Pressure-volume Relationship Research Articles

Bi-ventricular elastic material parameters estimation using 3D CMR myocardial strains in rheumatic heart disease patients.

Understanding the elastic material behavior of myocardium during the diastolic phase is critical for evaluating cardiac function and improving treatments for diastolic abnormalities. This study introduces a novel multi-objective optimization framework that incorporates both strain and volume measurements to enhance the accuracy of myocardial property assessments in Rheumatic Heart Disease (RHD) patients and healthy controls. By employing global volume and strain measurements instead of segmented strains from the sixteen AHA regions, we achieve a robust alignment with the Klotz curve across all groups, indicating an accurate simulation of end-diastolic pressure-volume relationships (EDPVRs). Our approach uniquely integrates combinations of longitudinal, circumferential, and radial strains, resulting in an unprecedented reduction in errors between clinical and simulated strain values, with less than one percent difference for targeted parameters. The results demonstrate that the alignment between computational predictions and clinical measurements depends significantly on the choice of optimization target. The study reveals significant differences in tissue mechanics between RHD patients and healthy controls, with notable variations in ventricular stiffness and fiber orientations across optimization targets, confirmed through rigorous statistical analyses. The observed variations in fiber angles, particularly the smaller angles for longitudinal strains and steeper angles for circumferential strains, underscore the intricate relationship between myocardial fiber architecture and cardiac deformation, offering deeper insights into ventricular biomechanics. By presenting qualitative and quantitative differences in stress and strain distributions, this research advances the understanding of myocardial mechanics, highlighting the clinical relevance of fiber orientation and material properties in modeling cardiac mechanics and distinguishing diseased from healthy myocardial behavior.

Cerebral compliance assessment from intracranial pressure waveform analysis: Is a positional shift-related increase in intracranial pressure predictable?

Real-time monitoring of intracranial pressure (ICP) is a routine part of neurocritical care in the management of brain injury. While mainly used to detect episodes of intracranial hypertension, the ICP signal is also indicative of the volume-pressure relationship within the cerebrospinal system, often referred to as intracranial compliance (ICC). Several ICP signal descriptors have been proposed in the literature as surrogates of ICC, but the possibilities of combining these are still unexplored. In the present study, a rapid ICC assessment consisting of a 30-degree postural shift was performed on a cohort of 54 brain-injured patients. 73 ICP signal features were calculated over the 20 minutes prior to the ICC test. After a selection step, different combinations of these features were provided as inputs to classification models. The goal was to predict the level of induced ICP elevation, which was categorized into three classes: less than 7 mmHg ("good ICC"), between 7 and 10 mmHg ("medium ICC"), and more than 10 mmHg ("poor ICC"). A logistic regression model fed with a combination of 5 ICP signal features discriminated the "poor ICC" class with an area under the receiving operator curve (AUROC) of 0.80 (95%-CI: [0.73-0.87]). The overall one-versus-one classification task was achieved with an averaged AUROC of 0.72 (95%-CI: [0.61-0.83]). Adding more features to the input set and/or using nonlinear machine learning algorithms did not significantly improve classification performance. This study highlights the potential value of analyzing the ICP signal independently to extract information about ICC status. At the patient's bedside, such univariate signal analysis could be implemented without dependence on a specific setup.

A minimally invasive swine model of chronic kidney disease-associated heart failure.

