Right Ventricular Peak Systolic Pressure Research Articles

Dimethyl Sulfoxide Induces Hemolysis and Pulmonary Hypertension.

Vascular and lung injury are well established complications associated with hemolytic disorders, and hemolysis associated pulmonary hypertension (PH) has emerged as the most serious complication of sickle cell disease. The causal relationship between intravascular hemolysis and the development of PH is still under investigation. Previously we have shown that repetitive administration of hemolyzed autologous blood causes PH in rats. Dimethyl sulfoxide (DMSO), a widely used solvent and anti-inflammatory agent, induces hemolysis in vivo. We hypothesized that repetitive administration of DMSO would induce PH in rats. We also examined hemolysis-induced release of adenosine deaminase (ADA) and arginase from red blood cells, which may amplify hemolysis-mediated vascular injury. Acute administration of DMSO (1.5ml/30 min into the right atrium) induced intravascular hemolysis and pulmonary vasoconstriction. DMSO-induced increase in right ventricular peak systolic pressure (RVPSP) was associated with increased release of ADA. Notably, the acute increase in RVPSP was attenuated by administration of an adenosine A2A receptor agonist or by pretreatment of animals with ADA inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA). Repetitive administration of DMSO for 10 days produced anemia, hemoglobinuria, hemoglobinemia, splenomegaly, and development of PH. Histopathological analysis revealed pulmonary vascular remodeling. The presented data describe a new model of hemolysis induced PH, suggesting that hemolysis is mechanistically related to pulmonary hypertension, and pointing to a potential pathogenic role that adenosine deaminase and accelerated adenosine metabolism may play in hemolysis associated pulmonary hypertension.

Abnormal Pulmonary Artery Bending Correlates With Increased Right Ventricular Afterload Following the Arterial Switch Operation.

In transposition of great arteries, increased right ventricular (RV) afterload is observed following arterial switch operation (ASO), which is not always related to pulmonary artery (PA) stenosis. We hypothesize that abnormal PA bending from the Lecompte maneuver may affect RV afterload in the absence of stenosis. Thus, we sought to identify novel measurements of three-dimensional cardiac magnetic resonance (CMR) images of the pulmonary arteries and compare with conventional measurements in their ability to predict RV afterload. Conventional measurements and novel measurements of the pulmonary arteries were performed using CMR data from 42 ASO patients and 13 age-matched controls. Novel measurements included bending angle, normalized radius of curvature (Rc), and normalized weighted radius of curvature (Rc-w). Right ventricular systolic pressures (as the surrogate for RV afterload) were measured by either recent echocardiogram or cardiac catheterization. Conventional measurements of proximal PA size correlated with differential pulmonary blood flow (r = 0.49, P = .001), but not with RV peak systolic pressures (r = -0.26, P = .18). In ASO patients, Rc-w correlated with higher RV systolic pressures (r = -0.57, P = .002). Larger neoaortic areas and rightward bending angles correlated with smaller right pulmonary artery Rc (r = -0.48, P = .001; r = 0.41, P = .01, respectively). Finally, both pulmonary arteries had significantly smaller Rc compared to normal controls. Pulmonary arteries exhibit abnormal bends following ASO that correlate with increased RV afterload, independent of PA stenosis. Future work should focus on clinical and hemodynamic contributions of these shape parameters.

