Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Marotta, Helga (2009) Fisiopatologia ed approccio terapeutico all'ipertensione polmonare secondaria alle connettiviti sistemiche. Studio del microcircolo coronarico nella sclerosi sistemica. [Tesi di dottorato]

Full text disponibile come:

[img]
Anteprima
Documento PDF
2757Kb

Abstract (inglese)

The study during my Ph.D concerned two topics: follow-up of patients with pulmonary arterial hypertension related to connective tissue diseases and study of coronary microangiopathy in patients with systemic sclerosis, complicated or not by pulmonary arterial hypertension (PAH).

Physiopathology and therapy of pulmonary arterial hypertension related to connective tissue diseases

Pulmonary arterial hypertension is a severe complication of the connective tissue diseases, in particular systemic sclerosis. The Cattedra and UOC of Rheumatology is a regional Centre for the diagnosis and treatment of PAH. Since 2003, we have recruited 43 patients, 25 being still in follow-up nowadays. The diagnosis of PAH was performed by Doppler ultrasound examination (PSVD > 45 mmHg). Exercise capacity by 6m-WT and Doppler ultrasound were performed initially every 3 months and later every 6 months to verify the efficacy of the treatment or to highlight worsening of the vascular disease.
Our study presents the results of short and long-term follow-up; in the 13 patients treated with bosentan for one year, there was a statistically significant reduction of PSVD after 3, 6, and 12 months. The walking distance at 6m-WT was improved with a mean increase of 14 meters after 3 months, 27 meters after 6 months and 30 meters after 12 months. 8 patients improved also the WHO functional class.
In the 12 patients treated with bosentan for 2 years, the final mean values of PSVD were maintained at the levels registered after 12 months of therapy. The exercise capacity was instead statistically significantly reduced; in three cases there were complications of connective tissue diseases of the legs (venous thrombosis, tendonitis or arthritis) and in one case worsening of pulmonary fibrosis, which caused a reduction of the walking distance (mean value of 108 meters); moreover, the exercise capacity was reduced by a mean value of 79 meters even in the other 8 patients. These data suggest that the 6m-WT is not an adequate test to evaluate the exercise capacity in patients with PAH related to connective tissue diseases, according to literature.
In the following years, in the long-term follow-up of 9 patients, the PSVD tended to go up again, even if in not statistically significant amount: in particular, after 5 years, the PSVD was reduced in 3 patients, similar to the baseline in 2 and increased in 4. 5 patients were still able to perform the 6m-WT, but the mean walking distance was reduced of 122 meters compared to the baseline (p<0,001). The other 4 patients were unable to perform the test due to deterioration of PAH with dyspnoea in 2 cases and to heart failure in the other 2 cases.
These data demonstrate that the bosentan is a good therapy during the first year of treatment, maintains the stabilized values of PSVD during the second year, but loses efficacy in the following years; this suggests to improve its effect with a second drug having a different mechanism of action on PAH, to intervene on different etiopathological targets. In fact, the combination therapy appears to be the gold standard for PAH treatment.

Study of coronary microcirculation in systemic sclerosis

Systemic sclerosis is a connective tissue disease characterized by lesions of microcirculation, firstly functional and later organic. Heart is affected in 50-80% of patients, but frequently without signs and symptoms. In particular, the epicardial coronary arteries are angiographically normal, but the coronary flow is reduced. We investigated the coronary microangiopathy in 37 consecutive patients with systemic sclerosis by the non-invasive determination of coronary flow reserve (CFR); CFR is performed by transthoracic Doppler echocardiography, during infusion of adenosine, to detect early dysfunctions in cardiovascular system in asymptomatic patients. Also in our study CFR was reduced with respect to normal values (?2,5) in 60% of the patients (2,4±0,8 vs 3,3±0,4).
We correlated CFR with cutaneous involvement subsets, specific serum autoantibodies, duration of the disease, PAH related to systemic sclerosis and, in this group of patients, bosentan treatment. Nobody presented signs and symptoms of heart disease.
CFR is more reduced in the patients with limited scleroderma and positive ACA, even if in not statistically significant amount; there is no correlation with duration of the connective tissue disease. Mean values of CFR in patients with and without PAH are similar.
Our data and the literature demonstrate the absence of any correlation between CFR and PAH, instead patients with diffuse scleroderma and with limited scleroderma are easily predisposed to coronary microangiophaty and pulmonary vascular involvement, respectively.
In other words, the correlation is between diffuse scleroderma and coronary endothelium and between limited scleroderma and pulmonary endothelium.

