Pressure Overload Of Right Ventricle Research Articles

Unraveling the Impact of miR-146a in Pulmonary Arterial Hypertension Pathophysiology and Right Ventricular Function

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.

Robotic right ventricle is a biohybrid platform that simulates right ventricular function in (patho)physiological conditions and intervention

The increasing recognition of the right ventricle (RV) necessitates the development of RV-focused interventions, devices and testbeds. In this study, we developed a soft robotic model of the right heart that accurately mimics RV biomechanics and hemodynamics, including free wall, septal and valve motion. This model uses a biohybrid approach, combining a chemically treated endocardial scaffold with a soft robotic synthetic myocardium. When connected to a circulatory flow loop, the robotic right ventricle (RRV) replicates real-time hemodynamic changes in healthy and pathological conditions, including volume overload, RV systolic failure and pressure overload. The RRV also mimics clinical markers of RV dysfunction and is validated using an in vivo porcine model. Additionally, the RRV recreates chordae tension, simulating papillary muscle motion, and shows the potential for tricuspid valve repair and replacement in vitro. This work aims to provide a platform for developing tools for research and treatment for RV pathophysiology.

Interleukin-22 deficiency exacerbates right ventricular remodeling during pressure overload

Abstract Background Fibrosis and remodeling of right ventricle (RV) are associated with prognosis in patients with RV failure. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, play roles in tissue protection and wound repair. We have previously shown that IL-22 plays an important role in cardiac remodeling after acute myocardial infarction; however, the role of IL-22 in RV fibrosis and remodeling remains elusive. Purpose We investigated the role of IL-22 in the pathogenesis of RV remodeling during pressure overload. Methods Pulmonary artery banding (PAB) is performed by placing a 6-0 suture around the pulmonary artery over a 24 G needle in wild type mice (C57BL/6J) and IL-22 knockout mice (IL-22 KO). Only mice with moderate pulmonary artery stenosis (peak pressure gradient across the pulmonary band: 25–40 mmHg at 1 week after surgery by echo Doppler) were included in the study protocol. Two weeks after PAB, RV function was measured by echocardiography and real-time PCR analysis was performed to measure IL-22, IL-22 receptor subunit alpha 1 (IL-22RA1), and IL-22 signaling inhibitor IL-22 binding protein (IL-22BP). Results 2 weeks after PAB, IL-22 KO mice showed markedly increased RV weight (IL-22 KO mice vs. wild-type mice; RV/LV+IVS: 0.48±0.05 vs 0.40±0.02, P=0.002). IL-22 KO mice exhibited significant RV enlargement and RV dysfunction 2 weeks after PAB. (IL-22 KO mice vs wild type mice; RVEDV: 10±2.3mm2 vs 12.9±3.1mm2, P=0.005, TAPSE: 10.8±1.8mm vs 9.5±1.7mm, P=0.04, FAC: 35.2±7.8% vs 23±6.0%, P<0.001). The expression of IL-22, IL-22RA1 and IL-22BP in the RV tended to increase 2 weeks after PAB (wild-type mice with PAB (n=3) vs. wild-type mice with sham; IL-22: 0.0023 vs 0.0028, P=0.18 IL-22RA1: 1.489 vs 1.773, P=0.175, IL-22BP: 0.025 vs 0.067, p=0.005). Conclusion These results suggest that IL-22 is involved in RV remodeling during RV pressure overload.

Concurrent left ventricular pressure-loading improves right ventricular function, remodeling, and molecular signaling in response to pulmonary artery banding