VALIDATING THE USE OF PULMONARY ARTERY ACCELERATION TIME IN ESTIMATING PULMONARY PRESSURE IN NEONATES

Abstract BACKGROUND Estimation of right ventricular peak systolic pressure (RVSP) or pulmonary pressure using echocardiography is crucial in neonates with acute or chronic pulmonary hypertension. Conventionally in echocardiography, the maximal velocity of the Tricuspid Regurgitant jet (TR Vmax) is used to estimate the RVSP. However, TR jet can often be absent or unmeasurable in neonates, resulting in a need to search for alternative echocardiographic measures of pulmonary pressure in neonates. Pulmonary Artery Doppler Waveform Parameter known as Pulmonary Artery Acceleration Time (PAAT) has been investigated in adults and older children and found to be reliable in estimating pulmonary pressure. To date, no such validation study exists for neonates.Hence we designed this study to explore the role of Pulmonary Artery Acceleration Time in estimating pulmonary pressures in neonates. OBJECTIVES To identify the pulmonary artery doppler waveform parameter that most closely reflects pulmonary pressure and analyse the impact of baseline variables and measurement techniques on this relationship. DESIGN/METHODS This was a retrospective cohort analysis conducted at two tertiary neonatal intensive care units. All neonates who underwent Targeted Neonatal Echocardiographic(TnECHO) assessments over May 2014-May 2017 were assessed for eligibility. Neonates whose echocardiography revealed a complete, measurableTR jet were included. Baseline characteristics such as gestational age, chronological age at echo, weight, blood pressure, ventilation and diagnosis were collected. Echocardiographic parameters such as TR Vmax, Pulmonary artery doppler waveform parameters such as Right Ventricular Ejection Time (RVET) and Pulmonary Artery Acceleration Time (PAAT) were measured by a single expert operator. Pulmonary Vascular Resistance Index (PVRI) was calculated as a ratio between RVET and PAAT. Correlation between pulmonary artery waveforms and RVSP estimated from the TR jet was examined using Pearson or Spearman analysis as appropriate. Univariate and multivariate regression analysis was used to further explore the influence of relevant factors on this relationship. Ethical approval was obtained from the institutional ethic board. RESULTS 678 neonates with 1767 echocardiographic studies were screened for eligibility of which 201 scans were included. Mean gestational age of this cohort was 30.5+/-5.7 weeks with mean birthweight of 1635 +/-1115 grams. Pulmonary Vascular Resistance Index (ratio of RVET to PAAT) also known as indexed PAAT, measured by Pulsed Wave Doppler at the level of the main pulmonary artery was found to have the strongest correlation with RVSP estimated from TRVmax. [r=0.45,P<0.05]. Using regression analysis, we could generate an equation to estimate systolic pulmonary artery pressures(ESPAP) directly from PVRI. [ESPAP= 25.53 + 3.97xPVRI, p<0.0001]. At the multivariate level, factors such as the Systolic Blood Pressure at time of echocardiogram and the presence or absence of PDA were found to have a statistically significance influence on this relationship. Pulmonary Vascular Resistance Index could be measured on all eligible scans. Inter-observer and intra-observer reliability assessment completed on a random subset of 30 showed excellent reliability for PVRI. [ICC =0.88, P<0.000] CONCLUSION This important validation study shows that PAAT indexed to right ventricular ejection time(PVRI) has statistically significant correlation with pulmonary pressures as measured by TR jet in neonates. However the strength of correlation in neonates is moderate at best. The measurement is feasible with good interobserver agreement and potentially can play an important role in serial monitoring of pulmonary pressures in neonates without any demonstrable TR jet on echocardiography.

Signaling pathways underlying skeletal muscle wasting in experimental pulmonary arterial hypertension

BackgroundSkeletal muscle wasting contributes to the poor functional status and quality of life of patients with pulmonary arterial hypertension (PAH). The present study aims to characterize the molecular mechanism underlying skeletal muscle wasting in experimental PAH induced by monocrotaline (MCT). MethodsMale Wistar rats were randomly injected with saline solution (CONT; n=10) or MCT (MCT; 60mg/kg, s.c.; n=15). After 4weeks of MCT or vehicle administration, animals were anesthetized and submitted to right ventricular (RV) hemodynamic evaluation. Blood and gastrocnemius samples were collected and stored for analysis. ResultsMCT group developed PAH (70% increase in RV peak systolic pressure) RV dysfunction (increased end-diastolic pressure and Tau), and body and muscle wasting (reduction of 20%, 16% and 30% on body weight, gastrocnemius mass and fiber cross sectional area, respectively). Muscle atrophy was associated with a decrease in type I MHC. Circulating (C reactive protein, myostatin and IL-1beta) and local catabolic markers (MAFbx/atrogin-1, protease activity) were increased in MCT animals, while Akt/mTOR pathway was preserved. Mitochondria isolated from gastrocnemius of MCT animals showed decreased activity of ATP synthase, lower levels of Tfam, accumulation of oxidatively modified proteins together with reduced levels of paraplegin. ConclusionsOur data suggests an anabolic/catabolic imbalance in gastrocnemius from MCT-induced PAH rats. Accumulation of dysfunctional mitochondria due to the inefficiency of protein quality control systems to eliminate damaged proteins could also contribute to muscle atrophy in PAH.

