Right Ventricular Systolic Pressure Research Articles

Abstract 4137364: Sex differences in the right ventricle in the Sugen-Hypoxia rat model of pulmonary arterial hypertension

Background: An unexplained estrogen puzzle exists in pulmonary arterial hypertension (PAH): PAH occurs ~4 fold more frequently in women than men; however, women with PAH have better right ventricular (RV) function and survival than the men. Sex differences and the associated mechanism in RV in PAH are not well understood. Aim: To characterize sex differences in RV function and structure in PAH. Methods: Sprague-Dawley rats were injected with Sugen (SU5416, 25mg/kg), and subjected to 3 weeks of hypoxia, followed by 5 weeks of normoxia. Control rats received vehicle and stayed in normoxia for up to 8 weeks. RV pressure-volume, mitochondrial properties, weight, myocyte size, cell proliferation, and interstitial and perivascular (right coronary arteries, RCA) fibrosis were obtained. Results: Sugen-Hypoxia (SuHx) caused significant increases in RV systolic pressure (RVSP) and effective arterial elastance (Ea) in both sexes (P<0.05), but caused slightly greater increase in RV end-systolic elastance (Ees) in females vs males, leading to a preserved RV-pulmonary artery coupling (Ees/Ea) in females and a significant decrease in Ees/Ea in males (P<0.05). SuHx caused a significant increase in RV diastolic pressure only in males (P<0.05), which is associated with significantly higher amount of RV interstitial fibrosis in males vs females. In addition, SuHx caused significant increase in cell proliferation in both sexes (P<0.05) though with slightly greater in crease in males, which is well correlated with RV interstitial fibrosis. Whilst there was no sex difference in RV hypertrophy in SuHx rats as indicated by both fulton index and myocyte size, female RV had smaller myocytes than males at baseline, indicating a greater increase in myocyte size in response to SuHx. Finally, there was a significant increase in RCA fibrosis in male SuHx rats (P<0.05) but not in females, potentially leading to a greater degree of ischemia in male SuHx RV, and this is consistent with impaired mitochondrial properties (decreased mitochondrial fusion, membrane potential an superoxide) in male SuHx rat RV (P<0.05) but preserved mitochoindrial properties in females. Conclusions: SuHx resulted in similar level of RV afterload in both sexes, but compared to males, RV in females responded differently in both function (Ees and mitochondrial properties) and structure (myocyte size and fibrosis). Future studies on the associated mechanism are needed to gain therapeutic insight for RV in PAH.

Abstract 4142768: Association Between Right Ventricular-Pulmonary Arterial Coupling and Outcomes in Patients with Heart Failure with Preserved Ejection Fraction

Introduction: Right ventricle (RV)-pulmonary artery (PA) coupling reflects functional adaptation of RV to afterload. Impaired RV-PA coupling is associated with worse outcomes in patients with pulmonary hypertension. However, the association between RV-PA coupling and outcomes in patients with heart failure with preserved ejection fraction (HFpEF) is not well established. Objective: To assess the association between RV-PA coupling and outcomes in patients with HFpEF and determine an optimal cutpoint of the TAPSE/RVSP ratio for prediction of adverse events. Methods: Participants with a diagnosis of HFpEF were enrolled at the University of Toledo Medical Center from March 2012 and were followed until August 2023. The ratio of tricuspid annular plain systolic excursion (TAPSE) to right ventricular systolic pressure (RVSP) on echocardiogram was used as a measure of RV-PA coupling. The primary endpoint was death or heart failure hospitalization. ROC analysis was performed to determine an optimal cutpoint point for TAPSE/RVSP. Cox proportional hazards regression model was used to assess the association between TAPSE/RVSP and outcomes. Results: 83 participants (age 68.69 ± 10.72, 67.5% female) with HFpEF and available echocardiogram data were enrolled in the study. The median TAPSE/RVSP was 0.41. Death or heart failure hospitalization occurred in 51 (56.6%) individuals. Using ROC curve analysis, we identified the optimal cutpoint of TAPSE/RVSP of 0.31 which had a sensitivity of 57% and specificity of 88% for predicting mortality (AUC 0.756, 0.622-0.889). TAPSE/RVSP less than 0.31 was associated with higher risk of death or heart failure (HF) hospitalization (HR=2.61, CI=1.28-5.33, p= 0.008), death (HR=3.40, CI=1.34-8.64, p= 0.01), and HF hospitalization (HR=2.45, CI=1.06-5.68, p= 0.03). Conclusion: Worse RV-PA coupling was associated with worse outcomes in individuals with HFpEF. The TAPSE/RVSP cutpoint of <0.31 had a good specificity for prediction of adverse events including death or HF hospitalization.

Abstract 4117657: Targeting GPR39 for Hypoxia-induced Pulmonary Hypertension in Mice

Background: Primary pulmonary arterial hypertension (PAH) is a disease affecting young subjects. It has very poor prognosis and optimal treatment is not available. 15-hydroxyeicosatetraenoic acid (15-HETE), a potent vasoconstrictor, has been implicated in the pathogenesis of PAH. Elevated levels of 15-HETE have been shown to be associated with worse prognosis in patients with PAH. Oral ingestion of 15-HETE leads to development of PAH in rodents. We recently showed that 15-HETE is the endogenous agonist for the G-protein coupled receptor 39 (GPR39) present in vascular smooth muscle cells. Hypothesis: We, therefore, hypothesized that global deletion of GPR39 (knock-out [KO] mice) would protect from PAH by removing the receptor through which 15-HETE causes vasoconstriction. Methods: Accordingly, 13 wild-type (WT) and 16 KO mice were placed in a hypoxia chamber (10% O 2 ). Litter-mate controls (7 WT and 13 KO) were subjected to normoxia (room air, 21% O 2 ). At the end of 4 weeks heart rate as well as aortic and right ventricular (RV) pressures were measured (latter using micromanometer-tipped catheter), and the animals were then euthanized for measurement of RV wall thickness and RV size from which RV wall stress was calculated. Results: Heart rate and systolic blood pressure were not different between the 4 groups . WT hypoxic animals developed PAH with peak RV systolic pressures (RVSP) being significantly higher than normoxic WT and hypoxic WT and hypoxic KO mice. (Figure 1) Similar results were noted for RV end-diastolic pressure (Figure 2) and RV wall stress (Figure 3). Conclusions: By deleting GPR39, the target for 15-HETE, we were able to prevent hypoxia induced PAH and RV dysfunction. Pharmacological inhibition of GPR39 may open new frontiers in the treatment of PAH.

