Elevated Pressure Research Articles

Effects of elevated intraocular pressure on alpha ganglion cells in experimental glaucoma mice

Glaucoma is a leading cause of blindness worldwide and glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs. Combining some previous published results and some new data, this paper provides our current view on how high IOP (H-IOP) affects the light response sensitivity of a subset of RGCs, the alpha-ganglion cells (αGCs), as well as their presynaptic bipolar cells (DBCs and HBCs) and A2 amacrine cells (AIIACs) in dark-adapted mouse retinas. Our data demonstrate that H-IOP in experimental glaucoma mice significantly decreases light-evoked spike response sensitivity of sONαGCs and sOFFαGCs (i.e., raises thresholds by 1.5–2.5 log units), but not that of the tONαGCs and tOFFαGCs. The sensitivity loss in sONαGCs and sOFFαGCs is mediated by a H-IOP induced suppression of AIIAC response which is caused by a decrease of transmission efficacy of the DBCR→AIIAC synapse. We also provide evidence supporting the hypothesis that BK channels in the A17AC→DBCR feedback synapse are the H-IOP sensor that regulates the DBCR→AIIAC synaptic efficacy, as BK channel blocker IBTX mimics the action of H-IOP. Our results provide useful information for designing strategies for early detection and possible treatments of glaucoma as physiological changes occur before irreversible structural damage.

Elevated mitral valve pressure gradient following transcatheter edge-to-edge repair is independently associated with inferior outcomes in atrial, but not in ventricular secondary mitral regurgitation

Abstract Background In transcatheter mitral valve edge-to-edge repair (M-TEER), the goal of optimizing post-procedural residual mitral regurgitation inadvertently carries the risk of generating relevant mitral stenosis, resulting in an elevated mean mitral valve pressure gradient (MPG). In patients with primary mitral regurgitation, an elevated post-procedural MPG has been found to independently predict impaired outcomes. However, the effect of elevated post-procedural MPG on outcome after M-TEER in patients with secondary mitral regurgitation (SMR) has yet to be fully elucidated. This study investigated the impact of elevated MPG on outcome in the EuroSMR registry, a large, multi-center real-world cohort of patients with SMR. Methods This retrospective study included patients who underwent M-TEER for SMR between 2009 and 2021 in 12 centers. Patients were stratified into two groups based on SMR etiology: (1) ventricular SMR (vSMR), and (2) atrial SMR (aSMR). The etiology was considered as vSMR in patients with a left ventricular ejection fraction (LV-EF) <50% and aSMR in subjects with preserved left ventricular function (LV-EF ≥50%) and a markedly dilated left atrium (Left Atrial Volume Index [LAVi] ≥40ml/m2). According to the proposed M-VARC threshold, post-procedural MPG was assessed by discharge transthoracic echocardiography and was considered elevated if >5 mmHg. The primary endpoint was all-cause mortality after 5 years, with statistical analysis conducted using Kaplan-Meier and uni- and multivariable Cox Regression analysis. Results Among the 1703 patients in the study (vSMR: n=1420; aSMR: n=283), elevated post-procedural MPG was observed in 9.4% (n=133) of vSMR and 19.1% (n=54) of aSMR patients. Atrial fibrillation was significantly more prevalent in aSMR (78.4% vs. 57.1%, p<0.001). Patients with vSMR had a higher median surgical risk assessed by the EuroScore II (aSMR vs. vSMR: 7.0% [IQR 4.0, 13.1] vs. 4.9% [IQR 2.9, 8.5], p<0.001). Kaplan-Meier analyses for all-cause mortality after 5 years demonstrated significant differences in aSMR patients (low vs. elevated MPG: 48.9% vs. 69.8%, log-rank p<0.01), while there was no difference in vSMR patients (55.7% vs. 60.8%, log-rank p=0.66) (Figure 1). This observed effect remained significant even after accounting for common confounding factors: elevated MPG was an independent predictor for all-cause mortality in aSMR patients (HR=1.86; 95%-CI: 1.14-3.02, p=0.013) but not in vSMR patients (HR=1.00; 95%-CI: 0.74-1.35, p=0.99). Conclusion Our findings suggest that elevated post-procedural MPG is an independent predictor of adverse outcomes in patients with aSMR, but not in those with vSMR. This effect may partially be explained by a reduced left atrial function and higher rates of atrial fibrillation.Figure 1.Study flowchart

Impact of adjacent thoracic structures in negative left atrial remodelling in atrial fibrillation

