Right Ventricular End-systolic Pressure Research Articles

Microtubules distinctly contribute to the performance of the healthy and pressure-overloaded RV

Introduction: Microtubules (MT) are a key contributor to cardiomyocyte contractility and mechanics. Recently, our group reported that acute depolymerization of MT reduces viscosity and elasticity and alters anisotropy of healthy and pressure-overloaded right ventricular (RV) tissues. While RV free wall viscosity and elasticity are distinctly upregulated with chronic pressure overload, how organ function is affected by viscoelastic contribution of the MT remains unknown. Our aim was to investigate the role of MT polymerization in RV function from its effect on RV tissue viscoelasticity. We hypothesized that the MT differentially contributes to healthy and pressure-overloaded RV function. Methods: All procedures and methods were approved by Colorado State University IACUC. Pulmonary hypertension (PH) was induced in 6-week-old male rats via 3-week monocrotaline treatment. Healthy age- and sex-matched rats served as control. Pressure-volume (PV) relationships were obtained by RV catheterization before and after intramyocardial injections of 0.3mM colchicine (COL) to acutely depolymerize the MT network and reduce tissue viscoelasticity. Functional impacts were evaluated by monitoring changes in RV end-systolic pressure (ESP), cardiac output (CO), stroke volume (SV), ejection fraction (EF), dP/dt max and min, cardiac effciency (CE), and the end-systolic pressure-volume relation (ESPVR). Results: As expected, monocrotaline treatment induced marked PH and RV contractile dysfunction, indicated by a significant elevation of RV ESP with reduced CO and ESPVR. In the healthy RV, COL treatment led to marked reductions in all functional parameters, indicating that the MT network is critical to maintain RV performance and contractile function in the healthy heart. In the pressure-overloaded RV, COL treatment similarly reduced SV, CO, EF, and dP/dt max and min, but increased CE and ESPVR, indicating that MT depolymerization improved mechanical effciency and contractility. To rule out effects caused by bolus injections alone, we administered a similar quantity of saline and observed no effects on the PV parameters in healthy RV. Discussion: Our study is the first to investigate the acute effect of MT depolymerization on RV function in healthy and diseased states. We found distinct contributions of MT to the contractile function and mechanical effciency of healthy and pressure-overloaded RVs. These findings reveal a critical influence of tissue viscoelasticity on RV physiology and dysfunction, emphasizing the importance of considering myocardial viscoelastic behavior in future studies investigating cardiac remodeling and heart failure pathophysiology. This work is partially supported by the National Science Foundation (NSF) grant 2244994. 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.

Impact of Interventricular Interaction on Ventricular Function: Insights From Right Ventricular Pressure-Volume Analysis

BackgroundInterventricular interactions may be responsible for the decline in ventricular performance observed in various disease states that primarily affect the contralateral ventricle. ObjectivesThis study sought to quantify the impact of such interactions on right ventricular (RV) size and function using clinically stable individuals with left ventricular assist devices (LVADs) as a model for assessing RV hemodynamics while LV loading conditions were acutely manipulated by changing device speed during hemodynamic optimization studies (ie, ramp tests). MethodsThe investigators recorded RV pressure-volume loops with a conductance catheter at various speeds during ramp tests in 20 clinically stable HeartMate3 recipients. ResultsWith faster LVAD speeds and greater LV unloading, indexed RV end-diastolic volume increased (72.28 ± 15.07 mL at low speed vs 75.95 ± 16.90 at high speed; P = 0.04) whereas indexed end-systolic volumes remained neutral. This resulted in larger RV stroke volumes and shallower end-diastolic pressure-volume relationships. Concurrently, RV end-systolic pressure decreased (31.58 ± 9.75 mL at low speed vs 29.58 ± 9.41 mL at high speed; P = 0.02), but contractility, as measured by end-systolic elastance, did not change significantly. The reduction in RV end-systolic pressure was associated with a reduction in effective arterial elastance from 0.65 ± 0.43 mm Hg/mL at low speed to 0.54 ± 0.33 mm Hg/mL at high speed (P = 0.02). ConclusionsInterventricular interactions resulted in improved RV compliance, diminished afterload, and did not reduce RV contractility. These data challenge the prevailing view that interventricular interactions compromise RV function, which has important implications for the understanding of RV-LV interactions in various disease states, including post-LVAD RV dysfunction.

Effects of empagliflozin on right ventricular adaptation to pressure overload.

