Increase In Pulmonary Vascular Resistance Research Articles

Consensus on the procedure of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as group IV pulmonary hypertension, characterized by thrombotic occlusion of the pulmonary arteries leading to vascular stenosis or obstruction, progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, and eventual right heart failure. Unlike other types of pulmonary hypertension, the prognosis of CTEPH can be significantly improved by surgery, vascular intervention, and/or targeted drug therapy. Pulmonary endarterectomy (PEA) is the preferred treatment of choice for CTEPH. However, PEA is an invasive procedure with high operative risks, and is currently only performed in a few centers in China. Balloon pulmonary angioplasty (BPA) is an emerging interventional technique for CTEPH, serving as an alternative for patients who are ineligible for PEA or with residual pulmonary hypertension after PEA. BPA is gaining traction in China, but its widespread adoption is limited due to its complexity, operator skills, and equipment requirements, a lack of standard operating procedures and technical guidance, which limit the further improvement and development of BPA in China. To address this, a multidisciplinary panel of experts was convened to develop the Consensus on the Procedure of Balloon Pulmonary Angioplasty for the Chronic Thromboembolic Pulmonary Hypertension, which fomulates guidelines on BPA procedural qualification, perioperative management, procedural planning, technical approach, and complication prevention, with the aim of providing recommendations and clinical guidance for BPA treatment in CTEPH and standardizing its clinical application in this setting. Summary of recommendations: Recommendation 1: It is recommended that physicians who specialize in pulmonary vascular diseases take the lead in formulating the diagnostic and treatment plans for CTEPH, using a multidisciplinary approach.Recommendation 2: Training in BPA technique is critical; novice operators should undergo standardized operative training with at least 50 procedures under the guidance of experienced physicians before embarking on independent BPA procedures.Recommendation 3: BPA requires catheterization labs, angiography systems, standard vascular interventional devices and consumables, drugs, and emergency equipment.Recommendation 4: Patient selection for BPA should consider cardiac and pulmonary function, coagulation status, and comorbid conditions to determine indications and contraindications, thereby optimizing the timing of the procedure and improving safety.Recommendation 5: In experienced centers, patients deemed likely to benefit from early BPA, based on clinical and imaging features of CTEPH and without elevated D-dimer levels, could bypass standard 3-month anticoagulation therapy.Recommendation 6: BPA is a complex interventional treatment that requires thorough pre-operative assessment and preparation.Recommendation 7: The use of perioperative anticoagulants in BPA requires a comprehensive risk assessment of intraoperative bleeding by the operator for individualized decision making.Recommendation 8: A variety of venous access routes are available for BPA; unless contraindicated, the right femoral vein is usually preferred because of its procedural convenience and reduced radiation exposure.Recommendation 9: For the different types of vascular lesion in CTEPH, treatment of ring-like stenoses, web-like lesions, and subtotal occlusions should be prioritized before addressing complete occlusions and tortuous lesions, in order to reduce complications and improve procedural safety.Recommendation 10: A targeted, incremental balloon dilatation strategy based on vascular lesions is recommended for BPA.Recommendation 11: Intravascular pulmonary artery imaging technologies, such as OCT and IVUS can assist in accurate vessel sizing and confirmation of wire placement in the true vascular lumen. Pressure wires can be used to objectively assess the efficacy of dilatation during BPA.Recommendation 12: Endpoints for BPA treatment should be individually assessed, taking into account improvements in clinical symptoms, hemodynamics, exercise tolerance, and quality of life.Recommendation 13: Post-BPA routine monitoring of vital signs is essential; anticoagulation therapy should be initiated promptly post-procedure in the absence of complications. In cases of intraoperative hemoptysis, postoperative anticoagulation regimen adjustments should be adjusted according to the bleeding severity.Recommendation 14: If reperfusion pulmonary edema occurs during or after BPA, ensure adequate oxygenation, diuresis, and consider non-invasive positive-pressure ventilation if necessary, while severe cases may require early mechanical ventilation assistance or ECMO.Recommendation 15: In cases of intraoperative hemoptysis, temporary balloon occlusion to stop bleeding is recommended, along with protamine to neutralize heparin. Persistent bleeding may warrant the use of gelatin sponges, coil embolization, or covered stent implantation.Recommendation 16: For contrast imaging during BPA, non-ionic, low or iso-osmolar contrast agents are recommended, with hydration status determined by the patient's clinical condition, cardiac and renal function, and intraoperative contrast volume used.