Abstract Background Studies have established the significance of right ventricle (RV) function in individuals with many congenital heart diseases, however the impact of pressure overload (PO) on the RV, concomitant with changes in LV pressure, has yet to be fully understood. We have previously demonstrated that pulmonary artery banding (PAB) with simultaneous LVPO improved systolic function in both ventricles and reduced myocyte hypertrophy and collagen content compared to PAB alone1. These findings suggested that increasing LV afterload attenuated maladaptive RV remodeling and molecular signaling. Purpose We investigated whether the degree of LV afterload beneficially impacts RV function, remodeling, and molecular signaling pathways. Methods We established a model of double-banding (DB) in male Sprague-Dawley rats (n = 17) where the PA and transverse aorta were constricted with 16-gauge and 14-gauge needles, respectively. At 6-weeks post-surgery, Doppler-echocardiography was used to measure the flow velocity across the aortic constriction to divide the DB rats into moderate (DBMOD) and mild (DBMILD) groups. PAB-only (n=9) and Sham (n=9) groups were used as controls. All animals underwent echocardiography and cardiac catheterization 6-weeks post-surgery to assess RV/LV structure and hemodynamic function. Heart tissue was collected for Picrosirius red (PSR) staining to assess RV collagen content. Immunoblotting and RT-qPCR were used to quantify protein and transcripts of fibrosis and mechanotransduction pathways. Results Echocardiography identified increases in RV end-diastolic and end-systolic areas alongside a decrease in tricuspid annular plane systolic excursion (TAPSE) in PAB rats compared to shams. These changes were abrogated in DBMOD rats and to a lesser extent in DBMILD rats (p<0.001). Hemodynamic analyses identified significantly increased dP/dtmax/min, and end-systolic pressure-volume relationship in the PAB group, each of which returned to near-Sham levels in the DBMOD group (p<0.0001). PSR-staining revealed a significant decrease of RV fibrosis in the DBMOD group compared to PAB rats (p<0.05). Immunoblotting in RV tissue revealed increases in myocardin-related transcription factor A, and YAP/TAZ in PAB rats; protein expression returned to near-sham levels in the DBMOD group (p<0.05) with an intermediate expression in the DBMILD group (p<0.05). RT-qPCR of RV tissue revealed significantly increased collagen 1&3, TGFβ1, and CTGF transcripts which returned to baseline in the DBMOD group (p<0.05). Conclusion Our results indicate that the degree of LV pressure provides a beneficial impact on RV function, remodeling, and both Hippo and profibrotic signaling during RV PO. Our study demonstrates the importance of ventricular interdependence from a physiological and molecular level and suggests that modulating LV pressures during diseases that impact the RV (such as pulmonary hypertension) offer a potentially attractive therapeutic route.

Pitfalls in the Diagnosis of Peri-Operative Acute Pulmonary Embolism: A Case Report

An 80 years-old man with hypertension, atrial fibrillation, and coronary artery occlusion disease presented for an elective right femur bipolar hip arthroplasty under general anesthesia. Preoperative transthoracic echocardiography (TTE) showed only preexisting regional wall motion abnormality. During the reversal of muscular relaxation following surgery, there was a sudden decrease in blood pressure associated with rapid ventricular response, which was successfully treated by cardioversion. No decrease in end-tidal carbon dioxide level was observed during the hypotensive episode. However, despite fluid and blood resuscitation and vasopressor treatment, there was a repeated hemodynamic collapse postoperatively. A portable TTE showed dilated right atrium and right ventricle (RV), D-shaped left ventricle, and septal wall motion abnormalities consistent with RV pressure overload (McConnell’s sign). Computed tomography pulmonary angiography revealed multifocal PE (pulmonary embolism). Anticoagulation therapy was continued to avoid PE recurrence. The patient discharged uneventfully 30 days later. Perioperative PE is a rare and perhaps dangerous circumstance that can be challenging to diagnose when it happens under anesthesia. The likelihood of PE should always be suspected at the time of perioperative hemodynamic collapse.

The discrepancy between FDG uptake and myocardial fibrosis in patients with pulmonary arterial hypertension – PET/MRI study

