values of an S3 for various hemodynamic alterations— end-diastolic volume index ⬎100 mL/m2 (29), ejection fraction ⬍50% (30,31), regurgitant fraction ⱖ40%, and restrictive filling (32,33)—were estimated. Agreement between observers was estimated with the kappa statistic.
RESULTS Of the 580 patients, 299 (52%) had isolated mitral regurgitation (215 with valve prolapse, 84 with miscellaneous lesions), 121 (21%) had aortic regurgitation (54 with valve sclerosis or thickening, 30 with bicuspid valve, 37 with miscellaneous lesions), and 160 (28%) had primary left ventricular dysfunction (Table 1). An audible S3 was present in nearly half of the patients with primary left ventricular dysfunction, compared with about 15% of patients with valvular regurgitation (P ⬍0.001). The greater prevalence of an S3 in patients with primary left ventricular dysfunction was noted even in patients with severe disease (24% [45 of 186] of those with mitral and 20% [12 of 61] of those with aortic regurgitation whose regurgitant fraction was ⱖ40%, compared with 52% [57 of 110] of those with primary left ventricular dysfunction with an ejection fraction ⱕ35%; P ⬍0.001). The clinical and hemodynamic manifestations of the disease were more severe in patients with an S3 than in those without an S3 (Table 2). None of the 51 normal subjects had an S3; the absolute values of the regurgitant volume (4 ⫾ 3 mL) and fraction (5% ⫾ 3%) were minimal. Left ventricular diastolic volume was 73 ⫾ 16 mL/m2, and systolic volume was 28 ⫾ 13 mL/m2, with an ejection fraction of 62% ⫾ 8%. August 1, 2001
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Table 1. Clinical and Echocardiographic Characteristics of the Patients§
Characteristic
Mitral Regurgitation (n ⫽ 299)
Aortic Regurgitation (n ⫽ 121)
Primary Left Ventricular Dysfunction (n ⫽ 160)
47 (16)* 64 ⫾ 14*‡ 191 (64) 72 ⫾ 13*‡ 1.87 ⫾ 0.22 135 ⫾ 20*‡ 77 ⫾ 10‡ 46 (15)‡ 46 (15)*
14 (12)† 57 ⫾ 18†‡ 80 (66) 68 ⫾ 13†‡ 1.91 ⫾ 0.26 141 ⫾ 21†‡ 72 ⫾ 16†‡ 6 (5)†‡ 15 (12)†
73 (46)*† 68 ⫾ 11*† 107 (67) 80 ⫾ 15*† 1.89 ⫾ 0.22 126 ⫾ 21*† 75 ⫾ 11† 37 (23)† 93 (58)*†
38 ⫾ 15*‡ 112 ⫾ 32* 66 ⫾ 8*‡
47 ⫾ 27†‡ 117 ⫾ 42† 62 ⫾ 10†‡
104 ⫾ 43*† 147 ⫾ 45*† 30 ⫾ 9*†
45 ⫾ 18*‡
38 ⫾ 16†‡
27 ⫾ 14*†
73 ⫾ 23* 24 (8)*
70 ⫾ 21† 8 (7)†
43 ⫾ 11*† 88 (58)*†
S3 Age (years) Male sex Heart rate (beats/min) Body surface area (m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Atrial fibrillation Functional class III–IV Left ventricular size and function End-systolic volume index (mL/m2) End-diastolic volume index (mL/m2) Ejection fraction (%) Regurgitation severity Regurgitant fraction (%) Left ventricular diastolic filling Diastolic filling volume (mL/m2) Restrictive diastolic filling
* P ⬍ 0.05 for comparison between mitral regurgitation and left ventricular dysfunction. † P ⬍ 0.05 for comparison between aortic regurgitation and left ventricular dysfunction. ‡ P ⬍ 0.05 for comparison between mitral and aortic regurgitation. § Values are number (%) or mean ⫾ SD. S3 ⫽ third heart sound.
Diastolic Filling Characteristics Associated with an S3 Among all patients, an S3 was associated with an early filling wave of higher velocity (103 ⫾ 33 vs. 88 ⫾ 32 cm/ sec, P ⬍ 0.001) and a shorter deceleration time (163 ⫾ 50 vs. 206 ⫾ 53 msec, P ⬍0.001). In all three groups of patients, diastolic filling of those with an S3 was characterized by fast, early filling due to greater diastolic filling volume, restrictive diastolic filling with abrupt blood deceleration, or both (Table 3).