Role of endothelial cell-selective adhesion molecule in the regulation of pulmonary vascular resistance

Endothelial cell-selective adhesion molecule (ESAM) is a member of the endothelial cell junction adhesion molecules family, which plays an important role in the maintenance of endothelial barrier function in the pulmonary circulation. The role of ESAM in affecting pulmonary vascular resistance remains unknown. To examine the role of ESAM in pulmonary vascular resistance, whole lungs were isolated from 16-18 weeks old ESAM knock out (KO) mice and wild type (WT) littermates, ventilated and perfused. We found that pulmonary vascular resistance is significantly increased in the lung of ESAM KO mice compared to WT mice. Bradykinin-induced, endothelium-dependent reduction in the pulmonary vascular resistance was impaired in ESAM KO mice, whereas the direct NO donor, sodium nitroprusside-induced endothelium independent responses remained similar in WT and ESAM KO mice. U46619 mediated increases in pulmonary vascular resistance was significantly higher in ESAM KO mice. Inhibition of the NO synthesis with the L-NAME (0.2 mM for 10 minutes) augmented the U46619-mediated increase in pulmonary vascular resistance in WT mice, but it did not affect the U46619 response in the ESAM KO mice. The mRNA expression of pro-inflammatory cytokines, including interleukin-6 and tumor necrosis factor, was increased in the lungs of ESAM KO mice, whereas expression of collagen isoforms (type I and type III) and fibronectin were similar in WT and ESAM KO mice. Collectively, we propose that ESAM plays an important role in the maintenance of pulmonary vascular resistance, likely via preserving endothelial nitric oxide production in pulmonary arteries. AHA predoctoral award ID 917057. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lung capillary endothelium to arterial endothelium transition in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of loss of distal capillary endothelial cells (ECs) and obliterative vascular lesion formation remain unclear. Our recent single-cell RNA sequencing, spatial transcriptomics analysis, RNASCOPE, and immunostaining analysis showed that arterial ECs accumulation and loss of capillary ECs were evident in human PAH patients and pulmonary hypertension (PH) rodents. Pseudotime trajectory analysis of the single-cell RNA sequencing data suggest that lung capillary ECs transit to arterial ECs during the development of PH. Our study also identified CXCL12 as the marker for arterial ECs in PH. General capillary EC lineage tracing approach using Plvap-DreERT2;Tdtomato mice demonstrated that general capillary ECs gave rise to arterial ECs during PH development. Genetic deletion of HIF-2a or pharmacological inhibition of Notch4 normalized the arterial programming in PH. In conclusion, our study demonstrates that general capillary endothelium transits to arterial endothelium through the HIF-2a-Notch4 pathway during the development of PAH. Thus, targeting arterial EC transition might be a novel approach for treating PAH patients. This work was supported in part by NIH grant R00HL138278, R01HL158596, R01HL62794, R01HL169509, R01HL170096, AHA Career Development Award 20CDA35310084, The Cardiovascular Research and Education Foundation, Arizona Biomedical Research Centre funding (RFGA2022-01-06), and University of Arizona institution funding to Z.D. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Management of Pregnant Women with Atrial Septal Defect and Pulmonary Hypertension: A Case Report

