Circ J 2018; 82: 509 – 516 ORIGINAL ARTICLE doi: 10.1253/circj.CJ-17-0650 Myocardial Disease
Third and Fourth Heart Sounds and Myocardial Fibrosis in Hypertrophic Cardiomyopathy
Yoshimi Sato, MD; Tatsuya Kawasaki, MD, PhD; Sakiko Honda, MD; Kuniyasu Harimoto, MD; Shigeyuki Miki, MD, PhD; Tadaaki Kamitani, MD, PhD; Hirokazu Shiraishi, MD, PhD; Satoaki Matoba, MD, PhD
Background: The 4th heart sound (S4) is commonly heard in patients with hypertrophic cardiomyopathy (HCM). The 3rd heart sound (S3) is also audible in HCM patients regardless of the presence or absence of heart failure. These extra heart sounds may be associated with myocardial fibrosis because myocardial fibrosis has been suggested to affect left ventricular compliance.
Methods and Results: The present retrospective study evaluated 53 consecutive HCM patients with sinus rhythm who had no symptoms of heart failure and underwent an initial assessment including phonocardiography, echocardiography, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI). S3 was detected on phonocardiography in 13% of all patients, and S4 was recorded in 75% of patients. Patients with S3 had a higher incidence of LGE and larger LGE volumes (86% and 11.5±2.4 g/cm, respectively) than patients without S3 (33% and 2.5±0.8 g/cm, respectively; P=0.02 and P=0.002). The presence of S4 was not associated with MRI findings, including the incidence of LGE and LGE volume. The diagnostic value of S3 for the detection of LGE was highly specific (97%), with a low sensitivity (29%).
Conclusions: Myocardial fibrosis, as assessed by LGE, was associated with S3 but not with S4 in patients with HCM. These results may contribute to the risk stratification of patients with HCM.
Key Words: 3rd heart sound; 4th heart sound; Hypertrophic cardiomyopathy; Late gadolinium enhancement; Phonocardiography
he 4th heart sound (S4) is commonly heard in Methods patients with hypertrophic cardiomyopathy (HCM) T with a sinus rhythm.1,2 The derivation of S4 may be Study Population the result of a forceful left atrial contraction into a non- The present retrospective study was performed on 53 compliant left ventricle (LV).3,4 The third heart sound (S3) consecutive patients with HCM (mean age 66 years; range is also heard, although less frequently than S4, in patients 37–91 years) who underwent an initial assessment, including with HCM regardless of the presence or absence of heart phonocardiography, echocardiography, LGE-MRI, and failure.1,2 The exact mechanism responsible for S3 in HCM biomarker measurements, in Matsushita Memorial Hospital. patients remains unclear, reduced LV compliance due to All patients were clinically stable without symptoms of myocardial hypertrophy has been proposed.5 heart failure, such as dyspnea, fatigue, and edema. Although Patients with HCM often develop LV myocardial fibrosis, these initial examinations were not necessarily performed which may be assessed non-invasively using late gadolinium on the same day, there were no patients with clinical condi- enhancement (LGE) magnetic resonance imaging (MRI).6,7 tions that changed over the period of the assessments. The In addition to myocardial hypertrophy, myocardial fibrosis diagnosis of HCM was based on the conventional echocar- can alter LV compliance, which leads to the development diographic demonstration of LV end-diastolic thickness of S4 and S3; however, limited information is available on ≥15 mm and LV end-diastolic diameter (LVEDD) ≤55 mm the effects of myocardial fibrosis on these extra heart in the absence of any cardiac or systemic disorder that may sounds in patients with HCM. Thus, the aims of the present cause LV hypertrophy, such as severe hypertension, study were to examine the relationships between myocardial defined as blood pressure ≥160/100 mmHg, or aortic stenosis, fibrosis, as assessed by LGE-MRI, and S3 and S4 in defined as an aortic valve area <1.5 cm2. Exclusion criteria patients with HCM. were non-sinus rhythm, a previous history of myocardial
Received June 16, 2017; revised manuscript received August 1, 2017; accepted August 4, 2017; released online September 16, 2017 Time for primary review: 20 days Department of Cardiology, Matsushita Memorial Hospital, Moriguchi (Y.S., T. Kawasaki, S.H., K.H., S. Miki, T. Kamitani); Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (H.S., S. Matoba), Japan Mailing address: Yoshimi Sato, MD, Department of Cardiology, Matsushita Memorial Hospital, 5-55 Sotojima, Moriguchi 570-8540, Japan. E-mail: [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]
Circulation Journal Vol.82, February 2018 510 SATO Y et al.
