Improved Right Ventricle Function Research Articles

Pressure-dimension index and left ventricular sphericity index following HeartMate II and HeartMate 3 implantation.

This study aimed to compare the changes in the left ventricle (LV) and right ventricle (RV) geometry and performance after the implantation of HeartMate II (HMII) and HeartMate 3 (HM3). In addition, we investigated whether the echocardiographic parameters LV sphericity index (LVSI) and the novel pressure-dimension index (PDI) can predict post-operative right ventricular failure (RVF). Between 2012 and 2020, 46 patients [HMII (n=22) and HM3 (n=24)] met the study's criteria and had echocardiography tests pre-operatively, 6 and 12months post-operatively. The LVSI and PDI were calculated together with the standard LV and RV echocardiographic parameters. The mean follow-up was 24±7months. In both groups, the LV end-diastolic diameter (LVEDD) significantly decreased 12months post-operatively compared with the pre-operative values (HMII: 6.4±1.4cm vs. 5.7±0.9cm, P=0.040; HM3: 6.7±1.3cm vs. 5.5±0.9cm, P<0.01, respectively). RV function 12months post-operatively was better in the HM3 group than in the HMII group, as indicated by a significantly higher RV fractional area change (RVFAC) in the HM3 group than in the HMII group 12months post-operatively (35±12% vs. 26±16%, P=0.039), significantly higher tricuspid annular plane systolic excursion (TAPSE) in the HM3 group 12months post-operatively compared with the HMII group (13.9±1.9mm vs. 12.0±2.1mm, P=0.002), and the tissue Doppler estimated tricuspid annular systolic velocity (TASV) was also significantly higher in the HM3 group 12months post-operatively compared with the HMII group (11.5±2.7mm/s vs. 9.9±1.5mm/s, P=0.020). The LVSI value was significantly higher 12months post-operatively in the HMII group than in the HM3 group (1.2±0.4 vs. 0.8±0.2, P=0.001, respectively), indicating worse geometric changes. The PDI decreased 12months post-operatively in the HM3-group compared with the baseline (3.4±1.4mmHg/cm2 vs. 2.0±0.8mmHg/cm2, P<0.001). In the univariate and multivariate analyses, only the pre-operative PDI was a predictor of post-operative RVF [odds ratio: 3.84 (95% CI: 1.53-18.16, P=0.022)]. The area under the curve for pre-operative PDI was 0.912. The 2year survival was significantly better in the HM3 group (log-rank, P=0.042). The design of HM3 offered better geometrical preservation of the LV and enabled normal PDI values, leading to improved RV function, as indicated by better RVFAC, TAPSE, and TASV values. The use of pre-operative PDI as an additional tool for established risk scores might offer a better pre-operative predictor of RVF.

Selective inhibition of Histone deacetylases reverses vascular remodeling and improves right ventricle function in pulmonary hypertension

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Longfonds and CVON Background Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodeling of pulmonary vessels, leading to increased vascular resistance and ultimately right ventricle (RV) failure. Disturbed BMPR2/TGFβ signaling is a driver of disease progression. Inhibition of Histone deacetylases (HDACs) using small molecule inhibitors attenuated vascular remodeling, however, they worsened RV function in animal models of PAH. Objectives The aim of this study is to validate if the selective HDAC inhibitor Quisinostat reverses pulmonary vascular remodeling and improves RV function. Methods and results We found that protein levels of HDAC1 are increased in the lungs of PAH patients. Treating microvascular endothelial cells (MVECs) and smooth muscle cells of PAH patients with Quisinostat significantly decreased TGF-β signaling and strongly decreased cell proliferation and the levels of inflammatory cytokines. In the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, Quisinostat reversed abnormal vascular remodeling and improved RV function. Furthermore, Quisinostat could be combined safely with the contemporary PAH standard of care. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding, and no systemic or cardiotoxic effects were observed. Conclusions Our data demonstrate that selective inhibition of HDACs reverses pulmonary vascular remodeling and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH.

