Should We Change the Target of Therapy in Pulmonary Hypertension?

Despite the evolution of drug therapy in pulmonary arterial hypertension and the more aggressive treatment approach according to the guidelines, patients continue to have unacceptable mortality rates. Furthermore, specific drug therapy alone in chronic thromboembolic pulmonary hypertension also does not seem to have any beneficial impact on survival. As the function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension, the treatment strategy should focus on modifying factors involved in RV dysfunction. Although some previous reports demonstrated that the survival of patients with pulmonary hypertension was associated with mPAP, nevertheless, mPAP is still not considered as a target of therapy. There are many examples of effective mPAP lowering with early and aggressive drug therapy in pulmonary arterial hypertension, or with interventions in chronic thromboembolic pulmonary hypertension. This effective mPAP reduction can lead to reverse RV remodeling, and thus, improvement in survival. In this article, the importance of mPAP lowering is stated, as well as why the change of our current strategy and considering mPAP reduction as the target of therapy could make pulmonary hypertension a chronic but not fatal disease.

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.

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.

Sickle cell disease related chronic thromboembolic pulmonary hypertension: challenging clinical scenario.

Sickle cell disease (SCD), a haemoglobinopathy characterized by chronic haemolysis with acute exacerbations and vascular occlusion episodes, may be complicated by pulmonary hypertension. The latter may be caused by chronic thromboembolic disease of pulmonary artery branches and its management is not well-defined. Herein, we present a case of SCD complicated by chronic thromboembolic pulmonary hypertension of subsegmental pulmonary artery branches successfully treated with endothelin receptor antagonists, orally administered prostacyclin analogs and balloon pulmonary angioplasty. This challenging case highlights the need for clinical awareness of chronic thromboembolic pulmonary hypertension as a specific and potentially curable form of pulmonary hypertension complicating SCD course that may necessitate combined pharmacologic and interventional management.

Epidemiology and Management of Chronic Thromboembolic Pulmonary Hypertension in Greece. Real-World Data from the Hellenic Pulmonary Hypertension Registry (HOPE).

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a rare disease with poor prognosis if left untreated, characterized by pulmonary vascular bed obstruction due to unresolving thromboembolic material. The Hellenic pulmonary hypertension registry (HOPE) was launched in Greece in early 2015 and enrolls patients from all pulmonary hypertension subgroups in Greece. In total, 98 patients with CTEPH were enrolled from January 2015 until November 2019. Of these patients, 55.1% represented incident population, 50% were classified in the World Health Organization functional class II and 49% had a history of acute pulmonary embolism. The median values of pulmonary vascular resistance (PVR) and cardiac index were 7.4 (4.8) WU and 2.4 (1.0) L/min/m2, respectively, the mean diffusing capacity for carbon monoxide was 74.8 ± 20.6%, the median 6-minute walk distance was 347 (220) meters and the median value of N Terminal-pro brain natriuretic peptide was 506.0 (1450.0) pg/mL. In total, 60.2% of the patients were under pulmonary arterial hypertension-targeted therapy at the time of enrolment; specifically, riociguat was received by 35.7% of the patients and combination therapy was the preferred strategy for 16% of the patients. In total, 74 patients were evaluated for pulmonary endarterectomy (PEA), 34 (45.9%) were assessed as operable but only 23 of those (31.1%) finally underwent PEA. The remaining 40 patients were ineligible for PEA according to the operability assessment and 13 (17.6%) of them underwent balloon pulmonary angioplasty. The age of the non-operable patients was significantly higher than the operable patients (p < 0.001), while there was no significant difference with regard to the history of coagulopathies between the operable and non-operable patients (p = 0.33).

Practical Decision Algorithms for the Use of the Cardiovascular Polypill in Secondary Prevention in Europe.

