The Impact of Cardiovascular and Lung Comorbidities in Patients with Pulmonary Arterial Hypertension: A Systematic Review and Meta-analysis.

BACKGROUND: Contemporary patients with pulmonary arterial hypertension (PAH) are older and exhibit cardiovascular and/or lung comorbidities. Such patients have typically been excluded from major PAH drug trials. This systematic review compares baseline characteristics, hemodynamic parameters, and mortality rate between PAH patients with significant number of comorbidities compared to those with fewer or no comorbidities. ΜETHODS: A systematic literature search in PubMed and Cochrane databases was conducted searching for studies comparing PAH patients with more than two cardiovascular comorbidities and/or at least a lung comorbidity against those with fewer comorbidities. RESULTS: Seven observational studies were included. PAH patients with comorbidities were older, with an almost equal female-to-male ratio, shorter 6-minute walk distance, higher NT-proBNP levels, and lower lung diffusion for carbon monoxide. In terms of hemodynamics, they had higher mean right atrial pressure and pulmonary artery wedge pressure, lower mean pulmonary arterial pressure, pulmonary vascular resistance and mixed venous oxygen saturation. Pooled analysis of six studies demonstrated a higher mortality risk for PAH patients with comorbidities compared to those without (HR 1.86, 95% CI 1.20 to 2.89, p<0.001, I²=92%), with the subgroup of PAH patients with lung comorbidities having an even higher mortality risk (test for subgroup differences: p<0.001). Combination drug therapy for PAH was less frequently used in patients with comorbidities. CONCLUSIONS: Cardiovascular and lung comorbidities impact the clinical characteristics and outcomes of PAH patients, highlighting the need for optimal phenotyping and tailored management for this high-risk population.

Comparison of Contemporary Risk Scores in All Groups of Pulmonary Hypertension: A Pulmonary Vascular Research Institute GoDeep Meta-Registry Analysis.

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. RESEARCH QUESTION: Are risk scores originally developed for PAH predictive in PH groups 1 through 4? STUDY DESIGN AND METHODS: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including REVEAL Lite 2, REVEAL 2.0, ESC/ERS 2022, COMPERA 3-strata, and COMPERA 4-strata. RESULTS: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (33-52 mm Hg) and pulmonary vascular resistance of 7 WU (4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH). INTERPRETATION: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups.

Contribution of pressure and flow changes to resistance reduction after pulmonary arterial hypertension treatment: a meta-analysis of 3898 patients.

Background: Pulmonary arterial hypertension (PAH)-targeted therapies exert significant haemodynamic changes; however, systematic synthesis is currently lacking. Methods: We searched PubMed, CENTRAL and Web of Science for studies evaluating mean pulmonary artery pressure (mPAP), cardiac index/cardiac output (CI/CO) and pulmonary vascular resistance (PVR) of PAH-targeted therapies either in monotherapy or combinations as assessed by right heart catheterisation in treatment-naïve PAH patients. We performed a random-effects meta-analysis with meta-regression. Results: We included 68 studies (90 treatment groups) with 3898 patients (age 47.4±13.2 years, 74% women). In studies with small PVR reduction (<4 WU), CI/CO increase (R2=62%) and not mPAP reduction (R2=24%) was decisive for the PVR reduction (p<0.001 and p=0.36, respectively, in the multivariable meta-regression model); however, in studies with large PVR reduction (>4 WU), both CI/CO increase (R2=72%) and mPAP reduction (R2=35%) contributed significantly to the PVR reduction (p<0.001 and p=0.01, respectively). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral+prostanoid intravenous/subcutaneous combination therapy (mean difference -50.0%, 95% CI -60.8- -39.2%), compared to oral combination therapy (-41.7%, -47.6- -35.8%), prostanoid i.v./s.c. monotherapy (-31.8%, -37.6- -25.9%) and oral monotherapy (-21.6%, -25.4- -17.8%). Changes in haemodynamic parameters were significantly associated with changes in functional capacity of patients with PAH as expressed by the 6-min walking distance. Conclusion: Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable haemodynamic improvement in treatment-naïve PAH patients and may unmask the contribution of mPAP reduction to the overall PVR reduction in addition to the increase in CO.