Incomplete reverse remodeling in aged mice exposed to pulmonary hypertension-induced right ventricular failure

Right ventricle (RV) function is the strongest predictor of survival in pulmonary hypertension (PH) and age-related HF; however no therapies exist to improve RV function. Understanding mechanisms by which the RV undoes pathological remodeling (reverse remodeling) might aid in identifying therapies for this unmet need. Our objective was to determine whether the aged RV can undergo reverse remodeling following pathological afterload (PH). We hypothesized that return to normoxia after hypoxia-induced PH would result in attenuation of RV mass and improved RV function. We exposed male and female aged (~18 months) C57Bl6 mice to hypobaric hypoxia (HH) for 4 weeks before returning them to normoxia for 3 (WK3RR) or 6 (WK6RR) weeks. HH induced RV hypertrophy by RV myocyte area which was attenuated at Wk3RR and WK6RR in both male (Con: 425 μm2 ± 104, HH: 740 μm2 ± 125, WK3RR: 447 μm2 ± 129, WK6RR: 530 μm2 ± 187) and female mice (Con: 340 μm2 ± 116, HH: 770 μm2 ± 35, WK3RR: 516 μm2 ± 186, WK6RR: 655 μm2 ± 224). HH stimulated fibrosis by collagen deposition that was also reversed during normoxia re-exposure in male mice only (Con: 4.1% ± 1.0, HH: 10.8% ± 0.8, WK3RR: 4.2% ± 0.8, WK6RR: 2.5% ± 0.7). However, HH decreased RV systolic function by fractional area change (FAC) that was also not rescued by normoxia re-exposure. The aged RV can undergo morphological reverse remodeling in response to HH; however RV function does not improve with resolution of afterload. Further investigation into the mechanisms of reverse remodeling may identify potential drug therapies for maladaptive RV remodeling. AHA-Predoctoral Fellowship 897622 (BDM). 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.

Persistent pulmonary hypertension of the newborn infant (PPHN) due to premature closure of the ductus arteriosus (DA)

Abstract Objectives To describe the course of an infant with persistent pulmonary hypertension of the newborn (PPHN) secondary to premature closure of the ductus arteriosus (DA), a very rare phenomenon which can lead to adverse clinical outcomes. Case presentation A term infant was diagnosed with severe PPHN with echocardiographic features noted at 6 h after birth which included supra-systemic pulmonary pressures, severe isolated right ventricle (RV) hypertrophy, poor RV dysfunction and no ductal flow in the context of a structurally normal heart. There was maternal use of low-dose aspirin in pregnancy due to preeclampsia. There is a known association between use of prostaglandin synthase inhibitors such as aspirin with ductal closure leading to increased RV pressure. Treatment was commenced with positive pressure ventilation, inhaled nitric oxide (iNO) and milrinone. There was a limited response to iNO necessitating increasing the concentration of milrinone with a marked improvement in oxygenation. Following commencement of sildenafil, inhaled nitric oxide was gradually weaned and stopped in the third week and the infant extubated. The infant was discharged home on oral sildenafil at four weeks of age with no respiratory or feeding support. Echocardiographic features of raised right sided pressures persisted, but with reduced RV hypertrophy and septal flattening and improved RV function. Oral sildenafil was subsequently weaned and stopped at four months of age. Conclusions A severe form of PPHN due to premature closure of the DA requires early discussion with the cardiologist. The use of milrinone and sildenafil can lead to a favourable outcome.

Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate/High-Risk Pulmonary Embolism: Design of the Multicenter USAT IH-PE Registry and Preliminary Results.

Catheter-based revascularization procedures were developed as an alternative to systemic thrombolysis for patients with intermediate-high- and high-risk pulmonary embolisms. USAT IH-PE is a retrospective and prospective multicenter registry of such patients treated with ultrasound-facilitated, catheter-directed thrombolysis, whose preliminary results are presented in this study. The primary endpoint was the incidence of pulmonary hypertension (PH) at follow-up. Secondary endpoints were short- and mid-term changes in the echocardiographic parameters of right ventricle (RV) function, in-hospital and all-cause mortality, and procedure-related bleeding events. Between March 2018 and July 2023, 102 patients were included. The majority were at intermediate-high-risk PE (86%), were mostly female (57%), and had a mean age of 63.7 ± 14.5 years, and 28.4% had active cancer. Echocardiographic follow-up was available for 70 patients, and in only one, the diagnosis of PH was confirmed by right heart catheterization, resulting in an incidence of 1.43% (CI 95%, 0.036-7.7). RV echocardiographic parameters improved both at 24 h and at follow-up. In-hospital mortality was 3.9% (CI 95%, 1.08-9.74), while all-cause mortality was 11% (CI 95%, 5.4-19.2). Only 12% had bleeding complications, of whom 4.9% were BARC ≥ 3. Preliminary results from the USAT IH-PE registry showed a low incidence of PH, improvement in RV function, and a safe profile.