Background: Pulmonary Hypertension (PH) is a condition where there is an increase in Pulmonary Vascular Resistance (PVR) and an increase in the mean Pulmonary Arterial Pressure (mPAP) to more than 20 mmHg. PH can occur in someone with Congenital Heart Disease (CHD). PH conditions can aggravate pregnancy in women with CHD. Women with PH are recommended not to undergo pregnancy. However, it is possible for women with CHD with PH conditions to undergo pregnancy. In these conditions, optimizing PH therapy is essential so that pregnant women with PH do not experience a worsening of the condition and can carry out their pregnancy well until delivery. Case presentation: A 38-year-old female patient with a history of Atrial Septal Defect-Pulmonary Hypertension came for common control to the cardiac clinic with the pregnancy condition of her 4th child, who was just discovered when she was six months pregnant. Since giving birth to her third child, the patient began complaining of being quickly tired when doing activities accompanied by swollen legs that disappeared with rest. The patient went to a cardiologist for an echocardiography examination and was diagnosed with Atrial Septal Defect (ASD)-Pulmonary Hypertension (PH). Since then, the patient has been routinely treated by a cardiologist with Pulmonary Hypertension drugs, including Phospodiesterase5 (PDE5) inhibitors (Sildenafil) and Prostacyclin Analogue (Dorner). The patient had done Transesophageal Echocardiography (TEE) with the results of ASD secundum suitable for closure by the device. Patients with Right Heart Catheterization (RHC) results, ASD secundum with PH High Flow High Resistance reactive to Vasoreactivity Test. Since the patient was found to be pregnant, the patient continued to use Sildenafil and discontinued the use of Dorner. The patient then continued treatment in a multidisciplinary team. Conclusion: Management of pregnant women with CHD and PH is essential because the condition of PH itself further aggravates the condition of pregnancy. Medical management for PH in pregnant women follows the guidelines for the safety of drugs in pregnancy so that the choice of therapy is crucially related to the goal of treatment to control the PH condition in the patient but still pay attention to safety in pregnancy conditions. Keyword: Congenital Heart Disease, Phosphodiesterase-5 (PDE-5)- Inhibitor, Prostacyclin Analogue, Pulmonary Hypertension.

Clinical Features and Multimodality Diagnostic Tools of Pulmonary Hypertension

Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure (mPAP) above normal (> 20 mmHg) and an increase in pulmonary vascular resistance (pulmonary vascular resistance / PVR) above normal in resting settings. The pathophysiology of PH involves remodeling of the pulmonary vessels, from the main pulmonary arteries, lobar arteries, segmental arteries, distal arteries, pulmonary arterioles, capillaries to the postcapillary pulmonary veins. In general, the epidemiological figures for PH are not known with certainty. The United Kingdom reported a PH prevalence of 97 cases per one million people, with a female-to-male ratio of 1.8. The diagnostic strategy for PH focuses primarily on two issues. The primary objective is to improve the early detection of PH and expedite the transfer of patients at high risk for PAH, CTEPH, or other forms of severe PH to a PH center. The second objective is to identify the underlying disease, including left heart disease (Group 2 PH) and lung disease (Group 3 PH), as well as comorbidities, in order to assure proper classification, risk assessment, and therapy. The gold standard for detecting and categorizing pulmonary hypertension is right heart catheterization (RHC). Clinical scoring in the form of shortness of breath without any obvious cause accompanied by physical examination, ECG and Thorax X-ray images which depict an enlarged right heart have good specificity and sensitivity for the diagnosis of pulmonary hypertension in patients with congenital heart disease. A high right ventricular pressure, mean PAP, and BNP values during observation, as well as heart size on chest X-ray can be predictors of a poorer prognosis in this population. Keyword: Clinical Risk Scoring, Pulmonary Hypertension, Right Heart Catheterization.

