Hemodynamic Measurements Research Articles

The effect of NHFOV on hemodynamics in mild and moderately preterm neonates: a randomized clinical trial

The aim of this study is to study cardio-respiratory effects of nasal high-frequency oscillatory ventilation (NHFOV) vs. NCPAP as an initial mode of ventilation in moderate-late-preterm infants. A randomized controlled trial was conducted in NICU of Alexandria University Maternity Hospital (AUMH). One-hundred late-moderate-preterm infants were randomly assigned to either NHFOV-group (n = 50) or NCPAP-group (n = 50). For both groups, functional echocardiography was performed in the first 24 h to detect hemodynamic changes and respiratory outcome was monitored throughout the hospital stay. The main outcomes were hemodynamic measurements and myocardial function using functional echocardiography of those infants along with the respiratory outcome and complications. Kaplan–Meier survival plot was used representing time course of NCPAP and NHFOV failure. Left ventricular output values were not significantly different in both groups with median 202 ml/kg /min and IQR (176–275) in NCPAP-group and 226 ml/kg/min with IQR (181–286) in NHFOV group. Nevertheless, ejection fraction and fractional shortening were significantly higher in NHFOV-group with P 0.001. The time to weaning, the time to reach 30%-FIO2, the need for invasive ventilation, oxygen support duration, and maximal-FIO2 were significantly more in NCAPAP group. Conclusion: NHFOV is an effective and promising tool of non-invasive-ventilation which can be used as a primary modality of respiratory support in preterm infants with variable forms of respiratory distress syndrome without causing detrimental effect on hemodynamics or significant respiratory complications. Trial registration: NCT05706428 (registered on January 21, 2023).What is Known:• NHFOV might be beneficial as a secondary mode of ventilation and might have an impact on hemodynamics.What is New:• NHFOV can be used as an initial mode of ventilation with CDP beyond the reported pressure limits of CPAP without causing neither CO2 retention nor adverse hemodynamic consequences.

Intact DNA Repair in Differentiated Cardiomyocytes Is Essential for Maintaining Cardiac Function in Response to Pressure Overload in Mice

Introduction: DNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage-induced aging-related diseases. For example, deficient repair of endogenously generated DNA damage in mice with cardiomyocyte-restricted inactivation of Xpg, is associated with progressive heart failure (de Boer et al. Aging Cell 2023). Here we tested the hypothesis that unrepaired DNA damage in differentiated cardiomyocytes increases cardiac vulnerability in response to hemodynamic overload. Methods: At 8 weeks of age, αMHC-Xpgc/- and control (Ctrl) mice were subjected to pressure overload by mild transverse aortic constriction (TAC). Eight weeks after TAC, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements, followed by histological and molecular analyses. Results: Cardiomyocyte-restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction. TAC-induced LV hypertrophy was similar in both groups (Ctrl 38%; αMHC-Xpgc/- 34%). In Ctrl mice, LV hypertrophy was accompanied by minimal LV dilation and only modest changes in systolic and diastolic LV function. Conversely, TAC in αMHC-Xpgc/- produced severe LV dilation and dysfunction and resulted in overt backward failure, demonstrated by marked increases in LV end-diastolic pressure, left atrial weight and lung fluid weight. These changes were accompanied by further increases in the expression levels of the hypertrophic marker genes atrial natriuretic peptide and beta-myosin heavy chain. Moreover, lectin staining revealed a decrease in capillary density and TUNEL staining revealed further elevated levels of myocardial apoptosis in αMHC-Xpgc/--TAC mice as compared to Ctrl-TAC mice. In addition, a significant increase of myocardial collagen content was observed in αMHC-Xpgc/--TAC but not in Ctrl-TAC mice. Conclusion: Cardiomyocyte-restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to pressure-overload. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only under basal conditions, but also during increased cardiac loading conditions. Supported by the Dutch Heart Foundation [Grants 2017B018-ARENA-PRIME; 2021B008-RECONNEXT]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of a high-sugar mixed-meal on cerebral hemodynamics in young versus middle-aged adults

