Background
Chronic kidney disease (CKD) affects about one in ten adults [
1], and is principally caused by diabetes, or glomerulonephritis in china [
2]. Patients with stages 1–3 CKD have a high cardiovascular morbidity and mortality compared with healthy people [
3,
4]. However, the changes in cardiac structure and volume are relatively slight in stage 1–3 CKD patients who have a preserved cardiac ejection fraction [
5,
6]. Actually, diffuse myocardial interstitial fibrosis indeed occurs in mild to moderate CKD [
7], resulting in abnormality of intracardiac blood flow status [
8]. Therefore, accurate and reproducible evaluation on the early cardiac dysfunction were urgently need from the perspective of fluid dynamics in stages 1–3 CKD when the best opportunity of effective treatment exists.
Cardiac magnetic resonance, contrast particle imaging velocimetry and vector flow mapping (VFM) are mainly techniques for evaluating the intracardiac blood flow status. Compared to the other two techniques, VFM is more suitable for clinical application owing to its convenient, non-invasive and inexpensive characteristics [
9,
10], and its accuracy has been confirmed by particle imaging velocimetry [
11,
12]. Additionally, VFM, as a new echocardiographic technique, has no angle dependence or limitation of the region of interest, making it superior to traditional Doppler technology [
13]. Energy loss (EL) is an important hemodynamic parameter based on VFM technology, representing the amount of fluid energy that was lost as heat in the heart and indicating the efficiency of intracardiac blood flow [
14]. If the intracardiac blood flow displays pathological pattern, such as turbulence, jet or adverse direction, its EL increases correspondingly [
15]. Monitoring EL by VFM enables quantitative evaluation on the change of intraventricular hemodynamics. Left ventricular EL has been considered as a novel clinical index to detect cardiac dysfunction in diabetic [
15,
16] and a useful tool for the detection of subclinical cardiac dysfunction in patients with hypertrophic cardiomyopathy [
17]. Growing evidences show EL evaluation has received increasing attention in clinical practice [
18,
19], it might provide a new perspective on heart research.
Left ventricular EL bas been shown its efficacy in evaluation of intracardiac fluid dynamics in uremic hearts [
20]. Although patients with stages 1–3 CKD seems not to experience volume shifts and obvious left ventricular hypertrophy compared with end-stage CKD patients, intracardiac blood flow status has pathologically changed in their heart partly owing to the diffuse myocardial interstitial fibrosis. We speculated patients with stages 1–3 CKD experience impaired intracardiac blood flow efficiency, and left ventricular EL could be a novel echocardiographic parameter for assessing their cardiac dysfunction in terms of fluid mechanics, but the related research has not yet been known. Importantly, hypertension, as a main cardiovascular risk factor, is frequently detected in patients with mild to moderate CKD, unfortunately, it does not get enough attention in real-world until a serious cardiovascular event unexpectedly occurs [
21,
22]. Additionally, whether the hypertension have further effect on the blood flow efficiency in patients with stages 1–3 CKD remains largely unknown. Therefore, we quantitatively detected the left ventricular EL in stage 1–3 CKD patients using VFM, and further focused on the change of left ventricular EL in patients with poorly controlled hypertension. This study was expected to provide valuable clinical data to reduce the disproportionately risk of cardiovascular disease and slow, or halt the progression of CKD during the early stages.
Discussion
Intracardiac blood flow status has not been investigated in stage 1–3 CKD. In current study, the left ventricular EL in CKD stages 1–3 with primary glomerulonephritis were quantitatively analyzed using VFM technology. We found that patients with stages 1–3 CKD had increased left ventricular EL during diastole and systole, this hemodynamic abnormality was more significant in CKD patients with poorly controlled hypertension. Using correlation and multivariate regression analysis, we indicated blood pressure might play some role in the increased EL.
VFM, as a novel echocardiographic technology, has been shown to be capable to quantitatively evaluate EL derived from the velocity vector field of the blood flow in ventricle [
12]. EL value is supposed to demonstrate the impact of the viscous dissipation on cardiac change adapted to a physical condition [
20]. There was an increased diastolic EL in patients with stages 1–3 CKD, suggesting that this population had more intraventricular energy dissipation and less flow efficiency than the healthy participants. In present study, when the E-wave velocity or A-wave velocity was increased, the EL during diastole tended to be high. As the EL value is calculated from an equation, EL increases at the point where direction and size of velocity vectors change [
25]. If E-wave velocity or A-wave velocity increases, the rapid influx of blood flow makes a strong collision on the blood flow remained in the heart cavity, which results in changes of the velocity and direction of the blood flow, and more energy dissipation. Furthermore, the increase of myocardial collagen content and myocardial stiffness in early-stage CKD cause a reduction of active myocardial relaxation, then lead to a deterioration of diastolic function and a raise of filling pressure [
26]. E/e’ ratio was reported to have quality to predict left ventricular filling pressure [
27] and be a sensitive tool to detect diastolic function [
28]. In our study, the patients with stages 1–3 CKD had increased E/e’ ratio, which was consistent with the previous data [
29]. Moreover, the E/e’ ratio was shown as a predictor of diastolic EL in our data, indicating that diastolic dysfunction and increased filling pressure might play some role in the energy dissipation. From another point of view, when diastolic dysfunction happens, blood flow loses more energy during diastolic to achieve sufficient left ventricular filling, ensuring sufficient cardiac output. Therefore, we suggested EL might be a novel echocardiographic parameter for evaluating diastolic dysfunction in patients with stages 1–3 CKD from the perspective of hemodynamics. Which was consistent with the opinion in a previous study about EL of diabetic patients [
15]. Additionally, the pathological cardiac configurations, including abnormal heart size and ventricular wall thickness, transform blood flow status from the uniform laminar pattern into a chaotic one, causing increased EL. In present study, the LVMI had close relation with the diastolic EL in early CKD patients and been indicated as an independent predictor of the diastolic EL, suggesting a relation of hemodynamic abnormalities and pathological cardiac configuration in this population. Furthermore, we found that EL during late diastole showed similar results as total diastole. But EL during early diastole had no significant difference between the patients with early CKD and control participants, which may be attribute to the fluctuation of EL during early diastole with different degrees of diastolic dysfunction in patients [
30].
