Right Ventricle Contractility Research Articles

Right Ventricular Function and Oxidative Stress Improve with the Administration of Thyroid Hormones and Grape Juice in a Pulmonary Hypertension Model.

Adverse remodeling of lung vessels elevates pulmonary pressure and provokes pulmonary arterial hypertension (PAH). PAH results in increased right ventricle (RV) afterload, causing ventricular hypertrophy and the onset of heart failure. There is no specific treatment for maladaptive RV remodeling secondary to PAH. This study aims to explore two therapeutic approaches, grape juice (GJ) and thyroid hormones (TH), on PAH-induced oxidative stress and cardiac functional changes. Parameters of echocardiography related to lung vessel resistance (AT/ET ratio), RV contractility (TAPSE), and RV diastolic function (E/A peaks ratio) were evaluated. Also, total ROS, lipid peroxidation, antioxidant enzymes, calcium handling proteins, pro-oxidant and antioxidant protein expression were measured. Values of p<0.05 were considered statistically significant. Both GJ and TH treatments demonstrated reductions in pulmonary resistance (~22%) and improvements in TAPSE (inotropism ~11%) and AT/ET ratio (~26%) (p<0.05). There were no changes amongst groups regarding the E/A peak ratio. Although ROS and TBARS were not statistically significant, GJ and TH treatments decreased xanthine oxidase (~49%) levels and normalized HSP70 and calcium handling protein expression (p<0.05). However, only TH treatment ameliorated diastolic function (~50%) and augmented NRF2 immunocontent (~48%) (p<0.05). To the best of our knowledge, this study stands as a pioneer in showing that TH administered together with GJ promoted functional and biochemical improvements in a PAH model. Moreover, our data suggest that GJ and TH treatments were cardioprotective, combined or not, and exhibited their beneficial effects by modulating oxidative stress and calcium-handling proteins.

The impact of unilateral pulmonary artery stenosis on right ventricular to pulmonary arterial coupling in patients with transposition of the great arteries.

Unilateral pulmonary artery (PA) stenosis is common in the transposition of the great arteries (TGA) after arterial switch operation (ASO) but the effects on the right ventricle (RV) remain unclear. To assess the effects of unilateral PA stenosis on RV afterload and function in pediatric patients with TGA-ASO. In this retrospective study, eight TGA patients with unilateral PA stenosis underwent heart catheterization and cardiac magnetic resonance (CMR) imaging. RV pressures, RV afterload (arterial elastance [Ea]), PA compliance, RV contractility (end-systolic elastance [Ees]), RV-to-PA (RV-PA)coupling (Ees/Ea), and RV diastolic stiffness (end-diastolic elastance [Eed]) were analyzed and compared to normal values from the literature. In all TGA patients (mean age 12 ± 3 years), RV afterload (Ea) and RV pressures were increased whereas PA compliance was reduced. RV contractility (Ees) was decreased resulting in RV-PA uncoupling. RV diastolic stiffness (Eed) was increased. CMR-derivedRV volumes, mass, and ejection fraction were preserved. Unilateral PA stenosis results in an increased RV afterload in TGA patients after ASO. RV remodeling and function remain within normal limits when analyzed by CMR but RV pressure-volume loop analysis shows impaired RV diastolic stiffness and RV contractility leading to RV-PA uncoupling.

Função do Ventrículo Direito e Estresse Oxidativo Melhoram com a Administração de Hormônios da Tireoide e Suco de Uva em um Modelo de Hipertensão Pulmonar

Abstract Background Adverse remodeling of lung vessels elevates pulmonary pressure and provokes pulmonary arterial hypertension (PAH). PAH results in increased right ventricle (RV) afterload, causing ventricular hypertrophy and the onset of heart failure. There is no specific treatment for maladaptive RV remodeling secondary to PAH. Objectives This study aims to explore two therapeutic approaches, grape juice (GJ) and thyroid hormones (TH), on PAH-induced oxidative stress and cardiac functional changes. Methods Parameters of echocardiography related to lung vessel resistance (AT/ET ratio), RV contractility (TAPSE), and RV diastolic function (E/A peaks ratio) were evaluated. Also, total ROS, lipid peroxidation, antioxidant enzymes, calcium handling proteins, pro-oxidant and antioxidant protein expression were measured. Values of p&lt;0.05 were considered statistically significant. Results Both GJ and TH treatments demonstrated reductions in pulmonary resistance (~22%) and improvements in TAPSE (inotropism ~11%) and AT/ET ratio (~26%) (p&lt;0.05). There were no changes amongst groups regarding the E/A peak ratio. Although ROS and TBARS were not statistically significant, GJ and TH treatments decreased xanthine oxidase (~49%) levels and normalized HSP70 and calcium handling protein expression (p&lt;0.05). However, only TH treatment ameliorated diastolic function (~50%) and augmented NRF2 immunocontent (~48%) (p&lt;0.05). Conclusions To the best of our knowledge, this study stands as a pioneer in showing that TH administered together with GJ promoted functional and biochemical improvements in a PAH model. Moreover, our data suggest that GJ and TH treatments were cardioprotective, combined or not, and exhibited their beneficial effects by modulating oxidative stress and calcium-handling proteins.