Clinical Pathophysiologic Correlates of an S3 An S3 was associated with severe regurgitation and with severe ventricular alterations in all three groups (Table 3). In multivariate analyses (Table 4), an audible S3 was as-
sociated with a lower ejection fraction, a greater regurgitant fraction, and restrictive diastolic filling. In general, an audible S3 had a limited sensitivity but an acceptable specificity for these abnormalities (Table 4). Patients with mitral regurgitation and an audible S3 were more often men and had greater mean left ventricular volume, regurgitant fraction, and diastolic filling volume than those without an S3 (Table 3). An S3 was not associated with a lower mean ejection fraction in these patients. An audible S3 was independently associated with a greater regurgitant fraction and greater end-diastolic volume index (Table 4). Mean pulmonary systolic pressure was higher in patients with an S3 (52 ⫾ 18 vs. 40 ⫾ 11 mm Hg, P ⬍0.001), even after adjustment for regurgitant fraction or for diastolic filling volume (both P ⬍0.001).
Table 2. Left Ventricular Dysfunction by the Presence or Absence of a Third Heart Sound (S3)† P Value Manifestation or Measurement
S3
No S3
Univariate
Adjusted*
Functional class III–IV Atrial fibrillation Left atrial volume (mL) Cardiac index (L/min per m2) Systolic pulmonary artery pressure (mm Hg)
74 (55) 34 (25) 133 ⫾ 52 2.5 ⫾ 0.6 55 ⫾ 15
80 (18) 55 (13) 94 ⫾ 53 2.6 ⫾ 0.5 41 ⫾ 11
0.001 0.015 0.001 0.016 0.001
0.001 0.16 0.001 0.21 0.001
* Adjusted for types of heart disease (mitral regurgitation, aortic regurgitation, primary left ventricular dysfunction). † Values are number (%) or mean ⫾ SD. 98
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Table 3. Clinical and Echocardiographic Characteristics of Patients with and without a Third Heart Sound (S3)* Mitral Regurgitation Variable
Primary Left Ventricular Dysfunction
Aortic Regurgitation
S3 No S3 P S3 No S3 P S3 (n ⫽ 47) (n ⫽ 252) Value (n ⫽ 14) (n ⫽ 107) Value (n ⫽ 73)
Age (years) 65 ⫾ 13 Male sex 37 (79) Heart rate (beats/min) 74 ⫾ 12 Left ventricular size and function End-systolic volume index 50 ⫾ 15 (mL/m2) End-diastolic volume index 137 ⫾ 25 (mL/m2) Ejection fraction (%) 64 ⫾ 8 Regurgitation severity Regurgitant fraction (%) 58 ⫾ 10 Left ventricular diastolic filling Diastolic filling volume (mL/m2) 87 ⫾ 22 Restrictive diastolic filling (%) 7 (15)
63 ⫾ 14 154 (61) 71 ⫾ 13
0.33 0.02 0.18
49 ⫾ 18 11 (79) 77 ⫾ 23
58 ⫾ 17 69 (64) 67 ⫾ 11
0.07 0.30 0.13
37 ⫾ 14
0.001
84 ⫾ 34
42 ⫾ 22
0.001 112 ⫾ 39
0.001 163 ⫾ 50
111 ⫾ 37
107 ⫾ 30
No S3 P (n ⫽ 87) Value
68 ⫾ 12 51 (70) 84 ⫾ 14
67 ⫾ 11 0.92 56 (64) 0.47 77 ⫾ 14 0.001 98 ⫾ 45 0.04
0.001 155 ⫾ 41 141 ⫾ 48 0.05
66 ⫾ 8
0.19
49 ⫾ 12
64 ⫾ 8
0.001
28 ⫾ 8
32 ⫾ 9
42 ⫾ 18
0.001
51 ⫾ 13
36 ⫾ 15
0.001
32 ⫾ 13
23 ⫾ 14 0.001
71 ⫾ 22 17 (7)
0.001 0.07
79 ⫾ 31 3 (20)
69 ⫾ 19 5 (5)
0.37 0.09
43 ⫾ 11 49 (72)
42 ⫾ 11 0.82 39 (46) 0.001
0.01
* Values are number (%) or mean ⫾ SD.
