Original Article
Implications of Third Heart Sounds in Patients with Valvular Heart Disease
N Engl J Med 1992; 327:458-462August 13, 1992
- Abstract
- Abstract
Background.
The presence of third heart sounds in patients with valvular heart disease is often regarded as a sign of heart failure, but it may also depend on the type of valvular disease.
Methods.
We assessed the prevalence of third heart sounds and the relation between third heart sounds and cardiac function in 1281 patients with six types of valvular heart disease.
Results.
The prevalence of third heart sounds was higher in patients with mitral regurgitation (46 percent) or aortic regurgitation (28 percent) than in those with aortic stenosis (11 percent) or mitral stenosis (8 percent). The left ventricular ejection fraction was significantly lower (P<0.001) when a third heart sound was detected in patients with aortic stenosis (0.38, vs. 0.56 in those without third heart sounds) or mixed aortic valve disease (0.40 vs. 0.55). However, the ejection fraction was only slightly lower in patients with mitral regurgitation and third heart sounds (0.51 vs. 0.57, P = 0.03). The pulmonary-capillary wedge pressure was higher (P<0.001) when a third heart sound was detected in patients with aortic stenosis (18.6 mm Hg, vs. 12.1 mm Hg in those without third heart sounds). There was no association between the wedge pressure and third heart sounds in patients with mitral regurgitation. The prevalence of third heart sounds increased with the severity of mitral regurgitation.
Conclusions.
In patients with mitral regurgitation, third heart sounds are common but do not necessarily reflect left ventricular systolic dysfunction or increased filling pressure. In patients with aortic stenosis, third heart sounds are uncommon but usually indicate the presence of systolic dysfunction and elevated filling pressure. (N Engl J Med 1992;327:458–62.)
Media in This Article
Figure 1
Prevalence of Third Heart Sounds among 1281 Patients with Various Valvular Diagnoses.Figure 2
Left Ventricular Ejection Fraction in Patients with Various Valvular Diagnoses with (Hatched Bars) and without (Open Bars) Third Heart Sounds.Article Activity
- Article
A THIRD heart sound or S3 gallop (previously known as a ventricular or protodiastolic gallop) in an adult is usually interpreted as a sign of ventricular dysfunction. Its detection depends on the skill of the examiner and varies widely even among experienced physicians.1 Nevertheless, it is useful in guiding therapy2 for patients with heart disease and assessing their prognosis.3 It has been associated with clinical heart failure,4 elevated atrial pressure,2 , 3 and abnormal ventricular function5 6 7 in a variety of conditions.
S3 may arise from either the left or right ventricle and coincides with the rapid inflow of blood during early diastole.8 9 10 11 12 13 In the left ventricle S3 occurs when the limit of long-axis expansion is reached during diastole.9 10 11 The sound is theoretically a function of three factors: atrial pressure, early diastolic filling rate, and ventricular compliance. These factors may vary independently of one another in different disease states. If so, the usefulness of a third heart sound as a sign of elevated atrial pressure or abnormal ventricular systolic function may depend on the nature of the underlying heart disease, particularly in left-sided valvular heart disease, in which the patterns of diastolic filling and left ventricular compliance vary according to the valve involved (mitral or aortic) and the type of lesion (stenotic or regurgitant).
Third heart sounds are particularly common in patients with mitral regurgitation.4 , 14 , 15 Since mitral regurgitation augments early diastolic inflow to the left ventricle,16 an S3 in this setting may not be as reliable an indicator of left ventricular dysfunction as it is in the case of other valvular lesions. Our study tested this hypothesis by determining the relative frequency of third heart sounds in patients undergoing cardiac catheterization for valvular heart disease and by examining the association between third heart sounds in various types of valvular disease and measures of left ventricular performance.
Methods
The data base for this investigation was that of the Veterans Affairs Cooperative Study on Valvular Heart Disease. A goal of the parent study was to assess the effect of left ventricular function on prognosis in patients with valvular heart disease. The protocol was approved by the institutional review boards of 13 participating Veterans Affairs medical centers as well as a national human-rights committee. The details of the study protocol have been described elsewhere.17
Study Population
All patients undergoing cardiac catheterization for valvular heart disease at participating centers from 1977 to 1982 were eligible for screening. Informed consent was granted by 1482 qualifying patients, representing 72.8 percent of the screened population. The principal reasons for exclusion were life-threatening diseases of other organ systems, previous valve replacement, the patient's refusal, and a principal cardiac diagnosis after catheterization other than valvular heart disease. Complete data on the presence or absence of S3 and a final diagnosis based on the results of cardiac catheterization and angiography were available for 1464 patients. The mean age of the study population was 60 years (13 percent were less than 50 years old and 12 percent were 70 or older). Symptoms (dyspnea, fatigue, or angina) were absent in 8 percent of the patients, present only when activity was greater than the ordinary level in 27 percent, present with ordinary activity in 47 percent, and present at rest in 18 percent. Coronary artery disease (greater than 50 percent stenosis of one or more vessels) was present in 46 percent and previous myocardial infarction in 18 percent of the patients. The left ventricular ejection fraction was 0.50 or lower in 44 percent of the patients and 0.30 or lower in 8 percent.