Occult right ventricular dysfunction and right ventricular-vascular uncoupling in left ventricular assist device recipients

BackgroundCurrent assessments remain insensitive for detecting right heart failure post left ventricular assist device (LVAD). Sensitive pressure-volume loop assessments of right ventricle (RV) contractility may improve our appreciation of post-LVAD RV dysfunction. MethodsThirteen LVAD patients and 20 reference (non-LVAD) subjects underwent comparison of echocardiographic, right heart cath hemodynamic, and pressure-volume loop-derived assessments of RV contractility using end-systolic elastance (Ees), RV afterload by effective arterial elastance (Ea), and RV-pulmonary arterial (RV-PA) coupling (ratio of Ees/Ea). ResultsLVAD patients had lower RV Ees (0.20±0.08 vs. 0.30±0.15 mmHg/ml, p=0.01) and lower RV Ees/Ea (0.37±0.14 vs 1.20±0.54, p<0.001) versus reference subjects. Low RV Ees correlated with reduced RV septal strain, an indicator of septal contractility, in both the entire cohort (r=0.68, p=0.004) as well as the LVAD cohort itself (r=0.78, p=0.02). LVAD recipients with low RV Ees/Ea (below the median value) demonstrated more clinical heart failure (71% vs 17%, p=0.048), driven by an inability to augment RV Ees (0.22±0.11 vs 0.19±0.02 mmHg/ml, p=0.95) to accommodate higher RV Ea (0.82±0.38 vs 0.39±0.08 mmHg/ml, p=0.002). Pulmonary artery pulsatility index (PAPi) best identified low baseline RV Ees/Ea (≤0.35) in LVAD patients (AUC=0.80); during ramp study, change in PAPi also correlated with change in RV Ees/Ea (r=0.58, p=0.04). ConclusionsLVAD patients demonstrate occult intrinsic RV dysfunction. In the setting of excess RV afterload, LVAD patients lack the RV contractile reserve to maintain ventriculo-vascular coupling. Depression in RV contractility may be related to LVAD LV unloading which reduces septal contractility.

Pressure Overload and Right Ventricular Failure: From Pathophysiology to Treatment.

Right ventricular failure (RVF) is often caused by increased afterload and disrupted coupling between the right ventricle (RV) and the pulmonary arteries (PAs). After a phase of adaptive hypertrophy, pressure-overloaded RVs evolve towards maladaptive hypertrophy and finally ventricular dilatation, with reduced stroke volume and systemic congestion. In this article, we review the concept of RV-PA coupling, which depicts the interaction between RV contractility and afterload, as well as the invasive and non-invasive techniques for its assessment. The current principles of RVF management based on pathophysiology and underlying etiology are subsequently discussed. Treatment strategies remain a challenge and range from fluid management and afterload reduction in moderate RVF to vasopressor therapy, inotropic support and, occasionally, mechanical circulatory support in severe RVF.

How to incorporate tricuspid regurgitation in right ventricular-pulmonary arterial coupling.