Abstract Background Inflammatory processes play an important role in pulmonary arterial hypertension (PAH) pathophysiology. We previously confirmed that in case of right ventricle (RV) failure, changes of cytokines' levels are correlated with myocardial metabolic and hemodynamic alterations observed in PET/MRI hybrid imaging. Presence of late gadolinium enhancement (LGE) in RV insertion points (RVIPs) has been found in majority of PAH patients and is often recognized as evidence of myocardial fibrosis due to RV pressure overload. As qualitative and/or quantitative assessments of LGE may vary due to natural PAH progression or specific therapy, we hypothesized that simple presence of LGE at RVIPs is not unequivocal to fibrotic tissue (without metabolic activity). Purpose To check the relationship between LGE mass and 18F-fluorodexyglucose uptake in RV insertion points in PAH patients using PET/MRI hybrid imaging. Methods Twenty-eight clinically stable PAH patients (49.9±15.9 years) had simultaneous PET/MRI scans during baseline and follow up (FU) visits, Figure. 18F-fluorodexyglucose (FDG) was used as a tracer and its cardiac uptake was presented as a maximum standardized uptake value (SUV) for RV insertion points (SUV in RVIPS). Septal delayed enhancement mass was quantified in RVIPs and presented as LGE mass. Occurrences of clinical end-points (CEP, defined as death or clinical deterioration) were assessed during 24 months observation. Results LGE was found in RVIPs of all PAH patients. Mean LGE mass was 6.32±4.41 g and mean SUV in RVIPS was 7.28±5.36. Follow up values were 8.01±7.75g (p=0.4) and 5.80±3.16 (p=0.16), respectively. We observed significant correlation between baseline SUV in RVIPS and mean pulmonary pressure, mPAP (r=0.49, p=0.04) but no correlation was found between LGE mass and SUV in RVIPS (in both baseline and FU scans). Between baseline and follow up visits, 16 patients had CEP and needed PAH therapy escalation. CEP+ group of PAH patients presented higher baseline LGE mass (7.53±4.75 vs 3.92±2.21, p=0.04) and SUV in RVIPS (7.27±5.42 vs 6.01±4.52, p=0.4). In all CEP patients who initiated prostacycline therapy and survived (n=8, 50%), SUV in RVIPS decreased in FU PET scans together with an increase in LGE mass in MRI. At FU visits we also observed significant improvement of MRI-derived RV ejection fraction (45.1±9.6% to 52.4±12.9%, p=0.01), and mPAP (50.5±18.3 to 42.8±18.6 mmHg, p=0.03). Conclusions Effective PAH therapy have an impact on both LGE mass and FDG uptake in cardiac local tissue changes. Since there was no correlation between LGE mass and FDG uptake RV insertion points, the question arises what the cause of these LGE changes is. Increased fibrosis should cause diminished local glucose metabolism. This phenomenon opens new questions concerning pathophysiology processes in RVIPs and requires confirmation on bigger PAH population. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Center for Science in Poland

Comparison of left versus right ventricular contraction profile in failing and non-failing isolated human myocardium

The left ventricle (LV) and right ventricle (RV) of human heart demonstrate significant differences in embryology, form, and function. RV dysfunction may develop in association with LV dysfunction via multiple mechanisms. Conversely, RV pressure overload, as may occur with pulmonary hypertensive states, may compromise LV function. Our objective was to investigate the relationship of LV to RV contractile performance and examine the influence of heart failure (HF) on these relationships. Myocardial LV and RV trabeculae were dissected from non-failing (NF) and end-stage failing human hearts.

Abstract 13391: Increased LV Afterload Improves Rv Function in a Longitudinal Study of RV-Pressure Overloaded Mice

Introduction: The left ventricle (LV) is known to transfer kinetic mechanical energy to the right ventricle (RV) during systole. Normally, the RV relies on this mechanical assistance for up to 70% of its pressure generation. However, this biventricular relationship and its effect on RV function has not been explored in the progression in the pressure overloaded RV. In this study, we developed a longitudinal mouse model of pulmonary arterial (PA)-banding concomitant with transverse aortic constriction (TAC) to initiate an adaptive LV remodeling response. We hypothesized that adaptive LV remodeling would improve RV systolic function in an RV pressure overloaded setting. Methods: Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. Mild surgical TAC was performed on these mice 2-weeks (w) post-PAB. Steady-state free precession (SSFP) cardiac magnetic resonance (CMR) imaging (SSFP-CMR) was performed at 1w post-PAB, 1 w post-TAC (PAB-TAC) and 4 w and 7 w post-surgery (n=7). As controls we used Sham (n=5), TAC-only (n=4, TAC) as well as PAB-only (n=4, PAB) mice at 1, 4, and 7 w after surgery. These images were analyzed using feature-tracking (FT) software to compute measurements of ventricular volumes. Results: RV ejection fraction (RVEF) was reduced in PAB mice compared to Sham at 1w (p=0.02, 0.38±0.06 versus 0.52±0.08, respectively). After TAC, PAB-TAC mice showed an increase in RVEF compared to PAB-only mice at 4 w (p=0.03, 0.49±0.04 versus 0.39±0.08, respectively), and at 7 w (p=0.001, 0.50±0.06 versus 0.37±0.1, respectively). Similarly, tricuspid annular plane systolic excursion (TAPSE) showed a decrease in PAB mice compared to sham (p=0.002, 0.85±0.15mm versus 1.73±0.33mm, respectively) and an increase after TAC at 2 w (p=0.001, 1.55±0.29mm versus 0.85±0.15mm, respectively), 4 w (p=0.002, 1.75±0.32mm versus 0.93±0.21mm, respectively), and at 7 w post-surgery (p=0.001, 1.70±0.33mm versus 0.91±0.14mm, respectively). Conclusions: Even though LV-to-RV mechanical energy transfer is well established in normotensive animals, our data supports a mechanistic link between RV systolic function and LV pressure in remodeled and pressure-overloaded RVs.

