Dissertations / Theses on the topic 'Stenosi'

Nell’elaborato presentato si espone l’ecocardiografia tridimensionale tempo reale, le sue caratteristiche e i suoi vantaggi rispetto la tomografia (gold standard) e l’ecografia convenzionale. Nel dettaglio viene presentato uno studio riferito alle valvole cardiache e alle loro principali patologie, quali calcificazione e stenosi. Vengono introdotte la calcificazione dell’anulus mitralico, un processo cronico degenerativo nella base fibrosa della valvola mitrale; la stenosi mitralica, la quale si verifica a causa di un restringimento della valvola e una non totale o incompleta apertura della stessa; la malattia della valvola calcifica aortica, caratterizzata da uno spessore maggiore dei lembi, irrigidimento, calcificazione (senza una fusione delle commessure) e con una considerevole ostruzione; in fine la stenosi aortica, un progressivo restringimento della valvola aortica che rimane tutt’oggi un processo ancora da definire completamente e non esistono trattamenti in grado di cambiare il corso della malattia. Tramite l’elevata risoluzione, la tomografia computerizzata multistrato fornisce uno strumento di imaging di riferimento per la quantificazione di calcio e per il calcolo dell’area dell’orifizio in una valvola stenotica. I contro di questa tecnica consistono nell’esposizione da parte del paziente a dosi nocive di raggi x e nella inesistenza di un approccio quantitativo convalidato. Con l’avvento dell’ecocardiografia 3D real-time è diventato possibile superare i metodi di studio delle strutture cardiache, ovviare ai limiti delle già esistenti tecniche, aumentare la precisione delle misure di parametri per la quantificazione di calcificazione e stenosi.

BACKGROUND - La stenosi dell’arteria renale è presente dall’1% al 5% nelle persone affette da ipertensione arteriosa (1,2) e spesso si associa a vasculopatia periferica e a coronaropatia (3,4), infatti si ritrova nel 18% - 20% dei soggetti sottoposti a coronarografia (5) e nel 35% - 50% dei pazienti sottoposti ad angiografia vascolare periferica per malattia dei grossi vasi addominali o degli arti inferiori (6). I quadri clinici ad essa correlati sono l’ipertensione nefrovascolare e la nefropatia ischemica cronica. La maggior parte dei casi è secondaria a lesioni aterosclerotiche, localizzate prevalentemente a carico del segmento prossimale dell’arteria renale o a livello ostiale. DISEGNO DELLO STUDIO - Sono stati raccolti retrospettivamente i dati di pazienti sottoposti ad angioplastica (PTA) e stenting dell’arteria renale da Novembre 2011 ad Aprile 2021 presso il Centro di Nefrologia dell’Ospedale Civile Sant’ Andrea (La Spezia). Lo scopo dello studio è di valutare la funzione renale, i valori di pressione arteriosa e il numero di farmaci antipertensivi a un anno dalla procedura di rivascolarizzazione dell’arteria renale. I pazienti inclusi nello studio erano soggetti affetti da stenosi critica dell’arteria renale (definita all’ecodoppler da una velocita di picco sistolico [VPS] superiore a 200 ml/min, e da un rapporto aortorenale [RAR] superiore al valore soglia di 3,5), bilaterale o monolaterale in monorene funzionale, secondaria ad aterosclerosi, che manifestavano ipertensione arteriosa malcontrollata (PA ≥140/90 mmHg) e refrattaria alla terapia in atto, e/o che presentavano un progressivo peggioramento della funzione renale, in assenza di altre cause apparenti. In totale abbiamo individuato 36 casi che rientravano in questi criteri. I pazienti inclusi erano affetti da insufficienza renale cronica (media ±DS eGFR 25,3±15,3 ml/min/1,73 m2), equamente divisi tra stadio III (33%, eGFR 30-60 ml/min/1,73 m2), stadio IV (31% eGFR 15-29 ml/min/1,73 m2) e stadio V (36%, eGFR <15 ml/min/1,73 m2). Abbiamo usato dei T-test per dati appaiati per valutare le differenze tra i parametri raccolti nei vari timepoint. RISULTATI - I risultati sulla funzione renale, espressa come creatinina sierica (mg/dl), evidenziavano un recupero funzionale rispetto al basale subito dopo la rivascolarizzazione (media ± DS 2,52 ± 1,61 vs 3,31 ± 2,47 mg/dl p<00.5), a distanza di 30 giorni (media ± DS creat. 2,36 ± 1,53 vs 3,19 ± 2,39 mg/dl p<0.05) e a 1 anno (media ± DS creat. 