Low Perfusion Pressure Research Articles

Cardiac surgery-associated acute kidney injury in cardiopulmonary bypass: a focus on sex differences and preventive strategies.

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a high-risk complication with well-recognized increased morbidity and mortality after cardiac surgery attributable in large part to cardiopulmonary bypass (CPB)-associated factors contributing to AKI including hemodilution, hypothermia, hypotension, and exposure to artificial surfaces. These conditions disrupt the renal microcirculation and activate local and systemic inflammatory responses to nonpulsatile flow and low perfusion pressure. The underlying mechanisms of CSA-AKI in CPB are not fully understood, and the incidence of CSA-AKI remains high at around 30%. Furthermore, women appear to be more vulnerable than men to the renal injury associated with CPB even though the overall incidence of cardiovascular and kidney diseases is lower in premenopausal women. Nevertheless, estrogen elicits renoprotective effects in several ways including mitigating inflammation, promoting natriuresis, and endothelial protection as shown in preclinical studies. However, women have higher rates of CSA-AKI and these are exacerbated in postmenopausal women. This leads to the conundrum of whether sex, age, and hormonal status differences influence CSA-AKI. In this review, we briefly discuss the pathophysiology of CSA-AKI in CPB and sex differences in kidney functions with a focus on the possible role of estrogen-specific effects in CPB and also possible differences in CPB in women including greater hemodilution. Furthermore, we review strategies to prevent CSA-AKI in CPB with a highlight for potential sex-specific strategies. Improving our understanding of the impact of sex and sex hormones on CSA-AKI initiation and development will allow us to better manage the CPB strategies delivered to all patients.

The Benefit of Nocturnal IOP Reduction in Glaucoma, Including Normal Tension Glaucoma.

Nocturnal intraocular pressure (IOP) profiling has shown that the peak IOP usually occurs at night, particularly in patients with glaucoma. Multiple studies have demonstrated that these nocturnal IOP elevations drive glaucomatous progression, often despite stable daytime IOP. Existing vascular dysregulation and decreased nighttime blood pressure compound the damage via low ocular perfusion pressure while elevated nocturnal IOP disrupts axonal transport. These findings are consistent with studies that indicate lowering nocturnal IOP is important for slowing glaucoma progression. Many of the current treatment options lower nighttime IOP significantly less than daytime IOP. Non-invasive IOP-lowering treatments that effectively lower nocturnal IOP remain an unmet need in the treatment of glaucoma.

The cardioprotective potential of soluble urokinase Plasminogen Activator Receptor (suPAR) in myocardial ischemia

Abstract Background and aims: Increased circulating soluble urokinase plasminogen activator receptor (suPAR) levels are associated with adverse cardiovascular outcomes, however, any cardiovascular-related functions remain unknown. This study aimed to (i) document haemodynamic profiles in isolated rat hearts under the influence of suPAR, and to (ii) explore any mechanisms triggered by suPAR following myocardial ischaemia-reperfusion. Methods We undertook a 4-pronged approach (Figure 1). A Langendorff isolated rat heart model was used to perfuse all hearts with Krebs-Henseleit solution flowing retrogradely through the aorta at 37°C. A balloon inserted into the left ventricle allowed measurements of ventricular pressure, and a pressure transducer placed above the aorta recorded perfusion pressure for coronary flow rates. The experimental protocol consisted an initial 30-minute stabilisation period, followed by 40 minutes of ischemia via buffer flow cessation. Hearts were subsequently recovered during 90 minutes of reperfusion, receiving either suPAR treatment or perfusion buffer as controls. An inhibitor arm comprising co-infusion of suPAR and a monoclonal antibody capable of binding to suPAR was also assessed. Troponin T was measured in outflow perfusates collected at specific intervals. Proteins from hearts in treatment groups were separated using gel electrophoresis, with Western blotting to visualise the phosphorylation status of kinases (Akt, STAT). High-flow respirometry and fluorometry were investigated in cardiac mitochondria to determine respiration rates and ATP production in ischaemia reperfusion under the influence of suPAR. Statistical analysis was conducted with ANOVA using SPSS. Results Hearts receiving suPAR infusion at reperfusion (n = 16) showed a significant increase in developed pressure (p = .017) and lower perfusion pressure (p = .02) compared to controls (n = 16), revealing that suPAR-treated hearts recovered with better contractility and vasodilatory properties post-ischaemia. suPAR’s haemodynamic profiles in the antibody group were similar to controls, attenuating suPAR-induced effects (n = 8). Outflow effluents in suPAR-treated hearts obtained >3 fold lower serial Troponin T values than controls (p < .001). Heart tissues receiving suPAR treatment revealed a 1.7-fold increase in Akt (p = .001) and a 3.8-fold increase in STAT3 phosphorylation compared to controls (p < .001) and the inhibitor group (p = .04). Finally, suPAR increased mitochondrial ATP production by 28% (p = .013) compared to controls after ischaemia. Conclusion This is a world-first demonstration of suPAR’s cardioprotective influences in isolated rat hearts recovering from ischaemia. suPAR’s ability to promote cardiac contractility and vasodilation was associated with lesser injury as shown by Troponin T reduction. Mechanistically, suPAR infusion upregulated two key cardioprotective pathways, which may also function to protect cardiac mitochondria.Figure 1 - Schematic of Methods

