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The contemporary literature on social change in Latin America reflects a perception of folk and modern systems as incompatible, even antagonistic entities. Consistent with this view, change in Indian communities is seen as following one of two basic forms; towards (i) assimilation into the national political, economic and social systems, or (ii) the development of isolationist subcultures. This paper explores the process by which communities, and consequently the individuals thereof, become characterized as traditional and conservative with respect to development. The varied, often opposing views of Indian reaction to change suggest a need for reviewing the analytical categories considered to be diagnostic of traditionalism., La littérature contemporaine sur les changements sociaux en Amérique latine reflète une perception des systèmes folkloriques et modernes comme des entités incompatibles et antagonistes. En rapport avec cette image, les changements dans les communautés indiennes sont vus sous une de ces deux formes : vers 1) l’assimilation à l’intérieur des systèmes nationaux politiques, économiques et sociaux, ou vers 2) le développement de sous-cultures isolationnistes. Cet article explore le processus par lequel les communautés et par conséquent les individus deviennent caractérisés comme traditionnels et conservateurs par rapport au développement. Les points de vue variés, et souvent opposés, sur les réactions des Indiens face au changement suggèrent un besoin de renouvellement des catégories analytiques comme diagnostic du traditionnalisme.

It is becoming increasingly clear that the right ventricle plays an important role in the circulatory system. Especially in disease states, right ventricular (RV) function may be of great importance. As such, knowledge on RV function in both health and disease is essential for clinicians. This chapter provides current available knowledge on RV function, starting with a brief description of ideas on RV function that have passed from the second century up to now. This will be followed by a description of the physiology of cardiomyocyte and RV contraction and relaxation. Furthermore, the most used and up till now most applicable method to describe RV myocardial systolic and diastolic function in terms of their stiffness (“elastances”) using the systolic and diastolic pressure-volume relationships is explained in detail. Finally, factors that are known to regulate RV function are discussed.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Supplemental material, sj-pdf-1-pul-10.1177_2045894020922810 for Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension by Kathryn S. Wilson, Hanna Buist, Kornelija Suveizdyte, John T. Liles, Grant R. Budas, Colin Hughes, Margaret R. MacLean, Martin Johnson, Alistair C. Church, Andrew J. Peacock and David J. Welsh in Pulmonary Circulation

Supplemental material, PUL897513 Supplemental material for Understanding longitudinal biventricular structural and functional changes in a pulmonary hypertension Sugen–hypoxia rat model by cardiac magnetic resonance imaging by Geeshath Jayasekera, Kathryn S. Wilson, Hanna Buist, Rosemary Woodward, Aysel Uckan, Colin Hughes, Margaret Nilsen, A Colin Church, Martin K. Johnson, Lindsay Gallagher, James Mullin, Mandy R. MacLean, William M. Holmes, Andrew J. Peacock and David J. Welsh in Pulmonary Circulation

Supplemental material, sj-pdf-1-pul-10.1177_2045894020922810 for Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension by Kathryn S. Wilson, Hanna Buist, Kornelija Suveizdyte, John T. Liles, Grant R. Budas, Colin Hughes, Margaret R. MacLean, Martin Johnson, Alistair C. Church, Andrew J. Peacock and David J. Welsh in Pulmonary Circulation

BACKGROUND: The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction. METHODS: Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event. RESULTS: Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g. hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35–0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35–1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients. CONCLUSIONS: Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients., SCOPUS: ar.j, info:eu-repo/semantics/published

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.MethodsWe performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.FindingsA locus atHLA-DPA1/DPB1within the class II major histocompatibility (MHC) region and a second nearSOX17were significantly associated with PAH. TheSOX17locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants nearSOX17alter gene regulation via an enhancer active in endothelial cells. PAH risk variants determined haplotype-specific enhancer activity and CRISPR-inhibition of the enhancer reducedSOX17expression. Analysis of median survival showed that PAH patients with two copies of theHLA-DPA1/DPB1risk variant had a two-fold difference (>16 years versus 8 years), compared to patients homozygous for the alternative allele.InterpretationWe have found that common genetic variation at loci inHLA-DPA1/DPB1and an enhancer nearSOX17are associated with PAH. Impairment of Sox17 function may be more common in PAH than suggested by rare mutations inSOX17. Allelic variation atHLA-DPB1stratifies PAH patients for survival following diagnosis, with implications for future therapeutic trial design.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, Inserm, Université Paris-Sud, and French ANR.

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Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170)

Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.

2011 to 2012 has seen an explosion in published research in the field of pulmonary vascular disease, especially pulmonary hypertension. In conjunction with this research has been an explosion in clinical interest in treating pulmonary hypertension. This is possible because we now have three different generic classes of drug therapy: endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclins. Clearly, however, we need to be careful that we are treating the correct disease with the correct drug and measuring the correct response. Herein, I will review the papers published over the last year that offer the most insight into the pathobiology, but also those that give us the clinical information we need in epidemiology, treatment and end-points so that we can treat this devastating group of disease.