Echocardiographic features of right ventricle in septic patients with elevated central venous pressure

BackgroundElevated central venous pressure (CVP) is deemed as a sign of right ventricular (RV) dysfunction. We aimed to characterize the echocardiographic features of RV in septic patients with elevated CVP, and quantify associations between RV function parameters and 30-day mortality.MethodsWe retrospectively reviewed a cohort of septic patients with CVP ≥ 8 mmHg in a tertiary hospital intensive care unit. General characteristics and echocardiographic parameters including tricuspid annular plane systolic excursion (TAPSE), pulmonary vascular resistance (PVR) as well as prognostic data were collected. Associations between RV function parameters and 30-day mortality were assessed using Cox regression models.ResultsEchocardiography was performed in 244 septic patients with CVP ≥ 8 mmHg. Echocardiographic findings revealed that various types of abnormal RV function can occur individually or collectively. Prevalence of RV systolic dysfunction was 46%, prevalence of RV enlargement was 34%, and prevalence of PVR increase was 14%. In addition, we collected haemodynamic consequences and found that prevalence of systemic venous congestion was 16%, prevalence of RV-pulmonary artery decoupling was 34%, and prevalence of low cardiac index (CI) was 23%. The 30-day mortality of the enrolled population was 24.2%. In a Cox regression analysis, TAPSE (HR:0.542, 95% CI:0.302–0.972, p = 0.040) and PVR (HR:1.384, 95% CI:1.007–1.903, p = 0.045) were independently associated with 30-day mortality.ConclusionsEchocardiographic findings demonstrated a high prevalence of RV-related abnormalities (RV enlargement, RV systolic dysfunction and PVR increase) in septic patients with elevated CVP. Among those echocardiographic parameters, TAPSE and PVR were independently associated with 30-day mortality in these patients.

Basic aspects of pathophysiology, diagnosis and treatment of patients with pulmonary arterial hypertension associated with human immunodeficiency virus infection: what has been achieved and what remains to be achieved?

Human immunodeficiency virus (HIV) infection is characterized by high morbidity and is a significant threat to human health, increasing global mortality. The number of people living with HIV infection is estimated by the United Nations Joint Program on Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (UNAIDS) to be 39 million (33.1-45.7 million) in 2022. With the introduction of highly effective antiretroviral therapy (cART) into clinical practice and the resulting increase in life expectancy in this cohort of patients, HIV-associated complications have come to the forefront, among which the most severe is pulmonary arterial hypertension (PAH), characterized by a progressive increase in pulmonary vascular resistance and pulmonary artery pressure, leading to the development of right ventricular failure. Subsequently, it became evident that this pathology can occur at all stages of HIV infection and, apparently, has no clear relationship with the degree of immunodeficiency, and is an independent predictor of mortality in patients with LAH-HIV, and therefore requires separate, close attention. This article provides an overview covering the basic pathophysiology, clinical manifestations, diagnosis and treatment of HIV-associated LAH (LAHHIV), emphasizing the challenges encountered at each stage. The review also considers current aspects aimed at studying LAH in patients with HIV, including new experimental drug therapies that take into account the interaction of different regimens with LAH-specific drugs.

The place of tadalafil in the treatment of PAH in the light of new clinical guidelines of the Eurasian Association of Cardiologists

Pulmonaryarterialhypertension(PAH)isalife-threateningcardiovascular disease that is characterized by a marked increase in pulmonary vascular resistance and pulmonary artery pressure due to obstructive remodeling of the pulmonary vascular bed with the development of right ventricular heart failure as a cause of premature mortality. Impaired synthesis and reduced bioavailability of nitric oxide is one of the key pathophysiological mechanisms of the development and progression of the disease. The review paper presents key data from the evidence base on the clinical use of tadalafil, a phosphodiesterase type 5 inhibitor (PDE5), which in August 2023 approved by the Pharmaceutical Committee of the Russian Ministry of Health for the indication – treatment of patients with PAH. Tadacardil from Canonpharma Production is the first and only drug in Russian practice today with the active substance tadalafil with the registered indication “PAH”, approved in the Eurasian Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 and available on the territory of the Russian Federation and the EAEU. Tadacardil is indicated for use in adult patients with PAH functional class II and III according to the WHO classification to increase exercise tolerance. The efficacy of tadalafil has been shown in idiopathic PAH and PAH associated with connective tissue diseases. The recommended dose is 40 mg (2 tablets of 20 mg) once a day. The paper describes the mechanism of action and pharmacological effects of PDE5 inhibitors, features of the pharmacokinetics of tadalafil in comparison with other drugs of the class. The advantages of Tadacardil from Canonpharma Production are the proven effecacy of use in patients with PAH, ease of use due to a single dose of 2 tablets of 20 mg once a day in a standard dose; good tolerability and favorable safety profile; proven bioequivalence to the reference drug. In light of the new Eurasian recommendations for the diagnosis and treatment of PH, tadalafil has a wide field for clinical use, which will improve the treatment options for patients with PAH both in mono- and combination therapy.