Chronic kidney disease (CKD) is on the rise, and over 50% of patients die from cardiac causes. Patients develop heart failure due to unelucidated reno-cardiac interactions, termed type 4 cardiorenal syndrome (CRS4). The aim of this study is to establish and characterize a reliable model of CRS4 in swine with marked cardiac diastolic dysfunction. Yorkshire pigs (19.9 ± 1.7 kg, 4 females and 5 males) underwent staged renal artery embolization using autologous clot. Echocardiogram, aortic pressure (AoP), renal angiogram, and blood samples were assessed monthly. At 4 mo, animals were euthanized after measuring glomerular filtration rate (GFR) and left ventricular (LV) pressure-volume parameters. Heart and kidneys were collected for postmortem analyses. Size-matched swine (n = 5; 43.7 ± 9.8 kg) served as controls. After three dose-titrated renal embolization, serum creatinine (SCr) and AoP increased by wk 10. At 4 mo, SCr (2.03 ± 0.45 vs. 1.34 ± 0.17 mg/dL, P = 0.013) and AoP (158 ± 16 vs. 121 ± 8 mmHg, P = 0.001) were higher, and GFR was lower (12 ± 3 vs. 131 ± 7 mL/min, P < 0.001) than size-matched controls. Although the LV ejection fraction was similar, the slope of the end-diastolic pressure-volume relationship was steeper in pigs after renal embolization (0.36 ± 0.09 vs. 0.17 ± 0.06, P = 0.003), indicating increased LV stiffness. LV mass index (2.73 ± 0.19 vs. 2.50 ± 0.13 g/kg, P = 0.043) and wall-thickness (11.4 ± 0.8 vs. 8.9 ± 1.2 mm, P = 0.003) increased. These were accompanied by histologically increased fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction. Repeat titrated renal embolization resulted in a model that exhibits advanced CKD and cardiac abnormalities consistent with CRS4.NEW & NOTEWORTHY Cardiac pathological changes consistent with heart failure with preserved ejection fraction can be induced in a large animal model by serial and titrated renal embolization of kidneys with autologous clot, leading to severe renal dysfunction and impaired cardiac diastolic function.

Human induced pluripotent stem cell-derived cardiomyocyte patches ameliorate right ventricular function in a rat pressure-overloaded right ventricle model.

Right ventricular (RV) failure following surgical repair of congenital heart disease affects survival. Human induced pluripotent stem cell-derived cardiomyocyte (hiPS-CM) sheet transplantation ameliorated left ventricular dysfunction in preclinical studies, indicating its efficacy in RV failure in congenital heart disease. This study aimed to evaluate whether hiPS-CMs could improve RV function in rats with pressure-overloaded RV failure. F344/NJcl-rnu/rnu rats underwent pulmonary artery banding (PAB) via left thoracotomy. Four weeks after PAB, hiPS-CM patch transplantation to the RV was performed in the hiPS-CM group (n = 33), and a sham operation was performed in the sham group (n = 18). We evaluated cardiac catheterization, positron emission tomography data, and pathological results 8weeks following PAB. RV end-diastolic pressure, the time constant of isovolumic relaxation, and end-diastolic pressure-volume relation were significantly ameliorated in the hiPS-CM group compared with in the sham group. Picrosirius red staining revealed that anti-fibrotic effects were significantly higher in the hiPS-CM group than in the sham group. Von Willebrand factor staining revealed significantly higher myocardial capillary vascular density in the hiPS-CM group than in the sham group. hiPS-CMs were detected in the epicardium 4weeks after hiPS-CM sheet transplantation. The angiogenic gene expression in the myocardium was significantly higher in the hiPS-CM group than in the sham group. Overall, in rats with pressure-overloaded RV failure, hiPS-CM patch transplantation could improve diastolic function, suppress ventricular fibrosis, and increase capillary density, suggesting that it is a promising treatment for RV failure.

Guidelines for assessing ventricular pressure-volume relationships in rodents.

Ventricular catheterization with a pressure-volume (PV) catheter is the gold-standard method for assessing in vivo cardiac function in animal studies, providing valuable 'load-independent' indices of systolic and diastolic heart performance. PV studies are commonly performed to elucidate mechanistic insights into cardiovascular disease using surgical and genetically engineered rat and mouse models, but there is considerable heterogeneity in how these studies are performed. Wide variation in protocol design, volume calibration, anesthesia, manipulation of cardiac loading conditions and how load-independent indices of cardiac function are derived, as well as in data analysis and reporting, is constraining reliability and reproducibility in the field. The purpose of this manuscript is to combine our collective expertise in performing open- and closed-chest left and right ventricle PV studies in rodents to provide consensus guidelines on how to perform, analyze and interpret these studies using either conductance or admittance PV catheters. We first review recent methodological reporting in rodent PV studies in this journal, and discuss important details required to improve reproducibility within and across PV studies. We then recommend steps to obtain high-quality PV data, from volume calibration to choice of anesthetic agent and acquiring load-independent indices of both systolic and diastolic function. We also consider between- and within-animal variation and recommend how to perform data analysis and visualization. We hope that this consensus paper guides those performing PV studies in rodents and helps align the field with best practices in surgical/analytical methodologies and reporting, facilitating better reliability and reproducibility in the PV field.