Abstract (italiano)

Il lavoro svolto nei tre anni di dottorato si è articolato in due argomenti: follow-up di pazienti affetti da ipertensione arteriosa polmonare secondaria alle connettiviti e studio del microcircolo coronarico in pazienti affetti da sclerodermia associata o meno a ipertensione arteriosa polmonare (PAH).

Fisiopatologia ed approccio terapeutico all'ipertensione polmonare secondaria alle connettiviti sistemiche

L'ipertensione arteriosa polmonare è una temibile complicanza delle connettiviti sistemiche, in particolare della sclerodermia. La Cattedra e UOC di Reumatologia è un Centro regionale per la diagnosi ed il trattamento della PAH. Dal 2003 ad oggi, abbiamo reclutato 43 pazienti, di cui attualmente vengono seguiti 25 in follow-up. La diagnosi di PAH è stata posta con ecocardiografia transtoracica per valori di PSVD > 45 mmHg. Dapprima a cadenza trimestrale e successivamente semestrale, i pazienti venivano sottoposti alla valutazione ecocardiografica e al 6m-WT per verificare l'efficacia della terapia o cogliere precocemente un eventuale peggioramento della malattia polmonare.
Il nostro studio riporta i risultati di un follow-up a breve e a lungo termine; nei primi 13 pazienti trattati per un anno con bosentan, vi è stata una riduzione della PSVD statisticamente significativa dopo 3, 6 e 12 mesi. La distanza percorsa al 6m-WT è aumentata in media di 14 metri dopo 3 mesi, 27 metri dopo 6 mesi e 30 metri dopo 12 mesi. In 8 soggetti vi è stato anche il miglioramento della classe funzionale WHO.
Dopo due anni di terapia, nei 12 pazienti il bosentan ha mantenuto ridotti rispetto al baseline i valori di PSVD, assestandoli su quelli registrati a 12 mesi. La tolleranza allo sforzo fisico invece è diminuita in modo significativo. Si sono manifestate alcune complicanze delle connettiviti a carico degli arti inferiori (in tre casi trombosi venosa, tendinite, artrite) e peggioramento della concomitante fibrosi polmonare in un caso, che hanno inciso notevolmente sulla riduzione della distanza percorsa in 6 minuti (in media di 108 metri); peraltro, anche negli altri 8 pazienti la capacità funzionale si è ridotta e la distanza percorsa è diminuita in media di 79 metri. Questi dati suggeriscono che il 6m-WT non rappresenta un adeguato test di valutazione della capacità di esercizio nei pazienti affetti da PAH secondaria alle connettiviti sistemiche, in accordo con i dati della letteratura.
Negli anni successivi, nei 9 pazienti in follow-up più lungo, la PSVD tendeva a risalire, seppur in modo non statisticamente significativo; in particolare, al quinto anno è rimasta ridotta in 3 pazienti, sovrapponibile al baseline in 2 ed aumentata in 4. Dopo cinque anni di trattamento, 5 pazienti erano ancora in grado di eseguire il 6m-WT, ma la distanza media percorsa al 6m-WT si è ridotta di 122 metri rispetto al baseline (p<0,001). Gli altri 4 pazienti non erano in grado di eseguire il test per il peggioramento della concomitante fibrosi polmonare in due di essi e per il deterioramento della PAH con dispnea ingravescente e scompenso cardiaco negli altri due.
Questi dati mostrano che la risposta al bosentan è buona nel primo anno di terapia, si assesta su valori stabilizzati nel secondo, per poi mediamente ridursi negli anni successivi; ciò suggerisce l'opportunità di potenziarne l'effetto associandovi un secondo farmaco, che agisca con un meccanismo d'azione diverso sulla PAH, in modo da intervenire su più targets etiopatogenetici; infatti, i trattamenti di combinazione sembrano costituire il gold standard nella terapia di questa temibile complicanza delle connettiviti sistemiche.

