Systolic time intervals derived from electrocardiographic gated intra-renal artery Doppler waveform associated with left ventricular systolic function

The aims of this study were to investigate the correlation between renal and cardiac STIs, including pre-ejection period (PEP), ejection time (ET), and PEP/ET, and to assess the diagnostic values of renal STIs in predicting left ventricular ejection fraction (LVEF) <50%. The cross sectional observation study enrolled 230 participants. The renal STIs, including renal PEP (rPEP), renal ET (rET), and rPEP/rET, were measured from electrocardiographic gated renal Doppler ultrasound and cardiac PEP, ET, and PEP/ET were measured from echocardiography. Renal STIs were correlated with cardiac STIs (all P < 0.001). Multivariate analyses showed that rPEP/rET was independently associated with LVEF (unstandardized coefficient β = −0.116, P = 0.046) and LVEF <50% (odds ratio = 2.145, per 0.11 increase; P = 0.017). The areas under the curve for rPEP, 1/rET, and rPEP/rET in predicting LVEF <50% were 0.773, 0.764, and 0.821, respectively. The sensitivity and specificity of rPEP/rET > 0.46 in prediction of LVEF <50% were 76.7% and 78.1%, respectively. Our study demonstrated that the novel parameters of renal STIs were significantly associated with cardiac STIs. However, the clinical application of renal STIs needs to be investigated in future studies.

arterial Doppler waveform. The applications of STIs are makers of global cardiac systolic function and predictors of adverse cardiac outcome in patients with heart failure 3,4,15 .
Owing to high cardiovascular morbidity and mortality, the increasing number of patients with chronic kidney disease (CKD) is an important healthcare issue in the world 16,17 . Renal ultrasonography is an useful image tool in noninvasive evaluation of renal anatomic and vascular information in patients with renal injury 18 . In addition to conventional gray-scale image, renal Doppler ultrasound can help to evaluate intra-renal vascular information. The popular parameter measured from renal Doppler ultrasound is renal resistive index (RI). Renal RI can reflect vascular resistance and serve as a predictor of renal damage and poor cardiovascular outcome [19][20][21] . Furthermore, renal RI was associated with left ventricular diastolic dysfunction 20 , but not associated with LVEF 22 .
Although STIs measured from Doppler ultrasound were associated with global cardiac systolic function, there was no study to evaluate whether renal STIs measured from renal Doppler ultrasound were also associated with cardiac systolic function. Hence, the aims of this study were to investigate the relationship between renal STIs measured from real-time internal electrocardiographic (ECG) gated renal Doppler ultrasound and cardiac STIs measured from echocardiography and to assess the diagnostic values of renal STIs in prediction of LVEF < 50% 23 .

