|Year : 2022 | Volume
| Issue : 1 | Page : 1-8
A narrative review of clinical applications of systolic time intervals
Smitha Pernaje Seetharam1, M S Vinutha Shankar1, Niranjan Reddy2
1 Department of Physiology, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Kolar, Karnataka, India
2 Department of Cardiology, R L Jalappa Narayana Heart Centre, Kolar, Karnataka, India
|Date of Submission||08-Oct-2021|
|Date of Decision||12-Feb-2022|
|Date of Acceptance||15-Mar-2022|
|Date of Web Publication||26-Apr-2022|
Smitha Pernaje Seetharam
Department of Physiology, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar - 563 103, Karnataka
Source of Support: None, Conflict of Interest: None
Systolic time interval (STI) estimation is an established noninvasive method for the quantifiable assessment of left ventricular (LV) performance in well-being and disease states; it stays valuable for clinical application and forms no burden to the subjects. This manuscript reviews the potential clinical applications and prognostic value of STI for the assessment of LV systolic function in cardiovascular disease (CVD). STIs could be obtained by several noninvasive imaging modalities such as transthoracic echocardiography, tissue Doppler imaging M-mode echocardiography, conventional echocardiography, and so on. In view of that, a literature review for studies reporting the clinical applications of STI in assessing LV systolic function among CVD patients was carried out using PubMed search. Accordingly, the current review describes how STI can be measured; reliability of cardiac time interval measurement in patients with CVD and its role in a clinical setting. With the advent of modern techniques, STI could be easily measured in a clinical setting. Likewise, STI parameter, particularly preejection period and LV ejection time ratio (PEP/LVET), has got the highest degree of correlation with LV ejection fraction (LVEF) in assessing LV performance. Furthermore, reproducibility of systolic ejection time (SET) achieved by the TDI M-mode method is outstanding and better when compared with the reproducibility of SET obtained by the conventional pulsed Doppler method. Furthermore, prolonged SET is independently related with enhanced outcomes among heart failure with reduced EF (HFrEF, i.e., EF ≤40%) but not HF with preserved EF (HFpEF, i.e., EF >40%) patients, indicating that stabilizing SET would be helpful in the case of systolic dysfunction. Clinically, tissue Doppler-derived time intervals could be beneficial to analyze abnormal cases in comparison with other invasive and noninvasive methods of ventricular function examination. Furthermore, phonoelectrocardiography-derived STI parameters, particularly electromechanical activation time-to-LVET ratio, may have a significant role in the diagnostic approach of heart failure (HF) in patients with undifferentiated dyspnea. In addition, in HF patients, PEP/LVET of >0.43 helps to detect LVEF <35% by pulsed Doppler echocardiography. Moreover, LVET continues to be an independent predictor of incident HF and provides incremental prognostic value on the future HF risk and death but not myocardial infarction. In conclusion, STI measurement could be useful, particularly in identifying LVEF <35% in the case of refractory HF patients. This could be beneficial in the selection of patients requiring cardiac resynchronization, specifically when accurate LVEF evaluation by echocardiography proves challenging in atrial fibrillation or if the evaluation is done by a trainee echocardiographer. Furthermore, the cardiac time intervals including SET can be acquired irrespective of rhythm. Good image quality is required for the assessment of LVEF. In contrast, evaluation of SET could be useful in the case of echocardiograms with poor quality images. As a final point, the present review suggests using an echocardiographic parameter like STIs to procure additional information regarding the risk of mortality in patients with HFrEF along with LVEF measurement.
Keywords: Cardiovascular disease, heart failure, left ventricular ejection fraction, left ventricular function, pulsed Doppler echocardiography, systolic time intervals
|How to cite this article:|
Seetharam SP, Shankar M S, Reddy N. A narrative review of clinical applications of systolic time intervals. J Pract Cardiovasc Sci 2022;8:1-8
|How to cite this URL:|
Seetharam SP, Shankar M S, Reddy N. A narrative review of clinical applications of systolic time intervals. J Pract Cardiovasc Sci [serial online] 2022 [cited 2022 May 24];8:1-8. Available from: https://www.j-pcs.org/text.asp?2022/8/1/1/344133
| Introduction|| |
Nowadays, cardiovascular diseases (CVD) have become the prominent source of mortality in India. A quarter of all mortality is due to CVD. Ischemic heart disease (IHD) and stroke are the chief causes and are accountable for >80% of CVD deaths. Hence, addition of cost-effective, easily available techniques like systolic time interval measurement in primary and secondary health-care settings in India along with routine standard investigations to supervise CVD is the need of the hour.