Experimental Evaluation of Ocular Rigidity and Pressure-Volume Relationship After Ex-Vivo Scleral Cross-Linking With Riboflavin and Ultraviolet A in Porcine Eyes.

Scleral cross-linking (SXL) with ultraviolet A (UVA) and riboflavin has already been used in laboratory studies for scleral stiffness increase as a potential treatment for progressive myopia and scleral ectasia. This study aims to investigate whether the regional application of scleral cross-linking (SXL) with ultraviolet A (UVA) and riboflavin in fresh porcine eye globes affects the ocular rigidity as well as its impact on intraocular pressure after an induced acute increase in the volume of intraocular fluid. The study included two groups of fresh porcine eyes: an experimental group (n=20) that underwent scleral cross-linking (SXL) with riboflavin and UVA applied to the posterior sclera and a control group (n=20) that did not receive SXL treatment. Subsequently, a balanced salt solution (volumes 50, 100, 150, and 200 μL) was administered into porcine globes via a syringe, and, at the same time, the intraocular pressure (IOP) was continuously monitored by a pressure sensor that was cannulated to the vitreous chamber. The relationship between volume and pressure was obtained, and the ocular rigidity coefficient (K) was calculated according to Friedenwald's law. Finally, scleral strips were dissected from the globes and were examined macroscopically. In the control group, the mean IOP observed entails gradual, statistically significant increases for higher volumes. Specifically, the mean IOP at 0 μL equals 10 mmHg (SD=0), whereas at 200 μL the mean IOP equals 33.83 mmHg (SD=4.060). The differences were statistically significant with p-values <0.001 in all cases. Similarly, the observed gradual IOP increases in the SXL group were statistically significant with p < 0.001 in all cases except for the comparison of volume 0 μL measurements to volume 50 μL, where the p-value equaled 0.003. Specifically in the SXL group, the mean IOP at 0 μL equals 10.00 mmHg (SD=0.000), the mean IOP at 50 μL equals 13.31 mmHg (SD=2.011), whereas the mean IOP at 200 μL equals 32.06 mmHg (SD=3.078). At no additional injected volume, the differences between the control and the SXL groups were statistically significant. The analysis regarding ocular rigidity indicated significantly higher scores in the control group (K50=0.00812, SD=0.03) compared to the SXL group (K50=0.00552, SD=0.027), t=2.844; p=0.007. The difference regards measures of volumes 0 to 50 μL, while all other rigidity measures were found to be non-significant. Interestingly, the ocular rigidity coefficient in the SXL-treated group did not show changes with an increase in IOP. The macroscopic appearance of the scleral strips showed a significantly increased stiffness of the SXL scleras against the control ones. This study showed that stiffened scleras did not induce substantial change in ocular rigidity and significant IOP elevations. Studying the biomechanical ocular response of laboratory scleral crosslinking applications supports the development of next-generation crosslinking procedures that may constitute potential therapeutic options for severe ophthalmic diseases likepathologic myopia.

A method of measuring the pressure-volume relationship of mortar using a thick-walled cylinder

A method for measuring the pressure-volume relationship of mortar is presented, involving axial compression of a mortar specimen in a thick-walled cylinder (TWC). Hoop strain at the outer wall of the TWC is measured to determine the average radial stress (σr) in a mortar specimen according to TWC theory. Axial stress (σa) of mortar is measured using a load cell. The pressure (P=σa+2σr3) acting on the mortar specimen is determined from the measured axial and radial stresses. Separately, axial displacement is measured to determine the current specimen volume. TWC was designed to measure mortar pressures exceeding 100 MPa within the elastic deformation regime of the TWC. Feasibility of the proposed method and influence of friction on the measured pressure-volume relationship were examined via a finite element simulation, followed by experimental manifestation of proposed method. The proposed method was found to be effective for measuring the pressure-volume relationship of mortar.