High-sugar mixed-meal consumption increases both glucose and insulin and elicits mixed vascular effects, with impairments in peripheral microvascular but improved conduit artery function. It is underexplored 1) if a high-sugar mixed-meal elicits vascular segment-specific effects within cerebrovasculature and 2) whether these responses are altered in middle-aged adults with cardiovascular disease (CVD) risk factors. This study sought to test the hypotheses that a high-sugar mixed-meal would elicit differential effects within the middle cerebral artery (MCA) versus downstream hemodynamics, and that changes in cerebral hemodynamics would be blunted among at-risk middle-aged adults compared to young adults. 21 young, healthy adults (24±6 years; 23.7±3.0 kg/m2) and 20 middle-aged adults (55±5 years; 28.2±5.2 kg/m2) with CVD risk factors (hypertension, obesity, or dyslipidemia) consumed a high-sugar mixed-meal consisting of 930 kcals (35.5 g fat, 129 g carbohydrates, 100.5 g sugar, 14 g protein). Vascular measures were taken prior to meal consumption and 30- and 60-min post-meal. MCA pulsatility index (PI), resistance index (RI), mean velocity, and conductance were assessed via transcranial Doppler. Mean arterial pressure (MAP) and common carotid artery diameter were assessed via automated oscillometric cuff and ultrasound, respectively. MCA PI and RI were taken as proxy measures of downstream vascular tone, while MCA mean velocity and conductance, and carotid artery diameter were taken as measures of larger artery cerebrovascular hemodynamics. MCA PI and RI were unchanged in middle-aged adults but increased at 30- (PI+Δ0.13±0.13 au; RI+Δ0.05±0.05 au) and 60-min (PI+Δ0.10 ±0.11 au; RI+Δ0.04±0.05 au) compared to baseline in young adults (p<0.05). MCA conductance increased at 30-min (+Δ0.04±0.08 cm/s per mmHg, p<0.05), carotid diameter increased at 60-min (+Δ0.13±0.20 mm, p<0.05), and MAP tended (p=0.07-0.09) to decrease at 30- (-Δ2.01±5.7 mmHg) and 60-min (-Δ2.26±6.54 mmHg) compared to baseline in both groups. MCA mean velocity was not significantly different across timepoints in both groups. These data suggest a high-sugar mixed-meal may transiently dilate larger cerebral arteries in both young and middle-aged adults but elicit vasoconstriction downstream of the MCA in young adults only. As such, our data suggest that 1) cerebrovascular response to a high-sugar mixed-meal may be vascular segment-specific, and 2) age and risk-factor burden may alter the sensitivity of vasculature downstream of the MCA to a high-sugar mixed-meal. Further research is needed to dissect mechanisms underlying the complex cerebrovascular response to a high-sugar mixed-meal in young versus middle-aged adults with CVD risk factors. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ventilatory Variability Is Increased at Rest in Pulmonary Arterial Hypertension

Ventilatory instability is associated with adverse outcomes in left heart failure, with periodic breathing during awake, rest, sleep and exercise (exercise oscillatory ventilation) associated with increased mortality. Increased peripheral and central chemoreflex sensitivities and impairment of cardiac output have been implicated as causative mechanisms of ventilatory instability in heart failure. As these factors are also present in pulmonary arterial hypertension (PAH), we tested the hypothesis that variability of breath-by-breath ventilation at rest would be increased in PAH compared with healthy controls. In fourteen patients with PAH (9 female, age 48.4±12.8 years, mean ± SD) and 14 healthy participants (9 female, age 49.4±14.2 years) breath-by-breath measurement of tidal volume and breathing frequency was undertaken with a pneumotachometer connected via a mouthpiece with nose-clip for 10 minutes while they rested awake and supine. Ventilatory (V̇E) variability was assessed using root mean square of successive differences (RMSSD), standard deviation (SD), average real variability (ARV, i.e., sum of absolute differences in successive observations), coeffcient of variation (CoV), as well as Poincaré analysis and compared between PAH and healthy controls (Student’s t-test). Correlations between measures of ventilatory variability and pulmonary hemodynamic characteristics, exercise capacity and function were assessed with Pearson’s correlation coeffcient. Resting V̇E was higher in PAH compared to healthy controls (14.3±1.1 and 12.1±0.5 L·min−1 respectively; p=0.009). Measures of variability for V̇E were increased in PAH compared to healthy controls. More specifically, RMSSD (3.59±1.36 vs. 2.48±0.87 L·min−1, p=0.017), SD (2.92±1.14 vs. 1.98±0.53 L·min−1, p=0.012), ARV (2.47±0.97 vs. 1.67±0.60 L·min−1, p=0.016), Poincaré SD1 (short-term variability, p=0.020) and SD2 (long-term variability, p=0.028) were increased in PAH compared to healthy controls, respectively. No correlations were found between measures of ventilatory variability and pulmonary hemodynamics (mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output), six-minute walk distance or WHO functional class. In summary, resting ventilatory variability is increased in PAH and not associated with haemodynamic factors and exercise capacity. Whether such raised ventilatory variability in PAH is related to increased chemoreflex sensitivity requires exploration. This study received funding support from the Greenlane Research and Educational Fund (21/01/4153), Health Research Council of New Zealand (19/687), and the Sidney Taylor Trust. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Cardiac and Cerebrovascular Response to Lower Body Negative Pressure in Patients with Postural Orthostatic Tachycardia Syndrome