Additional patient demographic and clinical characteristics for targeted recruitment and enrolled cohort. (PDF 34 kb)

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

There is increasing penetration of renewable generation in buildings and districts. There are challenges in making the effective use of this generation. The objective of the ORIGIN project (Orchestration of Renewable Integrated Generation In Neighborhoods) is to shape loads so that the fraction of energy consumed that is from local renewable generation is maximized, and energy imported from outside sources is minimized. This paper presents the overall approach taken in the ORIGIN project and explores building physics aspects of solar thermal storage system orchestration. The case study districts are briefly introduced and characteristics of their generation, buildings, districts and shiftable loads described. The orchestration approach taken in ORIGIN is then presented. At the core of the ORIGIN system is the orchestration algorithm which generates informational and control outputs to shape future loads to best meet the objectives. The model based approach used to quantify thermal and electrical load shifting opportunities for pre-charging, coasting or avoiding loads, while meeting thermal comfort and other demands, is described using a solar thermal storage system as an example. The future steps for the ORIGIN project; retrofit of the ORIGIN system into existing districts and potential for other future applications is briefly discussed.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Aims This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methods and results For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17–33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18–51 m; P Conclusion This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.

Background The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN). Methods In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians. Results The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%). Conclusions Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data.

Chapitre 1. Introduction L’hypertension pulmonaire est un syndrome de dyspnée, fatigue, douleur thoracique et syncope, causé par une augmentation de la résistance vasculaire pulmonaire (RVP) conduisant progressivement à la défaillance cardiaque droite(1). Le cathétérisme du cœur droit est indispensable au diagnostic et à l’évaluation de la gravité de l’hypertension pulmonaire. L’examen permet tout à la fois la quantification du processus morbide par une mesure de la RVP et de ses répercussions fonctionnelles par la mesure du débit cardiaque. Néanmoins, la multiplication des études thérapeutiques randomisées dans l’hypertension artérielle pulmonaire (HTAP) a montré l’inadéquation de ces mesures pour quantifier la réponse fonctionnelle des patients aux traitements(2,3). Ceci s’explique par les limitations de l’évaluation hémodynamique traditionnelle qui ne peut directement quantifier les déterminants de la performance ventriculaire droite (VD): précharge, postcharge et contractilité. Le but de ce travail a été d’étudier l’apport de nouvelles méthodes d’exploration, moins invasives, pour mieux comprendre l’adaptation VD à l’augmentation de postcharge, induite par l’hypertension pulmonaire. Le chapitre introductif est consacré à une revue des concepts de physiologie de base, à savoir :la description de l’état fonctionnel de la circulation pulmonaire par des relations pression-débit instantanées ou continues et de la fonction VD au départ des relations pression-volume ventriculaires. Les principales méthodes utilisées dans ce travail sont présentées, à savoir :l’échocardiographie traditionnelle, mais actualisée par l’introduction de nouveaux indices de fonction VD et l’imagerie par Doppler tissulaire (TDI). Chapitre 2. Faisabilité de l’étude semi-invasive de l’impédance vasculaire pulmonaire chez les patients souffrant d’hypertension artérielle pulmonaire Le calcul de RVP néglige les phénomènes de compliance vasculaire et de réflexion d’ondes, inhérents à l’aspect pulsatile du flux dans la circulation pulmonaire. Ceci sous-estime la charge hydraulique imposée au VD, en particulier dans l’hypertension pulmonaire(4). L’ensemble des forces qui s’opposent à l’éjection du VD peut être quantifié par une analyse fréquentielle des ondes de pression et de débit artériels pulmonaires et un calcul d’impédance vasculaire pulmonaire (PVZ). Néanmoins, cette méthode a été très peu appliquée chez l’Homme, en raison de sa complexité et surtout de son caractère invasif. Nous avons étudié la faisabilité de l’étude systématique de spectres de PVZ chez 22 patients souffrant d’HTAP, avec une méthode simplifiée, couplant le cathétérisme du cœur droit et l’échocardiographie-Doppler transthoracique. Les résultats montrent qu’il est possible d’obtenir au lit du malade des spectres de PVZ cohérents et sensibles aux interventions pharmacologiques. Chapitre 3. Etude par imagerie Doppler tissulaire de l’adaptation ventriculaire droite à la vasoconstriction pulmonaire hypoxique