Fluid dynamics of gas–liquid slug flow under the expansion effect in a microchannel

The expansion of bubbles in viscous fluids in microchannels is normally overlooked. The bubble dynamics in liquids with varying viscosities (1.15 ∼ 101.47 mPa·s) and contact angles (29.3 ∼ 137.6°) in a microchannel were investigated under various inlet pressure drops (8 ∼ 202 kPa). The findings indicate that bubble formation occurs within a squeezing-shearing regime over a wide Capillary number range of 0.0023–0.43. Interestingly, the wettability affects the bubble length rather than the bubble shape, and the poor wettability can hinders the decrease of length in higher viscosity fluids. Bubble expansion causes decreasing curvature radii of bubble caps, and non-linear rapid increases in its length and velocity along the microchannel. The bubble’s pressure–volume relation at the inlet and outlet confirms the validation of Boyle’s law in slug flow. A linear decline in pressure along the microchannel was deduced from this law. Further analysis suggests that besides the friction of the liquid slug, the pressure drop is influenced by the interface effect, film flow, and liquid circulation. Finally, a model for total pressure drop was developed, which effectively predicted the length and velocity of bubbles in the expansion process. This study offers valuable insights for a deeper understanding of bubble expansion behaviors in microchannels.

Abstract 4138716: A novel Urocortin-2 analog COR-1167 corrects cardiac and renal dysfunction on top of Empagliflozin in a rat model of acute decompensated heart failure

Introduction: Urocortin-2 (UCN-2) is a peptide belonging to the corticotropin-releasing factor family that has cardiovascular, renal, metabolic and anti-inflammatory actions and improves cardiac function in human heart failure (HF) and cardiorenal dysfunction in chronic HF models. However, UCN-2 has a short half-life and intravenous delivery limits its therapeutic use. COR-1167 was discovered as a stable UCN-2 analog with qd pharmacological effects when injected subcutaneously. Hypothesis: Whether COR-1167 exerts chronic cardiorenal protection in Acute Decompensated HF (ADHF) is unknown, and in particular on background of SGLT2 inhibition, therefore both treatments were tested in a rat model of ADHF. Methods: Rats had coronary artery ligation to induce MI and a reduced ejection fraction phenotype. Three months later, rats were treated with vehicle or Empagliflozin (Empa) at 10 mg/kg/day PO. One month after starting Empa, two acute decompensation events were induced by administrating NaCl solution (1.8 g/kg, PO) on Day 0 and Day 14. Empa treated ADHF rats received vehicle or COR-1167 (3 µg/kg/day) by SC injections starting at 12 hours after the first decompensation and all treatments continued for 14 days. The groups were ADHF, ADHF + Empa and ADHF + Empa + COR-1167 (n=7-10/group). Left ventricular (LV) hemodynamics (cardiac catheters), cardiac output (echocardiography) and LV tissue perfusion (magnetic resonance imaging), cardiac mitochondrial coupling and ATP production (Seahorse) were measured 1 day after the second decompensation, while urine volume (uVol) and urine Na + excretion (uNa + ) collected from metabolic cages were analyzed 7 days after the first decompensation. Results: Compared to ADHF control rats, Empa treatment had no effect on systolic blood pressure (SBP), cardiac output (CO), LV end systolic pressure volume relationship (LVESPVR), LV end diastolic pressure volume relationship (LVEDPR), mitochondrial coupling and ATP production, but it increased myocardial perfusion, uVol and uNa + excretion. Compared to ADHF + Empa rats, COR-1167 treatment increased SBP, CO, LVESPVR, myocardial perfusion, mitochondrial coupling and ATP production, uVol, uNa + , while decreasing LVEDPVR. Conclusion: In the setting of ADHF, significant cardiorenal benefits and decongestion occurred when COR-1167 was administered on top of an SGLT2 inhibitor.

