Usefulness of genetics for clinical reclassification and refinement of prognostic stratification in pulmonary arterial hypertension.

INTRODUCTION AND OBJECTIVES: Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies. METHODS: We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion. RESULTS: We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n=142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata. CONCLUSIONS: In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.

The impact of COVID-19 pandemic on pulmonary hypertension: What have we learned?

The coronavirus 2019 disease (COVID-19) pandemic threatened the Spanish health-care system. Patients with demanding conditions such as precapillary pulmonary hypertension (PH) faced a potentially severe infection, while their usual access to medical care was restricted. This prospective, unicentric study assessed the impact of COVID-19 on PH patients' outcomes and the operational changes in the PH network. Sixty-three PH patients (41 pulmonary arterial hypertension [PAH]; 22 chronic thromboembolic pulmonary hypertension [CTEPH]) experienced COVID-19. Overall mortality was 9.5% without differences when stratifying by hemodynamics or PAH-risk score. Patients who died were older (73.6 ± 5 vs. 52.2 ± 15.4; p = 0.001), with more comorbidities (higher Charlson index: 4.17 ± 2.48 vs. 1.14 ± 1.67; p = 0.0002). Referrals to the PH expert center decreased compared to the previous 3 years (123 vs. 160; p = 0.002). The outpatient activity shifted toward greater use of telemedicine. Balloon pulmonary angioplasty activity could be maintained after the first pandemic wave and lockdown while pulmonary thromboendarterectomy procedures decreased (19 vs. 36; p = 0.017). Pulmonary transplantation activity remained similar. The COVID-19 mortality in PAH/CTEPH patients was not related to hemodynamic severity or risk stratification, but to comorbidities. The pandemic imposed structural changes but a planned organization and resource reallocation made it possible to maintain PH patients' care.

The role of cardiopulmonary exercise testing in identifying and monitoring pulmonary veno-oclusive disease: a case report with ING.

Background: Pulmonary veno-occlusive disease (PVOD) is a subgroup of pulmonary arterial hypertension (PAH) where vascular remodelling affects mainly the post-capillary vessels. It is characterized by a particularly worse prognosis and by the risk of developing life-threatening pulmonary oedema, especially after PAH-targeted therapy. Therefore, suspicion of PVOD is crucial to guide the patient's management. In the absence of specific genetic or histological findings, diagnosis has traditionally relied on the recognition of non-invasive indicators associated with a high likelihood of PVOD. The cardiopulmonary exercise testing (CPET) arises as a promising additional tool both to identify these patients and to guide their management. Case summary: We report the case of a young female patient with dyspnoea and clinical suspicion of PVOD. The diagnostic workup is thoroughly described stressing the valuable and readily accessible information that CPET can provide, in addition to the data of radiological and lung function tests. Once diagnosed, she was started on PAH-targeted therapy with subsequent improvement. The patient underwent a complete reassessment with satisfactory findings, including those of the CPET. Discussion: Pulmonary veno-occlusive disease diagnosis is still one of the most difficult tasks that pulmonary hypertension physicians have to deal with. An accurate and timely PVOD diagnosis can be challenging, as it is to decide the most appropriate timing of referal to the lung transplant team, and CPET may serve these purposes. Through this case, we would like to review one of the typical clinical courses that PVOD may present and how to analyse the information provided by the diagnostic tests.

Novel Genetic and Molecular Pathways in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease.

Pulmonary Arterial Hypertension (PAH) is a severe complication of Connective Tissue Disease (CTD), with remarkable morbidity and mortality. However, the molecular and genetic basis of CTD-PAH remains incompletely understood. This study aimed to screen for genetic defects in a cohort of patients with CTD-PAH, using a PAH-specific panel of 35 genes. During recruitment, 79 patients were studied, including 59 Systemic Sclerosis patients (SSc) and 69 females. Disease-associated variants were observed in nine patients: 4 pathogenic/likely pathogenic variants in 4 different genes (TBX4, ABCC8, KCNA5 and GDF2/BMP9) and 5 Variants of Unknown Significance (VUS) in 4 genes (ABCC8, NOTCH3, TOPBP1 and CTCFL). One patient with mixed CTD had a frameshift pathogenic variant in TBX4. Two patients with SSc-PAH carried variants in ABCC8. A patient diagnosed with Systemic Lupus Erythematous (SLE) presented a pathogenic nonsense variant in GDF2/BMP9. Another patient with SSc-PAH presented a pathogenic variant in KCNA5. Four patients with SSc-PAH carried a VUS in NOTCH1, CTCFL, CTCFL and TOPBP1, respectively. These findings suggest that genetic factors may contribute to Pulmonary Vascular Disease (PVD) in CTD patients.

Radiological Findings in Multidetector Computed Tomography (MDCT) of Hereditary and Sporadic Pulmonary Veno-Occlusive Disease: Certainties and Uncertainties.

Pulmonary veno-occlusive disease (PVOD) is a very infrequent form of pulmonary arterial hypertension with an aggressive clinical course, poor response to specific vasodilator treatment, and low survival. Confirming a definitive diagnosis is essential to guide treatment and assess lung transplantation. However, in the absence of histological or genetic confirmation, the diagnosis is complex, requiring a clinical suspicion. Multidetector computed tomography (MDCT) is an essential part of the non-invasive diagnostic tools of PVOD. We retrospectively reviewed the MDCT findings from a consecutive series of 25 patients diagnosed with PVOD, 9 with the sporadic form and 16 with the hereditary form of the disease. The presence and extent of typical findings of the diagnostic triad were assessed in all patients (ground glass parenchymal involvement, septal lines, and lymphadenopathy). In our series, 92% of patients showed at least two of the radiological findings described as typical of the disease. All patients presented at least one typical radiological characteristic. The incidence of radiological findings considered typical is very high, however was not associated with greater hemodynamic severity nor to the development of acute lung edema. No significant differences were found between the two groups. A poorly expressive MDCT does not exclude the disease.