Physical Examination
Cardiologists participating in the study were requested to report the results of a physical examination performed just before cardiac catheterization. The actual examination might have been performed by a full-time staff member, fellow, or resident. The interval between the examination and catheterization was two days or less in 1083 patients (74 percent). In 168 patients the examination was performed after catheterization. On the basis of this examination the investigator specified "yes" or "no" on a standard form to indicate the presence or absence of S3. These data were missing in three cases. No specific instructions were provided regarding the definition of S3 or any other elements of the examination. No specific maneuvers (e.g., positioning, breathing, or use of a stethoscope bell) were requested to elicit S3, and the examiner was not asked to speculate about the origin of S3 (e.g., left or right ventricle). The examiner was unaware of how the data on S3 might be used in future analyses.
Catheterization Techniques
Pressures were measured by fluid-filled catheters with transducers positioned at the level of the right atrium. Quantitative single-plane left ventriculography was performed in the 30-degree right anterior oblique projection according to the method of Dodge and coworkers.18 , 19 Supravalvular aortic-root angiography was performed in most cases in which aortic regurgitation was suspected. Left ventricular volumes were measured from the ventriculograms and mean valve gradients calculated from pressure tracings in a central laboratory. Effective forward cardiac output was measured by the Fick principle or by the indicator-dilution method. Regurgitant volume (in liters per minute) was defined as the difference between the total left ventricular output measured angiographically and the effective forward output. The degree of aortic or mitral regurgitation was also assessed visually from the appropriate angiogram and graded as absent, mild, moderate, or severe.
Definition of Diagnoses
Patients were grouped according to the presence or absence of S3 in each of seven diagnostic categories, which were defined according to strict criteria involving hemodynamic and angiographic data. Aortic stenosis was defined as any measurable mean aortic-valve gradient with no associated regurgitation, as a mean gradient of ≥20 mm Hg but <50 mm Hg with less than moderate regurgitation, or as a mean gradient of ≥50 mm Hg with any degree of regurgitation. Mixed aortic stenosis and regurgitation was defined as moderate-to-severe regurgitation with a gradient of ≥20 mm Hg but <50 mm Hg. Aortic regurgitation was defined as any degree of regurgitation with an associated mean gradient of <20 mm Hg. Mitral stenosis was defined as any measurable mean mitral-valve gradient with mild associated regurgitation or none. Mixed mitral stenosis and regurgitation was defined as a mean gradient of ≥10 mm Hg with moderate or severe regurgitation. Mitral regurgitation was defined as any degree of regurgitation with an associated mean gradient of <10 mm Hg. Patients meeting the diagnostic criteria for both mitral and aortic valves or for one left-sided valve plus a primary right-sided valvular lesion were considered to have multivalvular disease.
Statistical Analysis
We used the chi-square test to analyze the differences in the prevalence of S3 in various diagnostic categories. Means of hemodynamic variables were compared between patients with and patients without S3 by unpaired t-test in each diagnostic category. The relation between the presence of S3 and the grade of mitral or aortic regurgitation was tested by the chi-square test. All statistical testing was two-sided. No corrections were made for multiple tests, so P values close to 0.05 may represent spurious findings.