Systolic time intervals (STIs) offer a time-sensitive translation of the successive phases of a cardiac cycle which are impacted physiologically by heart rate (HR), preload, afterload, and myocardial inotropic state which thus influences the left ventricular (LV) performance.
The term coronary artery disease (CAD), also called coronary heart disease and IHD, includes the reduction of blood flow to the cardiac muscle due to atherosclerosis in the coronary arteries.,, Coronary artery disease comprises stable angina, unstable angina, myocardial infarction, and sudden cardiac death.
This manuscript reviews the potential clinical applications of STIs to assess LV performance among CVD patients.
| Methodology|| |
Literature search of MEDLINE database was done and included original studies and review articles reporting the assessment of LV performance using STIs. In view of that, 8836 studies with accessible full-length articles in English language from 1960 to 2021 were considered.
Articles available with only abstracts, short communications, editorials, conference abstracts, and discussion papers were excluded. After screening full-length articles related to myocardial ischemia, articles reporting the importance of STI measurement in the case of other diseases, for example, thyroid diseases, malignancies, chronic obstructive pulmonary diseases, deficiency of Vitamin D, and anemia, were not included in this review.
After going through the articles, 23 appropriate studies were included in the current review [Figure 1]. Accordingly, review was narrated as method to measure STIs, reliability of STI measurement in patients with CVD, and its role in a clinical setting besides established techniques to assess LV performance. Brief summaries of the included articles are précised [Table 1].
|Figure 2: Line diagram depicting the measurements of preejection period and left ventricular ejection time from tissue Doppler imaging. STI: Systolic time interval; A': Late diastolic wave; E': Early diastolic wave; S: Systolic wave (adapted from: Cui, Wei and Roberson, David and Chen, Zhen and Madronero, Luisa and Cuneo, Bettina (2008). Systolic and Diastolic Time Intervals Measured from Doppler Tissue Imaging: Normal Values and Z-score Tables, and Effects of Age, Heart Rate, and Body Surface Area. Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography. 21. 361-70. 10.1016/j.echo. 2007.05.034)|
Click here to view
How systolic time interval is measured?
Weissler et al. 1961 obtained STIs with the simultaneous recording of the heart sounds (phonocardiogram), the central arterial pulse tracing (carotid pulse), and the electrocardiogram (ECG) [Figure 3].
|Figure 3: “Simultaneous recording of the heart sounds (phonocardiogram), carotid arterial pulse tracing, and the electrocardiogram in a normal subject (paper speed, 100 mm/s; time markers, 0.02 s). QS2 = Total electromechanical systole; SlS2 = Heart sound interval; LVET = Left ventricular ejection time; and PEP = Preejection period” (adapted from: Circulation, Volume XXXVII, February 1968)|
Click here to view
In our study, we measured STIs using pulsed Doppler echocardiography (using Vivid S5 echocardiograph machine developed by GE Healthcare, Israel, 2008) at cardiology outpatient department 1 week post percutaneous coronary intervention. Doppler gains were attuned at a sweep speed of 100 mm/s. Standard echocardiogram included assessment of LV parasternal long-axis view, parasternal short-axis (PSAX) view, and apical views (four-, two-, and three-chamber views). Accordingly, STIs determined from the aortic valve echocardiogram built on pulsed Doppler aortic acquisitions were as follows: the total electromechanical systole (QS2) is the interval from the initiation of the QRS complex on the ECG to the closing of the aortic valve on the echocardiogram. Preejection period (PEP) is the interval from the start of ventricular contraction to the start of aortic ejection. LV ejection time (LVET) is the interval ranging from the commencement to the end of aortic flow [Figure 4]a and [Figure 4]b.
