Balloon pulmonary angioplasty after pulmonary thromboendarterectomy

.Pulmonary thromboendarterectomy (PTE) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (CTEPH) as it can remove the chronic, fibrotic, flow-limiting organized thrombi within the pulmonary arterial bed, addressing the primum movens of the disease (1). Despite significant improvement in all haemodynamic parameters, residual pulmonary hypertension (PH) is frequent after PTE, ranging from 17% to 31% (2,3). There is no clear definition of residual PH after PTE, and the actual incidence of this condition has been difficult to quantify. Usually, moderate residual PH is well tolerated by patients and, as shown by data from the United Kingdom cohort, clinically relevant residual PH after PTE mainly occur when the mean pulmonary arterial pressure (mPAP) is greater than 30–35 mmHg (3). The risk of persistent/recurrent PH in the long-term underlines the importance of a systematic patient follow-up, even after PTE. Balloon pulmonary angioplasty (BPA) has been developed as a compassionate procedure for symptomatic patients with CTEPH who are ineligible for surgery or with persistent/recurrent PH after PTE. BPA is not able to remove clots as PTE, but it is able to restore the flow by fragmenting the thrombotic and fibrotic material, resulting in hemodynamic and clinical improvement. Selection of good candidates for BPA, especially after PTE, includes a complete re-assessment of the patient with persistent symptomatic PH after PTE at least four to six months after surgery using high quality imaging techniques such as computed tomography pulmonary angiography (CTPA), selective pulmonary angiography (to provide fine details) and right heart catheterization (RHC) to assess the hemodynamic impairment. However, these imaging techniques are not widely available and require expertise

A Combined Targeted and Whole Exome Sequencing Approach Identified Novel Candidate Genes Involved in Heritable Pulmonary Arterial Hypertension

The pathogenesis of idiopathic and heritable forms of pulmonary arterial hypertension is still not completely understood, even though several causative genes have been proposed, so that a third of patients remains genetically unresolved. Here we applied a multistep approach to extend identification of the genetic bases of such a disease by searching for novel candidate genes/pathways. Twenty-eight patients belonging to 18 families were screened for BMPR2 mutations and BMPR2-negative samples were tested for 12 additional candidate genes by means of a specific massive parallel sequencing-based assay. Finally, whole exome sequencing was performed on four patients showing no mutations at known disease genes, as well as on their unaffected parents. In addition to EIF2AK4, which has been already suggested to be associated with pulmonary veno-occlusive disease, we identified the novel candidate genes ATP13A3, CD248, EFCAB4B, involved in lung vascular remodeling that represent reliable drivers contributing to the disease according to their biological functions/inheritance patterns. Therefore, our results suggest that combining gene panel and whole exome sequencing provides new insights useful for the genetic diagnosis of familial and idiopathic pulmonary arterial hypertension, as well as for the identification of biological pathways that will be potentially targeted by new therapeutic strategies

Dissecting histone deacetylase role in pulmonary arterial smooth muscle cell proliferation and migration

Pulmonary Arterial Hypertension (PAH) is a rare and devasting condition characterized by elevated pulmonary vascular resistance and pulmonary artery pressure leading to right-heart failure and premature death. Pathologic alterations in proliferation, migration and survival of all cell types composing the vascular tissue play a key role in the occlusion of the vascular lumen. In the current study, we initially investigated the action of selective class I and class II HDAC inhibitors on the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) after exposure to Platelet Derived Growth Factor (PDGF). Class I HDAC inhibitors were able to counteract the hyperproliferative response to PDGF, reducing both proliferation and migration in PASMCs, while class II were ineffective. Selective silencing with siRNAs targeted against different HDACs revealed a major role of class I, and within this class, of HDAC1 in mediating PDGF-induced Akt Phosphorylation and Cyclin D1 (CycD1) expression. These results from these combinatorial approaches were further confirmed by the ability of a specific HDAC1 inhibitor to antagonize the PDGF action. The finding that HDAC1 is a major conductor of PDGF-induced patterning in PAH-PASMCs prompts the development of novel selective inhibitors of this member of class I HDACs as a potential tool to control lung vascular homeostasis in PAH

A pragmatic approach to risk assessment in pulmonary arterial hypertension using the 2015 European Society of Cardiology/European Respiratory Society guidelines

open12noTo optimise treatment of patients with pulmonary arterial hypertension (PAH), the 2015 European Society of Cardiology/European Respiratory Society guidelines recommend using risk stratification, with the aim of patients achieving low-risk status. Previous analyses of registries made progress in using risk stratification approaches, however, the focus is often on patients with a low-risk prognosis, whereas most PAH patients are in intermediate-risk or high-risk categories. Using only six parameters with high prognostic relevance, we aimed to demonstrate a pragmatic approach to individual patient risk assessment to discriminate between patients at low risk, intermediate risk and high risk of death.This work was supported by Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy and by the National Institute of Biostructures and Biosystems, Rome, Italy.openDardi, Fabio; Manes, Alessandra; Guarino, Daniele; Zuffa, Elisa; De Lorenzis, Alessandro; Magnani, Ilenia; Rotunno, Mariangela; Ballerini, Alberto; Lo Russo, Gerardo Vito; Nardi, Elena; Galiè, Nazzareno; Palazzini, MassimilianoDardi, Fabio; Manes, Alessandra; Guarino, Daniele; Zuffa, Elisa; De Lorenzis, Alessandro; Magnani, Ilenia; Rotunno, Mariangela; Ballerini, Alberto; Lo Russo, Gerardo Vito; Nardi, Elena; Galiè, Nazzareno; Palazzini, Massimilian