Incidence, predictability, and outcomes of systemic venous congestion following a fluid challenge in initially fluid-tolerant preload-responders after cardiac surgery: a pilot trial

BackgroundFluid administration has traditionally focused on preload responsiveness (PR). However, preventing fluid intolerance, particularly due to systemic venous congestion (VC), is equally important. This study evaluated the incidence and predictability of VC following a 7 ml/kg crystalloid infusion in fluid-tolerant preload-responders and its association with adverse outcomes.MethodsThis single-center, prospective, observational study (May 2023–July 2024) included 40 consecutive patients who were mechanically ventilated within 6 h of intensive care unit (ICU) admission after elective open-heart surgery and had acute circulatory failure. Patients were eligible if they were both fluid-tolerant and preload-responsive. PR was defined as a ≥ 12% increase in left-ventricular outflow tract velocity time integral (LVOT-VTI) 1 min after a passive leg raising (PLR) test. VC was defined by a portal vein pulsatility index (PVPI) ≥ 50%. Patients received a 7 ml/kg Ringer’s Lactate infusion over 10 min. The primary outcome was the incidence of VC 2 min post-infusion (early-VC). Secondary outcomes included VC at 20 min, the incidence of acute kidney injury (AKI) and severe AKI at 7 days, and ICU length of stay (LOS).Results45% of patients developed early-VC, with VC persisting in only 5% at 20 min. One-third of patients developed AKI, with 17.5% progressing to severe AKI. The median ICU LOS was 4 days. Patients with early-VC had significantly higher central venous pressure, lower mean perfusion pressure, worse baseline right ventricular function, and a higher incidence of severe AKI. While LVOT-VTI returned to baseline by 20 min in both groups, PVPI remained elevated in early-VC patients (p < 0.001). The LVOT-VTI versus PVPI regression line showed similar slopes (p = 0.755) but different intercepts (p < 0.001), indicating that, despite fluid tolerance and PR at baseline, early-VC patients had reduced right ventricular diastolic reserve (RVDR). Post-PLR PVPI predicted early-VC with an area under the curve of 0.998, using a threshold of 44.3% (p < 0.001).ConclusionPost-PLR PVPI effectively predicts fluid-induced early-VC in fluid-tolerant preload-responders, identifying those with poor RVDR. Its use can guide fluid management in cardiac surgery patients, helping to prevent unnecessary fluid administration and associated complications.Trial Registration: NCT06440772. Registered 30 May 2024. Retrospectively registered.

Cardiac power output ratio: Novel survival predictor after percutaneous ventricular assist device in cardiogenic shock.

Currently, there is limited data on prognostic indicators after insertion of percutaneous ventricular assist device (PVAD) in the treatment of cardiogenic shock (CS). This study evaluated the prognostic role of cardiac power output (CPO) ratio, defined as CPO at 24h divided by early CPO (30min to 2h), in CS patients after PVAD. Consecutive CS patients from the QEH-PVAD Registry were followed up for survival at 90days after PVAD. Among 121 consecutive patients, 98 underwent right heart catheterization after PVAD, with CPO ratio available in 68 patients. The CPO ratio and 24-h CPO, but not the early CPO post PVAD, were significantly associated with 90-day survival, with corresponding area under curve in ROC analysis of 0.816, 0.740, and 0.469, respectively. In multivariate analysis, only the CPO ratio and lactate level at 24h remained as independent survival predictors. The CPO ratio was not associated with age, sex, and body size. Patients with lower CPO ratio had significantly lower coronary perfusion pressure, worse right heart indices, and higher pulmonary vascular resistance. A lower CPO ratio was also significantly associated with mechanical ventilation and higher creatine kinase levels in myocardial infarction patients. In post-PVAD patients, the CPO ratio outperformed the absolute CPO values and other haemodynamic metrics in predicting survival at 90days. Such a proportional change of CPO over time, likely reflecting native heart function recovery, may help to guide management of CS patients post-PVAD.