Abstract Background Previous work has suggested that compression from external structures can promote negative atrial remodelling in atrial fibrillation (AF) [1]. This is mechanistically plausible, with many recognised risk factors in developing AF (age, hypertension, obesity, obstructive sleep apnoea, etc.) related through activation of the autonomic nervous system with an associated increase in atrial pressure and chronic elevation in wall stress [2,3]. Such negative remodelling contributes to the existence of arrhythmogenic atrial substrate [4]. This is highly significant when we consider catheter ablation of extrapulmonary vein targets. Purpose This study aims to investigate the relationship between abnormal conduction patterns indicative of potential AF drivers and their proximity to structures adjacent to the left atrium (LA). Methods Eight patients with paroxysmal or persistent AF, scheduled for an elective catheter ablation procedure using a charge density mapping (CDM) system [5] underwent pre-procedural cardiac MRI. 3D surface mesh reconstructions of individuals’ LA and adjacent structures (ascending aorta [AoA], descending aorta [AoD], and spine) were produced from 2D MRI slices using a proprietary graphical interface tool developed in MATLAB (Figure 1A & B) [6]. MRI derived LA geometries were registered with their CDM counterparts by the Iterative Closest Point algorithm (Figure 1C); this enabled integration of MRI LA geometries into the CDM system. Subsequently, non-contact intrachamber voltage measurements from individuals’ procedures were used to derive cardiac activation directly onto MRI LA geometries. Abnormal conduction patterns representing possible AF drivers (focal firing, rotational propagation, and pivoting propagation) [5] were quantified as occurrences per second at each vertex of MRI LA geometries (Figure 1D). These conduction patterns could then be visualised and assessed in the context of adjacent structures (Figure 1E), with the Euclidean distance between each vertex of the MRI LA geometries and the closest point to their adjacent structures being calculated. Results Mean age was 65±9 years; 4 patients (50%) were male; AF was paroxysmal in 3 (37%) and persistent in 5 (63%); median time since AF diagnosis was 1 (1-3.8) years; ablation type was de novo in 5 (63%) and retreatment in 3 (38%). Frequencies of pivoting and rotational propagation were notably higher in regions of the LA closer to the AoA, and lower near the AoD and spine (Figure 2A & B). Conversely, focal firing showed a less prominent trend, being more frequent in LA regions nearer the AoD and distant from the AoA (Figure 2C). Conclusions Compression from the ascending aorta may promote anterior LA remodelling in AF, leading to increased pivoting and rotational AF drivers. Clinically, this suggests a potential target for ablation therapy with an anterior seatbelt line connecting the right superior pulmonary vein to the mitral annulus.

Myocardial injury and heart failure biomarkers in acute intermittent porphyria

Abstract Background Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by the defect in the hydroxymethylbilane synthase gene, encoding the third enzyme in heme biosynthesis pathway. The main symptoms include abdominal pain, vomiting, paralysis, confusion. Exacerbation of AIP may manifest with elevation of blood pressure and tachycardia due to hyperactivity of sympathetic nervous system. Data regarding cardiac function in AIP are scarce. Purpose The aim of this study was to assess the myocardial injury and heart failure biomarkers during AIP exacerbations and remission. Methods This cohort prospective study encompassed patients at the age 18-65 years who had at least one exacerbation of AIP in their lifetime. Patients examined during the AIP exacerbations were reassessed in the remission phase. The concentrations of sodium, troponin T, CK-MB mass, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and metoxycatecholamines in blood were assessed. Blood pressure was measured with 24-hour ABPM. Echocardiography was performed according to the current recommendations. Results The total number of 70 patients with AIP were enrolled to the study (April 2019 - March 2023). We assessed 36 patients in both phases of disease, mean age 37 years (21-63), 75% females. The median of prior AIP exacerbations was 8. During the exacerbations a significant increase in the concentrations of NT-proBNP (250 [97 ; 501] vs. 89 [48 ; 140] pg/mL, p<0.001), metanephrine (49.0 [37.8 ; 61.2] vs. 41.4 [36.8 ; 53.3] pg/mL, p=0.009) and normetanephrine (169.8 [118.2 ; 327.2] vs. 93.2 [78.1 ; 120.9] pg/mL, p<0.001) was observed. Conversely, sodium concentrations decreased (136 [133 ; 140] vs. 140 [139 ; 142] mmol/L, p<0.001). There were no significant differences in the values of troponin (5.4 [4.0 ; 11.3] vs. 5.6 [3.7 ; 9.5] ng/L, p=0.445), CK-MB mass (1.88 [0.84 ; 2.64] vs. 1.21 [0.83 ; 2.80] ng/mL, p=0.80). In the acute phases of AIP the levels of NT-proBNP were correlated negatively with the values of sodium concentrations (r=-0.36, p=0.032) and positively with average systolic blood pressure (r=0.32, p=0.06). Echocardiography showed an increase in left ventricular (LV) mass indices in some patients hospitalized due to AIP symptoms. Sodium concentrations correlated negatively with these changes (r=-0.36, p=0.032). LV ejection fraction was slightly higher during AIP exacerbations. There were no significant differences in other parameters of LV systolic and diastolic function. Conclusions During acute intermittent porphyria (AIP) exacerbations there is an increase in the concentrations of NT-proBNP and catecholamines in blood. In most patients the levels of markers of myocardial injury, such as troponin and CK-MB mass, do not differ significantly between phases of disease. During AIP exacerbations some patients experience an increase in LV mass which may be associated with hyponatremia. In most cases cardiac function do not change significantly.Frequency of abnormal laboratory resultsResults of echocardiography

Health care utilisation in patients with mild pulmonary hypertension - EVIDENCE-PAH UK study