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

OBJECTIVE: In 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 Fontan patients by synthesising evidence of randomised controlled trials (RCTs). METHODS: A systematic search of PubMed, Cochrane Central Register of Controlled Trials and Web of Science databases, as well as of ClinicalTrials.gov, was performed. Primary outcomes were specific cardiopulmonary exercise test parameters: peak oxygen uptake (peak VO2), peak heart rate (peak HR), the minute ventilation/produced carbon dioxide (VE/VCO2) slope and the oxygen uptake, both measured at the anaerobic threshold (VO2@AT). RESULTS: Five RCTs were included in the analysis including 573 Fontan patients (mean age 21.2 years, 60% male). PAH-targeted therapies did not affect peak VO2 (mean difference (MD) 0.72, 95% CI -0.25 to 1.70) or peak HR (MD -0.67, 95% CI -3.81 to 2.47), but resulted in a small, significant improvement in VO2@AT (standardised MD 0.24, 95% CI 0.02 to 0.47). VE/VCO2 slope at the anaerobic threshold was also reduced (MD -1.13, 95% CI -2.25 to -0.01). CONCLUSIONS: Although PAH-targeted therapies did not affect exercise parameters at maximal effort, they induced slight improvements in indices of submaximal effort, measured at the anaerobic threshold. Pharmacological improvement of submaximal exercise seems to be a more suitable indicator of Fontan individuals' exercise capacity. Larger RCTs, recruiting specific subpopulations and focusing also on the anaerobic threshold, are warranted to draw more robust conclusions. PROSPERO REGISTRATION NUMBER: CRD42022306674.

Temporal Trends in Diagnostic Hemodynamics and Survival of Patients with Pulmonary Hypertension: A Single-Center Study.

Advances in the diagnosis and treatment of pulmonary hypertension (PH) have gradually improved the disease course. This retrospective cohort study aims to explore the diagnostic hemodynamic profile and survival of PH patients and their temporal changes, as well as investigate potential prognostic factors. Overall, 257 adult patients were diagnosed with PH following right heart catheterization (RHC) from January 2008 to June 2023 according to the hemodynamic cut-off values proposed by the corresponding ESC/ERS guidelines at the time RHC was performed. Of these patients, 46.3% were Group 1, 17.8% Group 2, 14.0% Group 3, 18.0% Group 4, and 3.0% Group 5 PH. Temporal improvement in both diagnostic hemodynamic profile and survival of patients with PH and pulmonary arterial hypertension (PAH) was identified after 2013. Survival analysis demonstrated 5-year survival rates of 65% in Group 1 PH (90.3% in idiopathic PAH) and 77% in Group 4 PH. PAH patients being at low risk at diagnosis presented a similar 1-year all-cause mortality rate (12.4%) with high-risk ones (12.8%), primarily due to non-PH-related causes of death (62%), while high-risk patients died mostly due to PH (67%). The observed improvements in diagnostic hemodynamic profiles and overall survival highlight the importance of timely diagnosis and successful treatment strategies in PH.

The Right Heart in Congenital Heart Disease.

PURPOSE OF REVIEW: To analyze the pathophysiologic importance of the right heart in different types of congenital heart disease (CHD), summarize current diagnostic modalities, and discuss treatment options. RECENT FINDINGS: The right ventricle (RV) plays a key role in disease progression and prognosis, either as the subpulmonary or as the systemic ventricle. Volume and/or pressure overload as well as intrinsic myocardial disease are the main factors for RV remodeling. Echocardiography and cardiac magnetic resonance imaging are important noninvasive modalities for assessing anatomy, size, and function of the right heart. Timely repair of related lesions is essential for preventing RV dysfunction. Few inconclusive data exist on conventional pharmacotherapy in CHD-related RV dysfunction. Cardiac resynchronization therapy and ventricular assist devices are an option in patients with advanced systemic RV failure. Right heart disease is highly related with adverse clinical outcomes in CHD. Research should focus on early identification of patients at risk and development of medical and interventional treatments that improve RV function.

Transcatheter closure of atrial septal defect in the elderly: a systematic review and meta-analysis.