Adaptation of the right ventricle (RV) to a progressively increasing afterload is one of the hallmarks of pulmonary arterial hypertension (PAH). Pressure-volume loop analysis provides measures of load-independent RV contractility, i.e., end-systolic elastance, and pulmonary vascular properties, i.e., effective arterial elastance (Ea). However, PAH-induced RV overload potentially results in tricuspid regurgitation (TR). TR makes RV eject to both PA and right atrium; thereby, a ratio of RV end-systolic pressure (Pes) to RV stroke volume (SV) could not correctly define Ea. To overcome this limitation, we introduced a two-parallel compliance model, i.e., Ea = 1/(1/Epa + 1/ETR), while effective pulmonary arterial elastance (Epa = Pes/PASV) represents pulmonary vascular properties and effective tricuspid regurgitant elastance (ETR) represents TR. We conducted animal experiments to validate this framework. First, we performed SV analysis with a pressure-volume catheter in the RV and a flow probe at the aorta in rats with and without pressure-overloaded RV to determine the effect of inferior vena cava (IVC) occlusion on TR. A discordance between the two techniques was found in rats with pressure-overloaded RV, not in sham. This discordance diminished after IVC occlusion, suggesting that TR in pressure-overloaded RV was diminished by IVC occlusion. Next, we performed pressure-volume loop analysis in rats with pressure-overloaded RVs, calibrating RV volume by cardiac magnetic resonance. We found that IVC occlusion increased Ea, suggesting that a reduction of TR increased Ea. Using the proposed framework, Epa was indistinguishable to Ea post-IVC occlusion. We conclude that the proposed framework helps better understanding of the pathophysiology of PAH and associated right heart failure.NEW & NOTEWORTHY This study reveals the impact of tricuspid regurgitation on pressure-volume loop analysis in right ventricle pressure overload. By introducing a novel concept of parallel compliances in the pressure-volume loop analysis, a better description is provided for the right ventricular forward afterload in the presence of tricuspid regurgitation.

Computational modelling of multi-temporal ventricular-vascular interactions during the progression of pulmonary arterial hypertension.

A computational framework is developed to consider the concurrent growth and remodelling (G&R) processes occurring in the large pulmonary artery (PA) and right ventricle (RV), as well as ventricular-vascular interactions during the progression of pulmonary arterial hypertension (PAH). This computational framework couples the RV and the proximal PA in a closed-loop circulatory system that operates in a short timescale of a cardiac cycle, and evolves over a long timescale due to G&R processes in the PA and RV. The framework predicts changes in haemodynamics (e.g. 68.2% increase in mean PA pressure), RV geometry (e.g. 38% increase in RV end-diastolic volume) and PA tissue microstructure (e.g. 90% increase in collagen mass) that are consistent with clinical and experimental measurements of PAH. The framework also predicts that a reduction in RV contractility is associated with long-term RV chamber dilation, a common biomarker observed in the late-stage PAH. Sensitivity analyses on the G&R rate constants show that large PA stiffening (both short and long term) is affected by RV remodelling more than the reverse. This framework can serve as a foundation for the future development of a more predictive and comprehensive cardiovascular G&R model with realistic heart and vascular geometries.

Imaging in Pulmonary Vascular Disease-Understanding Right Ventricle-Pulmonary Artery Coupling.

The right ventricle (RV) and pulmonary arterial (PA) tree are inextricably linked, continually transferring energy back and forth in a process known as RV-PA coupling. Healthy organisms maintain this relationship in optimal balance by modulating RV contractility, pulmonary vascular resistance, and compliance to sustain RV-PA coupling through life's many physiologic challenges. Early in states of adaptation to cardiovascular disease-for example, in diastolic heart failure-RV-PA coupling is maintained via a multitude of cellular and mechanical transformations. However, with disease progression, these compensatory mechanisms fail and become maladaptive, leading to the often-fatal state of "uncoupling." Noninvasive imaging modalities, including echocardiography, magnetic resonance imaging, and computed tomography, allow us deeper insight into the state of coupling for an individual patient, providing for prognostication and potential intervention before uncoupling occurs. In this review, we discuss the physiologic foundations of RV-PA coupling, elaborate on the imaging techniques to qualify and quantify it, and correlate these fundamental principles with clinical scenarios in health and disease. © 2022 American Physiological Society. Compr Physiol 12: 1-26, 2022.

Differential Response of Right Ventricular Contractility to Lung Ischemia-Reperfusion Injury: Large Animal Model to Study Sequential Single Lung Transplantation