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Introduction: Right ventricular (RV) dysfunction can occur after cardiac surgery. Although the exact mechanism is not well understood, it has been suggested to be associated with pericardial incision as well as other factors related to cardiac surgery. Speckle Tracking Echocardiography was performed to assess RV systolic and diastolic function before and after cardiac surgery. Methods: RV speckle tracking was performed by transthoracic echocardiography before (mean 20.4hrs ±27) and after surgery (mean 47hrs ±33) in 50 patients (mean age 67.2 years ±12, 64% male) undergoing a variety of cardiac operations: 3 coronary artery bypass grafts, 12 aortic valve replacement, 3 mitral or aortic valve mass removal, 16 open and 16 robotic-assisted minimally-invasive mitral valve repair. The following strain parameters were measured: systolic function parameters include RV free wall longitudinal strain (RV LS) and strain rate (RV LSR), and diastolic function parameter RV free wall longitudinal early strain rate relaxation (RV LSRe). Results: RV systolic function assessed by speckle tracking was significantly reduced after cardiac surgery: RV longitudinal strain -25.3% to -15.5% (p<0.001), RV longitudinal strain rate -1.5 to -0.94 (p<0.001). RV diastolic function assessed by speckle tracking was similarly reduced: RV longitudinal strain rate early relaxation 1.4 to 0.92 (p<0.001). Conventional assessment methods of RV function also showed significant reductions: TAPSE 24.7mm to 13.4mm (p<0.001), Tricuspid valve S’ 0.14m/s to 0.08m/s (p<0.001), RIMP 0.39 to 0.54 (p<0.001), RV E:e’ 4.3 to 7.2 (p<0.001). RV fractional area change, E:A ratio and RV systolic pressure estimation did not significantly change. There was no significant association for the reduction in RV systolic or diastolic function assessed by speckle tracking (RV LS, RV LSR, RV LSRe) with echo-based RV peak systolic pulmonary artery pressures, cross clamp or bypass time, time to extubation, vasoactive requirement or number of days in hospital. The association between the reduction in RV longitudinal strain and whether surgery was minimally invasive approached significance (p=0.055), with minimally invasive surgery having a smaller reduction in strain values. Conclusions: RV systolic and diastolic function decreases significantly after cardiac surgery. This reduction is independent of echo-based RV peak systolic artery pressure estimation, cross-clamp or bypass time, vasoactive requirements, intubation time or number of days in hospital. RV longitudinal strain reduction may be smaller if surgery is minimally invasive supporting the concept that RV dysfunction is associated with the size of pericardial incision. Larger studies are warranted to extend this finding.

Inhibitory effect of nitric oxide-induced total ginsenosides on right ventricular hypertrophy in rats

To observe the effect of total ginsenosides (TG) on right ventricular hypertrophy induced by monocrotaline (MCT) in rats, and study its relationship with the nitric oxide pathway. Male Sprague Dawley rats were randomly divided into the control group, the MCT model group, TG-treated (20, 40, 60 mg kg-1 d-1) groups, and the L-arginine (L-arg) th NO release, T + L-N and L-a + L-N groups were wi th NOS into study TG's effect 200 mg kg-1 d-1 group. Besides, and its relationship wi also set, intraperitoneally injected with TG 40 mg kg-1 d -1 and L-arg 200 mg kg-1 - d-1, and orally administered hibitor L-NAME 20 mg kg-1 d-1. After all of the groups were given drugs for 18 d, their right ventricular peak systolic pressure (RVSP) ventricular hypertrophy index (RVHI) and RVW/BW were determined. Ultra-structure of myocardial cells was observed with transmission electron microscope. The NO2 -/NO3 - content in myocardial tissues were detected with the nitrate reduction method. ANF and eNOS mRNA expressions in right ventricle tissues were detected by using real-time RT-PCR. Low, middle and high doses of TG and L-arg preventive administration could significantly reduce RVSP, RVHI, RVW/BW and ANF mRNA expressions (P < 0. 05) , and ameliorate cellular mitochondrial swelling and degeneration. L-NAME could prevent the effect of L-arg on above indexes, whereas L-NAME of the same dose could not impact the reducing effect of TG 40 mg kg -1 on above indexes. TG 60 mg kg -1 could raise eNOS mRNA expression, but TG 20 mg kg-1 and 40 mg kg-1 showed no effect. TG can significantly attenuate MCT-induced right cardiac hypertrophy in rats. Its anti-hypertrophic effect is partially realized through NO.

Survivin role in pulmonary arterial hypertension

Purpose: Survivin is an inhibitor of apoptosis expressed in the vascular lesions of pulmonary arterial hypertension (PAH) and is also involved in myocardial remodeling during left heart failure. The current work aims at: investigating right ventricular (RV) expression of survivin and smac/DIABLO (an inhibitor of survivin) throughout the hemodynamic and morphometric progression of monocrotaline (MCT)-induced PAH; and characterizing the effects of the survivin antagonist terameprocol in pulmonary artery smooth muscle cells (PASMC). Methods: Animal experiments were performed according to the Portuguese law for animal welfare and to the Principles of laboratory animal care (NIH Publication no. 85-23 revised 1985). Adult male Wistar rats received a subcutaneous injection of MCT (60 mg/kg) or equal volume of vehicle. On days 1, 3, 7, 14 and 21 after injection (n=7-12 per group per time-point), RV pressures were measured, heart and lungs were weighted and RV and lung samples were collected for histological analysis. Survivin and smac/DIABLO expression in the RV was determined by immunohistochemistry and western blotting. In a different protocol, a primary culture of PASMC isolated from sham and MCT-treated rats (day 21) was established and the effects of terameprocol in cell proliferation and apoptosis were evaluated by BrdU and TUNEL assays, respectively. Results: RV survivin expression was significantly increased in the MCT groups since day 7, when compared with the SHAM groups. Smac/DIABLO followed an inverse expression pattern with a significant decrease in the MCT groups identified since day 7. This time-point corresponded to the first evidence of RV hypertrophy in MCT-treated rats. Survivin overexpression preceded hemodynamic manifestations of the disease, which started at day 14 with significant increases in RV peak systolic pressure and absolute values of dP/dtmax and dP/dtmin. Terameprocol significantly inhibited proliferation and induced apoptosis of PASMC from sham and pulmonary hypertensive rats in a dose-dependent manner. The pattern of proliferation and apoptosis did not differ significantly between SHAM and MCT groups. Conclusions: Our results demonstrate that survivin upregulation and smac/DIABLO downregulation in the RV precede hemodynamic manifestations of PAH and pair RV hypertrophy, strongly suggesting a role in cardiac remodeling. Pharmacological inhibition of survivin halted cell proliferation and induced apoptosis of PASMC. These findings suggest that targeting survivin in PAH could have dual beneficial effects by reversing pulmonary vascular remodeling and myocardial hypertrophy.