Results
S3 was observed significantly more frequently in the patients with mitral regurgitation than in the patients with other valvular lesions (Fig. 1Figure 1
Prevalence of Third Heart Sounds among 1281 Patients with Various Valvular Diagnoses.) (chi-square = 63.5, P<0.001). Nearly half of the patients with mitral regurgitation (46 percent) had S3, as compared with only 18 percent of the other patients.Table 1Table 1
Hemodynamic and Quantitative Angiographic Findings in Patients with and Patients without Third Heart Sounds. compares the hemodynamic measurements of the patients with and without S3, grouped according to valvular diagnosis. The 183 patients with multivalvular disease are not included because of their complex physiologic features. S3 was associated with larger left ventricular volumes in all the patients except those with mitral stenosis. The strength of the association varied markedly with the valve lesion, however. It was most significant for patients with aortic stenosis and mixed aortic valve disease (P<0.001), but was insignificant or of borderline significance for patients with aortic regurgitation and mitral regurgitation (P = 0.03 to 0.12).A low left ventricular ejection fraction was strongly associated with the presence of S3 in patients with aortic stenosis and mixed aortic valve disease (P<0.001). S3 was present in 24 percent of the patients with aortic stenosis and ejection fractions of less than 0.50, as compared with 4 percent of those with ejection fractions of 0.50 or higher (P<0.001). Figure 2Figure 2
Left Ventricular Ejection Fraction in Patients with Various Valvular Diagnoses with (Hatched Bars) and without (Open Bars) Third Heart Sounds. compares these patients with those who had aortic regurgitation, mitral stenosis, or mixed mitral valve disease, in whom there was no association between the presence of S3 and the ejection fraction, and with those who had mitral regurgitation, in whom a third heart sound was associated with only a slightly lower ejection fraction (0.51 vs. 0.57, P = 0.03). S3 was present in 57 percent of the patients with mitral regurgitation and ejection fractions of less than 0.50, as compared with 30 percent of those with ejection fractions of 0.50 or higher (P = 0.01).S3 was significantly associated with elevation of the mean pulmonary-capillary wedge pressure or left atrial pressure in patients with aortic stenosis, mixed aortic valve disease, or mixed mitral valve disease, but not in patients with aortic regurgitation, mitral stenosis, or mitral regurgitation (Fig. 3Figure 3
Pulmonary-Capillary Wedge Pressure or Left Atrial Pressure in Patients with Various Valvular Diagnoses with (Hatched Bars) and without (Open Bars) Third Heart Sounds.). Sixteen percent of the patients who had aortic stenosis and pulmonary-capillary wedge pressures of ≥12 mm Hg had S3, as compared with 7 percent of the patients with wedge pressures of <12 mm Hg (P = 0.003). In contrast, S3 was present in 51 percent of the patients who had mitral regurgitation and pulmonary-capillary wedge pressures of ≥12 mm Hg, as compared with 29 percent of those with wedge pressures of <12 mm Hg (P = 0.02).When the visual grade of mitral regurgitation (as assessed by angiography) was compared among the patients with and without S3, a consistent, positive, and significant relation (P<0.001) was demonstrated between an increasing grade of regurgitation and the prevalence of S3. As indicated in Figure 4Figure 4
Prevalence of Third Heart Sounds among 1112 Patients with Complete Data on Both the Degree of Visually Graded Mitral Regurgitation and the Left Ventricular Ejection Fraction (LVEF)., this relation was independent of the left ventricular ejection fraction. Within each grade of regurgitation the prevalence of S3 was similar in patients with ejection fractions of less than 0.50 and in those with ejection fractions of 0.50 or higher (P = 0.67 to 0.92). When the angiographic grade of aortic regurgitation was similarly analyzed, an increased prevalence of S3 was noted only in patients who had severe regurgitation (prevalence in those with no regurgitation, 19 percent; mild regurgitation, 13 percent; moderate, 20 percent; and severe, 32 percent; P<0.001). The above analyses included all patients for whom appropriate data were available on S3 and the grade of regurgitation, including those with multivalvular disease and primary diagnoses other than mitral or aortic regurgitation.Because S3 can be heard in normal young people (so-called physiologic S3), we analyzed the prevalence of S3 according to age group. The prevalence of an S3 was not related to age within any of the diagnostic groups or for all the diagnostic groups combined (S3 was present in 20.3 percent of the 84 patients who were less than 45 years old, in 19.5 percent of the 636 patients who were at least 45 but less than 60, and in 21.9 percent of the 744 patients who were 60 or older; P = 0.54).
Discussion
The detection of S3 may be influenced by the skill of the examiner, medical therapy at the time of examination, and other diagnostic information available to the examiner. Although staff cardiologists were responsible for the accuracy and completeness of our data, we do not know which examinations were performed by staff members or resident physicians, and we have no data on variability between observers or in the findings of individual observers. Also, we do not know the extent to which associations may have been altered by treatment, although this risk was minimized by the close temporal proximity of the physical examinations and cardiac catheterizations (less than two days separated them in 74 percent of the patients). Although these factors might alter the absolute prevalence of S3, their effect should be distributed randomly among various diagnoses and therefore should not invalidate the comparisons between diagnoses. The likelihood of bias is further reduced because the physicians performing the examinations were unaware of how the S3 data might be used.