Figure 1. Representative results of phonocardiography and magnetic resonance imaging in two different cases. (A–C) Case 1. (A) The phonocardiogram shows the 4th heart sound (S4) before the 1st heart sound (S1), as well as the 3rd heart sound (S3) after the 2nd heart sound (S2), in a 49-year-old man with hypertrophic cardiomyopathy (HCM). (B) A cine image at the end- diastolic phase on magnetic resonance imaging (MRI) shows asymmetric septal hypertrophy with a maximum wall thickness of 25.4 mm. (C) Late gadolinium enhancement (LGE) is detected in the ventricular septum (arrows) and the area of the inferior ventricular septum-free wall junction (arrowhead). The late gadolinium enhancement (LGE) volume and %LGE in this patient were calculated to be 3.0 g/cm and 5.0%, respectively. (D–F) Case 2. (D) S4, but not S3, is seen on the phonocardiogram of a 77-year- old man with HCM. Myocardial hypertrophy is observed predominantly in the anterior and inferior walls and ventricular septum (E) without LGE (F).
infarction, clinically significant valvular heart disease antagonists, 12 had taken β-blockers (but only 1 had taken (including moderate or more severe mitral regurgitation), high doses, defined as carvedilol >10 mg/day, metoprolol renal dysfunction (defined as an estimated glomerular >5 mg/day, atenolol >50 mg/day, and propranolol filtration rate <60 mL/min/1.73 m2), mechanical device >30 mg/day), 3 had taken diuretics, and 3 had taken antiar- implantation, septal myectomy, alcohol septal ablation, or rhythmic drugs; none had taken amiodarone. Informed heart transplantation. Furthermore, HCM patients with consent for the assessments was obtained from all patients systolic dysfunction, defined as an LV ejection fraction with HCM. (LVEF) ≤50%, were excluded from the study because the prognosis for these HCM patients differs from that of MRI patients in other HCM subgroups.8,9 Coronary artery LGE-MRI was performed using a 1.5-Tesla imaging system disease was ruled out in all patients on the basis of con- (Signa HDx; GE Medical Systems, Milwaukee, WI, USA), ventional coronary angiography, multidetector computed as described previously.10–13 Briefly, the steady state free tomography, or exercise myocardial perfusion scintigraphy. procession of cine images was obtained and maximum Among all patients examined, 21 had taken calcium LV wall thickness and LV mass were calculated using
Circulation Journal Vol.82, February 2018 S3 and S4 and Myocardial Fibrosis in HCM 511 commercially available software (Plissimo Ex Version Milwaukee, WI, USA) using a standard method.17 Briefly, 1.0.4.5; Panasonic Medical Solutions, Osaka, Japan). LVEDD, LVEF, left atrial end-systolic diameter, mitral Approximately 10 min after an intravenous injection of early diastolic velocity (E), late diastolic velocity (A), and 0.1 mmol/kg gadopentetate dimeglumine (Magnevist; early septal mitral annular velocity (E′) were measured, Schering, Berlin, Germany), LGE images were obtained in and the E : A and E : E′ ratios were calculated. An LV long- and short-axis views at the basal, mid-, and apical outflow tract obstruction was considered present when the LV levels under serial breath-holds using a 2-dimensional, peak flow velocity was >2.5 m/s as determined by Doppler spoiled, and segmented inversion recovery and gradient- imaging under resting conditions or after the Valsalva echo sequence. LGE was defined as 2 standard deviations maneuver. above the mean signal intensity of an apparently normal myocardium, and the extent of LGE (LGE volume, Biomarkers expressed in g/cm) and the proportion of the LGE volume Serum concentrations of high-sensitivity cardiac troponin to LV mass, expressed as a percentage (%LGE), were T (hs-cTnT) and plasma concentrations of atrial natriuretic calculated. The location of LGE was identified on the basis peptide (ANP) and B-type natriuretic peptide (BNP) were of a 17-segment model of the LV: 1 apex segment on a measured using commercially available kits, as described vertical long-axis view and 16 segments on 3 short-axis previously10,18,19 (Elecsys Troponin T hs [Roche Diagnostics, views. Mannheim, Germany], MI02 Shionogi ANP [Shionogi & Co., Osaka, Japan], and MI02 Shionogi BNP [Shionogi & Phonocardiography Co.], respectively). The analytical range and normal A phonocardiogram was obtained at the apex as well as reference range of the assays were as follows: 0.003– at the right and left sternal borders in the half left lateral 99,900,000.000 and <0.014 ng/mL for hs-cTnT; 5.1–1,290.0 decubitus position as well as in the supine position at a and <43.0 pg/mL for ANP; and 4.0–2,000.0 and <18.4 pg/mL paper speed of 50 or 100 mm/s using a