Right ventricular (RV) failure is the prime cause of death in patients with pulmonary arterial hypertension. Novel treatment strategies that protect the RV are needed. Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, shows cardioprotective effects on the left ventricle in clinical and preclinical studies, but its direct effects on RV remain elusive. We investigated the effects of empagliflozin on RV dysfunction induced by pulmonary trunk banding (PTB). Male Wistar rats (116 ± 10 g) were randomized to PTB or sham surgery. One week after surgery, PTB animals received empagliflozin mixed into the chow (300 mg empagliflozin/kg chow; PTB-empa, n = 10) or standard chow (PTB-control, n = 10). Sham rats (Sham, n = 6) received standard chow. After five weeks, RV function was evaluated by echocardiography, cardiac MRI, and invasive pressure-volume measurements. PTB caused RV failure evident by decreased cardiac output compared with sham. PTB-empa rats had a 49% increase in water intake compared with PTB-control yet no differences in hematocrit or blood glucose. Treatment with empagliflozin decreased RV end-systolic pressures without any changes in RV cardiac output or ventricular-arterial coupling (Ees/Ea). The decrease in RV end-systolic pressure was complemented by a slight reduction in RV cross sectional area as a sign of reduced hypertrophy. Load-independent measures of RV systolic and diastolic function were not affected in PTB-empa rats compared with PTB-control. Empagliflozin treatment reduced RV end-systolic pressure in RV failure induced by pressure overload. Further studies are needed to elucidate whether this simply relates to a diuretic effect and/or additional independent beneficial RV effects.

Abstract 9592: The Super Relaxed State of Myosin Contributes to the Pathogenesis of Right Ventricular Dysfunction in Pulmonary Hypertension

Introduction: Patients with pulmonary hypertension (PH) often succumb to right ventricular (RV) failure yet little is known regarding the underlying pathological mechanisms. Recently, the transition of myosin from the disordered relaxed (DRX) to the super relaxed (SRX) state during diastole has been identified as a pathological feature contributing to myocardial dysfunction in heart failure. Using synchrotron radiation (SR) x-ray diffraction (SAXS), the proximity of myosin heads relative to actin in the in situ beating rat heart can be evaluated in different layers of the myocardial wall. We performed SR SAXS at different timepoints post-PH induction with simultaneous PV-loop acquisition to assess if SRX transition contributes to progressive global RV dysfunction in a rat model of PH. Methods: PH was induced in rats using the Sugen5416/3-week 10% hypoxia method, with rats being returned to normoxia for 3- (SuHx3wk) or 6-weeks (SuHx6wk) after the hypoxic period. SR SAXS was performed at BL40XU, SPring-8 Synchrotron, Japan. Global and site-specific RV myofilament phosphorylation status was also examined. Results: Compared to control rats (n=7), SuHx3wk (n=7) and SuHx6wk (n=7) rats exhibited progressive increases in RV size, RV end systolic pressure (ESP), RV dP/dt max and dP/dt min (all P<0.05 vs. Control). In the deeper subendocardial layer of the RV free wall, there were virtually no myosin heads within the proximity of actin at end diastole in SuHx6wk rats, whereas in the control and SuHx3wk rats, around 30-50% of myosin heads were in proximity to actin (P<0.05, SuHx6wk vs. Control and SuHx3wk). No significant differences in diastolic sarcomere length were found, suggesting a transition of myosin from DRX to SRX in the SuHx6wk rats. Importantly, indices for global RV function (ESP, dP/dt max, dP/dt min ) significantly correlated with diastolic myosin mass transfer values. Analysis of RV myofilament phosphorylation revealed a progressive and significant reduction in MLC-2v phosphorylation over the time course of PH in rats. Conclusion: PH is associated with progressive changes in global RV function, which may be attributed to a transition from DRX to SRX state of myosin in the RV. Reduced MLC-2v phosphorylation may underlie the DRX to SRX transition in PH.

Synchronous biventricular pressure‐volume loops in rodents using a closed‐chest approach

IntroductionThe assessment of left‐ and right‐sided cardiac function via closed‐chest pressure‐volume loops is important to understanding and diagnosing a wide range of cardiovascular pathologies. In the vast majority of pre‐clinical studies, either left‐ or right‐sided heart function is assessed in isolation, or, more recently, by sequentially right‐ and left‐sided catheterization1. Synchronous biventricular catheterization would offer a significant advancement for pre‐clinical research. To date, closed‐chest synchronous biventricular pressure‐volume loops have only been obtained in a few studies, limited to porcine models2. Here, we describe initial results from what we believe to be the first synchronous biventricular pressure‐volume loops obtained in the rodent using a closed‐chest approach.AimTo obtain biventricular pressure‐volume loops in the anesthetized rat using a closed‐chest approachMethodsA total of 8 Wistar rats were anesthetized with urethane (1.5mg/kg), tracheotomised, ventilated, and subsequently had a solid state catheter placed in the femoral artery to measure blood pressure, and admittance pressure‐volume catheters placed in the right‐ and left‐ventricle to obtain synchronous biventricular pressure‐volume loops. Admittance probes were set to different frequencies to avoid cross‐talk. All catheters were left to stabilize for a minimum of 10 min after which we extracted and averaged 1 minute of basal pressure‐volume indices.ResultsReliable ventricular pressure waveforms were obtained from both the left (i.e., left‐ventricular end‐systolic pressure = 106±12mmHg) and right (i.e., right‐ventricular end systolic pressure = 28±8mmHg) side in all eight animals, and we were able to obtain standard left‐sided pressure‐volume loops from all eight animals (i.e., stroke work = 22±5mmHg/ml). We were only able to obtain reliable right‐sided pressure‐volume loops in two of eight animals, due to poor volume signals in the remaining 6 animals. In the two animals we were able to obtain synchronous pressure‐volume loops there was clear evidence of ventricular dependence across the respiratory cycle (Fig.1).ConclusionsObtaining synchronous biventricular pressure‐volume loops using a closed‐chest approach in rats is possible but technically challenging. Further work is needed to better obtain right‐sided ventricular volumes.References Potus F. et al., J. Vis. Exp (160), e61088, doi:10.3791/61088 (2020). Lyhne MD. et al., J. Vis. Exp.(171), e62661, doi:10.3791/62661 (2021).

