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Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients With Acute Heart Failure
ARTICLE IN PRESS Journal of Cardiac Failure Vol. 00 No. 00 2019
Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients With Acute Heart Failure SHIH-HSIEN SUNG,1,4,5 CHI-JUNG HUANG,2 HAO-MIN CHENG,2,4 WEI-MING HUANG,1,4 WEN-CHUNG YU,1,4 AND CHEN-HUAN CHEN2,3,4,5 Taipei, Taiwan
ABSTRACT Background: The electromechanical activation time (EMAT) normalized by cardiac cycle length (%EMAT) and the third heart sound (S3) strength, as measured by automated acoustic cardiography, are predictive of postdischarge adverse events in patients with acute heart failure (AHF). The aim of this study was to evaluate whether the acoustic cardiography-guided management improves outcomes in patients with AHF when it is compared with the conventional therapy. Methods and Results: This prospective single-blind study randomized 225 patients with AHF (74.1 § 14.5 years of age, 26.2% women, and left ventricular ejection fraction 38.4 § 14.4%) before discharge to the EMAT-guided group (n = 114) with the postdischarge treatment goals to reduce %EMAT to < 15% and S3 < 5, and the symptom-guided group (n = 111) to adjust medications without knowledge of the results of acoustic cardiography. The primary endpoints were rehospitalization for heart failure and total mortality during 1-year follow-up. The 2 groups were well matched in age and predischarge %EMAT and S3 strength. After a mean follow-up period of 238.1 § 140.8 days, a significant reduction in the primary endpoints was seen in the EMATguided group compared with the symptom-guided group (43 events vs 61 events, P = 0.0095). KaplanMeier curves demonstrated significant differences in the time to first event, favoring the EMAT-guided group in the total study population (n = 225, hazard ratio and 95% confidence interval: 0.61, 0.42 0.91, log-rank P = 0.0129), as well as in the prespecified subgroup of patients with predischarge %EMAT > 15% (n = 85; 0.32, 0.16 0.65, P = 0.0008). Conclusions: In patients hospitalized due to AHF, EMAT-guided postdischarge management was superior to the conventional symptoms-driven therapy in terms of 1-year outcomes (ClinicalTrials.gov number NCT01298232) (J Cardiac Fail 2019;00:1 9) Key Words: Heart sounds, systolic time intervals, acoustic cardiogram, acute heart failure.
Introduction
independent predictor of all-cause and cardiovascular mortality.2 Although the S3 is an important clinical sign, poor physician agreement after auscultation about whether it is actually present or not reduces its general applicability.3,4 The systolic time intervals, including the pre-ejection period (PEP), the ejection time (ET) and their ratio (PEP/ET), have been related to cardiac performance and ventriculoarterial coupling.5,6 We have previously shown that PEP was positively associated with N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in a community-based population.7 However, the measurement of systolic time intervals is complicated, using either invasive or noninvasive techniques, and its value in the management of patients with heart failure remains to be established.5 Acoustic cardiography is a technology for automated quantification of heart sounds and systolic time intervals, including the electromechanical activation time (EMAT) (the time from Q-wave onset to the peak first heart sound), which constitutes the initial portion of PEP.8,9 EMAT is useful in detecting LV systolic dysfunction and resolving ambiguous values of B-type natriuretic peptide levels in
Abnormal heart sounds related to heart failure were first described in 1969,1 indicating that the dull, low-pitched third heart sound (S3) may reflect elevated left ventricular (LV) end-diastolic pressure. In an observational nationwide registry of acute heart failure (AHF) in Japan, the S3 was an From the 1Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; 3Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan; 4Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan and 5Institute of Public Health, National Yang-Ming University School of Medicine, Taipei, Taiwan. Manuscript received February 20, 2019; revised manuscript received September 17, 2019; revised manuscript accepted September 25, 2019. Correspondence and reprint requests to: Chen-Huan Chen, MD, National Yang-Ming University School of Medicine, 155 Li-Long St., Sec. 2, Shih-Pai, Taipei, Taiwan, R.O.C. 11221. Telephone: +886-2-28267202, Fax: +886-2-28209477. E-mail: [email protected] See page 8 for disclosure information. 1071-9164/$ - see front matter © 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.cardfail.2019.09.012
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ARTICLE IN PRESS 2 Journal of Cardiac Failure Vol. 00 No. 00 2019 patients with suspected heart failure.10 12 It has also been shown that a prolonged EMAT or an increased S3 strength is associated with adverse clinical outcomes.13,14 Given that patients with AHF are at high risk for postdischarge rehospitalization and mortality,15,16 optimal utilization of medical therapy is urgently needed. Currently, natriuretic peptide-guided therapy may provide only limited clinical benefits in the treatment of heart failure.17 19 We, therefore, conducted the present study to evaluate whether therapeutic guidance by acoustic cardiography would improve prognosis in patients with AHF compared to conventional symptom-guided therapy. Methods Study Population and Randomization
Patients who were admitted due to AHF were put on standard guidelines-directed medical therapy. Subjects, aged 18 years, who were stabilized after the initial in-hospital management were eligible. However, patients were excluded from this study because of 1) pacemaker-dependent rhythm, 2) end-stage renal disease that warranted dialysis, 3) hypertrophic obstructive cardiomyopathy, 4) acute coronary syndrome or stroke within 1 month prior to the index hospitalization, 5) cardiac or vascular diseases requiring surgical or percutaneous intervention within 6 months, 6) hemodynamically significant mitral and/or aortic valve disease, except secondary mitral regurgitation, 7) severe primary pulmonary or hepatic diseases, or 8) a life expectancy of < 1 year. Patients consented and were enrolled in the present study before hospital discharge. The participants were randomized in a 1:1 ratio into 2 treatment strategies, specifically, intensified (EMAT-guided) therapy or standard (symptom-guided) therapy, according to a random number table generated by Excel. The randomization was made in a block of 4 in order to keep the population size of both groups equal. In addition, subjects with normalized EMATs of 15%, representing the high-risk cohort, were prespecified for the randomization independently by using another random number table. Patients, but not the treating physicians, were blinded to the groups’ allocations. Study Protocol
After enrollment, patients were treated according to standard heart failure medical therapy guidelines and followed for 1 year, with scheduled visits at 2 weeks and 3, 6 and 12 months. At all visits, heart failure medications were adjusted according to the study’s protocol in collaboration with the treating physicians. Comprehensive Doppler echocardiographic examination and acoustic cardiography were performed within 24 hours before discharge. Acoustic cardiography was repeated at each scheduled study visit. The study was approved by the institutional review committee of Taipei Veterans General Hospital, and informed consent was given before
enrollment. The study protocol was registered on ClinicalTrials.gov (#NCT01298232). Acoustic Cardiography
At baseline and each study visit, a 10-second acoustic cardiogram was obtained from every patient to measure EMAT and S3 strength. The value of EMAT in milliseconds reflects the time required for the LV to generate sufficient force to close the mitral valve. The %EMAT was calculated as EMAT divided by cardiac cycle length; %EMAT 15 has been shown to correlate with lower left ventricle ejection fraction (LVEF), higher end-systolic and end-diastolic volume indices and worse clinical outcomes.20,21 S3 strength, a combination of intensity and persistence, is expressed as a score with the range of 0 10, and the presence of an S3 was defined as S3 strength 5, which has been demonstrated to indicate an LV end-diastolic pressure of 15 mmHg.22 Treatment Strategies
Patients who were randomized to the EMAT-guided group underwent medical therapy for heart failure with the goals of reducing %EMAT to < 15% and S3 to < 5, in addition to symptoms of New York Heart Association (NYHA) Functional Classification II. Patients who were randomized to the symptom-guided group had standard medical care, with the goal of reducing symptoms to NYHA Functional Classification II. The results of acoustic cardiography were blinded to the treating physicians in the symptom-guided group. In patients with LV systolic dysfunction, the recommended therapy was established as follows: all patients should receive an angiotensin-converting enzyme inhibitor in an adequate dosage unless contraindicated. If patients were intolerant to angiotensin-converting enzyme inhibitors, they were to receive angiotensin II receptor antagonists. In addition, all patients should receive one of the b-blockers proven to be beneficial in systolic dysfunction in adequate dosage (ie, metoprolol extended release, bisoprolol or carvedilol). If treatment targets were not achieved, the following treatment escalation would be applied unless contraindications existed for particular drugs: loop diuretics added or dosage increased or nitrates added or dosage increased In patients with preserved LV systolic function, acknowledged therapy guidelines do not exist. As a first step, symptoms and fluid retention should be treated with diuretics. In addition, all patients should be on an angiotensin II receptor antagonist or an angiotensin-converting enzyme inhibitor. If blood pressure is still elevated (ie, 140/90 mmHg), a -blocker should be added. If treatment targets were not yet reached, similar further treatment escalation was applied, as in patients with systolic dysfunction, with particular attention to tolerability. The primary efficacy variable was defined as the time to the first clinical event of either death or hospitalization due to heart failure within 1 year after randomization.
