Right Ventricular Systolic Pressure Research Articles

Abstract 14268: Prognostic Value of Clinical and Echocardiographic Factors in Atrial Functional Tricuspid Regurgitation

Introduction: Atrial functional tricuspid regurgitation (AFTR) is an increasingly recognized and prevalent clinical entity associated with adverse outcomes. Hypothesis: We evaluated the clinical and echocardiographic features of AFTR and those associated with poor prognosis. Methods: Consecutive patients with at least moderate-to-severe and isolated AFTR during 14 years were studied, and clinical and echocardiographic parameters including that for TR and the right heart were analyzed. Multivariable and receiver-operative characteristics analyses were performed to identify predictors and their thresholds for all-cause mortality during follow-up. Results: Amongst 155 AFTR patients (age 73±15, female 83%), 58(37%) were symptomatic, and 80 (52%) had atrial fibrillation. There were 77 (49%) deaths over a mean follow-up of 3.9±3.3 years. Multivariable analyses results are shown in the Table 1, were symptoms, right atrial strain and right ventricular systolic pressure (RVSP) were independently associated with mortality during follow-up with hazards ratios (95% confidence intervals, P-values) of 3.27 (1.18-9.04, P=0.022), 0.95 per 1% increase (0.92-0.98, P=0.01), and 1.05 per 1 mmHg increase (1.01-1.09, P=0.003). Area under curve (95% confidence interval) and optimal thresholds for the most important echocardiographic parameters to predict mortality were RVSP 0.80 (0.74-0.92) >44 mmHg, right atrial strain 0.73 (0.62-0.84) < +21%, and right ventricular free wall longitudinal strain 0.69 (0.57-0.81) > -18%. Conclusions: Significant AFTR is associated with adverse prognosis, therefore accurate diagnosis is critical. The key predictors of mortality include symptoms, reduced right atrial strain and higher RVSP, and their presence may prompt more aggressive medical and procedural therapies in AFTR patients that warrants further research.

Abstract 10384: Impact of Preexisting Pulmonary Hypertension on Outcomes in Patients Hospitalized With Covid-19

Introduction: Pulmonary hypertension (PH) is commonly associated with cardiopulmonary co-morbidities that increase morbidity and mortality risk with COVID-19. Hypothesis: This study aims to evaluate the association between preexisting PH and in-hospital outcomes in patients admitted with COVID-19. Methods: Consecutive patients at a large New England academic health system hospitalized with COVID-19 between March 1 and December 31, 2020, who had prior echocardiograms with documented estimated right ventricular systolic pressure (RVSP) were included. PH was defined as RVSP ≥30 mm Hg. Multivariable logistic regression adjusting for demographic and clinical characteristics was employed to relate PH to a primary outcome of all-cause mortality, and secondary outcomes including non-invasive positive pressure ventilation (NIPPV), myocardial infarction (MI), intensive care unit admission (ICU), and recurrent heart failure (HF) individually. Results: Of the 656 patients admitted, 395 (60.2%) had documented PH on a prior echocardiogram. PH patients were older, more likely to be men, and have cardiopulmonary and renal disease. Patients with PH had larger atrial size and higher E to early diastolic mitral annular tissue velocity (E/e') but similar left ventricular and right ventricular function compared to patients without PH. All-cause mortality (21% vs 10.3%, p= 0.001), need for ICU level of care (19% vs 13%, p = 0.046), NIPPV (23% vs 16%, p = 0.03), and recurrent HF (18% vs 5%, p < 0.001) were more common in patients with PH compared to those without. Unadjusted and adjusted odds ratios relating PH to study outcomes appear in the Table . Conclusions: Preexisting PH is independently associated with higher risk of all-cause mortality in patients who are hospitalized with COVID-19.

Abstract 15203: Single Cell Transcriptional Analysis Implicates Acta2 Positive Pericytes in Arterial Muscularization and Imbalance in Bmp and Angpt Signaling During Development of Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by marked vascular remodeling, inflammation and increased pulmonary vascular resistance. Pericytes normally play a key role in maintaining microvascular homeostasis; however, they can also contribute to increased muscularization of distal arterioles in PAH by giving rise to smooth cells (SMCs). Methods: Sprague-Dawley rats were injected with 20mg/kg SU subcutaneously and exposed to 3 weeks of chronic hypoxia (CH, 10% O2). Right ventricular systolic pressure (RVSP) was measured at baseline, 1, 3, 5, and 8-weeks, then lungs were explanted, digested, and dissociated into single cells which were sequenced using the 10x genomics platform. Results: RVSP was significantly elevated at 1 week after SU (47mmHg) reaching a plateau of >100 mmHg by 5 weeks. Dimensionality reduction of the scRNAseq data was performed using Uniform Manifold Approximation and Projection (UMAP) analysis resulting in 24 lung clusters and sub-clustering of stomal populations yielded seven clusters. In addition to fibroblasts, SMC/myofibroblasts and mesothelial cells, we identified 2 distinct pericyte clusters both expressing canonical pericyte markers such as Pdgfrb and Csgp4 ( Ng2 ) and differentiated by presence or absence of Acta2 . Acta2 + pericytes exhibited high expression of contractile markers (i.e., Myh11 and Tagln ), consistent with partial SMC differentiation, and underwent a substantial (>3-fold) expansion during PAH development. The Acta2 + pericytes also exhibited profound downregulation in the endothelial protective gene, Bmpr2 , with a reciprocal upregulation of Rbpms2 , a gene which inhibits BMP signaling. Similarly, reciprocal reduction in Angpt1 , an agonist of the endothelial Tie2 receptor and an increase in expression the partial Tie2 antagonist, Angpt2 , thereby favoring EC activation and inflammation. Conclusion: These results suggest expansion of Acta2 + pericytes in PAH may contribute to distal arteriolar muscularization as well as an imbalance in BMP/TGFß and ANGPT1/2 signaling, promoting EC apoptosis, activation, and inflammation in the SU/CH model.