Abstract Background ESC/ERS 2022 guidelines1, redefined precapillary pulmonary hypertension (PH) as patients with a mPAP>20mmHg,PVR>2WU and PAWP<15mmHg1.We and others identified patients with mildly elevated pulmonary artery(PA) pressures demonstrates a higher mortality2-4. It is important to understand healthcare resource utilisation(HRCU) in this newly defined group who now meet the thresholds for diagnosis, however, treatment options are limited. Purpose The EVIDENCE-PAH aims to describe mortality and hospitalisation outcomes, baseline demographics in mild elevations in PA pressure in a national cohort. We report preliminary analysis of HRCU from data obtained from NHS Hospital Episode Statistics(HES); inpatient admissions, outpatient(OP) and emergency attendances(AE). Method Retrospective analysis of all patients with a mPAP<25mmHg and a sample of patients with a mPAP≥25mmHg at index-right heart catheterisation(RHC), across all UK PH tertiary centres between 2009-2017 with hospitalisation data captured 24-months pre and post index-RHC. For analysis patients were categorised into 3 groups; normal haemodynamics(mPAP<21mmHg & PVR≤2WU), mild elevation in haemodynamics(mPAP<21mmHg & PVR>2WU, mPAP21-24mmHg with all PVR groups, mPAP>25mmHg & PVR≤3WU) and abnormal haemodynamics(mPAP>25mmHg & PVR>3WU). Results A total of 2413(82.3%) patients had complete records 24-months pre and post index-RHC; 561(23.2%), 1228(50.9%) and 624(25.9%) in the normal haemodynamic, mildly elevated haemodynamic and abnormal haemodynamic groups respectively. Figure 1, demonstrates HRCU; Unscheduled admissions are significantly higher in the abnormal haemodynamic group 24-months pre index-RHC compared to the normal/mild elevations in haemodynamic groups (p-value<0.05). There was reduction in unscheduled encounters 24-months post index-RHC in the normal/abnormal haemodynamic group. No significant difference identified in AE attendance and OP 24-months post across all haemodynamic groups. Total HRCU demonstrates a lower attendance 24-months post RHC in normal versus abnormal haemodynamic group (p-value<0.05). Multivariate analysis demonstrates unscheduled admissions 24-months pre/post index RHC, as an independent predictor of survival, adjusted for age, sex and haemodynamics (Figure 2;p-value<0.05). Conclusion Unscheduled admissions may act as a discriminator identifying advanced PH (abnormal haemodynamics), but not normal versus mild elevations in haemodynamics. Meanwhile AE and OP attendances fails to discriminate between normal and mild elevation in haemodynamics. Unscheduled admissions 24-months pre/post index RHC is an independent predictor of survival which may lend as a useful surrogate marker for mortality in the PH population as a whole. Although total HRCU appears high across haemodynamics groups referred to PH centre, in the 24-months post RHC HRCU increases in the mild/abnormal haemodynamic groups, this may represent ongoing unmet need in this group.

Hospital and one-year outcomes following a hypertensive urgency or emergency: a major challenge

Abstract Introduction Hypertension is an important issue, and recommendations are constantly evolving based on the latest research findings and directions. Hypertensive emergencies are defined as a severe elevation of blood pressure associated with organ damage. End organ damage was defined as the presence of one of the following findings: encephalopathy, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, acute heart failure, acute coronary syndrome, or aortic dissection. Furthermore, malignant hypertension is a HE characterized by small artery fibrinoid necrosis in the kidney, retina and brain. All these definitions are confusing, but what about their evolution? Objective:The present study aims to analyze the mortality in the short and long term (12months), the survival of the hypertensive patients, the frequency of malignant hypertension and hypertensive retinopathy. Methods For this purpose, we conducted a prospective study including all patients who followed or were diagnosed with hypertension and admitted to the emergency department for hypertensive urgency/emergency, from January to March 2023; after that, we studied the evolution of these patients for one year until January 2024. Demographic data, disease history, blood pressure, clinical presentation on admission, target organ involvement, ophthalmological examination and evolution during hospitalization were studied. Statistical analysis was performed using SPSS software. Preeclampsia and chronic renal failure were excluded.Result: Our work brought together 300 patients, mainly female, with an average age of 63.4. One hundred fifteen were admitted for HE and 185 for HU. The most common presenting symptoms at admission were headache, focal neurologic deficit and dyspnea. Malignant hypertension was identified in 9 patients based on optical coherence tomography angiography by identifying subclinical microvascular damage, and investigation is still in progress searching for hypertensive retinopathy grade III-IV Keith-Wagner in the second group. Patients were mainly hospitalized for hypertensive emergencies. Regarding their therapeutic management, except for the acute lowering of blood pressure in stroke, there was no consensus initially; ideally was to determine which organs are affected to assess the need for specific intervention other than lowering blood pressure. Overall, 49 had died from HE n=44/115(vs n=5/185 for HU). Of these, 33 have died at the Hospital (mortality was higher for HE and attributable to neurovascular emergencies rather than cardiovascular emergencies) and ten at 12 months. Conclusion Properly managing patients who come to the Emergency Department for BP elevation faces many difficulties. Can we still talk about hypertensive emergencies/urgency, discuss retinal lesions, and the importance of hypertension monitoring? However, all those definitions can be potentially life-threatening; these results justify better follow-up and treatment for these patients.

Right ventricular myocardial work in heart failure with preserved ejection fraction: insights from invasive cardiopulmonary exercise testing

Abstract Backgrounds Symptoms of heart failure with preserved ejection fraction (HFpEF) is closely related to elevated pulmonary capillary wedge pressure (PCWP) during exercise. The understanding of right ventricle myocardial work, assessing of right ventricular (RV) function utilizing RV pressure–strain loops, in HFpEF is lacking. Methods The study population underwent invasive cardiopulmonary exercise tests, measuring pressures at rest and during exercise to identify HFpEF. Echocardiography assessed LV and RV parameters. Right ventricular myocardial work was calculated using strain-rate and pressure curves, matching them with ECG data. RV global constructive work (RVGCW), RV global work index (RVGWI), RV global wasted work (RVGWW), and RV global work efficiency (RVGWE) were analysed and compared with invasively measured PCWP at resting and peak exercise. Results Between November 2017 and July 2023, 41 patients with adequate data were enrolled, and 21 were diagnosed with HFpEF. There were no significant differences in various echocardiographic parameters between HFpEF and non-HFpEF groups, except higher post-exercise PCWP and mean pulmonary artery pressure. HFpEF patients had higher RVGWW and lower RVGWE. RVGWW and RVGWE had higher predictive ability for HFpEF diagnosis compared to other echocardiographic parameters. While RVGCW (r = 0.0.504, P = 0.001 and r = 0.430, P = 0.006, respectively) and RVGWW correlated (r = 0.408, P = 0.008 and r = 0.621, P <0.001, respectively) with post-exercise ∆PCWP and exercise PCWP, only RVGWW (β=1.981, P=0.044 and β=4.323, p<0.001) being independently associated with both after adjustment for confounding factors. Conclusions RVGWW is a novel parameter that provides an integrative analysis of RV systolic function and correlates more closely with post-exercise ∆PCWP than other standard echocardiographic parameters in HFpEF.

