Pulmonary Vasodilator Research Articles

PULMOEAST: A Comprehensive Analysis of Pulmonary Hypertension in Eastern India.

Background Pulmonary hypertension (PH) is a debilitating cardiovascular disorder characterized by abnormally elevated blood pressure within the lungs. The diverse range of causes and varied clinical presentations contribute to the complexity of its diagnosis and management. In eastern India and surrounding areas, awareness of PH remains limited, and resources for its management are scarce. This study aims to address this knowledge gap by investigatingclinical characteristics and treatment approaches adopted for PH patients in eastern India. Methods This retrospective-prospective cohort study included patients diagnosed with PH, defined by a pulmonary artery systolic pressure (PASP) > 50 mmHgor amean pulmonary artery pressure (mPAP)>20 mmHg, between July 2015 and October 2023. Data retrieved from hospital records formed the retrospective cohort, while the prospective cohort comprised patients directly recruited for the study. Results The PULMOEAST study enrolled 93 patients with confirmed PH, divided into prospective (59 patients) and retrospective (34 patients) cohorts. The most prevalent cause of PH was congenital heart disease (CHD), with shunt lesions (59.13%), followed by complex CHD (13.97%) and idiopathic PH (20.43%). Six additional patients presented with rare causes of PH, and three experienced transient PH following atrial septal defectdevice closure. Geographic distribution revealed that 72.04% of patients originated from eastern India, while 18.27% hail from other eastern states and 8.6% from neighboring countries. Patients exhibited varying functional classes (FC), with 57 classified as FC-II and 31 classified as FC-III. Treatment strategies primarily involve supportive medications and pulmonary vasodilators. Monotherapy was administered to 26 patients (27.95%), dual therapy to 50 patients (53.76%), and triple therapy to one patient. Notably, 16 patients did not receive any vasodilator therapy as they were waiting for further evaluation. Among the vasodilator regimen, two patients received Selexipag. Three patients underwent intervention for shunt lesion closure, including one patient who received a fenestrated atrial septal occluder implant. Additionally, one patient underwent clot removal for pulmonary thromboembolism. Despite the overall positive response to treatment, the study recorded eight fatalities (8.6%) during the observation period. However, most patients exhibited significant improvement, including a decrease in functional class, during a mean follow-up duration of 14.31 months. Conclusion The PULMOEAST study undertook a comprehensive exploration of PH in eastern India and surrounding regions, revealing a stark dominance of CHD as the primary culprit. The study confirmed the pivotal role of echocardiography as a readily available and effective tool for both initial and follow-up evaluations in resource-scarce settings. It painted a hopeful picture by showcasing significant clinical improvement in most treated patients, with supportive medications and pulmonary vasodilators playing a crucial role. However, the diverse etiologies, limited access to PH-specific resources, and lack of widespread awareness within the region continue to pose substantial challenges for patients. The study underscores the need for refined diagnostic approaches, cost-effective management strategies, collaborative care initiatives, and enhanced patient education to optimize PH care and improve outcomes in eastern India.

Recurrent pulmonary hypertension after balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension

Balloon pulmonary angioplasty improves the hemodynamics of patients with inoperable chronic thromboembolic pulmonary hypertension; however, the clinical impact of recurrent pulmonary hypertension after balloon pulmonary angioplasty remains unclear. We retrospectively reviewed 262 consecutive patients with chronic thromboembolic pulmonary hypertension who underwent balloon pulmonary angioplasty between July 2009 and December 2020; 158 (65±12years; males, 20%; median follow-up period, 45 [26, 66]months) with follow-up right heart catheterization and no residual pulmonary hypertension were included. Recurrent pulmonary hypertension was defined as mean pulmonary arterial pressure <25mm Hg at the first evaluation after balloon pulmonary angioplasty and ≥25mm Hg at follow-up evaluation requiring additional treatment with balloon pulmonary angioplasty or pulmonary vasodilators. Recurrent pulmonary hypertension was observed in 11 patients; the state occupation probability of recurrence at 5years was 9.0% (95% confidence interval: 5.0%-18.9%). Only 1 case (0.6%) of recurrent pulmonary hypertension showed vascular restenosis and reocclusion of previously treated lesions, with more significant hemodynamic and exercise capacity deterioration than the other cases. Additional treatments for recurrent pulmonary hypertension (balloon pulmonary angioplasty in 9 patients, pulmonary vasodilators in 4 patients) improved the mean pulmonary arterial pressure from 27 [26, 29] to 22 [19, 23] mm Hg (p<0.01). Recurrence had a low probability of transitioning to death in an illness-death model. No specific risk factors for recurrent pulmonary hypertension were identified. Symptomatic recurrent pulmonary hypertension due to vascular restenosis or reocclusion after balloon pulmonary angioplasty was extremely rare. Most cases of recurrent pulmonary hypertension were mild, did not worsen clinically, and had favorable prognoses.

Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function.

(1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil's synergy with isoprenaline in RV and LV cardiomyocytes. We hypothesised that disease-related RV structural changes in cardiomyocytes would reduce contractile responses and cAMP/PKA signalling activity. (2) We induced PH in male Sprague Dawley rats using monocrotaline and isolated their ventricular cardiomyocytes. The effect of in vitro treprostinil and isoprenaline stimulation on contraction was assessed. FRET microscopy was used to study PKA activity associated with treprostinil stimulation in AKAR3-NES FRET-based biosensor-expressing cells. (3) RV cells exhibited maladaptive remodelling with hypertrophy, impaired contractility, and calcium transients compared to control and LV cardiomyocytes. Combining treprostinil and isoprenaline failed to enhance inotropy in PH RV cardiomyocytes. PH RV cardiomyocytes displayed an aberrant contractile behaviour, which the combination treatment could not rectify. Finally, we observed decreased PKA activity in treprostinil-treated PH RV cardiomyocytes. (4) PH-associated RV cardiomyocyte remodelling reduced treprostinil sensitivity, inotropic support, and impaired relaxation. Overall, this study highlights the complexity of RV dysfunction in advanced PH and suggests the need for alternative therapeutic strategies.

Inhaled Nitroglycerin for Pulmonary Edema in Air Medical Services: A Retrospective Pilot Study

ObjectiveThe use of traditional inhaled pulmonary vasodilators, such as nitric oxide, to treat symptomatic pulmonary edema is not practical in the air medical or prehospital environment because of difficulty with administration. A hospital-based critical care air medical transport service initiated a pilot study to investigate the use of inhaled nitroglycerin (iNTG) as an alternative pulmonary vasodilator. MethodsFor this pilot study, iNTG was administered using a jet nebulizer setup and concentrated nitroglycerin, both of which are widely available in acute care settings. In conjunction with medical oversight, transport personnel identified patients with respiratory distress secondary to pulmonary edema. Twenty-two months after initiating the protocol, a retrospective chart review was conducted. Data for patients receiving iNTG were retrospectively abstracted through a medical record search and manual chart review. ResultsTwelve patients received iNTG during the pilot study. Basic demographics, medical comorbidities, concurrent medications, laboratory values, and radiographic studies were collected for each patient. Basic statistics were performed to identify any potential trends. ConclusionThe administration of iNTG is feasible in an air medical transport setting and may provide a useful adjunct to treating patients with pulmonary edema and respiratory distress. Because iNTG delivery targets the pulmonary vasculature, this may be of particular benefit in patients with a poor hemodynamic profile. Larger randomized controlled or cohort studies are needed to specifically analyze and compare hemodynamics, diagnostics, and patient outcomes.

Updates in the Pharmacotherapy of Pulmonary Hypertension in Patients with Heart Failure with Preserved Ejection Fraction.

Pulmonary hypertension (PH) associated with left heart disease (LHD) is a complex cardiopulmonary condition where a variable degree of pulmonary congestion, arterial vasoconstriction and vascular remodeling can lead to PH and right heart strain. Right heart dysfunction has a significant prognostic impact on these patients. Therefore, preserving right ventricular (RV) function is an important treatment goal. However, the treatment of PH in patients with left heart disease has produced conflicting evidence. The transition from pure LHD to LHD with PH is a continuum and clinically challenging. The heart failure with preserved ejection fraction (HFpEF) patient population is heterogeneous when it comes to PH and RV function. Appropriate clinical and hemodynamic phenotyping of patients with HFpEF and concomitant PH is paramount to making the appropriate treatment decision. This manuscript will summarize the current evidence for the use of pulmonary arterial vasodilators in patients with HFpEF.

Sarcoidosis-Associated Pulmonary Hypertension

Sarcoidosis is characterized by non-necrotizing granulomatous aggregations affecting a range of organs, with thoracic structures involved in 90% to 95% of cases. This granulomatous disease can impact the pulmonary vasculature via different mechanisms resulting in sarcoidosis-associated pulmonary hypertension (SAPH). These include postcapillary disease (left heart disease), immune-mediated granulomatous vasculopathy, hypoxemia, thromboembolism, pulmonary vascular compression and/or stenosis by mediastinal lymph nodes/fibrosis, or sarcoidosis-related portal hypertension. SAPH is a serious complication, especially in those with end-stage lung disease. A thorough evaluation is crucial to delineate the predominant mechanism of PH in the affected individual. The management of SAPH is complex and necessitates a personalized, multifaceted approach, targeting the specific mechanisms and underlying pathologies. Such patients are best served at specialized Pulmonary Hypertension and Sarcoidosis Centers. A notable phenotype within SAPH is the “pulmonary arteriopathy” group, characterized by milder parenchymal disease and a favorable response to PAH-targeted therapy, whereas patients with active granulomatous inflammation are likely to respond to immunosuppression. Several PAH therapies have been used to treat SAPH, however, clear direction on the use of PAH therapies in SAPH is still lacking. Patients receiving pulmonary vasodilators should be carefully monitored for potential deterioration in gas exchange or development of pulmonary edema, which could suggest underlying left heart disease or pulmonary veno-occlusive disease. Timely referral for lung transplant evaluation is crucial for those with SAPH and severe parenchymal lung disease, ensuring a comprehensive and patient-centered care approach. Much work remains to be done to understand the exact pathogenesis of SAPH, as well as to develop therapies that clearly improve outcomes for these patients.