Abstract 12304: Right Ventricular Hemodynamics in COVID Patients With Shock

Introduction: Patients with serious COVID infections frequently develop shock. Their right-sided hemodynamic profiles have not been well characterized. Methods: In a prospectively collected database including 1997 patients hospitalized for COVID pneumonia from March 2020 to March 2021, 368 had shock requiring vasopressors. 327 had echocardiography to assess ventricular function and stroke volume based on clinical indications. LVEF (LV ejection fraction) and RVFAC (RV fractional area change) were measured using Simpson’s rule, stroke volume (SV) by aortic Doppler, and RVSP (RV systolic pressure) from tricuspid regurgitation velocity; 187 had evaluable data on all parameters. Patients were divided into groups with low or preserved RVFAC ( RVFAC L or RVFAC P , cutoff &lte35%), and low or normal cardiac index, (CI, CI L or CI N , cutoff &lte2.2 L/min/m 2 ). Results: Mean age: 65±12, LVEF 59.5±12.8, RVFAC 35.3±10.6, CI 2.41±0.89. Overall hospital mortality in this cohort with shock was 80%. Mean RVSP was 38.8±12.2, PEEP 11.0±3.7. 43% of patients had low RVFAC (&lt35%), and RVFAC correlated with other measures of RV function such as tricuspid annular peak systolic excursion (TAPSE) and lateral tricuspid annulus peak systolic velocity (S’). Higher RVSP correlated with lower CI (r=0.134, p= 0.016) but not with PEEP (r=0.03, p=0.70). Mortality did not differ significantly among groups, (p=0.19 by ANOVA) but was highest in the group with low RVFAC and low CI. ( Figure ) Conclusion: RV dysfunction is common in patients with severe COVID-19 and shock. Although RV dysfunction is probably associated with a worse prognosis, outcome in COVID may be tied to pulmonary recovery. Whether treatment targeted at RV dysfunction will improve outcome remains uncertain.

Abstract 12518: Echocardiographic Features and Natural History of Right Ventricular Dysfunction in Cardiac Sarcoidosis With or Without Pulmonary Involvement

Introduction: Cardiac sarcoidosis (CS) is a non-ischemic disease which can present with right ventricular (RV) dysfunction, but there is a paucity of research describing RV function and natural history in CS. Methods: We queried a registry of 512 CS patients for those with baseline and follow-up echocardiography (TTE). Demographics, medications, and baseline/follow-up TTE data were collected. RV-pulmonary arterial (RV-PA) coupling was approximated by ratio of tricuspid annular plane systolic excursion to estimated pulmonary artery systolic pressure (TAPSE:ePASP). Results: Our query yielded 343 CS patients with mean age 56y (σ=12y), who were predominantly male (67%) and white (90%) with a median follow-up 4y (interquartile range 4.1y). Most had pulmonary sarcoidosis (68%). Baseline TTE data showed left ventricular ejection fraction 48% (σ=14), abnormal RV function with RV systolic pressure (ePASP) 34 mmHg (σ=11), TAPSE 21mm (σ=5), RV S′ 0.14 m/s (σ=0.07), and RV-PA uncoupling (TAPSE:ePASP 0.69 mm/mm Hg, σ=0.25). Baseline RV function parameters did not differ by pulmonary involvement of sarcoidosis. 92% received immunosuppression and 65% received neurohormonal blockade. In long-term follow-up, the overall cohort demonstrated a trend towards worsening of both RV S’ and RV-PA coupling (P=.02 and P=.003 for linear trend, respectively) but stable ePASP (P=.11). Trends in both non-invasive ePASP and RV-PA coupling were similar in patients with and without pulmonary involvement (P=.48 and P=.79, respectively). Conclusions: In our large CS cohort with extensive follow-up, metrics of RV function and RV-PA coupling are often abnormal at CS diagnosis. Echocardiographic measures of PASP tend to remain stable but markers of RV dysfunction, including RV-PA coupling, tend to worsen throughout the disease course irrespective of pulmonary sarcoidosis. More granular phenotyping of pulmonary hypertension in CS is required to better understand this relationship.