commercially for BNP. available device (MES-1000; Fukuda-Denshi, Tokyo, Japan),14,15 as shown in Figure 1. Measurements included Statistical Analysis 4 frequencies: low, lower-middle, higher-middle, and high Categorical variables were compared by the Chi-squared frequency. The cut-off frequency, attenuation, Nyquist rate, test or Fisher’s exact test where appropriate. Continuous and differential sensitivity were: 50 Hz, −6 dB/octave (oct), variables are expressed as the mean ± SD and were com- 1, and −32 dB, respectively, for the low frequency; 50 Hz, pared using Student’s t-test. LGE volume, %LGE, and −18 dB/oct, 3, and −32 dB for the lower-middle frequency; levels of biomarkers (hs-cTnT, ANP, and BNP) are 160 Hz, −24 dB/oct, 4, −16 dB for the higher-middle fre- expressed as the mean±SEM and were compared using the quency; and 315 Hz, −24 dB/oct, 4, and 0 dB for the high Mann-Whitney U-test or Kruskal-Wallis test followed by frequency. When an apex cardiogram was recorded, a Bonferroni correction for multiple comparisons because of simultaneous apical phonocardiogram was obtained near possibly skewed distributions. The Spearman rank correla- the apex because the microphone of the apex cardiogram tion coefficient was used to examine relationships between was placed exactly at the apex. indices of S3 and S4 and the LGE volume and %LGE. In the present study, S3 was defined as an extra sound Two-sided P<0.05 was considered significant. The predictive that had a predominant distribution at the apex as well as value of the presence of S3 for the detection of LGE was a low frequency that occurred after the 2nd heart sound also examined by multiple logistic regression analysis after (S2) during early diastole and coinciding with the peak of adjustment for baseline characteristics that had P-values the rapid-filling wave on an apex cardiogram if available.16 <0.05 in univariate analyses. All calculations were per- Similarly, S4 was considered present when a low-frequency formed using SPSS version 11.0 (SPSS Inc., Chicago, IL, sound was recorded best at the apex after the onset of the USA) and StatView 5.0 (SAS Institute Inc., Cary, NC, P wave of an electrocardiogram and before the onset of the USA). QRS complex, coinciding with a large peaked A wave in 16 an apex cardiogram if available. Both S3 and S4 needed Results to have an amplitude of ≥1.0 mm on the phonocardiogram with the above-described settings. The presence or absence MRI revealed maximal LV wall thickness of 21.0±5.7 mm of S3 and S4 was assessed by 2 experienced cardiologists; and an LV mass of 66.8±21.7 g/cm. The location of myo- disagreement was resolved by consensus. All analyses, cardial hypertrophy was the ventricular septum in 42 including the time interval between the onset of the P wave patients (79%), the anterior wall in 16 (31%), the apex in 11 on the electrocardiogram and S4, as well as that between (21%), the lateral wall in 11 (21%), and the inferior wall in the onset of S2 and S3 and the amplitudes of S3 and S4, 2 (4%). LGE was detected in 21 of 53 patients (44%): the were measured in the low-frequency range of the phono- ventricular septum in 15, the anterior wall in 8, the apex in cardiogram in the same setting. Although the duration of 4, and the inferior wall in 2. Median LGE volume was S3 was also measured, that of S4 was not because it is often 6.0 g/cm (range 0.1–25.3 g/cm) and median %LGE was difficult to clearly separate S4 from the 1st heart sound 11.0% (range 0.2%–38.0%). (S1).11 The presence or absence of S3 and S4 on auscultation S3 was observed in 7 of 53 patients with HCM (13%), was also assessed in all but 2 patients by a single experienced and S4 was detected in 40 patients (75%). There were no cardiologist who was unaware of the results of phonocar- significant differences in heart rate on phonocardiography diography. between patients with and without S3 (62±13 vs. 63±11 beats/min, respectively; P=0.65) or between patients Echocardiography with and without S4 (62±10 vs. 66±13 beats/min, respec- An echocardiographic examination was performed using tively; P=0.89). Table 1 lists the clinical characteristics of commercially available equipment (Vivid 9; GE Healthcare, patients with and without S3 or S4. The presence of S3 was
Circulation Journal Vol.82, February 2018 512 SATO Y et al.