ANMCO/SIC Consensus statement on pulmonary arterial hypertension

Pulmonary hypertension (PH) is a frequent pathological condition worldwide, mainly secondary to cardiovascular and respiratory diseases, with a poor prognosis. Pulmonary arterial hypertension (PAH) is a rare form that affects the arterial pulmonary vasculature. PH and PAH are characterized by non-specific symptoms and a progressive increase of pulmonary vascular resistance that results in progressive, sometimes irreversible, right ventricular dysfunction. In recent years, a growing medical and social commitment on this disease allowed more accurate diagnosis in shorter times. However, the gap between guidelines and clinical practice remains a challenge for all medical doctors involved in the disease management. Considering the needs to share and describe diagnostic and therapeutic pathways, to measure the results obtained and to address the economical and organizational problems of this disease, all involved figures should collaborate to improve its prognostic impact and health expenses. In this consensus document, the PH experts of the Italian Association of Hospital Cardiologists (ANMCO) together with those of the Italian Society of Cardiology (SIC), address 1) definition, classification and unmet needs of PH and PAH; 2) classification and characteristics of centers involved in the diagnosis and treatment of the disease; 3) proposal of organization of a diagnostic-therapeutic pathway, based on robust and recent scientific evidence.

Use of sildenafil for the treatment of neonatal persistent pulmonary hypertension

Introduction: Persistent pulmonary hypertension of the newborn is a neonatal respiratory and vascular pathology with a high mortality rate. Furthermore, its prevalence is 1 to 2 per 1000 live births, accounting for 8%-10% of neonatal deaths. The therapeutic approach involves supporting pulmonary recruitment and pharmacological vasodilation, most notably sildenafil. Methodology: The study is a narrative review of the literature that was carried out from the PUBMED database using the keywords “Persistent Pulmonary Hypertension of the Newborn” and “Sildenafil”, with the time filter in the last 30 years (1994- 2023). Discussion: Physiologically, during fetal life, the lungs remain filled with fluids, but immediately after birth, pulmonary vascular resistance decreases drastically, allowing alveolar oxygen tension and ventilation to be possible. However, in the pathogenesis of neonatal persistent pulmonary hypertension, there is an increase in pulmonary vascular resistance and remodeling of the vascular structure after birth, which potentiate this exaggerated vasoconstriction. Therefore, the standard exam for investigating the pathology is echocardiography. Sildenafil is a drug used to treat neonatal persistent pulmonary hypertension, as it enhances better blood flow and better delivery of oxygen to tissues, through its physiopharmacology aimed at vasodilation secondary to inhibition of phosphodiesterase-5. Conclusion: Neonatal persistent pulmonary hypertension is still one of the main neonatal pathologies with high morbidity and mortality in the neonatal population, due to the complexity of presentations and the variation in therapeutic responses to pharmacotherapy.

Inhaled Pulmonary Vasodilators for the Treatment of Right Ventricular Failure in Cardio-Thoracic Surgery: Is One Better than the Others?