S3 is the result of altered dynamics of left ventricular relaxation during diastole, such that the ventricle vibrates on the sudden cessation of early ventricular filling.12 , 13 , 16 Marked left ventricular dilatation seems to be a prerequisite in most cases. Our findings suggest that systolic dysfunction, elevated filling pressure, or both usually accompany S3 when the left ventricular stroke volume is normal or reduced, as in aortic stenosis. However, when the left ventricular stroke volume and diastolic filling rate are increased, as in mitral or aortic regurgitation, S3 is a more common finding but is a less specific sign of systolic dysfunction or elevated filling pressure. This is so because three mechanisms (augmented early diastolic filling, increased stroke volume, and systolic dysfunction) can produce S3 in patients with mitral regurgitation. Our findings are consistent with experimental work in which S3 could be produced in dogs by either acute volume loading (mitral regurgitation) or myocardial dysfunction (hypoxemia).11 The suggestion that early diastolic filling is a cause of S3 is supported not only by the high prevalence of S3 gallops (46 percent) in our patients with mitral regurgitation, but also by the increasing prevalence of S3 as the angiographic grade of mitral regurgitation increased — a relation that was independent of the left ventricular ejection fraction. That the same relation is not apparent in patients with aortic regurgitation is probably due to differences in the time course of ventricular filling and in systolic loading between aortic and mitral regurgitation.
Although S3 may be physiologic in healthy young subjects, its prevalence was not associated with age in our study. Most of our patients were over 45 years old, and very few were less than 30, when physiologic S3 is most likely.
Third heart sounds were least prevalent in patients with mitral stenosis (8 percent). This is a logical observation, because rapid early filling of the left ventricle, one of the elements causing S3, is severely impaired by the inflow obstruction of the stenotic mitral valve. The third heart sounds reported in these nine patients may have originated in the right ventricle rather than the left ventricle or may have been an opening snap mistakenly identified as S3. It is also possible that these sounds represented true left ventricular S3 in patients with mild stenosis.
The criteria for our diagnostic categories were unavoidably arbitrary. Visual rather than quantitative grading of valvular regurgitation was used for diagnostic classification. Although quantitative methods may be more precise under optimal circumstances, visual assessment has proved to be a more practical method of classifying large numbers of patients, many of whom have rhythm disturbances affecting the accuracy of measurements of regurgitant volume. The diagnostic criteria allowed the inclusion of some patients with very mild valvular stenosis, provided that the catheterization data supported valvular disease as the primary cardiac diagnosis. The common feature of all the patients was that they had clinical findings severe enough to warrant diagnostic catheterization. Our conclusions should therefore apply to the spectrum of patients encountered in clinical practice.
S3 in patients with aortic stenosis or mixed aortic valve disease is a strong indicator of left ventricular failure, which may require pharmacologic or surgical therapy. In contrast, a third heart sound in patients with isolated aortic or mitral regurgitation does not necessarily indicate left ventricular failure or dysfunction. Thus, the association between the presence of a third heart sound and hemodynamic function in patients with valvular heart disease has important, but different, implications for therapy depending on the specific valve lesion.
Supported by the Cooperative Studies Program, Medical Research Service, Department of Veterans Affairs.
Presented in part at the 62nd Scientific Session of the American Heart Association, New Orleans, November 15, 1989.
*See the Appendix for a list of the members of the study group.
We are indebted to Mrs. Elizabeth Brosnihan for assistance in the preparation of the manuscript and to William H. Gaasch, M.D., for his advice.
Source Information
From the Research Services, Veterans Affairs Medical Centers, West Roxbury, Mass. (E.D.F., B.J.K.), Hines, III. (W.G.H.), Denver (K.E.H.), and Tucson, Ariz. (G.K.S.). Address reprint requests to Dr. Folland at the Cardiac Catheterization Laboratory, Medical Center of Central Massachusetts, 119 Belmont St., Worcester, MA 01605.
Appendix
In addition to the authors, the participants in the Veterans Affairs Cooperative Study on Valvular Heart Disease were as follows: Cochairman's Office, Denver Veterans Affairs Medical Center: R. Johnson and A. Birdwell; Cochairman's Office, Tucson Veterans Affairs Medical Center, Tucson, Ariz.: M. Haluza; Hines Veterans Affairs Cooperative Studies Program Coordinating Center, Veterans Affairs Medical Center, Hines, Ill.: C. Oprian, T. Kim, and M.E. Vitek; and current participating investigators: M. Crawford (University of New Mexico, Albuquerque), F.L. Grover (Veterans Affairs Medical Center, San Antonio, Tex.), S. Khuri (Veterans Affairs Medical Center, West Roxbury, Mass.), M. Hwang (Veterans Affairs Medical Center, Hines, Ill.), and D.C. Miller (Veterans Affairs Medical Center, Palo Alto, Calif.); and S. Rahimtoola (University of Southern California, Los Angeles), consultant.
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