Periods of low renal perfusion pressure are associated with acute kidney injury following paediatric cardiac surgery.

Acute kidney injury is associated with worse outcomes after cardiac surgery. The haemodynamic goals to ameliorate kidney injury are not clear. Low post-operative renal perfusion pressure has been associated with acute kidney injury in adults. Inadequate oxygen delivery may also cause kidney injury. This study evaluates pressure and oximetric haemodynamics after paediatric cardiac surgery and their association with acute kidney injury. Retrospective case-control study at a children's hospital. Patients were < 6 months of age who underwent a Society of Thoracic Surgery-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery categories ≥ 3. Low renal perfusion pressure was time and depth below several tested thresholds. The primary outcome was serum creatine-defined acute kidney injury in the first 7 days. Sixty-six patients (median age 8 days) were included. Acute kidney injury occurred in 36%. The time and depth of renal perfusion pressure < 42 mmHg in the first 24 hours was greater in acute kidney injury patients (94 versus 35 mmHg*minutes of low renal perfusion pressure/hour, p = 0.008). In the multivariable model, renal perfusion pressure < 42 mmHg was associated with acute kidney injury (aOR: 2.07, 95%CI: 1.25-3.82, p = 0.009). Mean arterial pressure, central venous pressure, and measures of inadequate oxygen delivery were not associated with acute kidney injury. Periods of low renal perfusion pressure (<42 mmHg) in the first 24 post-operative hours are associated with acute kidney injury. Renal perfusion pressure is a potential modifiable target that may mitigate the impact of acute kidney injury after paediatric cardiac surgery.

Application Analysis of Low-Pressure Perfusion Combined with Occluder in Holmium Laser Lithotripsy for Patients with Middle and Upper Ureteral Calculi.

Ureteroscopic holmium laser lithotripsy has become one of the main methods of treating ureteral calculi. However, in the treatment of middle and upper ureteral calculi, ureteroscopy is difficult to operate owing to the high location of calculi. Thus, how to improve the treatment effect and reduce the stone migration has become the focus in clinical settings. On this basis, we evaluated the application effect of low-pressure perfusion combined with occluder in holmium laser lithotripsy for patients with middle and upper ureteral calculi. This retrospective study selected 107 patients with middle and upper ureteral calculi who underwent low-pressure perfusion combined with ureteroscopic holmium laser lithotripsy from January 2021 to December 2022. We excluded 7 patients who did not meet the criteria, and ultimately included 100 patients. According to whether the occluder was used during the surgery, 100 patients were divided into groups A (n = 52, occluder) and B (n = 48, without occluder). The stone-migration rate during surgery, stone-clearance rate at 3 months after surgery, perioperative indicators, postoperative complication rate, and postoperative quality of life between the two groups were compared. The stone-migration rate in group A was significantly lower than that in group B, with statistically significant difference (p < 0.05). Both groups had no significant difference in stone-clearance rate at 3 months after surgery (p > 0.05). Group A had a significantly lower index of EuroQol (EQ) Five Dimensions Questionnaire and significantly higher score of EQ-Visual Analogue Scale than group B (all p < 0.001). Compared with the simple application of low-pressure perfusion, the combined application of low-pressure perfusion and occluder in ureteroscopic holmium laser lithotripsy can effectively reduce the stone migration and improve the postoperative quality of life.

Low Mean Perfusion Pressure Indexed to Body Surface Area is a Powerful Predictor of Poor Outcomes After Heart Transplantation in Patients With High Pre-Transplant Venous Pressure: A Clinical Study With Physiological Insights From Mathematical Modelling of Biventricular Heart Failure