2,04 ± 1,16 vs 2,99 ± 2,40 mg/dl p<0.05). Riguardo la pressione arteriosa, una significativa riduzione dei valori di pressione sistolica e diastolica si verificava nel sottogruppo di pazienti di età ≤ 75 anni (media ± DS PAS post-procedura vs basale, 144,62 ± 12,55 vs 168,18 ± 36,40 mmHg, p< 0,01; 1 anno vs basale 143,95 ± 21,10 vs 167,83 ± 38,16 mmHg, p<0.05) (media ± DS PAD post-procedura vs basale, 73,62 ± 9,62 vs 83,07 ± 21,75 mmHg, p< 0,05; 1 anno vs basale 75,20 ± 9,02 vs 83,33 ± 23,10 mmHg, p=0.07). Anche in termini di riduzione del numero di farmaci antipertensivi, si dimostrava una diminuzione della terapia subito dopo la procedura (n° farmaci media ± DS post-procedura vs basale 2,28 ± 1,11 vs 3,21 ± 1,43, p<0.01), mentre si assistiva ad un aumento a distanza di 1 anno (n° farmaci media ± DS, 1 anno vs basale, 3,00 ± 1,41 vs 3,23 ± 1,42, p= 0,47), sebbene il controllo pressorio fosse comunque migliore rispetto al basale a parità di numero di farmaci. CONCLUSIONI - Nonostante l’esiguità numerica del nostro campione, questo studio dimostra come la rivascolarizzazione dell’arteria renale, in caso di stenosi bilaterale o monolaterale in monorene funzionale, determini un vantaggio significativo sul recupero della funzione renale e un miglior controllo pressorio. Il nostro risultato è discordante rispetto agli studi maggiori presi in considerazione (ASTRAL e CORAL) (7,8) che non riscontravano un beneficio clinicamente rilevante in termini di funzione renale o di prevenzione di eventi clinici cardio-renali (quali infarto acuto del miocardio, ictus cerebri, angina, scompenso cardiaco,angioplastica periferica, insufficienza renale progressiva o inizio di terapia sostitutiva) a favore della rivascolarizzazione, tra due gruppi messi a confronto (PTA +/- stenting vs terapia medica). La differenza dei risultati è verosimilmente legata ai criteri di inclusione della popolazione studiata e alla nostra stretta aderenza alle indicazioni alla procedura di angioplastica. BIBLIOGRAFIA: 1. Derkx FH, Schalekamp MA. Renal artery stenosis and hypertension. Lancet1994; 344:237-9. 2. Ram CV. Renovascular hypertension. Curr Opin Nephrol Hypertens 1997; 6:575- 9. 3. Olin JW, Melia M, Young JR, Graor RA, Risius B. Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990;88:46N-51N. 4. Harding MB, Smith LR, Himmelstein SI, et al. Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol 1992; 2:1608-16. 5. Rihal CS, Textor SC, Breen JF, McKusick MA, Grill DE, Hallett JW, Holmes DR. Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography. Mayo Clin Proc. 2002; 77:309 –316 6. Olin JW, Melia M, Young JR, Graor R, Risius B. Prevalence of atherosclerotic RAS in patients with atherosclerosis elsewhere. Am J Med. 1990; 88:46N–51N. 7. The ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 2009; 361:1953-62 8. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, Cohen DJ, Matsumoto AM, Steffes M, Jaff MR, Prince MR, Lewis EF, Tuttle KD, Shapiro JI, Rundback JH, Massaro JM., D’Agostino and Dworkin LD, for the CORAL Investigators*. Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis N Engl J Med 2014; 370:13-22
BACKGROUND - Renal artery stenosis (RAS) is present from 1% to 5% in people affected by arterial hypertension (1,2) and it is often associated with peripheric artery disease and coronary artery disease (3,4); as the matter of fact, it is a common find in people undergoing cardiac catheterization (18- 20%) (5) or angiography for aorto-iliac and lower extremities diseases (6). Clinical presentations are renovascular hypertension and ischemic nephropathy. The major cause of renal artery stenosis is an atherosclerotic lesion localized in the proximal segment or to the ostium. STUDY – This is a retrospective study focused on patients who underwent renal artery angioplasty and stenting in the last ten years, from November 2011 to April 2021, in the Nephrology Department, at Sant’Andrea Hospital, La Spezia (Italy). The purpose of the study is to evaluate kidney function, blood pressure and the number of antihypertensive drugs after one year from the revascularization. Patients included had uncontrolled and refractory to medical therapy arterial hypertension (PA ≥140/90 mmHg), and/or progressive worsening of renal function, secondary to bilateral or unilateral stenosis in one functional kidney, that was identified at the color-doppler ultrasound examination by a peak systolic velocity (PSV) > 200 ml/min and an aortic-renal ratio greater than 3,5. We found 36 patients who respected these inclusion criteria. They were all affected by chronic kidney disease (CKD) (mean ±SD eGFR 25,3±15,3 ml/min/1,73 mq), equally divided into stage 3 (33%, eGFR 30-60 ml/min/1,73 mq), stage 4 (31% eGFR 15-29 ml/min/1,73 mq) and stage 5 (36%, eGFR <15 ml/min/1,73 mq). We used paired t-tests to evaluate the differences between the parameters collected at the various time points. RESULTS – Kidney function, measured as serum creatinine (SCr) (mg/dl),improved immediately after the revascularization (mean ± SD SCr 2,52 ± 1,61 vs 3,31 ± 2,47 mg/dl p<00.5), after 30 days (mean ± SD SCr creat. 