Table 1. Clinical Characteristics of Patients With and Without Third (S3) or Fourth (S4) Heart Sounds S3 S4 P value P value Present (n=7) Absent (n=46) Present (n=40) Absent (n=13) Age (years) 57±11 67±12 0.03 64±12 72±12 0.06 No. women 1 (14) 10 (22) 0.55 7 (18) 4 (31) 0.92 BMI (kg/m2) 23.2±1.7 24.1±3.6 0.32 23.6±3.1 25.3±4.0 0.18 Echocardiography LVEDD (mm) 45±8 44±6 0.78 44±6 44±8 0.68 LVEF (%) 65±6 65±6 0.97 66±6 64±4 0.10 LAD (mm) 37±4 37±6 0.80 37±5 38±7 0.79 E wave (cm/s) 73±21 64±18 0.32 64±19 70±18 0.39 A wave (cm/s) 52±28 76±21 0.07 70±25 83±19 0.09 E/A 1.9±1.6 0.9±0.4 0.15 1.1±0.8 0.9±0.4 0.30 Mitral annular E′ (cm/s) 5.0±1.6 4.6±1.6 0.57 4.8±1.6 4.2±1.3 0.25 E/E′ 16.2±7.0 15.3±5.9 0.76 14.6±5.5 17.9±7.0 0.14 LV outflow tract obstruction 2 (29) 3 (7) 0.12 3 (8) 2 (15) 0.91 Magnetic resonance imaging Location of hypertrophy* 0.96 0.87 Septal 7 (100) 35 (76) 31 (78) 11 (85) Anterior 2 (29) 14 (30) 12 (30) 4 (31) Apical 2 (29) 9 (20) 9 (23) 2 (15) Lateral 2 (29) 9 (20) 9 (23) 2 (15) Inferior 0 2 (4) 1 (3) 1 (8) Maximal wall thickness (mm) 23.2±6.6 20.6±5.5 0.27 20.4±5.3 22.8±6.7 0.19 LV mass (g/cm) 75.1±18.5 65.6±22.1 0.28 66.1±19.8 69.1±27.8 0.67 LGE 6 (86) 15 (33) 0.02 17 (43) 4 (31) 0.34 LGE volume (g/cm) 11.5±2.4 2.5±0.8 0.002 3.8±1.0 2.6±1.3 0.52 %LGE 15.2±2.8 3.3±1.1 0.001 4.8±1.3 3.4±1.6 0.55 Biomarkers High-sensitivity cTnT (ng/mL) 0.020±0.009 0.013±0.002 0.35 0.014±0.003 0.013±0.003 0.98 ANP (pg/mL) 81±16 69±7 0.38 69±6 78±15 0.59 BNP (pg/mL) 129±34 96±17 0.16 102±19 93±25 0.89 Data are given as the mean ± SD or as n (%), except late gadolinium enhancement (LGE) indices and biomarkers, which are given as the mean ± SE. *Some patients had 2 or more hypertrophic sites. ANP, atrial natriuretic peptide; BMI, body mass index; BNP, B-type natriuretic peptide; cTnT, cardiac troponin T; LAD, left atrial dimension; LV, left ventricular; LVEDD, LV end-diastolic diameter; LVEF, LV ejection fraction.
associated with a younger age, but not with echocardio- 86%, and a negative predictive value (NPV) of 67%. graphic indices or hypertrophic sites as assessed by MRI. Measurements of hs-cTnT, ANP, and BNP were possible The incidence of LGE, LGE volume, and %LGE were in 52 (98%), 52 (98%), and 51 (96%) patients, respectively, significantly higher in patients with than without S3. The with mean concentrations of 0.014 ng/mL (range 0.003– presence of S4 was not significantly associated with 0.072 ng/mL) for hs-cTnT, 71 pg/mL (range 17–195 pg/mL) echocardiographic indices or MRI findings, including the for ANP, and 100 pg/mL (range 6–582 pg/mL) for BNP. incidence of LGE, LGE volume, and %LGE. There were no significant differences in the concentrations There was no significant difference between those with of these 3 biomarkers between patients with and without and without S3 in terms of the proportion of patients S3 or S4 (Table 1). taking calcium antagonists (14% vs. 43%, respectively; In the 7 HCM patients with S3, the time interval from P=0.15), β-blockers (29% vs. 22%, respectively; P=0.42), the onset of S2 to S3 was 180±43 ms (range 120–240 ms); 3 diuretics (0% vs. 7%, respectively; P=0.77), and antiar- patients had a time interval ≥200 ms. As shown in Table 2, rhythmic drugs (0% vs. 7%, respectively; P=0.77). Among the time interval from the onset of S2 to S3 was positively all 53 patients, 7 had both S3 and S4, 33 had S4 but not S3, correlated with LGE volume (correlation coefficient=0.82, and 13 did not have either S3 or S4; no patients had S4 but P=0.04) and %LGE (correlation coefficient=0.86, P=0.04). not S3. The presence of S3 was associated with an increased The duration and amplitude of S3 were 82±40 ms and incidence of LGE and increased LGE volume and %LGE 2.6±2.6 mm, respectively; these parameters were not corre- (Figure 2). Multiple logistic regression analysis after lated with LGE variables. The interval period from the P adjustment for age showed that S3 was an independent wave to S4 and the amplitude of S4 were 109±33 ms and predictor for the presence of LGE (odds ratio [OR] 10.4; 6.2±5.1 mm, respectively; these parameters were not corre- 95% confidence interval 1.1–99.9; P=0.04). The diagnostic lated with LGE volume or %LGE in any of the 40 patients value of the presence of S3 was highly specific for the with S4. detection of LGE, with a sensitivity of 29%, specificity of During a mean follow-up period of 24 months (range 97%, accuracy of 70%, positive predictive value (PPV) of 3–39 months), 6 patients with S3 and 8 patients without S3
Circulation Journal Vol.82, February 2018 S3 and S4 and Myocardial Fibrosis in HCM 513
Figure 2. Late gadolinium enhancement (LGE) and extra heart sounds. (A) Incidence of LGE, (B) LGE volume, and (C) %LGE are significantly higher in patients with both 3rd (S3) and 4th (S4) heart sounds (n=7) than in patients who have S4 but not S3 (n=33), or in patients who have neither S3 nor S4 (n=13). No patient had S3 but not S4. Data are the mean ± SD. *P<0.05 compared with patients who have S4 but not S3 and patients who do not have either S3 or S4.