The deleterious consequences of chronically elevated venous pressure in patients with profound right ventricular or biventricular dysfunction are well known, including renal and hepatic dysfunction, and volume overload. The only option for these patients, if they fail optimal medical treatment, is a heart transplant, as they are not candidates for left ventricular assist device therapy. Mean perfusion pressure (MPP) is important in the outcomes of critically ill patients with high venous pressure. The question arises whether MPP is important for the outcomes of heart transplants in patients with elevated pre-transplant venous pressure. Medical management of heart failure patients with reduced ejection fraction involves lowering the systemic afterload with vasodilators while awaiting a transplant. We hypothesised that when venous pressure is elevated prior to transplant, a substantial reduction in systemic arterial elastance (Ea) through vasodilation may significantly decrease MPP, resulting in compromised end-organ function and consequent unfavourable outcomes after heart transplantation. This study aims to investigate whether a low MPP serves as a risk factor for adverse outcomes in heart transplant recipients with high venous pressure. A retrospective analysis was conducted on 250 heart transplant recipients undergoing isolated heart transplantation at a single institution from October 2012 to March 2020. Right atrial pressure (RAP) of more than 15 mmHg was considered high. Additionally, Ea calculated as the ratio of end-systolic pressure to stroke volume, and MPP calculated as the difference between mean arterial pressure and RAP were considered in our analysis. The outcomes of transplantation were measured in terms of 90-day mortality and survival up to 7 years. High RAP was a significant risk factor for short-term and medium-term survival if Ea was low (<2.7 mmHg/mL, the median value). This group had 39.39% in-hospital mortality compared to 14.49% for RAP<15 mmHg (p∼0.005). When Ea was high, this difference in survival was not evident: 8% for RAP<15 mmHg vs 4.8% for RAP>15 mmHg (p∼0.550). This effect was mediated through a lower MPP, and the mortality due to lower MPP increased strikingly with higher body surface area (BSA). A negative correlation was observed between MPP indexed to BSA (MPPI) and the Model for End-Stage Liver Disease score (r∼-0.3580, p<0.0001) as well as creatinine (r∼-0.3551, p<0.0001). MPPI less than 40 mmHg/m2 was associated with poorer short-term (23.2% for MPPI<40 mmHg/m2 vs 7.1% for MPPI>40 mmHg/m2, p∼0.001) and medium-term survival. The impact of high RAP and low Ea on survival was evident even on medium-term follow-up; only 30% survival at 7 years follow-up for high RAP and low Ea vs 75% for RAP<15 mmHg (p∼0.0033). The acceptable blood pressure during vasodilator therapy in patients with high RAP needs to be higher, especially in those with higher BSA. MPPI less than 40 mmHg/m2 is a risk factor for survival, in the short and medium-term, after heart transplantation.

Glaucoma: from pathogenic mechanisms to retinal glial cell response to damage

Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs) leading to visual loss. Degeneration of RGCs and loss of their axons, as well as damage and remodeling of the lamina cribrosa are the main events in the pathogenesis of glaucoma. Different molecular pathways are involved in RGC death, which are triggered and exacerbated as a consequence of a number of risk factors such as elevated intraocular pressure (IOP), age, ocular biomechanics, or low ocular perfusion pressure. Increased IOP is one of the most important risk factors associated with this pathology and the only one for which treatment is currently available, nevertheless, on many cases the progression of the disease continues, despite IOP control. Thus, the IOP elevation is not the only trigger of glaucomatous damage, showing the evidence that other factors can induce RGCs death in this pathology, would be involved in the advance of glaucomatous neurodegeneration. The underlying mechanisms driving the neurodegenerative process in glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress and neuroinflammation. In glaucoma, like as other neurodegenerative disorders, the immune system is involved and immunoregulation is conducted mainly by glial cells, microglia, astrocytes, and Müller cells. The increase in IOP produces the activation of glial cells in the retinal tissue. Chronic activation of glial cells in glaucoma may provoke a proinflammatory state at the retinal level inducing blood retinal barrier disruption and RGCs death. The modulation of the immune response in glaucoma as well as the activation of glial cells constitute an interesting new approach in the treatment of glaucoma.

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evolving from the Post COVID-19 Syndrome.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID-19 Syndrome (PCS). A fraction of the PCS patients develop the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and the expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing the constriction of resistance vessels and of precapillary sphincters, which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis, which is already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of microcirculatory and precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in predisposed patients because the interaction causes a particular kind of perfusion disturbance-capillary ischemia/reperfusion-which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter, in turn, worsens the vascular situation through the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

Mean Ocular Perfusion Pressure Effect During Pars Plana Vitrectomy on the Foveal Avascular Zone: A Pilot Study.

