Vena Cava Occlusion Reveals Site-Specific Preload Dynamics: Implications for Volume Management in Heart Failure

Heart failure (HF) remains a major global health challenge, with congestion being the leading cause of hospitalization [1]. While guideline-directed medical therapy (GDMT) targets maladaptive remodeling, effective volume management is essential to prevent decompensation. Strategies include diuretics, sodium restriction, and monitoring of weight, symptoms, and biomarkers such as natriuretic peptides, troponin, galectin-3, and ST2. Current practice prioritizes non-invasive imaging and biomarker assessment, reserving invasive hemodynamic monitoring for advanced or acute cases [2,3]. Preload manipulation provides a dynamic assessment of ventricular function by transiently increasing end-diastolic pressure (EDP) and volume (EDV), engaging the Frank-Starling mechanism. This approach can uncover latent abnormalities in contractility, compliance, and ventricular-arterial coupling (Ea/Ees), which are often impaired in HF with preserved ejection fraction (HFpEF) due to arterial stiffness and diastolic dysfunction. Elevated EDP and end-systolic pressure (ESP) in HFpEF reflect reduced compliance and increased afterload, contributing to increased myocardial workload and an increased risk of arrhythmias. Recent work emphasizes the diagnostic value of invasive hemodynamic assessment during exercise and preload modulation for accurate HFpEF phenotyping [4] and highlights the potential of non-invasive modalities such as diastolic stress echocardiography and strain imaging for dynamic evaluation [5]. Hemodynamic monitoring has evolved from invasive catheter-based techniques (e.g., pulmonary artery catheter, PiCCO) to less invasive options, including implantable sensors such as CardioMEMS and advanced imaging modalities [6]. While invasive methods provide precise measurements, they carry procedural risks and require expertise. Non-invasive techniques such as echocardiography and MRI offer safer alternatives but may lack accuracy under dynamic conditions. Combining invasive and non-invasive approaches can optimize assessment and management, ensuring accurate diagnosis and monitoring [7]. This combination ensures a more complete understanding of the patient’s hemodynamic status [8]. Furthermore, innovative experimental models using tunable soft robotic sleeves have demonstrated controlled preload and afterload modulation in HFpEF physiology, enabling precise evaluation of device performance and ventricular mechanics [9]. Despite these advances, there is limited evidence on how transient preload manipulation can be leveraged to reveal subclinical abnormalities in ventricular mechanics and ventricular-arterial coupling, particularly in HFpEF. Most current assessments rely on static measurements, which may fail to capture dynamic changes in hemodynamics. This study aims to evaluate the impact of controlled preload alteration on pressure-volume relationships and coupling indices. This article seeks to determine whether dynamic hemodynamic testing can improve phenotyping and risk stratification in HF care.

Comparing methodologies for preload and afterload manipulation in preclinical heart failure (HF) animal models is essential for understanding how different experimental setups and measurement techniques influence cardiac outcomes. Preload, governed by the Frank-Starling mechanism, defines the relationship between stroke volume (SV) and end-diastolic volume (EDV), reflecting the heart’s ability to augment SV in response to increased ventricular filling, provided other factors remain constant. This relationship is modulated by venous return, blood volume, and ventricular compliance, making precise and reproducible techniques critical for assessing cardiac function in HF models. Experimental techniques for manipulating afterload in animal models include pharmacologic agents such as phenylephrine to increase afterload and nitroprusside to decrease it, as well as mechanical methods like aortic balloon occlusion and external aortic compression (Table 1, Table 2 and Table 3). Vasoactive infusions can also modulate systemic vascular resistance, thereby altering afterload. These interventions influence pressure-volume (PV) loops by shifting the end-systolic pressure-volume relationship (ESPVR) rightward with increased afterload, reflecting greater pressure generation at higher end-systolic volumes without intrinsic changes in contractility.