|Figure 4: (a) Line diagram depicting the measurements of preejection period and left ventricular ejection time using pulsed Doppler echocardiography. (b). Measurements of preejection period and left ventricular ejection time in an ischemic heart disease patient 1 week post revascularization with percutaneous coronary intervention: PEP (2 MV A Dur) = 97 ms, left ventricular ejection time (3 MV A Dur) = 275 ms, PEP/LVET = 0.35. Cross-sectional area of aortic orifice (LVOT: Left ventricular outflow tract or 1 L) = 2.2 cm|
Click here to view
| Discussion|| |
Physiological understanding of systolic time intervals
PEP/LVET ratio has been utilized as a degree of cardiovascular contractility; conversely, LVET and PEP/LVET are influenced by the HR as well as parasympathetic activity. Interestingly, PEP is not significantly changed by variations in HR. Accordingly, LVET and PEP/LVET should be revised for the basic HR (resulting in LV ejection time index [LVETI]), whereas the need for HR correction of PEP (i.e., PEP index) is pugnacious.
Reliability and reproducibility of STI measurement in a clinical setting
A study conducted in France included 134 heart failure (HF) patients and 43 control subjects. The authors found that with the progressively changed LV ejection fraction (LVEF), PEP was significantly prolonged, LVET was significantly shortened, and the ratio of PEP/LVET (P < 0.001) was increased. In the case of HF patients, a correlation between LVEF and PEP/LVET was found (with r = 0.55). Based on receiver operating characteristic curve analyses, the area under the curve was obtained as 0.91 for PEP/LVET >0.43, which permitted the authors to identify LVEF <35% with a sensitivity of 87% and a specificity of 84%. Thus, STI can be effortlessly and precisely measured in a clinical setting and it could be used for spotting LV systolic dysfunction. Likewise, this method is probable to have would-be applications in the supervision of HF patients.
A study by Bennet et al. 1971 concluded that measurement of STI is valuable in assessing LV dysfunction after acute myocardial infarction (AMI) and it seemed promising as a diagnostic and prognostic tool among 24 AMI patients. Though, further study is needed to appreciate the mechanisms accountable for the shortened LVET and QS2 intervals.
Another study by Khanna et al. 1973 examined the short-term effects of altered preload on STIs among 17 AMI patients and 7 subjects without AMI having normal hemodynamics. The authors found that in patients with AMI, effects of altered preload on STI could provide a more accurate index of LV function than the STIs when measured alone.
According to a study by Parker et al., 1974, excellent correlations were shown between contractility indices and ejection fraction in the case of 36 male patients with electrocardiographically and angiographically evident coronary artery disease. However, STIs were found to be not reliable indices of ventricular function. Hence, it is doubtful whether STIs are of value in the clinical assessment of coronary artery disease or not?
A study was conducted on 593 children with normal echocardiogram results in Illinois. Wherein, five time intervals were measured from tissue Doppler imaging (TDI), namely isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT), ejection time (ET), systolic time (St), and diastolic time (Dt). Furthermore, Tei index (TX) and St/Dt were calculated. The study measured longitudinal directed TDI waves [Figure 2] from three places such as mitral annulus, tricuspid annulus, and basal interventricular septum from an apical four-chamber view. All seven time interval measures at all of the three sampling sites correlated well with age, HR, and body surface area (P < 0.001–P < 0.003), except the mitral annulus TX (P = 0.1) on univariate analysis. On multivariate analysis, IVCT, IVRT, and TX correlated well with age at all three sites (P < 0.001). Conversely, when the intervals were corrected for HR on dividing by square root of R-R interval, both corrected IVCT and corrected IVRT turned out to be constants at all three locations. Thus, for real-world clinical applications, corrected IVCT, corrected IVRT, and TX were constant at all three places. In addition, ET, systolic time, diastolic time, and St/Dt correlated very well with HR at all three locations (P < 0.001). Moreover, at faster HRs, ET, St, and Dt all decreased, whereas St/Dt augmented at faster HRs.