S wave resolution in standard electrocardiography aVL lead in 48 hours from admission of severe acute pulmonary embolism is associated to favorable outcome in various subgroups of patients

Abstract Background An electrocardiography record does not serve for the diagnosis of pulmonary embolism. Still, it can indirectly, accurately, and without delay display acute right ventricle overload which represents the main feature of the severe disease. The aim of this study is to investigate the association of a single ECG sign change, the resolution of S wave in aVL lead with the outcome of severe PE patients. Methods Data from this investigation are gained from the Regional PE Registry (REPER) with prospectively variable definition and collection. Among 1814 patients with acute PE, 212 intermediate-high and high-risk PE patients had recorded S wave in aVL and if there was a resolution of this sign in the 48 hours from the admission to the hospital. Of the 145 (68.4%) were treated with thrombolytic therapy. Association between S wave in aVL resolution and all-cause hospital mortality in various subgroups of patients was estimated with Cox regression and Kaplan-Meier’s (KM) curves. Results S wave resolution in aVL in 48 h was recorded in 135 (63.7%) patients. Patients treated with thrombolysis had a higher frequency of S wave resolution compared to those treated with anticoagulant therapy only (76.3% vs 54.5%, p=0.01). The in-hospital mortality rate was significantly lower in patients with S wave resolution regardless of the patient sex (1.4% vs 25.8%, p&amp;lt;0.001 in men, and 6.1% vs 34.8% in women) age (1.1% vs 31.0%, p&amp;lt;0.01 in patients&amp;lt;70 y, and 9.1% vs 31.4%, p&amp;lt;0.01 in patients≥70y), thrombolytic therapy (2.9% vs 26.2%, p&amp;lt;0.01 in patients treated with thrombolysis, and 6.2% vs 37.1%, p&amp;lt;0.01 in patients who did not), duration of symptoms (3.0% vs 44%, p&amp;lt;0.01 in patients with symptoms less than 24 hours, and 4.4% vs 25%, p&amp;lt;0.01 in patients who had symptoms more than 24 hours before admission) and risk (3.2% vs 18%, p&amp;lt;0.01 in intermediate-high risk PE, and 4.9% vs 55.6%, p&amp;lt;0.01 in high-risk PE). KM Log Rank p for hospital survival regarding S wave aVL resolution was 0.003 for patients who did not treated with thrombolysis, and &amp;lt;0.001 in patients treated with thrombolysis (figure 1 and 2). Conclusion S wave resolution in aVL in the 48 h of acute intermediate-high and high-risk PE patients is an excellent sign of improvement of right ventricle function, and it is associated with better outcomes whenever patients are treated or not with thrombolysis, or if they belong to high-risk or intermediate-high risk subgroup.KM S wave resolution and NO thrombolysisKM S wave resolution and thrombolysis

The Right Heart in Congenital Heart Disease.

To analyze the pathophysiologic importance of the right heart in different types of congenital heart disease (CHD), summarize current diagnostic modalities, and discuss treatment options. The right ventricle (RV) plays a key role in disease progression and prognosis, either as the subpulmonary or as the systemic ventricle. Volume and/or pressure overload as well as intrinsic myocardial disease are the main factors for RV remodeling. Echocardiography and cardiac magnetic resonance imaging are important noninvasive modalities for assessing anatomy, size, and function of the right heart. Timely repair of related lesions is essential for preventing RV dysfunction. Few inconclusive data exist on conventional pharmacotherapy in CHD-related RV dysfunction. Cardiac resynchronization therapy and ventricular assist devices are an option in patients with advanced systemic RV failure. Right heart disease is highly related with adverse clinical outcomes in CHD. Research should focus on early identification of patients at risk and development of medical and interventional treatments that improve RV function.

Right ventricle to pulmonary artery coupling after transcatheter aortic valve implantation-Determinant factors and prognostic impact.