Perioperative Right Ventricular Dysfunction and Abnormalities of the Tricuspid Valve Apparatus in Patients Undergoing Cardiac Surgery.

Right ventricular (RV) dysfunction frequently occurs after cardiac surgery and is linked to adverse postoperative outcomes, including mortality, reintubation, stroke, and prolonged ICU stays. While various criteria using echocardiography and hemodynamic parameters have been proposed, a consensus remains elusive. Distinctive RV anatomical features include its thin wall, which presents a triangular shape in a lateral view and a crescent shape in a cross-sectional view. Principal causes of RV dysfunction after cardiac surgery encompass ischemic reperfusion injury, prolonged ischemic time, choice of cardioplegia and its administration, cardiopulmonary bypass weaning characteristics, and preoperative risk factors. Post-left ventricular assist device (LVAD) implantation RV dysfunction is common but often transient, with a favorable prognosis upon resolution. There is an ongoing debate regarding the benefits of concomitant surgical repair of the RV in the presence of regurgitation. According to the literature, the gold standard techniques for assessing RV function are cardiac magnetic resonance imaging and hemodynamic assessment using thermodilution. Echocardiography is widely favored for perioperative RV function evaluation due to its accessibility, reproducibility, non-invasiveness, and cost-effectiveness. Although other techniques exist for RV function assessment, they are less common in clinical practice. Clinical management strategies focus on early detection and include intravenous drugs (inotropes and vasodilators), inhalation drugs (pulmonary vasodilators), ventilator strategies, volume management, and mechanical support. Bridging research gaps in this field is crucial to improving clinical outcomes associated with RV dysfunction in the near future.

Impact of collateral vessels on Fontan circulation by using 0-1 dimensional Fontan circulation model considering concepts of oxygen supply and consumption

Abstract Background/Purpose In patients with univentricular heart disease, the Fontan operation has played a significant role in improving cyanosis and reducing the volume load on the systemic ventricle. However, Fontan patients may develop various complications, and their hemodynamics may deteriorate gradually, resulting in a poor long-term survival rate. Development of collateral vessels before and/or after the Fontan operation is one of the significant problems, and the patients may suffer from advanced cyanosis and heart failure. Although recent studies about the collateral vessels by MRI showed that a significant amount of blood is flown through the collateral vessels, little is known about its effect on the Fontan circulation. Therefore, understanding the mechanism and impact of collateral vessels on the Fontan circulation is important. Methods A 0-1-dimensional Fontan circulation hemodynamic model was developed to reproduce the hemodynamic changes of the blood flow in the entire body by introducing two types of collateral vessels (VVC: veno-venous collateral, APC: aorto-pulmonary collateral) into the model considering clinical status. Also, giving various conditions by ranging catecholamine dose and introducing the concept of oxygen delivery and consumption by changing workloads, arterial and central venous oxygen saturations (SaO2 and SvO2) are predicted in the Fontan circulation models. To evaluate the cardiac function, considering the impact of collateral vessels, four representative values were examined: (1) cardiac output (CO) per minute; (2) Ees relative to arterial elastance (Ees/Ea); (3) ejection fraction; and (4) the stroke work (SW) to pressure-volume area (PVA) ratio (SW/PVA). Results SaO2 and SvO2 were less in Fontan circulations with both VVC and APC present (92% and 54%) than those without collateral vessels (96% and 62%). Also, with collateral vessels, Ees/Ea was decreased while SW/PVA was increased, leading to poor perfusion to the tissue. Regardless of the presence or absence of collateral circulation, SaO2 and SvO2, and systemic blood flow rate decreased when pulmonary vascular resistance was high. By administering catecholamine at 10 microgram/kg/min, in the presence of both VVC and APC, SvO2 was increased from 53% to 58%, while SaO2 was decreased from 92% to 88%. Conclusions The simulated results of arterial and venous blood oxygen saturations and systemic blood flow rate were well-reproduced, matching the previously reported clinical results. It is suggested that pulmonary vasodilators may be beneficial in increasing blood oxygen saturation and improving tissue perfusion, even in Fontan patients with collateral vessels. However, the catecholamine's positive effect is limited. For reproducing various conditions of Fontan circulations, it is necessary to collect actual measurement data from a variety of patients and validate the predicted value to increase the credibility of the model.Arterial and venous oxygen saturationsPressure and volume curves