Abstract 13585: In Patients With Right Bundle Branch Block, ECG Z-Axis QRS-T Voltage-Time-Integral Predicts Right Ventricular Structure and Function

Introduction: Right bundle branch block (RBBB) is the most common His-Purkinje conduction abnormality seen on ECG. It is currently unclear if there are any quantitative ECG differences in RBBB without and with structural right ventricular (RV) disease. Our aim was to evaluate quantitative ECG predictors of echocardiographic RV measurements [tricuspid annular plane systolic excursion (TAPSE), tissue Doppler imaging RV S’, RV basal and mid diameters, RV systolic pressure (RVSP)]. Hypothesis: QRS-T VTI in patients with RBBB is a marker for adverse RV remodeling and dysfunction. Methods: We included adults with ECG demonstrating typical RBBB and echocardiogram performed within 3 months of each other in 2010-2020. Orthogonal X, Y, Z ECG leads were reconstructed using Kors matrix. In addition to overall QRS duration, QRS voltages and QRS/QRS-T VTIs from 12 standard leads, X, Y, Z leads, and 3D (root-mean-square) ECG were evaluated. Age, sex and BSA-adjusted linear regressions were used to assess associations between ECG variables and RV measurements. We separately generated ROC curves for predicting abnormal RV measurements from ECG variables. Results: We included 782 patients (33% women, 71±14 years). Amongst the ECG variables, BSA-indexed Z-axis QRS-T VTI (VTI QRST-Z *√BSA) was the strongest independent predictor of all 5 RV measurements (Table 1a shows a comparison of QRS duration, Z-axis amplitude and VTI). VTI QRST-Z *√BSA cutoff 62 μVsm had a sensitivity 62.7% and specificity 65.7% to distinguish presence of ≥3 abnormal out of the 5 RV measurements (Table 1b). Conclusions: Adverse RV remodeling causes augmentation of the anterior-posteriorly directed QRS-T potential which is seen as a change in Z-axis VTI. VTI QRST-Z *√BSA could be used as a marker for right heart failure in patients with RBBB.

Abstract 10753: Phosphodiesterase Type 5 Inhibition and C-c Chemokine Receptor-2 Disruption Synergistically Protect Against Pulmonary Arterial Hypertension in Monocrotaline-Treated Rats: Potential Synergism of Anti-inflammatory Agents and Pulmonary Vasodilator Therapy

BACKGROUND: Whether conventional pulmonary vasodilator therapy and anti-inflammatory agents synergistically protect against pulmonary arterial hypertension (PAH) is unknown. Hypothesis: We tested the hypothesis that a phosphodiesterase type 5 (PDE5) inhibitor and disruption of C-C chemokine receptor (CCR)-2, a receptor for MCP-1, synergistically protect against PAH in monocrotaline (MCT)-treated rats. Methods: Study1:Seven-week-old male Ccr2 (-/-) rats, generated by using the CRISPAR/ Cas9 genome editing technology, or wild-type littermates, treated with MCT (60mg/kg) or vehicle, were subjected to hemodynamic, morphometric and immunohistochemical analyses and mRNA and protein expression studies on day21 (n=40, 4 groups). Study 2: Tadarafil (10mg/kg/d), a PDE5 inhibitor, or vehicle was administered in Ccr2 (-/-) or wild-type MCT rats on days 21-42 (n=71, 4 groups) for evaluating survival and were evaluated hemodynamically on day28. Results: Study1: MCT treatment increased right ventricular systolic pressure (RVSP), an index of right ventricular hypertrophy (Fulton index), indices of pulmonary vascular diseases (%medial wall thickness, %muscularization) and the number of perivascular CD68-positive macrophages in WT rats, all of which were decreased by Ccr2 (-/-) (p<.05). Similarly, an increase in mRNA expression of inflammatory cytokines (IL6 ,TNFa, MCP1, IL1b, TGFb) and a decrease in BMPR2 pathways (BMPR2, pSmad1/5/9 and ID1) as well as an increase in endothelial apoptosis (% cleaved Caspase 3 positive CD31 cells) and a decrease in NO pathways (eNOS and phospho-eNOS/eNOS) in lungs in wild-type MCT rats were reversed by Ccr2 (-/-) on day21 (p<.05) with comparable PDE5 expression. Study2: Tadarafil administration or CCR2(-/-)(p=.03 and p=.02) alone improved the survival in wild type MCT rats. A double intervention synergistically improved the survival in separately treated groups (p=.02 vs CCR2(-/-), p=.04 vs Tadarafil) in MCT rats. Tadarafil treatment on days21-28 decreased RVSP and Fulton index in CCR2(-/-) MCT rats (p<.05). Conclusions PDE5 inhibition and CCR-2 disruption synergistically protect against PAH in MCT-treated rats, suggesting an adjunctive role of a CCR2 inhibitor on top of administering a PDE5 inhibitor for PAH.