Abstract 12362: Association Between GP130 Signaling, Microtubule Regulation, and RV Function in Porcine RV Pressure Overload

Introduction: Pulmonary arterial hypertension (PAH) is a rare but lethal disease, which results in rightventricle (RV) failure. Unfortunately, there are no available therapies to directly combat RV failure and improvesurvival in PAH. We previously showed antagonism of the GP130 signaling pathway prevents microtubuleremodeling and enhances RV function in rat PAH. However, rodent models does not always recapitulatehuman physiology, which may limit translatability of our finding. Therefore, we examined the relationshipsbetween GP130 activation, microtubule regulation, t-tubule structure, and RV function in porcine RV pressureoverload. Methods: Pulmonary artery banding (PAB) was performed on old Yorskhire piglets and animals wereevaluated 4 weeks after. Immunoblots of RV extracts were probed with GP130, STAT3, phosphorylatedSTAT3, α-tubulin, β-tubulin, and detyrosinated α-tubulin primary antibodies to quantify GP130 activation andmicrotubule remodeling respectively. T-tubule architecture was examined using confocal microscopy. Finally,cardiac MRI quantified RV structure and function. Results: PAB pigs exhibited induction of GP130 signaling with higher levels of GP130, STAT3, andpSTAT3. Additionally, there was evidence of microtubule remodeling with elevated expression of α-, β-, anddetyrosinated α-tubulin. Confocal microscopy revealed t-tubule derangements in PAB pigs. Cardiac MRIshowed PAB pigs had significantly increased RV end systolic volume, reduced RV ejection fraction, andimpaired RV-pulmonary artery coupling. Finally, GP130 and tubulin expression levels were inverselyassociated with RV ejection fraction and RV-pulmonary artery coupling. Conclusion: Increased expression of GP130 and tubulin is associated with lower RV ejection fraction andworse RV-PA coupling. Future studies are needed to determine if GP130 antagonism enhances RV function inporcine RV pressure overload.

Histological and haemodynamic characterization of right ventricle in sedentary and trained rats with heart failure with preserved ejection fraction.

What is the central question of this study? Right ventricle (RV) dysfunction is highly prevalent in heart failure with preserved ejection fraction (HFpEF), nearly doubling the risk of death: what are the RV functional and structural changes in HFpEF and how does aerobic exercise impact them? What is the main finding and its importance? The HFpEF ZSF1 rat model presents RV structural and functional changes mimicking the human condition. Aerobic exercise prevented the decline in , lowered surrogate markers of RV overload (e.g., higher mean and maximum systolic pressure) and improved diastolic dysfunction (e.g., end-diastolic pressure and relaxation time constant). This emphasizes the importance of using exercise to manage HFpEF. Right ventricle (RV) dysfunction is highly prevalent in heart failure with preserved ejection fraction (HFpEF) and is a marker of poor prognosis. We assessed the obese ZSF1 rat model of HFpEF to ascertain if these animals also develop RV dysfunction and evaluated whether aerobic exercise could prevent this. Obese ZSF1 rats were randomly allocated to an aerobic exercise training group (n=7; treadmill running, 5days/week, 60min/day, 15m/min for 5weeks) or to a sedentary group (n=7). We used lean ZSF1 rats (n=7) as the control group. After 5weeks, rats were submitted to an exercise tolerance test and invasive haemodynamic evaluation, killed and samples from the RV collected for histological analysis. Obese sedentary ZSF1 rats showed lower , RV pressure overload (e.g., higher mean and maximum systolic pressure) and diastolic dysfunction (e.g., higher minimum and end-diastolic pressure and relaxation time constant), paralleled by RV cardiomyocyte hypertrophy. Except for cardiomyocyte hypertrophy, aerobic exercise prevented these functional changes. Our data support that this model of HFpEF shows functional and structural changes in the RV that resemble the human HFpEF phenotype, reinforcing its utility to understand this pathophysiology and to adress novel therapeutic targets to manage HFpEF. In addition, we showed that aerobic exercise is cardioprotective for the RV. A deeper knowledge of the mechanisms underlying the benefits of aerobic exercise could also lead to the identification of therapeutic targets to be further explored.