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 3 Echocardiographic Evaluation
All study subjects received a comprehensive Doppler and M-mode echocardiographic examination, according to the American Society of Echocardiography criteria. All of the following dimensions were measured online from the 2D, guided M-mode echocardiogram: aortic root diameter, left atrial dimension, LV internal dimension at end systole and end diastole, and thickness of the interventricular septum and LV posterior wall. LV mass and LVEF were calculated using the biplane Simpson method. Statistical Analysis
According to our previous work, about 50% of the patients with AHF would be rehospitalized because of heart failure or mortality during a follow-up duration of 1 year.23 The presence of high %EMAT may carry an additional 40% risk of postdischarge adverse events.13 Assuming that EMAT-guided management could reduce the excessive risks in the study population to 20%, the calculated sample size needed with a type 1 error of 0.05 and an achieved power of 0.8 was 186. With an estimated attrition of 10% we, therefore, enrolled at least 204 subjects in this study. Mean and standard deviation for continuous variables and number (percentage) for categorical variables were used to describe the characteristics of the participants in this study. Comparisons between study groups were made with 2-sample t tests for continuous variables and the x2 or Fisher exact test for categorical variables. Trends in %EMAT and S3 strength during the study period were examined using the generalized estimating equations approach for repeated measures.24 Kaplan-Meier survival curve analysis was applied to evaluate the benefits of EMAT-guided therapy. The hazard ratios and their 95% confidence intervals for the relative effectiveness of EMAT-guided vs symptom-guided therapy were estimated using Cox regression models. All statistical significances were set a priori at P < 0.05, and all statistical analyses were carried out by SAS 9.4 (SAS Institute, Cary, NC, USA). Results A total of 225 subjects (74.1 § 14.5 years, 73.8% men) were enrolled in this study. There were 114 patients randomized to the EMAT-guided group and 111 patients in the standard symptom-guided group (Fig. 1). The baseline characteristics of the study population are shown in Table 1. There was no significant difference between the 2 groups regarding ages, body mass indexes, comorbidities, blood pressures, renal function, lipid profiles, NT-proBNP levels, or the initial discharge medications. However, the symptom-guided group was more likely to be male, and the EMAT-guided group had higher triglyceride levels and higher percentages of statin prescriptions at discharge. Left atrial diameter, LV size and LVEF were not significantly
different in the 2 groups. Measures resulting from acoustic cardiography were also similar. Outcomes: EMAT-Guided vs Aymptom-Guided Therapy
During a mean follow-up duration of 238 § 141 days, 104 subjects encountered either mortality (n = 34) or rehospitalization for heart failure (n = 70). Compared with symptom-guided therapy, EMAT-guided management did reduce the primary endpoints of all-cause death or rehospitalization due to heart failure within 1 year (Fig. 2A) (37.7% for the EMAT-guided group vs 55.0% for the symptom-guided group; hazard ratio 0.61, 95% confidence interval 0.42 0.91, log-rank P = 0.0129). However, the overall survival in the 2 groups was not different (Fig. 2B) (hazard ratio 1.03, 95% confidence interval 0.61 1.75, log-rank P = 0.9087). Among the high-risk cohort with %EMAT 15%, 42 patients received EMAT-guided therapy, and 43 patients were treated with the symptom-guided therapy. The Kaplan-Meier survival curve analysis demonstrated a significantly higher event-free survival in the EMAT-guided group than in the symptom-guided group (Fig. 3A) (hazard ratio 0.32, 95% confidence interval 0.16 0.65, log-rank P = 0.0008). Compared to a 13% risk reduction in patients with %EMAT < 15%, there was a significant interaction (interaction P = 0.02) of EMAT-guided therapy for patients with %EMAT of < 15% or 15%. In addition, EMATguided therapy was associated with a significant reduction in all-cause mortality in this high-risk cohort, compared to the symptom-guided treatment group (Fig. 3B) (hazard ratio 0.33, 95% confidence interval 0.12 0.91, log-rank P = 0.0244). The stratified analyses demonstrated that the advantage of EMAT-guided therapy over symptom-guided therapy was consistent among patients < 75 or 75 years, men or women and with or without atrial fibrillation, chronic kidney disease or reduced LVEF (Fig. 4).
Medication Adjustments and Changes of %EMAT and S3 Strength
Within 1 year of management, patients randomized to the EMAT-guided group had more adjustments of diuretics and/or nitrates but not of renin-angiotensin-system blockers, b-blockers or mineralocorticoid receptor antagonists compared with the symptom-guided group (Fig. 5). Although %EMAT was nonsignificantly reduced in both groups (Fig. 6A), S3 strength was significantly diminished in the EMAT-guided group but not in the symptom-guided group (Fig. 6B). The proportions of %EMAT 15% or S3 strength 5 for each study visit also demonstrated similar trends (Supplementary Fig. 1 and Fig. 2). When we analyzed the last measurement of %EMAT prior to any adverse event, if any, the %EMAT was related to clinical outcomes in the symptom-guided group but not in the EMAT-guided group. (Fig. 7)
ARTICLE IN PRESS 4 Journal of Cardiac Failure Vol. 00 No. 00 2019
Fig. 1. Diagram of the study flow.