Abstract 4136701: A combined approach of cardiac magnetic resonance and CardioMEMS to assess right ventricular dysfunction during exercise in HFpEF-PH

Background: Right ventricular dysfunction (RVD) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with shortened life expectancy. Early identification of these at-risk patients could facilitate the initiation of future treatments. Evaluating the RV during exercise has proven to enhance the diagnostic accuracy in revealing RVD that is not detectable at rest. The CardioMEMS device has emerged as a non-invasive tool to remotely monitor pulmonary artery pressures (PAP) and enable early identification of clinical worsening. Research Questions: Using a hybrid approach of combined real-time CMR-derived volume measurements with CardioMEMS-derived PAP measurements, we aimed to identify RVD during exercise which is not detectible at rest in a population of patients with HFpEF and pulmonary hypertension (PH). Methods: In this prospective cohort study, we used a hybrid approach of two consecutive exercise tests in HFpEF patients ( Figure 1 ). First, PAP were measured using the CardioMEMS signal on a supine bike at rest, and 25%, 50%, and 75% of peak power output determined previously on an upright cycle ergometer. Subsequently, volumes were derived by CMR at rest and during exercise at 25% and 50% of peak power output. The RV end-systolic pressure-volume relationship (RVESPVR), a surrogate of RV contractility, was calculated as mean PAP divided by RV end-systolic volume. RV contractile reserve, as a marker of RVD during exercise, was calculated as the ratio of peak exercise to resting RVESPVR, with values &lt; 2.0 indicating impairment. Results: Fourteen patients with HFpEF-PH were included (age 76.6±6.9 years, 57% women). Eleven (79%) had impaired RV contractile reserve during exercise ( Table 1 ). Although not significant, RVESPVR at rest tended to be better in the group with RVD during exercise (0.47±0.17 vs 0.27±0.03; P=0.070). Peak VO 2 was significantly reduced in patients with RVD during exercise (13.1±2.0 vs. 18.6±6.4%; P&lt;0.021). Conclusion: A new hybrid approach combining cardiac MRI and CardioMEMS is feasible during exercise in HFpEF patients and identifies RVD in approximately eighty percent of patients with HFpEF and elevated mPAP at inclusion. Evaluation of RV contractility at rest showed a discordant trend, pointing out the need to test the RV during exercise. Further research is needed to determine if this approach can predict progression of RVD over time and serve as a risk stratification tool for these patients.

A Theoretical Framework to Quantify Ecosystem Pressure-Volume Relationships.

'Water potential' is the biophysically relevant measure of water status in vegetation relating to stomatal, canopy and hydraulic conductance, as well as mortality thresholds; yet, this cannot be directly related to measured and modelled fluxes of water at plot- to landscape-scale without understanding its relationship with 'water content'. The capacity for detecting vegetation water content via microwave remote sensing further increases the need to understand the link between water content and ecosystem function. In this review, we explore how the fundamental measures of water status, water potential and water content are linked at ecosystem-scale drawing on the existing theory of pressure-volume (PV) relationships. We define and evaluate the concept and limitations of applying PV relationships to ecosystems where the quantity of water can vary on short timescales with respect to plant water status, and over longer timescales and over larger areas due to structural changes in vegetation. As a proof of concept, plot-scale aboveground vegetation PV curves were generated from equilibrium (e.g., predawn) water potentials and water content of the above ground biomass of nine plots, including tropical rainforest, savanna, temperate forest, and a long-term Amazonian rainforest drought experiment. Initial findings suggest that the stored water and ecosystem capacitance scale linearly with biomass across diverse systems, while the relative values of ecosystem hydraulic capacitance and physiologically accessible water storage do not vary systematically with biomass. The bottom-up scaling approach to ecosystem water relations identified the need to characterise the distribution of water potentials within a community and also revealed the relevance of community-level plant tissue fractions to ecosystem water relations. We believe that this theory will be instrumental in linking our detailed understanding of biophysical processes at tissue-scale to the scale at which land surface models operate and at which tower-based, airborne and satellite remote sensing can provide information.

