Isovolumic contraction (IVC) is the early phase of systole. During this time period, the myocardial fibers begin to contract but have not developed enough pressure in the ventricles to overcome the aortic and pulmonary end-diastolic pressures in order to open the valves and consequently the ventricular volumes remain unchanged. The IVC starts approximately at the left atrioventricular pressure crossover and ends at the diastolic ventriculoaortic pressure crossover. The isovolumic contraction time (IVCT) is defined as the interval between the closing of the atrioventricular valves and the opening of the semilunar valves.  It can be measured by 3 echocardiographic methods of M-mode, pulse-wave Doppler (PWD), and tissue Doppler Imaging (TDI).[3–5] Clinically, the IVCT obtained by these methods for the same patients is not consistent and has caused misunderstanding (or confusions) in clinical diagnosis and treatment.[6–12]
Many researchers attribute the discrepancies to the fact that IVCT was not measured in the same cardiac cycle.[13,14] The start of IVC wave S1 on TDI represents the end of atrial muscle contraction and the beginning of voluntary ventricular muscle contraction, whereas the end of the IVC wave S1 represents the end of IVC along with opening of aortic valve and beginning of ventricular pumping.[15–18] In addition, it has been confirmed that IVC wave S1 on TDI is synchronous to the first derivative of the left ventricular pressure (dP/dt).[19,20] Thus, the period of S1 has been considered as the IVCT over years in clinical practice.[21–24] However, our data indicated that the mitral valve did not close at the start of S1 based on the TDI video imaging. We hypothesize that there may be a previously unidentified phase in the cardiac cycle, which occurs just before the real IVC. This phase has not been noticed due to low temporal resolution and may be the main reason causing the IVCT discrepancies by 3 echocardiographic methods.
The present study is to investigate whether there is a potentially unidentified phase causing the different results of IVCT. The electric mechanical delay time (EMD), IVCT, and pre-ejection period (PEP) obtained by M-mode, PWD and TDI, respectively, were analyzed.
2 Materials and methods
2.1 Clinical data of subjects
The study recruited 30 healthy individuals, including 18 men and 12 women, with mean age of 30 ± 6 years (range 20–40 years). Inclusion criteria: no family history of coronary heart disease. The electrocardiogram (ECG) was normal and the heart rate was 60 to 100 times/min, without arrhythmia. The cardiac x-ray examination was normal. (4) Blood pressure < 140/90 mm Hg (18.62 /11.97 kPa). (5) Individuals that could withstand strenuous physical exertion. Exclusion criteria: A low ST segment, or abnormal T wave (flat, bidirectional or inverted T wave), or pathological Q wave was shown on ECG. Individuals with the change of heart shape on the x-rays. The underlying diseases such as cardiovascular diseases were excluded. High-quality echocardiographic imaging was performed in these individuals. The clinical data of patients were listed in Table 1. All subjects signed the informed consent and this study was approved by the Institutional Review Board at the Affiliated Hospital to Changchun University of Traditional Chinese Medicine (Ethical approval number CCZYFYLL2012[K]001).
The GE Vivid 7 Dimension echocardiography system (General Electric Healthcare Vingmed Ultrasound, Horten, Norway) with a 1.5 to 4.3 MHz transducer, a built-in work station, and an image analysis and postprocessing ultrasound system was used for Echocardiography. Transthoracic imaging was performed with subjects in the left lateral position. All recordings were made with a simultaneous superimposed ECG to identify the electrical and mechanical phases of each cardiac cycle. Recordings were made at sweep speeds of 100 mm/s. By adjusting the ECG, the lead with an obvious Q wave was selected. If no Q wave was available, the lead with a clear R wave was selected. Initially, the routine diagnostic images of color-flow mapping and continuous-wave Doppler spectrum were obtained. Ejection fraction was measured in all subjects by the biplane modified Simpson method.