Discussion In the study population of AHF, optimization of postdischarge heart failure therapy guided by acoustic cardiography targeting a %EMAT of < 15% and an S3 strength < 5 might improve the clinical outcomes of all-cause mortality and readmissions for heart failure within 1 year. For the high-risk patients with baseline %EMAT 15%, the effect size might even be greater. Intensifying medical therapy with diuretics and/or nitrates in the presence of high %EMAT or high S3 strength scores might be a better strategy than the conventional strategy of treatment adjustment by means of physicians’ monitoring heart failure symptoms and signs. The study results expand our previous observational studies in patients with AHF regarding the advantage of acoustic cardiography in risk assessment.25,26 Although there have been great advancements in the past decades, the long-term outcomes of patients with heart failure remain dismal,27 and the number of heart failure-related deaths has increased steadily from 2009
to 2014.28 Heart failure has become the leading cause of hospitalization in persons older than 65 years of age.29 Compared with chronic heart failure, patients hospitalized for acute heart failure with either preserved or reduced LVEF are characterized by worse clinical outcomes, and the risk of death is high in the early period after discharge.30,31 Although the prognostic value of natriuretic peptides has been established in patients with AHF,32 the guidance of heart failure therapy to reach an NT-proBNP reduction of > 30% during hospitalization did not improve the postdischarge clinical outcomes.33 Moreover, the objective of achieving an individual or a universal NT-proBNP target by serial measurements and subsequent intensification of guideline-recommended therapies did not provide significant clinical benefits in patients with AHF.17,19 In contrast, the CHAMPION (Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) trial demonstrated a significant reduction in hospitalizations for patients with NYHA class III heart failure who were managed with a
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 5 Table 1. Baseline Characteristics of the Study Population EMAT-guided, n = 114 Age, years 74.7 § 13.7 Men, n (%) 76 (66.7) 23.5 § 4.8 Body mass index, kg/m2 Smoker, n (%) 16 (14.0) HFrEF, n (%) 72 (63.2) *NT-proBNP, pg/L 3.85 § 0.43 Comorbidities, n (%) Hypertension 89 (78.1) Diabetes 38 (33.3) Stroke 8 (7.0) CAD 50 (43.9) Atrial fibrillation 33 (29.0) Laboratory and hemodynamic measures SBP, mmHg 124.6 § 26.8 DBP, mmHg 69.8 § 12.8 Heart rate, minute 1 76.4 § 15.2 Creatinine, mg/dL 1.8 § 1.1 Cholesterol, mg/dL 157.0 § 44.2 HDLc, mg/dL 41.3 § 14.8 LDLc, mg/dL 99.2 § 40.1 Triglyceride, mg/dL 101.5 § 45.8 Cardiac structure and function LA dimension, mm 45.0 § 8.6 LVIDd, mm 56.0 § 8.9 IVSd, mm 11.4 § 3.3 PWd, mm 11.3 § 2.4 LVIDs, mm 43.1 § 10.9 LVEF, % 38.0 § 13.9 Measures of acoustic cardiography EMAT, msec 112.9 § 23.6 %EMAT, % 14.3 § 3.7 S3 4.3 § 2.1 Presence of S3, n (%) 30 (26.3) Medications at discharge, n (%) RAS blockers 50 (43.9) ß-blockers 73 (64.0) MRA 45 (39.5) Diuretics 82 (71.9) Nitrates 78 (68.4) Digoxin 24 (21.1) Statins 34 (29.8) Antiplatelet agents 56 (49.1)
Symptomguided, n = 111
P value
73.5 § 15.3 90 (81.1) 24.2 § 4.4
0.52 0.01 0.30
19 (17.1) 62 (55.9) 3.85 § 0.55
0.52 0.26 0.99
80 (72.1) 38 (34.2) 4 (3.6) 48 (43.2) 31 (27.9)
0.30 0.89 0.25 0.93 0.87
124.1 § 25.1 69.8 § 12.2 73.1 § 12.2 1.9 § 1.5 148.8 § 35.2 43.3 § 13.3 93.3 § 28.8 84.3 § 37.3
0.89 0.99 0.07 0.38 0.17 0.39 0.27 0.007
47.2 § 7.9 58.0 § 11.1 11.4 § 3.0 11.4 § 2.5 44.5 § 14.1 38.8 § 15.0
0.06 0.16 1.00 0.67 0.45 0.68
117.4 § 23.3 14.3 § 3.8 4.5 § 2.1 33 (29.7)
0.15 0.96 0.63 0.57
44 (39.6) 66 (59.5) 45 (40.5) 72 (64.9) 66 (59.5) 23 (20.7) 20 (18.0) 48 (43.2)
0.52 0.48 0.87 0.25 0.16 0.95 0.04 0.38
CAD, coronary artery disease; DBP, diastolic blood pressure; EMAT, electromechanical activation time; %EMAT, normalized EMAT; HDLc, high-density lipoprotein cholesterol; IVSd, interventricular septal thickness at diastole; LA, left atrium, LDLc, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; LVIDd, left ventricular internal dimension at diastole; LVIDs, left ventricular internal dimension at systole; MRA, mineralocorticoid antagonist; PWd, posterior wall thickness at diastole; RAS, renin-angiotensin system; SBP, systolic blood pressure. *N-terminal pro-B type natriuretic peptide (NT-proBNP) was log transformed.
wireless implantable hemodynamic monitoring system.34,35 The present study showed a prominent reduction in postdischarge readmissions for patients with AHF by targeting %EMAT and S3 strength, measures of
LV mechanical properities20,36 that outperformed B-type natriuretic peptide in the prediction of LV systolic dysfunction.37 Given that natriuretic peptides are highly confounded by noncardiac factors,38 using natriuretic peptides as a guide to modulate heart failure therapies is not recommended. In the CHAMPION trial and the present study, direct measures of LV hemodynamics might contribute to the best management of patients with heart failure. EMAT is a time interval based on a fine balance between intrinsic myocardial contractility, preload and afterload. We have demonstrated previously that %EMAT could further improve the risk stratifications with NT-proBNP in patients with AHF.21,26 In addition, the presence of S3 has outperformed other congestive physical signs in the prediction of clinical outcomes in AHF, even with atrial fibrillation.2,4 Both high %EMAT and S3 may suggest increased preload and upcoming decompensation, which could be alleviated by diuretics and/or nitrates. In the present study, physicians were encouraged to prescribe or uptitrate diuretics and/or nitrates in the presence of a high %EMAT or a high S3 strength score. The favorable results of nitrate therapy in patients with chronic systolic heart failure has been proposed in the Veterans Administration Cooperative Study, supporting the clinical benefits of reducing cardiac preload and afterload in the management of heart failure.39 Although none of the clinical trials have shown survival benefits of diuretics, both diuretics and vasodilators are recommended by the guidelines for managing AHF.40 Diuretics and vasodilators are believed to decongest the LV and lungs in AHF, but they may prevent further deterioration of heart failure and the subsequent hospitalizations in patients at risk for decompensation. Setoguchi et al have shown that readmission for heart failure was a strong predictor of mortality in a total of 14,374 patients with AHF.41 In this current study, we identified patients at risk of decompensation by a %EMAT of 15% and/or S3 strength 5, and then up-titrated diuretics and/or nitrates to prevent rehospitalizations due to heart failure. The prespecified medication changes may support the proper therapeutic strategies in response to high %EMAT and/or S3 that would improve clinical outcomes. The reduction of rehospitalization for heart failure may further contribute to the decrease in mortality in high-risk patients with %EMATs of 15% in this study. Although the %EMAT was not shortened in the EMAT-guided group (Supplementary Figs. 1A and 2A), neither of the previous studies has shown that diuretics and nitrites could reduce the PEP index in patients with heart diseases.42,43 On the other hand, the S3 strength was attenuated in the EMATguided group but not in the symptom-guided group. (Supplementary Figs. 1 and 2).
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Fig. 2. Event-free survival curves of the study population, stratified by either EMAT-guided therapy or symptom-guided therapy. A) Events included all-cause mortality and heart failure hospitalizations. B) Mortality. CI, confidence interval; EMAT, electromechanical activation time; HR, hazard ratio.
Fig. 3. Event-free survival curves of the patients with baseline %EMAT 15%, stratified by either EMAT-guided therapy or symptomguided therapy. A) Events included all-cause mortality and heart failure hospitalizations. B) Mortality. CI, confidence interval; EMAT, electromechanical activation time; HR, hazard ratio.
Study limitations
There are several limitations in this study. First, this was a single-center study, and the sample size was relatively small. The baseline characteristics were not fully matched between the 2 groups. In addition, we were not able to calculate the impact of nonscheduled visits, which were not recorded, on the study results. Neither did we measure NT-proBNP levels at each study visit. However, the clinical benefits of the EMAT-guided therapy on top of standard management, in both the total study population and in the subgroup analysis, have been demonstrated clearly. Second,
the study was single-blinded, which could be a potential source of bias. However, we have adjudicated the primary endpoints by physicians who were blinded to the treatment assignment so as to alleviate this bias. Third, renin-angiotensin-system blockers, b-blockers and mineralocorticoid receptor antagonists were prescribed only to 42%, 62% and 40% of the study population before discharge, and 55% of them had reduced LVEF. Moreover, the preparations of nitrate and diuretics were not restricted; therefore, the prognostic values related to the dosages of nitrates or diuretics could not be evaluated. Given that the adherence to the guideline-recommended treatments might be a concern in
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 7
Fig. 4. Stratified analyses of the study population by age of < 75 or 75 years, men or women, the presence of atrial fibrillation, chronic kidney disease or left ventricular ejection fraction (LVEF) 40%. EMAT, electromechanical activation time.
this study, the generalizability of the study’s results in patients with AHF remains debatable. Multicenter, larger scale studies, specified for heart failure with either preserved or reduced LVEF, are needed to validate the clinical benefits of EMAT-guided management in AHF. Conclusions In the present study of patients with AHF, we have shown the advantages of acoustic cardiography-guided therapy on top of standard management to reduce postdischarge heart failure readmissions and mortality. A high %EMAT or S3 strength might indicate that patients are at risk of decompensation and mortality, and intensification of diuretics and/or vasodilators therapy might mitigate the consequential adverse events. Future multicentered, randomized trials with larger sample sizes and longer follow-up periods are warranted to confirm the benefits of acoustic cardiography in the management of AHF. Acknowledgments Fig. 5. The proportion of patients with medication adjustment during the study visits. Heart failure (HF)-specific drugs included renin-angiotensin system blockers, b-blockers and mineralocorticoid receptor antagonists. Error bars indicate means and 95% confidence intervals. EMAT, electromechanical activation time.