The main objective of cardiovascular disease (CVD) prevention is to reduce morbidity and mortality. Despite recommendations on evidence-based pharmacological treatment and lifestyle changes, the control of CV risk factors such as hypertension or dyslipidaemia is not optimal. The use of a CV polypill, including guideline-recommended drugs, as a baseline therapy, may contribute to improving risk factors control either by improving the treatment adherence or by the synergistic effect of its components. The CNIC-Polypill is the first CV polypill approved in Europe as an effective strategy for secondary prevention, which contains acetylsalicylic acid, atorvastatin (in two optional doses), and ramipril (in three optional doses) in a single pill. The present practical clinical document aims to provide a guide for patient management after an acute coronary syndrome (ACS) or with chronic CVD (CCVD) with a strategy based on the CNIC-Polypill, also considering the need to add other therapies for a personalized treatment. The most suitable clinical scenarios for the CNIC-Polypill use are discussed: (a) in patients after an ACS at discharge, (b) in patients with CCVD (chronic coronary syndrome, stroke, or peripheral artery disease) with uncontrolled low-density lipoprotein cholesterol (LDL-c) and/or blood pressure levels and (c) in patients with CCVD with well-controlled risk factors to simplify treatment and reduce polypharmacy in the context of CCVD prevention.

Echocardiography in Pulmonary Arterial Hypertension: Is It Time to Reconsider Its Prognostic Utility?

Pulmonary arterial hypertension (PAH) is characterized by an insult in the pulmonary vasculature, with subsequent right ventricular (RV) adaptation to the increased afterload that ultimately leads to RV failure. The awareness of the importance of RV function in PAH has increased considerably because right heart failure is the predominant cause of death in PAH patients. Given its wide availability and reduced cost, echocardiography is of paramount importance in the evaluation of the right heart in PAH. Several echocardiographic parameters have been shown to have prognostic implications in PAH; however, the role of echocardiography in the risk assessment of the PAH patient is limited under the current guidelines. This review discusses the echocardiographic evaluation of the RV in PAH and during therapy, and its prognostic implications, as well as the potential significant role of repeated echocardiographic assessment in the follow-up of patients with PAH.

Use of the Prostacyclin Receptor Agonist Selexipag in Patients With Pulmonary Arterial Hypertension Associated With Eisenmenger Syndrome.

Eisenmenger syndrome is a multisystem disorder and the most severe form of pulmonary arterial hypertension in adult congenital heart disease. Pulmonary arterial hypertension represents a fatal disease, characterized by increased pulmonary vascular resistance, right heart failure, and death. Although therapeutic management has rapidly advanced in recent years, these patients were not included in randomized controlled trials for specific pulmonary arterial hypertension drugs, except for bosentan. However, in clinical practice we apply treatment strategies combining drugs targeting multiple pathobiological pathways. We present 3 patients with Eisenmenger syndrome and their improvement after starting treatment with selexipag, an oral selective IP prostacyclin receptor agonist.

Balloon Pulmonary Angioplasty as a Treatment in Chronic Thromboembolic Pulmonary Hypertension: Past, Present, and Future.

PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH) is a major cause of precapillary pulmonary hypertension leading to right heart failure and death if left untreated. In addition to pulmonary endarterectomy, which is considered the standard of care, and specific drug therapy that is not however expected to offer relief from the mechanical component of the disease, the therapeutic options for CTEPH have expanded with the development of balloon pulmonary angioplasty (BPA). The purpose of this review is a better understanding and evaluation of BPA as a treatment option in CTEPH patients. RECENT FINDINGS: With the evolution of BPA almost all over the world, more centers outside Japan, which remains the leader for the technique, presented their results confirming the efficacy, safety, and feasibility of this procedure as a complementary strategy in the treatment algorithm of CTEPH. Summarizing, more data from all over the world confirm that BPA is a challenging but potentially effective intervention for the treatment of inoperable CTEPH patients. However, there is a need for standardization of the technique, and furthermore, large, international, multicenter randomized controlled trials comparing BPA with the other treatment modalities of CTEPH are imperative.

Cardiac Catheterization versus Echocardiography for Monitoring Pulmonary Pressure: A Prospective Study in Patients with Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Standard echocardiography is important for pulmonary arterial hypertension (PAH) screening in patients with connective tissue disease (CTD), but PAH diagnosis and monitoring require cardiac catheterization. Herein, using cardiac catheterization as reference, we tested the hypothesis that follow-up echocardiography is adequate for clinical decision-making in these patients. We prospectively studied 69 consecutive patients with CTD-associated PAH. Invasive baseline pulmonary artery systolic pressure (PASP) was 60.19 ± 16.33 mmHg (mean ± SD) and pulmonary vascular resistance (PVR) was 6.44 ± 2.95WU. All patients underwent hemodynamic and echocardiographic follow-up after 9.47 ± 7.29 months; 27 patients had a third follow-up after 17.2 ± 7.4 months from baseline. We examined whether clinically meaningful hemodynamic deterioration of follow-up catheterization-derived PASP (i.e., > 10% increase) could be predicted by simultaneous echocardiography. Echocardiography predicted hemodynamic PASP deterioration with 59% sensitivity, 85% specificity, and 63/83% positive/negative predictive value, respectively. In multivariate analysis, successful echocardiographic prediction correlated only with higher PVR in previous catheterization (p = 0.05, OR = 1.235). Notably, in patients having baseline PVR > 5.45 WU, echocardiography had both sensitivity and positive predictive values of 73%, and both specificity and negative predictive value of 91% for detecting hemodynamic PASP deterioration. In selected patients with CTD-PAH echocardiography can predict PASP deterioration with high specificity and negative predictive value. Additional prospective studies are needed to confirm that better patient selection can increase the ability of standard echocardiography to replace repeat catheterization.

