Third-Heart-Sound Revisited: A Correlation with N-Terminal Pro Brain Natriuretic Peptide and Echocardiography to Detect Left Ventricular Dysfunction

Varun S Narain, Aniket Puri, Harpreeet S Gilhotra, PA Sadiq, Sanjay Mehrotra,
Sudhanshu K Dwivedi, Ram K Saran, Vijay K Puri.

Departments of Cardiology and Medicine, King George Medical University, Lucknow

Background: Auscultation of the third heart sound is an age-old sign for predicting ventricular dysfunction. New technology and biomarkers like two-dimensional echocardiography and N-terminal pro brain natriuretic peptide, respectively, have sidelined the utility of this sign, which does not involve any cost and is readily accessible. We sought to find the predictive accuracy of third heart sound and its correlation with N-terminal pro brain natriuretic peptide and ejection fraction using two-dimensional echocardiography to detect left ventricular dysfunction in patients of acute coronary syndrome.

Methods and Results: One hundred and ten patients presenting with acute coronary syndrome [acute ST elevation myocardial infarction (n=74) and non-ST elevation myocardial infarction (n=36)] were prospectively studied. A senior cardiologist, blinded to N-terminal pro brain natriuretic peptide and ejection fraction results auscultated for a left ventricular third heart sound in each patient. Ejection fraction was measured using modified Simpson’s technique on two-dimensional echocardiography and N-terminal pro brain natriuretic peptide was measured using electrochemiluminiscence assay. Median levels of N-terminal pro brain natriuretic peptide were used to provide a dichotomous approach for analysis of the data. Third heart sound was present in 40 patients (acute ST elevation myocardial infarction: n=27, non-ST elevation myocardial infarction: n=13) and absent in 70 patients (acute ST elevation myocardial infarction: n=47, non-ST elevation myocardial infarction: n=23). The sensitivity and specificity of third heart sound for predicting N-terminal pro brain natriuretic peptide above median was 65.5% and 92.7%, respectively. The positive and negative predictive value was 90% and 73%, respectively. The N-terminal pro brain natriuretic peptide of those having third heart sound was 4081±2705 pg/ml compared to 1239.3±1169 pg/ml in those without third heart sound (p<0.001). The sensitivity of third heart sound to detect ejection fraction < 45% was 67.9% while the specificity was 74.4%. The positive and the negative predictive values were 47.5% and 87.1%, respectively. The ejection fraction of patients having third heart sound was 47.5±11.3% compared to 56±10.4% without third heart sound (p<0.001).

Conclusions: Auscultation of third heart sound has a good specificity and predictive value for predicting elevated N-terminal pro brain natriuretic peptide and left ventricular dysfunction. Thus age-old clinical cardiology still holds its forte in this new era of technology-driven cardiology. (Indian Heart J 2005; 57: 31–34)

Key Words: Third heart sound, N-terminal pro brain natriuretic peptide, Left ventricular dysfunction

Auscultation of the third heart sound (S3) is an age-old sign for predicting left ventricular (LV) dysfunction. For most of this century, the stethoscope has served as a critical diagnostic tool in cardiovascular evaluation. Most importantly there is no cost involved and it is readily accessible. The new technology and biomarkers like two-dimensional (2D) echocardiography and N-terminal pro brain natriuretic peptide (NT- ProBNP) respectively, have sidelined the utility of this physical sign as an indicator of LV dysfunction. S3 is produced by the ‘sudden cessation of distention of the ventricle in early diastole’, as was first described by Potain in 1876.1 Abnormal S3 is seen due to the limitation of the longitudinal expansion of LV from altered physical properties. It is heard 120-200 ms after A2 and is a low frequency sound best heard in the left lateral position.2

The S3, when encountered in the older individual without primary valvular disease or disease states marked by high cardiac output, usually signifies reduced systolic function of one or both ventricles together with increased filling pressure within the affected chamber.3 When encountered in this setting, this sound virtually ensures that the left ventricular ejection fraction (LVEF) is below 50%; moreover, it is regularly present when the ejection fraction (EF) drops below 30%.4 The presence of S3 even when found in the setting of primary valvular disease, usually signals the presence of systolic dysfunction together with elevation of LV filling pressure.5,6 Imaging techniques that demonstrate ventricular enlargement and reduced systolic wall motion provide similar information, but the S3 additionally signifies the presence of an abnormally high filling pressure, and thus decompensation of the involved ventricle.