Since the cardiac cycle is continuous, abnormality in blood flow can last from diastole to systole. It had been confirmed by VFM in patients with a reduced LVEF [
31], in whom the abnormal intraventricular vortex last from diastole to systole. Physiologic vortex starts at the ventricle side the mitral valve in diastolic phase, then passes through the isovolumetric contraction phase and finally disappears in the ejection phase [
32]. The vortex turns the blood flow from the left ventricular inflow tract to the outflow tract, effectively transferring energy and avoiding excessive dissipation of energy. On the contrary, the pathological vortex displays a scattered distribution and a long duration [
33], dissipates more energy, resulting in an increased EL. In addition to the elevated diastolic El, our data demonstrated that patients with early CKD had increased systolic EL during total systole, isovolumic contraction and ejection phase, suggesting a coexistence of impaired blood flow efficiency in diastole and systole, which was consistent with a previous research [
20]. We speculated that the increased systolic EL may be a continuation of the hemodynamic abnormality in diastole. Additionally, Frank-Starling mechanism is a coupling mechanism accepted widely between afterload and cardiac contraction. When afterload increases, the contractility of left ventricle increases to ensure a sufficient ejection volume [
34]. The increased contraction of left ventricle intensifies the interaction between blood flows, as well as the blood flow and ventricular wall [
35], causing more energy dissipation. Moreover, SBP, a clinical indicator representing cardiac afterload, was shown as the predictor of systolic EL in patients with stages 1–3 CKD in present study. We considered the mechanism of the increased systolic EL in patients with stages 1–3 CKD may be a compensatory of the Left ventricular blood flow in response to the elevated afterload. Importantly, LVMI was closely associated with systolic EL, and shown as a predictor of the systolic EL in the patients with stages 1–3 CKD, suggesting pathological cardiac configuration contributes to the abnormality of left ventricular blood flow during systole [
33,
36]. Overall, the increased systolic EL coexisted with the increased diastolic EL in patients with stages 1–3 CKD, the mechanism of systolic EL may be a continuation of the hemodynamic abnormality in diastole, or a hemodynamic compensatory mechanism in response to afterload, or related to the pathological cardiac configuration due to CKD.
Patients with stages 1–3 CKD generally have no serious complications and frequently experience hypertension, edema, proteinuria and anemia, leading to hypoproteinemia and increased BMI. Using correlation and stepwise multiple regression analysis, we found only the SBP was the predictor of systolic EL in patients with stages 1–3 CKD, suggesting that the clinical presentation had little bearing on the result of assessment of left ventricular EL. Hypertension, as a main cardiovascular risk factor, is a main clinical symptom in patients with stages 1–3 CKD. However, it does not get enough attention in real-world. In present study, 41.67% of patients had poorly controlled hypertension, suggesting a poor condition of blood pressure management in CKD during the early stages. Unexpectedly, our data confirmed stage 1–3 CKD patients with poorly controlled hypertension had higher left ventricular EL compared to those patients with well-controlled hypertension or with no hypertension, indicating hypertension was a crucial contributor for intracardiac blood flow abnormality in early-stage CKD. Hypertension can increase cardiac afterload and damage cardiac configuration in the background of CKD, then further deteriorate hemodynamic abnormalities. Blood pressure management, is considered as the main target of CKD treatment. Our date revealed the importance of hypertension control from the perspective of hemodynamics in early-stage CKD when the best treatment time window exists. Considering the harmfulness of cardiovascular complications and the high prevalence of poorly controlled hypertension, Patients with CKD stage 1–3 are supposed to pay more attention to their blood pressure level.
The present research has several limitations. Although CKD related to diabetes has become more prevalent than CKD related to glomerulonephritis in China, the recruited CKD participants in current study were only patients with primary glomerulonephritis. This relatively single patient population may hinder the universalization of our findings in all CKD patients. Additionally, this work was a single-center cross-sectional study with a relatively small sample size, which might contribute to the result (without statistical difference) of left ventricular EL during isovolumic diastole. The changes in left ventricular EL values in patients with stages 1–3 CKD should be validated by further multi-center, large-scale longitudinal studies. Furthermore, Although the recruited CKD participants all accepted professional treatment according to CKD clinical guidelines, we did not evaluate the influence of the treatment protocols on the results in this cross-sectional study without therapeutic intervention.
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