Distinct time courses and mechanics of right ventricular hypertrophy and diastolic stiffening in a male rat model of pulmonary arterial hypertension.

Although pulmonary arterial hypertension (PAH) leads to right ventricle (RV) hypertrophy and structural remodeling, the relative contributions of changes in myocardial geometric and mechanical properties to systolic and diastolic chamber dysfunction and their time courses remain unknown. Using measurements of RV hemodynamic and morphological changes over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we discriminated the contributions of RV geometric remodeling and alterations of myocardial material properties to changes in systolic and diastolic chamber function. Significant and rapid RV hypertrophic wall thickening was sufficient to stabilize ejection fraction in response to increased pulmonary arterial pressure by week 4 without significant changes in systolic myofilament activation. After week 4, RV end-diastolic pressure increased significantly with no corresponding changes in end-diastolic volume. Significant RV diastolic chamber stiffening by week 5 was not explained by RV hypertrophy. Instead, model analysis showed that the increases in RV end-diastolic chamber stiffness were entirely attributable to increased resting myocardial material stiffness that was not associated with significant myocardial fibrosis or changes in myocardial collagen content or type. These findings suggest that whereas systolic volume in this model of RV pressure overload is stabilized by early RV hypertrophy, diastolic dilation is prevented by subsequent resting myocardial stiffening.NEW & NOTEWORTHY Using a novel combination of hemodynamic and morphological measurements over 10 wk in a male rat model of PAH and a mathematical model of RV mechanics, we found that compensated systolic function was almost entirely explained by RV hypertrophy, but subsequently altered RV end-diastolic mechanics were primarily explained by passive myocardial stiffening that was not associated with significant collagen extracellular matrix accumulation.

Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload-Induced Right Ventricular Failure.

BackgroundIn complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure.Methods and ResultsWe created a murine model of RV pressure overload by pulmonary artery banding and compared with sham‐operated controls. Gene expression by RNA‐sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload‐induced RV failure. RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4‐hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 versus RV hypertrophy 334.3±30.65 versus RV failure 165.4±36.72 pmol/(s×mL), P<0.0001). Mitochondrial fission protein DRP1 (dynamin 1‐like) trended toward an increase, while MFF (mitochondrial fission factor) decreased and fusion protein OPA1 (mitochondrial dynamin like GTPase) decreased. In contrast, transcription of electron transport chain genes increased in the left ventricle of RV failure.ConclusionsPressure overload‐induced RV failure is characterized by decreased transcription and activity of electron transport chain complexes and increased oxidative stress which are associated with decreased energy generation. An improved understanding of the complex processes of energy generation could aid in developing novel therapies to mitigate mitochondrial dysfunction and delay the onset of RV failure.