Abstract 12025: Fatty Acid-Binding Proteins Promote Pulmonary Arterial Hypertension via Upregulation of Endothelial Glycolysis

Introduction: Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Hypothesis: We hypothesis that endothelial fatty acid metabolism is critical for obstructive vascular remodeling in the pathogenesis of PAH. Methods: A severe mouse model of PH Egln1 Tie2Cre mice were bred with Fabp45 -/- mice to generate Egln1 Tie2Cre / Fabp45 -/- mice. Single-cell RNA sequencing (scRNA-seq) analysis and metabolomic analysis were used to profile the pulmonary cells in Egln1 Tie2Cre mice and Egln1 Tie2Cre / Fabp45 -/- mice. Human hPAEC from idiopathic PAH patients and healthy donors, monocrotaline (MCT)-induced and Sugen5416/hypoxia (SuHx)-induced PH rats were used to measure fatty acid-binding protein 4 and 5 (FABP4 and FABP5) expression. siRNA mediated knockdown of FABP4 and FABP5 and lentivirus mediated FABP4 and 5 overexpression were performed to study cell proliferation, apoptosis, glycolysis, fatty acid oxidation. Echocardiography, hemodynamics, histological and immunostaining assay were performed to evaluate the PH phenotypes. Results: Both FABP4 and 5 were highly induced in the ECs of Egln1 Tie2Cre mice and PAECs from IPAH patients, as well as the whole lungs of MCT and SuHx-induced PH rats. Knockdown or overexpression of FABP4-5 reduced or enhanced EC proliferation, starvation-induced Caspase 3/7 activity, glycolysis and fatty acid oxidation. Genetic deletion of Fabp4 and 5 in Egln1 Tie2Cre mice exhibited a reduction of right ventricular systolic pressure (RVSP), RV hypertrophy, and attenuation of pulmonary vascular remodeling, prevention of right heart failure. Fabp4-5 deletion also normalized EC glycolysis gene programming, reduced HIF-2a expression and endothelial proliferation in Egln1 Tie2Cre mice. Conclusions: FABP4 and 5 control EC glycolysis and contribute to the development of severe PH.

Abstract 14950: Single-Cell Transcriptomic Analysis Reveals Emergence of Inflammatory and Activated Arterial Endothelial Cells Promoted by Cross-Talk With Mural Cells During Development of Severe Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by occlusive arterial remodelling thought to be triggered by endothelial cell (EC) injury; however, the pathobiological mechanisms are poorly understood. We employed single cell RNA sequencing (scRNAseq) to define transcriptomic changes in the SU5416/chronic hypoxia (SU/CH) rat model. Methods: Sprague-Dawley rats were injected with 20mg/kg SU subcutaneously and exposed to 3 weeks of CH (10% O 2 ). Right ventricular systolic pressure (RVSP) was measured at baseline, 1, 3, 5, and 8-weeks, then lungs were explanted, digested, and dissociated into single cells which were sequenced using the 10x genomics platform. Results: Elevation of RVSP plateaued at >100 mmHg by 5 weeks. Dimensionality reduction of the scRNAseq data was performed using Uniform Manifold Approximation and Projection (UMAP) analysis resulting in 24 lung clusters. Cell prioritization analysis performed using Augur identified vascular cells as the most affected by SU/CH, including arterial ECs, pericytes, and gCap ECs. After sub-clustering the EC populations, eight distinct clusters were identified representing all expected subtypes (capillary, arterial, venous, and lymphatic). As well, two novel EC clusters were detected. The first showed reduced expression of classical EC genes ( Cdh5 , Cldn5 ) and increased proinflammatory markers ( RT1-Da , Cd74 ), termed ‘inflammatory’ ECs. The second was an arterial cluster that exhibited reduced expression of Dll4 and increased Cxcl12 and Fn1 , termed ‘activated’ arterial ECs. Both populations emerging at 1-week post SU, persisting throughout PAH progression. While many EC populations showed marked differential gene expression (DGE) at 1 week, the activated arterial cluster was the only cluster showing progression of DGE throughout progression of PAH. Receptor-ligand analysis with NicheNet identified activated arterial ECs as a top receiver cell responding to multiple ligands, including Bmp4/5 , Col4a1 , and Vegfa/c, which were largely derived from mural fibroblasts. Conclusion: Emergence of inflammatory and activated arterial ECs likely contribute to vascular remodelling associated with PAH promoted by cross-talk with lung stromal cells.

Abstract 13318: Shared Genetic Architecture of RV-PA Coupling and Measures of Adiposity

Introduction: The right ventricle’s ability to adapt to load stress, termed RV-PA coupling, is a major determinant of survival in pulmonary hypertension. However, the etiologic drivers of impaired RV-PA coupling are incompletely understood. One approach to identifying etiologic factors is through the study of the genetic architecture underlying impaired RV-PA coupling. We previously showed shared genetic risk between adiposity and RV size. Thus, we interrogated a polygenic predictor of RV-PA coupling to determine whether it shares genetic risk with adiposity. Methods: In 3493 adult subjects of European ancestry in Vanderbilt Univ. Medical Center’s de-identified DNA biobank (BioVU) with an available echocardiogram, RV-PA coupling was calculated as the ratio of tricuspid annular plane systolic excursion (TAPSE) to estimated RV systolic pressure (RVSP). The association between three measures of obesity and RV-PA coupling was examined using 2-sample inverse variance weighted (IVW) meta-analysis, and MR-Egger to assess for pleiotropy. Genetic instruments for obesity were constructed using prior summary statistics for body mass index (BMI), waist circumference, and whole body fat mass. Results: Median age of cohort was 63, 54% female. Median and IQR of variables were as follows: TAPSE 2.0 [1.6, 2.4], RVSP 31 [25, 40], TAPSE/RVSP 0.6 [0.4, 0.8]. By 2-sample MR, we found a significant negative association between genetically determined waist circumference and RV-PA coupling (β=-0.34, p=0.004) (Figure). We found similar negative associations between RV-PA coupling and BMI (β=-0.41, p=0.01) and whole body fat mass (β=-0.55 p=0.005). Units for estimates were log change in outcome (TAPSE/RVSP) per change in exposure. Conclusions: Our findings suggest shared genetic architecture between measures of adiposity and RV-PA coupling, supporting the notion that pathophysiologic mechanisms underlying adiposity may be play a causal role in impaired RV-PA coupling.