Right ventricular (RV) dysfunction and pulmonary hypertension (PH) have been previously associated with unfavorable outcomes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI), but little is known about the effect of right ventricle (RV) to pulmonary artery (PA) coupling. Our study aimed to evaluate the determinant factors and the prognostic value of RV-PA coupling in patients undergoing TAVI. One hundred sixty consecutive patients with severe AS were prospectively enrolled, between September 2018 and May 2020. They underwent a comprehensive echocardiogram before and 30 days after TAVI, including speckle tracking echocardiography (STE) for myocardial deformation analysis of the left ventricle (LV), left atrium (LA), and RV function. Complete data on myocardial deformation was available in 132 patients (76.6 ± 7.5 years, 52.5% men) who formed the final study population. The ratio of RV free wall longitudinal strain (RV-FWLS) to PA systolic pressure (PASP) was used as an estimate of RV-PA coupling. Patients were analyzed according to baseline RV-FWLS/PASP cut-off point, determined through time-dependent ROC curve analysis, as follows: normal RV-PA coupling group (RV-FWLS/PASP ≥0.63, n = 65) and impaired RV-PA coupling group (RV-FWLS/PASP < 0.63, n = 67). A significant improvement of RV-PA coupling was observed early after TAVI (0.75 ± 0.3 vs. 0.64 ± 0.3 before TAVI, p < 0.001), mainly due to PASP decrease (p < 0.001). LA global longitudinal strain (LA-GLS) is an independent predictor of RV-PA coupling impairment before and after TAVI (OR = 0.837, p < 0.001, OR = 0.848, p < 0.001, respectively), while RV diameter is an independent predictor of persistent RV-PA coupling impairment after TAVI (OR = 1.174, p = 0.002). Impaired RV-PA coupling was associated with a worse survival rate (66.3% vs. 94.9%, p-value < 0.001) and emerged as an independent predictor of mortality (HR = 5.97, CI = 1.44-24.8, p = 0.014) and of the composite endpoint of death and rehospitalization (HR = 4.14, CI = 1.37-12.5, p = 0.012). Our results confirm that relief of aortic valve obstruction has beneficial effects on the baseline RV-PA coupling, and they occur early after TAVI. Despite significant improvement in LV, LA, and RV function after TAVI, RV-PA coupling remains impaired in some patients, it is mainly related to persistent pulmonary hypertension and is associated with adverse outcomes.

Targeting Wnt-ß-Catenin-FOSL Signaling Ameliorates Right Ventricular Remodeling.

The ability of the right ventricle (RV) to adapt to an increased pressure afterload determines survival in patients with pulmonary arterial hypertension. At present, there are no specific treatments available to prevent RV failure, except for heart/lung transplantation. The wingless/int-1 (Wnt) signaling pathway plays an important role in the development of the RV and may also be implicated in adult cardiac remodeling. Molecular, biochemical, and pharmacological approaches were used both in vitro and in vivo to investigate the role of Wnt signaling in RV remodeling. Wnt/β-catenin signaling molecules are upregulated in RV of patients with pulmonary arterial hypertension and animal models of RV overload (pulmonary artery banding-induced and monocrotaline rat models). Activation of Wnt/β-catenin signaling leads to RV remodeling via transcriptional activation of FOSL1 and FOSL2 (FOS proto-oncogene [FOS] like 1/2, AP-1 [activator protein 1] transcription factor subunit). Immunohistochemical analysis of pulmonary artery banding -exposed BAT-Gal (β-catenin-activated transgene driving expression of nuclear β-galactosidase) reporter mice RVs exhibited an increase in β-catenin expression compared with their respective controls. Genetic inhibition of β-catenin, FOSL1/2, or WNT3A stimulation of RV fibroblasts significantly reduced collagen synthesis and other remodeling genes. Importantly, pharmacological inhibition of Wnt signaling using inhibitor of PORCN (porcupine O-acyltransferase), LGKK-974 attenuated fibrosis and cardiac hypertrophy leading to improvement in RV function in both, pulmonary artery banding - and monocrotaline-induced RV overload. Wnt- β-Catenin-FOSL signaling is centrally involved in the hypertrophic RV response to increased afterload, offering novel targets for therapeutic interference with RV failure in pulmonary hypertension.

Right Ventricular Architectural Remodeling and Functional Adaptation in Pulmonary Hypertension.