Porcine Model of the Arterial Switch Operation: Implications for Unique Strategies in the Management of Hypoplastic Left Ventricles

There are no reports on the performance of the arterial switch operation (ASO) in a normal heart with normally related great vessels. The objective of this study was to determine whether the ASO could be performed in a healthy animal model. Cardiopulmonary bypass (CPB) and coronary translocation techniques were used to perform ASO in neonatal piglets or a staged ASO with prior main pulmonary artery (PA) banding. Primary ASO was performed in four neonatal piglets. Coronary translocation was effective with angiograms confirming patency. Piglets could not be weaned from CPB due to right ventricle (RV) dysfunction. To improve RV function for the ASO, nine piglets had PA banding. All survived the procedure. Post-banding RV pressure increased from a mean of 20.3 ± 2.2 mmHg to 36.5 ± 7.3 mmHg (p = 0.007). At 58 ± 1 days post-banding, piglets underwent cardiac MRIs revealing RV hypertrophy, and RV pressure overload with mildly reduced RV function. Catheterization confirmed RV systolic pressures of 84.0 ± 6.7 mmHg with LV systolic pressure 83.3 ± 6.7 mmHg (p = 0.43). The remaining five PA banded piglets underwent ASO at 51 ± 0 days post-banding. Three of five were weaned from bypass with patent coronary arteries and adequate RV function. We were able to successfully perform an arterial switch with documented patent coronary arteries on standard anatomy great vessels in a healthy animal model. To our knowledge this is the first time this procedure has been successfully performed. The model may have implications for studying the failing systemic RV, and may support a novel approach for management of borderline, pulsatile left ventricles.

ECG CHANGES IN PATIENTS WITH RIGHT VENTRICULAR HYPERTROPHY DUE TO CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION. ONE YEAR AFTER BALLOON PULMONARY ANGIOPLASTY

Objective:Chronic thromboembolic pulmonary hypertension (CTEPH) due to chronic pressure overload of right ventricle (RV) leads to heart failure with poor outcomes. For inoperable CHEPH balloon pulmonary angioplasty (BPA) is a treatment option with good long-term results. The 12-lead electrocardiogra

Human Neonatal Thymus Mesenchymal Stem/Stromal Cells and Chronic Right Ventricle Pressure Overload.

Right ventricle (RV) failure secondary to pressure overload is associated with a loss of myocardial capillary density and an increase in oxidative stress. We have previously found that human neonatal thymus mesenchymal stem cells (ntMSCs) promote neovascularization, but the ability of ntMSCs to express the antioxidant extracellular superoxide dismutase (SOD3) is unknown. We hypothesized that ntMSCs express and secrete SOD3 as well as improve survival in the setting of chronic pressure overload. To evaluate this hypothesis, we compared SOD3 expression in ntMSCs to donor-matched bone-derived MSCs and evaluated the effect of ntMSCs in a rat RV pressure overload model induced by pulmonary artery banding (PAB). The primary outcome was survival, and secondary measures were an echocardiographic assessment of RV size and function as well as histological studies of the RV. We found that ntMSCs expressed SOD3 to a greater degree as compared to bone-derived MSCs. In the PAB model, all ntMSC-treated animals survived to the study endpoint whereas control animals had significantly decreased survival. Treatment animals had significantly less RV fibrosis and increased RV capillary density as compared to controls. We conclude that human ntMSCs demonstrate a therapeutic effect in a model of chronic RV pressure overload, which may in part be due to their antioxidative, antifibrotic, and proangiogenic effects. Given their readily available source, human ntMSCs may be a candidate cell therapy for individuals with congenital heart disease and a pressure-overloaded RV.

Optimizing the Personalized, Risk-Adjusted Management of Pulmonary Embolism: An Integrated Clinical Trial Programme.

Acute pulmonary embolism (PE) contributes significantly to the global burden of cardiovascular disease. The severity of the acute PE event determines the expected estimated risk of early death. This risk is influenced by the degree of dysfunction of the right ventricle (RV), as assessed by the presence of acute RV pressure overload on imaging and/or elevated cardiac biomarkers, and by demographic and clinical factors, including relevant comorbidities. Haemodynamic instability and cardiogenic shock is at the top of the PE severity spectrum, as it represents the most extreme manifestation of RV failure and a key determinant of poor prognosis. Ideally, risk-adjusted treatment should implement: (1) optimized timing and regimens of reperfusion therapy for unstable patients; (2) early discharge and continuation of anticoagulation treatment at home (low-risk PE); or (3) hospital admission and clinical/haemodynamic monitoring in patients at intermediate risk. The challenge is now to provide the basis for a comprehensive personalized, risk-adjusted care for patients with acute PE. The aim of the integrated academic clinical trial programme of the Center for Thrombosis and Hemostasis at the University of Mainz is to develop and prospectively validate, in multinational studies, strategies for reperfusion and anticoagulant treatment of acute PE across the entire spectrum of early risk as well as clinical pathways for post-PE patient care and follow-up.