aiguë chez le sujet sain La déprivation en oxygène dans l’air respiré induit une vasoconstriction des petites artères pulmonaires, responsable d’une hypertension pulmonaire modérée. Nous avons étudié la fonction VD par échocardiographie-Doppler conventionnelle et TDI chez 25 volontaires, au cours de la vasoconstriction pulmonaire hypoxique et lors de l’administration intraveineuse de faibles doses de dobutamine (reproduisant la tachycardie associée à la stimulation orthosympathique). Les résultats montrent une adaptation de la fonction des deux ventricules, essentiellement diastolique à droite et systolique à gauche. Ces effets peuvent être expliqués par la conjonction d’une activation sympathique et l’adaptation de la fonction du VD nécessaire à la préservation du couplage entre fonction ventriculaire et postcharge. Chapitre 4. Etude par imagerie Doppler tissulaire de l’adaptation ventriculaire droite à l’hypertension pulmonaire hypoxique, en altitude L’exposition à la haute altitude est un modèle naturel d’hypertension pulmonaire hypoxique. Nous avons étudié la fonction du VD par échocardiographie-Doppler conventionnelle et TDI chez 15 sujets sains au niveau de la mer, dans les premières heures d’exposition à l’altitude (La Paz, Bolivie - 3750 m) et après 10 jours d’acclimatation (Potosi - 4850 m), et chez 20 sujets natifs de l’Altiplano bolivien (~ 4000 m). Les résultats montrent que l’exposition aiguë ou subaiguë à l’altitude s’accompagne d’une hypertension pulmonaire modérée, avec maintien de la fonction systolique du VD et modifications mineures de sa fonction diastolique. Pour une même gravité d’hypertension pulmonaire, l’adaptation chronique des sujets natifs se caractérise par des altérations à la fois systoliques VD et diastoliques ventriculaires droite et gauche. Chez certains sujets, l’hypertension pulmonaire hypoxique peut être rapidement sévère. Nous en avons rapporté un cas dont l’échocardiographie-Doppler avec TDI montre l’existence d’une défaillance cardiaque droite, avec dilatation des cavités droites du cœur, mouvement paradoxal du septum interventriculaire, dilatation de la veine cave inférieure, et raccourcissement myocardique postsystolique prédominant à l’apex, le tout dans un contexte d’examen clinique négatif. Ce cas illustre l’apport de l’échocardiographie avec TDI en tant qu’outil non invasif, d’extension de l’examen clinique du cœur, et suggère que le diagnostic de défaillance cardiaque droite aiguë devrait faire partie de la liste des complications médicales de l’exposition à la haute altitude. Chapitre 5. Etude par imagerie Doppler tissulaire de l’adaptation ventriculaire droite à l’hypertension pulmonaire chronique Chez les patients souffrant d’hypertension pulmonaire chronique, la symptomatologie et le pronostic sont essentiellement déterminés par l’adaptation de la fonction VD à la postcharge. Nous avons exploré la fonction VD par échocardiographie-Doppler complétée par TDI chez 18 patients souffrant d’hypertension pulmonaire, de type HTAP ou hypertension pulmonaire chronique d’origine thrombo-embolique (CTEPH), lors du cathétérisme du cœur droit inclus dans le bilan diagnostic initial. Les résultats montrent une diminution des indices de contraction régionale, prédominante au niveau de l’apex de la paroi libre VD, et des modifications de la relaxation des deux ventricules. Nous montrons également un quasi retour à la normale de la fonction VD, avec une disparition des anomalies à prédominance apicale, au cours d’un test de réversibilité chez un patient HTAP dit « répondeur » (importante diminution de la pression artérielle pulmonaire moyenne à l’administration de vasodilatateurs pulmonaires). Chapitre 6. Application des techniques non invasives modernes à l’étude de la circulation pulmonaire et de la fonction ventriculaire droite chez les patients souffrant de sclérodermie Les patients souffrant de sclérodermie sont à risque de développer de l’HTAP. Néanmoins, le rendement des techniques de dépistage non invasives est décevant. Nous avons émis l’hypothèse que la détection d’une hypertension pulmonaire dans la sclérodermie peut être améliorée par l’échocardiographie d’effort. Nous avons mesuré, par échocardiographie-Doppler, chez 25 patients sclérodermiques, les pressions artérielles pulmonaires et le débit cardiaque, au repos et à l’effort, de façon à déterminer une RVP « dynamique », et corrélé les résultats à l’évaluation échocardiographie-Doppler avec TDI. Les résultats montrent que les patients sclérodermiques présentent fréquemment une altération de la fonction diastolique du VD en présence d’une pression artérielle pulmonaire systolique normale au repos mesurée à partir de la vitesse maximale du jet de régurgitation tricuspide. Cette dysfonction est corrélée au temps d’accélération du flux pulmonaire (indicateur de l’élastance artérielle pulmonaire) et à la RVP dynamique (mesure raffinée de la RVP). Nous en concluons que l’altération de la fonction diastolique du VD est fréquente dans la sclérodermie, et reflète, vraisemblablement, une hypertension pulmonaire latente., info:eu-repo/semantics/published