Barriers to the widespread use of this clinical tool involve unfamiliarity with physical diagnosis and clinical skills. As more sophisticated laboratory tests become available, they have the potential to replace our clinical skills and there is a risk that those skills will subsequently deteriorate as was seen in some recent studies.7,8 NT-ProBNP and 2D echocardiography are standards to identify LV dysfunction but the simple auscultation of S3 can reliably predict LV dysfunction and obviate the need for these expensive tests. Levels of NT-ProBNP also correlate with LV dilation, remodeling, dysfunction, and death among patients presenting with acute ST elevation myocardial infarction (STEMI).9 NT-ProBNP is a marker of LV dysfunction and has been established as a sensitive tool to diagnose heart failure.14,15 Therefore, we sought to find out the accuracy of S3 to suitably predict LV dysfunction and see its correlation with NT-ProBNP and EF in a patient population of acute coronary syndrome (ACS).

Methods

We studied 110 patients admitted to our department presenting with a diagnosis of ACS which included acute STEMI (n=74) and non-ST elevation MI (NSTEMI) (n=36). These patients were prospectively studied and a senior cardiologist, blinded to NT-ProBNP and EF results auscultated for an LV S3 in each patient. Blood was drawn in a fasting state within 8 hours of auscultation and assayed using the Elecsys ProBNP Electrochemi-luminiscence sandwich assay kit provided by Roche Diagnostics. The test is a 2 polyclonal antibody directed against NT-ProBNP, and has a measuring range of 5-35000 pg/ml. All patients were subjected to a detailed echocardiography and Doppler evaluation. Qualitative and quantitative assessment of segmental and global LV dysfunction was done in all patients with a Hewlett Packard Sonos 5500 machine and its calculation software. Patients were evaluated using modified Simpson’s technique to calculate the EF. The study was cleared by the ethics committee of the university and conformed to the guidelines of good clinical practice which included getting an informed consent from the patients. SPSS 11.5 software was used for analysis of the data obtained. The student’s t test, Fisher’s exact test and Chisquare test were used to test the significance between the study groups. Risk analysis was carried out by calculating odds ratio (OR) and 95% confidence interval (CI).

Results

S3 was present in 40 (36%) patients with more positives in STEMI group as compared to NSTEMI group [STEMI: n=27 (67%) v. NSTEMI: n=13 (33%)] and S3 was absent in 70 patients (STEMI: n=47, NSTEMI: n=23). The median levels of NT-ProBNP (1525 pg/ml) were taken to provide a dichotomous analysis of the data; the levels were above median in 90% (36/40) of the patients having S3 versus 27% (19/70) of those without S3. The maximal sensitivity of S3 to detect LV dysfunction, as defined with NT-ProBNP above median was 65.5% and the specificity was 92.7%. The positive predictive value was 90% while the negative predictive value was 73%. The mean NT-ProBNP of those having S3 in the full cohort was 4081±2705 pg/ml versus 1239±1169 pg/ml in those without S3 (p<0.001), with a Chi-square value of 40.23 (p<0.00001) and OR of 24.16 (95% CI 7.06-102.1). The presence of S3 was also correlated with a low EF (<45%) and the maximal sensitivity of S3 to detect EF below 45% was 67.9% while the specificity was 74.4%. The positive predictive value was 47.5% and the negative predictive value was 87.1%. The EF of patients in the cohort having S3 was 47.5±11.3% versus 56.0 ± 10.4% in those without S3 (p<0.001) with Chi-square value of 16.10 (p<0.001) and OR of 6.13 (CI 2.2-17.48) for the presence of S3 to indicate LV dysfunction as correlated with low EF (Table 1).

When the two subgroups (i.e. STEMI and NSTEMI) were analyzed separately, in the STEMI cohort NT - ProBNP levels in patients with S3 were 4436±2919 pg/ml versus 1554±1275 pg/ml in those without S3 (p<0.001), while in the NSTEMI cohort NT-ProBNP with S3 it was 3342±2110 pg/ml and 595±491 pg/ml in those without S3 (p<0.001). No significant difference was seen in the NTProBNP levels if S3 was present, depending on the type of MI i.e. STEMI or NSTEMI. In patients having S3 along with a STEMI, NT-ProBNP levels were 4436±2919 pg/ml while in NSTEMI with S3 it was 3342±2110 pg/ml (p=0.25).