Right ventricular failure (RFV) is a potential complication following cardio-thoracic surgery, with an incidence ranging from 0.1% to 30%. The increase in pulmonary vascular resistance (PVR) is one of the main triggers of perioperative RVF. Inhaled pulmonary vasodilators (IPVs) can reduce PVR and improve right ventricular function with minimal systemic effects. This narrative review aims to assess the efficacy of inhaled nitric oxide and inhaled prostacyclins for the treatment of perioperative RVF. The literature, although statistically limited, supports the clinical similarity between them. However, it failed to demonstrate a clear benefit from the pre-emptive use of inhaled nitric oxide in patients undergoing left ventricular assist device implantation or early administration during heart-lung transplants. Additional concerns are related to cost safety and IPV use in pathologies associated with pulmonary venous congestion. The largest ongoing randomized controlled trial on adults (INSPIRE-FLO) is addressing whether inhaled Epoprostenol and inhaled nitric oxide are similar in preventing RVF after heart transplants and left ventricular assist device placement, and whether they are similar in preventing primary graft dysfunction after lung transplants. The preliminary analysis supports their equivalence. Several key points may be achieved by the present narrative review. When RVF occurs in the setting of elevated PVR, IPV should be the preferred initial treatment and they should be preventively used in patients at high risk of postoperative RVF. If severe refractory postoperative RVF occurs, IPVs should be combined with complementary pharmacology (inotropes and inodilators). If unsuccessful, right ventricular mechanical support should be established.

Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

An increasing number of hypertensive persons travel to high altitude while using antihypertensive medications such as betablockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, β-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). In seven healthy male lowlanders, pulmonary artery pressure was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a three-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release maneuvers were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. At SL, PROP increased Ppa and PVR from (mean±SEM) 14±1 to 17±1mmHg and from 69±8 to 108±11dyn*s*cm-5 (21 and 57% increase, p=0.01 and p<0.0001). The PVR response to PROP was amplified at HA to 76% (p<0.0001, p[interaction]=0.05). At both altitudes, PROP+GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9±0.5 to 1.7±0.2 at HA (p<0.0001) and to 1.2±0.2 with PROP, and further decreased to 0.9±0.2%*mmHg-1 with PROP+GLYC (p=0.01). Our data show that β-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that β-adrenergic blockade exaggerates HPV for the management of mountaineers using β-blockers for prevention or treatment of cardiovascular conditions.

Possible Hereditary Pulmonary Arterial Hypertension: from Clinical to Genetic Investigation in Precision Medicine Era

Background: Pulmonary Hypertension is a life-threatening disease characterized by a progressive increase of pulmonary vascular resistance that often leads to right ventricular (RV) failure and death. Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). At least 6% of all PAH cases are familial in origin known as Familial Pulmonary Arterial Hypertension (FPAH) and display autosomal dominant inheritance with incomplete penetrance. While early diagnosis is associated with improved long-term survival, however at present, most patients are diagnosed at a very advanced stage of HPAH indicating that the early screening for HPAH is crucial. In this regard, genetic testing is an effective strategy for the early diagnosis and management of PAH, specifically Hereditary Pulmonary Arterial Hypertension (HPAH). We present two cases of Familial Pulmonary Arterial Hypertension and in-depth analysis of diagnostic cascade to allow an earlier and more reliable diagnosis of possible Hereditary Pulmonary Arterial Hypertension (HPAH). Case Illustration: Familial cases, a 44-years old man and his son a 17-years old boy, came with chief complaint of dyspnea. His daughter or his sister passed away when 4 years old due to PH. Both patients had been subsequently diagnosed with PAH with possible HPAH after the exclusion of primary and secondary heart anomalies using electrocardiography, echocardiography, and cardiac marker test. Both patients subsequently were performed right heart catheterization (RHC). Conclusions: We describe familial cases of pulmonary hypertension with clinically presenting right-sided heart failure. Diagnostic investigation was performed according to recent guideline to rule out and rule in all the possible cause of pulmonary hypertension. However, the final assessment showed unknown cause of pre-capillary pulmonary hypertension. Therefore, genetic investigation should be performed in precision medicine era due to high possibility of hereditary pulmonary arterial hypertension.

Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension.

Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods. Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance. Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.