Invasive haemodynamic assessment shows the obesity-HFpEF phenotype is common amongst patients with symptomatic AF

Abstract Background The obesity-HFpEF phenotype is a unique form of heart failure associated with elevated LA and RA pressures, cardiac remodelling and poor exercise capacity. The influence of this HFpEF phenotype amongst patients with AF is unknown. Objective We sought to determine the influence of the obesity-HFpEF phenotype amongst patients with symptomatic AF, using invasive testing, imaging and cardiopulmonary exercise testing to assess haemodynamics, cardiac remodelling and exercise capacity in patients undergoing AF ablation. Methods Consecutive patients with symptomatic AF due to undergo an AF ablation procedure were recruited. Participants were grouped according to the presence of obesity if body mass index (BMI) exceeded 30kg/m2. Mean LA pressure (mLAP) and mean RA pressure (mRAP) were measured invasively at AF ablation and HFpEF was defined as mLAP>15mmHg at rest or after infusion of 500mls saline. Cardiac remodelling was assessed using transthoracic echocardiography. Exercise capacity was evaluated using cardiopulmonary exercise testing and AF symptoms and quality of life were assessed using the AF Symptom Severity Questionnaire. Results Of 120 participants, 44 (36.7%) were obese and 76 (63.3%) were non-obese (Table 1). Despite younger age (p=0.003), obese participants were more likely to have a coexistent diagnosis of HFpEF (84.1% vs 67.1%, p=0.043). In addition to higher mLAP (p<0.001), obesity was associated with higher mRAP (p<0.001) compared to non-obese patients. Obesity was not associated with differences in LV volume (p=0.559) or function (p=0.381) but was associated with larger LA volumes (p=0.032). On functional assessment, obese participants demonstrated a higher burden of AF symptoms (p=0.049), poorer quality of life (p=0.017) and a trend towards reduced exercise capacity (p=0.068). Conclusion Obese patients with AF demonstrate characteristic features of the obesity-HFpEF phenotype, including elevated LA and RA pressure, left atrial enlargement and poorer functional capacity. Novel treatments for the obesity-HFpEF phenotype, such as GLP-1 inhibitors, may be useful in obese patients with AF.

Coronary microvascular dysfunction in heart failure: observations from the MICRO registry

Abstract Background Heart failure (HF) is one of the leading causes of hospitalization in the elderly. Coronary microvascular dysfunction (CMD), among other risk factors, is linked to the pathogenesis and clinical manifestations of HF. Purpose This abstract aims to summarize key findings from a comprehensive analysis of CMD in subgroups of HF, shedding light on its association with hemodynamic parameters. Methods Patients experiencing recurrent angina (CCS II-IV) and no relevant epicardial stenosis were enrolled in a prospective registry (MICRO). Epicardial and microvascular responses (pressure, resistance and flow) were assessed at rest and during adenosine and acetylcholine testing. The impact of an elevated left ventricular end-diastolic pressure (LVEDP) in the absence of clinical signs of HF was also investigated. Results Overall, 188 patients (63% (118) women, mean age 65±11 years) with angina and no epicardial stenosis were enrolled. Patients with HF (n=26) displayed lower hyperemic flow in response to endothelium-independent adenosine (5.2±3.1 vs. 7.3±4.4; P=0.004), lower coronary flow reserve (2.9±1.5 vs. 4.4±1.1; P<0.001) and microvascular resistance reserve (3.3±2.1 vs. 5.2±2.7; P<0.001), and increased microvascular resistance during adenosine-induced hyperemia (25±21 vs. 17±11; P=0.045). An increased LVEDP without clinical signs of HF was not associated with a lower coronary flow reserve (4.3±1.9 vs. 2.6±1.2; P=0.006) or microvascular resistance reserve (4.9±2.1 vs. 2.8±1.7; P=0.004). Microvascular resistance during acetylcholine (endothelium-dependent)-induced hyperemia was lower in HF patients (36.2±23.5 vs. 57.4±37.8; P=0.018). Conclusion(s) Patients with heart failure displayed signs of impaired microvascular endothelium-independent responses while endothelium-dependent reactivity appears to be maintained. An elevated LVEDP without clinical HF was not associated with impaired coronary microvascular function.