Studio del microcircolo coronarico nella sclerosi sistemica

La sclerodermia è una malattia del tessuto connettivo caratterizzata da lesioni prima funzionali e poi organiche del microcircolo; l'interessamento cardiaco è segnalato dal 50 all'80% dei pazienti, ma spesso senza segni e sintomi evidenti; in particolare, le arterie coronarie epicardiche sono angiograficamente indenni, mentre vi è una riduzione del flusso coronarico. Abbiamo perciò studiato la microangiopatia coronarica in 37 pazienti consecutivi affetti da sclerodermia grazie alla valutazione della riserva coronarica (CFR): tale metodo non invasivo si avvale di un ecocardiogramma transtoracico, durante infusione di adenosina, e può individuare precocemente un'alterazione del circolo coronarico in pazienti asintomatici. Anche nel nostro studio la CFR è risultata ridotta rispetto ai valori normali (?2,5) nel 60% dei pazienti (2,4±0,8 vs 3,3±0,4).
Abbiamo correlato i valori della CFR con la forma clinica della connettivite, il pattern anticorpale, la durata della malattia, la concomitante presenza della PAH e in questo gruppo di pazienti, la terapia con bosentan. Nessun paziente presentava sintomi da riferirsi ad interessamento cardiaco.
La CFR è risultata maggiormente ridotta nei pazienti con la forma limitata di malattia ed ACA positivi, sebbene non statisticamente significativa; non vi è correlazione con la durata della connettivite. I valori medi di CFR nei pazienti sclerodermici con e senza PAH sono sostanzialmente sovrapponibili.
Considerando i nostri dati e quelli della letteratura, riteniamo che non vi sia correlazione tra CFR e PAH, bensì che i pazienti sclerodermici affetti dalla forma diffusa di malattia vadano maggiormente incontro alla microangiopatia del circolo coronarico e quelli affetti dalla forma limitata all'interessamento vascolare polmonare.
In altri termini la correlazione è tra forma diffusa ed endotelio coronarico da una parte e forma limitata ed endotelio polmonare dall'altro.

Statistiche Download - Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Cozzi, Franco
Correlatore:Tona, Francesco
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE REUMATOLOGICHE
Data di deposito della tesi:01 Febbraio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):PAH, bosentan, PSVD, CFR, microangiopatia coronarica
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/16 Reumatologia
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Clinica e Sperimentale
Codice ID:1867
Depositato il:01 Feb 2009
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. The New England Journal of Medicine. 2004; 351:1425-36. Cerca con Google

Galiè N, Torbicki A, Barst R. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. European Heart Journal. 2004; 25:2243-2278. Cerca con Google

Simmoneau G, Galiè N, Rubin LJ. Clinical classification of pulmonary arterial hypertension. Journal of the American College of Cardiology. 2004; 43:5S-12S. Cerca con Google

McLaughlin VV, Rich S. Pulmonary hypertension. Current Problems in Cardiology. 2004; 29(10):575-634. Cerca con Google

Galiè N, Manes A, Branzi A. Evaluation of pulmonary arterial hypertension. Current Opinion in Cardiology. 2004; 19:575-581. Cerca con Google

Barst RJ, McGoon M, Torbicki A. Diagnosis and differential assessment of pulmonary arterial hypertension. Journal of America College of Cardiology. 2004; 12:40S-47S. Cerca con Google

D’Alonzo GE, Barst RJ, Ayres SM. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Annals of Internal Medicine. 1991; 115:343-349. Cerca con Google

Mukerjee D, St George D, Coleiro B, Knight C, Denton CP, Davar J, Black CM, Coghlan JG. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Annals of the Rheumatic Disease. 2003; 62:1088-1093. Cerca con Google

McLaughlin VV. Survival in patients with pulmonary arterial hypertension treated with first-line bosentan. European Journal of Clinical Investigation. 2006; 36(S3):10-15. Cerca con Google

Salvi SS. Alpha1-adrenergic hypothesis for pulmonary hypertension. Chest. 1999; 115:1708-1719. Cerca con Google

Cutai M, Rounds S. Hypoxic pulmonary vasoconstriction physiologic significant, mechanism and clinic relevance. Chest. 1990; 97:709-718. Cerca con Google

Ghali JK, Liao Y, Cooper RS, Cao G. Changes in pulmonary hemodynamics with aging in a predominantly hypertensive population. America Journal of Cardiology. 1992;70:367-370. Cerca con Google

Farber HW, Loscalzo J. Mechanism of disease: pulmonary arterial hypertension. The New England Journal of Medicine. 2004; 351:1655-1665. Cerca con Google