2,36 ± 1,53 vs 3,19 ± 2,39 mg/dl p<0.05) and after one year (mean ± SD SCr creat. 2,04 ± 1,16 vs 2,99 ± 2,40 mg/dl p<0.05). Regarding arterial hypertension, a significant reduction of both systolic (SBP) and diastolic (DBP) blood pressure has been detected in the subgroup of people under 75 years old (mean ± SD SBP after vs before, SBP 144,62 ± 12,55 vs 168,18 ± 36,40 mmHg, p< 0,01; one year after vs before, SBP 143,95 ± 21,10 vs 167,83 ± 38,16 mmHg, p<0.05) (mean ± SD after vs before, DBP 73,62 ± 9,62 vs 83,07 ± 21,75 mmHg, p< 0,05; one year after vs before, DBP 75,20 ± 9,02 vs 83,33 ± 23,10 mmHg, p=0.07). The number of antihypertensive drugs dropped immediately after the angioplasty (mean ± SD n° tablets 2,28 ± 1,11 vs 3,21 ±1,43, p<0.01), while after one year there was an increment of pharmacotherapy (mean ± SD n° tablets 3,00 ± 1,41 vs 3,23 ± 1,42, p= 0,47),even if blood pressure was better controlled than before the procedure withthe same amount of therapy. CONCLUSION – Although our population was quite small, we demonstrated the advantages of renal artery revascularization in atherosclerotic renovascular disease, as demonstrated by kidney function and blood pressure control. Our results disagree with the major studies considered (ASTRAL and CORAL), that did not detect any relevant clinical benefit from revascularization, in term of renal function and occurrence of major adverse cardiovascular and renal events (i.e. myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy), between two groups compared (revascularization group vs medical therapy alone group). The contrasting results are probably due to our strict adhesion to endovascular treatment indications and to the different inclusion criteria that they used. REFERENCES: 1. Derkx FH, Schalekamp MA. Renal artery stenosis and hypertension. Lancet 1994; 344:237-9. 2. Ram CV. Renovascular hypertension. Curr Opin Nephrol Hypertens 1997; 6:575- 9. 3. Olin JW, Melia M, Young JR, Graor RA, Risius B. Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990; 88:46N-51N. 4. Harding MB, Smith LR, Himmelstein SI, et al. Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol 1992; 2:1608-16. 5. Rihal CS, Textor SC, Breen JF, McKusick MA, Grill DE, Hallett JW, Holmes DR. Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography. Mayo Clin Proc. 2002; 77:309 –316 6. Olin JW, Melia M, Young JR, Graor R, Risius B. Prevalence of atherosclerotic RAS in patients with atherosclerosis elsewhere. Am J Med. 1990; 88:46N–51N. 7. The ASTRAL Investigators. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med 2009; 361:1953-62 8. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, Cohen DJ, Matsumoto AM, Steffes M, Jaff MR, Prince MR, Lewis EF, Tuttle KD, Shapiro JI, Rundback JH, Massaro JM., D’Agostino and Dworkin LD, for the CORAL Investigators*. Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis N Engl J Med 2014; 370:13-22

Le malattie cardiovascolari, e in particolar modo l’aterosclerosi, costituiscono attualmente la principale causa di ospedalizzazione e mortalità nei paesi occidentali. Questa patologia porta allo sviluppo all’ interno del vaso sanguigno di placche, che negli stadi avanzati della malattia, possono portare ad una parziale o completa occlusione. In base alle attuali linee guide, la diagnosi della patologia aterosclerotica prevede che il paziente venga sottoposto ad una serie di test provocativi non invasivi volti a documentare i segni indiretti della malattia. In presenza di tale documentazione il paziente viene sottoposto a coronarografia al fine di confermare la malattia aterosclerotica e in tal caso di procedere con tecniche di rivascolarizzazione. Negli ultimi anni è apparso evidente il limite di questo percorso sia per quanto riguarda la non infallibilità dei test provocativi in termini di sensibilità e specificità, e sia per quanto concerne i limiti stessi della coronarografia. A tal proposito, in questo lavoro, vogliamo presentare nuove tecniche che potrebbero cambiare gli scenari della cardiologia e analizzare i vantaggi che queste possono portare in termini di costi per il sistema nazionale e di qualità di vita per il paziente.