Introduction: Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive heart rate response upon standing and symptoms that drastically reduce quality of life. Symptoms are often cerebral in nature (e.g., dizziness, headache), however the relationship between the underlying physiology and the symptoms is unknown. We tested the hypothesis that, compared to healthy controls (HC) individuals with POTS would have greater decreases in cardiac, and cerebral hemodynamic function during a simulated orthostatic challenge (lower-body negative pressure; LBNP) measured using magnetic resonance (MR) imaging. Methods: Eleven patients with POTS (17±1yrs; 1 male) and 10 HC (18±2yrs; 1 male) were studied at rest (supine in MRI) and during 20-minutes of -25mmHg LBNP. Symptoms were measured by Vanderbilt Orthostatic Symptom Score (VOSS). Heart rate and blood pressure (BP) were measured using an automated cuff and finger pulse oximeter, respectively. Left and right ventricular volumes, ejection fraction, stroke volume (SV), and cardiac output (Qc) were determined by cardiac MR. Cerebral oxygen utilization (VO2) was calculated as cerebral blood flow (CBF) multiplied by venous oxygen saturation (SVO2), measured by MR phase contrast and susceptomtery-based oximetry in the superior sagittal sinus. Results: At rest, there were no differences between groups for any cardiac hemodynamic measure (p>0.05 for all), however cerebral SvO2 and VO2 were lower in the POTS group (p=0.02 for both). In response to LBNP, patients with POTS had greater VOSS (25±21 vs 5±12; p=0.02). Heart rate increased in response to LBNP (p<0.001), but the increase was not different between groups (HC: +9±8bpm; POTS: +13±11bpm; p=0.35). SV and Qc decreased during LBNP (both, p<0.01), despite no change in mean arterial BP (p=0.13) which did not differ between groups (HC: +9±8mmHg; POTS: 3±6mmHg; p=0.377). Additionally, both left and right ventricular volumes as well as ejection fraction decreased during LBNP (p<0.01 for all). The decreased Qc during LBNP coincided with lower CBF in the superior sagittal sinus (p=0.01) although the response was not different between groups (HC: -17±13ml/min; POTS: -25±32ml/min; p=0.51). Cerebral SvO2 also decreased during LBNP (p=0.03) indicating increased oxygen extraction, resulting in no change in cerebral VO2 during LBNP (p=0.28) and no difference between groups in the VO2 response (HC: -0.2±3.7ml/min; POTS: +1.1±2.0ml/min; p=0.33). Conclusion: In response to a simulated orthostatic challenge (-25mmHg LBNP), patients with POTS do not have impaired cardiac function or cerebral oxygenation despite having a higher symptom score; however, a stronger stimulus may have been necessary to expose differences. Further investigations are needed to elucidate mechanisms of autonomic dysfunction in this population. Women and Children's Health Research Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex Differences in Central Hemodynamics of Patients with Untreated Obstructive Sleep Apnea