Long-acting CRF2 receptor agonist COR-1389 improves cardiopulmonary function parameters in monocrotaline-induced pulmonary hypertension and right heart failure rat model

Abstract Background Pulmonary hypertension (PH) associated with right heart failure (RHF) poses a significant therapeutic challenge. Short term studies have shown that urocortin-2 (UCN-2) administration, either intravenously or subcutaneously, can ameliorate cardiac and/or pulmonary parameters in human heart failure (HF) and in animal models of PH and RHF. Purpose This study aimed to evaluate the potential benefits of COR-1389, a long-acting CRF2 receptor agonist, on cardiopulmonary function and adverse remodeling in a rat model of monocrotaline (MCT)-induced PH and RHF. Method Monocrotaline (40 mg/kg) was administered subcutaneously in rats on Day-0 to induce PH and RHF, while the control group received vehicle. After 14 days, MCT-injected rats were evenly allocated into two groups based on echocardiography parameters of accelerated time/ejection time ratio and tricuspid annular plane systolic excursion (TAPSE), before receiving either COR-1389 (100 ug/kg) or its vehicle subcutaneously every 4 days for 14 days. On Day-28, echocardiography was repeated in all groups, followed by right heart catheterization to directly measure pulmonary hemodynamics. Heart and lung samples were prepared for histological analysis. Results By Day-28, MCT-treated rats exhibited significantly elevated mean pulmonary arterial pressure (mPAP) and right ventricular (RV) mass (Fulton Index/BW), along with decreased RV function (increased TAPSE) and reduced cardiac output (CO) compared to control rats. These changes were accompanied by severe tissue remodeling, including increased vascular muscularization (alpha-smooth muscle actin content) and pulmonary arterial wall thickening, RV fibrosis, and cardiomyocyte hypertrophy. Following 14 days of curative treatment, MCT+COR-1389 compared to MCT, significantly decreased mPAP and RV mass (Fulton Index/BW), while RV function improved (reduced TAPSE) and CO was increased. Moreover, COR-1389 attenuated adverse pulmonary vascular remodeling (reduced muscularization and arterial wall thickening), RV fibrosis, and cardiomyocyte hypertrophy, consistent with its hemodynamic effects. Conclusions Chronic CRF2 agonism with COR-1389 improved dysregulated cardiac and pulmonary function and structure in the MCT rat model, suggesting its potential for the treatment of PH and RHF.

The safety and efficacy of treprostinil for the treatment of pulmonary arterial hypertension: a systematic review and meta-analysis of randomized controlled trials

Abstract Introduction Pulmonary arterial hypertension (PAH) is a severe and life-threatening condition characterized by increased pulmonary vascular resistance and elevated mean pulmonary artery pressure. Treprostinil, a prostacyclin analog, has vasodilatory and anti-remodeling effects on pulmonary arterial smooth muscle cells, indicating promising benefits in enhancing exercise capacity, improving hemodynamics, and reducing morbidity in patients with PAH. Aim The primary objective of this systematic review and Meta-analysis is to assess the efficacy and safety of Treprostinil in patients with PAH. Methods We systematically searched PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov from inception until July 2023. Randomized controlled trials comparing Treprostinil with Placebo were selected. We used the mean values to compare continuous data and odds ratio (OR) for dichotomous outcomes with their 95% confidence interval (CI). Results We included 7 studies with a total of 2,447 patients. The Treprostinil group was favored over the control group in terms of 6-minute walk distance (6MWD) (Mean difference (MD), meters (m)) (MD = 15.16 m, 95% confidence interval (CI) (10.42 – 19.90 )). Subgroup analysis based on the route of administration revealed a 6MWD of (MD = 13.55 m (95% CI (7.82 – 19.28)) for oral administration and (MD = 17.49 m, 95% CI (6.01 – 28.89)) for intravenous (IV)/subcutaneous (SC) administration, indicating enhanced exercise capacity. When evaluating the efficacy of Treprostinil for oral administration, there was a slight but non-significant trend toward functional improvement (Odds Ratio (OR): 1.36; 95% CI: 0.95 to 1.93) and no significant change in maintaining functional status (OR: 0.94; 95% CI: 0.59 to 1.51). In terms of functional deterioration, the risk was also not significantly reduced (OR: 0.84; 95% CI: 0.36 to 1.98). Safety assessment of the drug was based on clinical, mortality, and adverse events outcomes. Clinically, Treprostinil demonstrated a protective effect against disease progression, evidenced by a reduced risk of clinical worsening (OR: 0.69; 95% CI: 0.52 to 0.91). Mortality rates were not significantly impacted by Treprostinil addition (OR: 0.95; 95% CI: 0.57 to 1.58 for oral, 0.80; 95% CI: 0.32 to 1.98 for IV/SC). However, the incidence of adverse events was notably higher among Treprostinil-treated patients, particularly with oral administration. Conclusion The addition of Treprostinil therapy for patients with PAH significantly improved exercise capacity, as evidenced by an increase in the 6MWD compared to control groups and demonstrated a reduced risk of clinical worsening. The incidence of adverse events was higher among Treprostinil-treated patients, especially with oral administration, potentially impacting quality of life.Forest plot of the 6MWD

Prognosis in patients with residual pulmonary hypertension after transcatheter edge-to-edge repair for secondary mitral regurgitation