Abstract 14954: Mitochondrial C-Src Regulates Impaired Mitochondrial Bioenergetics in Right Ventricles in Pulmonary Hypertension

Introduction: Pulmonary hypertension (PH) has poor prognosis with presence of right ventricular (RV) dysfunction. However, no RV targeted therapies are available. Mitochondrial (Mito) energy deficiency is detrimental on RV function in PH, but the underlying mechanism remains unclear. Tyrosine kinase phosphorylation (P-Tyr) has been a critical regulatory mechanism in mito. While mito localized c-Src is recognized as the major tyrosine kinase, little is known regarding its role in RV in PH. Hypothesis: We hypothesized that mito c-Src regulates impaired mito bioenergetics in RV in PH. Methods: PH was induced in adult Sprague-Dawley (SD) rats by injecting 20 mg/kg SU5416, followed by 3 wks of hypoxia (10% FiO 2 ) and then 4 wks of normoxia exposure. Control rats injected with vehicle were kept in normoxia. After echocardiography and hemodynamics, RV tissues were collected for mito respiration using high resolution O2K-FluoRespirometer, mito morphology using electron microscopy, and biochemical assays. Cardiomyocytes and H9c2 cells were used for in vitro mechanistic studies. Results: Compared to controls, PH rats show increased RV systolic pressure and RV dysfunction. Mito complex I-coupled oxidative phosphorylation and electron transfer capacity are significantly reduced in RV of PH rats (O 2 flux per mass: 216±21 vs. 90±19 and 209±22 vs. 91±22 pmol·s-1·mg-1, respectively, p <0.01, n=6 each), which is associated with decreased ATP but no changes in mito membrane integrity, mito DNA content, or mito size. Mito c-Src kinase activity and expression are significantly reduced in RV of PH rats and in dysfunctional RV of human patients. Chemical or molecular inhibition of mito c-Src results in a similar reduction of mito respiration in culture as found in RV of PH rats and is associated with decreased ATP production. Mito c-Src phosphorylates NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2), a critical protein for complex I, and P-Tyr of NDUFV2 is reduced in RV of PH rats. Conclusions: Impaired mito bioenergetics is associated with progression of RV dysfunction. Basal mito c-Src kinase activity is required for mito bioenergetics and mito c-Src-dependent P-Tyr of NDUFV2 may serve as a regulatory mechanism in impaired RV mito bioenergetics in settings of PH.

Abstract 10766: Analysis of Cardiac Ct Anatomy in Patients With Severe Tricuspid Regurgitation Considered for Transcatheter Intervention

Introduction: Severe tricuspid regurgitation (TR) is associated with considerable morbidity/mortality in an elderly population with multiple comorbidities. There is interest in transcatheter interventions to manage severe TR in this population. Understanding right heart (RH) anatomy has implications for patient/device selection for transcatheter intervention. Hypothesis: We analyzed RH anatomy by CT of patients referred for TR therapy to determine transcatheter tricuspid intervention device sizing needs. Methods: Retrospective Mayo Clinic study of 29 patients considered for intervention of severe TR from 3/1/2016-12/15/2020; echocardiogram and CT angiogram obtained in all patients. Results: Mean age was 83±8 (83% female), 100% had atrial fibrillation, and 62% had chronic kidney disease ≥3a. 97% were symptomatic, 93% were prescribed loop diuretics, and 24% had device leads. Mean tricuspid annular plane systolic excursion 16.8±4.5 mm, effective regurgitant orifice area (EROA) 81±33 mm 2 , and cardiac index 2.6±0.6 L/min/m 2 . 41% had at least moderate right ventricular (RV) dysfunction with a mean RV systolic pressure of 46±16 mmHg. Patients receiving intervention had significantly larger EROA (101±33 v. 63±22 mm 2 , P=0.033), shorter tricuspid leaflet tenting length (6.5±3.0 v. 8.9±2.7 mm, P=0.042), and smaller annuloplasty diagnostic perimeter during diastole (120.1±16.6 v. 131.1±7.4 mm, P=0.041). Intervention patients tended to have better right ventricular function, smaller RV and IVC size, and more severe symptoms. Max tricuspid annulus diameter in systole and diastole was 51±5 and 53±7 mm, respectively. Conclusions: Severe TR patients referred for transcatheter intervention present with severe RH enlargement with a large proportion having tricuspid annulus dimensions outside the range for current devices available in clinical trials. These data have implications for device development/selection and procedural feasibility.