L’Intelligenza Artificiale è un campo dell’informatica che da tempo si afferma come valido strumento alternativo per la risoluzione di problemi tipicamente riservati esclusivamente all’intelletto umano. Se in principio gli algoritmi sfruttati nel campo dell’Intelligenza Artificiale erano basati su insiemi di regole codificate da esperti del dominio di applicazione dell’algoritmo, con l’arrivo del secondo millennio questo approccio è stato superato in favore di algoritmi che sfruttano grandi quantità di dati ed elevata potenza di calcolo per fare scelte ottimali. Un esempio di questo approccio può essere Deep Blue, che nel 1996, anche grazie ad un database di 4mila aperture e un’architettura che permetteva 11 GFLOPS fu la prima macchina a vincere una partita a scacchi contro un grande maestro. Col passare degli anni, l’aumentare degli investimenti e della ricerca, questo approccio ha portato alla strutturazione del campo dell’Apprendimento Automatico (Machine Learning, in inglese) dal quale sono scaturiti numerosi avanzamenti che hanno influenzato una moltitudine di ambiti: dall’agricoltura di precisione alla traduzione automatica, dal riconoscimento di frodi con carte di credito alla farmaceutica, dal marketing alla visione artificiale e molti altri, inclusa la medicina. Questo lavoro si concentra su proprio questioni relative al campo della medicina. In particolare si occupa di provare a riconoscere se le stenosi coronariche di un paziente sono gravi o meno attraverso l’uso di angiografie coronariche invasive e tomografie coronariche angiografiche; in maniera da diminuire delle angiografie coronariche invasive effettuate su pazienti che non ne hanno davvero bisogno.

La stenosi valvolare aortica è la più frequente patologia valvolare cardiaca nei paesi sviluppati come diretta conseguenza dell’aumentata aspettativa di vita. In Europa si stima che il numero di soggetti sintomatici per stenosi valvolare aortica aumenterà da 1.3 milioni nel 2025 a 2.1 milioni in 2050. Di conseguenza la stenosi aortica ha e avrà un forte impatto sulla salute pubblica e sui costi che ne determina, poiché spesso associata a un declino funzionale dei pazienti ed aumentata incidenza di ospedalizzazione. D’altra parte è noto che la stenosi valvolare aortica severa non trattata si associa a prognosi infausta con una sopravvivenza del 50% a 2 anni dall’insorgenza dei sintomi e del 20% a 5 anni. Ad oggi non esiste una terapia medica efficace per la stenosi valvolare aortica in quanto andando a costituire un’ostruzione meccanica, resta di competenza del cardiochirurgo o del cardiologo interventista. La sostituzione valvolare aortica, sia essa chirurgica o percutanea, resta pertanto il solo trattamento definitivo per la stenosi valvolare aortica. Nel tempo il rischio operatorio è estremamente diminuito e i vantaggi in termini di miglioramento della qualità di vita sono evidenti. Questo progetto di ricerca prevede pertanto un’analisi delle più recenti tecnologie per il trattamento chirurgico della stenosi valvolare aortica a partire dalla tipologia di approccio chirurgico, se mini-invasivo o tradizionale, fino all’utilizzo delle più recenti protesi biologiche sutureless studiandone i vantaggi, svantaggi e risultati. Prima ancora, tuttavia, saranno analizzati i meccanismi di biologia molecolare alla base dell’eziologia della stenosi aortica al fine di poter identificare precocemente i pazienti, di prevedere l’andamento della patologia e forse, in futuro, anche di ipotizzare una terapia farmacologica mirata.
Aortic valve stenosis is the most frequent heart valve disease in developed countries as a direct consequence of increased life expectancy. In Europe it is estimated that the number of people symptomatic of aortic valve stenosis will increase from 1.3 million in 2025 to 2.1 million in 2050. Consequently, aortic stenosis has and will have a strong impact on public health and the costs it determines, as it is often associated with a patients functional decline and with an increased incidence of hospitalization. On the other hand, it is known that untreated severe aortic valve stenosis is associated with a poor prognosis with a survival of 50% at 2 years from the onset of symptoms and 20% at 5 years. To date, there is no effective medical therapy for aortic valve stenosis as it constitutes a mechanical obstruction. Aortic valve replacement, be it surgical or percutaneous, therefore remains the only definitive treatment for aortic valve stenosis. Over time, the surgical risk has greatly decreased and the advantages in terms of improving the quality of life are evident. This research project therefore provides for an analysis of the most recent technologies for the surgical treatment of aortic valve stenosis starting from the type of surgical approach, whether minimally invasive or traditional, up to the use of the most recent sutureless biological prostheses, studying their advantages, disadvantages and results. Before that, however, the molecular biology mechanisms underlying the etiology of aortic stenosis will be analyzed in order to be able to identify patients early, to predict the course of the disease and perhaps, in the future, also to hypothesize a targeted drug therapy.