OBJECTIVE: Despite the establishment of transcatheter closure as the treatment of choice in adults with secundum atrial septal defects (ASDs), the effectiveness of this approach in the elderly is disputed. This systematic review and meta-analysis aims to explore the impact of transcatheter ASD closure in patients ≥60 years old. METHODS: We systematically searched four major electronic databases (PubMed, CENTRAL (Cochrane Central Register of Controlled Trials), Scopus and Web of Science), ClinicalTrials.gov, article references and grey literature. Primary outcomes were the right ventricular end-diastolic diameter (RVEDD) and the New York Heart Association functional class change, whereas secondary outcomes included systolic pulmonary arterial pressure (sPAP), left ventricular end-diastolic diameter (LVEDD), brain natriuretic peptide (BNP), tricuspid valve regurgitation (TR) change, as well as the rate of atrial arrhythmias and all-cause mortality. RESULTS: In total, 18 single-arm cohorts comprising 1184 patients were included. RVEDD was reduced after ASD closure (standardised mean difference (SMD) -0.9, 95% CI -1.2 to -0.7). Elderly patients had 9.5 times higher odds of being asymptomatic after ASD closure (95% CI 5.06 to 17.79). Furthermore, ASD closure improved sPAP (mean difference (MD) -10.8, 95% CI -14.6 to -7), LVEDD (SMD 0.8, 95% CI 0.7 to 1.0), TR severity (OR 0.39, 95% CI 0.25 to 0.60) and BNP (MD -68.3, 95% CI -114.4 to -22.1). There was a neutral effect of ASD closure on atrial arrhythmias. CONCLUSIONS: Transcatheter ASD closure is beneficial for the elderly population since it improves functional capacity, biventricular dimensions, pulmonary pressures, TR severity and BNP. However, the incidence of atrial arrhythmias did not change significantly after the intervention. PROSPERO REGISTRATION NUMBER: CRD42022378574.

Understanding and managing cardiac involvement in systemic sclerosis.

INTRODUCTION: Cardiac involvement is common in systemic sclerosis occurring in up to 80% of patients. Primary myocardial dysfunction results from impairment of coronary microvascular circulation, myocardial inflammation and fibrosis with the prevalence of atherosclerosis remaining contradictory. AREAS COVERED: This review presents the various aspects of cardiac involvement in SSc from a pathophysiological, clinical, diagnostic and therapeutic standpoint. Imaging modalities with emerging role in the understanding of mechanisms and prompt diagnosis of myocardial fibrosis namely cardiac magnetic resonance are also discussed. EXPERT OPINION: Cardiac involvement in SSc - and particularly primary myocardial disease - remains a challenge as clinical symptoms manifest in advanced stages of heart failure and convey poor prognosis. Over the last years the introduction of sophisticated imaging methods of myocardial function has resulted in a better understanding of the underlying pathophysiological processes of myocardial damage such as microvasculopathy, inflammation, diffuse or focal fibrosis. Such developments could contribute to the identification of patients at higher risk for subclinical heart involvement for whom diligent surveillance and prompt initiation of therapy with cardioprotective and/or immunosuppressive drugs coupled with invasive interventions namely radiofrequency ablation, implantable cardioverter-defibrillator when indicated, may improve long-term outcomes.

Right Heart Catheterization in Pediatric Pulmonary Arterial Hypertension: Insights and Outcome from a Large Tertiary Center.

Aim: To define the clinical characteristics, hemodynamics, and adverse events for pediatric patients with pulmonary arterial hypertension (PAH) undergoing right heart catheterization (RHC). Methods: The large referral single center data of 591 diagnostic RHC procedures performed between 2005 and 2020 on pediatric PAH patients was retrospectively collected and analyzed. Results: A total of 591 RHC procedures performed on 469 patients with congenital heart disease (CHD)-PAH (median age 8.8 years, 7.9% New York Heart Association (NYHA) class > II, 1.5% with syncope) and 122 patients with idiopathic PAH (median age of 9.0 years, 27.0% NYHA class > II, 27.0% with syncope) were included. Of those, 373 (63.1%) procedures were performed under general anesthesia. Eighteen patients (18/591, 3.0%) suffered adverse events (mainly pulmonary hypertensive crisis, PHC, n = 17) during the RHC procedure, including 14 idiopathic pulmonary arterial hypertension (IPAH) patients and 4 CHD-PAH patients, and one IPAH patient died in hospital 63 hours after RHC. The risk of developing PHC was significantly increased in patients with IPAH (OR = 14.02, 95%CI: 4.49−43.85, p < 0.001), atrial blood gas pH < 7.35 (OR = 12.504, 95%CI: 3.545−44.102, p < 0.001) and RAP > 14 mmHg (OR = 10.636, 95%CI: 3.668−30.847, p < 0.001). Conclusions: RHC is generally a low-risk procedure in pediatric patients with PAH. However, PHC occur in approximately 3% of patients. Therefore, RHC should be performed in a large, experienced referral pediatric cardiology center, especially in pediatric patients with IPAH requiring general anesthesia.