Cell-Based Therapy in Cardiac Regeneration: An Overview.

Although pioneering preclinical research on the use of cell therapy for cardiac regeneration was conducted in the last quarter of the 20th century,1,2 a preponderance of advances have occurred in the 21st century, making this a relatively young field. In the first important clinical trial of cardiac cell therapy, begun in 2001, Menasche et al3 implanted autologous skeletal myoblasts into postinfarct scar at the time of coronary artery bypass surgery. Although the transplanted cells remained viable and exhibited contraction, they formed the nidus for serious ventricular tachyarrhythmias, which led to premature discontinuation of the trial. Despite this outcome, the trial energized the field, accelerating both preclinical and clinical research, albeit not with skeletal myoblasts. The extensive progress in cardiac regeneration is reviewed in this Compendium, and as occurs frequently in science, important observations have led to more questions and challenges (Table). View this table: Table. Important Challenges to Cell Therapy for Cardiac Regeneration Many cell types have been evaluated as candidates for cardiac regeneration. Among the earliest clinical trials, Zeiher’s group infused autologous bone marrow-derived progenitor cells into the coronary arteries of patients with acute,4 as well as healed myocardial infarction (MI)5 and reported improvements in left ventricular (LV) function. However, these results have not been fully confirmed by later studies, as pointed out in the review in the Compendium by Banarjee, Bolli, and Hare.6 Pittenger et al7 were among the first to direct attention to bone marrow-derived (stromal) mesenchymal stem cells (MSCs), emphasizing that these cells proliferated extensively in culture and suggesting that they could be attractive candidates for transplantation. In 2004, Chen et al8 reported that intracoronary infusion of autologous bone marrow-derived MSCs improved cardiac function. Zimmet and Hare pointed out that MSCs lack histocompatibility type II markers and elude rejection by …

Left-Ventricular Energetics in Pulmonary Arterial Hypertension-Induced Right-Ventricular Hypertrophic Failure.

Pulmonary arterial hypertension (PAH) alters the geometries of both ventricles of the heart. While the right ventricle (RV) hypertrophies, the left ventricle (LV) atrophies. Multiple lines of clinical and experimental evidence lead us to hypothesize that the impaired stroke volume and systolic pressure of the LV are a direct consequence of the effect of pressure overload in the RV, and that atrophy in the LV plays only a minor role. In this study, we tested this hypothesis by examining the mechanoenergetic response of the atrophied LV to RV hypertrophy in rats treated with monocrotaline. Experiments were performed across multiple-scales: the whole-heart in vivo and ex vivo, and its trabeculae in vitro. Under the in vivo state where the RV was pressure-overloaded, we measured reduced systemic blood pressure and LV ventricular pressure. In contrast, under both ex vivo and in vitro conditions, where the effect of RV pressure overload was circumvented, we found that LV was capable of developing normal systolic pressure and stress. Nevertheless, LV atrophy played a minor role in that LV stroke volume remained lower, thereby contributing to lower LV mechanical work output. Concomitantly lower oxygen consumption and change of enthalpy were observed, and hence LV energy efficiency was unchanged. Our internally consistent findings between working-heart and trabecula experiments explain the rapid improvement of LV systolic function observed in patients with chronic pulmonary hypertension following surgical relief of RV pressure overload.