PI3K p85α/HIF-1α accelerates the development of pulmonary arterial hypertension by regulating fatty acid uptake and mitophagy.

Pulmonary arterial hypertension (PAH) is characterized by lipid accumulation and mitochondrial dysfunction. This study was designed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on fatty acid uptake and mitophagy in PAH. Peripheral blood samples were obtained from PAH patients. Human pulmonary arterial smooth muscle cells and rat cardiac myoblasts H9c2 were subjected to hypoxia treatment. Male Sprague-Dawley rats were treated with monocrotaline (MCT). Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary artery remodeling, and lipid accumulation were measured. Cell proliferation and ROS accumulation were assessed. Mitochondrial damage and autophagosome formation were observed. Co-immunoprecipitation was performed to verify the interaction between HIF-1α and CD36/PI3K p85α. HIF-1α, CD36, Parkin, and PINK1 were upregulated in PAH samples. HIF-1α knockdown or PI3K p85α knockdown restricted the expression of HIF-1α, PI3K p85α, Parkin, PINK1, and CD36, inhibited hPASMC proliferation, promoted H9c2 cell proliferation, reduced ROS accumulation, and suppressed mitophagy. CD36 knockdown showed opposite effects to HIF-1α knockdown, which were reversed by palmitic acid. The HIF-1α activator dimethyloxalylglycine reversed the inhibitory effect of Parkin knockdown on mitophagy. In MCT-induced rats, the HIF-1α antagonist 2-methoxyestradiol (2ME) reduced RVSP, RVHI, pulmonary artery remodeling, lipid accumulation, and mitophagy. Recombinant CD36 abolished the therapeutic effect of 2ME but inhibited mitophagy. Activation of Parkin/PINK1 by salidroside (Sal) promoted mitophagy to ameliorate the pathological features of PAH-like rats, and 2ME further enhanced the therapeutic outcome of Sal. PI3K p85α/HIF-1α induced CD36-mediated fatty acid uptake and Parkin/PINK1-dependent mitophagy to accelerate the progression of experimental PAH.

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Cordycepin against Pulmonary Arterial Hypertension in Rats.

Pulmonary Arterial Hypertension (PAH) is a fatal disease with high morbidity and mortality. Cordycepin has anti-inflammatory, antioxidant and immune enhancing effects. However, the role of Cordycepin in the treatment of PAH and its mechanism is not clear. The Cordycepin structure and PAH-related gene targets were obtained from public databases. The KEGG and GO enrichment analysis of common targets was performed in DAVID. PPI networks were also mapped using the STRING platform. AutoDock Vina, AutoDockTools, ChemBio3D and Pymol tools were selected for molecular docking of key targets. The therapeutic effects of Cordycepin on PAH were observed in Monocrotaline (MCT)-induced PAH rats and platelet-derived growth factor BB (PDGFBB)-induced rat pulmonary artery smooth muscle cells (PASMCs). The right ventricular systolic pressure (RVSP) was detected. HE staining, Western Blot, Scratch assay, EDU and TUNEL assays were used, respectively. Through Network Pharmacology and molecular docking, the Cordycepin-PAH core genes were found to be TP53, AKT1, CASP3, BAX and BCL2L1. In MCT-induced PAH rats, the administration of Cordycepin significantly reduced RVSP, and inhibited pulmonary vascular remodeling. In PDGFBB-induced PASMCs, Cordycepin reduced the migration and proliferation of PASMCs and promoted apoptosis. After the Cordycepin treatment, the protein expressions of TP53, Cleaved CASP3 and BAX were significantly increased, while the protein expressions of p-AKT1 and BCL2L1 were significantly decreased in MCT-PAH rats and PDGFBB-induced PASMCs. This study identified that TP53, AKT1, CASP3, BAX, and BCL2L1 were the potential targets of Cordycepin against PAH by ameliorating pulmonary vascular remodeling, inhibiting the abnormal proliferation and migration of PASMCs and increasing apoptosis of PASMCs. which provided a new understanding of the pharmacological mechanisms of Cordycepin in the treatment of PAH.

Pulmonary valve acceleration fraction as a novel echo parameter to evaluate systolic pulmonary artery pressure during exercise echocardiography