6 mm Hg, P ⬍0.001), even after adjustment for ejection fraction, regurgitant fraction, or diastolic filling volume (all Ps ⬍0.001). Among patients with primary left ventricular dysfunction, those with an audible S3 had more restrictive diastolic filling, a lower mean ejection fraction, a greater mean mitral regurgitant fraction, and a faster heart rate
Patients with aortic regurgitation and an audible S3 had a lower mean ejection fraction and greater mean left ventricular volume and regurgitant fraction than those without an S3 (Table 3). An audible S3 was independently associated with greater regurgitant fraction and lower ejection fraction (Table 4). Mean pulmonary systolic pressure was higher in those with an S3 (49 ⫾ 16 vs. 36 ⫾
Table 4. Independent Determinants and Diagnostic Value of an Audible Third Heart Sound
Group, Hemodynamic Alteration Overall (n ⫽ 580) Systolic left ventricular dysfunction‡ Severe regurgitation§ Restrictive diastolic filling (deceleration time ⱕ150 msec) Mitral regurgitation (n ⫽ 299) Left ventricular enlargement (end-diastolic volume index ⬎100 mL/m2) Severe regurgitation§ Aortic regurgitation (n ⫽ 121) Systolic left ventricular dysfunction‡ Severe regurgitation§ Primary left ventricular dysfunction (n ⫽ 160) Restrictive diastolic filling (deceleration time ⱕ150 msec) Severe regurgitation§
Odds Ratio (95% Confidence Interval)*
P Value†
Specificity
Positive Predictive Value
Negative Predictive Value
Sensitivity
5.6 (3.6–7.8) 1.6 (1.1–2.3) 5.6 (3.6–8.6)
0.001 0.001 0.02
45 27 50
87 81 85
60 57 49
78 55 85
20 (6.8–58)
0.02
25
98
96
47
17 (5.8–52)
0.007
24
98
96
44
19 (6.0–62) 7.1 (1.8–28)
0.001 0.03
60 20
93 97
43 86
96 54
3.0 (1.6–5.9)
0.001
56
70
72
54
2.4 (1.1–5.5)
0.04
63
58
26
87
* Indicates the univariate odds of a particular hemodynamic alteration in those with an S3 compared with the odds in those without an S3. † P value as determined in multivariate logistic regression models. ‡ Left ventricular ejection fraction ⬍50%. § Regurgitant fraction ⱖ40%. August 1, 2001
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than those without an S3 (Table 3). An S3 was independently associated with greater functional mitral regurgitation and restrictive left ventricular filling (Table 4). Mean pulmonary systolic pressure was greater in those with an S3 than in those without an S3 (59 ⫾ 13 vs. 46 ⫾ 13 mm Hg, P ⬍0.001), despite similar diastolic filling volumes (Table 3). Ejection fraction was not independently associated with an S3. In patients with no restrictive filling and a regurgitant fraction ⬍40%, an S3 was heard in 37% (11 of 30) of those with an ejection fraction ⬍35% and 24% (8 of 34) of those with an ejection fraction of 35% to 49% (P ⫽ 0.25).
Interobserver Agreement about the Presence of an S3 Among the 102 patients who were initially examined by an internist and who had more than one clinical examination, the agreement between observers about the presence or absence of an audible S3 was 88% (kappa, 0.56 ⫾ 0.11). Among the 101 patients initially examined by a cardiologist and who had more than one clinical examination, the agreement between observers about the presence or absence of an audible S3 was 91% (kappa, 0.75 ⫾ 0.08).