<h3>Purpose</h3> Early outcome after lung transplantation (LTx) is often characterized by the presence of primary graft dysfunction (PGD). The exact role of the right ventricle (RV) in development of PGD and perioperative outcome is unknown. Firstly, increased afterload due to PGD might compromise RV function. Secondly, increased contractility and cardiac output (CO) of RV might contribute to pulmonary edema accumulation after reperfusion. We developed a unique large animal model to study RV behavior in a setting of pulmonary ischemia-reperfusion injury (IRI). <h3>Methods</h3> The left lung (LL) of a domestic pig in clamping group [CLA] was clamped (3h warm ischemia) and reperfused (3h) in situ (n=6). During the final hour of reperfusion, contralateral right lung (RL) was clamped to force RV CO to the injured LL. Control animals [CON] were fully instrumented (n=5) and followed for 6 hours. The RV function was monitored using a conductance catheter measuring pressure-volume (PV) loops. Lung injury was assessed by wet to dry (W/D) ratio and ex-vivo computed tomography (CT). Data was analyzed in time using 2-way ANOVA test or student T-test. <h3>Results</h3> Pulmonary vascular resistance (PVR) rose significantly at hour 6 in [CLA], reflecting an increase of afterload due to IRI and RL camping (<i>fig. A</i>). RV Contractility was stable in [CON]. In [CLA], it increased in 2 animals (<i>fig. D</i>) and 4 animals developed RV failure (<i>fig. B</i>). Lungs were injured as reflected by higher W/D ratio (<i>p=0.0019</i>) and parenchymal density on CT (<i>p=0.0089</i>) of [CLA] LL compared to [CON]. <h3>Conclusion</h3> RV response to increased afterload resulting from IRI occurs in a dichotomized way: with increased contractility or with failure. This occurs when the contralateral lung is clamped and mimics a specific intra-operative situation of sequential single LTx. Our model should be considered as an innovative platform to study the possible benefit of ECLS devices on RV function and PGD development after LTx.

Right-sided heart reperfusion ("Berlin bridge technique") for right ventricle support during left ventricular assist device (LVAD) implantation.

Right-sided heart reperfusion ("Berlin bridge technique") for right ventricle support during left ventricular assist device (LVAD) implantation.

A Meta-Analysis Comparing Venoarterial (VA) Extracorporeal Membrane Oxygenation (ECMO) to Impella for Acute Right Ventricle Failure.

The right ventricular complication happens when the right ventricle (RV) fails to move sufficient blood through the pulmonary circle to enable enough left ventricular pumping. A significant pulmonary embolism/right-sided myocardial infarction may cause this to develop suddenly in a previously healthy heart, but many of the patients treated in the critical care unit have gradual, compensated RV failure as a result of chronic heart and lung disease. RV failure management aims to decrease afterload and improve right-side filling pressures. Vasoactive medications have a lower effect on lowering vascular obstruction in the pulmonary circulation than in the systemic circle because the vascular tone is lower in the pulmonary circulation. Any factors that induce an elevation in pulmonary vascular tone must be addressed, and selective pulmonary vasodilators must be administered in a prescription that does not result in systemic hypotension or compromise oxygenation. The system-based systolic arterial pressure should be kept near the RV systolic pressure to ensure RV perfusion. When these efforts prove futile, judicious application of inotropic medications for better RV contractility may help ensure cardiac output. After obtaining the finest medical treatment, certain individuals may need the implantation of a mechanical circulatory support device.This meta-analysis is intended to compare the Impella and venoarterial (VA) extracorporeal membrane oxygenation (ECMO) mechanical supports for patients with acute right ventricular failure. This comparison should demonstrate the best mechanical support between the two through thorough analysis.The analysis was begun by data collection from relevant sites; PUBMED and EMBASE were searched in collaboration with Google Scholar. Keywords were searched: Impella for acute right ventricle failure and VA ECMO for acute right ventricle failure. The results that were close to the search titles had their respective articles downloaded for further scrutiny.The search finally brought 1001 related articles that were exposed to further analysis to find more refined and closer articles within the needs of this meta-analysis. After extensive scrutiny, 23 articles were found to be the best for these analyses. The data showed that VA ECMO had better results than Impella for acute RV failure. However, the data were not statistically significant, as either the numbers of the studies were not enough or the null hypothesis was true and there was no true difference between them. More studies will be needed to confirm this.

Echocardiographic Assessment of Right Ventricular-Arterial Coupling in Predicting Prognosis of Pulmonary Arterial Hypertension Patients.