Thoracic bilateral sympathectomy attenuates oxidative stress and prevents ventricular remodelling in experimental pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease that affects the pulmonary vasculature, leading to increased afterload and eventually right ventricular (RV) remodelling and failure. Bilateral sympathectomy (BS) has shown promising results in dampening cardiac remodelling and dysfunction in several heart failure models. In the present study, we investigated whether BS reduces pulmonary arterial remodelling and mitigates RV remodelling and failure. PAH was induced in male Wistar rats by intraperitoneal injection of monocrotaline. Rats were divided into 3 groups, involving untreated PAH (n = 15), BS-treated PAH (n = 13) and non-manipulated control rats (n = 13). Three weeks after PAH induction, the rats were anaesthetized and RV function was assessed via the pressure-volume loop catheter approach. Upon completion of the experiment, the lungs and heart were harvested for further analyses. BS was found to prevent pulmonary artery remodelling, with a clear reduction in α-smooth muscle actin and endothelin-1 expression. RV end-systolic pressure was reduced in the BS group, and preload recruitable stroke work was preserved. BS, therefore, mitigated RV remodelling and cardiomyocyte hypertrophy and diminished oxidative stress. We showed that thoracic BS may be an important treatment option for PAH patients. Blockade of the sympathetic pathway can prevent pulmonary remodelling and protect the RV from oxidative stress, myocardial remodelling and function decay.

Immunomodulation Therapy Using Tolerogenic Macrophages in a Rodent Model of Pulmonary Hypertension.

Inflammation plays a major role in the pathogenesis of pulmonary hypertension (PH). We sought to investigate the effects of a cell-based immunomodulation in a dysimmune model of PH. PH was induced in athymic nude rats using semaxinib (Su group, n = 6). Tolerogenic macrophages (toM) were generated from monocyte isolation and then injected either the day before semaxinib injection (Prevention group, n = 6) or 3 weeks after (Reversion group, n = 6). Six athymic nude rats were used as controls. In vivo trafficking of toM was investigated with bioluminescence imaging showing that toM were mainly located into the lungs until 48 h after injection. Right ventricular (RV) end-systolic pressure and RV systolic function were assessed at 4 weeks using echocardiography. Morphometric analysis and RNA sequencing of the lungs were realized at 4 weeks. Rats treated with toM (Prevention and Reversion groups) had a significantly lower RV end-systolic pressure at 4 weeks (respectively, 25 ± 8 and 30 ± 6 mmHg vs. 67 ± 9 mmHg, P < 0.001), while RV systolic dysfunction was observed in Su and Reversion groups. Mean medial wall thickness of small arterioles was lower in Prevention and Reversion groups compared with the Su group (respectively, 10.9% ± 0.8% and 16.4% ± 1.3% vs. 28.2% ± 2.1%, P < 0.001). Similarly, cardiomyocyte area was decreased in rats treated with toM (150 ± 18 and 160 ± 86 μm2 vs. 279 ± 50 μm2, P < 0.001). A trend toward upregulation of genes involved in pulmonary arterial hypertension pathobiology was found in Su rats, while KCNK3 was significantly downregulated (fold-change = 9.8, P < 0.001). Injection of toM was associated with a less severe phenotype of PH in rats exposed to angioproliferative stress. Preserved expression of KCNK3 may explain the protective effect of toM.