DISCUSSION We found that an audible S3 was present in nearly half of patients with left ventricular dysfunction and in about 15% of those with organic valve regurgitation and was associated with severe clinical and hemodynamic manifestations of the underlying disease. Previous studies have reported that 26% to 69% of patients with left ventricular dysfunction have an S3 (13,18,34 –36), as well as 28% to 67% of those with valvular regurgitation (10,11). Patients with an S3 had higher left ventricular filling pressures and altered left ventricular filling that was characterized by restrictive filling (abrupt deceleration), an increased volume, or both. An S3 does not necessarily imply a decreased ejection fraction, however. In patients with valvular regurgitation, an S3 is a marker of severe regurgitation. It is also an indicator of marked left ventricular enlargement in patients with mitral regurgitation and a decreased ejection fraction in patients with aortic regurgitation. In patients with primary left ventricular dysfunction, an S3 indicates marked functional mitral regurgitation and advanced diastolic dysfunction (excess ventricular stiffness), rather than profound systolic dysfunction. An S3 is generated by the vibration of the ventricular wall in early diastole (4 – 6), due to increased early inflow followed by abrupt deceleration of blood (5) as a result of reversed intraventricular gradients (37). This mechanism is valid whether an S3 is physiologic or pathologic 100
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(2,5,38). These mechanisms of sound generation (39) provide insight into the alterations of diastolic filling that led to audible S3 in our study. We observed that S3 was associated with increased early filling velocity, reflecting an increased inflow volume, restrictive left ventricular physiology, or both. Restrictive left ventricular filling, diagnosed by an abrupt deceleration of ventricular inflow, is due to excess cavity (ventricular and atrial) stiffness (26), which causes increased filling pressures. Increased diastolic stiffness of the left ventricle is common (5,37) among patients with primary left ventricular dysfunction and presumably explains why about half of these patients had an S3. Previous studies in this area were limited by small (10) or selected (11) samples, by examiners aware of the study (2,10,12) or with little experience (11), by limited analysis (2,10,12), or by grouping different diseases (11,39). In addition, methods for quantifying regurgitation and for measuring systolic and diastolic ventricular function are relatively recent. This is most important among patients with mitral regurgitation because left ventricular dysfunction can cause functional mitral regurgitation (27) or be a consequence of advanced mitral regurgitation (31). This may explain why there is disagreement about the association of an S3 with the degree of mitral regurgitation (11), with decreased ejection fraction in aortic regurgitation (10,11), as well as with severe systolic (18,32) or diastolic (13,32,38) dysfunction, or with functional mitral regurgitation (13,32) among patients with primary left ventricular dysfunction. In primary left ventricular dysfunction, we found that an audible S3 was associated with the degree of diastolic, rather than systolic, dysfunction, reflecting restrictive diastolic filling and high filling pressures secondary to reduced ventricular compliance. Functional mitral regurgitation also contributes to an audible S3 and to marked hemodynamic alterations in these patients (27). The combination of restrictive filling and functional mitral regurgitation may explain the poor outcome associated with an audible S3 (9,33,40). In mitral regurgitation due to primary valvular disease, we found that an S3 is directly related to the severity of regurgitation, as others have shown (14). This association was suggested by indirect evidence (2,12), but discordant data were obtained with catheterization (11). An S3 was also associated with marked left ventricular dilatation (2), which has prognostic implications in organic mitral regurgitation (29). In aortic regurgitation, an audible S3 was also a marker of severe regurgitation and left ventricular dysfunction (decreased ejection fraction). This association with a low ejection fraction, which had been controversial (10,11), has important prognostic implications (30). In the present study, the presence of an S3 was ascertained in routine practice by experienced clinicians (41).
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We found that the clinical diagnosis of an audible S3 had acceptable reproducibility. Phonocardiography may have improved the diagnostic accuracy, but the test is rarely used in clinical practice. We did not use resident physicians, whose diagnostic acumen is less certain (42). Our results have several clinical implications. Among patients with primary left ventricular dysfunction, an audible S3 reflects severe diastolic dysfunction (restrictive filling) and greater functional mitral regurgitation, implying a higher risk of hemodynamic complications (13,27) and a poor prognosis (9,33,40). Therefore, in patients with an audible S3, a comprehensive hemodynamic assessment and vigorous therapeutic approaches are warranted (20). In patients with valvular regurgitations, S3 carries a high probability of severe regurgitation, as well as adverse hemodynamic characteristics. Because qualitative assessment may underestimate the degree of regurgitation (43), an audible S3 should lead to quantitative assessment of regurgitation (24), with consideration of valve replacement surgery.
12. 13.
14. 15.
16. 17. 18.
19. 20. 21.
ACKNOWLEDGMENT Dr. C. M. Tribouilloy was supported by a grant from the Federation Franc¸aise de Cardiologie.
22.
23.
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