In response to an increased afterload in pulmonary arterial hypertension (PAH), the right ventricle (RV) adapts by remodeling and increasing contractility. The idea of coupling refers to maintaining a relatively constant relationship between ventricular contractility and afterload. Twenty-eight stable PAH patients (mean age 49.5 ± 15.5 years) were enrolled into the study. The follow-up time of this study was 58 months, and the combined endpoint (CEP) was defined as death or clinical deterioration. We used echo TAPSE as a surrogate of RV contractility and estimated systolic pulmonary artery pressure (sPAP) reflecting RV afterload. Ventricular–arterial coupling was evaluated by the ratio between these two parameters (TAPSE/sPAP). In the PAH group, the mean pulmonary artery pressure (mPAP) was 47.29 ± 15.3 mmHg. The mean echo-estimated TAPSE/sPAP was 0.34 ± 0.19 mm/mmHg and was comparable in value and prognostic usefulness to the parameter derived from magnetic resonance and catheterization (ROC analysis). Patients who had CEP (n = 21) had a significantly higher mPAP (53.11 ± 17.11 mmHg vs. 34.86 ± 8.49 mmHg, p = 0.03) and lower TAPSE/sPAP (0.30 ± 0.21 vs. 0.43 ± 0.23, p = 0.04). Patients with a TAPSE/sPAP lower than 0.25 mm/mmHg had worse prognosis, with log-rank test p = 0.001. the echocardiographic estimation of TAPSE/sPAP offers an easy, reliable, non-invasive prognostic parameter for the comprehensive assessment of hemodynamic adaptation in PAH patients.

The Right Ventricle in COVID-19.

Infection with the novel severe acute respiratory coronavirus-2 (SARS-CoV2) results in COVID-19, a disease primarily affecting the respiratory system to provoke a spectrum of clinical manifestations, the most severe being acute respiratory distress syndrome (ARDS). A significant proportion of COVID-19 patients also develop various cardiac complications, among which dysfunction of the right ventricle (RV) appears particularly common, especially in severe forms of the disease, and which is associated with a dismal prognosis. Echocardiographic studies indeed reveal right ventricular dysfunction in up to 40% of patients, a proportion even greater when the RV is explored with strain imaging echocardiography. The pathophysiological mechanisms of RV dysfunction in COVID-19 include processes increasing the pulmonary vascular hydraulic load and others reducing RV contractility, which precipitate the acute uncoupling of the RV with the pulmonary circulation. Understanding these mechanisms provides the fundamental basis for the adequate therapeutic management of RV dysfunction, which incorporates protective mechanical ventilation, the prevention and treatment of pulmonary vasoconstriction and thrombotic complications, as well as the appropriate management of RV preload and contractility. This comprehensive review provides a detailed update of the evidence of RV dysfunction in COVID-19, its pathophysiological mechanisms, and its therapy.

EFFECTS OF A GLUCAGON LIKE PEPTIDE-1 AGONIST AND RHO-KINASE INHIBITOR ON PULMONARY AND RIGHT VENTRICLE FUNCTION IN PULMONARY HYPERTENSIVE RATS WITH AND WITHOUT INSULIN RESISTANCE

Objective: Insulin resistance is now recognized as an important factor in the development of pulmonary hypertension (PH). Increased activation of RhoA/Rho-kinase (ROCK) inhibits the protective actions of endothelial nitric oxide (NO) synthase (eNOS) signaling in diabetes and PH. Glucagon like peptide-1 (GLP-1) agonists were shown to reverse these pathological changes. We investigated how liraglutide (GLP-1 agonist) and fasudil (ROCK inhibitor) treatments affect the progression of pulmonary and right ventricle (RV) dysfunction in PH rats with insulin resistance. Design and method: SU5416 (20 mg/kg) was administered to male Wistar and prediabetic Goto-Kakizaki (GK) rats followed by 3 weeks of chronic hypoxia (SuHx) or normoxia exposure. Osmotic pumps delivered a continuous infusion of liraglutide (1 mg/kg/d) or fasudil (100 mg/kg/d) for the final 3 weeks in some SuHx rats. Synchrotron microangiography of the left lung was performed in vivo. Results: During chronic hypoxia 30% mortality occurred due to RV failure associated with thrombosis in GK rats. Systolic RV pressure was 74 mm Hg and 128 mm Hg in GK and Wistar SuHx rats respectively. Prediabetes exacerbated pulmonary arteriole-artery rarefaction (two-fold occlusion increase) and pulmonary vasoconstriction, with acetylcholine (ACh)-mediated constriction at 3 weeks and loss of NO donor mediated dilation at 6 weeks SuHx. Wistar SuHx maintained ACh-mediated dilation in resistance vessels despite pronounced overall vasoconstriction of all branching orders. Neither strain differed in ROCK1/2 protein expression. Notably, liraglutide and fasudil improved pulmonary vasodilation, but only liraglutide halted vascular remodeling. Fasudil increased phosphorylation of eNOS at Ser1177 in the RV of GK SuHx. Liraglutide reduced RV systolic pressure and Fulton indices, while fasudil elevated RV pressure to 104 mm Hg in the GK SuHx. Conclusions: Reduced NO bioavailability contributes to exacerbated pulmonary arterial rarefaction and depressed RV contractility associated with prediabetes in SuHx rats. GLP-1 agonist treatment did not ameliorate endothelin-1/ROCK- mediated suppression of eNOS phosphorylation in the RV as observed with fasudil. While liraglutide intervention prevented pulmonary microvessel occlusion, inhibition of both ROCK1/2 isoforms with fasudil increased occlusion formation suggesting that ROCK1 might act to inhibit pulmonary microvessel muscularization.