Abstract 13499: Unravelling the Pathophysiology of Right Ventricular Maladaptive Hypertrophy in Chronic Pulmonary Hypertension Through Imaging and Omics

Introduction: Right ventricular (RV) failure is the strongest determinant of survival in chronic pulmonary hypertension (PH), but its pathophysiological mechanisms remain unclear. Hypothesis: In addition to RV pressure overload, compounds liberated from the pulmonary vascular damage (identifiable by omics) may exert a detrimental effect on RV function in PH. Methods: Four different experimental models of RV pressure overload in 48 Yucatan pigs were developed: chronic postcapillary PH by pulmonary veins banding (M1); chronic PH by aorto-pulmonary shunting (M2); RV pressure overload by PA banding (thus without PH) (M3); and sham procedure (M0). Animals were evaluated at 1, 5 and 8 months after surgery by right heart catheterization, cardiac magnetic resonance (CMR), and blood/histological sampling. Unsupervised proteomic and metabolomic analyses were performed and compared among experimental groups and to the severity of RV dysfunction. Results: A total of 33 pigs completed follow-up (M1,n=8; M2,n=6; M3,n=10; and M0,n=9). As expected, M1&M2-animals developed chronic PH, whereas M3-animals had severely increased RV systolic pressure without PH (Table). M3-pigs developed more severe RV hypertrophy (significantly higher mass on CMR and cardiomyocyte area on histology), but maintained normal function. In contrast, M1&M2 animals developed RV systolic disfunction and increased myocardial apoptosis in M1. Plasma metabolomic and proteomic patterns differed among groups, highlighting greater inflammation and taurine/arginine deficiency in PH models (M1&M2), coagulation disturbances in M1, and predominant lipidomic changes in M3. Key proteins/metabolites from coagulation, complement system and apolipoproteins pathways significantly associated with RV performance. Conclusion: Maladaptive RV hypertrophy in PH is associated with significant changes in plasma proteins and metabolites. Their identification may help to identify potential targets.

Impact of Rapid Weight Loss after Bariatric Surgery in Systemic Inflammatory Response and Pulmonary Hemodynamics in Severely Obese Subjects with Pulmonary Hypertension.

Pulmonary hypertension (PH) can be associated with obesity. The excessive production of proinflammatory mediators by dysfunctional adipocytes may enhance remodeling of the pulmonary vasculature and worsen pulmonary hemodynamics. This study aimed to describe the changes in pulmonary arterial pressures and systemic inflammation in patients with obesity with PH after bariatric surgery (BaS). In this retrospective cohort study, we compared patients with PH who underwent BaS from 2008 to 2018 at our institution (group 1) to a group of severely obese patients with PH (group 2). Echocardiographic right ventricular systolic pressure (RVSP) was used as an indirect measurement of pulmonary arterial pressures. Red blood cell distribution width (RDW) was used as a marker of systemic inflammation. A total of 40 patients were included, 20 per group. In group 1, the RVSP decreased from 44.69 ± 7.12 mmHg to 38.73 ± 12.81 mmHg (p = 0.041), and the RDW decreased from 15.22 ± 1.53 to 14.41 ± 1.31 (p = 0.020). In group 2, the RVSP decreased from 60.14 ± 18.08 to 59.15 ± 19.10 (0.828), and the RDW increased from 15.37 ± 1.99 to 15.38 ± 1.26 (0.983). For both groups, we found a positive correlation between RVSP and RDW changes, although the correlation was not statistically significant. Previous studies suggest BaS could be a safe and effective procedure to achieve weight loss in obese patients with PH, with an additional modest improvement in pulmonary hemodynamics. The results of this study reinforce this observation and suggest that such improvement could be related to a decrease in systemic inflammation. Further prospective studies with bigger samples are needed to better understand these findings.

Echocardiographic changes after arteriovenous fistula creation in hemodialysis patients.

Pulmonary hypertension (PH) is common in end-stage renal disease (ESRD) patients and is associated with increased all-cause and cardiovascular mortality in this group. There is scarce data on the long-term effect of arteriovenous fistula (AVF) creation on pulmonary hypertension (PH) and the reflected changes in echocardiographic measurements. This is a retrospective study of 54 patients who underwent AVF creation between 2009 and 2014 and with echocardiographic evaluations before and after surgery. We analyzed pairwise changes in right ventricular systolic pressure (RVSP), right atrial pressure (RAP) during systole, left ventricular mass (LVM), tricuspid regurgitation (TR), mitral E/E' ratio, and ejection fraction (EF), as well as the factors that predicted change in RVSP after surgery. The median time for the preoperative echocardiogram was 0.3 years (interquartile range (IQR) 0.2-0.7 years) prior to AVF creation, while the follow-up echo was done 1.3 (0.6-2.1) years after surgery. 67% of the patients had RVSP>37 mmHg at baseline. There was a significant reduction in RVSP after AVF creation compared to baseline (median 33 (IQR 26-43) vs. 46mmHg, p=0.0015), with 59% of the patients experiencing a decrease and 19% remaining stable. There were also significant decreases in LVM (201 (143-256) vs. 215 (163-276), p=0.045) and RAP systole (10 (10-15) vs. 3 (3-8); p<0.001) after surgery. Higher preoperative weight (p=0.038) and RVSP (p=0.006), and use of loop diuretics (p=0.015) were significantly associated with improvement in RVSP after AVF creation. Our results suggest that AVF creation is associated with a significant reduction or stable measurements of RVSP in the ESRD population, likely due to an improvement in volume status.