The effect of endogenous estrogen on Doppler-estimated right ventricular systolic pressure during exercise

We evaluated the effect of endogenous estrogen levels on exercise-related changes in right ventricular systolic pressure (RVSP) of healthy, eumenorrheic, sedentary women. Volunteers were studied at two separates phases of the menstrual cycle (LO and HI estrogen phases), exercised on a semi-supine ergometer with escalating workload and monitored continuously by 12-lead ECG and automated blood pressure cuff. At each exercise stage, Doppler echocardiography measurements were obtained and analyzed to determine RVSP. Fourteen subjects (age 24 ± 5) were studied. Exercise duration was significantly higher on the HI estrogen day, but no significant differences in hemodynamic response to exercise were found between the two study days. There were also no significant differences with respect to heart rate (HR) acceleration during early exercise, as well as resting and peak RVSP, HR, blood pressure, and rate pressure product. Doppler-estimated RVSP demonstrated a linear relationship to HR at a ratio of 1 mm Hg (1 mm Hg = 133.3224 Pa) for every 5 bpm (beats per minute) increase in HR. There were no differences in the slope of this relationship between HI and LO estrogen phases of the menstrual cycle. Our findings did not demonstrate any effect of endogenous estrogen levels on the modulation of the pulmonary vascular response to exercise in healthy women.

Abstract 230: Gender Differences in the Development of Experimental Pulmonary Hypertension and Associated Right Ventricular Remodeling: The Role of Estrogen Rescue

17-beta estradiol or Estrogen (E2) pre-treatment has been shown to attenuate the development of pulmonary hypertension (PH). Here, we aim to investigate the gender differences and the effect of ovariectomy on the development of experimental PH and adverse right ventricular (RV) remodeling. We also evaluate the therapeutic potential of E2 in rescuing PH and adverse RV remodelling in male and female rats. Male and female (intact and ovariectomized (OVX)) rats were treated with a single injection of monocrotaline (MCT, 60mg/kg, s.c.) to induce PH. Twenty one days after MCT, rats developed severe PH. At this point, one set of rats from each group was left untreated to develop PH-induced right ventricular failure (RVF), whereas the other set received E2 (42.5 ug/kg/day, 10-day slow release s.c. pellets). E2-treated rats were observed for an additional 12 days after cessation of therapy to check whether the effects of therapy were long-lived. Saline treated rats served as control (CTRL). Serial echocardiography was performed to monitor cardiopulmonary hemodynamics. Direct RV catheterization was terminally performed to record RV peak systolic pressure (RVPSP). The expression of novel extracellular matrix (ECM) enzymes A Disintegrin And Metalloproteinase (ADAM15 and 17) and Osteopontin (OPN) were assessed by RT-PCR. Intact females developed less severe PH than males and OVX females at day 30 (RVPSP: Females=62±3, Males=74±3, OVX=77±3 mm Hg, p&lt;0.05 vs. respective CTRL). E2 therapy resulted in rescue of PH in all groups (RVPSP: Females=36±4, Males=38±2, OVX=44±2 mm Hg, p&lt;0.05 vs. respective PH-RVF). Intact females also developed less severe RV remodeling compared to males and OVX females. Expression of OPN increased ∼7-9-fold in PH-RVF males and OVX but only ∼2-fold in intact females, (p&lt;0.05 vs. CTRL for all). E2 reversed OPN upregulation in all groups (p&lt;0.05 vs. PH-RVF). Novel ECM-degrading Disintegrin-Metalloproteinases ADAM15 and ADAM17 transcripts were also elevated ∼2-fold in all PH-RVF animals (p&lt;0.05 vs. CTRL). E2-therapy reversed RV remodeling in all groups (p&lt;0.05 vs. PH-RVF). In conclusion, intact females are more protected against the development of PH compared to males and OVX females. E2 rescues PH and adverse RV remodeling in all groups.