Pulmonary vasoconstriction plays a major role in the acute phase of pulmonary embolism in pigs

Abstract Background Pulmonary vascular resistance (PVR) increases in acute pulmonary embolism (PE) due to both mechanical obstruction and pulmonary vasoconstriction. Attenuation of adverse pulmonary vasoconstriction has shown promise as a treatment of acute PE in experimental studies. However, clinical trials have failed to replicate these beneficial effects in PE patients. Time may be a factor in this discrepancy between experimental and clinical studies. In experimental PE studies, PVR acutely increases and decreases within hours. Meanwhile in clinical trials, the time from symptom onset to study inclusion is often days, at which time PVR may already be decreased. Whether this decrease in PVR is due to reduced mechanical obstruction by endogenous fibrinolysis or attenuation of adverse pulmonary vasoconstriction is unknown. Purpose To investigate the contribution of the mechanical obstruction and pulmonary vasoconstriction to PVR in two days following PE in pigs. Methods In a controlled animal study, using an estabilished model of autologous PE in pigs (PE, n=12 ∼60 kg), changes in pulmonary hemodynamics and clot burden were evaluated. CT pulmonary angiograms were performed at baseline (BL), after acute PE and the following two days, quantifying clot burden using the Qanadli Obstruction Score. Hemodynamics were evaluated with real-time biventricular catheterization and systemic invasive pressures. To evaluate the vasoactive component, pulmonary vasodilators sildenafil (bolus 0.1 mg/kg) and oxygen (inspired fraction of oxygen 40%) were administered. Results Following PE, both mean PVR (Figure 1A) and pulmonary obstruction scores (Figure 1B) increased. PVR decreased at day one and remained unchanged at day two (Figure 1A). Meanwhile, mean obstruction score decreased slightly at day one but remained elevated throughout the study (Figure 1B). Vasodilatation induced by sildenafil and oxygen (SIL+OXY) decreased PVR at day zero but displayed no effect on the subsequent days (Figure 1A). Conclusion Pulmonary vasoconstriction and mechanical obstruction both contributed to the increase in PVR during the acute phase of PE. PVR decreased towards levels of baseline already day one and remained unchanged at day two. The contribution of pulmonary vasoconstriction decreased at day one and two, while the mechanical obstruction remained significantly increased. Accordingly, the effects of pulmonary vasodilators were only present in the acute phase of PE.Figure 1

The prevalence and significance of the EIF2AK4 variants in the patients with pulmonary arterial hypertension

Abstract Background Eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) has been reported to be the causative gene of pulmonary veno-occlusive disease (PVOD).[1] Although some patients with pulmonary arterial hypertension (PAH) also carry the EIF2AK4 variants, its importance remains unclear. Purpose The purpose of this study was to evaluate the prevalence and significance of EIF2AK4 variants in patients with PAH. Methods The whole exome sequencing were performed in total 162 patients with idiopathic or heritable PAH. The clinical data including the high-resolution CT scanning, pulmonary function test, laboratory data at diagnosis, and therapeutic response to pulmonary vasodilator were evaluated. Results We identified the heterozygous variants of EIF2AK4 in 6 (3.7%) patients. Among them, 2 patients also had bone morphogenetic protein receptor type 2 (BMPR2) variants which were defined as pathogenic by American College of Medical Genetics and Genomics classification. The other 4 patients did not have known PAH associated gene variants. Although the typical findings of PVOD such as interlobular septal thickening and enlarged mediastinal lymph nodes, were not identified by the CT scanning, the median percent diffusing capacity for carbon monoxide of patients with EIF2AK4 heterozygous variants was reduced to 45.6%. In addition, 4 of 6 patients received prostacyclin injection therapy because oral combination therapy was ineffective, and 2 patients died. Moreover, none of the 6 patients reached mean pulmonary arterial pressure≤30 mmHg despite the combination therapy. We also identified homozygous EIF2AK4 variants in 2 patients with PAH. They did not have the known causative variants of PAH. CT scanning at diagnosis did not detect any characteristic of PVOD in either of the two patients. Although the pulmonary vasodilator was initiated without induction of pulmonary edema, one patient was refractory to the therapy. Conclusions The genetic analysis is crucial for accurate diagnosis even in patients diagnosed with PAH because heterozygous or homozygous variants in EIF2AK4 could be involved in the disease pathology.