Although surgery with prosthetic valve replacement is the gold standard for severe aortic stenosis (AS) treatment, there are still about one third of patients that are not operated because of inoperability criteria or high surgical risk. Therefore, with the ageing of global population, the lengthening in life-expectancy and the consequent growing need to treat elderly patients with severe AS, there is a wide population who would benefit from a less invasive way of replacing the aortic valve. Transcatheter aortic valve implantation (TAVI) allows the aortic valve to be implanted without a sternotomy, with beating heart and without the need for routine cardiopulmonary support. This technique, pioneered by Alain Cribier and co-workers in 2002, has been used in more than 20,000 patients throughout the world. Currently, two transcatheter devices are approved for clinical use and are commercially available in Europe, i.e. the balloon expandable device (Edwards Sapien XT valve, Edwards LifeSciences) and the self-expandable (SE) device (CoreValve Revalving System; Medtronic). The acute success rate of this procedure is now increasing to about 95% in expert hands. In addition, several studies have shown that these prosthetic valves maintain good hemodynamic characteristics over both the shortand medium-term. However, we must await long-term results on potential complications and on the durability of transcatheter valves before this treatment approach can be applied to younger patients or to patients at low surgical risk. In this study we report our perspective single centre experience about TAVI in a high volume centre, the Department of Cardiac, Thoracic and Vascular Sciences of the University of Padua, using both balloon expandable and SE devices, through all the currently available vascular approaches. We report on early and follow up results, focusing on both clinical outcome and haemodynamic performance of the devices. We also investigated some peculiar fields of application, such as the treatment of bioprosthesis dysfunction, and speculated on the main potential procedural complications, such as the conduction disorders and the periprosthesis leakage. We strongly believe that, once some current limitations and concerns are overcome, this emerging technique will have a very fast and wide spread. However, it should not be forgotten that, in order to guarantee the extraordinary success of this new minimally invasive procedure, the heart team approach should remain a key-point. This will allow to select the best device and the most appropriate vascular access for each patient, as well as to guarantee the best technical result and the necessary post-procedural care.
Sebbene la chirurgia tradizionale sia la tecnica di scelta per il trattamento della stenosi aortica serrata, nella pratica clinica tuttavia circa un terzo dei pazienti non viene sottoposto a chirurgia sostitutiva per inoperabilità o eccessivo rischio chirurgico. Con l’aumentare dell’età media della popolazione, l’entità di questo problema è destinato ad aumentare, per cui vi è una sempre più ampia popolazione di pazienti che potrebbe beneficiare di tecniche operatorie meno invasive. L’impianto di valvola aortica per via transcatetere (TAVI) consente di applicare una protesi aortica evitando la sternotomia, l’arresto cardioplegico e senza la necessità di circolazione extracorporea. Questa tecnica è stato introdotta nel 2002 da Alain Cribier e dai suoi collaboratori e oggigiorno nel mondo sono stati eseguiti ormai oltre 20.000 interventi di TAVI. Attualmente esistono due dispositivi transcatetere approvati per uso clinico e disponibili in commercio in Europa, la valvola espandibile su palloncino (Edwards Sapien XT, Edwards Lifesciences) e la valvola auto-espandibile (CoreValve Revalving System, Medtronic). Il tasso di successo procedurale di questa procedura è attualmente in aumento e supera il 95% in mani esperte. Inoltre, diversi studi stanno dimostrando che queste protesi valvolari hanno buone caratteristiche emodinamiche sia a breve che a medio termine. Tuttavia, è necessario attendere risultati più a lungo termine sulle potenziali complicanze e sulla durata di queste valvole transcatetere, prima che questo tecnologia possa essere applicata anche in pazienti più giovani o a minor rischio chirurgico. In questo studio è riportata la nostra esperienza prospettica monocentrica nell’ambito della TAVI, raccolta in un centro ad alto volume, il Dipartimento di Scienze Cardiache, Toraciche e Vascolari dell'Università di Padova, utilizzando entrambi i dispositivi, espandibile su pallone ed autoespandibile, tramite tutti i gli approcci vascolari attualmente disponibili. Sono riportati i risultati immediati ed al follow-up, sia dal punto di vista del miglioramento clinico che della performance emodinamica delle protesi. Sono stati analizzati anche alcuni campi particolari di applicazione della metodica, come ad esempio il trattamento della disfunzione di bioprotesi, e abbiamo discusso sulle principali potenziali complicanze procedurali, come ad esempio i disturbi della conduzione cardiaca e i leak periprotesici. Dall’esperienza fino ad ora maturata, noi siamo fermamente convinti che, non appena alcune attuali limitazioni ed alcune perplessità saranno chiarite, questa tecnica emergente subirà una rapidissima ed ampia diffusione. Tuttavia non bisogna dimenticare che, per continuare a garantire lo straordinario successo di questa nuova metodica, il concetto di heart team, e quindi di una stretta collaborazione fra diversi specialisti, deve rimanere un punto centrale e irrinunciabile, per poter selezionare la miglior protesi ed il più appropriato approccio in ogni paziente, oltre che per garantire un perfetto risultato tecnico e le necessarie cure ed assistenze post-procedurali.