Effects of panax notoginseng saponins on pulmonary vascular remodeling in rats with pulmonary hypertension and its mechanisms

Objective: To investigate the effects of panax notoginseng saponins (PNS) on pulmonary vascular remodeling and SIRT1/FOXO3a/p27 pathway in pulmonary arterial hypertension (PAH) rats. Methods: Male SD rats weighing 200~250g were randomly divided into control group, monocrotaline group (MCT) and monocrotaline + panax notoginseng saponins group (MCT+PNS), with 10 rats in each group. The rats in control group were injected intraperitoneally with normal saline 3 ml/kg on the first day, then injected intraperitoneally with normal saline 2.5 ml/kg every day. The rats in MCT group were injected intraperitoneally with MCT 60 mg/kg on the first day, followed by daily injection of normal saline 2.5 ml/kg. In MCT+PNS group, 60 mg/kg MCT was injected intraperitoneally on the first day, and 50 mg/kg PNS was injected intraperitoneally every day. The above models were fed conventionally for 4 weeks. After the modeling was completed, the mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP) of rats in each group were detected by right heart catheter method, weighed and calculated right ventricular hypertrophy index (RVHI), and the pulmonary vascular structure and morphological changes were observed by HE and Masson staining. The protein and gene expressions of SIRT1, FOXO3a, p27, PCNA and Caspase-3 were detected by qPCR and Western blot. Results: Compared with control group, mPAP, RVSP and RVHI in MCT group were increased significantly (P＜0.01), pulmonary vessels were thickened significantly and collagen fibers were increased, protein and gene expressions of SIRT1, FOXO3a, p27 and Caspase-3 were decreased (P＜0.05 or P＜0.01). The protein and gene expressions of PCNA were increased (P＜0.05). Compared with MCT group, the levels of mPAP, RVSP and RVHI in MCT+PNS group were decreased significantly (P＜0.05 or P＜0.01), pulmonary vascular thickening was alleviated and collagen fibers were reduced. The protein and gene expressions of SIRT1, FOXO3a, p27 and Caspase-3 were increased (P＜0.05 or P＜0.01), while the protein and gene expressions of PCNA were decreased (P＜0.05 or P＜0.01). Conclusion: Panax notoginseng saponins can relieve pulmonary vascular remodeling in rats with pulmonary hypertension by activating SIRT1/FOXO3a/p27 pathway.

Right ventricular energy metabolism in a porcine model of acute right ventricular pressure overload after weaning from cardiopulmonary bypass.

Acute right ventricular pressure overload (RVPO) occurs following congenital heart surgery and often results in low cardiac output syndrome. We tested the hypothesis that the RV exhibits limited ability to modify substrate utilization in response to increasing energy requirements during acute RVPO after cardiopulmonary bypass (CPB). We assessed the RV fractional contributions (Fc) of substrates to the citric acid cycle in juvenile pigs exposed to acute RVPO by pulmonary artery banding (PAB) and CPB. Sixteen Yorkshire male pigs (median 38 days old, 12.2kg of body weight) were randomized to SHAM (Ctrl, n=5), 2-h CPB (CPB, n=5) or CPB with PAB (PAB-CPB, n=6). Carbon-13 (13 C)-labeled lactate, medium-chain, and mixed long-chain fatty acids (MCFA and LCFAs) were infused as metabolic tracers for energy substrates. After weaning from CPB, RV systolic pressure (RVSP) doubled baseline in PAB-CPB while piglets in CPB group maintained normal RVSP. Fc-LCFAs decreased significantly in order PAB-CPB > CPB > Ctrl groups by 13 C-NMR. Fc-lactate and Fc-MCFA were similar among the three groups. Intragroup analysis for PAB-CPB showed that the limited Fc-LCFAs appeared prominently in piglets exposed to high RVSP-to-left ventricular systolic pressure ratio and high RV rate-pressure product, an indicator of myocardial oxygen demand. Acute RVPO after CPB strongly inhibits LCFA oxidation without compensation by lactate oxidation, resulting in energy deficiency as determined by lower (phosphocreatine)/(adenosine triphosphate) in PAB-CPB. Adequate energy supply but also metabolic interventions may be required to circumvent these RV energy metabolic abnormalities during RVPO after CPB.