Evaluation of liver and renal function tests together with histopathological alterations in rabbits infected with a virulent strain of Proteus vulgaris

Introduction and Aim: Gram-negative bacterium Proteus vulgaris is found in animal and human guts. This bacterium can cause renal and vesical calculi, septicemia, and wound infection-related pyrexia. Antibiotics may not cure respiratory infections. This study infected rabbits with a virulent strain of P. vulgaris from bovine mastitis to examine metabolic and histological changes in various organs. Materials and Methods: This study was carried out on twenty domestic rabbits of both sexes which were divided into two groups. The first group received 1010 CFU\ml\ of virulent Proteus vulgaris subcutaneously. While the second group (control) received subcutaneously 1 cc of phosphate buffered saline (pH = 7.2). On 3,7, 14 days of infection, the animals were checked for their biochemical parameters (AST, ALT, ALP, blood urea and creatinine). Histological alterations in various organs were also studied. Results: The infected group showed substantial increases (P0.01) in liver enzymes (AST, ALT, and ALP) at 3, 7, and 14 days compared to the control group. In contrast, the infected group showed a substantial rise (P 0.01) in blood urea and creatinine levels at 3, 7, and 14 days compared to pre-infection levels and the control group. Histological analysis of lung tissue showed dilated alveolar gaps with hemorrhagic and fibrinous exudates and many alveolar macrophages. These findings included pulmonary vasodilation and congestion. Intramuscular edema, cellular infiltration, intramuscular hemorrhage, and congestion was present in heart tissue with little muscle fiber separation. The intestines had significant patch proliferation and mononuclear cell infiltration. Blood vascular congestion and mononuclear cell infiltration were also seen in the liver and kidney. Conclusion: Experimental infection with pathogenic bacterium Proteus vulgaris raised rabbits' blood urea, creatinine, and liver enzymes AST, ALT, and alkaline phosphatase. Cardiovascular, renal, hepatic, intestinal, and pulmonary tissues showed significant postmortem changes.

Multiple coronary artery microfistulae are common and progress in adult patients late after Fontan operation

Abstract Background Coronary angiograms of adult Fontan patients sometimes show the abnormal multiple coronary artery microfistulae (mCAFs) that drain directly into the ventricular chamber. They look like coronary artery fistulae or Thebesian vein. Angiographically detectable mCAFs are a rare finding sometimes associated with myocardial ischemia due to coronary steal and volume overload of ventricles in non-CHD adults. However, there are limited data concerning these mCAFs in the setting of CHD patients. Purpose The aim of this study is to demonstrate presence, character, and changes with growth of mCAFs in adult patients late after Fontan operation. Methods This study is single-center retrospective review of adults (16 years old or older) with Fontan circulation patients who had undergone cardiac catheterization for routine Fontan surveillance between 2009-2022. We assessed the presence of angiographically detectable mCAFs from ascending aortography. After identification of the characteristic cases, we examined the ventricular morphology, the portion of drainage, and compared with previous findings of angiograms. SaO2, EF of main ventricle, CVP, EDP of main ventricle, BNP, and use of pulmonary vasodilators were compared between mCAFs(+) group and mCAFs(-) group. We also reviewed clinical manifestation and findings of exercise stress ECG of the patients. Pulmonary atresia with intact ventricular septum was excluded because abnormal coronary arterial communications have been well documented in this condition. Results Among 90 Fontan patients who had undergone catheterization, significant mCAFs were observed in a total of 18 cases (20%). There were 10 right-dominant single ventricle, 4 left-dominant single ventricle, and 4 unbalanced two ventricles. In all cases, including left-dominant single ventricle, all fistulae drained into right ventricle cavity, never into left ventricle. The patients who underwent serial catheterizations demonstrated that the dilation and tortuosity of fistulae progressed over time. The comparison of two groups showed SaO2 was low, BNP and CVP was high significantly in mCAFs(+) group. There were no significant differences in other factors including age at catheterization and the use of pulmonary vasodilators. Among 10 patients who had underwent exercise stress ECG, only 1 patient showed ST segment depression. None had clinical history of chest pain, and arrhythmia, and ischemic event. Conclusions MCAFs are common and progress in adult patients late after Fontan operation. Although the clinical significance and etiology of these findings remains uncertain, particular attention should be given to subclinical Fontan failure caused by hhigh CVP, volume overload, and myocardial ischemia for the future of adult Fontan patients who have prominent mCAFs.