Subharmonic microbubble emissions for noninvasively tracking right ventricular pressures

Right heart catheterization is often required to monitor intra-cardiac pressures in a number of disease states. Ultrasound contrast agents can produce pressure modulated subharmonic emissions that may be used to estimate right ventricular (RV) pressures. A technique based on subharmonic acoustic emissions from ultrasound contrast agents to track RV pressures noninvasively has been developed and its clinical potential evaluated. The subharmonic signals were obtained from the aorta, RV, and right atrium (RA) of five anesthetized closed-chest mongrel dogs using a SonixRP ultrasound scanner and PA4-2 phased array. Simultaneous pressure measurements were obtained using a 5-French solid state micromanometer tipped catheter. Initially, aortic subharmonic signals and systemic blood pressures were used to obtain a calibration factor in units of millimeters of mercury per decibel. This factor was combined with RA pressures (that can be obtained noninvasively) and the acoustic data from the RV to obtain RV pressure values. The individual calibration factors ranged from -2.0 to -4.0 mmHg/dB. The subharmonic signals tracked transient changes in the RV pressures within an error of 0.6 mmHg. Relative to the catheter pressures, the mean errors in estimating RV peak systolic and minimum diastolic pressures, and RV relaxation [isovolumic negative derivative of change in pressure over time (-dP/dt)] by use of the subharmonic signals, were -2.3 mmHg, -0.8 mmHg, and 2.9 mmHg/s, respectively. Overall, acoustic estimates of RV peak systolic and minimum diastolic pressures and RV relaxation were within 3.4 mmHg, 1.8 mmHg, and 5.9 mmHg/s, respectively, of the measured pressures. This pilot study demonstrates that subharmonic emissions from ultrasound contrast agents have the potential to noninvasively track in vivo RV pressures with errors below 3.5 mmHg.

Three-dimensional analysis of interventricular septal curvature from cardiac magnetic resonance images for the evaluation of patients with pulmonary hypertension

Although abnormal septal motion is a well-known sign of increased pulmonary arterial pressures, it is not routinely used to quantify the severity of pulmonary hypertension (PH). This determination relies on invasive measurements or Doppler echocardiographic estimation of right ventricular (RV) pressures, which is not always feasible or accurate in patients with PH. We hypothesized that dynamic 3D analysis of septal curvature from cardiac magnetic resonance (CMR) images may reveal differences between patients with different degrees of PH. Forty-four patients (14 controls; 30 PH patients who underwent right heart catheterization) were studied using CMR and echocardiography. CMR imaging was performed using Philips 1.5T scanner with a phased-array cardiac coil, in a retrospectively gated steady-state free precession cine mode at 30 frames per cardiac cycle. Patients were divided into 3 subgroups according to pulmonary arterial pressure. CMR images were used to reconstruct dynamic 3D left ventricular endocardial surfaces, which were analyzed to calculate septal curvature throughout the cardiac cycle. 3D curvature analysis was feasible in 88% patients. Septal curvature showed different temporal patterns in different groups. Curvature values progressively decreased with increasing severity of PH, and correlated well with invasive pressures (r-values 0.78-0.79), pulmonary vascular resistance (r = 0.83) and Doppler-derived RV peak-systolic pressure (r = 0.75). 3D analysis of septal curvature from CMR images may become a useful component in the CMR examination in patients with known or suspected PH.

Proinflammatory Events in Right Ventricular Damage During Pulmonary Embolism: Effects of Treatment With Ketorolac in Rats

Right ventricular (RV) damage contributes to poor clinical outcome after pulmonary embolism (PE). Our studies show that neutrophils contribute to RV dysfunction in rat PE. Present studies examine effects of the nonsteroidal anti-inflammatory drug, ketorolac, upon RV inflammation and dysfunction. RV inflammatory gene expression significantly increased 6 and 18 hours after PE [cytokine-induced neutrophil chemoattractant-1 (CINC-1) 18-fold and 24-fold; cyclooxygenase-2 21-fold and 32-fold]. Eighteen hours after PE, there was significant upregulation of adhesion molecules (selectin E 18-fold; intercellular adhesion molecule 1 14-fold), influx of neutrophils (myeloperoxidase activity 21-fold), depressed RV function (RV peak systolic pressure = 24 +/- 3 vs. 40 +/- 1 mm Hg; maximum rate of pressure development = 444 +/- 79 vs. 1533 +/- 146; maximum rate of pressure decrease = -357 +/- 50 vs. -651 +/- 44), and release of cardiac troponin I (7.8 +/- 1.9 ng/mL) compared with vehicle. Ketorolac (10 mg/kg, intraperitoneally) significantly reduced expression of CINC-1, cyclooxygenase-2, selectin E, and intercellular adhesion molecule 1, lowered neutrophil influx, improved RV function (RV peak systolic pressure was 34 +/- 3 mm Hg; maximum rate of pressure development = 1288 +/- 146; maximum rate of pressure decrease = -611 +/- 92), and marginally reduced cardiac troponin I release (P < 0.07) compared with PE alone. Ketorolac reduced CINC-1 stimulated chemotaxis of isolated neutrophils. PE converted cardiac tissue into a proinflammatory phenotype. Ketorolac reduced RV inflammatory genes, reduced neutrophil influx, and improved RV function in rat PE.