Purpose: To evaluate the effect of mean ocular perfusion pressure on the foveal avascular zone (FAZ) area in eyes with successful retinal detachment (RD) surgery. Methods: This prospective pilot fellow eye-controlled study measured the intraoperative mean ocular perfusion pressure in eyes having surgery for rhegmatogenous RD (RRD). Postoperatively, the FAZ area was measured; the change was calculated as the difference in the FAZ area between the operated eye and the contralateral control eye. Results: The study comprised 8 patients with a mean age (±SD) of 53.38 ± 13.92 years. The mean superficial FAZ area was not different between operated eyes and control eyes, while the deep FAZ area was significantly larger in operated eyes. There was a strong negative correlation between the mean ocular perfusion pressure and the change in the deep FAZ area (Spearman ρ, -0.73; P = .04); the correlation between the mean ocular perfusion pressure and the change in the superficial FAZ area was not significant (Spearman ρ, -0.24; P = .57). A significant linear regression was found between the mean ocular perfusion pressure and the change in the deep FAZ area (R2 = 0.388). The predicted enlargement of the deep FAZ area was 0.03 mm with every 1 mm Hg decrease in the mean ocular perfusion pressure. Conclusions: Lower intraoperative mean ocular perfusion pressure is associated with enlargement of the deep FAZ area in eyes having successful RRD surgery.

Risk factors and macular microvascular changes in open angle glaucoma progression: A longitudinal study using OCT‐A

Aims/Purpose: To investigate prospectively macular microvascular changes in patients with glaucoma and identify common characteristics among the progressive eyes.Methods: A 12‐month prospective longitudinal study was performed with 124 open‐angle‐glaucoma‐eyes (GE). Glaucomatous progression was defined as a decrease of ≥5 μm in average or ≥7 μm in a sector of RNFL thickness. OMAG OCT microangiography (Angioplex, HD OCT, Cirrus 5000, Zeiss) was used to analyse the macular region. The statistical analysis was performed using the SPSS version 23.0 statistical package (SPSS Inc., IL).Results: Among the GE group, 22.36% of eyes showed progression, being the decrease of the Complete Region Macular Vessel Density (MVD) and Macular Capillary Perfusion Density (MPD) greater (−1.14 mm/mm2 and −3.18%) compared to non‐progressive eyes (−0.42 mm/mm2 and −1.02%) [p = 0.123 and 0.057], being the temporal and superior sectors for both MVD and MPD, the ones that showed greater differences (−1.44 mm/mm2, −1.11 mm/mm2, −3.6% and −2.95% respectively) [p &gt; 0.05 for all]. Characteristics as elevated intraocular pressure (IOP) (17.29 vs 14.87 mmHg), thinner central corneal thickness (CCT) (521.53 vs 538.65 μm) and lower ocular perfusion pressure (OPP) (45.88 vs 49.21 mmHg) were significantly different in those progressive GE [p &lt; 0′05 for all]. Nevertheless, increased vertical cup to disc ratio (CDV) (0.64 vs 0.63) and minimum ganglion cell layer thickness (GCLM) (58,82 vs 56.51 μm) were not significantly different in progressive GE [p = 0.768 and 0.249].Conclusions: Data showed that when glaucomatous progression took place, stronger vascular changes occurred in the macular area, as greater decrease of MVD and MPD specially in the temporal and superior sectors. In addition, common characteristics as elevated intraocular pressure, thinner central corneal thickness and lower ocular perfusion pressure were identified in progressive GE. Nevertheless, further research with larger population and larger follow‐up is needed to obtain stronger results.

Risk factors of post-operative optic nerve injury after vitrectomy: a systematic review

Background Vitrectomy is a common procedure used to treat various disorders in the back of the eye. Although it is generally considered safe and effective, there is a risk of complications, including optic nerve damage, which can lead to vision problems. The aim of this study is to determine risk factors of optic nerve injury after vitrectomy for various indications. Methods We conducted a systematic review through literature search via Cochrane, PubMed, Scopus, and Embase, as well as a hand search of relevant journals with the keywords: “(postoperative optic nerve injury) AND (vitrectomy) AND (risk factor)”. The inclusion criteria were: (1) patients with postoperative optic nerve injury after vitrectomy, (2) clinical trial, case-control, or cohort study, (3) analyzing risk factors of optic nerve injury after vitrectomy, (4) published in the last 15 years and conducted in English. For risk of bias assessment, we used the risk of bias (RoB) 2.0 for randomized controlled trials and the ROBINS-E tool for observational studies. Results Thirteen eligible studies were included in this study. We found that damage to the optic nerve can happen either during or after a vitrectomy procedure. This is linked to four main risk factors: removing the internal limiting membrane, having a lower average ocular perfusion pressure, using silicone oil as a tamponade agent, and using ICG as an ILM staining agent. Conclusions Removing the internal limiting membrane, having a lower average ocular perfusion pressure, using silicone oil as a tamponade agent, and using ICG as an ILM staining agent were associated with the occurrence of optic nerve injury following vitrectomy. Our study has limitations, including more retrospective studies than prospective ones and difficulties in combining and analyzing information from individual studies. Additionally, merging data from various studies is challenging due to differences in original research. PROSPERO registration CRD42023453533 (22/08/2023).