Tuder RM, Cool CD, Geraci MW. Postacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. American Journal of Respiratory Critical Care Medicine. 1999; 159:1925-32. Cerca con Google

Mason NA, Springall DR, Burke M. High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. Journal of Pathology 1994; 266:L46-L52. Cerca con Google

Giaid A. Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. New England Journal of Medicine. 1995; 333:214-221. Cerca con Google

Prakash A, Perry CM. Bosentan. American Journal Cardiovascular Drugs.2002; 5-335-342. Cerca con Google

Hachulla E, Coghan JG. A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism. Annals of the Rheumatic Disease. 2004; 63:1009-1014. Cerca con Google

Price LC, Howard LS. Endothelin receptor antagonists for pulmonary arterial hypertension: rationale and place in therapy. American Journal of Cardiovascular Drugs. 2008;8(3):171-85. Review. Cerca con Google

MacLean MR. Pulmonary hypertension and the serotonin hypotesis: where are we now? International Journal of Clinical Practice. 2007; 61 (S156), 27- 31. Cerca con Google

Abenhaim L, Moride Y, Brenot F. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. The New England Journal of Medicine. 1996;335:609-616. Cerca con Google

Marcos E, Adnot S, Pham MH. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. American Journal Respiratory Critical Care Medicine. 2003; 168:487-493. Cerca con Google

Kakishita M, Nishimiki T, Okano Y. Increased plasma levels of adrenomedullin in patients with pulmonary Hypertension. Clinical Science. 1999; 96:33-39. Cerca con Google

Petkov V, Mosgoeller W, Ziesche R. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. Journal of Clinical Investigation. 2003;111:1339-1346. Cerca con Google

Said SI. The vasoactive intestinal peptide gene is a key modulator of pulmonary vascular remodeling and inflammation. Annals of the New York Academy Science. 2008 Nov;1144:148-53. Cerca con Google

Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or chronic hypoxia: modulation of gene expression by nitric oxide. Journal of Clinical Investigation. 1995; 95:1798-1807 Cerca con Google

Sehgal PB, Mukhopadhyay S. Dysfunctional intracellular trafficking in the pathobiology of pulmonary arterial hypertension. America Journal of Respiratory Cell and Molecular Biology. 2007; 37:31-37. Cerca con Google

White RJ, Meoli DF, Swarthout RF, Kallop DY, Galaria II, Harvey JL, Miller CM, Blaxall BC, Hall CM, Pierce RA, Cool CD, Taubman MB. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. American Journal of Phiysiology - Lung Cellular and Molecular Physiology. 2007; 293:583-590. Cerca con Google

Montani D, Perros F, Dorfműller P, Durand-Gasselin I Eddahibi S, Simonneau G, Souza R, Humbert M. Platelet- derived growth factor expression and function in idiopathic pulmonary arterial hypertension. American Journal Respiratory Critical Care Medicine. 2008;178(1):81-88. Cerca con Google

Humbert M, Montani D, Perros F, Dorfmüller P, Adnot S, Eddahibi S. Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension. Vascular Pharmacology. 2008 Oct-Dec;49(4-6):113-8 Cerca con Google

Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. The Journal of Clinical Investigation. 2008 Jul;118(7):2372-9. Review. Cerca con Google

Peled N, Bendayan D, Shitrit D, Fox B, Yehoshua L, Kramer MR. Peripheral endothelial dysfunction in patients with pulmonary arterial hypertension. Respiratory Medicine. 2008 Dec;102(12):1791-6. Cerca con Google

McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension. The impact of epoprostenol therapy. Circulation. 2002;106:1477-1482 Cerca con Google

Rachel J. Davies and Nicholas W. Morrell. Molecular mechanisms of pulmonary arterial hypertension: role of mutations in the bone morphogenetic protein type II receptor. Chest. 2008; 1271–1277. Cerca con Google

Star GP, Giovinazzo M, Langleben D. Effects of bone morphogenic proteins and transforming growth factor-beta on In-vitro production of endothelin-1 by human pulmonary microvascular endothelial cells. Vascular Pharmacology. 2009;50(1-2):45-50. Cerca con Google

Hong HK, Lee YJ, Lee E, Park SO, Han C, Beppu H, Li E, Raizada MK, Bloch KD, Oh SP. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation. 2008; 12;118:722-730. Cerca con Google