Advanced echocardiographic phenotyping of critically ill patients with coronavirus-19 sepsis: a prospective cohort study

BackgroundSepsis is characterized by various hemodynamic alterations which could happen concomitantly in the heart, pulmonary and systemic circulations. A comprehensive demonstration of their interactions in the clinical setting of COVID-19 sepsis is lacking. This study aimed at evaluating the feasibility, clinical implications, and physiological coherence of the various indices of hemodynamic function and acute myocardial injury (AMI) in COVID-19 sepsis.MethodsHemodynamic and echocardiographic data of septic critically ill COVID-19 patients were prospectively recorded. A dozen hemodynamic indices exploring contractility and loading conditions were assessed. Several cardiac biomarkers were measured, and AMI was considered if serum concentration of high-sensitive troponin T (hs-TNT) was above the 99th percentile, upper reference.ResultsSixty-seven patients were assessed (55 males), with a median age of 61 [50–70] years. Overall, the feasibility of echocardiographic parameters was very good, ranging from 93 to 100%. Hierarchical clustering method identified four coherent clusters involving cardiac preload, left ventricle (LV) contractility, LV afterload, and right ventricle (RV) function. LV contractility indices were not associated with preload indices, but some of them were positively correlated with RV function parameters and negatively correlated with a single LV afterload parameter. In most cases (n = 36, 54%), echocardiography results prompted therapeutic changes. Mortality was not influenced by the echocardiographic variables in multivariable analysis. Cardiac biomarkers’ concentrations were most often increased with high incidence of AMI reaching 72%. hs-TNT was associated with mortality and inversely correlated with most of LV and RV contractility indices.ConclusionsIn this comprehensive hemodynamic evaluation in critically ill COVID-19 septic patients, we identified four homogeneous and coherent clusters with a good feasibility. AMI was common and associated with alteration of LV and RV functions. Echocardiographic assessment had a clinical impact on patient management in most cases.

The preventive and therapeutic effects of AAV1-KLF4-shRNA in cigarette smoke-induced pulmonary hypertension.

We found previously that KLF4 expression was up‐regulated in cultured rat and human pulmonary artery smooth muscle cells (PASMCs) exposed to cigarette smoke (CS) extract and in pulmonary artery from rats with pulmonary hypertension induced by CS. Here, we aim to investigate whether CS‐induced pulmonary hypertension (PH) is prevented and ameliorated by targeted pulmonary vascular gene knockdown of KLF4 via adeno‐associated virus 1 (AAV1)‐KLF4‐shRNA in vivo in rat model. The preventive and therapeutic effects were observed according to the different time‐point of AAV1‐KLF4‐shRNA intratracheal administration. We tested haemodynamic measurements of systemic and pulmonary circulations and observed the degree of pulmonary vascular remodelling. In the preventive experiment, KLF4 expression and some pulmonary circulation hemodynamic measurements such as right ventricular systolic pressure (RVSP), mean right ventricular pressure (mRVP), peak RV pressure rate of rise (dP/dt max) and right ventricle (RV) contractility index were increased significantly in the CS‐induced PH model. While in the prevention group (AAV1‐KLF4‐shRNA group), RVSP, mRVP, dP/dt max and RV contractility index which are associated with systolic function of right ventricle decreased and the degree of pulmonary vascular remodelling relieved. In the therapeutic experiment, we observed a similar trend. Our findings emphasize the feasibility of sustained pulmonary vascular KLF4 gene knockdown using intratracheal delivery of AAV1 in an animal model of cigarette smoke‐induced PH and determined gene transfer of KLF4‐shRNA could prevent and ameliorate the progression of PH.