Table 2. Relationships Between LGE Indices and Features of Third (S3) or Fourth (S4) Heart Sounds LGE volume (g/cm) %LGE Correlation coefficient P value Correlation coefficient P value S3 (n=7) Interval from S2 (ms) 0.82 0.04 0.86 0.04 Amplitude (mm) −0.01 0.77 −0.01 0.77 Duration (ms) −0.13 0.65 −0.28 0.41 S4 (n=40) Interval from P wave (ms) −0.24 0.14 −0.23 0.15 Amplitude (mm) −0.035 0.83 −0.036 0.82 LGE, late gadolinium enhancement.
Figure 3. Follow-up phonocardiography. (A) Neither 3rd (S3) nor 4th (S4) heart sounds were observed at the initial assessment of a 65-year-old woman with hypertrophic cardiomyopathy (HCM). (B,C) Magnetic resonance imaging showed a hypertrophied ventricular septum (B) with mildly positive late gadolinium enhancement (LGE) in the inferior ventricular septum-free wall junction (C; arrow). (D) Note that 27 months later soft S3 develops (arrow), along with soft S4 (arrowhead); the inset shows the same data on an enlarged vertical scale.
Circulation Journal Vol.82, February 2018 514 SATO Y et al. underwent repeated phonocardiography. All 6 HCM tions in all patients. The age of subjects also needs to be patients with S3 at initial phonocardiography had S3 at the taken into consideration. In a previous study,2 a higher time of the follow-up study. None of the remaining 8 incidence of S3 (39.7% in non-obstructive HCM and 36.5% patients without S3 at the initial study had S3 in the follow- in obstructive HCM) was observed in relatively young up study, except for 1 patient, in whom LGE was positive patients (on average, 34.1 years, including other dilated and soft S3 and S4 developed 27 months after initial cardiomyopathies) compared with those in the present phonocardiography (Figure 3). study. Even in the present study, HCM patients with S3 Among the 51 patients in whom auscultation assessment were significantly younger than HCM patients without S3. was performed by a single experienced cardiologist, S3 was In addition, heart rate has been identified as a factor affecting detected on auscultation in 4 of 7 patients who had S3 on S3, with slower heart rates more likely to produce S3.5 In phonocardiography. Two patients had S3 on auscultation the present study, no significant differences were observed despite the absence of S3 on phonocardiography. The in the heart rate between patients with and without S3 at concordance regarding S3 between auscultation and the time of phonocardiography. phonocardiography was 71%. The incidence of LGE, LGE Conditions associated with the development of patho- volume, and %LGE were significantly higher in patients logical S3 include a high left atrial pressure, ventricular with S3 on auscultation than in those without S3 on enlargement, and, most commonly, impaired LV function.5 auscultation (83% vs. 36% [P=0.02], 8.8±3.4 vs. 3.0±0.9 g/cm Thus, S3 is often observed in patients with dilated cardio- [P=0.04], and 10.4±3.7% vs. 3.9±1.1% [P=0.03], respec- myopathy and extensive ischemic heart disease as well as tively). The presence of S3 on auscultation for the detection valvular heart diseases (e.g., severe mitral regurgitation). of LGE had a sensitivity of 24%, specificity of 97%, accuracy In a study on unselected patients subjected to phonocardi- of 67%, PPV of 83%, and NPV of 64%. S4 was heard in 28 ography, echocardiography, and cardiac catheterization of 39 patients with S4 on phonocardiography, whereas 5 within a 4-h period in which more than 70% of patients patients were diagnosed with S4 on auscultation despite had coronary artery disease,28 important determinants of the absence of evidence of S4 on phonocardiography S3 included heart failure symptoms, increased E : A and (concordance=69%). The presence of S4 on auscultation E : E′ ratios, lower LVEF, and higher BNP concentrations. was not significantly associated with the incidence of LGE, None of these findings is consistent with the results of the LGE volume, or %LGE (52% vs. 22% [P=0.08]; 4.6±1.2 vs. present study. This may be explained by differences in 1.9±1.0 g/cm [P=0.10], and 5.8±1.6% vs. 2.5±1.2% [P=0.10], baseline characteristics (i.e., patients with ischemic heart respectively). disease and patients with HCM). It is also important to note that pathological S3 appears to be heard in non- 5 Discussion compliant LV, for example HCM regardless of heart failure. In the present study, S3 was associated with myocardial The present study showed that S4 was commonly observed fibrosis as assessed by LGE-MRI. Because determinants of (75%) and that S3 was not rare (13%) in patients with LV compliance are supposed to include myocardial fibrosis, HCM. The presence of S3 was correlated with a high the results of the present study are acceptable; however, incidence of LGE and an increased LGE volume and direct evidence of the underlying mechanisms has not yet %LGE, but not with echocardiographic indices or bio- been obtained. markers (i.e., hs-cTnT, ANP, and BNP). The diagnostic In the present study, the interval from the onset of S2 to value of S3 for the detection of LGE was highly specific S3 was positively