The ghrelin receptor agonist AC01 improves cardiac function in non-human primates and in mice with heart failure by increasing cardiomyocyte contractility

Abstract Background Current therapy for Heart Failure (HF) includes neurohormonal antagonist and modulator drugs that improve remodelling, symptoms and clinical outcomes. However, these drugs do not target the underlying problem of reduced contractility. Improving cardiac contractility without harmful consequences is an unmet need in heart failure therapy. The human peptide hormone ghrelin increases cardiac output in HF patients and increases contractility in murine cardiomyocytes. Purpose We aim to study the cardiovascular effects of a novel oral small molecule ghrelin receptor agonist, AC01, in in vivo and ex vivo mouse models and in non-human primates. Methods HF mice (N=11) underwent pressure-volume loops analysis of cardiac functional and hemodynamic to assess the effects of intravenous AC01 (N=7) or placebo (N=4). Primary cardiomyocytes isolated from HF (N=3) and SHAM (N=5) mice, were treated with combinations of vehicle, AC01, ghrelin receptor antagonist (D-Lys-3-GHRP-6) and pertussis toxin (PTX, a Gαi signalling inhibitor). Live cell imaging was performed to assess cardiomyocyte fractional shortening and Ca2+ signalling, while biochemistry assays were employed to measure PKA activity, and phosphorylation of cardiac Troponin I (cTnI). Cynomolgus monkeys (N=6) were instrumented with devices to measure pulse contour, central aortic blood pressure and ECG devices. Cardiovascular effects of AC01 following single oral dosing were assessed through pulse contour hemodynamic modelling and analysis of autonomic system activation. Results In HF mice, AC01 significantly improved cardiac output (p&amp;lt; 0.01), stroke volume (p&amp;lt; 0.001), and ejection fraction (p&amp;lt; 0.001), and increased nominally the end-systolic pressure-volume curve relationship. In cardiomyocytes, AC01 dose-dependently improved fractional shortening (p&amp;lt; 0.01) without increasing Ca2+ transient amplitudes. AC01 reduced PKA activity (p&amp;lt; 0.05) and reduced phosphorylation of cTnI at Serine 23-24 (p&amp;lt; 0.01). These effects were blocked by pre-treatment with either D-Lys-3-GHRP-6 or PTX. In monkeys, oral AC01 sustainably increased cardiac output (p&amp;lt; 0.05) and stroke volume (p&amp;lt; 0.05) and reduced heart rate without altering central systolic blood pressure or causing tachycardia or arrhythmia. Conclusions AC01 improved CO, SV, and EF in HF mice by increasing contractility in a load-independent fashion. AC01 increased cardiomyocyte contractility without affecting Ca2+ transient amplitudes, through ghrelin receptor Gαi signalling, leading to reduced phosphorylation of cTnI. AC01 improved left ventricle systolic function in monkeys. AC01 is a first in class novel inotrope, which improves contractility in different species without harmful mobilization of Ca2+. AC01 should be explored for the treatment of patients with heart failure.graphical abstract

Benefit of combination therapy with dapagliflozin and eplerenone on cardiac function and fibrosis in rats with non-diabetic chronic kidney disease

Patients with chronic kidney disease (CKD) are at a high risk of cardiovascular (CV) complications. In these patients, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce CV events. Mineralocorticoid receptor antagonists (MRAs) exert similar benefits in diabetic CKD, though their effects in non-diabetic CKD remain unclear. This study aimed to evaluated whether the combination of Dapagliflozin (DAPA) and Eplerenone (EPLE) would have positive effects on cardiorenal functions in a non-diabetic CKD model. CKD was induced in rats via 5/6 nephrectomy, followed by treatment with DAPA (5 mg/kg/day PO), EPLE (100 mg/kg/day PO) or the combination for 3 months following CKD induction. Cardiorenal functions were assessed after the treatment period. All treated groups showed reduced kidney fibrosis though plasma creatinine and urea levels remained unchanged. Compared to untreated CKD, EPLE or DAPA/EPLE reduced left ventricle (LV) end-diastolic pressure and LV end-diastolic pressure volume relationship, whereas DAPA alone did not achieve significant reductions. Compared to untreated CKD, EPLE and DAPA/EPLE improved cardiac perfusion but DAPA alone did not. Cardiac fibrosis in CKD was blunted by either DAPA or EPLE alone, with the combination showing an additive effect. In conclusion, co-treatment with DAPA and EPLE enhances diastolic function, cardiac perfusion and reduces myocardial fibrosis in non-diabetic CKD rats.