A prospective observational study by Sorensen et al. 2018 included African-Americans (n = 1980) of the Atherosclerosis Risk in Communities. Subjects underwent echocardiography, and LVET was measured using pulsed-wave Doppler. A short LVET was associated with younger age, in the case of men, increase in diastolic blood pressure, and prevalence of diabetes, tachycardia, elevated blood sugar levels, and poorer fractional shortening. During a median follow-up of 17.6 years, 384 of them had the incidence of HF, 158 had a myocardial infarction, and 587 of them died. In univariate analysis, a lower LVET was significantly associated with increased risk of all events (P < 0.05 for all). Nevertheless, after multivariable adjustment for confounding variables, LVET persisted as an independent interpreter only of incident HF (hazard ratio: 1.07, P = 0.010 per 10-ms decrease). In addition, LVET provided incremental prognostic information on the risk of future HF and death but not myocardial infarction.
Ninety-eight healthy MBBS students aged 19–21 years were included in a study by Sadaf et al. 2020. Measurement of arterial blood pressures (in all four limbs) and the cardiac time interval determination (PEP, ET, UT, DT, PD, and ES) was done by PeriScope™. The study concluded that since sex, anthropometric values, and blood pressure affect cardiac time intervals, these must be adjusted for when drawing conclusion about LV performance.
A study by Trabelsi et al. 2020 included total of 855 patients with dyspnea and suspected HF. Echocardiographic measurements of LV ejection fraction (LVEF), testing of B-type natriuretic peptide (BNP) levels, and computerized phonoelectrocardiography to assess STIs including electromechanical activation time (EMAT), LVET, and EMAT/LVET ratio were done. STI diagnostic accuracy was calculated. A significantly higher EMAT and lower LVET was found in patients with HF (n = 530) compared to non-HF patients. Receiver operating characteristic curve c-statistic was 0.74, 0.72, and 0.78 for EMAT, LVET, and EMAT/LVET, respectively. The sensitivity and specificity of EMAT/LVET were 72% and 88%, respectively. EMAT/LVET ratio had the maximum correlation with LVEF (r = 0.48). Positive likelihood ratio was found to be 1.8 with BNP alone and was 3.6 with BNP along with EMAT/LVET ratio in patients with intermediate BNP. Patients without HF had STIs not significantly altered from those with preserved LVEF (≥45%). Hence, phonoelectrocardiography-derived STI parameters, particularly EMAT/LVET ratio, may have a significant role in the diagnostic approach of HF in patients with undifferentiated dyspnea.
A total of 545 HF patients (171 with reduced EF, i.e., HF with reduced EF (HFrEF) of 30%, and 374 with preserved EF, i.e., HFpEF of 54%) met eligibility criteria in a study by Patel et al. 2020. Among patients with HFrEF vs. HFpEF, median LV systolic ET (SET) was found to be shorter (280 ms vs. 315 ms, P < 0.001), median PEP obtained was longer (114 ms vs. 89 ms, P < 0.001), and median relaxation time was shorter (78.7 ms vs. 93.3 ms, P < 0.001). Death or HF hospitalization occurred in the case of 26.9% (n = 46) HFrEF and 11.8% (n = 44) HFpEF patients. Multivariable logistic regression analyses showed that longer SET was independently associated with better outcomes among HFrEF but not HFpEF patients, suggesting a possible role for stabilizing SET as a helpful approach in patients with systolic dysfunction. Further research should be done to appreciate normal ranges for SET and to discover the history of SET with advanced systolic dysfunction.
In a study by Wiley et al. 2021, data from 158 healthy participants (19.09 ± 1.84 years) were available for analyses. Cardiac autonomic balance (CAB) and cardiac autonomic regulation (CAR) values were calculated using both high-frequency HR variability (HF-HRV) and the root mean square of successive differences (RMSSD), along with PEP of STI and LVET. HR variability HF-HRV is a chronotropic measure (reflects parasympathetic nervous system activity) whereas PEP of STI has both chronotropic and inotropic activities (reflects sympathetic activity) and LVET (chronotropic measure). Analyses showed a significantly weaker correlation between CAB and CAR calculated using LVET for both HF-HRV (z = 5.12, P < 0.001) and RMSSD (z = 5.26, P < 0.001) than with PEP. Accordingly, researchers should consider calculating CAB and CAR using LVET and HF-HRV measures instead of calculating a combination of PEP and HF-HRV measures.