Nailfold Videocapillaroscopy for the Evaluation of Peripheral Microangiopathy in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic and refractory autoimmune joint disease that affects multiple organs. Several methods have been applied for the study of microvascular endothelial dysfunction, which is considered an important component of vascular disease in RA. Implementation of nailfold videocapillaroscopy (NVC) represents a viable choice, as the skin is an easily accessible window for the non-invasive, real-time assessment of subtle microcirculation abnormalities. Although NVC is routinely used in the rheumatology field, especially for the diagnostic workout of Raynaud's phenomenon, accumulating evidence suggests a role in the evaluation of systemic vasculopathy associated with autoimmune rheumatic disorders. The current paper aims to provide an overview of NVC as a valuable clinical aid for the assessment of peripheral microcirculation in RA. Previous studies characterizing the capillaroscopic pattern in RA are summarized, along with associations with disease-related characteristics. Most available reports have mainly focused on the descriptions of non-specific morphological alterations that may reflect endothelial injury over the course of the disease. Still, the exact pattern of structural and functional capillaroscopic alterations and their clinical significance in RA remains a subject of ongoing research.

A framework of deep learning networks provides expert-level accuracy for the detection and prognostication of pulmonary arterial hypertension.

AIMS: To test the hypothesis that deep learning (DL) networks reliably detect pulmonary arterial hypertension (PAH) and provide prognostic information. METHODS AND RESULTS: Consecutive patients with PAH, right ventricular (RV) dilation (without PAH), and normal controls were included. An ensemble of deep convolutional networks incorporating echocardiographic views and estimated RV systolic pressure (RVSP) was trained to detect (invasively confirmed) PAH. In addition, DL-networks were trained to segment cardiac chambers and extracted geometric information throughout the cardiac cycle. The ability of DL parameters to predict all-cause mortality was assessed using Cox-proportional hazard analyses. Overall, 450 PAH patients, 308 patients with RV dilatation (201 with tetralogy of Fallot and 107 with atrial septal defects) and 67 normal controls were included. The DL algorithm achieved an accuracy and sensitivity of detecting PAH on a per patient basis of 97.6 and 100%, respectively. On univariable analysis, automatically determined right atrial area, RV area, RV fractional area change, RV inflow diameter and left ventricular eccentricity index (P < 0.001 for all) were significantly related to mortality. On multivariable analysis DL-based RV fractional area change (P < 0.001) and right atrial area (P = 0.003) emerged as independent predictors of outcome. Statistically, DL parameters were non-inferior to measures obtained manually by expert echocardiographers in predicting prognosis. CONCLUSION: The study highlights the utility of DL algorithms in detecting PAH on routine echocardiograms irrespective of RV dilatation. The algorithms outperform conventional echocardiographic evaluation and provide prognostic information at expert-level. Therefore, DL methods may allow for improved screening and optimized management of PAH.

The impact of cardiovascular comorbidities associated with risk for left heart disease on idiopathic pulmonary arterial hypertension: Data from the Hellenic Pulmonary Hypertension Registry (HOPE).

Whereas younger female patients were diagnosed with idiopathic pulmonary arterial hypertension (IPAH) in 1980s, it is now frequently encountered in elderly patients with cardiovascular comorbidities (CVCs) associated with increased risk for left heart disease. We present data until November 2019 regarding specific features and clinical outcomes of IPAH population from the Hellenic Pulmonary Hypertension Registry (HOPE). Patients were divided into two groups based on the presence of ≥ or <3 CVCs, arterial hypertension, diabetes mellitus, obesity, presence of coronary artery disease, or atrial fibrillation. Overall, 77 patients with IPAH (55.1 [interquartile range, IQR: 24.1] years, 62.8% women) have been recorded. Fifteen patients (19.2%) had ≥3 CVCs, while 25 (32%) were over 65 years old. Patients with ≥3 CVCs were older, presented an almost equal female to male ratio, walked less in 6-min walk test, and had lower mean arterial pulmonary pressure and pulmonary vascular resistance at baseline than patients with less CVCs. Fewer patients with ≥3 CVCs received PAH-specific treatment compared to patients with less comorbidities (n = 11 [73.3%] versus n = 58 [95.5%], p = 0.02). During a median follow-up period of 3.8 (IQR: 2.7) years, 18 patients died (all-cause mortality 24.3%). Male sex and older age were independent predictors of mortality and/or lung transplantation, while CVCs did not have a significant impact on clinical outcomes. In this nationwide, register-based study, the epidemiology of IPAH involves older patients with CVCs, who seem to have less hemodynamic compromise, but worse functional impairment and are treated less aggressively with PAH pharmacotherapy.