Therapeutic alternatives in chronic thromboembolic pulmonary hypertension: from pulmonary endarterectomy to balloon pulmonary angioplasty to medical therapy. State of the art from a multidisciplinary team

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease with a very complex pathophysiology differing from other causes of pulmonary hypertension (PH). It is an infrequent consequence of acute pulmonary embolism that is frequently misdiagnosed. Pathogenesis has been related to coagulation abnormalities, infection or inflammation, although these disturbances can be absent in many cases. The hallmarks of CTEPH are thrombotic occlusion of pulmonary vessels, variable degree of ventricular dysfunction and secondary microvascular arteriopathy. The definition of CTEPH also includes an increase in mean pulmonary arterial pressure of more than 25 mmHg with a normal pulmonary capillary wedge of less than 15 mmHg. It is classified as World Health Organization group 4 PH, and is the only type that can be surgically cured by pulmonary endarterectomy (PEA). This operation needs to be carried out by a team with strong expertise, from the diagnostic and decisional pathway to the operation itself. However, because the disease has a very heterogeneous phenotype in terms of anatomy, degree of PH and the lack of a standard patient profile, not all cases of CTEPH can be treated by PEA. As a result, PH-directed medical therapy traditionally used for the other types of PH has been proposed and is utilized in CTEPH patients. Since 2015, we have been witnessing the rebirth of balloon pulmonary angioplasty, a technique first performed in 2001 but has since fallen out fashion due to major complications. The refinement of such techniques has allowed its safe utilization as a salvage therapy in inoperable patients. In the present keynote lecture, we will describe these therapeutic approaches and results

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: a clinical consensus statement of the ESC working group on pulmonary circulation and right ventricular function.

The current treatment algorithm for chronic thromboembolic pulmonary hypertension (CTEPH) as depicted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnosis and treatment of pulmonary hypertension (PH) includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and medical therapies to target major vessel pulmonary vascular lesions, and microvasculopathy. Today, BPA of >1700 patients has been reported in the literature from centers in Asia, the US, and also Europe; many more patients have been treated outside literature reports. As BPA becomes part of routine care of patients with CTEPH, benchmarks for safe and effective care delivery become increasingly important. In light of this development, the ESC Working Group on Pulmonary Circulation and Right Ventricular Function has decided to publish a document that helps standardize BPA to meet the need of uniformity in patient selection, procedural planning, technical approach, materials and devices, treatment goals, complications including their management, and patient follow-up, thus complementing the guidelines. Delphi methodology was utilized for statements that were not evidence based. First, an anatomical nomenclature and a description of vascular lesions are provided. Second, treatment goals and definitions of complete BPA are outlined. Third, definitions of complications are presented which may be the basis for a standardized reporting in studies involving BPA. The document is intended to serve as a companion to the official ESC/ERS guidelines

BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis.

BACKGROUND: Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. METHODS: We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort. FINDINGS: Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m(2); all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15-1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00-1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality). INTERPRETATION: Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations. FUNDING: Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, The National Center for Advancing Translational Sciences, The National Institutes of Health, National Natural Science Foundation of China and Beijing Natural Science Foundation.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/S2213-2600(15)00544-

Challenges in pulmonary hypertension: Managing the unexpected

The diverse challenges associated with diagnosis and management of patients with pulmonary hypertension are illustrated in this case-based review. Case 1 describes a patient diagnosed with pulmonary arterial hypertension (PAH) with right heart failure and active systemic lupus erythematosus who was effectively treated with an up-front triple combination of PAH therapies and immunosuppressive therapy. In case 2, a diagnosis of pulmonary veno-occlusive disease was reached after a combined approach of clinical suspicion, physical examination, and invasive and noninvasive tests. Cautious PAH therapy and high-dose diuretics provided clinical benefit in this patient and served as a bridge to lung transplantation. These cases highlight the need for ongoing follow-up of patients with PAH, comprising frequent assessment of treatment success and continued diagnostic evaluation

The burden of comorbidities in pulmonary arterial hypertension

Patients with comorbidities are often excluded from clinical trials, limiting the evidence base for pulmonary arterial hypertension (PAH)-specific therapies. This review aims to discuss the effect of comorbidities on the diagnosis and management of PAH. The comorbidities discussed in this review (systemic hypertension, obesity, sleep apnoea, clinical depression, obstructive airway disease, thyroid disease, diabetes, and ischaemic cardiovascular event) were chosen based on their prevalence in patients with idiopathic PAH in the REVEAL registry (Registry to EValuate Early and Long-term PAH disease management). Comorbidities can mask the symptoms of PAH, leading to delays in diagnosis and also difficulty evaluating disease progression and treatment effects. Due to the multifactorial pathophysiology of pulmonary hypertension (PH), the presence of comorbidities can lead to difficulties in distinguishing between Group 1 PH (PAH) and the other group classifications of PH. Many comorbidities contribute to the progression of PAH through increased pulmonary artery pressures and cardiac output, therefore treatment of the comorbidity may also reduce the severity of PAH. Similarly, the development of one comorbidity can be a risk factor for the development of other comorbidities. The management of comorbidities requires consideration of drug interactions, polypharmacy, adherence and evidence-based strategies. A multidisciplinary team should be involved in the management of patients with PAH and comorbidities, with appropriate referral to supportive services when necessary. The treatment goals and expectations of patients must be managed in the context of comorbidities