Effect of a short course of parenteral treprostinil therapy on right heart structure and function in pulmonary arterial hypertension

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, leading to increased afterload and right-sided heart failure. It is important to routinely assess disease progression and treatment response, with echocardiography an increasingly recognized important component of risk assessment. Parenteral prostacyclin therapy has been shown to be associated with improvements in right-sided cardiac structure and function, which are prognostic in PAH. Purpose To describe changes in right-sided cardiac structural and functional parameters after a short course of parenteral treprostinil. Methods The EXPEDITE trial (NCT03497689) was a 16-week open-label study of WHO Functional Class (FC) II or III patients with PAH designed to assess short-term (expedited) induction therapy with parenteral treprostinil over 2-8 weeks, to facilitate transition to comparable doses of oral treprostinil. The subset of patients in the per-protocol population that had clinical and/or echocardiographic data available at both baseline (prior to initiation of parenteral treprostinil) and end of induction (2-8 weeks) were included for analysis. Changes in each parameter were analyzed using the non-parametric Wilcoxon signed-rank test. Results In the per-protocol population of EXPEDITE (n=29), the median age was 56 years, 62% were female, and 79% were white. At baseline, 52% were classified as WHO FC II and 48% WHO FC III. Patients were on either no (n=6, 21%), 1 (n=11, 38%), or 2 (n=12, 41%) background PAH therapies. The end of the parenteral treprostinil induction period occurred at Week 2 (n=1), Week 4 (n=5), or Week 8 (n=23); the median (interquartile range) parenteral treprostinil dose achieved was 23.8 (20, 39.3) ng/kg/min. Median changes from baseline to the end of the parenteral treprostinil induction period for this analysis are shown in Table 1. There were directional changes for most measures of right-sided cardiac structure and function that reflected overall improvement; two key markers of cardiac function, cardiac output and NT-proBNP significantly improved. Conclusions In this trial of expedited parenteral treprostinil induction, we saw favorable directional trends in changes in right heart structure and function that were achieved in 8 weeks or less, including some statistically-significant parameters known to have prognostic value in PAH. The relatively rapid improvements we observed in this small cohort may signal important changes in risk status, and support treatment guidelines emphasizing importance of early improvement in the first 3-6 months following treatment. Furthermore, changes in cardiac structure and function often occur before other clinically-evident indicators of disease progression, and early response to treatment has been shown to impact long-term outcomes in patients with PAH. Larger studies with short-term serial right heart imaging assessment to confirm findings are warranted.Table 1

Abstract 17370: Activation of Endothelial GCN2 Kinase Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and pulmonary vascular remodeling that result in right heart failure. Published studies show that recessive mutations in the EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) resulting in reduction of GCN2 are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients and EIF2AK4 mutation was also found in PAH patients although very rare. Objective: To determine the role of endothelial GCN2 kinase in the pathogenesis of PAH. Results: Employing Eif2ak4 -/- mice, we found that loss of GCN2 induced neither spontaneous PVOD nor pulmonary hypertension (PH). In response to chronic hypoxia, loss of GCN2 inhibited hypoxia-induced PH and pulmonary vascular remodeling. RNA-sequencing analysis of mouse lung samples indicated Endothelin-1 as the downstream target of GCN2 in regulating pulmonary vascular remodeling and PH. In cultured human lung microvascular endothelial cells, GCN2 was phosphorylated and activated in response to hypoxia, which mediated hypoxia-induced Endothelin-1 expression through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Endothelial cell-targeted nanoparticle delivery of plasmid DNA expressing Endothelin-1 selectively in endothelial cells in Eif2ak4 -/- mice markedly reversed the phenotype in response to hypoxia. Furthermore, nanoparticle delivery of the CRIPSR/Cas9 system-mediated knockout of Eif2ak4 in adult C57BL/6 mice also attenuated hypoxia-induced PH. Additionally, monocrotaline-induced vascular remodeling and PH in rats were inhibited by GCN2 inhibitor A-92 treatment. In lung samples of idiopathic PAH patients, we observed endothelial GCN2 hyperphosphorylation of pulmonary vascular lesions, without marked differences in GCN2 mRNA and protein levels compared to normal donor lungs. Conclusion: These studies demonstrate that endothelial GCN2 activation mediates pulmonary vascular remodeling and PAH development through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients without GCN2 loss of function mutations.