A study conducted in Switzerland proposed an artificial intelligence-based method to evaluate LV end-systolic elastance (Ees) (a major factor determining the systolic function and ventricular-arterial interface) using PEP and ET. The authors developed a testing pattern using virtual subjects (different hemodynamic cases: N = 4,645) from a formerly validated in silico model. Results displayed that Ees could be prophesied with extreme precision attaining a normalized RMSE = 9.15% (r = 0.92) for a range of Ees values from 1.2 to 4.5 mmHg/ml. The suggested model had great sensitivity, with the measurement errors of ±10%–30% of the actual value in blood pressure, bestowed with low test errors for the diverse levels of noise (RMSE was not >0.32 mmHg/ml). A great sensitivity was stated for systolic timing feature measurement errors. Hence, it showed that Ees can be accurately evaluated from the conventional arm pressure and echocardiographic PEP and ET parameters.
In another study, a total of 997 patients with HFrEF (mean age: 67 ± 11 years, 74% of males) went through echocardiographic scan including TDI. During a median follow-up of 3.4 years, 165 (17%) patients passed away. The mortality risk was increased by 9% per 10-ms decline in SET (per 10-ms decrease: HR – 1.09; 95% confidence interval [CI] [1.06–1.13], P < 0.001). The association could retain its significance even after multivariable adjustment for various clinical and echocardiographic parameters (per 10-ms decrease: HR – 1.06; 95% CI (1.01–1.11), P = 0.030). Reproducibility of SET achieved by the TDI M-mode echo was exceptional (intraclass correlation coefficient: 0.98 and interclass correlation coefficient: 0.95) and better compared to the reproducibility of SET attained by the traditional method (intraclass correlation coefficient: 0.93 and interclass correlation coefficient: 0.73). The reproducibility of LVEF was modest (intraclass correlation coefficient: 0.73 and interclass correlation coefficient: 0.63). In addition, the SET provided incremental prognostic information with regard to predicting mortality when combined with the established clinical predictors of mortality in patients with HFrEF.
| Conclusion|| |
TDI-derived time intervals could be beneficial to analyze abnormal cases, in comparison with other invasive and noninvasive methods of ventricular function examination, in sensitivity, specificity, and predictive value assessment, and to determine its use clinically.
Furthermore, noninvasive STI measurement could recognize HF in patients admitted to emergency department with acute dyspnea. It is predominantly helpful in patients with reduced ejection fraction. Assuming its potential advantages, STI measurements should be practically considered when echocardiography is not readily available.
Furthermore, STI measurement could be useful, particularly in identifying LVEF <35% in the case of refractory HF patients. This could be beneficial in the selection of patients requiring cardiac resynchronization, specifically when accurate LVEF evaluation by echocardiography proves challenging in atrial fibrillation or if the evaluation is done by a trainee echocardiographer. Furthermore, STI measurement could be useful clinically among cardiovascular disease patients in assessing their LV performance. In addition, STIs retain its prognostic value during the course after acute myocardial illness. Accordingly, the present review suggests using STIs to procure additional information regarding the risk of mortality in patients with HFrEF along with LVEF measurement.
The study was approved by the Institutional Ethics Committee (IEC No. DMC/KLR/IEC/648/2021-22 dated 4-3-2022).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Prabhakaran D, Jeemon P, Roy A. Cardiovascular diseases in India: Current epidemiology and future directions. Circulation 2016;133:1605-20.
Hassan S, Turner P. Systolic time intervals: A review of the method in the non-invasive investigation of cardiac function in health, disease and clinical pharmacology. Postgrad Med J 1983;59:423-34.
Bhatia SK. Biomaterials for Clinical Applications (Online-Ausg. ed.). New York: Springer; 2010. p. 23. Archived from the Original on 10 January, 2017.
Mendis S, Puska P, Norrving B, editors. Global Atlas on Cardiovascular Disease Prevention and Control. France: World Health Organization; 2011. p. 3-18.
Wong ND. Epidemiological studies of CHD and the evolution of preventive cardiology. Nat Rev Cardiol 2014;11:276-89.
Weissler AM, Peeler RG, Roehll WH Jr. Relationships between left ventricular ejection time, stroke volume, and heart rate in normal individuals and patients with cardiovascular disease. Am Heart J 1961;62:367-78.
Samson R. Changes in systolic time intervals in acute myocardial infarction. Br Heart J 1970;32:839-46.