We performed M-mode measurements by placing the cursor across the mitral and aortic valves in the parasternal long- or short-axis plane. Sweep speeds were kept high at 100 mm/s. EMDm (EMD measured by M-mode) was measured from the onset of the QRS complex until the closure of mitral valve, and PEPm (PEP measured by M-mode) was measured from the onset of the QRS complex until the opening of the aortic valve. IVCTm (IVCT measured by M-mode) was calculated with the formula of IVCTm = PEPm–EMDm.
PWD across the mitral and aortic valves was assessed in each subject. The usual size of the pulsed Doppler gate was 2 mm. For optimal acquisition, care was taken to direct the transducer beam as close as possible to the flow direction <20° in selected planes. EMDd (EMD measured by PWD) was measured from the onset of the QRS complex to the end of AM, and PEPd (PEP measured by PWD) was measured from the onset of the QRS complex to the onset of the spectrum of the aortic valve. IVCTd (IVCT measured by PWD) was calculated as IVCTd = PEPd–EMDd.
TDI was conducted using the same equipment. Color TDI was superimposed on the underlying two-dimensional gray-scale images (four-chamber apical views). At least ten consecutive beats were recorded, and the images were analyzed by EchoPac software (General Electric Healthcare Vingmed Ultrasound). The region of interest was continuously positioned within the interrogated segment. The tissue velocity curve was obtained. EMDt (EMD measured by TDI) was measured from the onset of the QRS complex to the end of Am, and PEPt (PEP measured by TDI) was measured from the onset of the QRS complex to the onset of Sm. IVCTt (IVCT measured by TDI) was measured from the end of Am to the onset of Smor calculated with the formula of IVCTt = PEPt–EMDt. The starting point of the cardiac cycle segment of interest was the onset of the QRS complex. MCT was measured from the onset of the QRS complex to the closure time of the mitral valve, while ICMC was measured from the onset of IVC wave S1 to the closure of the mitral valve (Fig. 1). Afterwards, transform velocity mode was transformed into strain mode by using update key to obtain the strains (SI) from the onset of IVC to the closure time of mitral valve. The subjects’ heart rate was observed during each measurement. The measurements were used only if no more than 100 ms variation in R-R interval was observed.
2.3 Statistical analysis
For each echocardiographic parameter, the mean over at least 3 heart beats was calculated. All results were expressed as mean ± standard deviation. Statistical analysis was performed using SPSS software (Version 15.0, SPSS, Chicago). As tested by one sample K-S test, EMD, PEP and IVCT values were in normal distribution. Thus, one-way ANOVA was used to compare EMD, PEP, and IVCT values obtained by each of the 3 measurement methods, as well as to compare MCT, EMDd, and EMDm, ICMC, (EMDm–EMDt), and (EMDd–EMDt), ICMC, (IVCTt–IVCTd), and (IVCTt–IVCTm). Pearson's correlation analysis was used to define relationships of MCT with EMDd and EMDm and those of ICMC with EMDm–EMDt, ICMC and EMDd–EMDt, IVCTt–IVCTd, and IVCTt–IVCTm. A P-value < .05 was considered to be statistically significant. Two independent observers analyzed all the recordings and the inter-observer variability was analyzed by intraclass correlation coefficient (ICC) test. An ICC score ≥ 0.75 was considered as good reliability.
3.1 The results of EMD, IVCT and PEP obtained by the 3 methods
The 3 methods of M-mode, PWD and tissue Doppler Imaging (TDI) were performed to measure the values of EMD, IVCT, and PEP. The differences in EMD, IVCT, and PEP obtained by these 3 methods were analyzed. As listed in Table 2, EMDt (12.20 ± 5.62 ms) was significantly lower than EMDm (34.69 ± 9.27ms) and EMDd (34.63 ± 10.46 ms) (both P < .0001). There was no significant difference between EMDm and EMDd (P > .05). IVCTt (56.24 ± 13.49 ms) was significantly higher than IVCTm (35.97 ± 9.71 ms) and IVCTd (36.05 ± 11.23 ms) (both P < .0001). However, IVCTm was not significantly different from IVCTd (P > .05). Furthermore, no significant differences were found among PEPm (71.90 ± 18.55 ms), PEPd (72.01 ± 17.81 ms), and PEPt (71.76 ± 16.7 9 ms) (P > .05).