Abstract Background/Introduction Long-COVID is a disabling chronic condition. Some patients have features of exercise-induced pulmonary hypertension (PHT) but non-invasive assessment during exercise stress echo (SE) is often limited by absence of reliable jet of tricuspid regurgitation (TR). We aimed to investigate novel Doppler echo parameters elicited from right ventricular (RV) outflow tract to aid diagnosis of exercise induced PHT among patients referred to our centre with Long-COVID symptoms. Purpose We investigated the ratio of the pulmonary valve acceleration time (PV AccT) to RV ejection time (RV ET) to calculate the pulmonary acceleration fraction (PV AccT/RV ET), thereby adjusting to heart rate. To identify its utility to estimate pulmonary artery pressure (PASP) during SE we correlated the PV AccT/RV ET and the TR-estimated RV systolic pressure (RVSP) in patients referred for evaluation of exercise-induced PHT in Long-Covid patients. Methods We developed a dedicated Covid-19 SE protocol to assess RV and pulmonary hemodynamics. From November 2022 to February 2023 all consecutive patients with Long-COVID symptoms underwent supine bike exercise with 3-min increments of workload of 25W. We did not evaluate the inferior vena cava during exercise, therefore estimated pressures from maximal TR jet velocities only. Results We enrolled 93 consecutive patients. The mean age was 50.1 years, 42.9% were female. No patients had RV impairment or RVSP >40mmHg at baseline. The average exercise time was 12.4 minutes, only 33% achieved the sub-maximum target heart rate (THR), in 50/93 (53.7%) reasons for termination were recorded as shortness of breath. The pulmonary acceleration fraction could be recorded in every patient at rest and at stress, while 20/92 (21.7%) patients had insufficient spectral Doppler profile of TR to estimate RVSP. The PV acceleration fraction was correlated with the available RVSPs during exercise (Spearman’s ϱ -0.446 (95% CI -0.606- -0.251[p<0.0001]). ROC analysis indicated a pulmonary acceleration fraction ≤0.44 was associated with the maximum Youden index to discriminate an increase in RVSP >20mmHg during exercise (AUC =0.731 [p<0.001]) with a sensitivity and specificity of 70.0% and 80.0%. In logistic regression analysis, a PV acceleration fraction ≤0.44 was independently associated with an increase in RVSP>20mmHg during exercise independently of age, gender and baseline LVEF, LVEDV, TAPSE and baseline RVSP (p<0.001). Conclusions Significant proportion of Long-COVID patients are limited by symptoms and not able to achieve THR during exercise. PV Acc T/ PV ET correlates well to RVSP and can be used to estimate PA pressure. A threshold of 0.44 appears independently associated with a benchmark of PA systolic pressure increase of >20mmHg. Further studies needed to evaluate this new marker of pulmonary hypertension in other group of patients.

Echocardiographic predictors of mortality in cardiac intensive care unit patients with pulmonary hypertension

Abstract Background Pulmonary Hypertension (PH) is a diverse condition associated with elevated mortality. We sought to determine the association of Transthoracic Echocardiography (TTE) parameters with in-hospital mortality in patients with PH admitted to Cardiac Intensive Care Unit (CICU). Methods We included 1 Clinic CICU admissions from 2007 to 2018, with available TTE parameters within the first day of CICU admission who had PH defined as an estimated right ventricular systolic pressure (RVSP) ≥36 mmHg. The primary outcome was in-hospital mortality, evaluated using logistic regression. Results We included 3085 unique CICU patients with PH, predominantly WHO group 2 and 3. Median age was 73.7 (63.8, 82.4) years, and 1343 (43.5%) were females. Heart failure (65.6%) and respiratory failure (34.0%) were the most common admission diagnoses. The median RVSP was 47 (41, 56) mmHg, and 1314 (42.6%) had RVSP ≥50 mmHg. A total of 337 (10.9%) patients died during hospitalization. In-hospital deaths had higher RVSP (51 versus 47 mmHg, p <0.001), reflecting higher right atrial (RA) pressure (14 versus 10 mmHg, p <0.001) (Figure). In-hospital mortality increased with worse TTE parameters reflecting Right Ventricle-Pulmonary Artery (RV-PA) coupling, such as Tricuspid Annular Plane Systolic Excursion/ Right Ventricular Systolic Pressure (RVSP), Tricuspid Annular Systolic Velocity (TASV)/RVSP and TASV/ Tricuspid Regurgitation velocity ratios. Conclusion In CICU patients with PH, we have identified the specific Doppler TTE parameters with strong associations with outcomes. Specifically, RA pressure and parameters of RV-PA coupling had the highest discrimination for in-hospital mortality. Comprehensive Doppler TTE is valuable for identification of high-risk PH patients to facilitate further investigation plans, management, and prognostication. Figure: In-hospital mortality in association with right ventricular (RV) function and right atrial pressure (RAP).In-hospital mortality in association wit

Pathobiological characterization of pulmonary hypertension associated with heart failure with preserved ejection fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is an age-related cardiometabolic disease associated with vascular inflammation in cardiac tissue, pulmonary congestion and right ventricular dysfunction. Patients with HFpEF often develop pulmonary hypertension (PH) and right ventricular (RV) hypertrophy. Pulmonary vascular remodeling contributes to combined post- and precapillary PH (CpcPH), which is associated with worse outcome in humans. A recently developed meta-inflammatory murine HFpEF model approximates the characteristics of human HFpEF. Herein, HFpEF is induced by metabolic (high-fat diet (HFD)) and hypertensive stress (inhibition of constitutive NO synthase by Nω-nitro-1-arginomethyl ester (L-NAME)) over a 12-week period of time. With a focus on PH, we have developed a 'three-hit' model based on this model with a supplementary 21- or 42-day hypoxia phase (HFpEF-CpcPH). Methods Adult C57BL/6N mice were fed HFD for 15 or 18 weeks and supplied with L-NAME (0,5g/L or 1g/L) via drinking water, including a final period of 21 or 42 days, respectively, of hypoxia (normobaric, 10 % oxygen) or normoxia. Transthoracic echocardiography was performed using a small animal ultrasound device (Vevo 3100, Visual Sonics) and measurement of right ventricular systolic pressure (RVSP) using a Millar® pressure catheter (Mil-SPR-1000) inserted into the right ventricle. Right ventricular hypertrophy was measured as the ratio of the wet weight of the right ventricle to the left ventricle including the septum (RV/LV+S). Results Administration of HFD and L-NAME had no significant effect on RVSP in either HFpEF-normoxia group (15 weeks (n=8) or 18 weeks (n=5)) compared to the control group (n=8, n=5). 21 days of hypoxia increased RV systolic pressure (RVSP) to 37.05±1.6 (PH, n=8) and 40.33±0.87 mmHg (HFpEF-CpcPH, n=8) respectively, while 42 days of hypoxia caused no further increase (35.1±3.5 mmHg (PH, n=5) and 35.24±3.47 mmgHg (HFpEF-CpcPH, n=4)), respectively. RV hypertrophy (RV/LV+S) was significantly increased after 21 days of hypoxia in HFpEF-CpcPH compared to HFpEF (n=8) (34.42±1.75 vs. 24.93±1.1). Again, 42 days of hypoxia did not lead to a further increase in RV hypertrophy (35.2±3.9 vs. 25.80±4.39) in HFpEF-CpcPH, even though there was a significant difference compared to the HFpEF group. As expected, the heart weight/body weight ratio was significantly increased in HFpEF-CpcPH compared to HFpEF at both time points. However, mice under the prolonged hypoxia phase showed a significantly greater decrease in body weight, which complicates the interpretation of the results. Conclusion In summary, we could show that in the meta-inflammatory HFpEF model no significant PH can be observed within the investigated periods of time. However, a 21 day hypoxia phase was sufficient to induce a HFpEF-CpcPH phenotype. This model provides an important basis to develop new therapeutic approaches.