Abstract Background Pulmonary hypertension (PH) is an independent prognostic predictor in patients with heart failure (HF). Recently, transcatheter edge-to-edge repair (TEER) for secondary mitral regurgitation (MR) has been reported to reduce HF hospitalizations and mortality. Elevated pulmonary artery pressure (PAP) before TEER is associated with a poor prognosis; however, the impact of residual PH after TEER on clinical events has not been investigated. Purpose The purpose of this study is to clarify whether residual PH influences outcomes in patients with HF treated by TEER for secondary MR. Methods We included 63 patients who underwent TEER for severe secondary MR and post-procedural right heart catheterization in our institute from January 2016 to August 2023. Mean PAP after TEER was categorized as increased (>20mmHg) versus not increased (≤20mmHg), and we investigated the clinical outcomes between the two groups. The primary endpoint is a composite outcome of all-cause mortality and HF hospitalization. Results Among 63 patients, the average age was 78 years, and 60.3% were male. All patients had Secondary MR, and 52 patients (82.6%) had ventricular Secondary MR—right heart catheterization after TEER revealed a mean PAP of 21.6±7.7 mmHg, pulmonary vascular resistance (PVR) of 2.7±1.4 wood unit (WU), and pulmonary artery wedge pressure (PAWP) of 12.2±5.9 mmHg. Patients with residual PH had higher composite outcome rates of death from any cause or HF hospitalization compared to those without PH (56.1% vs. 19.5%; hazard ratio: 2.62; 95% confidence interval: 1.1 to 6.9; p=0.03). Multivariate Cox regression analysis showed that residual PH and higher PAWP after TEER were associated with higher mortality (hazard ratio: 1.14; 95% confidence interval: 1.03 to 1.28; p=0.01). Conclusion Our results suggest that patients with residual PH after TEER have a poor prognosis. Residual PH and high PAWP after TEER are associated with mortality.

Clinical utility of fibrosis-4 index in predicting increased right atrial pressure

Abstract Introduction Fibrosis-4 (FIB-4) index, derived from serum aspartate transaminase, alanine aminotransferase, platelet count and age, is an easily measurable marker reflecting hepatic fibrosis. Recently, FIB-4 index has been reported to be associated with cardiac events in heart failure (HF) patients. We examined whether FIB-4 index was useful in predicting elevated right atrial pressure (RAP) in comparison with directly measured RAP. Methods We studied consecutive 293 HF patients who underwent right heart catheter (RHC) examinations at our institution between Sep 2021 and May 2023. The exclusion criteria were as follows: viral or metabolic chronic hepatic diseases, thrombocytopenia. The subjects received RHC examination and blood test on the same day, and echocardiography within 3 days from the RHC examination. On top of FIB-4 index, diameter of inferior vena cava (IVC) and its respiratory changes were measured as a conventional method to estimate RAP. Results A total of 252 patients (mean 64.7 years of age, 52.8% men) were eligible for this study. FIB-4 index was significantly correlated with mean RAP (r = 0.39, p < 0.001). ROC curve analysis revealed that 1.80 was the optimal cutoff value of FIB-4 index to predict increased RAP > 10mmHg (AUC 0.74, p < 0.001, sensitivity 76.1%, specificity 74.0%). As shown in Figure, the diagnostic accuracy increased when FIB-4 index was combined with IVC diameter (AUC 0.77), which was significantly higher than the combination (AUC 0.71) of IVC diameter alone (AUC 0.71, p < 0.001, cutoff 17mm, sensitivity 67.6%, specificity 71.8%) and IVC respiratory changes alone (AUC 0.61, p = 0.005, cutoff 53%, sensitivity 77.5%, specificity 44.2%). Conclusions FIB-4 index was clinically useful in predicting increased RAP, especially when it was combined with IVC diameter.

A propensity score matched analysis of transcatheter aortic valve replacement in failed bioprosthetic valves

Abstract Introduction While recently published data indicate similar long-term results of transcatheter aortic valve replacement (TAVR) compared to surgical procedures, surgical aortic valve replacement (SAVR) remains the standard of care in low-risk patients. However, since life expectancy increases, a non-negligible number of patients experience bioprosthetic valve dysfunction with the need for reintervention, but long-term data of TAVR in failed bioprosthetic valves is scarce. Purpose The aim of the study was to analyse long-term data of patients with TAVR in failed bioprosthetic valves compared to patients with native valve TAVR. The primary endpoint was 6-year all-cause mortality and the main secondary endpoint was echocardiographic valve function. Methods Patients undergoing TAVR for severe aortic valve disease between December 2012 and December 2020 were retrospectively analysed. Prior TAVR or aortic valve homografts led to exclusion from the study. A 2:1 propensity score matching by the optimal neighbor matching algorithm was performed to overcome differences in baseline characteristics. Results Between December 2012 and December 2020, 3,423 patients received TAVR for severe aortic valve disease and met inclusion criteria for the study. Of those, 3,287 patients underwent native valve TAVR, whereas 136 patients experienced bioprosthetic valve dysfunction and were treated with TAVR-in-SAV. After 2:1 propensity score matching, baseline characteristics without any relation to prior SAVR were similar between both groups. Concerning postprocedural echocardiographic function, a less pronounced gradient reduction (57.0 vs. 71.0 %, p < 0.01, Figure 1) and a higher number of patients with elevated mean pressure gradient > 20 mmHg could be found after prior SAVR (19.4 vs. 3.0 %, p < 0.01). However, there was no difference regarding 6-year all-cause mortality between both groups (log rank test p = 0.8, Figure 2). Conclusions Besides a less pronounced gradient reduction and higher mean aortic pressure gradients after TAVR-in-SAV compared to patients with native valve TAVR, no differences in 6-year all-cause mortality could be observed in a propensity score matched analysis.Reduction of mean pressure gradient6-year all-cause mortality

Right ventricular outflow tract arrhythmias in patients with obstructive sleep apnea- electrophysiological insights