However, a significant difference was seen between the groups with regards to the NT-ProBNP levels if S3 was absent (1554±1275 pg/ml in STEMI v. 595±491 pg/ml in NSTEMI (p=0.005). Similarly, when the EF was analyzed separately in the two subgroups, in the STEMI cohort EF in patients with S3 it was 47±11% versus to 54±10% in those without S3 (p<0.001), while in the NSTEMI cohort EF with S3 was 49±11% versus 61±9.7% without S3 (p< 0.01). Again, no significant difference was seen in EF depending on the type of MI, if S3 was present (p=0.60) while difference was significant when S3 was not present (p=0.02) (Table 2). The correlation of S3, NT-ProBNP and low EF showed a positive correlation in the full cohort and in the STEMI subgroup but significant correlation was not seen in the NSTEMI cohort presumably due to the small size of myocardial damage and lesser LV dysfunction (Table 3).

Discussion

The presence of LV dysfunction is the most important prognostic factor in assessing risk in patients with ACS. In the present practice LV functions, as measured by 2D echocardiography and more recently NT-ProBNP, have assumed importance as gold standards both for detecting LV dysfunction and for prognosticating in ACS. Not long ago, the role of S3 as a clinical sign was considered a reliable indicator of LV dysfunction and an adverse prognostic index in ACS. Of late, interest in this clinical sign seems to have diminished and the skills needed to identify it also seem to be declining.7 The common belief associated with S3 is that it is abnormal beyond 40 years of age and is recognized by the ‘company it keeps’.10 As a matter of fact it is produced by the decreased rate of filling into ventricle along with the ventricle having a large end-systolic volume;11 it may also be produced by the dynamic impact of LV to chest wall in these patients.12 More importantly the presence of S3 in AMI reflects severe LV dysfunction and also predicts a higher mortality.13 In recent time the data regarding BNP/NTProBNP is accumulating rapidly and its usefulness is being reiterated. BNP is a marker of high LV end-diastolic pressure in symptomatic patients of LV dysfunction14 and its usefulness in the diagnosis of heart failure in an urgent care setting has been established.15,16 Recently data is emerging on the role of NT-ProBNP in risk stratification of patients of ACS. Its value in predicting both short- and longterm poor outcome, including LV dysfunction and mortality has been shown by a recent meta analysis by Galvani et al.17 Packer18 has raised doubts regarding the usefulness of BNP and the decisional cut off levels required to diagnose heart failure, but data continues to pour in with a number of studies favoring the role of BNP/NT-ProBNP in diagnosing and guiding therapy. Cleland and Goode19 stated that natriuretic peptides have evolved from being fashionable to useful, to being necessary now. Although clinical judgment, along with the utility of S3, is supreme but in this era of evidence-based medicine it would be prudent to quantify the same if possible, specially to root out the alarming decline in clinical skills as was reported by Magione and Nieman.7 Study by Marcus et al.16 also brought out the usefulness of the S3 in predicting an elevated level of BNP. They studied a heterogeneous group of 100 consecutive adult outpatients presenting to a general cardiology clinic prospectively and measured BNP levels within 8 hours. They concluded that mean BNP levels were significantly higher in patients with an S3. The presence of S3 was 41% sensitive and 97% specific for elevated BNP levels.

In our study this clinical sign was associated with significantly higher mean levels of NT-proBNP in the presence of an auscultable S3 (4081± 2705 pg/ml v. 1239±1169 pg/ml, p<0.001) irrespective of whether the patient had STEMI or NSTEMI. Using a cut off median value 1532 pg/ml, the correlation of S3 to predict NT-ProBNP above median in patients of ACS had a sensitivity of 65.5% and specificity of 92.7%. The positive and negative predictive values were 90% and 73% respectively for S3 to indicate high NT-ProBNP. This in turn suggests LV dysfunction along with poorer adverse outcomes and need for more attention to this sign. However, absence of S3 could have different implications in the two groups i.e. STEMI and NSTEMI. Absence of S3 in a transmural MI (STEMI) was still associated with high mean NT-ProBNP levels (1554±1275 pg/ml), while in NSTEMI, mean levels were significantly lower (595±491 pg/ml) thus suggesting that LV dysfunction may still be present albeit sub clinically, that is not detectable as far as S3 is concerned. Although decisional cut off levels, specially in ACS, have not been ascertained yet the median levels provide useful dichotomous approach.

ACS ranges from unstable angina to a small nontransmural MI to a large transmural MI with NT-ProBNP levels rising in a continuum depending on the size of the infarct and degree of LV dysfunction. S3 appears at a point somewhere along the curve where LV dysfunction is hemodynamically significant. By this time NT-ProBNP levels are also significantly high. Our findings suggest that S3 must be meticulously looked whether the patient has NSTEMI or STEMI, as the presence of this cost-free test does away with the need for expensive investigations which may not be universally available. If S3 is absent and the patient has NSTEMI, one can safely rule out LV dysfunction, and expect a good prognosis. In case of an STEMI however, if S3 is absent, NT-ProBNP may need to be measured and is required for prognostication as LV dysfunction might still be present.