Epidemiology and management of Staphylococcus Aureus infective endocarditis in adult patients with congenital heart disease: A single tertiary center experience.

BACKGROUND: Infective endocarditis (IE) is a potentially lethal disease for adults with congenital heart disease (ACHD). Staphylococcus aureus (SA) is one of the commonest pathogens, identified in patients with ACHD and IE. This study aims to analyse the epidemiology, clinical characteristics and in-hospital management of IE due to SA (SAIE) in ACHD. METHODS: This is a single center retrospective study on documented episodes of SAIE in ACHD patients, treated at the Royal Brompton Hospital between 1999 and February 2020. RESULTS: Thirty-seven ACHD patients had an episode of SAIE (mean age 35.5 ± 14.9 years). More than half (51.3%), had a cardiac lesion of at least moderate complexity, with left ventricular outflow tract lesions being the most frequent. Twenty-four (64.9%) patients had a history of at least one previous open-heart surgery, and prosthetic material was used in 20 patients. A predisposing event was identified in 11 episodes (29.7%). Surgery was performed during the same admission in 24 (64.9%) patients, with early surgery (≤ 7 days from admission) performed in 12 patients. Early operation was associated with a shorter in-hospital stay compared to a later operation during the same admission or medical management [28.5 (IQR 23) vs. 43.5 (IQR 30) days, P = 0.028]. In-hospital mortality was 8.1%. Renal dysfunction at admission was associated with in-hospital multiorgan complications and/or death (OR 7.50, 95% CI, 1.18-47.67, P = 0.03). CONCLUSION: SAIE remains a life-threatening complication, necessitating cardiac surgery in the majority of ACHD patients. Ongoing educational investment on prevention and timely SAIE detection is warranted.

Balloon Pulmonary Angioplasty in Patients with Chronic Thromboembolic Pulmonary Hypertension in Greece: Data from the Hellenic Pulmonary Hypertension Registry.

Balloon pulmonary angioplasty (BPA) is a novel and promising treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are ineligible for pulmonary endarterectomy (PEA) and for those with persistent or recurrent pulmonary hypertension after PEA. We present the results of BPA procedures in CTEPH patients included in the Greek Pulmonary Hypertension Registry, evaluating the real-life efficacy and safety. We analyzed data from 180 BPA procedures (2−17/patient, mean 8 ± 4/patient, 1248 dilated vessels, 0−18/session). Significant improvements were observed in mean pulmonary arterial pressure (a reduction by 44%, p < 0.001), pulmonary vascular resistance (reduction by 60%, p < 0.001), and NT-proBNP (decrease by >70%, p: 0.003), while cardiac index improved modestly (9% increase, p = 0.143). We had 37 BPA-related non-fatal complications (20.6% in all interventions), predominantly including hemoptysis. Overall survival was 91%, 75% and 62% at 3, 4 and 5 years, respectively. Therefore, BPA may be a promising therapeutic option in patients with CTEPH in Greece.

Eisenmenger Syndrome: JACC State-of-the-Art Review.

Although major breakthroughs in the field of pediatric cardiology, cardiac surgery, intervention, and overall care improved the outlook of congenital heart disease, Eisenmenger syndrome (ES) is still encountered and remains a complex clinical entity with multisystem involvement, including secondary erythrocytosis, increased thrombotic and bleeding diathesis, high arrhythmogenic risk, progressive heart failure, and premature death. Clearly, care for ES is best delivered in multidisciplinary expert centers. In this review, we discuss the considerable recent progress in understanding the complex pathophysiology of ES, means of prognostication, and improvement in clinical outcomes achieved with pulmonary arterial hypertension-targeted therapies. Additionally, we delineate areas of uncertainty in various aspects of care, discuss gaps in current evidence, and review current status in less privileged countries and propose initiatives to reduce disease burden. Finally, we propose the application of emerging technologies to enhance the delivery and quality of health care related to ES and beyond.

Haemoptysis in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease: Insights on Pathophysiology, Diagnosis and Management.