Patients with obstructive sleep apnea (OSA) have increased risk for cardiovascular diseases. Data from the Atherosclerosis Risk in the Communities and Sleep Heart Health Study suggest that OSA is more deleterious to females versus males, although mechanistic data are lacking. Estimates of central (aortic) blood pressure (BP) are superior in predicting future cardiovascular events than traditional brachial BP measurements. While patients with OSA have altered central hemodynamics (e.g., higher aortic pulse wave velocity; PWV), potential sex differences are unexplored. We tested the hypothesis that females with OSA (n=7, 50±3yrs, 35.1±1.9kg/m2, 22.2±7.6 events/hr) have worse central hemodynamics than males with OSA (n=9, 47±3yrs, 35.0±1.4kg/m2, 31.7±6.2 events/hr). Data collection consisted of an overnight sleep study (polysomnography) to identify the presence, and characterize the severity, of OSA via the apnea-hypopnea index (AHI). Then, duplicate measures of central (aortic) and peripheral (brachial) BP, as well as central artery stiffness (PWV) and wave reflection (AIx), were made in the morning after ≥15min of quiet, supine rest. Additional hemodynamic measurements were made if data differed by ≥2% (AIx) or ≥0.5m/s (PWV). Data that met these criteria were averaged and used for analysis. Comparisons were made using two-tailed, independent samples t-tests or nonparametric Mann-Whitney Rank Sum tests, as indicated. No differences were observed in age (p=0.44), body mass index (p=0.96), nor AHI (p=1.00) between sexes. Similarly, no sex differences were observed in brachial systolic (female vs. male: 129±7 vs. 134±8mmHg, p=0.83), diastolic (77±5 vs. 85±4mmHg, p=0.26), or mean BP (96±6 vs. 101±5mmHg, p=0.45). Similarly, central systolic (122±6 vs. 125±7mmHg, p=0.96), diastolic (78±5 vs. 86±4mmHg, p=0.25), and augmentation (21±2 vs. 15±2mmHg, p=0.07) BP did not differ between sexes. Resting heart rate was also comparable between groups (67±3 vs. 65±2bpm, p=0.64). However, AIx (AIx; 42±3 vs. 35±4%) and AIx normalized to a heart rate of 75bpm (42±3 vs. 30±3%) were higher in females with OSA relative to males with OSA (p<0.05 for both). Interestingly, the forward (30±3 vs. 28±2mmHg, p=0.63) and reflected (20±2 vs. 18±2mmHg, p=0.44) pulse heights, as well as PWV (7.3±0.6 vs. 7.4±0.6m/s, p=0.85), were similar between groups. Our data indicate that despite a trend towards higher BP in males with OSA (~5mmHg) that may be clinically, though not statistically different, females with OSA have a higher AIx. As AIx is positively associated with left ventricular hypertrophy, these data also suggest that altered central (aortic) hemodynamics may contribute to the sex differences in cardiovascular risk with OSA. This work was supported by the National Institutes of Health T32-HL007111 and U54AG044170 (JMB), HL065176 (PS and VKS), and HL134885 (VKS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PDZ-Binding Kinase, a Novel Regulator of Vascular Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is high blood pressure in the lungs that originates from structural changes in small resistance arteries. A defining feature of PAH is the inappropriate remodeling of pulmonary arteries (PA) leading to right ventricle failure and death. Although treatment of PAH has improved, the long-term prognosis for patients remains poor, and more effective targets are needed. Gene expression was analyzed by microarray, RNA sequencing, quantitative polymerase chain reaction, Western blotting, and immunostaining of lung and isolated PA in multiple mouse and rat models of pulmonary hypertension (PH) and human PAH. PH was assessed by digital ultrasound, hemodynamic measurements, and morphometry. Microarray analysis of the transcriptome of hypertensive rat PA identified a novel candidate, PBK (PDZ-binding kinase), that was upregulated in multiple models and species including humans. PBK is a serine/threonine kinase with important roles in cell proliferation that is minimally expressed in normal tissues but significantly increased in highly proliferative tissues. PBK was robustly upregulated in the medial layer of PA, where it overlaps with markers of smooth muscle cells. Gain-of-function approaches show that active forms of PBK increase PA smooth muscle cell proliferation, whereas silencing PBK, dominant negative PBK, and pharmacological inhibitors of PBK all reduce proliferation. Pharmacological inhibitors of PBK were effective in PH reversal strategies in both mouse and rat models, providing translational significance. In a complementary genetic approach, PBK was knocked out in rats using CRISPR/Cas9 editing, and loss of PBK prevented the development of PH. We found that PBK bound to PRC1 (protein regulator of cytokinesis 1) in PA smooth muscle cells and that multiple genes involved in cytokinesis were upregulated in experimental models of PH and human PAH. Active PBK increased PRC1 phosphorylation and supported cytokinesis in PA smooth muscle cells, whereas silencing or dominant negative PBK reduced cytokinesis and the number of cells in the G2/M phase of the cell cycle. PBK is a newly described target for PAH that is upregulated in proliferating PA smooth muscle cells, where it contributes to proliferation through changes in cytokinesis and cell cycle dynamics to promote medial thickening, fibrosis, increased PA resistance, elevated right ventricular systolic pressure, right ventricular remodeling, and PH.

Application of homocysteine as a non-invasive and effort-free measurements for risk assessment of patients with pulmonary hypertension.