Evaluation of right ventricular contractile reserve with exercise stress echocardiography

Right ventricular (RV) contractile reserve reflects the ability of RV to adapt to elevated afterload. RV functional response to exercise is challenging but could represent an important prognostic factor, especially in pulmonary arterial hypertension (PAH) patients. To assess different RV contractile reserve evaluation methods in a cohort of PAH patients and controls, using exercise stress echocardiography (ESE). We prospectively included 12 patients with PAH and 12 healthy volunteers. An ESE (using tilt-table ergometer) was performed in all patients to assess RV function at rest and under peak exercise. Changes in these parameters during exercise were calculated to quantify the RV contractile reserve. 3D RV function as well as peak systolic strain, pulmonary pressures, TAPSE, pulmonary VTI and pulmonary output (using the right ventricular outflow tract diameter) were assessed in all patients. Our patient group was composed by PAH patients, 52 ± 11 years; mean age of our control group was 31 ± 6 years. PAH patients achieved an exercise with a mean workload of 70 ± 26.4 Watts. There was no complication after the exercise test in all patients. Change in TAPSE was not significantly different between patients and controls ( P = 0.17), whereas change in pulmonary VTI, pulmonary output and RV peak systolic strain was highly discriminant (respectively P = 0.03, P = 0.009 and P = 0.0009). Regarding RV contractile reserve parameters, RV end-systolic pressure area ratio (peak/rest) was not statistically different between controls and patients ( P = 0.14) whereas change in TAPSE/sPAP, RV peak strain/sPAP, 3D RV EF/sPAP were significantly different ( P = 0.005, P = 0.0008, P = 0004). Changes in pulmonary output, RV peak systolic strain as well as changes in TAPSE/sPAP but mainly RV peak strain/sPAP, 3D RV EF/sPAP represent consistent and feasible tools to assess RV contractile reserve.

Evaluation of right ventricular contractile reserve with exercise stress echocardiography

Right ventricular (RV) contractile reserve reflects the ability of RV to adapt to elevated afterload. RV functional response to exercise is challenging but could represent an important prognostic factor, especially in pulmonary arterial hypertension (PAH) patients. We aimed, using exercise stress echocardiography (ESE), to assess different RV contractile reserve evaluation methods in a cohort of PAH patients and controls. We prospectively included 12 patients with PAH and 12 healthy volunteers. An ESE (using tilt-table ergometer) was performed in all patients to assess RV function at rest and under peak exercise. Changes in these parameters during exercise were calculated to quantify the RV contractile reserve. 3D RV function as well as peak systolic strain, pulmonary pressures, TAPSE, pulmonary VTI and pulmonary output (using the right ventricular outflow tract diameter) were assessed in all patients. Our patient group was composed by PAH patients, 52 ± 11 years; mean age of our control group was 31 ± 6 years. PAH patients achieved an exercise with a mean workload of 70 ± 26.4 Watts. There was no complication after the exercise test in all patients. Change in TAPSE was not significantly different between patients and controls ( P = 0.17), whereas change in pulmonary VTI, pulmonary output and RV peak systolic strain was highly discriminant (respectively P = 0.03, P = 0.009 and P = 0.0009). Regarding RV contractile reserve parameters, RV end-systolic pressure area ratio (peak/rest) was not statistically different between controls and patients ( P = 0.14) whereas change in TAPSE/sPAP, RV peak strain/sPAP, 3D RV EF/sPAP were significantly different ( P = 0.005, P = 0.0008, P = 0004). Changes in pulmonary output, RV peak systolic strain as well as changes in TAPSE/sPAP but mainly RV peak strain/sPAP, 3D RV EF/sPAP represent consistent and feasible tools to assess RV contractile reserve.

Extracorporeal CO2 removal and regional citrate anticoagulation in an experimental model of hypercapnic acidosis.

Low flow extracorporeal veno-venous CO2 removal (ECCO2 R) therapy is used to remove CO2 while reducing ventilation intensity. However, the use of this technique is limited because efficiency of CO2 removal and potential beneficial effects on pulmonary hemodynamics are not precisely established. Moreover, this technique requires anticoagulation that may induce severe complications in critically ill patients. Therefore, our study aimed at determining precise efficiency of CO2 extraction and its effects on right ventricular (RV) afterload, and comparing regional anticoagulation with citrate to systemic heparin anticoagulation during ECCO2 R. This study was performed in an experimental model of severe hypercapnic acidosis performed in two groups of three pigs. In the first group (heparin group), pigs were anticoagulated with a standard protocol of unfractionated heparin while citrate was used for ECCO2 R device anticoagulation in the second group (citrate group). After sedation, analgesia and endotracheal intubation, pigs were connected to a volume-cycled ventilator. Severe hypercapnic acidosis was obtained by reducing tidal volume by 60%. ECCO2 R was started in both groups when arterial pH was lower than 7.2. Pump Assisted Lung Protection (PALP, Maquet, Rastatt, Germany) system was used to remove CO2 . CO2 extraction, arterial pH, PaCO2 as well as systemic and pulmonary hemodynamic were continuously followed. Mean arterial pH was normalized to 7.37 ± 1.4 at an extracorporeal blood flow of 400 mL/min, coming from 7.11 ± 1.3. RV end-systolic pressure increased by over 30% during acute hypercapnic acidosis and was normalized in parallel with CO2 removal. CO2 extraction was not significantly increased in citrate group as compared to heparin group. Mean ionized calcium and MAP were significantly lower in the citrate group than in the heparin group during ECCO2 R (1.03 ± 0.20 vs. 1.33 ± 0.19 and 57 ± 14 vs. 68 ± 15 mm Hg, respectively). ECCO2 R was highly efficient to normalize pH and PaCO2 and to reduce RV afterload resulting from hypercapnic acidosis. Regional anticoagulation with citrate solution was as effective as standard heparin anticoagulation but did not improve CO2 removal and lead to more hypocalcemia and hypotension.