Abstract 325: Administration Of Apelin Modulates Myocardial Expression Of Apelin-apj And Improves Right Ventricular Performance In Mct-induced Pulmonary Hypertension

Background: Apelin (AP) is the endogenous vasoactive ligand of APJ receptor. It is widely expressed in the heart and lungs and has important cardiovascular functions such as endothelium-dependent vasodilatation and positive inotropic effect. However, the role of apelin-APJ system in pulmonary hypertension (PH) remains to be clarified. Objective: To evaluate the chronic effects of apelin in: right ventricular (RV) myocardial function; cardiac expression of apelin and APJ in healthy and MCT-PH rats Methods: Male Wistar rats were randomly injected with MCT (60mg/Kg, sc) or vehicle (CTR, day 0). One week later, half of these animals were randomly treated with Pyr-apelin-13 (200μg/Kg/day, ip) or a similar volume of vehicle. The study resulted in 4 groups: CTR; AP; MCT and MCT+ AP. At day 24, animals were instrumented to record RV peak systolic (Pmax) pressures, dP/dtmax, dP/dtmin and time constant Tau. Also, heart and lungs were weighted and transmural RV samples were collected for relative quantification of mRNA by real-time RT-PCR. Results are on table . Conclusions: In healthy rats, exogenous apelin potentiates its endogenous production with no significant changes in APJ. MCT-induced PH resulted in a significant down-regulation of apelin-APJ system, which might play a role in the systolic and diastolic dysfunction observed in this model. This down-regulation was completely reverted by chronic administration of exogenous apelin. Therefore, apelin upregulates the cardiac apelin-APJ system exerting beneficial effects on cardiac remodeling and function, namely, by decreasing PH, RV diastolic function and hypertrophy. These results reveal the importance of apelin-APJ system in the pathophysiology of PH, suggesting that apelin is a potential therapeutic target in this disease. Results table

Abstract 2586: Tricuspid Valve Repair During Left Ventricular Assist Device Insertion

Purpose Right ventricular (RV) failure is associated with significant post-operative morbidity and mortality after left ventricular assist device (LVAD) insertion. Concomitant tricuspid valve repair (TVR) in the setting of tricuspid regurgitation (TR) is frequently performed to improve RV function after LVAD insertion. This study compared outcomes of patients with TR after LVAD insertion with and without TVR. Methods This was a retrospective case control study of 70 patients with matched degrees of TR undergoing LVAD implantation from 2000 to 2006 (Heartmate1, Heartmate2, DeBakey MicroMed). The TVR group consisted of patients undergoing LVAD insertion with TVR (n=24). The control group consisted of patients undergoing LVAD insertion without TVR (n=46). TR was quantified as 0 (none) to 4+ (severe) on echocardiography preoperatively and postoperatively. RV dysfunction score was defined as 0 (none), 1 (mild), 2 (moderate), or 3 (severe) on echocardiography. Postoperative clinical parameters, complications, and outcomes were evaluated. Results The TVR group and control group were similar in age (55y±15 vs 53y±12 respectively), gender distribution (18/24 male vs 42/46 male), ejection fraction (16%±5 vs 16%±6), LVAD score (preoperative measure of risk assessment 0–10), TR, mean PAP, CVP, and peak RV systolic pressure. In the TVR group, TR decreased from 2.0±0.8 to 0.7±0.5 post-operatively (p&lt;0.001). In the control group, TR also decreased from 2.2±0.7 to 1.3±0.8 (p&lt;0.001). In the TVR group, RV dysfunction score fell from 2.1±0.6 to 1.4±1.0 (p=0.01). In the control group, RV dysfunction score fell from 2.1±0.8 to 0.8±1.1 (p=0.049). Bypass time was higher in the TVR group (124±33min vs 66±46min). Incidence of acute renal failure (ARF) was lower in the TVR group (OR 0.2, p=0.02). There were no differences between the two groups regarding need for post-operative RVAD, early extubation, ICU LOS, bridge to transplant rate, or 30 day mortality. Conclusion Patients with TR requiring LVAD insertion had no improved survival when TVR was performed simultaneously. Bypass time was prolonged when TVR was performed. Patient groups with and without TVR had similar decreases in TR and improvement in RV dysfunction. Incidence of ARF was lower in the TVR group.