Similar observations were made when S3 was correlated with LVEF as measured on 2D echocardigraphy. Patients with an S3 had a lower LVEF whether having STEMI or NSTEMI. Those without S3 had a significantly higher LVEF in NSTEMI group only (61±9.7% v. 54±10.0%, p<0.05). This strengthens our view that the presence of S3 in STEMI or NSTEMI and its absence in NSTEMI means you may not require a 2D echocardiography if the latter is not readily accessible. Sensitivity of S3 to detect LVEF <45% (67.9%) was comparable to the sensitivity of detecting raised NTProBNP (65.5%) but the specificity to detect low EF in the presence of S3 with echocardiography (74.4%) was much lower than with NT-ProBNP (92.7%), possibly because of the inter- and intra-observer variability which is inherent while using 2D echocardiography.

Conclusions: Auscultation of the third heart sound has good specificity and predictive values for predicting LV dysfunction, and correlates suitably with expensive tests such as NT-ProBNP levels and 2D echocardiography. Thus, the age-old clinical cardiology still holds its forte in this new era of technology-driven cardiology.

Correspondence:

Dr Aniket Puri,
B - 58 Sector A,
Mahanagar Lucknow 226006.
e-mail: aniket1@sancharnet.in, aniketpuri@hotmail.com

References

  1. Potain PC. Concerning the cardiac rhythm called gallop rhythm. Bull Mem Soc Med Hop Paris 12:137, 1876; In: Major RH (ed). Classic Description of Disease, 3rd ed. Springfield, IL, Charles C Thomas, 1948, p388

  2. Ozawa Y, Smith D, Craige E. Origin of the third heart sound. II Studies in human subjects. Circulation 1983; 67: 399–404

  3. Shah PM, Yu PN. Gallop rhythm: hemodynamic and clinical correlation. Am Heart J 1969; 78: 823–828

  4. Patel R, Bushnell DL, Sobotka PA. Implications of an audible third heart sound in evaluating cardiac function. West J Med 1993; 158: 606–609

  5. Abdulla AM, Frank MJ, Erdin RA Jr, Canedo MI. Clinical significance and hemodynamic correlates of the third heart sound gallop in aortic regurgitation: a guide to optimal timing of cardiac catheterization. Circulation 1981; 64: 464–471

  6. Folland ED, Kriegel BJ, Henderson WG, Hammermeister KE, Sethi GK. Implications of third heart sounds in patients with valvular heart disease. N Engl J Med 1992; 327: 458–462

  7. Mangione S, Nieman LZ. Cardiac auscultatory skills of internal medicine and family practice trainees: a comparison of diagnostic proficiency. JAMA 1997; 278: 717–722

  8. Conti CR. The stethoscope: the forgotten instrument in cardiology? Clin Cardiol 1997; 20: 911–912

  9. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347: 161–167

  10. Craige E. Gallop rhythm. Prog Cardiovasc Dis 1967; 10: 246–261

  11. Reddy PS, Meno F, Curtis EI, O’Toole JD. The genesis of gallop sounds. Investigation by quantitative phono- and apexcardiography. Circulation 1981; 63: 922–933

  12. Shaver JA, Reddy PS, Alvares RF, Salerni R. Genesis of physiologic third heart sound. Am J Non Invas Cardiol 1987; 1: 39–55

  13. Braunwald E, Antman EM. Acute myocardial infarction. In: Braunwald, Zipes, Libby (eds). Heart Disease, 6th ed. Harcourt International, 2001; p 1130

  14. Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J 1998; 135: 825–832

  15. Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R, Lenert L, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent care setting. J Am Coll Cardiol 2001; 37: 379–385

  16. Marcus GM, Michaels AD, De Marco T, McCulloch CE, Chatterjee K. Usefulness of the third heart sound in predicting an elevated level of B-type natriuretic peptide. Am J Cardiol 2004; 93: 1312–1313

  17. Galvani M, Ferrini D, Ottani F. Natriuretic peptides for risk stratification of patients with acute coronary syndromes. Eur J Heart Fail 2004; 6: 327–333

  18. Packer M. Should B-type natriuretic peptide be measured routinely to guide the diagnosis and management of chronic heart failure? Circulation 2003; 108: 2950–2953

  19. Cleland JC, Goode K. Natriuretic peptides for heart failure. Fashionable? Useful? Necessary? Eur J Heart Fail 2004; 6: 253–255