Rubin LJ. BMPR2 mutation and outcome in pulmonary arterial hypertension: clinical relevance to physicians and patients. American Journal of the Respiratory Critical Care Medicine. 2008; 15;177(12):1300-1301. Cerca con Google

Du L, Sullivan CC, Chu D. Signaling molecole in non-familial pulmonary hypertension. The New England Journal of Medicine. 2003; 348:500-509. Cerca con Google

Hoeper MM. Pulmonary arterial hypertension in collagen vascular disease. European Respiratory Journal. 2002; 19.571-579. Cerca con Google

Ahmadi-Simab K, Hellmich B, Gross WL. Bosentan for severe pulmonary arterial hypertension related to systemic sclerosis with interstitial lung disease. European Journal of Clinical Investigation. 2006; 36S:44-48. Cerca con Google

Coral-Alvarado P, Quintana G, Garces FM, Cepeda LA, Caminos JE, Rondon F, Iglesias-Gamarra A, Restrepo JF. Potential biomarkers for detecting pulmonary arterial hypertension in patients with systemic sclerosis. Rheumatology. 2008;25:455-467. Cerca con Google

Schachna L, Wigley FM, Chang B, White B, Wise RA, Gelber AC. Age and risk of pulmonary arterial hypertension in scleroderma. Chest. 2003; 124:2098-2104. Cerca con Google

Battle RW, Davitt MA, Cooper SM, Buchley LM, Leib ES, Beglin PA, Tischler MD. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest. 1996; 110:1515-1519. Cerca con Google

Hanitsch LG, Burmester GR, Witt C, Hunzelmann N, Genth E, Krieg T, Lehmacher W, Melchers I, Meurer M, Müller-Ladner U, Schulze-Lohoff E, Becker M, Sunderkoetter C; DNSS centers, Riemekasten G. Skin sclerosis is only of limited value to identify SSc patients with severe manifestations--an analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register. Rheumatology. 2009 Jan;48(1):70-3. Cerca con Google

Hegewald MJ, Markewitz B, Elliot CG. Pulmonary hypertension: clinical manifestations, classification and diagnosis. International Journal of Clinical Practice. 2007;61(suppl.156),5-14. Cerca con Google

Gaine S. Pulmonary hypertension. JAMA. 2000; 284:3160-3168. Cerca con Google

Gaine S. Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352:719- 725. Cerca con Google

McLure LER, Peacock AJ. Imaging of he heart in pulmonary hypertension. International Journal of Clinical Practice. 2007; 61 (suppl. 156), 15-26. Cerca con Google

Ciurzyński M, Bienias P, Lichodziejewska B, Kurnicka K, Szewczyk A, Glińska-Wielochowska M, Kurzyna M, Błaszczyk M, Liszewska-Pfejfer D, Pruszczyk P. Non-invasive diagnostic and functional evaluation of cardiac involvement in patients with systemic sclerosis. Clinical Rheumatology. 2008;27(8):991-7. Cerca con Google

Ghio S, Klersy C, Magrini G, D'Armini AM, Scelsi L, Raineri C, Pasotti M, Serio A, Campana C, Viganò M. Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension. International Journal of Cardiology. 2008 Dec; 11:366-371. Cerca con Google

Hemnes AR, Champion HC. Right heart function and haemodynamics in pulmonary hypertension. International Journal of Clinical Practice. 2008 Jul;(S160):11-9. Review Cerca con Google

The 6-minute walk test in scleroderma--how measuring everything measures nothing. Impens AJ, Wangkaew S, Seibold JR. Rheumatology. 2008 Oct;47 S5:68-9. Cerca con Google

American Thoracic Society. ATS statement: guidelines for the six-minute walk test. American Journal Respiratory Critical Care Medicine. 2002;166:111-117. Cerca con Google

Galiè N, Seeger W, Naeije R, Simonneau G, Rubin LJ. Comparative analysis of clinical trails and evidence-based treatment algorithm in pulmonary arterial hypertension. Journal of the American College of Cardiology. 2004; 43(12S):81-88. Cerca con Google

Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-587. Cerca con Google

Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium channel blockers on survival pulmonary hypertension. The New England Journal of Medicine. 1992;327:76-81. Cerca con Google

Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension. Updated ACCP evidence-based clinical practice guidelines. Chest. 2007; 131:1917-1928. Cerca con Google