Global indices of right ventricle (RV) function provide limited insights into mechanisms underlying RV remodeling in pulmonary hypertension (PH). While RV myocardial architectural remodeling has been observed in PH, its effect on RV adaptation is poorly understood. Hemodynamic assessments were performed in 2 rodent models of PH. RV free wall myoarchitecture was quantified using generalized Q-space imaging and tractography analyses. Computational models were developed to predict RV wall strains. Data from animal studies were analyzed to determine the correlations between hemodynamic measurements, RV strains, and structural measures. In contrast to the PH rats with severe RV maladaptation, PH rats with mild RV maladaptation showed a decrease in helical range of fiber orientation in the RV free wall (139º versus 97º; P=0.029), preserved global circumferential strain, and exhibited less reduction in right ventricular-pulmonary arterial coupling (0.029 versus 0.017 mm/mm Hg; P=0.037). Helical range correlated positively with coupling (P=0.036) and stroke volume index (P<0.01). Coupling correlated with global circumferential strain (P<0.01) and global radial strain (P<0.01) but not global longitudinal strain. Data analysis suggests that adaptive RV architectural remodeling could improve RV function in PH. Our findings suggest the need to assess RV architecture within routine screenings of PH patients to improve our understanding of its prognostic and therapeutic significance in PH.

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling

BackgroundMalignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF.MethodsRats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM.ResultsHigh-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy.ConclusionDAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

The Right Ventricle: From Embryologic Development to RV Failure.

The right ventricle (RV) and left ventricle (LV) have different developmental origins, which likely plays a role in their chamber-specific response to physiological and pathological stress. RV dysfunction is encountered frequently in patients with congenital heart disease (CHD) and right heart abnormalities emerge from different causes than increased afterload alone as is observed in RV dysfunction due to pulmonary hypertension (PH). In this review, we describe the developmental, structural, and functional differences between ventricles while highlighting emerging therapies for RV dysfunction. There are new insights into the role of fibrosis, inflammation, myocyte contraction, and mitochondrial dynamics in the pathogenesis of RV dysfunction. We discuss the current state of therapies that may potentially improve RV function in both experimental and clinical trials. A clearer understanding of the differences in molecular alterations in the RV compared to the LV may allow for the development of better therapies that treat RV dysfunction.

The impact of transcatheter edge-to-edge repair on right ventricle-pulmonary artery coupling in patients with functional mitral regurgitation.

The impact of transcatheter edge-to-edge repair on right ventricle-pulmonary artery coupling in patients with functional mitral regurgitation.

Computational models of ventricular mechanics and adaptation in response to right-ventricular pressure overload.

Pulmonary arterial hypertension (PAH) is associated with substantial remodeling of the right ventricle (RV), which may at first be compensatory but at a later stage becomes detrimental to RV function and patient survival. Unlike the left ventricle (LV), the RV remains understudied, and with its thin-walled crescent shape, it is often modeled simply as an appendage of the LV. Furthermore, PAH diagnosis is challenging because it often leaves the LV and systemic circulation largely unaffected. Several treatment strategies such as atrial septostomy, right ventricular assist devices (RVADs) or RV resynchronization therapy have been shown to improve RV function and the quality of life in patients with PAH. However, evidence of their long-term efficacy is limited and lung transplantation is still the most effective and curative treatment option. As such, the clinical need for improved diagnosis and treatment of PAH drives a strong need for increased understanding of drivers and mechanisms of RV growth and remodeling (G&R), and more generally for targeted research into RV mechanics pathology. Computational models stand out as a valuable supplement to experimental research, offering detailed analysis of the drivers and consequences of G&R, as well as a virtual test bench for exploring and refining hypotheses of growth mechanisms. In this review we summarize the current efforts towards understanding RV G&R processes using computational approaches such as reduced-order models, three dimensional (3D) finite element (FE) models, and G&R models. In addition to an overview of the relevant literature of RV computational models, we discuss how the models have contributed to increased scientific understanding and to potential clinical treatment of PAH patients.