Methods
This is a cross-sectional observation study enrolled participants who received echocardiographic examination due to suspected cardiovascular diseases in a regional hospital in Taiwan from June 2012 to December 2012 ( Fig. 1). Patients with atrial fibrillation (number, n = 4), significant aortic or mitral valve diseases (n = 2), left bundle branch block (n = 1), inadequate image visualization (n = 3), history of unilateral or bilateral renal artery stenosis (n = 0), unilateral or bilateral nephrectomy (n = 2), end stage renal disease receiving renal replacement or renal transplantation therapy (n = 3), acute kidney injury (n = 2), and acute unilateral or bilateral hydronephrosis (n = 5) were excluded. Ethics statement. The study methods were carried out in accordance with the approved guidelines. The study protocols were approved by the institutional review board committee of the Kaohsiung Medical University Hospital (KMUHIRB-E(II)-20160015). Written informed consent was obtained from all subjects.
Renal Doppler ultrasound study. Ultrasonographic examinations were performed using multi-functional duplex Doppler ultrasonography with a CX50 (Philips) ultrasound machine with a 2.5-MHz pulsed Doppler frequency and a 3.5-MHz convex array transducer. The image of the kidneys was determined by B-mode and renal blood flow was visualized with color-Doppler sonography superimposed on B-mode image while the patient was in the supine position. We applied internal ECG signal into Doppler ultrasound. Then, intra-renal Doppler signals were obtained from the arcuate arteries at the cortico-medullary junction. The renal RI was calculated as (peak systolic velocity -minimum diastolic velocity)/peak systolic velocity 24 . The renal PEP (rPEP) was measured from the onset of the QRS complex to the foot of the renal pulse Doppler waveform. The renal ET (rET) was measured from the foot to the dicrotic notch of the renal pulse Doppler waveform (Fig. 2). The rPEP and rET were determined three times for each kidney and then the values from bilateral kidneys were averaged to obtain the mean value for later analysis. All measurements were performed by one experienced physician who was blinded to the other data of the subjects.
Echocardiographic assessment. A single experienced cardiologist performed all echocardiographic examination and acquired image using the Vivid 7 (General Electrics). Left ventricular internal diameter (LVID), interventricular septal wall thickness (IVST), left ventricular posterior wall thickness (LVPWT), trans-mitral E wave velocity (E), E-wave deceleration time, trans-mitral A wave velocity and early diastolic mitral velocity (Ea), were measured by standard chamber quantification and measurement 13,25 . We calculated LVEF and Left ventricular mass by the modified Simpson's method and the Devereux-modified method, respectively 26 . Left ventricular mass index was calculated by dividing left ventricular mass by body surface area. PEP was measured from the onset of the QRS complex on the electrocardiogram to the onset of systolic flow from the left ventricular outflow tract (LVOT). ET was measured from the onset to the end of LVOT systolic flow 13 . The PEP and ET were obtained from 3 consecutive beats and then the data were averaged to give the mean value for later analysis. All echocardiographic parameters were acquired from 3 continued beats and measured from offline EchoPAC software by a single experienced cardiologist.
Collection of demographic, medical, and laboratory data. Baseline medication, personal characteristic, and laboratory data were collected from medical records. The value of estimated glomerular filtration rate (eGFR) was calculated by the equation of Modification of Diet in Renal Disease study 27 . Participants with CKD were defined as those with evidence of kidney damage lasting for more than 3 months 28 and an eGFR < 60 ml/min/1.73m 2 .
Reproducibility. Thirty patients were randomly selected for evaluation of the interobserver variability of renal STIs measurement by two independent observers. To obtain intraobserver variability, the same measurement was repeated 1 week apart. Mean percentage error was calculated as the absolute difference divided by the average of the two observations. Statistical analyses. Baseline data are expressed as percentages or mean ± standard error. The differences in items between renal and echocardiographic STIs were checked by Student's t-test. The relationship between two continuous variables was assessed using a bivariate correlation method (Pearson's correlation). Bland-Altman plots were used to assess the agreements between renal and echocardiographic STIs. The regression of the average and the difference between renal and echocardiographic STIs (renal STIs minus echocardiographic STIs) was analyzed. Significant variables in the univariate analysis were further analyzed by multivariate stepwise linear regression and backward logistic regression to identify the determinants of LVEF and LVEF < 50%, respectively. Receiver operating characteristic (ROC) curve was constructed for the prediction of LVEF < 50%. A difference was considered significant if the P value was less than 0.05. Statistical analysis was performed using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA).  Table 3. Determinants of LVEF and LVEF <50% in multivariate analysis in all study patients.