correlated with LGE volume and %LGE, (97%), with a low sensitivity (29%). Conversely, the presence despite the limited number of patients with S3. Time intervals of S4 was not correlated with echocardiographic indices, were ≥200 ms in 3 of 7 patients with S3, although S3 generally LGE findings, or biomarker levels. appears almost 100–200 ms after S2.16 These findings Since the description of S3 by Pontains in the 19th indicate that the mechanisms responsible for S3 in patients century,20 its detection has been valuable because it is a with HCM may differ from those in other diseases (e.g., good indicator of ventricular dysfunction and is indepen- dilated cardiomyopathy and mitral regurgitation) because dently associated with adverse outcomes.5,21,22 The proposed a pressure-flow study performed on dogs revealed that the mechanisms responsible for S3 include internal production relatively early timing of S3 may be due to a high LV filling (valvular origin or ventricular origin) and external produc- rate produced by volume loading and elevated afterload.29 tion (chest wall origin).5,23,24 Although debate regarding the The results of the present suggest that a high LV filling rate mechanisms underlying S3 has persisted, a ventricular origin is not a major cause of the development of S3 in patients (i.e., ventricular vibrations as a consequence of rapid filling with HCM. This appears to be supported by the fact that in early diastole) is most widely accepted.23,24 It is important neither BNP nor ANP concentrations were associated with to note that physiological S3 is common in healthy children the presence or absence of S3 in the present study, because and adolescents,5 even in adults approaching their 40 s.25 levels of these biomarkers may become elevated with Nevertheless, S3 in the present study was considered to be increases in ventricular and atrial pressure.30,31 Further pathological because of the age of the patients (i.e., 57 studies are warranted to examine the features of S3 in years on average) and underlying cardiac conditions (i.e., association with filling rates, as well as myocardial fibrosis myocardial hypertrophy associated with HCM). in HCM patients. The incidence of S3 in HCM patients in the present study S4 is considered to be derived primarily from vibrations was 13%. In other studies, the incidence varied, ranging in the mitral valve leaflets and chordae tendineae when the from 4% to nearly 40%.2,26,27 This discrepancy may be ventricles expand as a result of the rapid inflow of blood by explained by a number of factors, such as detection methods atrial contractions.32 Because S4 has its origins in impaired (i.e., auscultation vs. phonocardiography) and detection ventricles, such as a non-compliant LV or one with limited skills (i.e., experts vs. non-experts). In the present study, distensibility,3,4 it is reasonable to assume that myocardial phonocardiography was used to assess S3 with clear defini- fibrosis is related to the development of S4. However, this
Circulation Journal Vol.82, February 2018 S3 and S4 and Myocardial Fibrosis in HCM 515 association was not observed in the present study. These Acknowledgments results indicate that the presence of S4 has limited utility as The authors thank Drs Hiroki Sugihara, Haruhiko Adachi, and a marker of myocardial fibrosis. Although the underlying Hiroshi Katsume for their thoughtful comments on the manuscript. mechanisms have not yet been elucidated, the presence of S4 may be too common for it to be a good indicator for the Conflict of Interest detection of myocardial fibrosis. Three-quarters of patients with a sinus rhythm had S4, whereas the incidence of None declared. positive LGE was 40%. Factors other than myocardial fibrosis may be responsible for S4, because the ventricular References walls may become less distensible not only because of 1. Shaver JA, Alvares RF, Reddy PS, Salerni R. Phonoechocar- myocardial fibrosis, but also myocardial hypertrophy and diography and intracardiac phonocardiography in hypertrophic 16 cardiomyopathy. Postgrad Med J 1986; 62: 537 – 543. ischemia. These conditions are considered to coexist in 2. Kawai C, Sakurai T, Fujiwara H, Matsumori A, Yui Y. Hyper- most patients with HCM.33–35 trophic obstructive and non-obstructive cardiomyopathy in Japan: Diagnosis of the disease with special reference to endomyo- Clinical Implications cardial catheter biopsy. Eur Heart J 1983; 4(Suppl F): 121 – 125. 3. Goodwin JF. The frontiers of cardiomyopathy. Br Heart J 1982; Myocardial fibrosis as assessed by LGE-MRI has been 48: 1 – 18. 36 38 associated with adverse outcomes in patients with HCM. – 4. Shaver JA, Salerni R, Reddy PS. Normal and abnormal heart A systemic review including 1,063 HCM patients over a sounds in cardiac diagnosis. Part I: Systolic sounds. Curr Probl mean follow-up period of 3.1 years showed that LGE had Cardiol 1985; 10: 1 – 68. significant prognostic value for all-cause mortality (OR 5. Constant J. The third heart sound (S3). In: Constant J, editor. 