Theoretical and experimental investigation of flexible air spring stiffness in a tuned liquid column gas damper for vertical vibration control

This study investigates the effectiveness of equivalent linear air spring stiffness in a Vertical Tuned Liquid Column Gas Damper (VTLCGD) for reducing vertical structural vibrations, particularly considering different sealing conditions. The VTLCGD system, designed with a single sealed vertical air column, allows flexible frequency tuning by adjusting the air spring stiffness. It aims to be used in low-frequency structures where conventional VTLCGD designs with two sealed ends are less efficient. The geometric configuration and working principle of the VTLCGD are first described. The equation of motion is derived using liquid dynamic equilibrium and the pressure-volume relationship, with expressions for natural frequency and control force validated through shaking table tests conducted with varying VTLCGD lengths. Experimental investigations are conducted to examine the parameters affecting damper performance using pressure data. The system's vibration reduction performance is then numerically evaluated on a cantilevered floor subjected to human walking. The numerical results, based on the equation of motion for liquid displacement and natural frequency, show good agreement with experimental data, which confirms the effectiveness of using linearized air spring stiffness for frequency tuning. The effects of total liquid length and height difference on control force are further investigated, and a polytropic index of 1.2 is determined for the VTLCGD frequency formula. The VTLCGD system achieves a maximum vibration reduction of 52.63 % in acceleration response on the cantilevered floor compared to the uncontrolled case. Moreover, the variation in stiffness due to changes in the sealing condition is presented to validate the damper's adaptability over a wide frequency range.

Arterial Properties and Ventricular-Arterial Interactions in Severe Aortic Stenosis: Impact on Prognosis.

Systemic arterial properties contribute to clinical heterogeneity and outcomes in degenerative calcific aortic stenosis (AS). Lumped parameters of afterload have previously been associated with adverse left ventricular remodeling, mortality, and poor exercise tolerance in this population, but most studies did not assess pulsatile aortic pressure-flow relations, the gold standard method for assessing arterial load. Moreover, arterial compliance is highly dependent on non-pulsatile (mean) arterial pressure, which influences prognosis in this population. We retrospectively studied 135 patients with severe AS with same-day catheterization and echocardiogram. Invasive aortic pressures and echocardiographic flow waveforms were used to assess pressure-flow and pressure-volume relations using Windkessel modeling and wave separation analyses. We used Cox regression to assess the relationship between pulsatile load and time to death and heart failure hospital admission (DHFA). Total arterial compliance accounting for pressure-dependence (PD-TAC) was independently predictive of all-cause mortality (HR=0.80, 95%CI=0.66-0.97; p=0.023) and DHFA (HR=0.70; 95%CI=0.50-0.97; p=0.031) even after adjustment for age, race, gender, BMI, and comorbidities, while other arterial parameters were not. In patients with severe AS, pressure-dependent arterial compliance predicts adverse outcomes, while traditional pulsatile arterial load measures do not. Our findings suggest that methods accounting for pressure load on the arterial wall are advantageous in this population in which lower mean pressure can result from severe stenosis and ventricular dysfunction.

The Combination of Valsartan and Spironolactone Mitigated Mitral Regurgitation-Induced Cardiac Dysfunction in a Novel Rat Model.

Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin-aldosterone system inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction, its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/d), spironolactone (80 mg/kg/d), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared with that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced heart failure.

MMP-8 causes leftward shift in end-diastolic pressure-volume relationship and may explain the development of diastolic dysfunction in septic cardiomyopathy.