Current guideline-recommended multiparameters used to assess the risk levels of pulmonary arterial hypertension (PAH) are invasive hemodynamic measurements or effort-dependent exercise tests. Serum natriuretic peptide is only one kind of effort-free biomarker that has been adopted for risk assessment. This study aimed to investigate the application of homocysteine as a non-invasive and effort-free measurement for the risk assessment of patients with PAH. Samples of 50 patients diagnosed with PAH via right heart catheterization were obtained, and the patients were divided into low-, intermediate- and high-risk groups for further analysis. Additionally, serum N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and homocysteine levels of monocrotaline (MCT)-induced PAH rats were analyzed at each week with progressed severity of PAH, and they were sacrificed on day 28 with pathology being assessed. Hyperhomocysteinemia was an independent predictor (odds ratio [OR]: 1.256; 95% confidence interval [CI]: 1.002-1.574) and showed a linear correlation with NT-proBNP. Hyperhomocysteinemia could discriminate between low/intermediate and high-risk levels in PAH with a cut-off value in 12 μmol/L. Moreover, the elevated homocysteine levels by weeks in MCT rats also demonstrated the association between homocysteine and the severity of PAH. Homocysteine can be a non-invasive and effort-free risk assessment for patients with pulmonary hypertension. Homocysteine level had a linear correlation with NT-proBNP level, and patients with hyperhomocysteinemia had a higher risk level, higher NT-proBNP level, and decreased lower diffusing capacity for carbon monoxide. The correlation between homocysteine level and PAH severity was also demonstrated in MCT rats.

Continuous Right Ventricular Pressure Monitoring in Cardiac Surgery

Right ventricular (RV) dysfunction in cardiac surgery can lead to RV failure, which is associated with increased morbidity and mortality. Abnormal RV function can be identified using RV pressure monitoring. The primary objective of the study is to determine the proportion of patients with abnormal RV early to end-diastole diastolic pressure gradient (RVDPG) and abnormal RV end-diastolic pressure (RVEDP) before initiation and after cardiopulmonary bypass (CPB) separation. The secondary objective is to evaluate if RVDPG before CPB initiation is associated with difficult and complex separation from CPB, RV dysfunction, and failure at the end of cardiac surgery. Prospective study. Tertiary care cardiac institute. Cardiac surgical patients. Cardiac surgery. Automated electronic quantification of RVDPG and RVEDP were obtained. Hemodynamic measurements were correlated with cardiac and extracardiac parameters from transesophageal echocardiography and postoperative complications. Abnormal RVDPG was present in 80% of the patients (n = 105) at baseline, with a mean RVEDP of 14.2 ± 3.9 mmHg. Patients experienced an RVDPG > 4 mmHg for a median duration of 50.2% of the intraoperative period before CPB initiation and 60.6% after CPB separation. A total of 46 (43.8%) patients had difficult/complex separation from CPB, 18 (38.3%) patients had RV dysfunction, and 8 (17%) had RV failure. Abnormal RVDPG before CPB was not associated with postoperative outcome. Elevated RVDPG and RVEDP are common in cardiac surgery. RVDPG and RVEDP before CPB initiation are not associated with RV dysfunction and failure but can be used to diagnose them.

Pediatric Heart Transplantation in the Context of Severe Pulmonary Hypertension Secondary to Restrictive Cardiomyopathy—Case Report

The aim of this study is to analyze the feasibility of performing an isolated heart transplant in patients with severe pulmonary hypertension as a result of restrictive cardiomyopathy. The results present the clinical course from the diagnosis of restrictive cardiomyopathy at the age of 2 until the heart transplant at 8 years old. Initially, the patient was considered for multiorgan transplantation, heart and lungs, due to extremely high pulmonary resistance. However, due to the prolonged waiting period for a donor and the worsening condition of the child, a decision was made to perforate the atrial septum with the implantation of an atrial flow regulator system. After conducting control hemodynamic measurements, the qualification was changed to an isolated heart transplant, accepting the high operative risk associated with the still elevated pulmonary resistance index of 4.9 Wood units. This study describes the medical problems that occurred during postoperative treatment. The patient underwent an orthotopic heart transplant in her eighth year of life. Postsurgery, complications were observed, including generalized seizures and heart transplant rejection reaction. Immunosuppressive therapies were applied, and efforts were made to combat anemia and electrolyte disorders. While the cardiovascular system and heart parameters improved, there were some difficulties in controlling heart rhythm and stabilizing electrolyte levels.