The effect of exercise on RV-PC coupling in asymptomatic patients with significant primary mitral regurgitation

Abstract Background Right ventricular–pulmonary circulation (RV-PC coupling) serves as an index to evaluate RV function in relation to underlying RV afterload. Although impaired RV-PC coupling has been proposed as a predictor of adverse outcomes in heart failure (HF) patients with secondary mitral regurgitation (MR), there is limited data available for patients with primary MR. Purpose The objective of this study was to assess and compare alterations in RV-PC coupling during exercise with bicycle stress echocardiography in individuals with asymptomatic moderate to severe primary MR (MR group) and normal subjects (Control group). Μethods All patients and controls underwent stress echocardiography with a supine bicycle. RV systolic function was evaluated with TAPSE and S’. The non-invasively measured RV-PC coupling was evaluated by indexing TAPSE and S’ to right ventricular systolic pressure (RVSP) during baseline echocardiogram and peak workload stages of bicycle SE. Results Among the 48 patients in the MR group (mean age 53.5±15.16 years, 58.3% female), 39 patients had moderate MR(81.3%), 5 patients had moderate-to-severe MR(10.4%), and 4 patients had severe MR(8.3%). The duration of stress echocardiogram was significantly shorter in the MR group compared to control group (8.11±2.39 min vs 10.5±1.05 min, respectively; p<.001). Left Ventricular Ejection Fraction (LVEF) was within normal limits in both groups {70.7±11.9 % vs 72.6±12.1 %(p=NS} and the dimensions of left ventricular cavity (end-diastolic and end-systolic diameters) were significantly larger in the MR group compared to control group (49.25±5.21 mm vs 45.6±4.08mm (p .016) and 31.81±4.27mm vs 29.07±4.21mm (p .033) respectively}. TAPSE and RVSP increased from baseline to peak dose [23.48 ±3.05mm vs 29.94±3.48mm (p < .001), 8.54±4.56mmHg vs 43.79±5.27mmHg (p < .001), respectively]. There were no significant differences in TAPSE/RVSP and S’/RVSP between the two groups at rest. However, a significantly steady decrease was observed from baseline to peak dose (0.84±0.16 mm/mmHg vs 0.72±0.19mm/mmHg (p <.001) and 0.52±0.11 cm/sec/mmHg vs 0.50±0.15 cm/sec/mmHg (p .004), respectively). Conversely, these parameters did not exhibit a significant decrease in the control group. Finally, there was no significant correlation observed between the changes in the index TAPSE/RVSP , ratio E/E’ and systolic blood pressure. Conclusions RV-PC coupling decreases during exercise in asymptomatic patients with moderate to severe MR, independently of left ventricular dynamic changes. In contrast , there is no significant change in RV-PC coupling observed in the control group. Therefore, future studies should aim to evaluate the incremental role of this novel index not only in the assessment and evaluation of patients with MR but also as a potential prognostic marker.TAPSE/RVSP GraphTable of echocardiographic measurements

Sex differences in the long-term outcomes of moderate rheumatic mitral stenosis

Abstract Background There are limited data on the sex differences in the long-term outcomes of moderate mitral stenosis (MS). Purpose This study aimed to investigate sex differences in long-term outcomes of moderate AS. Methods From the Multicenter mitrAl STEnosis with Rheumatic etiology (MASTER) registry of 3,140 patients, we included patients with moderate MS (1.5 < mitral valve area ≤ 2.0 cm2) between January 2000 and December 2021 who had not undergone previous percutaneous of surgical treatment of MS. Primary outcomes were a composite of all-cause death, heart failure (HF) hospitalization, ischemic stroke, and mitral valve intervention. We analyzed clinical and echocardiographic variables based on sex. Results A total of 788 patients (mean 62.2 ± 12.9 years, women 74.5%) were followed over a mean duration of 7.0 ± 6.0 years. During follow-up, 287 patients (36.4%) experienced primary outcomes. Women (n=587) had more atrial fibrillation (AF) (p=0.022), higher left ventricular (LV) ejection fraction (EF) (p<0.001), and smaller LV chamber (LV mass index; p<0.001) compared to men. Primary outcomes did not differ for both sexes (p=0.285). However, on the analysis of both sexes according to right ventricular systolic pressure (RVSP), men with elevated RVSP had poorer outcomes (p<0.001) but women did not differ (p=0.238) (Figure 1). On the multivariate Cox regression analysis, elevated RVSP was the only factor that was independently associated with poorer outcomes (hazard ratio [HR], 1.30 [95% CI, 1.10-1.05], p=0.005) in men. However, in women, several factors including older age (HR 1.02, 95% CI 1.00-1.03, p=0.012), presence of AF (HR 2.40, 95% CI 1.66-3.48, p<0.001), decreased LV EF (HR 0.98, 95% CI 0.97-1.00, p=0.007), and higher mean diastolic pressure gradient (HR 1.09, 95% CI 1.01-1.17, p=0.027) showed the independent association with poorer outcome, but not in RVSP (Figure 2). Conclusions In moderate MS, RVSP showed a significant prognostic role in men, but in women, various comorbidities other than that were associated with prognosis. Therefore, different follow-up strategy using specific parameters for each gender would be needed.