The clinical syndrome of neurogenic claudication due to lumbar spinal stenosis (LSS) is a frequent source of pain in the lower back and extremities, impaired walking, and other forms of disability in the elderly. Although the incidence and prevalence of symptomatic lumbar spinal stenosis have not been established, this condition is one of the most frequent indication for spinal surgery in patients older than 65 years of age. The treatment strategy depends on the severity of clinical symptom. After nonoperative treatement failure, surgical decompression should be considered. Aim of our prospective non-randomized clinical study was to analized short term results, efficancy, and complications after decompression and interspinous distraction surgery for severe multilevel LSS, and to analyzed difference in body and spine balance and movement using gait analysis,. Between March 2009 and March 2010 12 patients were selected for our study. 4 (33.3%) were female, 8 (66.7%) were male. Mean age at surgery was 63.50±15.23 (range 39-82) years. A mean of 2.50±0.80 (range 1-4) sympthomatic levels were treated for patient. Mean operative time was 90.42±18.40 minutes. In all procedures there was just light intraoperative blood loss. Mean hospitalization was 3.08±1.08 days. There was a mean return to walk after 1.83±0.58 days. Results of our short term prospective nonrandomized clinical study shown that decompressive recalibrage plus interspinous distraction is an effective and safe procedure for severe multilevel LSS. Patients had improvement both on sympthoms and on functionality and capacity. All patients were satisfied for the procedure, with a personal satisfaction rate (0-10) of 8.33±1.53. After surgery there were significant statistical improvement in VAS pain (pv=0.000), in ODI lumbar function (pv=0.000), and in SF36 health status (pv=0.000). Gait analysis showed an objective, and not just subjective, improvement in patient functionality and capacity. Trials proved a global improvement in spinal range of motion after surgery (pv=0.001 both on flexion-extension, and on lateral bending, and on axial rotation), with re-distribution of plantar anterior-posterior loading, and better plantar loading distribution on static trials, signs of improved balance. There were reduction of postures to prevent pain. There was a statistical improvement in walking capacity. It will be important to continue follow-up of patients, implementing sample, in order to verify long-term follow-up, real focus on treatment choice.
La stenosi del canale vertebrale lombare (LSS) è una patologia tipica dell’età avanzata che si manifesta classicamente con claudicatio neurogenica, o spinale, e disabilità progressiva nella deambulazione associata o meno a lombalgia- lombosciatalgia. Sebbene l’incidenza e la prevalenza delle forme sintomatiche di LSS non sia stata ancora bene stabilita, questa patologia degenerativa è la principale causa di chirurgia vertebrale nei pazienti oltre i 65 anni. Il trattamento dei pazienti con LSS si basa sulle sue manifestazioni cliniche. Dopo iniziale fallimento di terapie conservative, diversi autori consigliano il trattamento chirurgico. Scopo del nostro lavoro clinico prospettico non randomizzato è stato studiare risultati, efficacia, e complicanze a breve termine del trattamento della LSS mediante recalibraggio decompressivo associato ad artrorisi interspinosa, analizzando mediante la gait analysis il reale effetto su equilibrio e motilità della colonna segmentale lombare e globale. Tra Marzo 2009 e Marzo 2010 sono stati selezionati per il nostro studio 12 pazienti, 4 (33.3%) femmine, 8 (66.7%) maschi. L’età media era 63.50±15.23 (range 39-82) anni. Sono stati trattati in media 2.50±0.80 (range 1-4) livelli stenotici sintomatici per paziente. Il tempo operatorio medio è stato 90.42±18.40 minuti. Le perdite ematiche intraoperatorie sono state trascurabili. Il ritorno alla deambulazione autonoma è avvenuto dopo una media di 1.83±0.58 giorni dall’intervento. La durata media dell’ospedalizzazione è stata 3.08±1.08 giorni. I risultati del nostro studio clinico prospettico non randomizzato a breve termine dimostrano come l’intervento di recalibraggio associato a distrazione interspinosa Coflex sia procedura