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% (P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.

Abstract P377: Short-Chain Fatty Acids Improve Cardiac Function in a Hypertensive Rat Model of Heart Failure

Hypertension-induced ventricular remodeling contributes significantly to the progression of heart failure (HF). The global increase in HF prevalence results in heightened cardiovascular morbidity and mortality, yet treatment options remain limited. The gut microbiota ferments indigestible dietary fibers, producing essential metabolites such as short-chain fatty acids (SCFAs), amino acids metabolites. We hypothesize that direct oral administration of SCFAs modulates mucosal immune cells, thereby ameliorating the heart failure with preserved ejection fraction (HFpEF) phenotype in the double-transgenic rat (dTGR) model. Four-week-old male rats, double-transgenic for human renin and angiotensinogen (dTGRs), were utilized. These dTGR rats exhibit classical symptoms of HFpEF, including hypertension, inflammation, and fibrosis in the heart and kidneys. The rats were randomized into five experimental groups: healthy non-transgenic vehicle-treated controls (wild type), vehicle-treated dTGR, and dTGR treated with either acetate, propionate, or butyrate. Following a 3-week treatment period, comprehensive phenotyping was conducted, including echocardiography, Millar-tip catheterization, gene expression analysis, and histological examination. SCFA administration improves diastolic function, as evidenced by alterations in the end-diastolic pressure-volume relationship measured via Millar-tip catheter. Notably, butyrate treatment had the most pronounced effect on alleviating diastolic dysfunction and reducing blood pressure. Additionally, gene expressions such as atrial natriuretic peptide, connective tissue growth factor, and myosin heavy chain alpha and beta showed improvement in SCFA-treated dTGR HFpEF rats compared to vehicle-treated counterparts. Furthermore, SCFA treatment ameliorated cardiac inflammation. Our data suggest that SCFAs, particularly butyric acid, enhance hypertensive diastolic dysfunction and cardiac gene expression in dTGR rats, underscoring their therapeutic potential in HF.

Intraoperative right ventricular end-systolic pressure–volume loop analysis in patients undergoing cardiac surgery: A proof-of-concept methodology

BackgroundPerioperative right ventricular (RV) dysfunction is associated with increased morbidity and mortality in cardiac surgery patients. This study aimed to demonstrate proof of concept in generating intraoperative RV pressure–volume (PV) loops and conducting an end-systolic PV relationship (ESPVR) analysis using data obtained from routinely used intraoperative monitors. MethodsAdult patients undergoing cardiac surgery with the placement of a pulmonary artery catheter (PAC) between May 2023 and March 2024 were included prospectively. The PV loops were generated using 3-dimensional echocardiographic RV volume data and continuous RV pressure data obtained from a PAC. The volume–time and pressure–time curves were digitized using the semiautomatic WebPlotDigitizer program and synchronized to reconstruct an RV PV loop and analyze ESPVR using the previously validated single-beat method. ResultsIntraoperative RV PV loops were generated for 25 patients, including 17 patients with preserved RV systolic function (group 1) and 8 patients with reduced systolic function (group 2). Mean Ees, Ea, and Ees/Ea ratio were 0.63 ± 0.25 mm Hg/mL, 0.60 ± 0.23 mm Hg/mL, and 1.0 8 ± 0.31 mm Hg/mL, respectively, by the Pmax method and 0.56 ± 0.32 mm Hg/mL, 0.60 ± 0.23 mm Hg/mL, and 0.91 ± 0.21 mm Hg/mL, respectively, by the V0 method. Group 1 had a significantly higher Ees compared to group 2 regardless of the calculation method and a larger Ees/Ea ratio calculated by the V0 method. ConclusionsIt is clinically feasible to derive RV PV loops from routine hemodynamic and echocardiographic data. With further validation and technological support, this can be a potential real-time intraoperative RV function monitoring tool.

Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2D). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2D with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2D and HFpEF remain unknown. A total of 24 patients with T2D and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. In patients with T2D and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2D and HFpEF. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.