Abstract Background Obstructive sleep apnea (OSA) was associated with atrial fibrillation and heart failure. Furthermore, the arrhythmic sudden death during sleep in patients with OSA raises serious concerns. Non-ischemic ventricular arrhythmias arise frequently from the right ventricular outflow tract (RVOT). The involvement of obstructive sleep apnea in the genesis of arrhythmia (premature ventricular contraction or tachycardia) originating specifically in the RVOT is not yet coherently established. Purpose This study aims to demonstrate the possible relationship between untreated obstructive sleep apnea and the occurrence of RVOT arrhythmia and to follow the electrophysiological features and outcomes after radiofrequency catheter ablation (RFA) in patients carrying this double burden. Methods One-hundred-twelve (112) consecutive asymptomatic and symptomatic patients admitted with RVOT arrhythmia ((PVCs and VTs) underwent a sleep study (polysomnography). Apnea was set out as the cessation of breathing and hypopnea was defined as shallow, slow, and restricted breathing occurring in episodes of ten seconds or more. The patients had normal left and right ventricle ejection fractions and no structural cardiovascular disease or other known extracardiac arrhythmia predisposing conditions. No significantly elevated systolic pressure in the pulmonary artery was assessed at echocardiography. Every patient was investigated by electrophysiologic study (EPS) and RFA of the clinical ventricular arrhythmia was immediately performed. Practicing and former professional athletes were excluded. Results Seventy-eight (69 %) of the included patients had an apnea-hypopnea index > 10/h. The included patients had the following characteristics: mean age 52 ± 8 years, 62% males, 81% had a BMI >30kg/m². The cardiac electrophysiologic study did not induce sustained VTs. The distribution of the PVCs and non-sustained VTs evidenced a predilection for the superior, septal and anterior (68%) and also superior and anterolateral aspects of the RVOT (23%). Radiofrequency catheter ablation (RFA) guided by activation mapping, precocity (the site of earliest activation > 30 ms before the setting of the QRS complex) and pace-mapping were performed in all patients. Immediate success was obtained in 98 patients (88%). After a mean follow-up of 24± 6 months, 28 patients (28%) from the success arm had a recurrence of the PVCs or the non-sustained VTs, 22 patients (22%) with and 6 patients (6%) without sleep apnea. Conclusions RVOT arrhythmia genesis and relapse after successful RFA seem highly associated with sleep apnea. Furthermore, patients with sleep apnea are more prone to have recurrent arrhythmias after radiofrequency catheter ablation in the absence of appropriate control of OSA.

LA reservoir strain predicts elevated left atrial pressure in patients with Veno-Arterial (VA) extracorporeal membrane oxygenator (ECMO) support for cardiogenic shock

Abstract Background Veno-arterial (VA) extracorporeal membrane oxygenator (ECMO) is not a left ventricular (LV) support system as it increases aortic pressure and LV afterload due to retrograde blood flow in the aorta. This can lead to complications such as increased LV volume (LV distention), increased LV and left atrial (LA) pressures, and pulmonary edema. We sought to investigate the correlation between LA strain and invasive LA pressure (LAP) in patients with ECMO support for cardiogenic shock undergoing atrial septostomy with stenting. Methods and Results A total of 24 consecutive patients (52±20 years; 83% were male) undergoing atrial septostomy with stenting while being on ECMO support for cardiogenic shock for left heart decompression were analyzed. LAP was measured immediately after transeptal puncture and before deployment of interatrial septal stent. A comprehensive echocardiogram was performed in all patients prior to atrial septostomy. Median time difference between echocardiogram and LAP measurement was 3.5 (0.5-20) hours. LA strain analysis was performed using the TomTec Arena 2D-cardiac performance analysis (CPA) software. LA reservoir strain was measured at peak systole during the reservoir phase in a single apical 4-chamber view. Intraclass correlation coefficients between 2 different investigators were excellent (All> 0.95). Median LA reservoir strain and LAP were 3.2 (0.5-1) % and 23 (8-53) mmHg, respectively. LA reservoir strain significantly correlated with LAP (r=0.53, p=0.034). LA reservoir strain of < 1.5% can effectively predict markedly elevated LAP (LA> 30 mmHg) (OR =9.9, p =0.0016). Conclusions LA reservoir strain significantly correlated with invasive LAP. With the advent of strain imaging software, LA reservoir strain is a feasible, reproducible, noninvasive, and straightforward method to predict the need for left heart decompression and/or to guide optimal afterload management in patients with VA-ECMO for cardiogenic shock. Further a prospective simultaneous echocardiographic and invasive LAP study is needed.

Development of a minimally invasive technique to measure the interstitial fluid pressure for remote monitoring of heart failure

Abstract Background Heart failure (HF) induces fluid interstitial retention, leading to oedema and elevated interstitial fluid pressure (IFP).1-3 There is a clinical need for remotely assessing IFP and understanding its correlation with cardiopulmonary haemodynamics for early treatment optimization in HF. IFP can be measured from a preserved fluid pocket formed by a subcutaneous perforated capsule in animals.4 However, the structural understanding of tissue neovascularization within a perforated capsule and the temporal relationship between altered cardiopulmonary haemodynamics and IFP remains unknown. Purpose To determine the neovascularisation of the perforated capsule over time and demonstrate the relationship between haemodynamic metrics of congestion (CVP, PAP, and LVEDP) and IFP during HF development. Methods Ten 45-55kg swine were implanted with subcutaneous perforated capsules. Perforated capsule characterisation included MicroCT using MicroFil cast (Fig. 1A) and microscopy initially at 3 and 6 weeks. A perforated capsule containing a PTFE (polytetrafluoroethylene) membrane was subcutaneously implanted in animals and chronic stability was studied at 90 using MicroCT and microscopy. After 3 weeks of perforated capsule implantation, HF was induced under general anaesthesia with 12-16 mg/kg/hour of esmolol (i.v.) and 0.9% NaCl (10% body weight, i.v.) and fluid was removed to euvolemia via ultrafiltration (Fig 2A). Concurrent measurements of IFP from perforated capsules and haemodynamic metrics of congestion were made using interventional techniques. Results MicroCT and microscopy have demonstrated perforated capsule neovascularization containing a central fluid pocket at 3 weeks and loss at 6 weeks due to continued tissue growth (Fig 1B-E). The perforated capsule at 90 days demonstrated fluid pocket preservation due to the PTFE membrane on MicroCT and microscopy (Fig. 1F-G). During the development of HF and offloading, there is a strong correlation between IFP and haemodynamic metrics of congestion (Fig. 2B). Conclusion We have developed a minimally invasive technique for continuous IFP measurement demonstrating a relationship between IFP and cardiac filling pressure in HF. IFP assessment offers a direct measure of fluid status and an indirect measure of haemodynamics, facilitating early treatment optimisation.

