One of the main goals of HD therapy is to remove from the patient the excess fluid that accumulates in the body due to kidney failure. Optimal fluid volume management is an essential component of HD adequacy, but the amplitude of volume fluctuation is still a quite challenging clinical condition. In fact, HD in patients with end-stage renal disease (ESRD) removes a large amount of fluid from the body in a few hours. Therefore, patients with ESRD on HD are characterized by central volume fluctuations related to volume expansion in the interdialytic period and fluid loss during HD. They also tend to have changes in cardiac structure and function, which have been recognized as key prognostic factors [1]. A myriad of mechanisms, such as chronic volume and pressure overload, anemia, uremia, high-flow arteriovenous shunts, fluid retention, abnormal calcium and phosphate metabolism, and hyperparathyroidism, can lead to cardiac abnormalities [2]. Furthermore, HD-induced acute hemodynamic changes in electrolytes, arterial pressure, blood volume, and sympathovagal balance can negatively impact cardiac function [3]. In fact, patients with chronic kidney disease exhibit a pronounced risk for cardiovascular events: 50% of all patients with chronic kidney disease stages 4 to 5 have cardiovascular diseases, and cardiovascular mortality accounts for approximately 40% to 50% of all deaths in patients with advanced chronic kidney disease (stage 4) as well as ESRD (stage 5), compared with 26% in controls with normal kidney function [4].

Changes in left ventricular (LV) volume during HD will alter LV contraction and strain. The acute effect of HD on echocardiographic indices of cardiac structure and function has been evaluated in several studies; however, their results are not uniform. Eventually, the heart and the arterial system behave as an interconnected system and not as isolated structures; thus, the evaluation of the interaction of cardiac contractility with the arterial system would provide a more comprehensive understanding of cardiovascular function and cardiac energetics. However, there is still scanty data on changes in volumes, contractility, intraventricular pressure gradient distribution, and vascular properties in response to changes in loading conditions and their impact on the outcome.

The concept that the cardiovascular system works better when the heart and the arterial system are coupled has been well demonstrated [5-7]. When the heart pumps blood into the vascular tree at a rate and volume that matches the capability of the arterial system to receive it, both cardiovascular performance and its associated cardiac energetics are optimal [8]. A contractility or arterial tone that is too high or too low decouples these processes and can lead to cardiac failure independent of myocardial ischemia or the toxic effects of sepsis and related systemic disease processes. This optimization means that the LV workload and the arterial system optimally match when the LV ejects the blood into the arterial system and is quantified by ventriculo-arterial coupling (VAC) parameters. This process is optimized without excessive changes in LV pressure, and the mechanical energy of LV ejection is completely transferred from the ventricle to the arterial system [9].

VAC can be defined as the ratio of the arterial elastance (Ea) to the ventricular elastance (Ees). This ratio was first proposed by Suga and Sagawa [10] as a method to evaluate the mechanical efficiency of the cardiovascular system and the interaction between cardiac performance and vascular function. The Ea/Ees ratio has been consistently demonstrated to be a reliable and effective measure of cardiovascular performance [11]. The balance between myocardial oxygen consumption and the mechanical energy required to perform this work appears to be optimal when the heart and the peripheral vascular system are coupled (ie, the Ea/Es is near unity). In this case, the LV provides an adequate stroke volume with the lowest possible energetic consumption [12]. Thus, VAC is an effective index of the mechanical performance of the LV and the dynamic modulation of the cardiovascular system.

The relevance of VAC as a parameter of hemodynamic optimization could be related to the fact that VAC is a parameter of cardiovascular efficiency whereas the classical hemodynamic parameters are exclusively parameters of cardiovascular efficacy.

With these concepts in mind, the main scientific questions and hypotheses of this project are:

Accordingly, we sought to study patients with ESRD to assess (1) VAC parameters before and after the HD session, and (2) the value of VAC parameters in predicting adverse outcomes.

This research is designed as an observational cohort study with a prospective approach. Participants will be enrolled and monitored over a period of time to assess how hemodynamic changes induced by HD influence future outcomes. As an observational study, the researchers will not intervene but will simply collect and analyze data as events occur naturally during the study period.

The following study centers were used:

Patients with ESRD undergoing permanent HD in a specialized center in Astana, Kazakhstan, will be recruited (Textbox 1).

Patients will be followed up for 18 months. Clinical variables and intradialytic changes in VAC parameters will be related to outcome events. The primary endpoint will be a composite of all causes of death, nonfatal myocardial infarction, and hospitalization due to worsening heart failure. Based on previous studies, we expect a mortality rate of around 10% per year [13], an incidence of acute myocardial infarction of 3.9 per 1000 patients per year [14], and an incidence of hospitalization due to worsening heart failure of 5.8 per 100 persons per year [15].

The schedule of the study project including enrolment and assessment is outlined in Table 1.

The sample size was calculated based on 95% CI, margin of error 5%, and estimated incidence of cardiovascular events 30%, as follows:

where N is the sample size, is a critical value from the standard normal distribution corresponding to the desired 95% CI (1.96), P is the proportion of estimated incidence (0.3), and E is the desired margin of error (0.05) [16].