The study was supported by Taipei Veterans General Hospital (V100C-145, V101C-092, V102C-119, V103B017, V104C-172, and V104E12-003-MY3); Ministry of Science and Technology (MOST 103-2314-B-010-050-
ARTICLE IN PRESS 8 Journal of Cardiac Failure Vol. 00 No. 00 2019
Fig. 6. Changes of %EMAT A) and S3 B) across the study period. Data are presented as the mean § standard errors of the mean. EMAT, electromechanical activation time.
3.
4.
5. 6.
7. Fig. 7. The last measure of %EMAT in the study population. EMAT, electromechanical activation time. 8.
MY2); and Ministry of Health and Welfare, Taiwan grant (MOHW-105-TDU-B-211-133017, MOHW106-TDU-B211-113001, MOHW107-TDU-B-211-123001).
9.
Disclosures
10.
None declared. 11.
Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.card fail.2019.09.012.
12.
References 1. Origin of the third heart sound. Br Med J 1969;3:193. 2. Minami Y, Kajimoto K, Sato N, Aokage T, Mizuno M, Asai K, et al. Third heart sound in hospitalised patients with acute
13.
heart failure: insights from the ATTEND study. Int J Clin Pract 2015;69:820–8. Ishmail AA, Wing S, Ferguson J, Hutchinson TA, Magder S, Flegel KM. Interobserver agreement by auscultation in the presence of a third heart sound in patients with congestive heart failure. Chest 1987;91:870–3. Caldentey G, Khairy P, Roy D, Leduc H, Talajic M, Racine N, et al. Prognostic value of the physical examination in patients with heart failure and atrial fibrillation: insights from the AFCHF trial (Atrial Fibrillation and Chronic Heart Failure). JACC Heart Fail 2014;2(1):15–23. Lewis RP, Rittogers SE, Froester WF, Boudoulas H. A critical review of the systolic time intervals. Circulation 1977;56 (2):146–58. Cheng HM, Yu WC, Sung SH, Wang KL, Chuang SY, Chen CH. Usefulness of systolic time intervals in the identification of abnormal ventriculo-arterial coupling in stable heart failure patients. Eur J Heart Fail 2008;10:1192–200. Cheng HM, Chuang SY, Hsu PF, Chou P, Chen CH. Systolic time intervals revisited: correlations with N-terminal probrain natriuretic peptide in a community population. Heart Vessels 2005;20:256–63. Wen YN, Lee AP, Fang F, Jin CN, Yu CM. Beyond auscultation: acoustic cardiography in clinical practice. Int J Cardiol 2014;172:548–60. Diamant B, Killip T. Indirect assessment of left ventricular performance in acute myocardial infarction. Circulation 1970;42:579–92. Roos M, Toggweiler S, Jamshidi P, Zuber M, Kobza R, Meier R, et al. Noninvasive detection of left ventricular systolic dysfunction by acoustic cardiography in cardiac failure patients. J Card Fail 2008;14:310–9. Zuber M, Kipfer P, Attenhofer Jost CH. Usefulness of acoustic cardiography to resolve ambiguous values of B-type natriuretic peptide levels in patients with suspected heart failure. Am J Cardio 2007;100:866–9. Maisel AS, Peacock WF, Shah KS, Clopton P, Diercks D, Hiestand B, et al. Acoustic cardiography S3 detection use in problematic subgroups and B-type natriuretic peptide “gray zone”: secondary results from the Heart failure and Audicor technology for Rapid Diagnosis and Initial Treatment Multinational Investigation. Am J Emerg Med 2011;29:924–31. Chao T-F, Sung S-H, Cheng H-M, Yu W-C, Wang K-L, Huang C-M, et al. Electromechanical activation time in the prediction
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 9
14. 15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
26.
27.
28.
of discharge outcomes in patients hospitalized with acute heart failure syndrome. Internal Medicine 2010;49:2031–7. Wang S, Liu M, Fang F, Shang Q, Sun JP, Sanderson JE, et al. Prognostic value of acoustic cardiography in patients with chronic heart failure. Int J Cardiol 2016;219:121–6. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006;47:76–84. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Crespo Leiro M, Drozdz J, et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2013;15:808–17. Eurlings LW, van Pol PE, Kok WE, van Wijk S, Lodewijksvan der Bolt C, Balk AH, et al. Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. J Am Coll Cardiol 2010;56:2090–100. Pfisterer M, Buser P, Rickli H, Gutmann M, Erne P, Rickenbacher P, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIMECHF) randomized trial. JAMA 2009;301:383–92. Lainchbury JG, Troughton RW, Strangman KM, Frampton CM, Pilbrow A, Yandle TG, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53–60. Efstratiadis S, Michaels AD. Computerized acoustic cardiographic electromechanical activation time correlates with invasive and echocardiographic parameters of left ventricular contractility. J Card Fail 2008;14:577–82. Chao TF, Sung SH, Cheng HM, Yu WC, Wang KL, Huang CM, et al. Electromechanical activation time in the prediction of discharge outcomes in patients hospitalized with acute heart failure syndrome. Intern Med 2010;49:2031–7. Marcus GM, Gerber IL, McKeown BH, Vessey JC, Jordan MV, Huddleston M, et al. Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function. JAMA 2005;293:2238–44. Sung SH, Yu WC, Cheng HM, Lee CW, Lin MM, Chuang SY, et al. Excessive wave reflections on admission predict post-discharge events in patients hospitalized due to acute heart failure. Eur J Heart Fail 2012;14:1348–55. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics 1988;44:1049–60. Chao TF, Sung SH, Cheng HM, Yu WC, Wang KL, Huang CM, et al. Electromechanical activation time in the prediction of discharge outcomes in patients hospitalized with acute heart failure syndrome. Internal Medicine 2010;49:2031–7. Chang CC, Sung SH, Yu WC, Cheng HM, Chen CH. Nighttime electromechanical activation time, pulsatile hemodynamics, and discharge outcomes in patients with acute heart failure. ESC Heart Fail 2015;2:184–93. Mamas MA, Sperrin M, Watson MC, Coutts A, Wilde K, Burton C, et al. Do patients have worse outcomes in heart failure than in cancer? a primary care-based cohort study with 10-year followup in Scotland. Eur J Heart Fail 2017;19:1095–104. Ni H, Xu J. Recent trends in heart failure-related mortality: United States, 2000-2014. NCHS Data Brief 2015;231:1–8.
29. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557–73. 30. Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, Filippatos G, Ruschitzka F, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail 2016;18:613–25. 31. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 2007;116:1482–7. 32. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330–7. 33. Stienen S, Salah K, Moons AH, Bakx AL, van Pol P, Kortz RAM, et al. NT-proBNP (N-terminal pro-B-type natriuretic peptide)-guided therapy in acute decompensated heart failure: PRIMA II randomized controlled trial (can NT-ProBNPguided therapy during hospital admission for acute decompensated heart failure reduce mortality and readmissions?). Circulation 2018;137:1671–83. 34. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. 35. Abraham WT, Stevenson LW, Bourge RC, Lindenfeld JA, Bauman JG, Adamson PB, et al. Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet 2016;387:453–61. 36. Roos M, Toggweiler S, Zuber M, Jamshidi P, Erne P. Acoustic cardiographic parameters and their relationship to invasive hemodynamic measurements in patients with left ventricular systolic dysfunction. Congest Heart Fail 2006;12(Suppl 1): 19–24. 37. Kosmicki DL, Collins SP, Kontos MC, Zuber P, Kipfer P, Attenhofer Jost C, et al. Noninvasive prediction of left ventricular systolic dysfunction in patients with clinically suspected heart failure using acoustic cardiography. Congest Heart Fail 2010;16:249–53. 38. Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357–68. 39. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration cooperative study. N Engl J Med 1986;314: 1547–52. 40. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC): developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. 41. Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure. Am Heart J 2007;154:260–6. 42. Balasubramanian V, Behl A, Das GS, Wadhwa AK, Mathew OP, Hoon RS. Effect of digoxin and diuretics on high altitude left ventricular dysfunction. Circulation 1978;57:1180–5. 43. Sawayama T, Ochiai M, Marumoto S, Matsuura T, Niki I. Influence of amyl nitrite inhalation on the systolic time intervals in normal subjects and in patients with ischemic heart disease. Circulation 1969;40:327–35.
Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients With Acute Heart Failure SHIH-HSIEN SUNG,1,4,5 CHI-JUNG HUANG,2 HAO-MIN CHENG,2,4 WEI-MING HUANG,1,4 WEN-CHUNG YU,1,4 AND CHEN-HUAN CHEN2,3,4,5 Taipei, Taiwan
ABSTRACT Background: The electromechanical activation time (EMAT) normalized by cardiac cycle length (%EMAT) and the third heart sound (S3) strength, as measured by automated acoustic cardiography, are predictive of postdischarge adverse events in patients with acute heart failure (AHF). The aim of this study was to evaluate whether the acoustic cardiography-guided management improves outcomes in patients with AHF when it is compared with the conventional therapy. Methods and Results: This prospective single-blind study randomized 225 patients with AHF (74.1 § 14.5 years of age, 26.2% women, and left ventricular ejection fraction 38.4 § 14.4%) before discharge to the EMAT-guided group (n = 114) with the postdischarge treatment goals to reduce %EMAT to < 15% and S3 < 5, and the symptom-guided group (n = 111) to adjust medications without knowledge of the results of acoustic cardiography. The primary endpoints were rehospitalization for heart failure and total mortality during 1-year follow-up. The 2 groups were well matched in age and predischarge %EMAT and S3 strength. After a mean follow-up period of 238.1 § 140.8 days, a significant reduction in the primary endpoints was seen in the EMATguided group compared with the symptom-guided group (43 events vs 61 events, P = 0.0095). KaplanMeier curves demonstrated significant differences in the time to first event, favoring the EMAT-guided group in the total study population (n = 225, hazard ratio and 95% confidence interval: 0.61, 0.42 0.91, log-rank P = 0.0129), as well as in the prespecified subgroup of patients with predischarge %EMAT > 15% (n = 85; 0.32, 0.16 0.65, P = 0.0008). Conclusions: In patients hospitalized due to AHF, EMAT-guided postdischarge management was superior to the conventional symptoms-driven therapy in terms of 1-year outcomes (ClinicalTrials.gov number NCT01298232) (J Cardiac Fail 2019;00:1 9) Key Words: Heart sounds, systolic time intervals, acoustic cardiogram, acute heart failure.
Introduction
independent predictor of all-cause and cardiovascular mortality.2 Although the S3 is an important clinical sign, poor physician agreement after auscultation about whether it is actually present or not reduces its general applicability.3,4 The systolic time intervals, including the pre-ejection period (PEP), the ejection time (ET) and their ratio (PEP/ET), have been related to cardiac performance and ventriculoarterial coupling.5,6 We have previously shown that PEP was positively associated with N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in a community-based population.7 However, the measurement of systolic time intervals is complicated, using either invasive or noninvasive techniques, and its value in the management of patients with heart failure remains to be established.5 Acoustic cardiography is a technology for automated quantification of heart sounds and systolic time intervals, including the electromechanical activation time (EMAT) (the time from Q-wave onset to the peak first heart sound), which constitutes the initial portion of PEP.8,9 EMAT is useful in detecting LV systolic dysfunction and resolving ambiguous values of B-type natriuretic peptide levels in
Abnormal heart sounds related to heart failure were first described in 1969,1 indicating that the dull, low-pitched third heart sound (S3) may reflect elevated left ventricular (LV) end-diastolic pressure. In an observational nationwide registry of acute heart failure (AHF) in Japan, the S3 was an From the 1Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; 3Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan; 4Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan and 5Institute of Public Health, National Yang-Ming University School of Medicine, Taipei, Taiwan. Manuscript received February 20, 2019; revised manuscript received September 17, 2019; revised manuscript accepted September 25, 2019. Correspondence and reprint requests to: Chen-Huan Chen, MD, National Yang-Ming University School of Medicine, 155 Li-Long St., Sec. 2, Shih-Pai, Taipei, Taiwan, R.O.C. 11221. Telephone: +886-2-28267202, Fax: +886-2-28209477. E-mail: [email protected] See page 8 for disclosure information. 1071-9164/$ - see front matter © 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.cardfail.2019.09.012
1
ARTICLE IN PRESS 2 Journal of Cardiac Failure Vol. 00 No. 00 2019 patients with suspected heart failure.10 12 It has also been shown that a prolonged EMAT or an increased S3 strength is associated with adverse clinical outcomes.13,14 Given that patients with AHF are at high risk for postdischarge rehospitalization and mortality,15,16 optimal utilization of medical therapy is urgently needed. Currently, natriuretic peptide-guided therapy may provide only limited clinical benefits in the treatment of heart failure.17 19 We, therefore, conducted the present study to evaluate whether therapeutic guidance by acoustic cardiography would improve prognosis in patients with AHF compared to conventional symptom-guided therapy. Methods Study Population and Randomization
Patients who were admitted due to AHF were put on standard guidelines-directed medical therapy. Subjects, aged 18 years, who were stabilized after the initial in-hospital management were eligible. However, patients were excluded from this study because of 1) pacemaker-dependent rhythm, 2) end-stage renal disease that warranted dialysis, 3) hypertrophic obstructive cardiomyopathy, 4) acute coronary syndrome or stroke within 1 month prior to the index hospitalization, 5) cardiac or vascular diseases requiring surgical or percutaneous intervention within 6 months, 6) hemodynamically significant mitral and/or aortic valve disease, except secondary mitral regurgitation, 7) severe primary pulmonary or hepatic diseases, or 8) a life expectancy of < 1 year. Patients consented and were enrolled in the present study before hospital discharge. The participants were randomized in a 1:1 ratio into 2 treatment strategies, specifically, intensified (EMAT-guided) therapy or standard (symptom-guided) therapy, according to a random number table generated by Excel. The randomization was made in a block of 4 in order to keep the population size of both groups equal. In addition, subjects with normalized EMATs of 15%, representing the high-risk cohort, were prespecified for the randomization independently by using another random number table. Patients, but not the treating physicians, were blinded to the groups’ allocations. Study Protocol
After enrollment, patients were treated according to standard heart failure medical therapy guidelines and followed for 1 year, with scheduled visits at 2 weeks and 3, 6 and 12 months. At all visits, heart failure medications were adjusted according to the study’s protocol in collaboration with the treating physicians. Comprehensive Doppler echocardiographic examination and acoustic cardiography were performed within 24 hours before discharge. Acoustic cardiography was repeated at each scheduled study visit. The study was approved by the institutional review committee of Taipei Veterans General Hospital, and informed consent was given before
enrollment. The study protocol was registered on ClinicalTrials.gov (#NCT01298232). Acoustic Cardiography
At baseline and each study visit, a 10-second acoustic cardiogram was obtained from every patient to measure EMAT and S3 strength. The value of EMAT in milliseconds reflects the time required for the LV to generate sufficient force to close the mitral valve. The %EMAT was calculated as EMAT divided by cardiac cycle length; %EMAT 15 has been shown to correlate with lower left ventricle ejection fraction (LVEF), higher end-systolic and end-diastolic volume indices and worse clinical outcomes.20,21 S3 strength, a combination of intensity and persistence, is expressed as a score with the range of 0 10, and the presence of an S3 was defined as S3 strength 5, which has been demonstrated to indicate an LV end-diastolic pressure of 15 mmHg.22 Treatment Strategies
Patients who were randomized to the EMAT-guided group underwent medical therapy for heart failure with the goals of reducing %EMAT to < 15% and S3 to < 5, in addition to symptoms of New York Heart Association (NYHA) Functional Classification II. Patients who were randomized to the symptom-guided group had standard medical care, with the goal of reducing symptoms to NYHA Functional Classification II. The results of acoustic cardiography were blinded to the treating physicians in the symptom-guided group. In patients with LV systolic dysfunction, the recommended therapy was established as follows: all patients should receive an angiotensin-converting enzyme inhibitor in an adequate dosage unless contraindicated. If patients were intolerant to angiotensin-converting enzyme inhibitors, they were to receive angiotensin II receptor antagonists. In addition, all patients should receive one of the b-blockers proven to be beneficial in systolic dysfunction in adequate dosage (ie, metoprolol extended release, bisoprolol or carvedilol). If treatment targets were not achieved, the following treatment escalation would be applied unless contraindications existed for particular drugs: loop diuretics added or dosage increased or nitrates added or dosage increased In patients with preserved LV systolic function, acknowledged therapy guidelines do not exist. As a first step, symptoms and fluid retention should be treated with diuretics. In addition, all patients should be on an angiotensin II receptor antagonist or an angiotensin-converting enzyme inhibitor. If blood pressure is still elevated (ie, 140/90 mmHg), a -blocker should be added. If treatment targets were not yet reached, similar further treatment escalation was applied, as in patients with systolic dysfunction, with particular attention to tolerability. The primary efficacy variable was defined as the time to the first clinical event of either death or hospitalization due to heart failure within 1 year after randomization.