Abstract 13214: Right Ventricular-Vascular Coupling in Acute Hemodynamic Stress: A Simple Method of Estimation and Relationship With Right Ventricular Ejection Fraction and Afterload

Objectives: Gold standard of right ventricular (RV) function is ratio of end-systolic to arterial elastance from synchronized volume and pressure measurements. Quantification of ventricular-vascular coupling (VVc) using non-simultaneous common right heart catheterization and cardiac imaging has been described. Hypothesis: VVc estimated from simultaneous pressure and volume measurements using Swan-Ganz TM (Edwards Lifesciences, Irvine, CA) advanced technology catheters would be feasible and clinically relevant. Methods: 32 mechanically ventilated adult critically ill trauma/general surgery patients were enrolled within 6 hours of admission. Hemodynamics were transduced every 12 hours for 48 hours. VVc was quantified as ratio of pulmonary artery (PA) effective elastance (E a ) to RV maximal end-systolic elastance (E max ). Mean PA pressure (mPAP) was used as surrogate of RV end-systolic pressure. Right ventricular end-systolic volume index (ESVI) was calculated as difference of end-diastolic volume index and stroke volume index (SVI). E(a) was calculated as (mPAP - PCWP)/SVI and E(max) as mPAP/ESVI. Results: Serial E a /E max inversely correlated with RV ejection fraction (RVEF) (r = -0.89, p a /E max (r = 0.66, 0.61, 0.68, 0.66, 0.52, p ≤ 0.004). Non-survivors (n = 7) had higher E a /E max (indicating uncoupling) at 48 hours (2.3 ± 1.8 vs. 1.4 ± 1.8, p = 0.036). AUC for Ea/Emax at 48 hours and mortality was comparable to RVEF. Conclusions: In mechanically ventilated critically ill and/or injured adults, estimation of VVc using advanced technology pulmonary artery catheter is feasible. E a /E max is related to PVR and inversely related to RVEF and PAC. Estimation of E a /E max may assist in optimization of resuscitation.

Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor.

Pulmonary hypertension (PH) is associated with features of obesity and metabolic syndrome that translate to the induction of PH by chronic high-fat diet (HFD) in some inbred mouse strains. We conducted a genome-wide association study (GWAS) to identify candidate genes associated with susceptibility to HFD-induced PH. Mice from 36 inbred and wild-derived strains were fed with regular diet or HFD for 20 weeks beginning at 6-12 weeks of age, after which right ventricular (RV) and left ventricular (LV) end-systolic pressure (ESP) and maximum pressure (MaxP) were measured by cardiac catheterization. We tested for association of RV MaxP and RV ESP and identified genomic regions enriched with nominal associations to both of these phenotypes. We excluded genomic regions if they were also associated with LV MaxP, LV ESP, or body weight. Genes within significant regions were scored based on the shortest-path betweenness centrality, a measure of network connectivity, of their human orthologs in a gene interaction network of human PH-related genes. WSB/EiJ, NON/ShiLtJ, and AKR/J mice had the largest increases in RV MaxP after high-fat feeding. Network-based scoring of GWAS candidates identified epidermal growth factor receptor (Egfr) as having the highest shortest-path betweenness centrality of GWAS candidates. Expression studies of lung homogenate showed that EGFR expression is increased in the AKR/J strain, which developed a significant increase in RV MaxP after high-fat feeding as compared with C57BL/6J, which did not. Our combined GWAS and network-based approach adds evidence for a role for Egfr in murine PH.

Sex Differences in Immunology: More Severe Development of Experimental Pulmonary Hypertension in Male Rats Exposed to Vascular Endothelial Growth Factor Receptor Blockade.