Cardiac inflammation contributes to right ventricular dysfunction following experimental pulmonary embolism in rats

Acute right ventricular (RV) failure following pulmonary embolism (PE) is a strong predictor of poor clinical outcome. Present studies test for an association between RV failure from experimental PE, inflammation, and upregulated chemokine expression. Additional experiments test if neutrophil influx contributes to RV dysfunction. PE was induced in male rats by infusing 24 μm microspheres (right jugular vein) producing mild hypertension (1.3 million beads/100 g, PE1.3), or moderately severe hypertension (2.0 million beads/100 g, PE2.0). Additional rats served as vehicle sham (0.01% Tween 20, Veh). In vivo RV peak systolic pressures (RVPSP) increased significantly, and then declined following PE2.0 (51 ± 1 mm Hg 2 h; 49 ± 1, 6 h; 44 ± 1, 18 h). RV generated pressure of isolated, perfused hearts was significantly reduced in PE2.0 compared with PE1.3 or Veh. MCP-1 protein (ELISA) was elevated 21-fold and myeloperoxidase activity 95-fold in RV of PE2.0 compared with Veh or PE1.3. CINC-1, CINC-2, MIP-2, MCP-1, and MIP-1α mRNA also increased in RV of PE2.0. Histological analysis revealed massive accumulation of neutrophils (selective esterase stain) and monocyte/macrophages (CD68, ED-1) in RV of PE2.0 hearts in regions of myocyte damage. Electron microscopy showed myocyte necrosis and phagocytosis by inflammatory cells. LV function was normal and did not show increased inflammation after PE2.0. Treatment with anti-PMN antibody reduced RV MPO activity and prevented RV dysfunction. Conclusions-PE with moderately severe pulmonary hypertension (PE2.0) resulted in selective RV dysfunction, which was associated with increased chemokine expression, and infiltration of both neutrophils and monocyte/macrophages, indicating that a robust immune response occurred with RV damage following experimental PE. Experimental agranulocytosis reduced RV, suggesting that neutrophil influx contributed to RV damage.

2-Methoxyestradiol mediates the protective effects of estradiol in monocrotaline-induced pulmonary hypertension

When exposed to chronic hypoxia or toxin monocrotaline (MCT), female animals develop less severe pulmonary arterial hypertension (PH) compared to males; ovariectomy (OVX) exacerbates PH, and OVX animals treated with estradiol (E2) develop less severe disease. There is a line of evidence suggesting that cardiovascular protective effects of E2 are mediated by its major metabolite, 2-methoxyestradiol (2ME). Recently, we have shown that 2ME attenuates the development and retards the progression of MCT-induced pulmonary hypertension in male rats. We hypothesized that the protective effects of E2 in experimental PH are mediated by 2ME. Subsets of intact and OVX female rats were injected saline (Cont and OXV groups) or MCT (60 mg/kg; MCT and OVX-MCT groups) and some of OVX-MCT animals were treated with 2ME (10 μg/kg/h via osmotic minipumps; OVX-MCT + 2ME). After 28 days, MCT caused PH, i.e., increased right ventricular peak systolic pressure (RVPSP) and right ventricle/left ventricle + septum (RV/LV + S) ratio, induced inflammatory response in the lungs and caused media hypertrophy (media thickness and % media index) and adventitia widening of small size pulmonary arteries. Ovariectomy exacerbated the disease, i.e., further increased RVPSP, and RV/LV + S ratio, and augmented vascular remodeling and inflammatory response. In diseased OVX rats, treatment with 2ME prevented the worsening of PH and attenuated the inflammatory response and vascular remodeling. No mortality was recorded in the OVX-MCT + 2ME group vs. 10% and 36% mortality in the MCT and OVX-MCT group, respectively. This study suggests that 2-methoxyestradiol (a major non-estrogenic metabolite of E2) may mediate the protective effects of estradiol in MCT-induced PH, and warrants further evaluation of 2ME for treatment of PH.

Medroxyprogesterone Acetate Attenuates and Tibolone Prevents the Development of Monocrotaline‐Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is predominantly a female disease, yet little is known regarding the effects of female hormones in PH, and oral contraceptives and hormone replacement therapy have been suggested as potential risk factors for PH. Recently we have shown that progesterone attenuates the development of monocrotaline (MCT)-induced PH in ovariectomized (OVX) rats. Therefore, we investigated the effects of medroxyprogesterone acetate (MPA, a synthetic progestin) and tibolone (TIB, a combined steroidal progestogenic and estrogenic compound) on the development of MCT-induced PH. OVX rats were randomly administered either saline (CONT, n=7), MCT (60mg/kg i.p., n=10), MCT+MPA (10mg/kg/day, s.c.; MPA group; n=8) or MCT+TIB (2mg/kg/day, p.o.; TIB group; n=8). After 35 days the right ventricular peak systolic pressure (RVPSP) was assessed. MCT significantly elevated RVPSP (58.1±2.6 vs. 28.6±1.1 mmHg, MCT vs. CONT) and increased right ventricle/left ventricle+septum ratio (RV/LV+S: 0.411±0.0210 vs. 0.247±0.007, MCT vs. CONT; p<0.001). MPA attenuated the development of PH and tibolone prevented MCT from inducing PH (RVPSP: 40.1±3.7 and 33.0±3.5 mmHg; RV/LV+S: 0.327±0.023 and 0.260±0.015; MPA and TIB, respectively). MCT induced a 30% mortality, with no mortality in MPA or TIB groups. This study suggests that progestins and combined progestin/estrogen compounds may have protective effects in PH and warrants further investigation of the progestin estrogen interactions in pulmonary hypertension. (Supported by AHA Award #0455778U)