Prognostic value of the right coronary venous anatomy in patients undergoing cardiac resynchronization therapy

Abstract Background The size and distribution of the coronary veins (CV) reflect both intracavitary pressure and myocardial blood flow, and therefore, in patients with cardiomyopathy, CV anatomy could potentially become a biomarker of disease severity. While the left coronary veins have been well described, there are few descriptions of the right CV system. Purpose Given these considerations, the aim of the study was to evaluate the anatomy of the right CV system and its potential prognostic significance in patients with advanced cardiomyopathy. Methods We analyzed CV angiograms from 121 patients (age 67±14 years) undergoing cardiac resynchronization therapy (CRT). The right ventricular (RV) veins were seen to fill during the injection of contrast through multiple connections with the left sided venous system. Patients were followed for a median of 43 [IQR 3-73] months, during which 12 patients expired. Results Anterior cardiac veins (ACV), which overlay the RV wall were observed in 85 (70%) patients and had a maximum ostial diameter of 2.04±0.8 mm. Multiple ACVs were seen in 62 patients. These veins were observed to empty directly into the venous sinus of right atrium (VSRA), into the RV, the right atrium (RA), or into the small cardiac vein (SCV) in 68, 9, 5, and 3 patients respectively. The right marginal vein (RMV) was visualized in 21 (17%) patients, had a diameter of 2.3±1.2 mm, and ran a course along the right border of the RV, emptying directly into RV, RA or into VSRA in 9, 4 and 8 patients respectively. The VSRA present in 91 (75%) patients, coursed parallel to the right coronary sulcus, collecting blood from the ACV’s and RMV’s and drained into the RA (Figure A); in 7 patients, 2 VSRA ostia were noted. VSRA lengths and diameters varied (11-119 mm, mean 41±25 mm) and (1.2-6.9mm, mean 2.7±1.2mm) respectively. The VSRA lengths correlated significantly with RV fractional area change, RV systolic pressure, tricuspid regurgitation severity evaluated by echocardiography, and P wave amplitude in ECG lead II (r=-0.65; p=0.041, r=0.88; p=0.019, r=0.52; p=0.030, and r=0.79; p=0.031 respectively). The VSRA diameters, which were significantly larger in patients with obstructive sleep apnea (3.6±1.5 vs. 2.3±1.2mm; p=0.021) correlated significantly with RV systolic pressure, and tricuspid regurgitation severity by echocardiography (r=0.77; p=0.009, and r=0.63; p=0.006 respectively). Patients who expired during follow-up had a significantly longer VSRA than patients who remained alive (Figure B). The VSRA length, RV fractional area change, and baseline QRS duration independently predicted survival in a Cox multivariate model that also included age and left ventricular ejection fraction. Conclusions RV venous system demonstrates a highly variable anatomy that has not been previously well described. The size of the VSRA correlated with parameters of RV function and predicted survival in patients undergoing CRT.Figure

Parathyroid hormone exacerbates pulmonary hypertension via parathyroid hormone receptors on pulmonary artery smooth muscle cells

Abstract Background Pulmonary hypertension (PH) is a right heart failure disease and can be fatal. Parathyroid hormone (PTH) is a bone metabolism hormone and regulates calcium and phosphorus homeostasis. Previous studies have suggested that PTH affects the cardiovascular system and influences cardiovascular diseases. We hypothesized that PTH may play a role in the pathogenesis of PH. Purpose This study aimed to investigate whether PTH has a critical role in pulmonary hemodynamics. Method Serum PTH levels were measured in patients with PH or suspected PH undergoing right heart catheterization. We tested whether the regulation of PTH and the PTH receptor (PTH1R) affected PH in hypoxia (Hx)-induced PH model mice and Sugen/hypoxia (SuHx)-induced PH model ras. Hx mice were treated with PTH daily for 3 weeks or with an inhaled AAV-shRNA system to knockdown PTH1R expression in the lung. SuHx rats underwent parathyroidectomy (PTx). We measured physical data and right ventricular systolic pressure (RVSP) in these models. Human pulmonary artery smooth muscle cells (PASMCs) were cultured and treated with PTH to examine the direct effects of PTH. Result In the clinical study, we enrolled 30 participants and found serum PTH levels correlated with mean pulmonary artery pressure (r = 0.67) and pulmonary vascular resistance (r = 0.62). The ROC curve showed a cut-off PTH level of 46.0 pg/mL (68.2% sensitivity, 100% specificity) to predict PH. In animal models, PTH treatment exacerbated right ventricular hypertrophy and increased right ventricular systolic pressure (RVSP) in Hx mice compared with non-treated Hx mice (Figure 1). In contrast, knockdown of PTH1R in the lungs improved PH in Hx mice, and PTx significantly suppressed PH in SuHx rats (Figure 2). PTH promoted migration and proliferation through PTH receptor-ERK signaling in PASMCs. Conclusion Our clinical and experimental data showed that PTH exacerbates PH and suggest that PTH/PTH1R signaling would be a new target for PH treatment.