Lunch Symposium

Pulmonary arterial hypertension (PAH), defined as the presence of artery pulmonary artery pressure &gt; 20 mmHg, pulmonary artery wedge pressure [Formula: see text]15 mmHg, and pulmonary vascular resistance (PVR) &gt; 2Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjögren’s syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of CTD-PAH proposed worldwide. This symposium would highlight the most updated 2022 ESC/ERS guideline in the disease management of PAH, including latest haemodynmaic definitions of PAH, new risk stratification approach at reassessment and updated PAH treatment recommendations. In addition to the guideline update, important discussion would cover the important diagnostic, and screening algorithm for early detection of CTD-PAH and clinical experiences in managing difficult CTD-PAH cases.

Bibliometric and visual analysis of hypoxic pulmonary hypertension from 2013 to 2022

Hypoxic pulmonary hypertension (HPH) is caused by chronic persistent hypoxia, which leads to the continuous increase of pulmonary artery pressure and pulmonary vascular resistance. In recent years, there has been a substantial increase in research on HPH. To study the trends of HPH research over the last decade, we used WOSCC to search for relevant research on this topic, and dealt with the relevant information using VOSviewer, CiteSpace, and R-tool. Our results show that the number of publications on HPH has generally increased in the last decade, albeit not significantly, while the average number of citations has been declining year by year. Researchers from the USA top the list with 5498 publications, who widely cooperate with researchers from other countries, followed by those from China. Kurt R. Stenmark has an authoritative position in this field, ranking first with 635 citations. American Journal of Physiology Lung Cellular and Molecular Physiology and Pulmonary Circulation have published 151 articles on HPH in the last 10 years, but the former has higher impact factor and article quality. Circulation proved its leadership in this field with 8812 citations. Our findings reveal the trends in HPH research and should provide researchers with plenty of useful information.

Relationship of Main Pulmonary Artery (Truncus Pulmonalis) Diameter With Hospital Stay and Mortality in Pulmonary Hypertension Patients Admitted to the Emergency Department.

Pulmonary hypertension (PH) is a haemodynamic and pathophysiological disease significantly associated with morbidity and mortality. The increase in pulmonary vascular resistance, high pulmonary artery pressure and wall tension that occurs in PH results in dilatation of the main pulmonary artery (truncus pulmonalis), one of the largest and most important vessels in the body. The aim of this study is to investigate the relationship between the diameter of the truncus pulmonalis and hospitalization, length of hospital stay, and mortality in patients diagnosed with PH. Demographic characteristics, number of Emergency Department (ED) admissions, post-admission status, treatment, truncus pulmonalis diameter, and mortality were evaluated statistically through the patient files of 115 PH patients who presented to the ED of Fırat University Faculty of Medicine,Elazığ, Türkiye, between January 2022 and December 2022. Of the 115 PH patients who came to the ED, 70 (60.8%) were women and 45 (39.2%) were men, with a mean age of 78.77±8.72 years. Fifty-one of these patients were discharged from the ED after treatment, and 64 were hospitalized. The mean length of hospital stay was two (min=0, max=38) days. Thoracic CT scans demonstrated that the mean diameter of the truncus pulmonalis of the patients was 34.874±3.288 mm (35.20±3.6509 mm in women, 34.367±2.5836 mm in men; p₌0.351) and there was no statistically significant relationship with mortality (p=0.496), hospitalization (p=0.806), and length of hospital stay (p=0.416). There was a statistically significant relationship between mortality rate and male gender (p=0.02) and comorbidity (p=0.001). It was determined that there was no statistically significant relationship between the truncus pulmonalis diameter and gender, comorbidity, hospitalization, length of hospital stay, and mortality in this study in which single-centre one-year admissions of PH, which differ in aetiology, epidemiology, and demographic features were examined. However, among the patient demographics, a significant relationship was determined between gender and the number of comorbidities and mortality.