Abstract 21421: Identification of Nherf1 as a Regulator of Right Ventricle Cardiomyocyte Hypertrophic Remodeling With Implications for Pulmonary Hypertension

Introduction &amp; Hypothesis: The molecular mechanisms underlying right ventricle (RV) hypertrophic remodeling (both adaptive and maladaptive) in response to sustained pressure overload, such as that experienced during pulmonary hypertension (PH), are inadequately understood. Our previous work demonstrating a role for the cytosolic organizer protein p47 phox in pressure overload-induced RV hypertrophy and our recent publication on a direct interaction between p47 phox and ERM-binding cytoskeletal protein Nherf1 lead us to hypothesize that Nherf1 is a regulator of RV cardiomyocyte hypertrophy. Methods &amp; Results: Cardiomyocyte-derived H9C2 cells and RV rat neonatal cardiomyocytes isolated from 1-day-old pup hearts (RV-RNCM) were subjected to neurohormonal hypertrophic stimulation using angiotensin II (AngII, 1 &amp; 10 μM). RV pressure overload was induced in mice by pulmonary artery banding (PAB; 3wk). AngII treatment resulted in H9C2 and RV-RNCM hypertrophy and induced Nherf1 protein expression. The AngII-induced hypertrophy was attenuated by Nherf1 gene knockdown using siRNA. Moreover, Co-IP studies revealed an Nherf1-p47 phox association in H9C2 cells that is enhanced by pro-hypertrophic AngII-treatment. Sequential loss of function strategies educated by novel in silico gene network analyses of PH gene intersected with cardiomyopathy gene networks, combined with a careful consideration of our previous findings and the literature, identified potential involvement of Hippo pathway transcriptional co-activators Yap/Taz, water channel aquaporin1 (Aqp1), and apoptosis signal-regulating kinase 1 (Ask1) in this pathway. In vitro , co-IP studies revealed a Nherf1-Yap association and interruption of Ask1 or Aqp1 reduced AngII-induced cardiomyocyte cellular hypertrophy. In vivo , PAB induced an increase in Nherf1 expression and association with p47 phox . Conclusion: The present study supports a new role for Nherf1 in mediating pro-hypertrophic cardiomyocyte cellular responses and implicates a molecular network previously not connected to either the RV or Nherf1. These data identify potential therapeutic targets for RV dysfunction in PH and shed light on novel molecular mechanisms so far untested in the pressure overloaded right heart.

Effect of Chronic Treatment With Zamicastat on Right Ventricle Pressure Overload in the Rat Monocrotaline Lung Injury Model of Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is defined, foremost, as a plexogenic arteriopathy with subtotal luminal obliteration that increases pulmonary vascular resistance and imposes a hemodynamic stress on the right ventricle (RV) leading to RV hypertrophy and failure that contributes to premature death. There is experimental and clinical evidence that supports a relation between PAH and the sympathetic nervous system (SNS), indicating that PAH can be mediated, at least partly, by SNS hyperactivation. A strategy for the modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) by inhibiting dopamine β‐hydroxylase (DβH), the enzyme that catalyzes the conversion of dopamine (DA) to NE in sympathetic nerves. Here, we evaluated the effect of 18‐day oral treatment with the DβH inhibitor zamicastat on RV pressure overload in the monocrotaline (MCT)‐induced pulmonary hypertension (PH) model in the rat.MCT increased RV systolic pressure (54.7±2.9 vs 32.3±1.0 mmHg, p&lt;0.0001), mean RV pressure (23.9±1.7 vs 16.6±1.1 mmHg, p&lt;0.001), and decreased heart rate (240.0±5.9 vs 285.8±7.6 beats/min, p&lt;0.0001) in vehicle‐treated rats, as compared to pre‐MCT values. Zamicastat treatment prevented the MCT‐induced increase in mean RV pressure (change from baseline: +1.9±1.5 vs +7.4±1.8 mmHg, p&lt;0.05). Likewise, the HR decrease was significantly attenuated in the zamicastat group as compared to the vehicle group (change from baseline: −14.3±9.7 vs −45.8±8.1 beats/min, p&lt;0.05). Chronic zamicastat treatment decreased NE levels (480.5±43.9 vs 712.1±46.5 ng/mg protein, p&lt;0.005) and increased DA levels (533.0±49.7 vs 12.3±2.3 ng/mg protein, p&lt;0.0001) in adrenal gland homogenates of MCT‐treated rats, as compared to vehicle group demonstrating robust inhibition of DβH.In conclusion, the DβH inhibitor zamicastat reverses heart rate and RV pressure changes, two hallmarks of PAH, in the rat MCT lung injury model.Support or Funding InformationThis work was supported by BIAL ‐ Portela &amp; Ca, S.A.