Severity of pulmonary hypertension and pregnancy outcomes: newer insights from the M-PAC registry

Abstract Background Pregnancy outcomes in women with pulmonary hypertension remain suboptimal. Pregnant women with pulmonary hypertension (PH) are placed in the modified WHO category IV, regardless of the severity or etiology of PH. Earlier studies have indicated that pregnancy outcomes may differ based on the etiology, with more favourable outcomes observed with PH related to left to right shunts. However, it is possible that the pregnancy outcomes may vary based on the severity of PH also. Purpose To analyse pregnancy outcomes in women with PH and investigate differences based on disease severity. Methods M-PAC Registry, is a single center prospective study of pregnancies in women with heart diseases, conducted between July 2016 and December 2019 in a low-and middle-income country from South Asia, whose methodology and outcomes have been published(1). The current study analysed pregnancies with PH enrolled in the M-PAC registry. The tricuspid regurgitation velocity obtained during transthoracic echocardiography, was used to estimate right ventricular systolic pressure (RVSP). Based on the estimated RVSP, PH was classified into three groups; mild (36-45 mm of Hg), moderate (46-64 mm of Hg) and severe (≥ 65 mm of Hg). The differences in the maternal and foetal outcomes among the groups were analysed. Results Of the 1029 pregnancies complicated by heart disease enrolled in the M-PAC registry, 352(34.2%)had PH. Among these 352 pregnancies, 186(52.8%) had mild, 73 (20.7%) had moderate and 93 (26.5%) had severe PH. Adverse maternal cardiac events occurred in 77 pregnancies (21.8%), with heart failure in 53(15.1%) and mortality in 10(2.8%). The composite adverse foetal event rate was 38.6%, foetal loss at 9.7%, low birth weight at 28.9%, and preterm labour at 7.1%. The mean (±standard deviation) RVSP was higher in pregnancies with adverse maternal outcome (58.81±16.9 vs 51.16±15.9; P < 0.001) or adverse foetal outcome (58.10±17.3 vs 49.52±14.9; P < 0.001)compared to those without. When comparing the three groups, pregnancies with mild PH exhibited significantly lower rates of adverse maternal and fetal events compared to those with severe and moderate PH (Fig-1 and Table-1). Mild PH was associated with outcomes similar to those without PH in the M-PAC registry. Conclusion The severity of PH significantly correlated with the adverse pregnancy outcomes. Women with mild PH tend to experience pregnancy outcomes comparable to those without PH, suggesting that pregnancy should not be deemed contraindicated in this subgroup. Therefore, re-evaluation of the placement of PH within the modified World Health Organization (mWHO) classification is warranted, considering the severity of PH.Figure 1:Pregnancy Outcomes & PH SeverityTable-1 PH Severity & Pregnacny Outcomes

Validation of the MIDA mortality risk score in a surgical cohort of patients with primary mitral regurgitation

Abstract Background and aim The MIDA scale is a prognostic tool for stratification of short- and long-term mortality risk in patients with primary mitral regurgitation (PMR). The aim of this study is to validate the MIDA (1) score in our population of PMR treated with surgery. Methods Retrospective analysis of a prospective cohort of patients with PMR who underwent mitral valve surgery in a tertiary care center from 2014 to 2022. The necessary parameters for calculating the MIDA Score (age, symptoms, atrial fibrillation, left atrial diameter, right ventricular systolic pressure (RVSP), left ventricular end-systolic diameter (LVESD), and LV ejection fraction (LVEF)) were collected, and the MIDA score for each patient was calculated. Thereafter, patients were classified into seven different risk groups. One year and long-term mortality during follow-up were recorded. A logistic regression analysis was performed to evaluate the association of each parameter with outcomes. Finally, curves for the cumulative incidence of all-cause mortality according to the MIDA score were generated with the Kaplan–Meier method. Results A total of 349 patients were included. Mean age was 68.5 [12.4] years, 55.8% were male, and the median LVEF was 60% (55-65). Mean follow up was 3.28 (2) years. One year mortality occurred in 29 (8.3%) patients, and long-term mortality in 59 (16.9%). According to the MIDA score, the distribution of patients in each subgroup was as follows: score 0 (n=28), score 1-2 (n=35), score 3-4 (n=60), score 5-6 (n=99), score 7-8 (n=81), score 9-10 (n=35), score > 11 (n=11). Most of our cohort was classified as intermediate-risk patients, with a median score of 6 (3-8). In the univariable logistic regression analysis, age, symptoms before surgery and RVSP were the only MIDA parameters significantly associated with mortality (Table-Figure 1). In our population, the discriminatory capacity of the MIDA score, was moderate, with an area under the ROC curve of 0.676 CI (0.624-0.725) for one year mortality, and 0.702 (0.651-0.749) for long term mortality. The best cut-off point for predicting one-year and long-term mortality was a MIDA score of 7. Kaplan-Meier curves for mortality during follow-up are shown in Figure 2. Conclusions The MIDA score showed a fair discriminatory capacity in our surgical cohort of patients with PMR. Variables included in the score that had a significant association with mortality were age, presence of symptoms and elevated RVSP. LV parameters included in the MIDA, which are the current class I indication for surgery, did not show a significant association with outcomes. Different echocardiographic variables to evaluate cardiac damage in PMR are needed to achieve better stratification.Table-Figure 1Figure 2

Sex differences in outcomes among patients undergoing transcatheter atrial septal defect closure: Do they benefit equally?