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 3 Echocardiographic Evaluation
All study subjects received a comprehensive Doppler and M-mode echocardiographic examination, according to the American Society of Echocardiography criteria. All of the following dimensions were measured online from the 2D, guided M-mode echocardiogram: aortic root diameter, left atrial dimension, LV internal dimension at end systole and end diastole, and thickness of the interventricular septum and LV posterior wall. LV mass and LVEF were calculated using the biplane Simpson method. Statistical Analysis
According to our previous work, about 50% of the patients with AHF would be rehospitalized because of heart failure or mortality during a follow-up duration of 1 year.23 The presence of high %EMAT may carry an additional 40% risk of postdischarge adverse events.13 Assuming that EMAT-guided management could reduce the excessive risks in the study population to 20%, the calculated sample size needed with a type 1 error of 0.05 and an achieved power of 0.8 was 186. With an estimated attrition of 10% we, therefore, enrolled at least 204 subjects in this study. Mean and standard deviation for continuous variables and number (percentage) for categorical variables were used to describe the characteristics of the participants in this study. Comparisons between study groups were made with 2-sample t tests for continuous variables and the x2 or Fisher exact test for categorical variables. Trends in %EMAT and S3 strength during the study period were examined using the generalized estimating equations approach for repeated measures.24 Kaplan-Meier survival curve analysis was applied to evaluate the benefits of EMAT-guided therapy. The hazard ratios and their 95% confidence intervals for the relative effectiveness of EMAT-guided vs symptom-guided therapy were estimated using Cox regression models. All statistical significances were set a priori at P < 0.05, and all statistical analyses were carried out by SAS 9.4 (SAS Institute, Cary, NC, USA). Results A total of 225 subjects (74.1 § 14.5 years, 73.8% men) were enrolled in this study. There were 114 patients randomized to the EMAT-guided group and 111 patients in the standard symptom-guided group (Fig. 1). The baseline characteristics of the study population are shown in Table 1. There was no significant difference between the 2 groups regarding ages, body mass indexes, comorbidities, blood pressures, renal function, lipid profiles, NT-proBNP levels, or the initial discharge medications. However, the symptom-guided group was more likely to be male, and the EMAT-guided group had higher triglyceride levels and higher percentages of statin prescriptions at discharge. Left atrial diameter, LV size and LVEF were not significantly
different in the 2 groups. Measures resulting from acoustic cardiography were also similar. Outcomes: EMAT-Guided vs Aymptom-Guided Therapy
During a mean follow-up duration of 238 § 141 days, 104 subjects encountered either mortality (n = 34) or rehospitalization for heart failure (n = 70). Compared with symptom-guided therapy, EMAT-guided management did reduce the primary endpoints of all-cause death or rehospitalization due to heart failure within 1 year (Fig. 2A) (37.7% for the EMAT-guided group vs 55.0% for the symptom-guided group; hazard ratio 0.61, 95% confidence interval 0.42 0.91, log-rank P = 0.0129). However, the overall survival in the 2 groups was not different (Fig. 2B) (hazard ratio 1.03, 95% confidence interval 0.61 1.75, log-rank P = 0.9087). Among the high-risk cohort with %EMAT 15%, 42 patients received EMAT-guided therapy, and 43 patients were treated with the symptom-guided therapy. The Kaplan-Meier survival curve analysis demonstrated a significantly higher event-free survival in the EMAT-guided group than in the symptom-guided group (Fig. 3A) (hazard ratio 0.32, 95% confidence interval 0.16 0.65, log-rank P = 0.0008). Compared to a 13% risk reduction in patients with %EMAT < 15%, there was a significant interaction (interaction P = 0.02) of EMAT-guided therapy for patients with %EMAT of < 15% or 15%. In addition, EMATguided therapy was associated with a significant reduction in all-cause mortality in this high-risk cohort, compared to the symptom-guided treatment group (Fig. 3B) (hazard ratio 0.33, 95% confidence interval 0.12 0.91, log-rank P = 0.0244). The stratified analyses demonstrated that the advantage of EMAT-guided therapy over symptom-guided therapy was consistent among patients < 75 or 75 years, men or women and with or without atrial fibrillation, chronic kidney disease or reduced LVEF (Fig. 4).
Medication Adjustments and Changes of %EMAT and S3 Strength
Within 1 year of management, patients randomized to the EMAT-guided group had more adjustments of diuretics and/or nitrates but not of renin-angiotensin-system blockers, b-blockers or mineralocorticoid receptor antagonists compared with the symptom-guided group (Fig. 5). Although %EMAT was nonsignificantly reduced in both groups (Fig. 6A), S3 strength was significantly diminished in the EMAT-guided group but not in the symptom-guided group (Fig. 6B). The proportions of %EMAT 15% or S3 strength 5 for each study visit also demonstrated similar trends (Supplementary Fig. 1 and Fig. 2). When we analyzed the last measurement of %EMAT prior to any adverse event, if any, the %EMAT was related to clinical outcomes in the symptom-guided group but not in the EMAT-guided group. (Fig. 7)
ARTICLE IN PRESS 4 Journal of Cardiac Failure Vol. 00 No. 00 2019
Fig. 1. Diagram of the study flow.
Discussion In the study population of AHF, optimization of postdischarge heart failure therapy guided by acoustic cardiography targeting a %EMAT of < 15% and an S3 strength < 5 might improve the clinical outcomes of all-cause mortality and readmissions for heart failure within 1 year. For the high-risk patients with baseline %EMAT 15%, the effect size might even be greater. Intensifying medical therapy with diuretics and/or nitrates in the presence of high %EMAT or high S3 strength scores might be a better strategy than the conventional strategy of treatment adjustment by means of physicians’ monitoring heart failure symptoms and signs. The study results expand our previous observational studies in patients with AHF regarding the advantage of acoustic cardiography in risk assessment.25,26 Although there have been great advancements in the past decades, the long-term outcomes of patients with heart failure remain dismal,27 and the number of heart failure-related deaths has increased steadily from 2009
to 2014.28 Heart failure has become the leading cause of hospitalization in persons older than 65 years of age.29 Compared with chronic heart failure, patients hospitalized for acute heart failure with either preserved or reduced LVEF are characterized by worse clinical outcomes, and the risk of death is high in the early period after discharge.30,31 Although the prognostic value of natriuretic peptides has been established in patients with AHF,32 the guidance of heart failure therapy to reach an NT-proBNP reduction of > 30% during hospitalization did not improve the postdischarge clinical outcomes.33 Moreover, the objective of achieving an individual or a universal NT-proBNP target by serial measurements and subsequent intensification of guideline-recommended therapies did not provide significant clinical benefits in patients with AHF.17,19 In contrast, the CHAMPION (Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) trial demonstrated a significant reduction in hospitalizations for patients with NYHA class III heart failure who were managed with a
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 5 Table 1. Baseline Characteristics of the Study Population EMAT-guided, n = 114 Age, years 74.7 § 13.7 Men, n (%) 76 (66.7) 23.5 § 4.8 Body mass index, kg/m2 Smoker, n (%) 16 (14.0) HFrEF, n (%) 72 (63.2) *NT-proBNP, pg/L 3.85 § 0.43 Comorbidities, n (%) Hypertension 89 (78.1) Diabetes 38 (33.3) Stroke 8 (7.0) CAD 50 (43.9) Atrial fibrillation 33 (29.0) Laboratory and hemodynamic measures SBP, mmHg 124.6 § 26.8 DBP, mmHg 69.8 § 12.8 Heart rate, minute 1 76.4 § 15.2 Creatinine, mg/dL 1.8 § 1.1 Cholesterol, mg/dL 157.0 § 44.2 HDLc, mg/dL 41.3 § 14.8 LDLc, mg/dL 99.2 § 40.1 Triglyceride, mg/dL 101.5 § 45.8 Cardiac structure and function LA dimension, mm 45.0 § 8.6 LVIDd, mm 56.0 § 8.9 IVSd, mm 11.4 § 3.3 PWd, mm 11.3 § 2.4 LVIDs, mm 43.1 § 10.9 LVEF, % 38.0 § 13.9 Measures of acoustic cardiography EMAT, msec 112.9 § 23.6 %EMAT, % 14.3 § 3.7 S3 4.3 § 2.1 Presence of S3, n (%) 30 (26.3) Medications at discharge, n (%) RAS blockers 50 (43.9) ß-blockers 73 (64.0) MRA 45 (39.5) Diuretics 82 (71.9) Nitrates 78 (68.4) Digoxin 24 (21.1) Statins 34 (29.8) Antiplatelet agents 56 (49.1)