Dowling JT, Sloman G, Urquhart C. Systolic time interval fluctuations produced by acute myocardial infarction. Br Heart J 1971;33:765-72.
Bennett ED, Smithen CS, Sowton E. An assessment of the haemodynamic alterations in acute myocardial infarction using the systolic time intervals. Thorax 1971;26:632-7.
Khanna PK, Shah PM, Kramer DH, Schaefer RA, Tager I. Effects of altered preload on left ventricular systolic time intervals in acute myocardial infarction. Br Heart J 1973;35:1102-8.
Parker ME, Just HG. Systolic time intervals in coronary artery disease as indices of left ventricular function: Fact or fancy? Br Heart J 1974;36:368-76.
Weissler AM, Stack RS, Lee CC, Reddy BP, Taylor ML. Left ventricular performance in coronary artery disease by systolic time intervals and echocardiography. Trans Am Clin Climatol Assoc 1976;87:36-47.
Lewis RP, Boudoulas H, Welch TG, Forester WF. Usefulness of systolic time intervals in coronary artery disease. Am J Cardiol 1976;37:787-96.
Boudoulas H, Lewis RP, Sherman JA, Bush CA, Dalamangas G, Forester WF. Systolic time intervals in atrial fibrillation. Chest 1978;74:629-34.
Gillilan RE, Parnes WP, Khan MA, Bouchard RJ, Warbasse JR. The prognostic value of systolic time intervals in angina pectoris patients. Circulation 1979;60:268-75.
Cui W, Roberson DA, Chen Z, Madronero LF, Cuneo BF. Systolic and diastolic time intervals measured from Doppler tissue imaging: Normal values and Z-score tables, and effects of age, heart rate, and body surface area. J Am Soc Echocardiogr 2008;21:361-70.
Anavekar NS, Oh JK. Doppler echocardiography: A contemporary review. J Cardiol 2009;54:347-58.
Reant P, Dijos M, Donal E, Mignot A, Ritter P, Bordachar P, et al.
Systolic time intervals as simple echocardiographic parameters of left ventricular systolic performance: Correlation with ejection fraction and longitudinal two-dimensional strain. Eur J Echocardiogr 2010;11:834-44.
Michael S, Graham KS, Davis Oam GM. Cardiac autonomic responses during exercise and post-exercise recovery using heart rate variability and systolic time intervals – A review. Front Physiol 2017;8:301.
Biering-Sørensen T, Querejeta Roca G, Hegde SM, Shah AM, Claggett B, Mosley TH Jr., et al.
Left ventricular ejection time is an independent predictor of incident heart failure in a community-based cohort. Eur J Heart Fail 2018;20:1106-14.
Sadaf S, Arifuddin MS, Rahman MZ, Hazari MA, Quadri SB. Correlation of systolic and diastolic time intervals with demographic and anthropometric parameters in young adults. J Pract Cardiovasc Sci 2020;6:23-32. [Full text]
Trabelsi I, Msolli MA, Sekma A, Fredj N, Dridi Z, Bzeouich N, et al.
Value of systolic time intervals in the diagnosis of heart failure in emergency department patients with undifferentiated dyspnea. Int J Clin Pract 2020;74:e13572.
Patel PA, Ambrosy AP, Phelan M, Alenezi F, Chiswell K, Van Dyke MK, et al.
Association between systolic ejection time and outcomes in heart failure by ejection fraction. Eur J Heart Fail 2020;22:1174-82.
Wiley CR, Pourmand V, Thayer JF, Williams DP. A close examination of the use of systolic time intervals in the calculation of impedance derived cardiac autonomic balance and regulation. Front Neurosci 2021;15:625276.
Bikia V, Adamopoulos D, Pagoulatou S, Rovas G, Stergiopulos N. AI-based estimation of end-systolic elastance from arm-pressure and systolic time intervals. Front Artif Intell 2021;4:579541.
Alhakak AS, Sengeløv M, Jørgensen PG, Bruun NE, Johnsen C, Abildgaard U, et al.
Left ventricular systolic ejection time is an independent predictor of all-cause mortality in heart failure with reduced ejection fraction. Eur J Heart Fail 2021;23:240-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]