Abstract Background Although sex differences in congenital heart disease are prevalent and relevant, there is limited research on their role in atrial septal defect (ASD) closure. We aimed to investigate sex differences in baseline characteristics, procedural and long-term outcomes of patients with transcatheter ASD closure. Methods Data from adult patients undergoing ASD closure between 2005-2016 were retrospectively analyzed. Results Of the 853 patients included, 281 (32.9%) were male and 572 (67.1%) were female. Females were more symptomatic at presentation than males (p < 0.001). Males had a higher frequency of cardiovascular comorbidities than females (p < 0.001). Although echocardiographic right ventricular (RV) diameter relative to body surface area was equal in males and females (2.49 cm/m2 versus 2.57 cm/m2; p = 0.072), males had more RV dysfunction (12.1% versus 7.6%; p = 0.028). In contrast, females had higher RV systolic pressures (39.71 mmHg versus 37.23 mmHg; p = 0.025), and were more likely to have moderate to severe tricuspid regurgitation (15.4% versus 8.9%; p = 0.007). Males had larger defects with use of larger implants (p < 0.05). Procedure-related complications were rare and did not differ by sex. At 12-month follow-up, both male and females showed comparable decreases in RV diameter (-0.57 cm versus -0.59 cm; p = 0.751), RV systolic pressure (-4.57 mmHg versus -6.31 mmHg; p = 0.094), and severity of tricuspid regurgitation (p = 0.173; Figure). After a mean follow-up of 3 years (SD = 5), no significant differences were observed in the incidence of death (incidence rate ratio (IRR) = 0.49 [95% CI 0.27-0.83]; p = 0.402), new onset atrial fibrillation (IRR = 3.22 [95% CI 2.57-3.99]; 0.063), cardioversion or ablation (IRR = 0.40 [95% CI 0.20-0.71], p = 0.335), stroke/TIA (IRR = 0.29 [95% CI 0.12-0.56]; p = 0.745), and pacemaker implantation (IRR = 0.29 [95% CI 0.12-0.57], p = 0.728). Conclusions Although patient profiles differed by sex, procedural and long-term outcomes were comparable, suggesting that transcatheter ASD closure can be safely performed in both males and females.Figure.Sankey Plot

Long-term outcomes of patients with apical hypertrophic cardiomyopathy: incorporation of a novel risk score

Abstract Background Apical hypertrophic cardiomyopathy (aHCM) is a subtype of HCM characterized by left ventricular hypertrophy predominantly in the apex. There is still limited data on factors associated with adverse outcomes in patients with aHCM. Objectives To a) describe the characteristics and b) develop a novel risk score associated with outcomes in aHCM patients. Methods A total of 462 patients (mean age 58±15 years, 68% male and 70% white) diagnosed with aHCM based on clinical, echocardiographic, and cardiac magnetic resonance (CMR) evaluation were included. The primary endpoint was all-cause death or aborted sudden cardiac death. Using the cox regression analysis, variables showing potential association with the composite endpoint were considered to develop an aHCM specific risk score. Results On echocardiography, the mean LV ejection fraction (LVEF) was 64±8%, and the mean LV mass was 223±72 g. A baseline CMR was performed in 246 (53%) patients, with delayed gadolinium enhancement in 170 (71%) patients with a mean percentage of 5±7%. Patients were followed-up for a mean of 68 months (range 1-248), with composite events occurring in 80 (17%) patients (death in 62 [13%] patients). Univariate Cox regression analysis identified age hazard ratio (HR) 1.06 (95% Confidence Interval or CI 1.04-1.08; p< 0.001), apical aneurysm HR 2.32 (95% CI 1.24-4.34 p=0.008), lower LVEF HR 0.96 (95% CI 0.94-0.99 p=0.002), higher right ventricular systolic pressure (RVSP) HR 1.04 (95% CI 1.02-1.06 p< 0.001), New York Heart Association Class IV HR 11.69 (95% CI 3.59-38.08 p< 0.001) and the presence of Atrial fibrillation HR 1.77 (95% CI 1.14-2.76 p=0.012). An aHCM specific risk score was subsequently created (Figure 1), with good discrimination (c-statistic=0.75) and good calibration with expected to observed ratio of 1.02 and a calibration slope of 0.91 (p-value for difference between expected and observed probabilities =0.22). The risk score ranges between 0 and 8 points, with higher score associated with a higher rate of composite events (Figure 2). Conclusion We developed a novel risk score which demonstrated incremental prognostic value for hard events in aHCM patients.Risk prediction modelKaplan Meier event-free survival curves

Hemodynamic monitoring during weaning from mechanical ventilation in critically ill pediatric patients: a prospective observational study

BackgroundCardiovascular dysfunction is a significant factor contributing to weaning failure in mechanically ventilated children. Understanding the cardiopulmonary pathophysiological changes that occur during weaning is a prerequisite for the early recognition of weaning failure of cardiovascular origin. This study aimed to assess the effect of weaning trials on central hemodynamics and to identify the indices predictive of cardiac-related weaning failure.MethodsThis prospective observational study was conducted in the Pediatric Intensive Care Unit (PICU) and included mechanically ventilated patients aged between 2 and 30 months who were on minimal ventilatory settings and ready for weaning. Patients who were hemodynamically unstable, diagnosed with neuromuscular diseases, or diagnosed with cardiac diseases were excluded. Hemodynamic parameters were evaluated during weaning from ventilation via echocardiography and noninvasive cardiometry during pressure support (PS) ventilation and at the end of the spontaneous breathing trial (SBT).ResultsThe study included 50 patients, comprising 30 males (60%) and 20 females (40%) with ages ranging from 2 to 30 months. Echocardiography revealed a significant increase in the cardiac index (CI), tricuspid annular plane systolic excursion (TAPSE), and the E/A ratio at the end of SBT. Moreover, right ventricular systolic pressure (RVSP) significantly decreased. Noninvasive cardiometry revealed a significant increase in the index of contractility (ICON) and CI at the end of SBT (p-value = 0.023 and < 0.001, respectively). Of the 12 (25%) patients who failed their first extubation trial, they exhibited a significantly lower CI and TAPSE (p values = 0.001 and 0.001, respectively).ConclusionThis study identified that weaning from mechanical ventilation in children is associated with hemodynamic changes, which can impact weaning success and reveal potential ventricular dysfunction. Bedside echocardiography was found to detect cardiac dysfunctions during weaning, and noninvasive cardiometry was considered a reliable tool that supports echocardiography for detecting changing trends in CI in PICUs. However, accurate values should be confirmed by echocardiography.