Comparative investigation of pulmonary vasodilating effects of inhaled Nitric Oxide (NO) gas therapy and inhalation of SIN-1, a new drug formulation containing an NO-donor metabolite

Abstract Background The management of acute pulmonary hypertension has recently been in the center of attention as Coronavirus Disease 2019 (COVID-19) might lead to acute respiratory distress syndrome associated with hypoxia-induced pulmonary vasoconstriction. Therefore inhalation therapy has been the object of several clinical trials. Purpose In this experimental study we aimed at investigating the hemodynamic effect of inhalative SIN-1a (3-morpholino-syndnonimine, the unstable active metabolite of molsidomine, stabilized by cyclodextrine) administration during physiological and pathological conditions in a large animal model. Methods Landrace pigs were randomized into the following experimental groups: iNO (inhaled nitric-oxide, n=3), SIN-1-5 (5 mg, n=3), SIN-1-10 (10 mg, n=3). Hemodynamic parameters were recorded after parallel insertion of PiCCO system and Swan-Ganz catheter. The effect of iNO and SIN-1 inhalation (30 min) was investigated under physiologic conditions and U46619, a thromboxane-receptor agonist induced pulmonary hypertension. Results The observed alterations after inhalation therapy were quite similar under physiological and pathological condition. Pulmonary arterial pressure (PAP) was decreased by all of these drugs, SIN-1-10 had similar effect as iNO (physiological contidiont: -36.1% iNO, -23.8% SIN-1-5, -35.5% SIN-1-10; U46619-induced pulmonary hypertension: -30.1% iNO, -22.1% SIN-1-5, -31.2% SIN-1-10). While iNO therapy did not influence the mean arterial pressure (MAP) and systemic vascular resistance (SVR) values, SIN-1 administration resulted in decreased MAP and SVR values. Pulmonary vascular resistance (PVR) was decreased by iNO greater than with using SIN-1. As a result of these alterations, the PVR/SVR ratio decreased markedly in the iNO group, while it was stepwisely increased in the SIN-1-5 and SIN-1-10 group. Conclusion The pulmonary vasodilator effect of SIN-1 was dose dependent, and in case of larger dose it was comparable to that of iNO. However, the vasodilatory effects of SIN-1 inhalation was not limited to the pulmonary circulation, a significant and dose-dependent systemic vasodilation could also be documented.

Retrospective analysis of confirmed cases of pulmonary veno-occlusive disease: a single tertiary referral center study

Abstract Background Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that primarily results in intimal fibrosis of the pulmonary venules and veins, the venous lesions are often associated with changes in interlobular septa, lung parenchyma, and pulmonary arterioles and arteries. Purpose We sought to study the clinical characteristics of patients with confirmed PVOD at a single large referral center. Methods We retrospectively reviewed data from a total of 675 patients with pulmonary hypertension (identified by ICD codes or search of text) from 2017 and 2022 from a database obtained from electronic medical records at our institution. Patients with group 2 pulmonary hypertension were excluded. Only 29 cases were confirmed by histology or genetic testing. Results Out of the 29 patients confirmed with PVOD, 28 (96.5%) had a characteristic histology (lung biopsy (55.1%), explanted lung for transplant (27.5%) and autopsy (13.7%)) and 1 (3.4%) had a positive genetic test for EIF2AK4 biallelic mutation. The age at diagnosis was 53±16 years, 14 (48.2%) were men, 2 (6.8%) had systemic scleroderma, 2 (6.8%) had psoriasis, 2 (6.8%) were exposed to cytotoxic agents, 16 (55.1%) were smokers and 2 (6.8%) had a family history of pulmonary hypertension. All patients had computed tomography of the chest but only 12 (41.3%) had all 3 typical features found in PVOD (ground glass opacities, interlobular septal thickening, and lymphadenopathy). The most common feature was interlobular septal thickening in 26 (89.6%), followed by ground glass opacities present in 25 (86.2%) and lymphadenopathy in 12 (41.3%) of the patients. At diagnosis, mean pulmonary artery pressure was 45±15 mmHg and pulmonary vascular resistance was 9±6 WU. The median DLCO was 41 (34-58) %. On echocardiogram, 14 (48.2%) had severely enlarged right ventricle (RV), RV function was ≥moderately reduced in 17 (58.6%), RV systolic pressure was 63±20 mmHg and 6 (20.6%) had pericardial effusion. Out of 21 (72.4%) patients who received pulmonary vasodilators, 4 (13.7%) received single agent. 10 (34.4%) received 2 agents, 6 (20.6%) 3 agents, and 1 (3.4%) received 4 agents. 35.7% of these treated patients reported an improvement or initial worsening of symptoms with subsequent improvement afterwards. 18 (62%) patients with PVOD died, 12 (41.3%) had a lung transplant and 6 (20.6%) were still alive without the transplant until the day data was collected. Mean duration from diagnosis to death and lung transplantation was 446 ± 405 days and 274±479 days respectively. Conclusion PVOD is a rare and lethal cause of pulmonary hypertension. When suspected, a trial of medical therapy should be initiated carefully. The evaluation for lung transplant should be considered early given its high mortality.