3.2 The results of MCT, ICMC, and the SI of mitral valve closure point obtained by TDI
To determine the possible reasons of the discrepancy, color TDI was performed. MCT (33.50 ± 10.06 ms) measured by TDI was not significantly different from EMDm or EMDd (P > .05). ICMC (24.55 ± 10.33 ms) did not significantly differ from (EMDm–EMDt) or (EMDd–EMDt) (P > .05) or from (IVCTt–IVCTd) or (IVCTt–IVCTm) (P > .05). Strain curve on apical 4-chamber view demonstrated that myocardium of the basal septum had shortened at the time of mitral valve closing, and the SI of mitral valve closure point was -1.31 ± 0.29% (Figs. 1 and 2). We also found a strong positive correlation between MCT and EMDd, MCT, and EMDm (r = 0.948, 0.941, respectively) and between ICMC and (EMDd–EMDt), ICMC, and (EMDm–EMDt), ICMC and (IVCTt–IVCTd), and, ICMC and (IVCTt–IVCTm) (r = 0.862, 0.920, 0.885, and 0.886, respectively).
These results indicate that there is ICMC in S1 wave, which is the possible reasons of the discrepancy between EMDt, and EMDm or EMDd, between IVCTt and IVCTm or IVCTd. ICMC is considered as the time of pre-isovolumic contraction (PIVC).
3.3 The results of inter-observer variability analysis
The individual variability of the interobserver was calculated. The ICC was 0.94 for EMDm, 0.96 for EMDd, 0.89 for EMDt, 0.97 for IVCTt, 0.95 for PEPm, 0.94 for PEPd, 0.97 for PEPt, 0.91 for MCT and 0.90 for ICMC, respectively. These results indicate that there was no significant difference between the two observers.
In this study, the age group of 20 to 40 years was selected to ensure normal reference index. Clinically, physiological condition and systolic function of the heart are optimal in this age group. We set the region of interest on the basal septum to obtain the parameters of TDI according to the fact that the mechanical activity of the heart ends at the basal myocardial wall.
The IVC refers to the state where the mitral valve is closed and the aortic valve is not opened, that is, no blood is flowing from the left atrium to the left ventricle. However, we observed that the mitral valve did not close at the onset of IVC wave S1 in clinical practice when reviewing each frame of the video of the color TDI step by step. In fact, some researchers have also noticed this phenomenon. For example, Yellin et al found negative flow at the mitral orifice during IVC. They interpreted this finding as an artificial effect and assumed that the mitral valve must already have been closed at the onset of IVC. Vogel et al also found that IVC started at or just before mitral valve closure in pigs, however, they did not study this further. Similarly, Goetz et al reported that the mitral valve was still open at the beginning of IVC in sheep. However, their discussion focused on isometric contraction. They believed that IVC were not discernable by echocardiography, because echocardiography was unable to give precise distances between two moving points due to the considerably longer temporal resolution (30 ms).
In our study, 3 parameters of EMD, PEP, and IVCT were obtained by M-mode, PWD and TDI echocardiography, respectively. The results found that EMDt was significantly shorter than EMDd or EMDm while IVCTt was significantly longer than IVCTd or IVCTm. In addition, PEP values obtained by these 3 methods were not significantly different.
In some studies, comparisons were done between these techniques by using the Tei index (IVCT+IVRT/ET). For instance, Meng et al argued that the IVCT measured by PWD was shorter than the IVCT measured by TDI because IVCT measured by PWD was in a different cardiac cycle and the point measured by PWD was less well defined compared to TDI. Also, Rojo et al found similar result that IVCTd was shorter than IVCTt, and they thought that IVCT was obtained from tissue velocity time intervals that were not exactly coincident with flow time intervals.