Patients on HD are often fragile and may not accept to undergo an additional investigation, although noninvasive. We will try to limit the number of noncompliant patients with several actions (Textbox 2).

Demographic characteristics, full medical history, and dialysis-related parameters of study participants will be recorded on purpose-built data-collecting sheets (Multimedia Appendix 2). The study design diagram of the chronological sequence of the echocardiographic evaluations is presented in Figure 1. SPIRIT (Standard Protocol Items: Recommendations for Interventional Trial) reporting guidelines [17] have been used (Multimedia Appendix 3). Concomitant care and interventions during the HD session will be left to the attending nephrologist.

2D and Doppler echocardiogram will be acquired by a skilled sonographer before and immediately after the HD session. Care will be taken in acquiring 2D apical views (4-chamber, 2-chamber, and long-axis views) aiming for the best visualization of the LV endocardial border. Images will be saved on digital media storage devices and analyzed offline at the echocardiographic core laboratory of our institution.

Echocardiographic images will be analyzed offline using dedicated software based on a mathematical model [18] (QStrain, Medis BV). The LV end-diastolic and end-systolic volumes and ejection fraction will be determined from the modified biplane Simpson method. Left atrial volume will be calculated using the biplane area-length method. LV volume and mass and left atrial volume will be subsequently indexed by body surface area. The peak early filling (E wave), the late diastolic (A wave) velocities, and the deceleration time will be assessed from the transmitral flow. The peak systolic (s’), early diastolic (e’), and late diastolic (a’) mitral annular velocities will be measured at the septal annulus using spectral Doppler.

LV volumes, estimated end-diastolic pressure, and brachial systolic and diastolic pressures will be used as input. The software reconstructs the pressure-volume (P-V) loop by determining the end-systolic pressure-volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR) using the single-beat algorithms previously described in the literature [19]. Once the EDPVR and ESPVR are identified, the end-diastolic and end-systolic LV volumes and systolic and diastolic brachial pressures will be used to close the P-V loop. Finally, the P-V relation will be depicted for the entire cardiac cycle where each point of the curve is described as (Vt, Pt). In the P-V loop, the classic phases of the cardiac cycle are displayed: isovolumetric contraction, ejection, isovolumetric relaxation, and diastolic filling (Figure 2).

Based on this integrated P-V loop, the hemodynamic parameters to be calculated, both before and after the HD session, are listed in Textbox 3.

The pre- and posthemodialysis changes will be calculated and considered as potential prognostic indicators.

This research involves a medical record review, image acquisition and analysis, and data analysis. Each participant will be assigned an ID number and all hard copy data collected or used during this study will be stored in a cabinet in the locked office of the study personnel. All electronic data will be stored on password-protected computers of the study personnel in their locked offices and the locked personnel building. Only essential research personnel will have access to any of these patient files.

Statistical analysis will be performed with Statistical Package Stata (StataCorp) and R-studio (Posit). All continuous variables will be presented as mean (SD) or median (IQR) based on their distribution. Paired comparisons of continuous variables will be performed with a 2-tailed paired Student t test or Wilcoxon test, when appropriate. Paired comparisons of categorical variables will be conducted with the McNemar test. Event-free survival for each of the echocardiographic and VAC parameters will be assessed using Kaplan-Meier analysis and compared with a log-rank test, where each index will be dichotomized according to the median of its distribution. The prognostic value will be determined using the Cox proportional hazards model. Differences will be considered statistically significant when P<.05. Interclass correlation coefficients (ICC) will be calculated to assess the inter- and intraobserver agreement of P-V loop measurements.

The study was approved by the Nazarbayev University Institutional Research Ethics Committee in July 2024 (Multimedia Appendix 4), and secured funding in August 2024, after a peer-reviewed process (Multimedia Appendix 5).

One of the physicians at the dialysis center will explain the aim of the study and the echocardiographic procedure. Written informed consent will be obtained from all participants before the procedure (Multimedia Appendix 6).

Participation in the study is on a voluntary basis, thus no compensation will be offered to patients.

Important protocol modifications during the study will be submitted to the Institutional Research Ethics Committee of Nazarbayev University for approval.

At least 323 patients are required to estimate the incidence of cardiovascular events with 95% CI and a 5% margin of error. Data collection is scheduled to occur between January 1, 2025, and June 30, 2025. As of March 18, 2025, a total of 32 participants have been recruited, who underwent echocardiogram before and after the HD session. Data analysis is planned to start in April 2025 and continue through June 2026, with certain data being collected concurrently during the analysis phase. The publication of study outcomes is tentatively projected in Winter 2027.

Our group has an established experience in advanced echocardiography and image postprocessing. We have applied strain and hemodynamic forces analysis in athletes and patients with hypertension [20]. Our group has already applied this method, including VAC analysis, in a preliminary group of patients with ESRD on maintenance HD. Two illustrative cases are represented in Figure 3.