39 Beside cardiology, 5th edn. Philadelphia: Lippincott Williams & 4.46) and for cardiac death (OR 2.92). More recently, in Wilkins, 1999; 181 – 194. a meta-analysis of 3,067 patients with HCM during an 6. Maron MS. Clinical utility of cardiovascular magnetic resonance average follow-up of 3.05 years,40 the rates of all-cause in hypertrophic cardiomyopathy. J Cardiovasc Magn Reson 2012; 14: 13. mortality, sudden cardiac death, and cardiac death in 7. Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, patients with LGE were significantly higher than those in Panse N, et al. Utility of cardiac magnetic resonance imaging in patients without LGE, and LGE was correlated with these the diagnosis of hypertrophic cardiomyopathy. Circulation 2005; adverse outcomes, even in patients with non-high-risk 112: 855 – 861. HCM according to conventional risk factors. The results 8. Hen Y, Iguchi N, Utanohara Y, Takada K, Machida H, Takara A, et al. Extent of late gadolinium enhancement on cardiac of the present study indicate that the detection of S3 is of magnetic resonance imaging in Japanese hypertrophic cardiomy- importance in the management and risk stratification of opathy patients. Circ J 2016; 80: 950 – 957. patients with HCM, and this is possible using phonocardi- 9. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, ography because of its convenience and cost-effectiveness Lesser JR, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic with very few contraindications. Further research is needed cardiomyopathy. Circulation 2006; 114: 216 – 225. in order to assess the predictive value of S3 on outcomes in 10. Kawasaki T, Sakai C, Harimoto K, Yamano M, Miki S, patients with HCM. Kamitani T. Usefulness of high-sensitivity cardiac troponin T and brain natriuretic peptide as biomarkers of myocardial fibrosis Study Limitations in patients with hypertrophic cardiomyopathy. Am J Cardiol 2013; 112: 867 – 872. The present analyses have several limitations. First, this 11. Kawasaki T, Harimoto K, Honda S, Sato Y, Yamano M, Miki study was a retrospective study conducted in a single center S, et al. Notched QRS for the assessment of myocardial fibrosis on selected patients. Therefore, the results may not be in hypertrophic cardiomyopathy. Circ J 2015; 79: 847 – 853. 12. Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, generalizable to the global HCM population. Some condi- Jarolim P, et al. Myocardial fibrosis as an early manifestation of tions affect the detection of S3; for example, reduced inflow hypertrophic cardiomyopathy. N Engl J Med 2010; 363: 552 – to the heart or a decreased ventricular volume may diminish 563. the loudness of S3.5 Although the reproducibility of S3 on 13. Rudolph A, Abdel-Aty H, Bohl S, Boyé P, Zagrosek A, Dietz R, phonocardiography was excellent in the present study, it is et al. Noninvasive detection of fibrosis applying contrast-enhanced cardiac magnetic resonance in different forms of left ventricular important to recognize that S3 may wax and wane, par- hypertrophy relation to remodeling. J Am Coll Cardiol 2009; 53: ticularly in the case of a soft S3. Given the concordance of 284 – 291. S3 between auscultation and phonocardiography and the 14. Honda S, Kawasaki T, Shiraishi H, Yamano M, Kamitani T, diagnostic value of S3 on auscultation, auscultation may Matoba S. Mitral valve prolapse revisited. Circulation 2016; 133: E380 – E382. also be used to identify S3 as a marker of myocardial fibrosis 15. Konishi E, Kawasaki T, Shiraishi H, Yamano M, Kamitani T. in patients with HCM. Nevertheless, it is important to note Additional heart sounds during early diastole in a patient with that a physical examination has inherent inaccuracies and hypertrophic cardiomyopathy and atrioventricular block. JC the reliance of S3 on auscultation over phonocardiography Cases 2015; 11: 171 – 174. 16. Tavel ME. Abnormalities of the heart sounds (transients). In: may be a limitation in clinical practice, even among Tavel ME, editor. Clinical phonocardiography and external 22,41,42 experienced clinicians. pulse recording. Chicago: Year Book Medical Publishers, 1971; 64 – 103. 17. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Conclusions Pellikka PA, et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography’s The detection of S3 on phonocardiography was associated Guidelines and Standards Committee and the Chamber Quan- with the presence of myocardial fibrosis, as assessed by tification Writing Group, developed in conjunction with the LGE-MRI, in patients with HCM. The diagnostic value of European Association of Echocardiography, a branch of the S3 was highly specific, but not sufficiently sensitive for the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440 – 1463. detection of myocardial fibrosis. These results may contribute 18. Goto T, Takase H, Toriyama T, Sugiura T, Sato K, Ueda R, et to the risk stratification of patients with HCM, even in the al. Circulating concentrations of cardiac proteins indicate the era of advanced imaging technologies. severity of congestive heart failure. Heart 2003; 89: 1303 – 1307.
Circulation Journal Vol.82, February 2018 516 SATO Y et al.