Symptomguided, n = 111
P value
73.5 § 15.3 90 (81.1) 24.2 § 4.4
0.52 0.01 0.30
19 (17.1) 62 (55.9) 3.85 § 0.55
0.52 0.26 0.99
80 (72.1) 38 (34.2) 4 (3.6) 48 (43.2) 31 (27.9)
0.30 0.89 0.25 0.93 0.87
124.1 § 25.1 69.8 § 12.2 73.1 § 12.2 1.9 § 1.5 148.8 § 35.2 43.3 § 13.3 93.3 § 28.8 84.3 § 37.3
0.89 0.99 0.07 0.38 0.17 0.39 0.27 0.007
47.2 § 7.9 58.0 § 11.1 11.4 § 3.0 11.4 § 2.5 44.5 § 14.1 38.8 § 15.0
0.06 0.16 1.00 0.67 0.45 0.68
117.4 § 23.3 14.3 § 3.8 4.5 § 2.1 33 (29.7)
0.15 0.96 0.63 0.57
44 (39.6) 66 (59.5) 45 (40.5) 72 (64.9) 66 (59.5) 23 (20.7) 20 (18.0) 48 (43.2)
0.52 0.48 0.87 0.25 0.16 0.95 0.04 0.38
CAD, coronary artery disease; DBP, diastolic blood pressure; EMAT, electromechanical activation time; %EMAT, normalized EMAT; HDLc, high-density lipoprotein cholesterol; IVSd, interventricular septal thickness at diastole; LA, left atrium, LDLc, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; LVIDd, left ventricular internal dimension at diastole; LVIDs, left ventricular internal dimension at systole; MRA, mineralocorticoid antagonist; PWd, posterior wall thickness at diastole; RAS, renin-angiotensin system; SBP, systolic blood pressure. *N-terminal pro-B type natriuretic peptide (NT-proBNP) was log transformed.
wireless implantable hemodynamic monitoring system.34,35 The present study showed a prominent reduction in postdischarge readmissions for patients with AHF by targeting %EMAT and S3 strength, measures of
LV mechanical properities20,36 that outperformed B-type natriuretic peptide in the prediction of LV systolic dysfunction.37 Given that natriuretic peptides are highly confounded by noncardiac factors,38 using natriuretic peptides as a guide to modulate heart failure therapies is not recommended. In the CHAMPION trial and the present study, direct measures of LV hemodynamics might contribute to the best management of patients with heart failure. EMAT is a time interval based on a fine balance between intrinsic myocardial contractility, preload and afterload. We have demonstrated previously that %EMAT could further improve the risk stratifications with NT-proBNP in patients with AHF.21,26 In addition, the presence of S3 has outperformed other congestive physical signs in the prediction of clinical outcomes in AHF, even with atrial fibrillation.2,4 Both high %EMAT and S3 may suggest increased preload and upcoming decompensation, which could be alleviated by diuretics and/or nitrates. In the present study, physicians were encouraged to prescribe or uptitrate diuretics and/or nitrates in the presence of a high %EMAT or a high S3 strength score. The favorable results of nitrate therapy in patients with chronic systolic heart failure has been proposed in the Veterans Administration Cooperative Study, supporting the clinical benefits of reducing cardiac preload and afterload in the management of heart failure.39 Although none of the clinical trials have shown survival benefits of diuretics, both diuretics and vasodilators are recommended by the guidelines for managing AHF.40 Diuretics and vasodilators are believed to decongest the LV and lungs in AHF, but they may prevent further deterioration of heart failure and the subsequent hospitalizations in patients at risk for decompensation. Setoguchi et al have shown that readmission for heart failure was a strong predictor of mortality in a total of 14,374 patients with AHF.41 In this current study, we identified patients at risk of decompensation by a %EMAT of 15% and/or S3 strength 5, and then up-titrated diuretics and/or nitrates to prevent rehospitalizations due to heart failure. The prespecified medication changes may support the proper therapeutic strategies in response to high %EMAT and/or S3 that would improve clinical outcomes. The reduction of rehospitalization for heart failure may further contribute to the decrease in mortality in high-risk patients with %EMATs of 15% in this study. Although the %EMAT was not shortened in the EMAT-guided group (Supplementary Figs. 1A and 2A), neither of the previous studies has shown that diuretics and nitrites could reduce the PEP index in patients with heart diseases.42,43 On the other hand, the S3 strength was attenuated in the EMATguided group but not in the symptom-guided group. (Supplementary Figs. 1 and 2).
ARTICLE IN PRESS 6 Journal of Cardiac Failure Vol. 00 No. 00 2019
Fig. 2. Event-free survival curves of the study population, stratified by either EMAT-guided therapy or symptom-guided therapy. A) Events included all-cause mortality and heart failure hospitalizations. B) Mortality. CI, confidence interval; EMAT, electromechanical activation time; HR, hazard ratio.
Fig. 3. Event-free survival curves of the patients with baseline %EMAT 15%, stratified by either EMAT-guided therapy or symptomguided therapy. A) Events included all-cause mortality and heart failure hospitalizations. B) Mortality. CI, confidence interval; EMAT, electromechanical activation time; HR, hazard ratio.
Study limitations
There are several limitations in this study. First, this was a single-center study, and the sample size was relatively small. The baseline characteristics were not fully matched between the 2 groups. In addition, we were not able to calculate the impact of nonscheduled visits, which were not recorded, on the study results. Neither did we measure NT-proBNP levels at each study visit. However, the clinical benefits of the EMAT-guided therapy on top of standard management, in both the total study population and in the subgroup analysis, have been demonstrated clearly. Second,
the study was single-blinded, which could be a potential source of bias. However, we have adjudicated the primary endpoints by physicians who were blinded to the treatment assignment so as to alleviate this bias. Third, renin-angiotensin-system blockers, b-blockers and mineralocorticoid receptor antagonists were prescribed only to 42%, 62% and 40% of the study population before discharge, and 55% of them had reduced LVEF. Moreover, the preparations of nitrate and diuretics were not restricted; therefore, the prognostic values related to the dosages of nitrates or diuretics could not be evaluated. Given that the adherence to the guideline-recommended treatments might be a concern in
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 7
Fig. 4. Stratified analyses of the study population by age of < 75 or 75 years, men or women, the presence of atrial fibrillation, chronic kidney disease or left ventricular ejection fraction (LVEF) 40%. EMAT, electromechanical activation time.
this study, the generalizability of the study’s results in patients with AHF remains debatable. Multicenter, larger scale studies, specified for heart failure with either preserved or reduced LVEF, are needed to validate the clinical benefits of EMAT-guided management in AHF. Conclusions In the present study of patients with AHF, we have shown the advantages of acoustic cardiography-guided therapy on top of standard management to reduce postdischarge heart failure readmissions and mortality. A high %EMAT or S3 strength might indicate that patients are at risk of decompensation and mortality, and intensification of diuretics and/or vasodilators therapy might mitigate the consequential adverse events. Future multicentered, randomized trials with larger sample sizes and longer follow-up periods are warranted to confirm the benefits of acoustic cardiography in the management of AHF. Acknowledgments Fig. 5. The proportion of patients with medication adjustment during the study visits. Heart failure (HF)-specific drugs included renin-angiotensin system blockers, b-blockers and mineralocorticoid receptor antagonists. Error bars indicate means and 95% confidence intervals. EMAT, electromechanical activation time.