Preload manipulation can be achieved via fluid infusion, leg elevation, pharmacologic agents (e.g., vasopressors), or experimentally through transient vena cava occlusion (VCO), a widely accepted and controllable technique. The inferior vena cava (IVC) contributes approximately 70% of total venous return from the lower body (legs, pelvis, abdomen). When the IVC is occluded, left ventricular (LV) preload drops substantially as less blood fills the ventricle. On a pressure-volume (PV) loop, this results in a leftward shift with a corresponding reduction in SV and cardiac output via the Otto-Frank-Starling mechanism. The V₀ intercept (volume-axis intercept of ESPVR) approaches zero, indicating near-complete LV unloading as the ventricle contracts toward its minimal volume (Figure 1). In early stages of preload reduction, ESPVR may transiently steepen due to compensatory inotropy, though myocardial contractility itself typically remains constant unless stimulated by neurohumoral activation, please see succinct summary in Table 4.

Study Design and Population: This comparative experimental study evaluated the hemodynamic effects of inferior vena cava occlusion (IVCO) versus superior vena cava occlusion (SVCO) on left ventricular (LV) pressure-volume dynamics. A total of 15 subjects were included in the initial groups (IVCO group: n = 7; SVCO group: n = 8). All subjects underwent invasive pressure-volume analysis under controlled conditions. Hemodynamic Measurements: Admittance PV studies were performed using an ADV500 control unit (Transonic Scisense, London, ON, Canada). Hemodynamic PV parameters were collected using the FA404 data acquisition system, and data analysis was completed with the dedicated PV module in LabScribe3 (iWorx Systems, Dover, NH, USA). Prior to catheterization, the catheter’s pressure sensor was hydrated for 30 min in a 50-mL Falcon conical centrifuge tube (Thermo Fisher Scientific, Waltham, MA, USA) containing 0.9% saline or phosphate-buffered saline at 38 °C. The pressure sensor was then balanced under the meniscus of the same 38 °C solution before PV catheterization. System setting parameters, including volume mode (W), premeasured blood resistivity, and myocardial properties obtained using the manufacturer’s probe, were entered into the ADV500 system. Independently assessed stroke volume from Transthoracic Echocardiography (TTE) using LV outflow Simpson’s calculation was also added to the system settings. After successful system setup, catheter hydration, and 7F pressure balancing, a single-pressure sensor, 48-inch-long pigtail catheter with a variable segment length (VSL) configuration was inserted through a 9F sheath. The VSL design allowed selection of the recording segment based on ventricular size; in this study, segment spacing from 1 to 4 (30–60 mm) was used. Under fluoroscopic guidance, the catheter was advanced through either the right carotid artery or the right femoral artery into the aortic arch. When the catheter approached the LV, the pressure tracing showed a characteristic aortic waveform before crossing the aortic valve. At this point, a 0.035-inch, 150-cm J-tip guidewire was inserted through the lumen to facilitate smooth catheter advancement across the valve and enable later fine-tuning of LV positioning. Preload Reduction Protocol: Preload reduction was achieved by transient balloon inflation in either the IVC or SVC for a standardized duration sufficient to induce measurable changes in LV filling. A 14F, 100-cm usable length valvuloplasty balloon catheter with a 30-mm inflated diameter and 50-mm balloon length was used to achieve stable IVCO. The balloon length was selected to ensure a reliable seal across the intrahepatic IVC segment, while the burst pressure rating (2 ATM) and introducer compatibility facilitated safe venous access. For smaller swine (<60 kg), a 28-mm balloon diameter is suitable to ensure full occlusion without excessive wall stress. During occlusion, LV pressure and volume were sampled at high temporal resolution (≥500 Hz) to capture dynamic changes. Parameters Assessed: The following indices were derived for each occlusion maneuver: Rate of LV volume decline (mL/s), Total LV volume reduction (mL), Time delay between volume decline and pressure response (s), Rate (slope) of LV pressure decline (mmHg/s). Data Analysis: Values were summarized as mean ± SD for each group. Differences between IVCO and SVCO were assessed using unpaired t-tests, with statistical significance set at p < 0.05. Comparative trends were visualized using pressure-volume loop overlays and tabulated summaries.

In contrast, superior vena cava occlusion (SVCO) affects about 30% of venous return from the upper body. The LV does not fully unload, and EDV remains relatively preserved. On the PV loop, this manifests as a smaller leftward shift, with V₀ shifting rightward or remaining stable, reflecting incomplete ventricular unloading. The ventricle may show reduced ability to empty, potentially due to afterload mismatch or altered filling dynamics.