Role of cyclophilin A in aggravation of myocardial ischemia reperfusion injury via regulation of apoptosis mediated by thioredoxin-interacting protein.

The progression and persistence of myocardial ischemia/reperfusion injury (MI/RI) are strongly linked to local inflammatory responses and oxidative stress. Cyclophilin A (CypA), a pro-inflammatory factor, is involved in various cardiovascular diseases. However, the role and mechanism of action of CypA in MI/RI are still not fully understood. We used the Gene Expression Omnibus (GEO) database for bioinformatic analysis. We collected blood samples from patients and controls for detecting the levels of serum CypA using enzyme-linked immunosorbent assay (ELISA) kits. We then developed a myocardial ischemia/reperfusion (I/R) injury model in wild-type (WT) mice and Ppia-/- mice. We utilized echocardiography, hemodynamic measurements, hematoxylin and eosin (H&E) staining, immunohistochemistry, enzyme-linked immunosorbent assay, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining to determine the role of CypA in myocardial I/R injury. Finally, we conducted an in vitrostudy, cell transfection, flow cytometry, RNA interference, and a co-immunoprecipitation assay to clarify the mechanism of CypA in aggravating cardiomyocyte apoptosis. We found that CypA inhibited TXNIP degradation to enhance oxidative stress-induced cardiomyocyte apoptosis during MI/RI. By comparing and analyzing CypA expression in patients with coronary atherosclerotic heart disease and in healthy controls, we found that CypA was upregulated in patients with Coronary Atmospheric Heart Disease, and its expression was positively correlated with Gensini scores. In addition, CypA deficiency decreased cytokine expression, oxidative stress, and cardiomyocyte apoptosis in I/R-treated mice, eventually alleviating cardiac dysfunction. CypA knockdown also reduced H2O2-induced apoptosis in H9c2 cells. Mechanistically, we found that CypA inhibited K48-linked ubiquitination mediated by atrophin-interacting protein 4 (AIP4) and proteasomal degradation of TXNIP, a thioredoxin-binding protein that mediates oxidative stress and induces apoptosis. These findings highlight the critical role CypA plays in myocardial injury caused by oxidative stress-induced apoptosis, indicating that CypA can be a viable biomarker and a therapeutic target candidate for MI/RI.

GLI1+ Cells Contribute to Vascular Remodeling in Pulmonary Hypertension.

The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs). Gli1Cre-ERT2; tdTomatoflox mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature. The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an Acta2high fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation. Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan.

Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan. Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30mg/kg), or MM07 (10mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment. Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4weeks of treatment. Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

Steady Flow Left Ventricle Unloading Is Superior to Pulsatile Pressure Augmentation Venting During Venoarterial Extracorporeal Membrane Oxygenation Support.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) shunts venous blood to the systemic arterial circulation to provide end-organ perfusion while increasing afterload that may impede left ventricle (LV) ejection and impair cardiac recovery. To maintain flow across the aortic valve and reduce risk of lethal clot formation, secondary mechanical circulatory support (MCS) devices are increasingly used despite limited understanding of their effects on cardiac function. This study sought to quantify the effects of VA-ECMO and combined with either intraaortic balloon pump (IABP) or percutaneous ventricular assist device (pVAD) on LV physiologic state and perfusion metrics in a porcine model of acute cardiogenic shock. Shock was induced through serial left anterior descending artery microbead embolization followed by initiation of VA-ECMO support and then placement of either IABP or pVAD. Hemodynamic measurements, LV pressure-volume loops, and carotid artery blood flow were evaluated before and after institution of combined MCS. The IABP decreased LV end-diastolic pressure by a peak of 15% while slightly increasing LV stroke work compared with decreases of more than 60% and 50% with the pVAD, respectively. The pVAD also demonstrated increased coronary perfusion and systemic pressure gradients in comparison to the IABP. Combined support with VA-ECMO and pVAD improves cardiovascular state in comparison to IABP.