efficace e sicura nel trattamento della stenosi del canale vertebrale lombare severa multilivello. Questo intervento, oltre alla risoluzione dei sintomi, porta ad un miglioramento della funzionalità e delle capacità dei pazienti. Tutti i pazienti erano soggettivamente soddisfatti dell’intervento effettuato, con un indice di soddisfazione personale medio di 8.83±1.11 su una scala da 0 a 10. Dopo l’intervento si ha un miglioramento statisticamente significativo del dolore (pv=0.000), della funzionalita’ lombare (pv=0.000), e dello stato di salute (pv=0.000). La gait analysis ha dimostrato un miglioramento della funzionalità e delle capacità dei pazienti non solo legato a questionari clinici soggettivi, ma rilevato oggettivamente. Si ha un miglioramento della motilità della colonna su tutti i 3 piani dello spazio (pv=0.001 sia per la flesso-estensione, che per la deviazione laterale, che per la rotazione assiale), una ridistribuzione dei carichi sull'asse antero-posteriore ed una migliorata distribuzione delle pressioni plantari durante le prove statiche, segno di maggiore equilibrio, una riduzione degli atteggiamenti posturali attuati per prevenire il dolore, un miglioramento delle capacità deambulatorie. Sarà importante tenere seguito nel tempo questo gruppo di pazienti, implementando sia il campione che il follow-up, per verificare l’effettiva tenuta nel tempo dei risultati, nodo cruciale nella scelta del trattamento.diante gait

Obiettivo: Scopo del nostro studio è stato quello di valutare la fattibilità, l’efficacia ed i benefici del posizionamento di un nuovo dispositivo interspinoso statico-dinamico, denominato “Falena”, in Pazienti con stenosi degenerativa del canale vertebrale lombare di grado moderato o severo e con età superiore a 50 anni, valutati con esami clinici e strumentali pre e post procedura. Materiali e Metodi: Nel periodo compreso tra Ottobre 2008 e Novembre 2009 sono stati arruolati 26 Pazienti (17M, 9F; età media 69 anni). I criteri di inclusione sono stati: Pazienti con età uguale o superiore a 50 anni che presentavano stenosi del canale vertebrale degenerativa con claudicatio neurogena. Tutti i Pazienti erano stati preliminarmente trattati, senza aver ottenuto benefici, con terapia farmacologica, fisioterapia ed iniezioni epidurali per almeno 6 mesi. La diagnosi di stenosi del canale vertebrale e dei forami di coniugazione è stata in tutti confermata mediante esame radiografico, esame RM o, in presenza di controindicazioni, con esame TC. Risultati: 26 Pazienti sono stati sottoposti al posizionamento di un singolo DI tipo “Falena” . Di questi, 20 (80%) sono stati posizionati a livello dello spazio interspinoso L4-L5; e 6 (20%) a livello dello spazio L3-L4. Il calibro del DI utilizzato è stato di 10 mm in 20 casi (16 a livello dello spazio interspinoso L4-L5 e 4 a livello dello spazio L3-L4). DI di 12 mm sono stati utilizzati nei restanti 6 casi (4 L4-L5 e 2 L3-L4). Tutti i pazienti hanno compilato i questionari ODI e VAS prima dell’intervento e ai controlli effettuati a 1 e 3 mesi. 12 pazienti sono sottoposti anche ad un follow up a 6 mesi. La durata del ricovero è stata di 3 giorni in tutti i pazienti tranne uno che presentava dolore alla ferita chirurgica e pertanto è stato trattenuto per 4 notti. In 22 pazienti (85%) è stata eseguita una RM prima e a 3 mesi dall’intervento per valutare l’altezza dello spazio intersomatico, l’area e i diametri del canale vertebrale a livello trattato. Nei restanti 4 pazienti (15%) è stato eseguito un esame TC prima e a 3 mesi dall’intervento a causa della presenza di controindicazioni alla RM. In nessun paziente è stata documentata la migrazione del DI durante il follow-up. In tutti i pazienti vi è stata una riduzione della sintomatologia clinica. Conclusioni: Lo studio evidenzia come l’uso di questo tipo di distanziatore interspinoso sia efficace, anche se nell’ambito di una casistica ristretta, nel ridurre significativamente la sintomatologia generata da stenosi degenerativa del canale vertebrale. Tale DI ha mostrato una buona facilità di posizionamento con incisione chirurgica limitata e, utilizzando macchinari ad alta tecnologia e in mani esperte, bassa incidenza di complicanze con rapido recupero dei pazienti con minimi tempi di degenza.