Manufacturing and Functional Characterization of Bioengineered Liver Grafts for Extracorporeal Liver Assistance in Acute Liver Failure.

Acute Liver Failure (ALF) is a life-threatening illness characterized by the rapid onset of abnormal liver biochemistries, coagulopathy, and the development of hepatic encephalopathy. Extracorporeal bioengineered liver (BEL) grafts could offer a bridge therapy to transplant or recovery. The present study describes the manufacture of clinical scale BELs created from decellularized porcine-derived liver extracellular matrix seeded entirely with human cells: human umbilical vein endothelial cells (HUVECs) and primary human liver cells (PHLCs). Decellularized scaffolds seeded entirely with human cells were shown to adhere to stringent sterility and safety guidelines and demonstrated increased functionality when compared to grafts seeded with primary porcine liver cells (PPLCs). BELs with PHLCs were able to clear more ammonia than PPLCs and demonstrated lower perfusion pressures during patency testing. Additionally, to determine the full therapeutic potential of BELs seeded with PHLCs, longer culture periods were assessed to address the logistical constraints associated with manufacturing and transporting a product to a patient. The fully humanized BELs were able to retain their function after cold storage simulating a product transport period. Therefore, this study demonstrates the manufacture of bioengineered liver grafts and their potential in the clinical setting as a treatment for ALF.

Low Ocular Perfusion Pressure Values at Rest and during Resistance Exercise in Offspring of Glaucoma Patients.

To compare the ocular perfusion pressure (OPP) response during physical exercise in individuals with and without a family history (FH+, FH-) of glaucoma. Thirty-four subjects, divided into FH+ and FH- groups, realized 3 min at rest, 3 min of isometric handgrip exercise at 30% of maximal voluntary contraction, followed by 3 min of recovery. Blood pressure (Dixtal® automatic device) and intraocular pressure (Goldmann applanation tonometer) were measured during rest, exercise, and recovery. The mean OPP (mOPP) was calculated. In the FH+ group (17 subjects), baseline mOPP values were significantly lower than in the FH- group (17 subjects) (right eye: P < 0.001, left eye: P < 0.001, respectively). During exercise, both the FH+ and FH- groups showed a similar increase in mOPP in both eyes (right eye: FH+: 38 ± 4 mmHg vs. 51 ± 7 mmHg, FH-: 48 ± 5 mmHg vs. 57 ± 9 mmHg, P < 0.001; left eye: FH+: 39 ± 3 mmHg vs. 51 ± 7 mmHg; FH-: 46 ± 5 mmHg vs. 58 ± 8 mmHg, P < 0.001, respectively). However, the FH+ group maintained significantly lower mOPP values compared to the FH- group in the right and left eyes (group effect: P = 0.002, P = 0.002, respectively). The percentage of increase in mOPP in the FH+ group was greater compared to the FH- group during exercise (right eye: 34.1% ± 15.9% vs. 22.1% ± 13.2%, respectively; P = 0.025; left eye: 33.2% ± 17.7% vs. 22.4% ± 13.7%, respectively, P = 0.056). mOPP increased during physical exercise in both groups, but the FH+ group had lower absolute values. In addition, the FH+ group appears to demonstrate a higher percentage increase in mOPP compared to the FH- group.

Effect of 24-h blood pressure dysregulations and reduced ocular perfusion pressure in open-angle glaucoma progression.

Low ocular perfusion pressure (OPP), which depends on the mean arterial pressure (MAP) and intraocular pressure (IOP), is associated with glaucoma. We studied 24-h MAP dysregulations and OPP in relation to the progression of glaucoma damage. We retrospectively analyzed 155 normal-tension glaucoma (NTG) and 110 primary open-angle glaucoma (POAG) patients aged 18 years old followed at the University Hospital Leuven with repeated visual field tests (n = 7000 measures, including both eyes) who underwent 24-h ambulatory blood pressure monitoring. Twenty-four-hour MAP dysregulations were variability independent of the mean (VIM), and the five lowest dips in MAP readings over 24 h. OPP was the difference between 2/3 of the MAP and IOP. Glaucoma progression was the deterioration of the visual field, expressed as decibel (dB) changes in mean deviation analyzed by applying multivariable linear mixed regression models. The mean age was 68 years (53% were women). High 24-h VIMmap was associated with glaucoma progression in POAG (P < 0.001) independently of the 24-h MAP level. The estimated changes in mean deviation in relation to dip MAP measures ranged from -2.84 dB [95% confidence interval (CI) -4.12 to -1.57] to -2.16 dB (95% CI -3.46 to -0.85) in POAG. Reduced OPP along with high variability and dips in MAP resulted in worse mean deviation deterioration. The progression of glaucoma damage associates with repetitive and extreme dips in MAP caused by high variability in MAP throughout 24 h. This progression exacerbates if 24-h MAP dysregulations occur along with reduced OPP.