The study was supported by Taipei Veterans General Hospital (V100C-145, V101C-092, V102C-119, V103B017, V104C-172, and V104E12-003-MY3); Ministry of Science and Technology (MOST 103-2314-B-010-050-
ARTICLE IN PRESS 8 Journal of Cardiac Failure Vol. 00 No. 00 2019
Fig. 6. Changes of %EMAT A) and S3 B) across the study period. Data are presented as the mean § standard errors of the mean. EMAT, electromechanical activation time.
3.
4.
5. 6.
7. Fig. 7. The last measure of %EMAT in the study population. EMAT, electromechanical activation time. 8.
MY2); and Ministry of Health and Welfare, Taiwan grant (MOHW-105-TDU-B-211-133017, MOHW106-TDU-B211-113001, MOHW107-TDU-B-211-123001).
9.
Disclosures
10.
None declared. 11.
Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.card fail.2019.09.012.
12.
References 1. Origin of the third heart sound. Br Med J 1969;3:193. 2. Minami Y, Kajimoto K, Sato N, Aokage T, Mizuno M, Asai K, et al. Third heart sound in hospitalised patients with acute
13.
heart failure: insights from the ATTEND study. Int J Clin Pract 2015;69:820–8. Ishmail AA, Wing S, Ferguson J, Hutchinson TA, Magder S, Flegel KM. Interobserver agreement by auscultation in the presence of a third heart sound in patients with congestive heart failure. Chest 1987;91:870–3. Caldentey G, Khairy P, Roy D, Leduc H, Talajic M, Racine N, et al. Prognostic value of the physical examination in patients with heart failure and atrial fibrillation: insights from the AFCHF trial (Atrial Fibrillation and Chronic Heart Failure). JACC Heart Fail 2014;2(1):15–23. Lewis RP, Rittogers SE, Froester WF, Boudoulas H. A critical review of the systolic time intervals. Circulation 1977;56 (2):146–58. Cheng HM, Yu WC, Sung SH, Wang KL, Chuang SY, Chen CH. Usefulness of systolic time intervals in the identification of abnormal ventriculo-arterial coupling in stable heart failure patients. Eur J Heart Fail 2008;10:1192–200. Cheng HM, Chuang SY, Hsu PF, Chou P, Chen CH. Systolic time intervals revisited: correlations with N-terminal probrain natriuretic peptide in a community population. Heart Vessels 2005;20:256–63. Wen YN, Lee AP, Fang F, Jin CN, Yu CM. Beyond auscultation: acoustic cardiography in clinical practice. Int J Cardiol 2014;172:548–60. Diamant B, Killip T. Indirect assessment of left ventricular performance in acute myocardial infarction. Circulation 1970;42:579–92. Roos M, Toggweiler S, Jamshidi P, Zuber M, Kobza R, Meier R, et al. Noninvasive detection of left ventricular systolic dysfunction by acoustic cardiography in cardiac failure patients. J Card Fail 2008;14:310–9. Zuber M, Kipfer P, Attenhofer Jost CH. Usefulness of acoustic cardiography to resolve ambiguous values of B-type natriuretic peptide levels in patients with suspected heart failure. Am J Cardio 2007;100:866–9. Maisel AS, Peacock WF, Shah KS, Clopton P, Diercks D, Hiestand B, et al. Acoustic cardiography S3 detection use in problematic subgroups and B-type natriuretic peptide “gray zone”: secondary results from the Heart failure and Audicor technology for Rapid Diagnosis and Initial Treatment Multinational Investigation. Am J Emerg Med 2011;29:924–31. Chao T-F, Sung S-H, Cheng H-M, Yu W-C, Wang K-L, Huang C-M, et al. Electromechanical activation time in the prediction
ARTICLE IN PRESS Effect of Acoustic Cardiography-guided Management on 1-year Outcomes in Patients Sung et al 9
14. 15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
26.
27.
28.
of discharge outcomes in patients hospitalized with acute heart failure syndrome. Internal Medicine 2010;49:2031–7. Wang S, Liu M, Fang F, Shang Q, Sun JP, Sanderson JE, et al. Prognostic value of acoustic cardiography in patients with chronic heart failure. Int J Cardiol 2016;219:121–6. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006;47:76–84. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Crespo Leiro M, Drozdz J, et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2013;15:808–17. Eurlings LW, van Pol PE, Kok WE, van Wijk S, Lodewijksvan der Bolt C, Balk AH, et al. Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. J Am Coll Cardiol 2010;56:2090–100. Pfisterer M, Buser P, Rickli H, Gutmann M, Erne P, Rickenbacher P, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIMECHF) randomized trial. JAMA 2009;301:383–92. Lainchbury JG, Troughton RW, Strangman KM, Frampton CM, Pilbrow A, Yandle TG, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53–60. Efstratiadis S, Michaels AD. Computerized acoustic cardiographic electromechanical activation time correlates with invasive and echocardiographic parameters of left ventricular contractility. J Card Fail 2008;14:577–82. Chao TF, Sung SH, Cheng HM, Yu WC, Wang KL, Huang CM, et al. Electromechanical activation time in the prediction of discharge outcomes in patients hospitalized with acute heart failure syndrome. Intern Med 2010;49:2031–7. Marcus GM, Gerber IL, McKeown BH, Vessey JC, Jordan MV, Huddleston M, et al. Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function. JAMA 2005;293:2238–44. Sung SH, Yu WC, Cheng HM, Lee CW, Lin MM, Chuang SY, et al. Excessive wave reflections on admission predict post-discharge events in patients hospitalized due to acute heart failure. Eur J Heart Fail 2012;14:1348–55. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics 1988;44:1049–60. Chao TF, Sung SH, Cheng HM, Yu WC, Wang KL, Huang CM, et al. Electromechanical activation time in the prediction of discharge outcomes in patients hospitalized with acute heart failure syndrome. Internal Medicine 2010;49:2031–7. Chang CC, Sung SH, Yu WC, Cheng HM, Chen CH. Nighttime electromechanical activation time, pulsatile hemodynamics, and discharge outcomes in patients with acute heart failure. ESC Heart Fail 2015;2:184–93. Mamas MA, Sperrin M, Watson MC, Coutts A, Wilde K, Burton C, et al. Do patients have worse outcomes in heart failure than in cancer? a primary care-based cohort study with 10-year followup in Scotland. Eur J Heart Fail 2017;19:1095–104. Ni H, Xu J. Recent trends in heart failure-related mortality: United States, 2000-2014. NCHS Data Brief 2015;231:1–8.
29. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557–73. 30. Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, Filippatos G, Ruschitzka F, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail 2016;18:613–25. 31. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 2007;116:1482–7. 32. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330–7. 33. Stienen S, Salah K, Moons AH, Bakx AL, van Pol P, Kortz RAM, et al. NT-proBNP (N-terminal pro-B-type natriuretic peptide)-guided therapy in acute decompensated heart failure: PRIMA II randomized controlled trial (can NT-ProBNPguided therapy during hospital admission for acute decompensated heart failure reduce mortality and readmissions?). Circulation 2018;137:1671–83. 34. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. 35. Abraham WT, Stevenson LW, Bourge RC, Lindenfeld JA, Bauman JG, Adamson PB, et al. Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet 2016;387:453–61. 36. Roos M, Toggweiler S, Zuber M, Jamshidi P, Erne P. Acoustic cardiographic parameters and their relationship to invasive hemodynamic measurements in patients with left ventricular systolic dysfunction. Congest Heart Fail 2006;12(Suppl 1): 19–24. 37. Kosmicki DL, Collins SP, Kontos MC, Zuber P, Kipfer P, Attenhofer Jost C, et al. Noninvasive prediction of left ventricular systolic dysfunction in patients with clinically suspected heart failure using acoustic cardiography. Congest Heart Fail 2010;16:249–53. 38. Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357–68. 39. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration cooperative study. N Engl J Med 1986;314: 1547–52. 40. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC): developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. 41. Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure. Am Heart J 2007;154:260–6. 42. Balasubramanian V, Behl A, Das GS, Wadhwa AK, Mathew OP, Hoon RS. Effect of digoxin and diuretics on high altitude left ventricular dysfunction. Circulation 1978;57:1180–5. 43. Sawayama T, Ochiai M, Marumoto S, Matsuura T, Niki I. Influence of amyl nitrite inhalation on the systolic time intervals in normal subjects and in patients with ischemic heart disease. Circulation 1969;40:327–35.