However, we do not believe the above explanations are adequate enough. M-mode, the simplest and oldest echocardiographic modality, with its 1000 samplings/second and discrete deflections, offers a relatively accurate means of observing mitral and aortic valve opening and closure. PWD detects blood flow in the heart when the mitral valve closes and mitral valve flow ceases. Thus, the time of the mitral valve closing as measured by M-mode should be the end of AM of PWD. In this study, EMDm showed no significant difference from EMDd. The same was observed between IVCTd and IVCTm. TDI, because of its high temporal resolution, is one of the most techniques by which to detect small differences in myocardial timings. The end of Am of TDI represents the terminating of atrial contraction and the beginning of ventricular muscle contraction. Then, does the end of Am of TDI occur at the same time as the end of AM of PWD? The answer is no. We observed that the end of Am occurred prior to the end of AM. That is to say, the closure of the mitral valve is not synchronous with the beginning of IVC wave.
Our results also showed that MCT was not significantly different from EMDm or EMDd. ICMC was not significantly different from (IVCTt–IVCTm), (IVCTt–IVCTd), (EMDm–EMDt), or (EMDd–EMDt). It was observed that mitral closure fell behind the onset of IVC S1 by 24.55 ± 10.33 ms. Moreover, an obvious myocardial displacement and shortening could be observed from velocity curve and strain curve during the period. Therefore, we conclude that there may be an undefined period, which is between the end of atrial contraction and the closure of mitral valve and can be distinguished by echocardiography. We name it as PIVC (pre-isovolumic contraction). The period is not an isovolumic phase but is included in the traditional isovolumic contraction phase, in which the cardiac muscle begins to contract while the mitral valve does not close. As a consequence, the blood continues to flow slowly from the left atrium into the left ventricle as a result of inertia and a counter pressure gradient.
PEP is a composite interval consisting of two time frames delimited by changes in LV pressure, EMD, and IVCT.[33–35] However, our conclusion is that PEP consisted of 3 parts: EMD, ICMC, and IVCT. The newly identified phase (ICMC) was named as PIVC. In addition, either IVCTd or IVCTm is the IVCT in its true sense. However, methods of measuring muscle contraction simultaneously in the same cardiac cycle are currently not available. Thus, future studies to further validate the potentially new phase of the cardiac cycle (PIVC) are still needed.
One limitation in our study was that the measures of EMD, PEP, and IVCT obtained using M-mode, PWD, and TDI were measured sequentially, not during the same cardiac cycle. Consequently, the accuracy of the results may be compromised by heart rate fluctuations. However, we excluded subjects with a difference more than 100 ms. Besides, ANOVA were used to analyze the heartbeats. Another limitation was that the sample size was relatively small.
To sum up, we identify a potentially new phase in the cardiac cycle, which is named as PIVC. It is not an isovolumic period. During PIVC, cardiac muscles start to contract while the mitral valve does not close and blood continues to flow slowly from the left atrium into the left ventricle as a result of inertia and a counter pressure gradient. This finding may be a complementary to the fundamental theory of heart physiology and may change and refine the traditional recognition. Further researches on the role of PIVC in heart disease are warranted.
We thank Prof. Yongquan Wang from the Department of Cardiology, China Medical University and Prof. Gensong Li from the Department of Physiology, China Medical University for useful discussions.
Formal analysis: Jili Fu.
Funding acquisition: Zhibin Cong.
Investigation: Bin Jiang.
Methodology: Yunyi Cong, Xue Wang.
Resources: Jianbo Lu, Mingyue Jin.
Supervision: Zhibin Cong.
Writing – original draft: Zhibin Cong.
Writing – review & editing: Zhibin Cong.
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