Use of extracorporeal membrane oxygenation during a decompressive hemicraniectomy for severe traumatic brain injury: illustrative case.

Decompressive hemicraniectomy (DHC) can be a life-saving treatment for patients with severe traumatic brain injury (TBI) with a focal mass lesion who develop refractory elevated intracranial pressure (ICP). Nonetheless, successful completion of this procedure requires maintaining hemodynamic and respiratory stability. Extracorporeal membrane oxygenation (ECMO) use in patients with respiratory or cardiac failure is well described in the literature and has become routinely used in patients with refractory hypoxia unresponsive to traditional mechanical ventilation strategies, but few cases of its use have been reported in the neurosurgical literature. Herein, the authors describe a unique case in which a man presented after an unwitnessed fall that caused severe TBI without a focal mass lesion. The patient subsequently developed medically refractory elevated ICP secondary to traumatic cerebral edema. He required DHC, but the procedure could only be completed safely with the utilization of intraoperative ECMO. As more is learned about the techniques and pitfalls of ECMO, its indications are rapidly expanding. The case presented describes the safe use of ECMO during a major neurosurgical procedure, showing that the technique can be completed safely and offering a therapeutic option for effectively addressing refractory hypoxia and hypercarbia in patients with severe TBI who require urgent or emergency neurosurgical procedures. https://thejns.org/doi/10.3171/CASE24264.

Ion Channel Piezo1 Induces Ferroptosis of Trabecular Meshwork Cells: A Novel Observation in the Pathogenesis in Primary Open Angle Glaucoma.

This study aims to elucidate the role of Piezo1, a mechanosensitive molecule, in trabecular meshwork cells (TMCs) in the context of Primary Open Angle Glaucoma (POAG), a leading cause of irreversible visual impairment. Dysfunction of the trabecular meshwork (TM) is a key factor in the elevated intraocular pressure (IOP) observed in POAG, yet the specific mechanisms leading to TM dysfunction are not fully understood. We performed cell stretching on human trabecular meshwork cells (HTMCs) and pharmacologically activated HTMCs with Yoda1 to study the role of Piezo1 in HTMCs. We focused on assessing cell viability, mitochondrial changes, lipid peroxidation, and the expression of ferroptosis-related targets such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). Cell stretching induces ferroptosis in HTMCs, and this phenomenon is reversed by Piezo1 knockdown. Additionally, pharmacological activation of Piezo1 also leads to ferroptosis in HTMCs. Furthermore, inhibiting the JNK/p38 signaling pathway was found to mitigate the ferroptotic response induced by Yoda1, thereby confirming that Piezo1 induces ferroptosis in TMCs through this pathway. Notably, our experiments suggest that Yoda1 may trigger ferroptosis in the TM of mouse eyes. Our findings demonstrate that the Piezo1 pathway is a crucial mediator of ferroptosis in TMCs, providing new insights into the pathogenic mechanisms of glaucoma, particularly POAG. This study highlights the potential of targeting the Piezo1 pathway as a therapeutic approach for mitigating TM dysfunction and managing POAG.

Seasonal Changes in Salicylic and Jasmonic Acid Levels in Poplar with Differing Stress Responses

Poplars are essential tree species with critical roles in wood production, ecological conservation, environmental protection, and climate change mitigation. Plants of different poplar populations exhibit varying responses to biotic and abiotic stresses, largely driven by phytohormones—key regulators of plant growth and stress responses. Phytohormones control fundamental processes such as cell division, growth, tissue differentiation, organ development, and resistance to environmental challenges such as temperature extremes and drought. In this study, we conducted a quantitative analysis of phytohormone levels in the leaves of two populations of poplar species from the same geographical region over a one-year period, covering the early, mid, and late growth stages. Our results revealed that salicylic acid (SA) and jasmonic acid (JA) concentrations in the stress-resistant poplar (RP) increased significantly during the late growth stage (September), particularly in response to elevated pathogen pressure and fluctuating climatic conditions. In contrast, the susceptible poplar (SP) consistently exhibited lower levels of SA and JA across all growth stages, particularly during the mid-growth stage (characterized by high temperatures and low precipitation) and the late growth stage, when pathogen stress typically intensifies. The limited increase in phytohormone levels in the SP suggests a weaker defense response compared with the RP. These findings demonstrate that climatic factors significantly influence the phytohormonal dynamics in poplars, with the RP exhibiting more robust regulation of SA and JA to mitigate both biotic and abiotic stresses. This study provides a theoretical framework for better understanding the resistance mechanisms in Populus and offers insights for improving stress tolerance in future breeding programs.