The Effects of Topical Anesthesia With Lidocaine 10% Spray Compared to Trans Tracheal and Glossopharyngeal Nerve Block in Hemodynamic Stability During Awake Intubation: A Randomized Controlled Trial

Hemodynamic changes is of great concern during awake intubation, particularly in patients with underlying medical conditions. As heterogeneities exist in regard to the best anesthesia drugs and techniques, herein, we aimed to investigate the effects of Lidocaine 10% spray compared to trans tracheal glossopharyngeal nerve block in hemodynamic stability in patients undergoing awake intubation. A total of 62 patients were included in this randomized clinical trial. Using a longitudinal interventional design, hemodynamic measures were statistically compared before intubation, one minute after intubation, and five minutes after intubation. The first group underwent topical anesthesia with Lidocaine 10% sprayed on the base of tongue and tonsillar pillar while the second group underwent trans tracheal and glossopharyngeal nerve block with simultaneous injection of Lidocaine 2%. Our results indicated that all hemodynamic parameters except for the pulse rate in both groups were significantly reduced after the intubation, which indicates the effectiveness of the interventions. However, the reduction in SBP, DBP, and MAP was significantly lower in the nerve block group compared to the Lidocaine spray group. Regarding the pulse rate, despite the significant decrease in the group of patients undergoing nerve block, those undergoing anesthesia with Lidocaine spray experienced a significant increase in the heart rate in the first minute after the operation. Finally, our research provides substantiation that employing a glossopharyngeal nerve block and trans tracheal block constitutes an efficacious method for local anesthetic during conscious intubation and can be a promising technique.

On the role of tissue mechanics in fluid–structure interaction simulations of patient‐specific aortic dissection

AbstractModeling an aortic dissection represents a particular challenge from a numerical perspective, especially when it comes to the interaction between solid (aortic wall) and liquid (blood flow). The complexity of patient‐specific simulations requires a variety of parameters, modeling assumptions and simplifications that currently hinder their routine use in clinical settings. We present a numerical framework that captures, among other things, the layer‐specific anisotropic properties of the aortic wall, the non‐Newtonian behavior of blood, patient‐specific geometry, and patient‐specific flow conditions. We compare hemodynamic indicators and stress measurements in simulations with increasingly complex material models for the vessel tissue ranging from rigid walls to anisotropic hyperelastic materials. We find that for the present geometry and boundary conditions, rigid wall simulations produce different results than fluid–structure interaction simulations. Considering anisotropic fiber contributions in the tissue model, stress measurements in the aortic wall differ, but shear stress‐based biomarkers are less affected. In summary, the increasing complexity of the tissue model enables capturing more details. However, an extensive parameter set is also required. Since the simulation results depend on these modeling choices, variations can lead to different recommendations in clinical applications.

Hemodynamical Evaluation of a New Surgically Implanted Pulsatile Right Ventricular Assist Device Driven by a Conventional Intra-Aortic Balloon Pump Console.

Severe right heart failure, often overlooked and challenging to manage, has prompted a growing interest in innovative approaches to provide functional support. This study uses experimentation in large porcine models to introduce a novel prototype of a pulsatile mechanical circulatory support device and document its effects when deployed as a right ventricular assist device (RVAD). The pulsatile ventricular assist platform (pVAP), featuring a membrane pump driven by an intra-aortic balloon pump console, actively generates pulsatile flow to propel right ventricular blood into the pulmonary artery. This novel prototype demonstrates promising potential in addressing the challenges of right heart failure management. After preliminary in vitro assessments, the pVAP was tested on seven porcine models in a healthy state and after the induction of right ventricular failure. During the procedure, a set of standard ( ie , standard-of-care) hemodynamic measurements was obtained. Additionally, invasive pressure-volume loop analysis was employed to examine left ventricular hemodynamics. Results indicated that activation of the pVAP during right ventricular failure significantly improved systemic hemodynamics and enhanced left ventricular function. This study sheds light on the potential of the pVAP in managing right heart failure.

Impact of pulmonary hypertension on outcomes after TEER in patients suffering from mitral regurgitation.

Data on associations of invasively determined hemodynamic parameters with procedural success and outcomes in patients suffering from mitral regurgitation (MR) undergoing transcatheter edge-to-edge repair of the mitral valve (M-TEER) is limited. We enrolled 239 patients with symptomatic MR of grade 2 + , who received M-TEER. All patients underwent extensive pre-interventional invasive hemodynamic measurements via right heart catheterization (mean pulmonary arterial pressure (mPAP), systolic- (PAPsys) and diastolic pulmonary arterial pressure (PAPdia), pulmonary arterial wedge pressure (PAWP), a-wave, v-wave, pulmonary vascular resistance (PVR), transpulmonary pressure gradient (TPG), cardiac index (CI), stroke volume index (SVI)). mPAP and PAWP at baseline were neither associated with procedural success, immediate reduction of MR, nor residual MR after 6months of follow-up. The composite outcome (All-cause mortality (ACM) and/or heart failure induced rehospitalization (HFH)) and HFH differed significantly after M-TEER when stratified according to mPAP, PAWP, PAPdia, a-wave and v-wave. ACM was not associated with the afore mentioned parameters. Neither PVR, TPG, CI nor SVI were associated with the composite outcome and HFH, respectively. In multivariable analyses, PAWP was independently associated with the composite outcome and HFH. PVR and SVI were not associated with outcomes. PAWP at baseline was significantly and independently associated with HFH and might serve as a valuable parameter for identifying patients at high risk for HFH after M-TEER. ACM and procedural success were not affected by pulmonary arterial pressure before M-TEER. We suggest that the post-capillary component of PH serves as the driving force behind the risk of HFH.