Estradiol Metabolites Attenuate Monocrotaline-Induced Pulmonary Hypertension in Rats

Pulmonary arterial hypertension (PH) is a deadly disease characterized by pulmonary arterial vasoconstriction and hypertension, pulmonary vasculature remodeling, and right ventricular hypertrophy. Our previous in vivo studies, performed in several models of cardiac, vascular, and/or renal injury, suggest that the metabolites of 17beta-estradiol may inhibit vascular and cardiac remodeling. The goal of this study was to determine whether 2-methoxyestradiol (2ME), major non-estrogenic estradiol metabolite, prevents the development and/or retards the progression of monocrotaline (MCT)-induced PH. First, a total of 27 male Sprague Dawley rats were injected with distillated water (Cont, n=6) or monocrotaline (MCT; 60 mg/kg, i.p.; n=21). Subsets of MCT animals (n=7 per group) received 2ME or its metabolic precursor 2-hydroxyestradiol (2HE; 10 microg/kg/h via osmotic minipumps) for 21 days. Next, an additional set (n=24) of control and MCT rats was monitored for 28 days, before right ventricular peak systolic pressure (RVPSP) was measured. Some pulmonary hypertensive animals (n=8) were treated with 2ME (10 microg/kg/h) beginning from day 14 after MCT administration. MCT caused pulmonary hypertension (ie, increased right ventricle/left ventricle+septum [RV/LV+S] ratio and wall thickness of small-sized pulmonary arteries, and elevated RVPSP) and produced high and late (days 22 to 27) mortality. Pulmonary hypertension was associated with strong proliferative response (PCNA staining) and marked inflammation (ED1+cells) in lungs. Both metabolites significantly attenuated the RV/LV+S ratio and pulmonary arteries media hypertrophy and reduced proliferative and inflammatory responses in the lungs. Furthermore, in diseased animals, 2ME (given from day 14 to 28) significantly decreased RVPSP, RV/LV+S ratio and wall thickness, and reduced mortality by 80% (mortality rate: 62.5% vs. 12.5%, MCT vs. MCT+2ME day 14 to 28). This study provides the first evidence that 2ME, a major non-estrogenic, non-carcinogenic metabolite of estradiol, prevents the development and retards the progression of monocrotaline-induced pulmonary hypertension. Further evaluation of 2ME for management of pulmonary arterial hypertension is warranted.

Increased Right Ventricular Afterload Induces Postsystolic Thickening of the Ventricular Septum in Nonischemic Hearts

We aimed to assess whether myocardial postsystolic thickening (PST) can be induced by an acute increase in right ventricular (RV) afterload and, thus, demonstrate that PST may have a nonischemic cause. In 8 anesthetized open-chest pigs, radial strains of the interventricular septum (IVS) and left ventricular inferolateral wall were obtained by Doppler tissue echocardiography before and during constriction of the pulmonary artery. After each constriction, RV peak systolic pressure increased from 30 +/- 5 to 57 +/- 8 mm Hg (P < .001). Peak systolic radial strain of the IVS decreased from 20.8% +/- 5.3% to 9.5% +/- 4.1% (P = .003), and PST of the IVS increased from 0.3% +/- 0.5% to 6.1% +/- 4.8% (P = .01). The onset of PST started 41 +/- 20 milliseconds after peak negative dP/dt of RV pressure. The inferolateral wall did not show PST. An acute increase in RV pressure causes a significant reduction in peak systolic strain of the IVS associated with the nonischemic appearance of PST.

775 Administration of ghrelin modulates its myocardial expression and attenuates neurohumoral activation in MCT-induced pulmonary hypertension

We recently showed that ghrelin (ghr), attenuates pulmonary hypertension (PH), right ventricular and pulmonary vascular remodelling in monocrotaline (MCT) rats. We also showed, in this model of selective right ventricular (RV) overload, failure of the non-overloaded left ventricle (LV), which correlated with autocrine/paracrine activation. In the present study we evaluated the effects of ghr on biventricular function, myocardial expression of ghr and autocrine/paracrine activation in MCT model. Adult Wistar rats were injected with MCT (60 mg/Kg, sc) or just the vehicle (day 0). One week later, animals treated with MCT were randomly divided and treated with ghr (100 ~g/Kg, BID, sc) or with a similar volume of vehicle. The study resulted in 3 groups: (i) control (Ctrl, n=7), (ii) MCT (n=9), (iii) MCT+ghr (n=9). At days 21-25 the animals were instrumented to record RV and LV peak systolic (Psys) pressures, dP/dtmax and time constant Tau. RV and LV transmural free-wall samples were collected to quantify, by real time RT-PCR, ghrelin, ppET-1 and ACE mRNA levels, which were normalized for GAPDH and expressed in arbitrary units (AU). Results: Results are presented as meand=SEM, are summarized in the table l(P<0.05: a vs. Ctrl; b vs. MCT).