Abstract 15848: Hardly a Windfall: Prescribing Practices in Pediatric Heart Failure Before and After Food and Drug Administration Approval

Background: Prior to the 2019 Food and Drug Administration (FDA) approval of ivabradine and sacubitril/valsartan, there were no medications approved for the treatment of pediatric heart failure (PHF). There are minimal data regarding the use of on- or off-label medications in PHF. Aims: We aim to describe medication use in PHF, factors associated with PHF medication use, and test the hypothesis that FDA approval is associated with changes in prescriber practice. Methods: Utilizing the Truven Health Marketscan Claims Encounter Database (2013-2021), we determined the prevalence of medication [diuretics, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), beta-blockers, pulmonary vasodilators, ivabradine, and sacubitril/valsartan] use in children ≤19yo with PHF and cardiomyopathy (CM), with a focus on use before and after FDA approval. Results: Of 2,218 children with PHF and CM, 76% were prescribed ≥ 1 HF medication. Diuretics (57%) and ACEi/ARBs (57%) were used most frequently ( Fig 1A) . Only 0.4% of patients were prescribed ivabradine and 3% sacubitril/valsartan. Patients enrolled in Medicaid were more likely to be prescribed HF medications than those with commercial insurance (OR 1.83, 95% CI 1.50-2.22). After FDA approval in 2019, sacubitril/valsartan prescription rose significantly from 0.4% in 2013-2018, to 3.9% in 2020-2021 (p &lt;0.001), and ivabradine use increased from 0.1% in 2018 to 0.5% (p = 0.043) in 2020-2021, but both remained rare (Fig 1B) . Conclusion: Diuretics and ACEi/ARBs are the most commonly used PHF medications, despite not being approved for this indication. The two FDA approved medications are used in ≤5% of patients. While FDA approval is important, it did not substantially influence physician prescribing behavior for PHF. Further study is needed to understand the value of FDA approval and the potential socioeconomic implications of the association between insurance type and medication use.

Abstract 13407: Long-Term Outcomes of Chronic Thromboembolic Pulmonary Hypertension Treated With Pulmonary Endarterectomy and Balloon Pulmonary Angioplasty: Results From the Japanese Prospective CTEPH Registry (CTEPH AC Registry)

Introduction: In Japan, balloon pulmonary angioplasty (BPA) is more commonly adopted in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared to European countries or US due to their expertise. However, there are no reports from regions where BPA is extensively practiced. Aims: This study aims to explore the treatment outcomes in Japan. Methods: The study involved a nationwide, prospective, observational registry that included all patients diagnosed with CTEPH from August 2018 to February 2023 in Japan. Patients were categorized as naïve or prevalent cases based on their previous reperfusion therapy (pulmonary endarterectomy and/or BPA) at the time of enrollment. Each case was further classified as operable or BPA group. The primary outcome measure was morbidity and mortality (MM) events since enrollment, which comprised all-cause death, CTEPH-related hospitalization, rescue reperfusion therapy, initiation of parenteral pulmonary vasodilators, and worsening of CTEPH characterized by a decrease in 6-minute walk distance greater than 15% and deterioration of the WHO functional class. Results: A total of 1194 patients, including naïve cases (operable: n = 54, BPA: n = 293) and prevalent cases (operable: n=125, BPA: n = 532), were identified. Among the naïve cases, there were no significant differences in age or disease severity between the operable and BPA groups. Among the prevalent cases, the BPA group was older (63 ± 13 vs. 58 ± 14 years old, p &lt; 0.0001) and had higher pulmonary vascular resistance (364 ± 279 vs. 293 ± 206 dyne*sec/cm5, p = 0.001) compared to the operable group. The results of primary outcome measures were comparable between both the groups (Figure). Conclusions: BPA as well as pulmonary endarterectomy is considered as safety and effective therapeutic option in CTEPH patients.

Abstract 17909: Pulmonary Hypertension is Associated With Morbidity, Mortality and Prolonged Hospitalization in Premature Infants With Bronchopulmonary Dysplasia