Background. The epidemiology of pulmonary hypertension (PH) is characterized by a female preponderance, whereas males share higher severity of the disease. Objective. To compare the severity of experimental PH between male and female athymic rats. Methods. PH was induced in 11 male and 11 female athymic rats (resp., SU_M and SU_F groups) using an inhibitor of VEGF-receptors I and II, semaxanib (40 mg/kg). After 28 days, right ventricular (RV) remodeling, systolic function, and hemodynamics were measured using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and RV myocardium were performed. Results. Four weeks after semaxanib injection, RV end-systolic pressure was higher in SU_M than in SU_F. Males developed marked RV enlargement and systolic dysfunction compared to females. Impairment of RV-PA coupling efficiency was observed only in SU_M. The smooth muscle cells of the pulmonary arteries switched from a contractile state to a dedifferentiated state only in males. Conclusions. Female athymic rats were protected against the development of severe PH. RV-PA coupling was preserved in females through limitation of pulmonary artery muscularization. Control of smooth muscle cells plasticity may be a promising therapeutic approach to reverse established vascular remodeling in PH patients.

Abstract 20669: Urocortin-2 Improves Right Ventricular Function in Pulmonary Arterial Hypertension

Introduction: Urocortin (UCN)-2 is a peptide highly expressed in the cardiovascular system and it has shown promising therapeutic effects in several studies in both humans and animal models of heart failure (HF). However, the role of UCN-2 in right ventricular (RV) failure is still unknown. Hypothesis: This study analyzed the effects of UCN-2 treatment in an animal model of RV HF, secondary to pulmonary arterial hypertension (PAH). Methods: Male Wistar rats (180-200g) randomly received monocrotaline (MCT, 60mg/Kg, s.c.) or vehicle. After 14 days, animals from these groups were randomly assigned to receive treatment with either UCN-2 (2.5μg/Kg/day, i.p.) or vehicle. The study resulted in 4 groups: control (CTRL) (n=12); CTRL+UCN-2 (n=10); MCT (n=9); MCT+UCN-2 (n=8). RV Pressure-Volume measurements were performed 24-25 days after MCT administration. Only significant results (mean±SEM, p&lt;0.05) are given. Results: MCT group developed PAH, as shown by: increased RV end-systolic pressure (MCT vs CTRL: 59±3 vs 26±1 mmHg) and end-diastolic pressure (MCT vs CTRL: 6.7±0.9 vs 3.5±0.7 mmHg), RV dilatation (MCT vs CTRL: 270±17 vs 215±12 μL), and decreased cardiac output (MCT vs CTRL: 29±3 vs 63±3 mL/min) and ejection fraction (MCT vs CTRL: 37±6 vs 72±2%). UCN-2 treatment resulted in attenuation of RV pressure increase (RVESP: 42±2 mmHg; RVEDP: 4.7±0.6 mmHg), dilatation (RVEDV: 212±4 μL), and in improved cardiac function (CO: 48±2 mL/min; EF: 58±2%). Conclusions: UCN-2 chronic treatment significantly reduced the worsening of RV function in PAH. These findings suggest that the UCN-2 pathway has a relevant role on the pathophysiology of PAH and RV failure, representing a potential therapeutic target.

Acute effects of levosimendan in experimental models of right ventricular hypertrophy and failure.

Pulmonary arterial hypertension (PAH) is a fatal disease, and the ultimate cause of death is right ventricular (RV) failure. In this study, we investigated the acute hemodynamic effects of levosimendan in two rat models of RV hypertrophy and failure. Wistar rats were randomized to receive sham surgery (n = 8), pulmonary trunk banding (PTB; n = 8), or monocrotaline injection (MCT; n = 7). RV function was evaluated at baseline and after injection of placebo and two concentrations of levosimendan (12 and 60 μg/kg) using magnetic resonance imaging, echocardiography, and invasive pressure recordings. PTB and MCT injection caused hypertrophy, dilatation, and failure of the RV compared with sham surgery. Levosimendan increased RV end systolic pressure (sham surgery: 16.0% ± 3.8% [P = 0.0038]; MCT: 9.9% ± 3.1% [P = 0.018]; PTB: 24.5% ± 3.3% [P = 0.0001]; mean ± SEM) compared with placebo. Levosimendan markedly increased RV stroke volume (SV) in the MCT group (29.1% ± 8.3%; P = 0.012), did not change RV SV in the PTB group (0.4% ± 4.5%; P = 0.93), and decreased RV SV in the sham surgery group (-10.9% ± 3.7%; P = 0.020). Nitroprusside, which was used to mimic the systemic arterial vasodilator action of levosimendan, did not influence RV function. These data demonstrate that levosimendan acutely improves the failing right heart in a MCT model of PAH and that the mechanism involves a direct acute positive inotropic effect on the hypertrophic and failing RV of the rat.