Patient #1 had 3.5 liters of fluid subtraction during the HD session with VAC improvement due to an increase in Ees (from 1.8 to 2.9 mm Hg/mL). The contractile reserve was not recruitable due to reduced preload (reduced stroke volume) and the patient had sinus tachycardia at the end of the HD session due to adrenergic activation. Patient #2 had 1.8 L of fluid subtraction, with poor tolerance and symptoms at the end of the HD session. The analysis of echocardiographic images revealed VAC worsening due to Ees decrease (from 2.6 to 1.2 mm Hg/mL). In this case, contractility is strongly dependent on preload, thus the LV did not tolerate the effective circulating volume reduction.

Data on the value of VAC in patients on HD are scanty and controversial. Moreover, no research on this topic has been conducted in the Republic of Kazakhstan. The results of this study will provide insights into the hemodynamic changes induced by HD in patients with ESRD and will improve the understanding of the pathophysiological events induced by acute volume depletion. The prognostic value of HD-induced VAC changes will be also assessed at follow-up.

The association between myocardial and arterial function markers has been used to describe and quantify VAC in hypertension [21-23], diabetes [24], and inflammatory diseases [25]. More specifically, combined ventricular and arterial stiffening has been demonstrated in patients with heart failure with preserved ejection fraction (HFpEF) [26]. In patients with heart failure, abnormal VAC is implicated in the pathophysiology of left and right heart clinical deterioration [27]. In addition, different patterns of abnormal VAC are recognized in heart failure with reduced ejection fraction versus HFpEF. The results of these studies suggest that in hypertension and diabetes, there is a close link between arterial stiffness and myocardial deformation, which appears to be a harbinger of HFpEF if left untreated. In addition, there is evidence that treatment options may improve both myocardial dysfunction and vascular stiffness and thus improve VAC. Systemic inflammatory processes and oxidative stress may cause an increase in arterial stiffness (leading to an increase in Ea) in parallel to myocardial stiffening (causing an increase in Ees), while anti-inflammatory treatment improves arterial stiffness in parallel with myocardial stiffness contributing to the reversal of ventricular-arterial decoupling.

VAC assessment has prognostic value in several clinical scenarios. Valvulo-arterial impedance can specifically describe the hemodynamic consequences of aortic stenosis and provide prognostic information in patients with aortic stenosis even when asymptomatic [28]. There is also evidence that VAC is associated with outcomes in patients with sepsis or after myocardial infarction [29,30].

In patients with renal dysfunction, increased arterial stiffness coupled with a matched increase in ventricular stiffness has been reported [31,32]. These findings have important hemodynamic consequences as a stiff heart-arterial system generates more systolic pressure changes for a given stroke volume.

Sasso et al [33] evaluated 15 patients on HD. They concluded that HD influences both Ees and Ea/Ees ratio acutely, although this effect seems due only to the acute reduction in preload and blood pressure, without any clinically significant effect on intrinsic LV contractility and VAC. In a study on 234 HD patients, Obokata et al [34] found that Ea/Ees ratio was independently associated with adverse outcomes, providing an incremental prognostic value over the clinical score and left ventricular ejection fraction. Recently, Zuo et al [35] used an approach similar to ours (pre- and posthemodialysis assessment of VAC). They concluded that VAC is a reliable index for stratifying the risk of cardiovascular diseases in HD patients.

The approach we are planning to use in this study allows a noninvasive assessment of the cardiovascular efficiency and the changes induced by volume changes during HD in patients with ESRD. The endocardial borders, evaluated by echocardiographic speckle tracking, can be used directly as input to the present model to provide a noninvasive assessment of VAC. Using standard echocardiographic images and advanced image analysis, we will be able to evaluate the heart-arterial system interaction from the VAC. We believe that, using this approach, a comprehensive analysis of the hemodynamic effects of volume changes induced by HD will be feasible. This will allow a better understanding of the pathophysiological changes induced by HD, with the potential of tailoring the optimal dialysis modalities and identifying those patients who are at higher risk of LV remodeling and future cardiovascular events.

Some challenges of this approach can be anticipated. First, echocardiographic image quality may affect proper visualization and tracking of the LV endocardial border. Second, a low frame rate can hamper the temporal resolution of the method. Finally, inter- and intraobserver reliability should be high to exclude changes due to variability.

Further research should investigate whether modifying VAC through targeted interventions could improve clinical outcomes in HD patients. Expanding the study to larger, multicenter cohorts would enhance the generalizability of our findings. In addition, incorporating advanced imaging techniques to assess VAC dynamically over time may provide deeper insights into its prognostic role in patients undergoing chronic HD.

The final results will be presented at the main international nephrology and cardiology meetings and conferences. The development and findings of the project will be reported in relevant international journals.

In conclusion, this research protocol outlines the process of noninvasive assessment of VAC before and after a HD session in patients with ESRD. The methodology we are applying does not require complex and sophisticated tools apart from the analysis software. We believe this approach will provide additional information to the relevant stakeholders and assist other researchers in developing similar studies in different clinical settings.