Ventricular strain patterns in multivalvular heart disease: a cross-sectional study

Multivalvular heart disease (MVD) is an aggregate of regurgitant and/or stenotic lesions of at least two cardiac valves. Ventricular tissue deformation imaging is a powerful predictor of subclinical myocardial dysfunction in patients with MVD.The aim of this study was to examine the left and right ventricular strain patterns in MVD as well as observe any association between right–sided valvular involvement (tricuspid or pulmonary valve lesion) with that of aortic and/or mitral valve lesion. Patients with at least moderate forms of MVD were included in the present study. 72 patients with mean age of 56.69 ± 14.59 years and various presentations of MVD were finally enrolled in this study. The commonest cause for MVD was rheumatic heart disease in these patients. Conventional 2-dimensional parameters as well as tissue deformation imaging parameters were assessed in offline mode for these patients. The Mean ± SD values for various quantitative 2D echocardiographic conventional and tissue deformation imaging were assessed. It was observed that LV strain parameters including the global longitudinal strain (GLS) were preserved whereas the RV strain parameters were mildly reduced (RV GLS total is − 19.49 ± 6.08%). Also, when conventional echocardiographic parameters were assessed to see any association between aortic and/or mitral valve disease with that of right-sided valvular lesions (tricuspid or pulmonary); 2D conventional echocardiographic parameters like left atrial dimension (p = 0.034), TAPSE (tricuspid annular plane systolic excursion) (p < 0.001), RVSP (right ventricular systolic pressure) (p < 0.001) and IVC (inferior vena cava) dimensions (p < 0.001) showed a statistically significant result; whereas, when strain parameters for LV and RV were assessed, they did not show any statistical difference for the same. In this series of patients with significant MVD, our findings suggest that ventricular strain parameters may be reliable markers of myocardial dysfunction, but may alter depending on the underlying combination of MVD, and right ventricular strain should also be an important parameter while assessing different combinations of MVD.

Tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, improves pulmonary vascular remodeling due to left heart disease in mice

BackgroundGroup 2 pulmonary hypertension (PH) represents PH caused by left heart disease (PH-LHD). LHD induces left-sided filling and PH, finally leading to pulmonary vascular remodeling. Tofogliflozin (TOFO) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in the treatment of diabetes. Recent studies have shown that SGLT2 inhibitors have beneficial effects on heart failure, but the effects of SGLT2 inhibitors on PH-LHD remain unclear. We hypothesized that TOFO has protective effects against pulmonary vascular remodeling in PH-LHD mice. MethodsWe generated two murine models of PH-LHD: a transverse aortic constriction (TAC) model; and a high-fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg/day) for 3 weeks. AKR/J mice were fed HFD and treated with TOFO (3 mg/kg/day) for 20 weeks. We then measured physical data and right ventricular systolic pressure (RVSP) and performed cardiography. Human pulmonary artery smooth muscle cells (PASMCs) were cultured and treated with TOFO. ResultsMice treated with TOFO demonstrated increased urine glucose levels. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RVSP. HFD increased body weight (BW) and RVSP compared with the normal chow group. TOFO treatment ameliorated increases in BW and RVSP induced by HFD. Moreover, PASMCs treated with TOFO showed suppressed migration. ConclusionsTOFO treatment ameliorated right heart overload and pulmonary vascular remodeling for PH-LHD models, suggesting that SGLT2 inhibitors are effective for treating PH-LHD.

Analysis of Cardiac Computed Tomography Anatomy in Patients With Severe Tricuspid Regurgitation Considered for Transcatheter Intervention

BackgroundSevere tricuspid regurgitation (TR) is associated with considerable morbidity/mortality in an elderly population with multiple comorbidities. There is interest in transcatheter interventions to manage severe TR. Understanding complex right heart (RH) geometry and tricuspid valve shape and size has implications for patient/device selection for transcatheter intervention. We characterized RH anatomy by computed tomography in patients with symptomatic severe TR considered for intervention. MethodsThe retrospective Mayo Clinic study included 29 patients with an echocardiogram and cardiac computed tomography angiogram considered for intervention of severe TR from March 01, 2016 to December 15, 2020. Patients were divided into 2 groups: intervention (surgical or transcatheter; n = 17) and medical management alone (n = 12). ResultsMean age was 83 ± 8 (83% female), 100% had atrial fibrillation, and 62% had chronic kidney disease ≥3a. Ninety-seven percent were symptomatic, 93% had been prescribed loop diuretics, and 24% had device leads. Mean tricuspid annular plane systolic excursion was 16.8 ± 4.5 mm, effective regurgitant orifice area was 81 ± 33 mm2, and cardiac index was 2.6 ± 0.6 L/min/m2. Forty-one percent had at least moderate right ventricular (RV) dysfunction with a mean RV systolic pressure of 46 ± 16 mmHg. Patients receiving intervention had significantly larger effective regurgitant orifice area (101 ± 33 vs. 63 ± 22 mm2, p = 0.033), shorter tricuspid leaflet tenting length (6.5 ± 3.0 vs. 8.9 ± 2.7 mm, p = 0.042), and smaller annuloplasty diagnostic perimeter during diastole (120.1 ± 16.6 vs. 131.1 ± 7.4 mm, p = 0.041). Intervention patients tended to have better right ventricular function, smaller RV and inferior vena cava size, and more severe symptoms. The maximal tricuspid annulus diameter in systole and diastole was 51 ± 5 and 53 ± 7 mm, respectively. ConclusionsSevere TR patients referred for transcatheter intervention present with severe RH enlargement with a large proportion having tricuspid annulus dimensions outside the range for current devices available in clinical trials. The presented data have implications for device development/selection and procedural feasibility.