Epidemiology and initial management of pulmonary arterial hypertension: real-world data from the Hellenic pulmOnary hyPertension rEgistry (HOPE).

Pulmonary arterial hypertension (PAH) is a heterogenous clinical entity with poor prognosis, despite recent major pharmacological advances. To increase awareness about the pathophysiology, epidemiology, and management of the disease, large national registries are required. The Hellenic pulmOnary hyPertension rEgistry (HOPE) was launched in early 2015 and enrolls patients from all pulmonary hypertension subgroups in Greece. Baseline epidemiologic, diagnostic, and initial treatment data of consecutive patients with PAH are presented in this article. In total, 231 patients with PAH were enrolled from January 2015 until April 2018. At baseline, about half of patients with PAH were in World Health Organization functional class II. The majority of patients with PAH (56.7%) were at intermediate 1-year mortality risk, while more than one-third were low-risk patients, according to an abbreviated risk stratification score. Half of patients with PAH were on monotherapy, 38.9% received combination therapy, while prostanoids were used only in 12.1% of patients. In conclusion, baseline data of the Greek PAH population share common characteristics, but also have some differences with other registries, the most prominent being a better functional capacity. This may reflect earlier diagnosis of PAH that in conjunction with the increased proportion of patients with atypical PAH could partially explain the preference for monotherapy and the limited use of prostanoids in Greece. Nevertheless, early, advanced specific therapy is strongly recommended.

Improving Survival in Patients with Pulmonary Arterial Hypertension: Focus on Intravenous Epoprostenol.

Pulmonary arterial hypertension represents a devastating disease, causing progressive increase of pulmonary vascular resistance leading to right ventricular dysfunction and death. Therapeutic management has rapidly advanced in recent years due to improved understanding of pathophysiology and new drugs have been developed; however, survival remains poor. Oral agents as phosphodiesterase type V inhibitors, the soluble guanylyl cyclase stimulator riociguat, the prostacyclin receptor agonist selexipag and the endothelin receptor antagonists have each achieved evidence-based validation and are recommended for pulmonary arterial hypertension. Initial oral monotherapy or combination therapy is recommended for patients with low or intermediate risk according to each patient's risk stratification. Intravenous epoprostenol is a synthetic prostacyclin and the first drug approved for the disease. Although it represents the only treatment shown to reduce mortality, it is underused. Survival rates for patients treated with oral combination drug therapies are lower than those for patients treated with initial combination therapies including intravenous epoprostenol. This raises the interesting question of whether intermediate risk pulmonary arterial hypertension patients should be routinely introduced to therapies including intravenous epoprostenol rather than combination oral therapies.

Pulmonary arterial hypertension associated with interferon-beta treatment for multiple sclerosis. Case report and literature review.

Drug-Induced Pulmonary Arterial Hypertension (PAH) represents a well-known entity, predominantly related to anorexigens. Interferon-ß (IFN) is considered to be a drug with a possible risk of inducing PAH. We report a patient with Multiple Sclerosis treated with IFN-ß who diagnosed with PAH and her course of disease under specific PAH drug therapy. A review of the literature in IFN-ß-induced PAH is provided.

Pulmonary Arterial Hypertension in Connective Tissue Disorders: The emerging role of screening and early diagnosis. A position paper for Greek Rheumatologists.