Abstract P2037: Activation Of A2A Adenosine Receptor Reduces Cardiac Dysfunction Resulting From Pulmonary Hypertension In Rats

Pulmonary hypertension (PH) is characterized by extensive pulmonary vascular remodeling, leading to right ventricle (RV) hypertrophy and dysfunction. This work evaluates the hypothesis that the activation of adenosine A2A receptor (AR-A2) by LASBio-1900 could interfere with the cardiac and vascular dysfunction on monocrotaline (MCT)-induced PH in rats. After 14 days of PH induction using a single injection of MCT (60 mg/kg i.p.), twelve male Wistar rats were randomly divided in groups and treated orally either with vehicle or LASSBio-1900 (180 μmol/kg/day). Hemodynamic parameters were obtained using the echocardiography and summarized in table 1. LASSBio-1900 reduced RV hypertrophy observed in PH because the Fulton index altered from 55.4 ± 2.3 to 35.3 ± 5.9% (p&lt;0.05). HP increased RV systolic and diastolic pressure from 19.2 ± 2.0 and 4.7 ± 1.0 to 51.5 ± 5.2 and 11.9 ± 1.3 mmHg, respectively. Ventricular dysfunction was recovered with LASSBio-1900 treatment reducing pressures to 28.4 ± 4.0 and 6.5 ± 0.8 mmHg, indicating improvement of RV dysfunction. Pulmonary arteriole (PA) muscularization was evaluated by alpha- smooth muscle actin stained and vessel medial wall area was expressed as the percentage of the portion positively stained relative to total transversal area. The increase of the wall thickness of distal PA from 61.7 ± 1.1 to 83.24 ± 1.82 % was reduced by LASSBio-1900 (75.2 ± 3.4 %). Perivascular collagen in PA was evaluated through picrosirius red staining and interstitial fibrosis was measured by obtaining the total collagen area per arteriole area. PH increased the perivascular collagen deposition in 15.1 ± 1.3% however, treatment with LASSBio-1900 reduced to 8.7 ± 1.4% (p&lt;0.05). Intense inflammation process on PH was confirmed with the increase of iNOS expression from 4.5 ± 0.3 (control) to 19.0 ± 0.9% (p&lt;0.05) with reduction to 8.7 ± 1.4% when treated with LASSBio-1900. In conclusion, the agonist of AR-A2, named LASSBio-1900 improved RV function and pulmonary structural alteration in PH, indicating a new alternative for treatment of PH-induced RV dysfunction.

Interaction between VA-ECMO and the right ventricle

BackgroundThe response of the right ventricle (RV) to the hemodynamic effects of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is currently unpredictable. We hypothesized that the presence of uni- or bi-ventricular failure before implantation and the cannulation strategy may influence this interaction. We sought to assess the RV performance during VA-ECMO support and identify RV-related predictors of successful weaning. MethodsChanges in RV size and function during VA-ECMO support by echocardiography were retrospectively analyzed in 87 consecutive adult patients between February 2008 and June 2017. Predictors of successful weaning due to myocardial recovery were evaluated by multivariable logistic regression. ResultsRV echocardiographic parameters did not vary significantly during VA-ECMO support and neither after stratification by the type of cannulation or the presence of isolated or biventricular failure. Successful weaning was conditioned by the absence of RV dysfunction before implantation (OR, 14.7; 95% CI, 13.3-140.3; p = 0.025) or in the last day of support (OR, 9.5; 95% CI, 1.6-54; p = 0.011) and was favored by a total or partial recovery of RV function during the assistance (OR, 6.2; 95%CI, 1.7-22.4; p = 0.005). RV improvement was more often observed in patients with acute RV failure and longer support, while VA-ECMO configuration, additional mechanical support, or pharmacological therapy had no effect. ConclusionsPreservation or improvement of RV function during VA-ECMO is essential for successful weaning. RV echocardiographic performance does not change significantly during VA-ECMO support and is not influenced by cannulation type or the presence of uni- or bi-ventricular failure before implantation.

In vivo evaluation of bioprinted cardiac patches composed of cardiac-specific extracellular matrix and progenitor cells in a model of pediatric heart failure.

Pediatric patients with congenital heart defects (CHD) often present with heart failure from increased load on the right ventricle (RV) due to both surgical methods to treat CHD and the disease itself. Patients with RV failure often require transplantation, which is limited due to lack of donor availability and rejection. Previous studies investigating the development and in vitro assessment of a bioprinted cardiac patch composed of cardiac extracellular matrix (cECM) and human c-kit + progenitor cells (hCPCs) showed that the construct has promise in treating cardiac dysfunction. The current study investigates in vivo cardiac outcomes of patch implantation in a rat model of RV failure. Patch parameters including cECM-inclusion and hCPC-inclusion are investigated. Assessments include hCPC retention, RV function, and tissue remodeling (vascularization, hypertrophy, and fibrosis). Animal model evaluation shows that both cell-free and neonatal hCPC-laden cECM-gelatin methacrylate (GelMA) patches improve RV function and tissue remodeling compared to other patch groups and controls. Inclusion of cECM is the most influential parameter driving therapeutic improvements, with or without cell inclusion. This study paves the way for clinical translation in treating pediatric heart failure using bioprinted GelMA-cECM and hCPC-GelMA-cECM patches.