Safety and outcomes with use of FlowTriever for mechanical thrombectomy i n acute pulmonary embolism

Objectives: Mortality in the pulmonary embolism (PE) risk categories has historically been reported between 30% and 40% in high-risk and &lt;15% in intermediate-risk group. In those who survive, there is a high rate of morbidity with dyspnea and exercise intolerance. Advanced therapies with a favorable safety profile have the potential to improve outcomes. We present the largest single-center data set studied to-date for safety, mortality, and outcomes post-mechanical thrombectomy including functional assessment 3 months post-discharge. Material and Methods: We analyzed retrospective database of patients with PE undergoing catheter directed mechanical thrombectomy (CDMT). We report clinical characteristics and outcomes stratified by PE risk categories. Comparison in the groups has been made using analysis of variance method. Results: A total of 365 patients were evaluated in the CDMT group. Among these 81 (22%) presented with high-risk and 261 (71%) with intermediate-risk PE. The average age at diagnosis was 61 ± 17 years with male-to-female distribution ratio of 1.2. Most common risk factors being reduced mobility (18%), malignancy (15%), recent surgery (13%), and hormonal therapy (12%). Mortality within 30 days of PE diagnosis was 8.6% (7/81) in high-risk, 1.7% (4/230) in intermediate-high-risk groups. There were no deaths in intermediate-low and low-risk group post-CDMT. Before thrombectomy, 349 (95%) patients had right heart strain, 307 (84%) had elevated troponin, and 197 (54%) had elevated B-type natriuretic peptide. Post-procedure echocardiogram at 3 month revealed improvement in the right ventricular (RV) fractional area change (27.53 ± 10.38% to 39.73 ± 8.3%, P &lt; 0.01), tricuspid annular plane systolic excursion (10.9 ± 8.3 mm to 21.81 ± 4.75 mm), and RV systolic pressure (43.96 ± 14.48 mmHg to 28.47 ± 7.88 mmHg, P &lt; 0.01). At 3 months post-thrombectomy, the majority (74%) of the patients fell into non-to-negligible functional limitation. Conclusion: We present a descriptive analysis of outcomes including improved mortality, and functional assessment of patients undergoing CDMT.

Immunoregulatory Macrophages Modify Local Pulmonary Immunity and Ameliorate Hypoxic Pulmonary Hypertension.

Macrophages play a significant role in the onset and progression of vascular disease in pulmonary hypertension, and cell-based immunotherapies aimed at treating vascular remodeling are lacking. To evaluate the effect of pulmonary administration of macrophages modified to have an anti-inflammatory/proresolving phenotype in attenuating early pulmonary inflammation and progression of experimentally induced pulmonary hypertension. Mouse bone marrow-derived macrophages were polarized in vitro to a regulatory (M2reg) phenotype. M2reg profile and anti-inflammatory capacity were assessed in vitro upon lipopolysaccharide/IFNγ (interferon-γ) restimulation, before their administration to 8- to 12-week-old mice. M2reg protective effect was evaluated at early (2-4 days) and late (4 weeks) time points during hypoxia (8.5% O2) exposure. Levels of inflammatory markers were quantified in alveolar macrophages and whole lung, while pulmonary hypertension development was ascertained by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy measurements. Bronchoalveolar lavage from M2reg-transplanted hypoxic mice was collected and its inflammatory potential evaluated on naive bone marrow-derived macrophages. M2reg macrophages expressing Tgfβ, Il10, and Cd206 demonstrated a stable anti-inflammatory phenotype in vitro, by downregulating the induction of proinflammatory cytokines and surface molecules (Cd86, Il6, and Tnfα) upon a subsequent proinflammatory stimulus. A single dose of M2reg attenuated hypoxic monocytic recruitment and perivascular inflammation. Early hypoxic lung and alveolar macrophage inflammation leading to pulmonary hypertension development was significantly reduced, and, importantly, M2reg attenuated right ventricular hypertrophy, right ventricular systolic pressure, and vascular remodeling at 4 weeks post-treatment. Adoptive transfer of M2reg halts the recruitment of monocytes and modifies the hypoxic lung microenvironment, potentially changing the immunoreactivity of recruited macrophages and restoring normal immune functionality of the lung. These findings provide new mechanistic insights into the diverse role of macrophage phenotype on lung vascular homeostasis that can be explored as novel therapeutic targets.

Suppressing the expression of steroidogenic acute regulatory protein (StAR) in the myocardium by spironolactone contributes to the improvement of right ventricular remodeling in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently leads to right ventricular (RV) remodeling. Aldosterone promotes vascular and RV remodeling. The upregulation of steroidogenic acute regulatory protein (StAR) stimulates aldosterone synthesis. However, the expression of StAR in the myocardium under PAH conditions remains unknown. To investigate the expression of StAR in the myocardium and its association with RV remodeling in PAH, utilizing spironolactone as a treatment. A PAH model was created using male Sprague-Dawley rats, which received a subcutaneous injection of Sugen5416 (20 mg/kg) and were exposed to hypoxia (10% O2) for 2 weeks, followed by 2 weeks of normoxia. The animals were then divided into two groups, with one group receiving spironolactone (25 mg/kg/day) for an additional 4 weeks, while the other group did not. H9c2 cells were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with or without spironolactone treatment. In the model rats, RV systolic pressure and the Fulton index, both of which increased upon exposure to Sugen5416 and hypoxia, significantly decreased with spironolactone treatment. In H9c2 cells, hypoxic exposure elevated aldosterone levels, while spironolactone treatment significantly suppressed aldosterone production. Suppression of StAR expression in the myocardium via spironolactone contributes to the improvement of RV remodeling in PAH. Spironolactone may offer a valuable therapeutic strategy for RV remodeling in patients with PAH.