A topological data analysis study on murine pulmonary arterial trees with pulmonary hypertension

Pulmonary hypertension (PH), defined by a mean pulmonary arterial blood pressure above 20 mmHg in the main pulmonary artery, is a cardiovascular disease impacting the pulmonary vasculature. PH is accompanied by chronic vascular remodeling, wherein vessels become stiffer, large vessels dilate, and smaller vessels constrict. Some types of PH, including hypoxia-induced PH (HPH), also lead to microvascular rarefaction. This study analyzes the change in pulmonary arterial morphometry in the presence of HPH using novel methods from topological data analysis (TDA). We employ persistent homology to quantify arterial morphometry for control and HPH mice characterizing normalized arterial trees extracted from micro-computed tomography (micro-CT) images. We normalize generated trees using three pruning algorithms before comparing the topology of control and HPH trees.This proof-of-concept study shows that the pruning method affects the spatial tree statistics and complexity. We find that HPH trees are stiffer than control trees but have more branches and a higher depth. Relative directional complexities are lower in HPH animals in the right, ventral, and posterior directions. For the radius pruned trees, this difference is more significant at lower perfusion pressures enabling analysis of remodeling of larger vessels. At higher pressures, the arterial networks include more distal vessels. Results show that the right, ventral, and posterior relative directional complexities increase in HPH trees, indicating the remodeling of distal vessels in these directions. Strahler order pruning enables us to generate trees of comparable size, and results, at all pressure, show that HPH trees have lower complexity than the control trees.Our analysis is based on data from 6 animals (3 control and 3 HPH mice), and even though our analysis is performed in a small dataset, this study provides a framework and proof-of-concept for analyzing properties of biological trees using tools from Topological Data Analysis (TDA). Findings derived from this study bring us a step closer to extracting relevant information for quantifying remodeling in HPH.

P80: Adding Intra-Aortic Balloon Pump Counter-Pulsation To Vasodilator Therapy Results In Better Organ Perfusion In Patients With Biventricular Heart Failure Awaiting A Heart Transplant

Background: Significant right ventricular dysfunction with elevated central venous pressure is associated with poor survival in heart failure patients with reduced ejection fraction (HFrEF). Heart transplant is often the only option for this group of patients, as they are not candidates for left ventricular assist device therapy. Medical management of HFrEF involves lowering the systemic afterload with vasodilators. While this therapy is very effective in isolated left ventricular dysfunction, in patients with biventricular dysfunction and high venous pressure, vasodilation can lead to low organ perfusion pressure, resulting in organ dysfunction. Organ perfusion pressure is calculated as the difference between mean arterial pressure and central venous pressure. We hypothesized that combining intra-aortic balloon pump (IABP) counter-pulsation with vasodilator therapy might be a good clinical option for stabilizing these patients while awaiting a heart transplant. Methods: To understand the hemodynamics of vasodilator and IABP therapy in biventricular heart failure, we used a closed-loop multiscale model of the entire cardiovascular system, including a one-dimensional model of the arterial tree coupled with a lumped model of the heart and IABP counter-pulsation. In addition, a baroreceptor model was also used to capture the physiological changes secondary to ventricular dysfunction realistically. Results: Our mathematical model accurately captures the features of the aortic pressure waveform with IABP support (Figure 1) and the hemodynamic consequences of the onset of right ventricular dysfunction (Table 1). Biventricular dysfunction leads to lower cardiac output and organ perfusion pressure when compared with isolated left ventricular dysfunction. Vasodilation during biventricular dysfunction increases the cardiac output but reduces the organ perfusion pressure further. IABP counter-pulsation increases cardiac output along with higher mean arterial pressure and hence higher organ perfusion pressure. The best results are seen when vasodilators are used in conjunction with IABP, where a “sweet spot” of maximal increase in cardiac output with the best possible organ perfusion pressure is obtained, and this combined additive effect of IABP counter-pulsation and vasodilation is also reflected across the renal vasculature (Table 1). Conclusion: Vasodilation with high venous pressure can lead to low organ perfusion pressure and consequent organ dysfunction. Fine-tuning IABP counter-pulsation and vasodilator seems to confer a substantial hemodynamic benefit in this setting.Figure 1. Simulated aortic pressure waveform with IABP support