Haemoptysis represents one of the most severe major bleeding manifestations in the clinical course of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). Accumulating evidence indicates that dysfunction of the pulmonary vascular bed in the setting of PAH predisposes patients to increased hemorrhagic diathesis, resulting in mild to massive and life-threatening episodes of haemoptysis. Despite major advances in PAH targeted treatment strategies, haemoptysis is still correlated with substantial morbidity and impaired quality of life, requiring a multidisciplinary approach by adult CHD experts in tertiary centres. Technological innovations in the field of diagnostic and interventional radiology enabled the application of bronchial artery embolization (BAE), a valuable tool to efficiently control haemoptysis in modern clinical practice. However, bleeding recurrences are still prevalent, implying that the optimum management of haemoptysis and its implications remain obscure. Moreover, regarding the use of oral anticoagulation in patients with haemoptysis, current guidelines do not provide a clear therapeutic strategy due to the lack of evidence. This review aims to discuss the main pathophysiological mechanisms of haemoptysis in PAH-CHD, present the clinical spectrum and the available diagnostic tools, summarize current therapeutic challenges, and propose directions for future research in this group of patients.

The use of pulmonary arterial hypertension therapies in Eisenmenger syndrome.

INTRODUCTION: For many years, treatment options for patients with Eisenmenger physiology had been restricted to conservative measures to alleviate multi-system complications. The use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with Eisenmenger syndrome (ES) changed the course of the disease, since they substantially improved clinical outcomes and increased survival. AREAS COVERED: In this review, we primarily focus on the use of PAH pharmacotherapies in ES. A literature search was carried out in PubMed, Scopus and Cochrane Database up to May 2021. We thoroughly discuss current evidence about mechanisms of action, safety, and efficacy of these agents and present challenges and gaps in literature regarding the recommended treatment approach. EXPERT OPINION: Unlike other forms of PAH, we usually treat patients with ES more conservatively as we lack evidence that aggressive management is safe and effective in this complex population. Several issues on the time of initiation of PAH-targeted therapies, choice between monotherapy vs. upfront combination therapy, and time of escalation still remain challenging and require further investigation. Therapeutic management should be guided by patients' individual evaluation based on available prognostic markers. More well-designed trials are warranted to assess the benefits of new PAH-targeted agents and combination therapies.

Gestational Hypertension and Preeclampsia: An Overview of National and International Guidelines.

IMPORTANCE: Gestational hypertension and preeclampsia are leading causes of maternal and perinatal morbidity and mortality worldwide. Τhe lack of effective screening and management policies appears to be one of the main reasons. OBJECTIVE: The aim of this study was to review and compare recommendations from published guidelines on these common pregnancy complications. EVIDENCE ACQUISITION: A descriptive review of guidelines from the National Institute for Health and Care Excellence, the Society of Obstetric Medicine of Australia and New Zealand, the International Society of Hypertension, the International Society for the Study of Hypertension in Pregnancy, the European Society of Cardiology, the International Federation of Gynecology and Obstetrics, the Society of Obstetricians and Gynaecologists of Canada, the American College of Obstetricians and Gynecologists, the International Society of Ultrasound in Obstetrics and Gynecology, the World Health Organization, and the US Preventive Services Task Force on gestational hypertension and preeclampsia was carried out. RESULTS: There is an overall agreement that, in case of suspected preeclampsia or new-onset hypertension, blood and urine tests should be carried out, including dipstick test for proteinuria, whereas placental growth factor-based testing is only recommended by the National Institute for Health and Care Excellence and the European Society of Cardiology. In addition, there is a consensus on the recommendations for the medical treatment of severe and nonsevere hypertension, the management of preeclampsia, the appropriate timing of delivery, the optimal method of anesthesia and the mode of delivery, the administration of antenatal corticosteroids and the use of magnesium sulfate for the treatment of eclamptic seizures, the prevention of eclampsia in cases of severe preeclampsia, and the neuroprotection of preterm neonates. The reviewed guidelines also state that, based on maternal risk factors, pregnant women identified to be at high risk for preeclampsia should receive low-dose aspirin starting ideally in the first trimester until labor or 36 to 37 weeks of gestation, although the recommended dose varies between 75 and 162 mg/d. Moreover, most guidelines recommend calcium supplementation for the prevention of preeclampsia and discourage the use of other agents. However, controversy exists regarding the definition and the optimal screening method for preeclampsia, the need for treating mild hypertension, the blood pressure treatment targets, and the postnatal blood pressure monitoring. CONCLUSIONS: The development and implementation of consistent international protocols will allow clinicians to adopt effective universal screening, as well as preventive and management strategies with the intention of improving maternal and neonatal outcomes.