19. Tedeschi S, Pilotti E, Parenti E, Vicini V, Coghi P, Montanari A, cardiography and external pulse recording. Chicago: Year Book et al. Serum adipokine zinc α2-glycoprotein and lipolysis in Medical Publishers, 1971; 44 – 63. cachectic and noncachectic heart failure patients: Relationship 33. Kawasaki T, Sugihara H. Subendocardial ischemia in hypertro- with neurohormonal and inflammatory biomarkers. Metabolism phic cardiomyopathy. J Cardiol 2014; 63: 89 – 94. 2012; 61: 37 – 42. 34. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link 20. Potain P. Concerning the cardiac rhythm called gallop rhythm. MS, et al. 2011 ACCF/AHA guideline for the diagnosis and Bull Soc Med Hop Paris 1876; 12: 137 – 166 (in French). treatment of hypertrophic cardiomyopathy: Executive summary: 21. Silverman ME. The third heart sound. In: Walker HK, Hall WD, A report of the American College of Cardiology Foundation/ Hurst JW, editors. Clinical methods: The history, physical, and American Heart Association Task Force on Practice Guidelines. laboratory examinations, 3rd edn. Boston: Butterworths, 1990; J Am Coll Cardiol 2011; 58: 2703 – 2738. 126 – 128. 35. Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, 22. Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic Charron P, et al. 2014 ESC guidelines on diagnosis and manage- importance of elevated jugular venous pressure and a third heart ment of hypertrophic cardiomyopathy: The Task Force for the sound in patients with heart failure. N Engl J Med 2001; 345: Diagnosis and Management of Hypertrophic Cardiomyopathy 574 – 581. of the European Society of Cardiology (ESC). Eur Heart J 2014; 23. Glower DD, Murrah RL, Olsen CO, Davis JW, Rankin JS. 35: 2733 – 2779. Mechanical correlates of the third heart sound. J Am Coll Cardiol 36. Rubinshtein R, Glockner JF, Ommen SR, Araoz PA, Ackerman 1992; 19: 450 – 457. MJ, Sorajja P, et al. Characteristics and clinical significance of 24. Mehta NJ, Khan IA. Third heart sound: Genesis and clinical late gadolinium enhancement by contrast-enhanced magnetic importance. Int J Cardiol 2004; 97: 183 – 186. resonance imaging in patients with hypertrophic cardiomyopathy. 25. Kupari M, Koskinen P, Virolainen J, Hekali P, Keto P. Prevalence Circ Heart Fail 2010; 3: 51 – 58. and predictors of audible physiological third heart sound in a 37. O’Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage population sample aged 36 to 37 years. Circulation 1994; 89: R, et al. Prognostic significance of myocardial fibrosis in hyper- 1189 – 1195. trophic cardiomyopathy. J Am Coll Cardiol 2010; 56: 867 – 874. 26. Bjarnason I, Jonsson S, Hardarson T. Mode of inheritance of 38. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert hypertrophic cardiomyopathy in Iceland: Echocardiographic EM, et al. Myocardial scar visualized by cardiovascular magnetic study. Br Heart J 1982; 47: 122 – 129. resonance imaging predicts major adverse events in patients with 27. Alvares RF. Diastolic function and prognosis in hypertrophic hypertrophic cardiomyopathy. J Am Coll Cardiol 2010; 56: 875 – cardiomyopathy. PhD Thesis, University of London, 1980. 887. 28. Shah SJ, Marcus GM, Gerber IL, McKeown BH, Vessey JC, 39. Green JJ, Berger JS, Kramer CM, Salerno M. Prognostic value Jordan MV, et al. Physiology of the third heart sound: Novel of late gadolinium enhancement in clinical outcomes for hyper- insights from tissue Doppler imaging. J Am Soc Echocardiogr trophic cardiomyopathy. JACC Cardiovasc Imaging 2012; 5: 2008; 21: 394 – 400. 370 – 377. 29. Van de Werf F, Minten J, Carmeliet P, De Geest H, Kesteloot 40. Briasoulis A, Mallikethi-Reddy S, Palla M, Alesh I, Afonso L. H. The genesis of the third and fourth heart sounds. A pressure– Myocardial fibrosis on cardiac magnetic resonance and cardiac flow study in dogs. J Clin Invest 1984; 73: 1400 – 1407. outcomes in hypertrophic cardiomyopathy: A meta-analysis. 30. Ruskoaho H, Leskinen H, Magga J, Taskinen P, Mäntymaa P, Heart 2015; 101: 1406 – 1411. Vuolteenaho O, et al. Mechanisms of mechanical load-induced 41. Mangione S, Nieman LZ. Cardiac auscultatory skills of internal atrial natriuretic peptide secretion: Role of endothelin, nitric medicine and family practice trainees: A comparison of diagnostic oxide, and angiotensin II. J Mol Med (Berl) 1997; 75: 876 – 885. proficiency [published erratum appears in JAMA 1998; 279: 31. Kinnunen P, Vuolteenaho O, Ruskoaho H. Mechanisms of atrial 1444]. JAMA 1997; 278: 717 – 722. and brain natriuretic peptide release from rat ventricular myocar- 42. March SK, Bedynek JL Jr, Chizner MA. Teaching cardiac dium: Effect of stretching. Endocrinology 1993; 132: 1961 – 1970. auscultation: Effectiveness of a patient-centered teaching confer- 32. Tavel ME. Normal sounds and pulses: Relationships and intervals ence on improving cardiac auscultatory skills. Mayo Clin Proc between the various events. In: Tavel ME, editor. Clinical phono- 2005; 80: 1443 – 1448.
Circulation Journal Vol.82, February 2018