790 Pacemaker lead and atrial thrombosis, a rare event but of high clinical importance

Abstract Aims Trans-venous lead-related thrombosis is an undervalued issue. Since the lack of guidelines or evidences regarding the best therapeutic option, treatment of endocavitary clots on pacemaker wire is left to individual decision between surgical catheter extraction, thrombolysis, or anticoagulation therapy. In some patients, the labile equilibrium between hemorrhagic and thrombotic events may further complicate management. Methods and results We report the case of a 86-years-old man with heart failure (HF) severely reduced ejection fraction due to chronic ischaemic cardiomyopathy and several co-morbidities. He had a reacution of HF requiring hospitalization secondary to new-onset atrial flutter. During hospital stay, in light of episodes of severe bradycardia, he underwent single-lead PM implantation. Few days after discharge he developed deep vein thrombosis in situ of PM electro catheter insertion (poor compliance to anticoagulation therapy was reported) which improved after few days of regular therapy assumption. After few months anticoagulation therapy was dismitted due to etiology unknown-anemization requiring transfusion, but 20 days later he was once again admitted, this time because of pulmonary embolism. Trans thoracic echocardiography (TTE) enlightened a severely dysfunctioning right ventricle and a mass in right atrium hanging the wire. Trans oesophageal echocardiography was then performed showing hyper-reflective and highly mobile material with numerous ‘arborizations’. Intravenous heparin was started as pulmonary embolism therapy. Once infective etiology was excluded, total body computer tomography was performed to investigate a possible paraneoplastic origin. Presence of a meningioma was enlightened. Heart-team evaluation excluded catheter extraction in light of patient’s frailty, while thrombolysis was controindicated. Vitamin K antagonists was then started. At 1 month follow up no further embolic neither haemorrhagic events were reported. TTE showed a reduction in mass dimension and an improvement in right ventricle function. Conclusions In a guidelines-lacking field, VKA can be an effective option in cases of lead-related thrombosis when surgery or thrombolysis is not suitable. Further studies are needed to establish their real effectiveness in management of E-C-related endocavitary thrombi.

Abstract 13094: Pharmacokinetics and Therapeutic Efficacy of Drpitor1a, a Novel Dynamin-Related Protein 1 Inhibitor, in a Preclinical Model of Pulmonary Arterial Hypertension

Introduction: Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission contributes to the pathogenesis of pulmonary arterial hypertension (PAH). We investigated the pharmacokinetic characteristics of Drpitor1a, a novel, small molecule, ellipticine Drp1 inhibitor (prepared in-house), and tested its therapeutic efficacy in a pilot study using the rat monocrotaline (MCT)-PAH model. Methods: A single dose of Drpitor1a (5mg/kg) was administered IV or PO to male and female rats (n=3/sex). Blood was collected at 0, 5 and 30 minutes, and at 1, 2, 4, 6, 8 and 24 hours post drug administration. Plasma, lung and right ventricle (RV) were collected and tissue concentration of Drpitor1a was measured using HPLC coupled with mass spectrometry. The effects of Drpitor1a on mitochondrial fission and cell proliferation were assessed in human PAH pulmonary artery smooth muscle cells (PASMC). In an MCT-PAH model, a catheter was implanted in the left jugular vein on day 14 post-MCT injection. Drpitor1a (1mg/kg) was administered by IV every 48 hours from day 17 to day 27. On day 28, RV function and pulmonary hemodynamics were assessed. Results: Drpitor1a’s half-life varies by sex (9.9±5.3 hours and 24.3±21.4 hours in male and female rats respectively). Oral bioavailability of Drpitor1a was similar in males (21.1%) and females (19.7%). Lung concentration of Drpitor1a was similar between males and females (0.441±0.015 nM/mg and 0.444±0.581 nM/mg, respectively). In the RV, Drpitor1a level was higher in females (0.102±0.053 nM/mg) than males (0.055±0.015 nM/mg). Drpitor1a inhibited mitochondrial fission and cell proliferation in human PAH PASMC. In addition, Drpitor1a regressed pulmonary artery medial thickening (25.5% vs 34.9%), inhibited RV hypertrophy (Fulton index: 0.33 vs 0.39) and improved RV function (TAPSE: 2.2mm vs 1.8mm) in female MCT-PAH rats. Conclusion: Drpitor1a is a potential therapeutic agent for preclinical PAH and may be more effective in females.