Study on attenuation of miR-1-mediated ischemia-induced arrhythmias and infarction in rats by means of fulvning granule

Patients post myocardial infarction (MI) have a high incidence of frequent and complex ventricular arrhythmias. miR-1 is involved in ischemia-induced arrhythmias. Fulvning Granule (FG) is a prescription for treating ischemia-induced arrhythmias. This research investigated therapeutic effect of FG on ischemia-induced arrhythmias in an depth way, focusing on expression of miR-1. 60 healthy Sprague Dawly rats were assigned to operation group, MI+normal saline group, MI+low dose of FG group, MI+moderate dose of FG group and MI+high dose of FG group, MI+propranolol group and MI+moderate dose of FG+propranolol group. Hemodynamic measurement, arrhythmia classification, infarct area evaluation and miR-1 level quantification with expression of PKA and SRF were adopted 4 weeks after operation. FG improved hemodynamic indexes and inhibited expression of miR-1. The optimal dose of FG was medium (P < 0.05). Combination of FG and propranolol further improved the hemodynamics indexes and inhibited the expression of miR-1, PKA and SRF (P < 0.05). FG regulated miR-1 expression via inhibition of Protein Kinase A (PKA) and serum response factor (SRF) expressions. Meanwhile, β-adrenoceptor/PKA signaling pathway played a role in regulating miR-1 expression, while Fulvning granule combined with propranolol and showed an antiarrhythmic role and improved cardiac function after myocardial infarction.

1 Sex Differences in Middle Cerebral Artery Velocity in Patients with Persistent Post-Concussion Convergence Insufficiency (PPCS-CI)

OBJECTIVES/GOALS: The objective of this study is to investigate the neurophysiological mechanism of vision therapy in male and female adolescents with persistent post-concussion convergence insufficiency (PPCS-CI). This study may improve diagnostics and inform more effective personalized point of care treatment strategies to remediate symptoms. METHODS/STUDY POPULATION: Participants (ages 11-25) were diagnosed with PPCS by a physician, CI was diagnosed by an optometrist and OBVAT was performed by certified therapists. Patients with PPCS-CI were randomly assigned to a therapy type (immediate therapy or natural recovery). Hemodynamic measures were examined in patients with PPCS-CI at baseline (1-3 months post-concussion), and post OBVAT to evaluate recovery outcomes. Non-invasive techniques were used to measure middle cerebral artery velocity (MCAv), blood pressure, heart rate, and end-tidal CO2 at rest and during objective symmetrical convergence step eye movements. Functional magnetic resonance imaging (fMRI) was acquired during convergence step eye movement experiments contrasted to sustained fixation and resting state data collection. RESULTS/ANTICIPATED RESULTS: To investigate the neural mechanism of OBVAT, eye movements, fMRI and physiological measures were collected in 8 patients with PPCS-CI (4 men and 4 women). Results show an 10% decrease in the MCA during 4-degree symmetrical convergent eye movement responses in males post-OBVAT and a 19% increase in MCA during convergent eye movement responses in females. Furthermore, there was a group level activation of the frontal eye fields, which improves post-OBVAT. The beta weights in the left frontal eye fields show a trending decrease in male patients post-OBVAT and trending increase in females. Males had a decrease in MCAv post OBVAT (baseline 83.6 ± 7.5 cm/sec & 75.7 ± 12.5 cm/sec post-OBVAT), while females show a significant increase post-OBVAT (baseline 53.77 ± 5.2 cm/sec & post-OBVAT 65.13 cm/sec ± 12.5). DISCUSSION/SIGNIFICANCE: This initial pilot demonstrates there may be different underlying pathophysiological outcomes associated with a concussion dependent on sex. This work may have direct implications on treatment strategies for male and female adolescent patients with PPCS-CI.