Pulmonary Arterial Hypertension is regarded as a devastating disease, complicating Connective Tissue Diseases. Although much progress has been achieved in the last 20 years, several unfulfilled needs in diagnosis and management of PAH in these patients may still be identified. After a systematic review of the literature and integrating results from the latest research articles, key clinical issues for the screening and diagnosis of Pulmonary Arterial Hypertension in Connective Tissue Disorder Patients and specifically Scleroderma patients are described in this article, allowing physicians to contribute to early diagnosis of patients with Scleroderma-associated Pulmonary Arterial Hypertension.

Balloon pulmonary angioplasty is a promising option in thalassemic patients with inoperable chronic thromboembolic pulmonary hypertension.

Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. ß-Thalassaemia, among other haematological disorders, develop PH which is not an infrequent finding and worsens the prognosis. Haemolysis, iron overload and hypercoagulable state are among the main pathogenetic mechanisms. Haemoglobinopathies and congenital haemolytic anaemia constitute a unique patients population more predisposed to developing chronic thromboembolic pulmonary hypertension (CTEPH). Although pulmonary endarterectomy is accepted as the best treatment for CTEPH, surgery in these patients poses significant practical challenges given the distinct nature of the disease. As drug therapy is not expected to offer relief from the mechanical obstructions of pulmonary arteries and the use of specific pulmonary arterial hypertension drugs is not established in thalassaemia patients, the novel technique of balloon pulmonary angioplasty (BPA) may emerge as a new therapeutic option for patients with inoperable CTEPH and thalassaemia. We are reporting the case of a thalassaemic patient with a history of splenectomy suffering from progressive severe pulmonary hypertension related to chronic thromboembolic disease, who was successfully treated by BPA with substantial improvement.

Cardiac Dual-source Computed Tomography for the Detection of Left Main Compression Syndrome in Patients with Pulmonary Hyper-tension.

INTRODUCTION: Left Main Compression Syndrome (LMCS) represents an entity described as the extrinsic compression of the left main coronary artery (LMCA) by a dilated pulmonary artery (PA) trunk. We examined the presence of LMCS in patients with pulmonary hypertension (PH) using dual-source computed tomography (DSCT), as a non-invasive diagnostic tool. METHODS: The following parameters were measured: PA trunk diameter (PAD), the distance between PAD and LMCA (LMPA) and the distance between PA and aorta (AoPA). These measurements were related with demographic, echocardiographic, hemodynamic and clinical parameters. Angiography was performed in two patients with LMCS suspected by cardiac computed tomographic angiography. Patients without PH but with angina were examined as controls, using DSCT cardiac angiography to assess the same measurements and to detect the prevalence of coronary artery disease. RESULTS: PA diameter value over 40.00 mm has been associated with PH and LMCS. Furthermore, LMCS did not occur at a distance smaller than 0.50 mm between the PA and the LMCA, and did not correlate with the distance between the PA and the aorta or with cardiac index and NT-proBNP. CONCLUSION: DSCT may represent the initial testing modality in PH patients with dilated PA trunk to exclude LMCS. A periodical rule-out of this rare entity, as assessed by DSCT, in patients with a severely dilated PA seems to be mandatory for PH patients contributing to survival improvement.

First application of coronary flow reserve measurement for the assessment of left main compression syndrome in pulmonary hypertension.

Left main compression syndrome (LMCS) refers to extrinsic compression of the left main coronary artery because of a dilated pulmonary artery trunk. The condition represents an unusual cause of angina, left ventricular dysfunction, and sudden cardiac death in patients with pulmonary hypertension. We present 2 patients with the syndrome who were followed with serial assessments of coronary flow reserve by transthoracic echocardiography to screen for LMCS-related ischemia.

Complications leading to sudden cardiac death in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a disease of small pulmonary arteries, characterized by vascular proliferation and remodeling. Progressive increase in pulmonary vascular resistance ultimately leads to right ventricular heart failure and death. PAH-specific drug therapy has improved clinical outcomes and survival. While the survival is better, progression of pulmonary vasculopathy contributes to pulmonary artery dilatation. Left main compression syndrome, pulmonary artery dissection, pulmonary artery rupture, and severe hemoptysis are reported as complications leading to sudden cardiac death, an event encountered more often in PAH patients. The advent of PAH-targeted drug therapy has reduced referral for lung transplantation; however, severe complications require rapid diagnosis, decision making, and possible registration on a lung transplantation waiting list. PAH referral centers provide multidisciplinary emergency care and specific therapeutic management, contributing to improved quality of life and survival for PAH patients. We review the complications leading to sudden death in PAH.