Introduction: Pulmonary hypertension (PH) is a common comorbidity in premature infants with bronchopulmonary dysplasia (BPD). We sought to assess factors associated with PH and determine its association with morbidity and mortality in a large contemporary BPD cohort. Hypothesis: PH is independently associated with increased mortality in premature neonates with BPD. Methods: This single center retrospective cohort study identified all infants with BPD born 2010-2021. BPD severity was defined by previously established literature guidelines. PH was defined at ≥ 36 weeks post-menstrual age by echocardiography (RV pressure &gt; 40 mmHg, eccentricity index &gt; 1.1), cardiac catheterization (mean pulmonary artery pressure &gt; 20 mmHg, pulmonary capillary wedge pressure ≤ 15 mmHg and pulmonary vascular resistance ≥ 3 iWU), or treatment with enteral pulmonary vasodilators. Outcomes of death, tracheostomy, hospital duration and comorbidities were compared against a positive PH diagnosis. Univariate and multivariable models were used to assess associations of PH and covariates with clinical outcomes. Results: The sample cohort consisted of 726 neonates (median Gestational Age: 26 weeks [IQR 25.0, 28.0], 48.4% female) with PH diagnoses in 190 (26%). 92 PH patients received enteral PH therapy, with 84 (44%) on mono and 8 (5%) on dual therapy, which was discontinued by a median age 9.5 months (IQR 6.6 - 15.3). Lower gestational age (p=0.016), higher BPD severity (p&lt;0.0001), and non-white race (p=0.002) were associated with PH in multivariable models. PH was associated with higher mortality rate (18% vs 5%, p &lt;0.0001), higher tracheostomy rate (50% vs 16%, p&lt;0.0001), and longer hospital duration (median 116 (IQR 61-182) vs 58 (IQR 11-132) days, p = 0.001) in univariate and multivariable models. PH was associated with pulmonary vein stenosis (9% vs 1%, p=0.001), but not NEC, ROP or IVH after adjusting for covariates. Conclusions: This study demonstrates that BPD-PH carries an independent risk for mortality and morbidity including BPD severity, tracheostomy, pulmonary vein stenosis, and longer hospitalization. Enteral pulmonary vasodilators were used in almost half of all PH patients, with resolution of PH within 1 year of diagnosis in the majority of infants.

Treatment of cardiogenic shock due to right ventricular involvement

The right ventricle is susceptible to changes in preload, afterload, and contractility. The answer is its dilation with dysfunction/acute failure; filling is limited to the left ventricle and cardiac output. Systemic venous congestion is retrograde to the right heart, it is involved in the genesis of cardiogenic shock due to right ventricle involvement. This form of shock is less well known than that which occurs due to left ventricular failure, therefore, treatment may differ. Once the primary treatment has been carried out, since no response is obtained, supportive treatment aimed at ventricular pathophysiology will be the next option. It is suggested to evaluate the preload for the reasoned indication of liquids, diuretics or even ultrafiltration. Restore or maintain heart rate and sinus rhythm, treat symptomatic bradycardia, arrhythmias that make patients unstable, use of temporary pacing or cardioversion procedures. Improving contractility and vasomotility, using vasopressors and inotropes, alone or in combination, the objective will be to improve right coronary perfusion pressure. Balance the effect of drugs and maneuvers on preload and/or afterload, such as mechanical ventilation, atrial septostomy and pulmonary vasodilators. And the increasing utility of mechanical support of the circulation that has become a useful tool to preserve/restore right heart function.

Light at the ENDothelium-role of Sox17 and Runx1 in endothelial dysfunction and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease that is characterized by an obliterative vasculopathy of the distal pulmonary circulation. Despite significant progress in our understanding of the pathophysiology, currently approved medical therapies for PAH act primarily as pulmonary vasodilators and fail to address the underlying processes that lead to the development and progression of the disease. Endothelial dysregulation in response to stress, injury or physiologic stimuli followed by perivascular infiltration of immune cells plays a prominent role in the pulmonary vascular remodeling of PAH. Over the last few decades, our understanding of endothelial cell dysregulation has evolved and brought to light a number of transcription factors that play important roles in vascular homeostasis and angiogenesis. In this review, we examine two such factors, SOX17 and one of its downstream targets, RUNX1 and the emerging data that implicate their roles in the pathogenesis of PAH. We review their discovery and discuss their function in angiogenesis and lung vascular development including their roles in endothelial to hematopoietic transition (EHT) and their ability to drive progenitor stem cells toward an endothelial or myeloid fate. We also summarize the data from studies that link mutations in Sox17 with an increased risk of developing PAH and studies that implicate Sox17 and Runx1 in the pathogenesis of PAH. Finally, we review the results of recent studies from our lab demonstrating the efficacy of preventing and reversing pulmonary hypertension in animal models of PAH by deleting RUNX1 expression in endothelial or myeloid cells or by the use of RUNX1 inhibitors. By investigating PAH through the lens of SOX17 and RUNX1 we hope to shed light on the role of these transcription factors in vascular homeostasis and endothelial dysregulation, their contribution to pulmonary vascular remodeling in PAH, and their potential as novel therapeutic targets for treating this devastating disease.

Pulmonary vasodilators and exercise in Fontan circulation: a systematic review and meta-analysis

ObjectiveIn Fontan circulation, pulmonary arterial hypertension (PAH)-targeted therapies could improve the patients’ exercise capacity. This study aimed to investigate the effects of PAH agents on different exercise parameters in stable...