Excess Protein O-GlcNAcylation Links Metabolic Derangements to Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.

The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-N-acetylglucosamine, which, when added to serines or threonines, modulates protein function through protein O-GlcNAcylation. Glutamine-fructose-6-phosphate amidotransferase (GFAT) regulates HBP flux, and AMP-kinase phosphorylation of GFAT blunts GFAT activity and O-GlcNAcylation. While numerous studies demonstrate increased right ventricle (RV) glucose uptake in pulmonary arterial hypertension (PAH), the relationship between O-GlcNAcylation and RV function in PAH is unexplored. Therefore, we examined how colchicine-mediated AMP-kinase activation altered HBP intermediates, O-GlcNAcylation, mitochondrial function, and RV function in pulmonary artery-banded (PAB) and monocrotaline (MCT) rats. AMPK activation induced GFAT phosphorylation and reduced HBP intermediates and O-GlcNAcylation in MCT but not PAB rats. Reduced O-GlcNAcylation partially restored the RV metabolic signature and improved RV function in MCT rats. Proteomics revealed elevated expression of O-GlcNAcylated mitochondrial proteins in MCT RVs, which fractionation studies corroborated. Seahorse micropolarimetry analysis of H9c2 cardiomyocytes demonstrated colchicine improved mitochondrial function and reduced O-GlcNAcylation. Presence of diabetes in PAH, a condition of excess O-GlcNAcylation, reduced RV contractility when compared to nondiabetics. Furthermore, there was an inverse relationship between RV contractility and HgbA1C. Finally, RV biopsy specimens from PAH patients displayed increased O-GlcNAcylation. Thus, excess O-GlcNAcylation may contribute to metabolic derangements and RV dysfunction in PAH.

Right Atrial Pacing to Improve Acute Hemodynamics in Pulmonary Arterial Hypertension

Pacing to increase resting heart rate (HR) is commonly employed in order to improve hemodynamics and cardiac output (CO), particularly in post-operative setting when right ventricle (RV) dysfunction is present. We tested if right atrial (RA) pacing improves RV hemodynamics acutely, and if the degree of baseline RV dysfunction modifies this relationship. We prospectively enrolled adult subjects with known or suspected pulmonary arterial hypertension (PAH) who underwent elective right heart catheterization between January 2013 and April 2016. RV pressure-volume (PV) analysis was performed with conductance catheters. RV volumes were calibrated by cardiac MRI same day. After measuring baseline PV data, a bipolar pacing wire was positioned in the RA and rate set to 80 to 90 beats per minute (bpm). Rate was increased in steps of 20 bpm. PV loops were recorded at end-expiration after 1 minute in each group: 80-99, 100-119, and 120-139 bpm. Parametric data were analyzed by Repeated Measures ANOVA, and non-parametric data were analyzed by Friedman Test. Baseline hemodynamic predictors of CO were analyzed by Repeated Measures simple linear regression. Twenty-three subjects were included in this analysis. Baseline mean RA pressure was 7 ± 3 mmHg with pulmonary vascular resistance of 5.2 ± 4.1 wood units. As HR increased with RA pacing, stroke volume (SV) declined in each pacing group (68±22, 61±19, 54±21 mL, respectively; p<0.001) with increase in CO (5.5±1.9, 6.2±1.9, 6.6±2.5 L/min; p<0.001). The dP/dt maximum increased (429, 490, 549 mmHg/s; p<0.001); however, RV-pulmonary arterial coupling (Ees/Ea) fell with pacing (0.97 vs 0.84 vs 0.78, p=0.009). No baseline hemodynamic parameter or measure of RV function modified the relationship between CO and RA pacing. Between-subject data had large variation; exclusion of non-PAH subjects (n=6) did not alter results. As heart rate increases with RA pacing, RV contractility and CO increase modestly at the expense of cardiac efficiency.

Differential effects of integrin-linked kinase inhibitor Cpd22 on severe pulmonary hypertension in male and female rats.