Swine models are particularly valuable in this context, given that their cardiovascular anatomy and physiology closely resemble those of humans [60,61]. In these models, transient IVC occlusion acutely reduces LV preload, decreasing systolic and diastolic pressures, lowering EDV, and reducing cardiac output [62]. This technique is especially valuable for studying HF pathophysiology and evaluating therapies in volume-overloaded or diuretic-resistant patients [18]. Transient VCO maneuvers reduce venous return and mean arterial pressure (MAP), triggering baroreflex-mediated compensatory responses like increased heart rate and systemic vascular resistance (SVR). Baroreflex sensitivity (BRS) can be assessed via ECG using slope and sequence methods that relate blood pressure fluctuations to heart rate variability. Experimental models have limitations, including anesthesia-induced alterations in autonomic tone, interspecies differences in reflex responses, mechanical constraints of occlusion techniques, and the confounding effects of heart rate variability on contractility indices like Ees. Acknowledging these factors is essential for ensuring critical rigor in data interpretation.

During brief transient occlusions (as typically employed in experimental settings), compensatory autonomic mechanisms like baroreflex activation, sympathetic stimulation, and RAAS engagement often remain incomplete or delayed [63]. This preserves intrinsic myocardial contractility, as indicated by stable Ees (end-systolic elastance), despite significant preload reductions. Ees calculations isolate the ventricle’s contractile state, minimizing preload and afterload influences. Even though IVC occlusion markedly reduces preload (and consequently SV and CO), myocardial force-generating capacity remains stable in the absence of physiologic stimuli like β-adrenergic activation. Notably, differential volume intercepts (V₀) reflect varying degrees of ventricular unloading rather than changes in contractility, confirming Ees stability across conditions (Figure 2).

Interestingly, arterial elastance (Ea), a measure of afterload representing the net arterial load the heart ejects against, remains relatively unchanged during both IVC and SVC occlusion (Figure 3). Neither intervention directly alters arterial properties such as systemic vascular resistance or arterial compliance. Since both maneuvers primarily affect venous return (preload) without acutely changing afterload determinants, Ea stays stable. As preload drops, SV and end-systolic pressure (ESP) fall proportionally. Because Ea is calculated as ESP divided by SV, and both decrease in parallel, the ratio and thus Ea remain constant (Figure 3). Furthermore, systemic resistance typically does not change during brief preload reductions unless compensatory reflexes are triggered, which is often not the case during short experimental occlusions. Additional load-independent or minimally load-dependent indices (e.g., PRSW, dP/dt max adjusted for preload, myocardial strain) that could provide complementary insights during transient preload/afterload alterations.

Dynamic PV loop analysis reveals distinct mechanical and autonomic patterns during transient versus sustained preload alterations. In the initial IVC occlusion, parallel declines in LVP and LVV at a steady heart rate reflect a purely mechanical preload reduction. ESP and heart rate data cluster tightly, indicating preserved myocardial contractility and hemodynamic stability. A slight heart rate increase near the end of occlusion signals early baroreflex-mediated sympathetic activation in response to falling arterial pressure and reduced ventricular filling. Notably, transient arrhythmic cycles often precede autonomic compensation, indicating that sudden preload reduction can transiently destabilize conduction, especially in compromised hearts.

In prolonged occlusions, preload reduction continues, but with more dispersed heart rate patterns and a blunted tachycardic response. This suggests baroreflex adaptation or vagal predominance, which diminishes sympathetic compensation over time. Clinically, this pattern indicates that prolonged preload reduction may limit reflex-mediated HR adjustments, contributing to hemodynamic instability or arrhythmic risk in advanced HF. The combination of preload dependency, reduced autonomic reserve, and diastolic dysfunction in HFpEF makes this patient population particularly vulnerable [18].

If modeled further, serial evaluation of Ees and Ea during transient and sustained occlusions could clarify how contractility and afterload interact under varying loading conditions in health and HF states. In HFpEF, rapid ESP rise, elevated EDP, low arterial compliance, and increased impedance predispose to arrhythmias, particularly during SVCO, where abrupt right atrial and ventricular preload drops destabilize conduction. Conversely, post-IVCO arrhythmias likely stem from afterload mismatch as Ea rises and Ees remains impaired.