Gabbay E, Fraser J, McNeil K. Review of bosentan in the management of pulmonary arterial hypertension. Vascular Health and Risk management. 2007; 3(6): 887-900. Cerca con Google

Garcia Hernández FJ, Castillo Palma MJ, González León R, Garrido Rasco R, Ocaňa Medina C, Sánchez Román J. Experience with Imatinib to treat pulmonary arterial hypertension. Arch Broncopneumology 2008; 44(12):689- 691. Cerca con Google

Channick RN, Simonneau G, Sitbon O. Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119-1123. Cerca con Google

Rubin IJ, Badesch DB, Barst RJ. Bosentan therapy for the pulmonary arterial hypertension. The New England Journal of Medicine. 2002;346:896-903. Cerca con Google

Galiè N, Hinderliter AL, Torbicki A. Effects of the oral endothelin-receptor antagonist Bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. America Journal of College of Cardiology. 2003;41:1380-1386. Cerca con Google

Sitbon O, Badesch DB, Channick RN. Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary hypertension: a 1- year follow-up study. Chest. 2003;124:247-254. Cerca con Google

Provencher S, Sitbon O, Humbert M. Long-term outcome with first line bosentan therapy in idiopatic pulmonary arterial hypertension. European Heart Journal. 2006;27:589-595. Cerca con Google

Girgis RF, Mathai SC, Krishnan JA. Long-term outcome of bosentan treatment in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with the scleroderma spectrum diseases. Journal of Heart and Lung Transplantation. 2005;24:1626-1631. Cerca con Google

Galiè N, Rubin LJ, Hoeper MM, Jansa P, Al-Hiti H, Meyer GMB, Chiossi E, Kusic-Pajic A, Simmoneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a doubleblind, randomised controlled trial. Lancet. 2008; Jun 21:2093-2100. Cerca con Google

Waxman AB. A review of sitaxsentan sodium in pateints with pulmonary arterial hypertension. Vascular Health and Risk management. 2007; 3(1): 151-157. Cerca con Google

Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival. Benza RL, Barst RJ, Galie N, Frost A, Girgis RE, Highland KB, Strange C, Black CM, Badesch DB, Rubin L, Fleming TR, Naeije R. Chest. 2008 Oct;134(4):775- 82. Cerca con Google

Barst RJ, Langleben D, Badesch D. Treatment of pulmonary arterial hypertension with the selective endothelin-a receptor antagonist sitaxsentan. American Journal College of Cardiology. 2006;47:2049-2056. Cerca con Google

Cheng JW. Ambrisentan for the management of pulmonary arterial hypertension. Clinical Therapy. 2008; 30(5): 825-833. Cerca con Google

Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008 Jun 10;117(23):3010-9. Cerca con Google

Garg N, Sharma MK, Sinha N. Role of oral sildenafil in sever pulmonary arterial hypertension: clinical efficacy and dose response relationship. International Journal of Cardiology. 2007; 120:306-316. Cerca con Google

Badesch DB, Hill NS, Burges G, Rubin LJ, Barst RJ, Galiè N, Simonneau G. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. The Journal of Rheumatology. 2007;34:1-6. Cerca con Google

Ruiz MJ, Escribano P, Delgado JF, Jimenez C, Tello R, Gomez A, Sarnz de la Calzada C. Efficacy of sildenafil as a rescue therapy for patients with severe pulmonary arterial hypertension and given long-term treatment with prostanoids: 2-year experience. Journal of Heart and Lung Transplantation. 2006; 25:1353-7. Cerca con Google

Avouac J, Wipff J, Kahan A, Allanore Y. Effects of oral treatment on exercise capacity in systemic sclerosis related pulmonary arterial hypertension: a meta-analysis of randomised controlled trials. Annals of the Rheumatic Disease. 2007;49:1-15. Cerca con Google

Sitbon O, Humbert M, Nunes H. Long term intravenous epoprostenol infusion in primary pulmonary arterial hypertension: prognostic factors and survival. Journal of American College of Cardiology. 2002;40:780-788. Cerca con Google

McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482. Cerca con Google

Badesch DB, Tapson VF, McGoon MD. Continous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomised, controlled trial. Annals of Internal Medicine. 2000;132:425-434. Cerca con Google

Oudiz RJ, Schilz RJ, Barst RJ, Galiè N, Rich S, Rubin LJ, Simonneau G. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest. 2004; 126:420-427. Cerca con Google