Discussion
In the present study, we found that renal STIs derived from ECG gated renal Doppler ultrasonography were significantly associated with cardiac STIs measured from echocardiography and were useful in identification of patients with LVEF < 50%.
Cardiac STIs affected by many physiological and pharmacologic factors are well-established parameters in assessment of global cardiac performance 3,[29][30][31][32] . In general, cardiac STIs may be affected by several medications, such as digitalis glycosides, catecholamines, propranolol, amyl nitrate, and calcium gluconate, through positive or negative inotropic effects 31,32 . The physiological meaning of cardiac PEP is composed of isovolumetric contraction time and electromechanical delay, i.e. time interval between initiation of ventricular depolarization and aortic valve opening 3,29,33 . Regardless of causes of heart failure, increased cardiac PEP is resulted from a decreased rate of left ventricular pressure rise (dP/dt) during isovolumic contraction period 3,34 . The PEP may prolong when patients with impairment of cardiac contractility, left bundle branch block, use of negative inotropic agents, decreased preload status, or increased afterload pressure 31,32 . The PEP may shorten when patients with aortic valve disease, use of positive inotropic agents, increased preload status, or decreased afterload pressure. Although the physiological meaning of cardiac ET is the period from beginning to finishing of left ventricular ejection, the factors contributed to ET are more complex 3 . The length of PEP, preload condition, strength of myocardial fiber, and inotropic agents are associated with ET period 3,29 . Unlike PEP, which respectively became shorten and lengthen by positive and negative inotropic agents, ET became shorten both by positive and negative inotropic agents 35,36 . Although Polak et al. showed ET measured from Doppler waveform of carotid artery was significantly associated with LVEF, they did not further evaluate their relationship by multivariate analysis 14 . In this study, all the parameters of renal STIs were correlated with LVEF and useful in prediction of LVEF < 50% in the univaiable analyses. Because gender, heart rate, clinical comorbidity, and medication use might influence STIs, we also assessed the determinants of renal STIs from different multivariate models 3,13,31 . Instead of rPEP and rET, rPEP/ rET was still an independent determinant of LVEF and useful in prediction of patients with LVEF < 50% in the multivariable analyses.
Although renal Doppler ultrasound was a popular image modality for evaluation of intra-renal hemodynamics, there were few studies researching the relationship between parameters of renal Doppler ultrasound and cardiac systolic function 20,37 . In our present study, renal RI was not significantly associated with LVEF. Hence, renal RI might be not a useful parameter in identification of patients with impaired left ventricular systolic function. Additionally, in the present study, cardiac PEP was calculated from onset of QRS to beginning of flow of left ventricular outflow tract. However, rPEP was calculated from onset of QRS to the foot of renal Doppler waveform. Because of the delay of arterial pulse wave from aorta to renal arcuate artery, rPEP was longer (mean difference 56.13 ms) than cardiac PEP in the present study. The physiological meaning of rPEP is composed of isovolumetric contraction time, electromechanical delay, and transmission of arterial pulse wave, i.e. time interval from initiation of ventricular depolarization to the foot of renal pulse Doppler waveform. Hence, renal STIs may be influenced by cardiac systolic function and arterial stiffness.
There were several different measurement methods of STIs. In the method developed by Weissle et al., they simultaneously recorded carotid pulse tracing, phonocardiography, and electrocardiography and then calculated STIs 1 . Recently, a radial artery tonometry was also used to evaluate STIs. In this method, they used high-fidelity pressure transducer, electrocardiography, and special software program to measure STIs 38 . In addition, brachial STIs could be automatically measured from an ABI-form device by an oscillometric method 13 . In the above methods, the high quality and complex equipments were needed to acquire the STIs. In the present study, when performing the renal echo, we used internal ECG signal and renal Doppler waveform to measure renal STIs. This method did not require additional complex equipment and software. Hence, our measurement of renal STIs had several advantages including cost-effectiveness, no need of extra operation, and renal-time calculation. Although echocardiography has been widely used for diagnosis and assessment of global cardiac function, the measurement of LVEF is difficult in patients with poor image visualization, extreme obesity, and severe pulmonary diseases 33 . Cardiac STIs and perhaps renal STIs were alternative parameters for evaluation of global left ventricular systolic function in these patients 33 . Hence, using renal Doppler ultrasonography, in addition to calculation RI to evaluate intra-renal vascular information, we can extra measure renal STIs to roughly assess global left ventricular systolic function.

Study limitations
There were several limitations to our study. First, our study was a cross-sectional observation design and only enrolled small number of cases in one regional hospital, which might limit study generality and cause selected bias. Second, due to lack of laboratory biomarkers of heart failure 39 , such as brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, galectin-3, or N-terminal propeptide of procollagen type III, we did not know the relationship between those biomarkers and renal STIs. Finally, lack of echocardiographic parameters of right ventricle 40 , we did not recognize the associations between renal STIs and right ventricular function.