Collectively, these findings advocate cautious, controlled preload modulation in both experimental and clinical settings, particularly in patients with borderline hemodynamics or heightened arrhythmic risk. They highlight the translational relevance of standardized, reproducible preload manipulation protocols and underscore the importance of concurrently monitoring mechanical, electrophysiologic, and autonomic parameters during volume management in HF.

This review compares transient inferior vena cava occlusion (IVCO) and superior vena cava occlusion (SVCO) in a preclinical swine model to delineate their differential effects on left ventricular (LV) hemodynamics assessed by pressure-volume (PV) loop analysis. Transient IVCO, which reduces systemic venous return by approximately 70%, induces a marked preload reduction that shifts the PV loop leftward and decreases stroke volume (SV) and cardiac output (CO), while transiently steepening the ESPVR due to early, load-dependent inotropic compensation. In contrast, SVCO affects only ~30% of venous return, producing modest preload reduction and incomplete LV unloading (Figure 3). Despite these differences in loading, contractility (Ees) remained stable across both perturbations, supporting the premise that brief occlusions do not fully recruit neurohumoral compensatory systems (Table 4). Corresponding changes in PRSW, stroke work, and mechanical efficiency largely reflected altered loading conditions rather than intrinsic myocardial contractile adaptation. These results emphasize the need for careful interpretation of PV-derived contractility metrics in settings where preload and afterload fluctuate, particularly in conditions such as HFpEF, shock states, or during therapeutic interventions (e.g., diuresis, vasodilation, or mechanical support). Misinterpreting load-dependent responses as changes in intrinsic myocardial function could lead to incorrect conclusions about contractile reserve, disease progression, or treatment efficacy. Importantly, the differential venous territories affected by SVCO and IVCO, upper systemic/cerebral vs. splanchnic and lower systemic, may variably influence right-sided filling dynamics and pulmonary pressures, which could secondarily modify LV preload. Although not directly assessed here, this highlights a key physiological interaction and a potential area for more detailed biventricular assessment in future experiments.

While the current analysis primarily focused on systolic metrics, diastolic behavior represents another important avenue for investigation. Load-dependent shifts in the end-diastolic pressure-volume relationship (EDPVR), filling pressures, or relaxation parameters could provide deeper insight into changes in ventricular compliance during transient preload alterations. Such information may be particularly relevant for translational modeling of HFpEF, where diastolic stiffness and impaired reserve are central pathophysiologic features. The heart rate (HR) responses observed in this study further underscore the dynamic nature of autonomic engagement during transient loading shifts. During IVCO, parallel declines in LV pressure and volume confirmed effective preload reduction, with HR initially stable but demonstrating a modest rise toward the end of the occlusion, consistent with early baroreflex activation (Figure 2). This response was most apparent during the initial brief occlusion, in which ESP–HR data remained tightly clustered until a small HR increase followed several arrhythmic beats. In contrast, the second, longer occlusion produced a more variable and attenuated HR response, suggesting a dampened baroreflex response, possibly related to limitations in vagal withdrawal, baroreceptor resetting, or reduced sympathetic recruitment. These findings support the concept that baroreflex sensitivity is time-dependent and more robust during brief perturbations (Table 4). Overall, the translational value of this work lies in demonstrating that not all preload-reducing maneuvers are physiologically equivalent. Understanding how different occlusion strategies alter cardiac loading, autonomic responses, and PV-derived contractility indices provides a more accurate framework for interpreting load-independent metrics, validating computational models, and refining experimental protocols for both healthy and HFpEF phenotypes. Future work incorporating biventricular assessment, diastolic function, longer perturbation paradigms, and integrative neurohumoral measurements would further strengthen the mechanistic insight and clinical applicability of this preclinical model.

During the preparation of this manuscript, the authors used Microsoft Copilot to support drafting and editing. All content generated by the tool was reviewed and revised as necessary, and the authors take full responsibility for the final published work.

Ethical review and approval were waived due to the analysis of existing data. Study was based on a retrospective record review, examining historical data without active intervention, and use of de-identified datasets and specimens.

Not Applicable.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

This research received no external funding.

The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.