Barst RJ, Galiè N, Naeije R, Simonneau G, Jeffs R, Arneson C, Rubin LJ. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. European Respiratory Journal. 2006; 28:1195- 1203. Cerca con Google

McLaughlin VV, Oudiz RJ, Frost A. Randomised study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. American Journal Respiratory Critical Care Medicine. 2006;174:1257-1263. Cerca con Google

Galiè N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Mane A, Sitbon O, Torbicki A, Delcoix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double- blind, placebo-controlled trial. Journal of the American College of Cardiology. 2002; 39:1496-1502. Cerca con Google

Badesh DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simmoneau G, McLaughlin VV. Medical therapy for pulmonary arterial hypertension. ACCP Evidence-based clinical practice guidelines. Chest. 2004; 126: 35-62. Cerca con Google

Mathai SC, Girgis RE, Fisher MR, Champion HC, Mouster- Harris T, Zaiman A, Hassoun PM. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. European Respiratory Journal. 2007; 29:469-475. Cerca con Google

Hoeper MM, Markevych E, Spiekerkoetter E, Welte T, Niedermeyer J. Goaloriented treatment and combination therapy for pulmonary arterial hypertension. European Respiratory Journal. 2005; 26:858-863. Cerca con Google

D’Andrea A, Stisi S, Bellissimo S, Vigorito F, Scotto di Uccio F, Tozzi N, Moscato F, Pezzullo E, Calabrò R, Scherillo M. Early impairment of myocardial function in systemic sclerosis: non invasive assessment by Doppler myocardial and strain rate imaging. European Journal of Echocardiography. 2005;6:407-418. Cerca con Google

Sulli A, Ghio M, Bezante GP, Deferrari L, Craviotto C, Sebastiani V, Setti M, Barsotti A, Cutolo M, Indiveri F. Blunted coronary flow reserve in sistemi sclerosis. Rheumatology. 2004;43:505-509. Cerca con Google

Trad S, Amoura Z, Beigelman C, Haroche J, Costedoat N, Boutinle TH. Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, indipendent of intestitial lung disease. Arthritis and Rheumatism. 2006;54:184-191. Cerca con Google

Tona F, Caforio AL, Montisci R, Angelini A, Ruscazio M, Gambino A. Coronary flow reserve by contrast-enhanced echocardiography: a new noninvasive diagnostic tool for cardiac allograft vasculopathy. American Journal of Transplantation. 2006;6:998-1003. Cerca con Google

Williams MH, Das C, Handler EC, Akram MR, Davas J, Denton CP. Systemic sclerosis associated pulmonary hypertension treated with first-line bosentan. European Journal of Clinical Investigation. 2006;36:10-15. Cerca con Google

Boulet K, Montani D, Jais X, Yaici A, Sitbon O, Simmoneau G, Humbert M. Therapeutic advances in pulmonary arterial hypertension. Therapeutic Advances in Respiratory Disease. 2008;2(4):249-265. Cerca con Google

Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A. Combination of bosentan with epopprostenol in pulmonary arterial hypertension: breathe-2. European Respiratory Journal. 2004;24:353-359. Cerca con Google

Montisci R, Vacca A, Garau P, Colonna P, Ruscazio M, Passiu G, Iliceto S, Mathieu A. Detecyion of early impairment of coronary flow reserve in patients with systemic sclerosis. Annals of the Rheumatic Disease. 2003;62:890-893. Cerca con Google

Kahan A, Nitemberg A, Foult JM, Amor B, Menkes CJ, Devaux JY. Decreased coronary reserve in primary sclerodermamyocardial disease. Arthritis and Rheumatism. 1985;28:637-646. Cerca con Google

Vacca A, Siotto P, Cauli A, Montisci R, Garau P, Ibba V, Mameli A, Passiu G, Iliceto S, Mathieu A. Absebce of epicardial coronary stenosis in patients with sistemi sclerosis with severe impairment of coronary flow reserve. Annals of the Rheumatic Disease. 2006;65:274-275. Cerca con Google

Allanore Y, Meune C, Vignaux O, Weber S, Legman P, Kahan A. Bosentan increases myocardial perfusion and function in systemic sclerosis: a magnetic resonance imaging and tissue-Doppler echography study. Journal of Rheumatology. 2006;33:2464-2469. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record