Pulmonary arterial hypertension (PAH) is a progressive fatal disease with no cure. Inhibition of integrin-linked kinase (ILK) reverses experimental pulmonary hypertension (PH) in male mice, but its effect on severe experimental PH in either male or female animals is unknown. We examined effects of ILK inhibitor Cpd22 on rats with SU5416/hypoxia-induced PH; treatment was performed at six to eight weeks after PH initiation. Five weeks after PH initiation, male and female rats developed similar levels of PH. Eight weeks after PH induction, vehicle-treated male rats had more severe PH than females. Cpd22-treated males, but not females, showed complete suppression of phospho-Akt in small pulmonary arteries (PAs), significantly lower PA medial thickness and percentage of fully occluded arteries, decreased systolic right ventricle (RV) pressure, PA pressure, RV hypertrophy, RV end-diastolic pressure, and improved RV contractility index compared to vehicle-treated group. Cpd22 suppressed proliferation of human male and female PAH pulmonary artery vascular smooth muscle cell (PAVSMC). 17β-estradiol had no effect as a single agent but significantly attenuated Cpd22-dependent inhibition of proliferation in female, but not male, PAH PAVSMC. Taken together, these data demonstrate that male rats develop more severe PH than females but respond better to Cpd22 treatment by reducing pulmonary vascular remodeling, PH, and RV hypertrophy and improving RV functional outcomes. 17β-estradiol diminishes anti-proliferative effect of Cpd22 in female, but not male, human PAH PAVSMC. These findings suggest potential attractiveness of ILK inhibition to reduce established PH in males and suggest that the combination with estrogen-lowering drugs could be considered to maximize anti-proliferative and anti-remodeling effects of ILK inhibitors in females.

429 Right ventricular longitudinal and radial fiber contractility in patients undergoing mitral valve surgery: a PREPARE-MVR substudy

Abstract Severe mitral regurgitation results in significant hemodynamic demands of not only the left, but the right ventricle (RV) as well. Increased pulmonary pressures and consequential pressure overload of the RV induces complex remodeling, which can be partially restored by mitral valve repair/replacement (MVR). MVR is associated with marked changes of RV deformation, however, the clinical significance of these changes is not well estabilished. The PREPARE-MVR study (PRediction of Early PostoperAtive Right vEntricular failure in Mitral Valve Replacement/Repair patients) aims to determine parameters, which may predict the perioperative risk of acute RV failure. In this current substudy, our aim was to determine the changes of RV global, longitudinal and radial fiber contractility before and following MVR. Our study group consisted of 27 MVR patients (mean age: 64 ± 12 years, m/f: 19/8). Transthoracic 3D echocardiography was performed before the operation and following intensive care unit discharge. 3D beutel model of the RV was created and RV end-diastolic volume index (EDVi) among with RV ejection fraction (RVEF) were calculated using commercially available software. For in-depth analysis of RV mechanics, we have decomposed the motion of the RV using our custom software (ReVISION) to determine longitudinal (LEF) and radial ejection fraction (REF). Right heart catheterization was also performed before MVR and 24 hours after MVR as well to measure pulmonary arterial mean systolic pressure (mPAP), pulmonary arterial wedge pressure (PAWP) and RV stroke work index (RVSWi). Using the aforementioned parameters, we have calculated RV longitudinal (longRVSWi) and RV radial stroke work index (radRVSWi), which represent RV longitudinal and radial fiber contractility. RV morphology did not change significantly according to RVEDVi (preop vs. postop: 71 ± 17 vs. 72 ± 20 mL/m², p = NS). RVEF slightly decreased after MVR (50 ± 6 vs. 48 ± 7 %, p &amp;lt; 0.05), however, RV motion pattern markedly changed. Postoperative LEF was significantly lower compared to preoperative values (25 ± 6 vs. 16 ± 6%, p &amp;lt; 0.0001), among with an increase in REF (21 ± 7 vs. 27 ± 7%, p &amp;lt; 0.01). As expected, mPAP and PAWP decreased in response to MVR (mPAP: 30 ± 10 vs. 25 ± 7 mmHg; PAWP: 19 ± 7 vs. 13 ± 3 mmHg, both p &amp;lt; 0.01). Global RV contractility decreased after surgery (RVSWi: 603 ± 355 vs. 474 ± 251 mmHg*mL/m², p &amp;lt; 0.05). While RV longitudinal contractility also significantly reduced (longRVSWi: 289 ± 179 vs. 166 ± 122 mmHg*mL/m², p &amp;lt; 0.001), radial contractility was maintained following MVR (radRVSWi: 240 ± 141 vs. 261 ± 144 mmHg*mL/m², p = NS). MVR is associated with marked changes of RV function and hemodynamics. RV longitudinal and radial contractility have distinct response to surgery, which may be important in postoperative patient management. The PREPARE-MVR study aims to examine the role of preoperative RV mechanics in clinical outcome.