IN THE HEART OF IT: A RARE PRESENTATION OF DISSEMINATED CRYPTOCOCCUS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Since the emergence of highly active antiretroviral therapy (HAART), incidence cryptococcosis has fallen. We discuss a rare presentation of disseminated cryptococcosis. CASE PRESENTATION: A previously well 31 year old woman presented with 3 weeks of nausea, vomiting & headache. She was sent to hospital when she developed dizziness & palpitations after a positive HIV test was found on an outpatient visit. Examination revealed diffuse adenopathy. Urine was positive for opiates, cannabinoids & barbiturates. Non-contrast computed tomography head revealed no acute abnormalities, but abdomen/pelvis found abdominal & retroperitoneal lymphadenopathy. On day 2, she developed diaphoresis, cold extremities with HR160bpm, BP89/53mmhg, RR44bpm, SpO289% & T100F. She was intubated & put on vasopressors. She subsequently had 3 PEA cardiac arrests with return of spontaneous circulation after several minutes. Bedside transthoracic echocardiogram (TTE) revealed a severely hypokinetic dilated right ventricle (RV) & underfilled left ventricle (LV). Bedside transesophageal echocardiogram noted hyperdynamic apex, akinetic base & echogenic material within the right pulmonary artery, concerning for a pulmonary embolism. Hemodynamic instability was refractory to thrombolytics & she was placed on veno-arterial ECMO. She was empirically given vancomycin, piperacillin-tazobactam & clindamycin/primaquine. Blood cultures were later positive for yeast, so caspofungin & fluconazole added. Follow-up TTE showed minimal improvement in RV or LV function. On day 3, after 24 hours off sedation, pupils were dilated & brainstem reflexes absent. Apnea test confirmed brain death. After expiration, HIV viral load was found to be 528,000 copies/ml (reference range: not detected), CD4 was <20 cells/mcl (490-1740cells/mcl), & Cryptococcus neoformans was isolated, with titer ≥1:2560 (normal: negative). DISCUSSION: Cryptococcosis is the most common fungal disease in HIV, but its incidence has decreased in the US. Earlier HIV diagnosis & HAART explain this. It most commonly affects the nervous system. Occasionally, blood cultures are positive indicating disseminated disease. We postulate that pulmonary vascular occlusion can occur due to disseminated cryptococcal infection. Cryptococcomas are extremely rare solid tumor-like masses which have been reported to invade the central nervous system & the skin. Our suspicion for this is high given her poor response to TPA & significant fungemia which likely led to right heart failure & cardiovascular collapse. Literature review identified one other such case. More common sequelae include meningitis or pulmonary involvement. Amphotericin B & Flucytosine represent the most potent therapy for severe disease. CONCLUSIONS: Cardiopulmonary collapse from right heart failure with disseminated cryptococcus is extremely rare. Early diagnosis & treatment of HIV remains the most important tool. REFERENCE #1: Bramantono, B., Danial, A., & Hadi, U. (2020). A case of an AIDS patient with Cryptococcus neoformans infection. The Pan African medical journal, 36, 88. https://doi.org/10.11604/pamj.2020.36.88.20406 REFERENCE #2: Gültaşli NZ, Ercan K, Orhun S, Albayrak S. MRI findings of intramedullary spinal cryptococcoma. Diagn Interv Radiol. 2007 Jun;13(2):64-7. PMID: 17562509. REFERENCE #3: Sperry BW, Howard EW, Gitterman S, Panza JA. A case of cryptogenic dyspnea: disseminated cryptococcosis. Am J Med. 2014 Aug;127(8):707-10. doi: 10.1016/j.amjmed.2014.04.007. Epub 2014 Apr 21. PMID: 24769024. DISCLOSURES: No relevant relationships by Janeen Grant-Sittol, source=Web Response No relevant relationships by Lena Makartian, source=Web Response No relevant relationships by Priya Patidar, source=Web Response No relevant relationships by Rani Sittol, source=Web Response