Transcatheter aortic valve implantation reduces grade of concomitant mitral and tricuspid valve regurgitation and pulmonary hypertension†

The presence of concomitant mitral (MR) or tricuspid regurgitation (TR) is a common issue in patients undergoing transcatheter aortic valve implantation (TAVI). The objective was (i) to analyse the outcomes of patients with concomitant moderate or more severe MR, (ii) to compare the outcomes with those of TAVI patients without concomitant MR and (iii) to evaluate the impact of TAVI on grade of concomitant MR. For creating a homogeneous study group, the study was restricted to transapical (TA)-TAVI patients. Since 2008, 615 patients have undergone TAVI at our institution, 386 of these using the TA approach with the Edwards SAPIEN™ bioprosthesis. Out of these, 116 (30.1%) presented with concomitant moderate or more severe MR. Mean logistic European System for Cardiac Operative Risk (EuroSCORE) was 18.1 ± 11.5%, EuroSCORE II 5.4 ± 0.7%. Intra- and post-hospital course, change in grade of MR, TR, right ventricular systolic pressure (RVSP) and tricuspid annular plane systolic excursion (TAPSE) were particularly analysed. Outcomes were compared with those of the remaining TA-TAVI patients (n = 270). Mean follow-up time was 471 ± 391 days, giving a total of 135 patient-years. Three patients (2.6%) died during primary hospital stay. Estimated 1-, 2-, 3- and 4-year survival rates were 76.7, 75.6, 68.3 and 50.6% for study and 78.1, 77.8, 61.1 and 55.0% for control groups, respectively. Postoperative morbidity and mortality did not differ significantly from those of the control group. Postoperatively, a significant reduction in MR (2.1 ± 0.2 to 1.5 ± 0.7; P < 0.01) and TR (1.9 ± 0.5 to 1.5 ± 0.7; P < 0.01) was observed. Likewise, RVSP decreased significantly from 46 ± 16 to 39 ± 15 mmHg (P < 0.01) and TAPSE non-significantly (21.9 ± 7.3 to 19.5 ± 5.5 mm; P = 0.07). After 3-6 months, 68.9% of the patients were at New York Heart Association (NYHA) Class I or II, 25% at Class III and 6.0% downgraded to Class IV. A reason for remaining in NYHA Class III or downgrading to NYHA Class IV could not be detected, and particularly, there was no impact of grade of MR/TR, left ventricular ejection fraction, TAPSE or right ventricular endsystolic pressure (RVESP) on outcomes or NYHA class. TA-TAVI in patients with concomitant moderate or more severe MR provides results comparable with those of TA-TAVI in general. Concomitant MR had no significant impact on the short- and mid-term outcomes. A significant reduction in MR, TR and pulmonary hypertension was observed after TA-TAVI during short-term follow-up. Nonetheless, a relevant number of patients did not experience an improvement in NYHA class.

Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.

Abstract 18705: Simian Immunodeficiency Virus Induces Pulmonary Arterial Hypertension in Rhesus Macaques: A Hemodynamic Study

Background: Our prior studies have shown that the Cyno Macaques and Resus Macaques infected with simian immunodeficiency virus (SIV) develop pulmonary arterial hyperplasia by histopathology. The hemodynamic changes with infection, however, remain unknown. The purpose of this study was to determine the relationship of the SIV infection and cardiac hemodynamic changes as assessed by invasive right heart catheterization. Methods: Five Rhesus macaques underwent pulmonary artery catheterization at baseline and 6 months after infection with SIV. Right atrial pressure (RAP), right ventricular end systolic pressure (RVESP), end diastolic pressure (RVEDP), and mean pulmonary artery pressure (mPAP) were measured directly using a pediatric pulmonary artery catheter. RV dp/dt min, dp/dt max, Tau and contractility index were calculated by Matlab software. In addition, mPAP was calculated in a larger cohort (n=24) by the regression formula: mPAP=RVSP*0.65+0.55 in order to validate this calculation in non-human primates. Results: After 6 months of SIV infection, RAP, RVSP, and mPAP increased significantly compared to baseline values. RVEDP trended toward being higher but was not statistically significant from baseline. The RV dp/dt min, dp/dt max and Tau didn’t show significant changes. The contractility index had a markedly decrease with SIV infection compared with baseline. Moreover, direct measure mPAP correlated well with the calculation of mPAP (R 2 =0.954; P&lt;0.0001). Conclusion: Based on the presented data we conclude that SIV induces pulmonary arterial hypertension in Rhesus monkeys concordant with the histopathological observation in our prior studies. SIV infection also decreases the RV contractility as well. These data suggest that this may be a viable large animal, preclinical model of PAH with hemodynamics and histology consistent with the human condition.