AVERAGE ACHIEVED BP &lt;130/80 MMHG IN HIGH-RISK MIDDLE-AGED AND OLDER HYPERTENSIVE PATIENTS PROVIDES STRONG CARDIOVASCULAR PROTECTION EXCEPT IN LEFT VENTRICULAR HYPERTROPHY

Objective: Evidence that reducing blood pressure (BP) to &lt;130/80 mmHg rather than to &lt;140/90 mmHg by antihypertensive treatment in hypertensive patients is conflicting. Left ventricular hypertrophy (LVH) is common in hypertension, and low perfusion pressure may result in ischemia in patients with LVH. We investigated whether average achieved BP &lt;130/80 mmHg implied cardiovascular benefits in high-risk middle-aged and older hypertensive patients who participated in the VALUE Trial. Considering a previous report of excess mortality in LVH patients with in-treatment systolic BP (SBP) &lt;130 mmHg, we paid special attention to whether the average achieved SBP &lt;130 mmHg may cause harm in similar patients with LVH. Design and method: Of the 15,245 participants, we identified 13,803 patients without cardiovascular events during the first six months after randomization during which previous medications were discontinued and study drugs up-titrated. Of these, 2,458 patients had LVH on an electrocardiogram (ECG). Cox analyses adjusted for age, gender, and baseline variables compared cardiac and all-cause mortality and other pre-specified endpoints for patients who achieved average SBP 130 - 139 mmHg (No LVH group n = 4,863, ECG LVH group n = 929) and &lt;130 mmHg (No LVH group n = 2,107, ECG LVH group n = 305). Reference groups were patients who achieved an average SBP &gt; = 140 mmHg following the first excluded six months (No LVH group n = 4,375, ECG LVH group n = 1,224). Results: The No LVH group with average achieved BP &lt;130/80 mmHg had a significantly lower incidence of all endpoints except for myocardial infarction. The ECG LVH group with average achieved SBP &lt;130 mmHg had increased cardiac mortality (HR = 1.98, p = 0.032) and all-cause mortality (HR = 1.74, p = 0.007), and SBP &lt;130 mmHg was not associated with a reduction in any endpoint. However, as in those without LVH, the ECG-LVH group had fewer strokes and heart failure with an average achieved diastolic BP &lt;80 mmHg. Conclusions: Our data suggest that target SBP &lt;130 mmHg may cause harm and needs further investigation in middle-aged and older patients with LVH detected by ECG. Otherwise, the average achieved BP &lt;130/80 mmHg prevents most cardiovascular endpoints in middle-aged and older hypertensive patients with high cardiovascular risk but without LVH.

Cerebral Small Vessel Disease in Elderly Patients With Menière's Disease.

Menière's disease (MD) is an inner ear disease characterized by vertigo attacks, progressive hearing loss, tinnitus, and the sensation of aural fullness. Although the exact pathophysiology of MD is unknown, endolymphatic hydrops is considered to be its histopathological hallmark. It has been suggested that endolymphatic hydrops results from lowered perfusion pressure due to cardiovascular comorbidity. Cardiovascular risk factors can cause cerebral small vessel disease (CSVD), visible on MRI. The presence of CSVD in turn raises the risk of developing a stroke. This study aimed to compare the presence of CSVD and cardiovascular risk factors in elderly patients with MD to a control cohort. Patients diagnosed with MD, aged 50 years and older, were retrospectively reviewed and compared with a control cohort. The primary outcome was the difference in CSVD on MRI imaging, which was assessed by the number of white matter hyperintensities using the ordinal Fazekas scale. The secondary outcome was the presence of brain infarctions on MRI. A total of 111 patients with MD were compared with a control cohort of 111 patients. No difference in the degree of white matter hyperintensities (P = 0.890) was found between the MD and control cohort. Brain infarctions were seen in 8 of 111 patients with MD and 14 of 111 patients from the control cohort (P = 0.261). CSVD is not more frequently visible on MRI in elderly patients with MD than in controls. This result does not support hypoperfusion-induced ischemia in the pathophysiology of MD.