Recent advances in the management of pulmonary arterial hypertension: lessons from the upfront combination of ambrisentan and tadalafil.

INTRODUCTION: The sixth World Symposium of Pulmonary Hypertension (sixth WSPH) brought to the forefront for the first time the value of earlier, aggressive management with an upfront oral combination in patients with pulmonary arterial hypertension (PAH) of low or intermediate risk. This was prompted by results from the AMBITION study (ambrisentan + tadalafil). A literature search was conducted to collect all evidence provided by upfront treatment with this combination, as well as other combinations under investigation at the time the manuscript was prepared. AREAS COVERED: The value of an upfront oral combination with ambrisentan and tadalafil is reviewed on the basis of topics discussed at the sixth WSPH, such as evidence in different PAH etiologies, according to risk stratification and in so-called 'atypical' patients where monotherapy is still recommended. Evidence in clinical practice is also reviewed. New evidence about the value of the upfront oral combination is also commented. Finally, tendencies in primary endpoints to assess the effect of PAH-targeted therapies (time to clinical worsening and hemodynamics) and their value are also reviewed. EXPERT OPINION: All above-mentioned aspects are put into perspective with regard to the impact of new advances on improving PAH management in clinical practice.

Unexpected Favourable Course of Coronavirus Disease 2019 in Chronic Thromboembolic Pulmonary Hypertension Patients / Curso favorable inesperado de la enfermedad por coronavirus 2019 en pacientes con hipertensión pulmonar tromboembólica crónica

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Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease.

Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.

Pulmonary Arterial Hypertension (PAH) is a rare and fatal disease where knowledge about its genetic basis continues to increase. In this study, we used targeted panel sequencing in a cohort of 624 adult and pediatric patients from the Spanish PAH registry. We identified 11 rare variants in the ATP-binding Cassette subfamily C member 8 (ABCC8) gene, most of them with splicing alteration predictions. One patient also carried another variant in SMAD1 gene (c.27delinsGTAAAG). We performed an ABCC8 in vitro biochemical analyses using hybrid minigenes to confirm the correct mRNA processing of 3 missense variants (c.211C > T p.His71Tyr, c.298G > A p.Glu100Lys and c.1429G > A p.Val477Met) and the skipping of exon 27 in the novel splicing variant c.3394G > A. Finally, we used structural protein information to further assess the pathogenicity of the variants. The results showed 11 novel changes in ABCC8 and 1 in SMAD1 present in PAH patients. After in silico and in vitro biochemical analyses, we classified 2 as pathogenic (c.3288_3289del and c.3394G > A), 6 as likely pathogenic (c.211C > T, c.1429G > A, c.1643C > T, c.2422C > A, c.2694 + 1G > A, c.3976G > A and SMAD1 c.27delinsGTAAAG) and 3 as Variants of Uncertain Significance (c.298G > A, c.2176G > A and c.3238G > A). In all, we show that coupling in silico tools with in vitro biochemical studies can improve the classification of genetic variants.

Curso clínico de la COVID-19 en pacientes con hipertensión arterial pulmonar / Clinical course of COVID-19 in pulmonary arterial hypertension patients

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Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4.

BACKGROUND: The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease. METHODS: Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. RESULTS: Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease. CONCLUSIONS: Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate management.

Comprehensive assessment of left ventricular myocardial function by two-dimensional speckle-tracking echocardiography.

BACKGROUND: Left ventricular ejection fraction (LVEF) results from the combined action of longitudinal and circumferential contraction, radial thickening, and basal and apical rotation. The study of these parameters together may lead to an accurate assessment of the cardiac function. METHODS: Ninety healthy volunteers, categorized by gender and age (≤ 55 and >  55 years), were evaluated using two-dimensional speckle tracking echocardiography. Transversal views of the left ventricle (LV) were obtained to calculate circumferential strain and left ventricular twist, while three apical views were obtained to determine longitudinal strain (LS) and mitral annular plane systolic excursion (MAPSE). We established the integral myocardial function of the LV according to: 1. The Combined Deformation Parameter (CDP), which includes Deformation Product (DP) - Twist x LS (° x %) - and Deformation Index (DefI) -Twist / LS (° / %)-; and 2. the Torsion Index (TorI): Twist / MAPSE (° / cm). RESULTS: The mean age of our patients was 50.3 ± 11.1 years. CDP did not vary with gender or age. The average DP was - 432 ± 172 ° x %, and the average DefI was - 0.96 ± 0.36 ° / %. DP provides information about myocardial function (normal, pseudonormal, depressed), and the DefI quotient indicates which component (s) is/are affected in cases of abnormality. TorI was higher in volunteers over 55 years (16.5 ± 15.2 vs 13.1 ± 5.0 °/cm, p = 0.003), but did not vary with gender. CONCLUSIONS: The proposed parameters integrate values of twisting and longitudinal shortening. They allow a complete physiological assessment of cardiac systolic function, and could be used for the early detection and characterization of its alteration.