P4: Nitrite-mediated, xanthine oxidase-dependent diminution of obesity-related hyperglycemia and cardiopulmonary dysfunction

Background Obesity is associated with elevated tissue and plasma xanthine oxidase (XO) levels and allied enhancement of reactive species formation contributory to systemic inflammation. Despite a long standing association between increased XO activity and negative clinical outcomes, recent reports describe a paradigm shift where XO may mediate beneficial actions by reducing NO 2 - to NO. While provocative, these observations contradict both reports of improved outcomes in similar models when XO is inhibited and reports revealing anoxia as a requisite for XO-mediated NO formation. Herein, we identify a vascular microenvironment where NO 2 - reductase activity of XO is operative in the presence of O2 as well as examine effects of XO inhibition vs. NO 2 - supplementation in a high-fat diet (HFD) model of obesity. Methods Purified XO, XO bound to heparin-Sepharose 6B and XO sequestered by endothelial cell glycosaminoglycans (GAGs) was used to examine NO 2 - reductase activity as assessed by several detection platforms including enhanced chemiluminescence (NO), EPR spin trapping O 2 - and amperometric O2 detection. Male C57Blk/j6 mice were subjected to a HFD (60% calories derived from fat) for 20 weeks and treated (drinking water) with the XO-specific inhibitor febuxostat (0.5 mg/L) or NaNO2 (100 mg/L) or both for the final 6 weeks. Age-matched controls were maintained on a standard rodent chow diet consisting of 15% of adjusted calories from fat. After 20 weeks on diets mice were analyzed for right ventricular (RV) pressure volume (PV) relationship using a PV conductance catheter under steady state conditions. Results Whereas NO 2 - reductase activity of XO free in solution is only operative under anoxia, sequestration of XO on endothelial cell GAGs confers the capacity for substantive NO formation in the presence of O2 (1–2% or ∼13–26 μM) with concomitant diminution of XO-derived ROS production (↓40%). Treatment with febuxostat: reduced fasting blood glucose (223 vs. 181 mg/dL), improved (39%) impaired glucose tolerance and diminished oxidative stress in lung, liver, heart and skeletal muscle. Febuxostat also improved indices related to obesity-mediated right ventricular (RV) dysfunction and the onset of pulmonary arterial hypertension including RV end systolic pressure (RVESP) (41.2 ± 7.3 vs. 27.2 ± 5.2 mmHg), RV contractility index, pulmonary vascular resistance (PVR) (2.51 ± 0.47 vs. 1.96 ± 0.24 mmHg/mL/min), mean pulmonary artery pressure (mPAP) (25.2 ± 3.7 vs. 18.5 ± 3.0 mmHg) and Tau (diastolic function) (6.8 ± 1.3 vs. 4.5 ± 0.9). Febuxostat significantly reduced RV hypertrophy (Fulton Index), pulmonary arteriole smooth muscle (SM) remodeling (α-SM actin staining) and pulmonary tissue macrophage infiltration. Treatment of HFD mice with NO 2 - produced similar yet more pronounced beneficial effects than febuxostat in all the parameters listed above. However, combined treatment with NO 2 - + febuxostat completely abolished these protective effects, suggesting the salutary actions of NO 2 - were mediated by XO. Conclusion These data demonstrate that under hypoxic/inflammatory conditions where vascular XO levels and subsequent XO-GAG interactions are enhanced, XO-catalyzed NO 2 - reduction increases NO generation, decreases ROS production and serves to diminish indices of obesity-mediated pathology. Disclosure Supported by AHA National Scientist Development-10SDG3560005 (E.E.K.).

ESTIMATED RIGHT VENTRICULAR SYSTOLIC TIME INTERVALS FOR THE ASSESSMENT OF RIGHT VENTRICULAR FUNCTION IN ACUTE RESPIRATORY DISTRESS SYNDROME

Right ventricular (RV) systolic time intervals (STIs) have been shown to accurately reflect RV function in patients with acute respiratory distress syndrome (ARDS). The measurement of RVSTIs requires phonocardiography to define the time of RV end systole. If RV end-systolic pressure (RVESP) can be derived from peak pulmonary artery (PA) systolic pressure, then the time of RV end systole, and hence, RVSTIs can be deduced without phonocardiography. We tested this possibility. In 34 patients with ARDS, RVESP was determined on the PAP curve at RV end systole, which was defined by phonocardiography. The ratios of RVESP/peak PA systolic pressure were obtained in each patient, the mean of which was 0.90 +/- 0.006. With an application of this value, the estimated RVSTIs were determined in other groups of patients. Right ventricular end-systolic pressure was estimated from the peak PA systolic pressure by multiplying 0.9. Then the point of RV end systole was determined on the electrocardiographic tracing that coincided with the point of RVESP on the PAP curve by simultaneous display of electrocardiograph and PAP curve. Total electromechanical systole was measured from the onset of the QRS complex to the point of RV end systole on the electrocardiograph. The onset of RV ejection was defined by PAP curve. The validity of this estimated RVSTIs was tested by comparing with the measured RVSTIs. By Bland-Altman analysis, the mean difference in RVSTIs between the two methods was 0.007, and bias was 0.0036, suggesting close agreement. The estimated RVSTIs can be used to accurately assess RV function.