Purpose of our study has been that to appraise the feasibility, the effectiveness and the benefits of the positioning of a new regulating static-dynamic interspinos device (ID), denominated "FALENA", in Patient with degenerative stenosis of the lumbar vertebral channel of moderate or severe degree and with superior age to 50, valued with clinical and instrumental examinations pre and post procedure. Materials and Methods: In the inclusive period between October 2008 and November 2009 26 Patients have been enlisted (17M, 9F; age middle 69 years). The criterions of inclusion have been: Patient with equal or superior age to 50 that introduced degenerative stenosis of the vertebral channel with neurogenic claudication. All the Patients had preliminarily been treated, without having gotten benefits, with pharmacological therapy, physiotherapy and epidural injections for at least 6 months. The diagnosis of stenosis of the vertebral channel and the perforate me of conjugation you/he/she has been in all confirmed through radiographic examination, examination RM or, in presence of side effects, with examination TC. Results: 26 patients have been submitted to the positioning of an individual Type "FALENA." Of these, 20 (80%) have been positioned to level of the interspinous space L4-L5; and 6 (20%) to level of the space L3-L4. The caliber of the ID used you/he/she has been of 10 mm in 20 cases (16 to level of the space interspinous L4-L5 and 4 to level of the space L3-L4). ID of 12 mm have been used in the remainders 6 cases (4 L4-L5 and 2 L3-L4). All the patients have compiled the questionnaires ODI and VAS before the intervention and to the controls effected to 1 and 3 months. 12 patients are also submitted to a follow up to 6 months. The duration of the refuge has been of 3 days all the patients except one that introduced pain to the surgical wound and therefore you/he/she has been held back for 4 nights. In 22 patients (85%) a RM has been performed before and to 3 months from the intervention to appraise the height of the intersomatic space, the area and the diameters of the vertebral channel to level essay. In the remainders 4 patient (15%) an examination TC has been performed before and to 3 months from the intervention because of the presence of side effects to the RM. In any patient you/he/she has been documented the migration of the Of during the follow-up. In all the patients you/he/she has been you a reduction of the symptomatic clinical. Conclusions: The study underlines as the use of this type of interspinous device is effective, even if within a narrow casuistry, in to meaningfully reduce the symptomatic produced by degenerative stenosis of the vertebral channel. Such Of you/he/she has shown a good facility of positioning with limited surgical incision and, using machineries to high technology and in experienced hands, low incidence of complications with rapid recovery of the patients with least times of hospitalization.

Abstract Objectives: Determine whether valve morphology, pulmonary annulus diameter, aortic/pulmonic annulus ratio, balloon-to-annulus ratio (BAR), prepulmonary balloon valvuloplasty (PBV), Doppler gradient, and residual Doppler gradient are independent predictors of immediate and long-term results after PBV in dogs as in humans. Animals, materials and methods: Retrospective study. Medical records of dogs that underwent PBV, from January 1999 to December 2008 were reviewed. All dogs with pre- and immediate (24 h) post-PBV echocardiographic examination were included. 126 dogs were selected. Immediate outcome was optimal when the dog survived the PBV and Doppler gradient was 50 mmHg. Long-term outcome (1 year) was optimal when the dog survived at least 1-year follow-up without symptoms and Doppler gradient was 50 mmHg. Results: Only pre-PBV Doppler gradient was identified as a significant independent predictor of immediate results (P < 0.001; OR 0.97, CI 0.96e0.98). Pre-PBV Doppler gradient and residual Doppler gradient were the only independent predictors of long-term results (P ¼ 0.036; OR 0.98, CI 0.96e0.99 and P ¼ 0.005; OR 0.95, CI 0.92e0.98, respectively).

L’Estenosi aòrtica (EAo) és la valvulopatia més comuna i que requereix amb més freqüència substitució valvular aòrtica (SVAo) en els països desenvolupats. La substitució valvular tant sigui per tècniques quirúrgiques com percutànies és l’únic tractament eficaç i aquest tractament està indicat quan hi ha símptomes associats o disfunció ventricular esquerra. En els últims anys, els bons resultats de la cirurgia cardíaca així com els significatius avenços de les tècniques percutànies han fet que ens plantegem el recanvi valvular aòrtic en fases més precoces de la malaltia, quan el pacient encara està asimptomàtic. Tot i això, la decisió entre realitzar una cirurgia precoç versus l’estratègia d’observar i detectar factors predictius d’esdeveniments (coneguda com “watchful waiting strategy”) és una decisió complexa que engloba una valoració global del pacient i continua essent un tema no resolt. Idealment, la intervenció s’ha de realitzar just quan el ventricle esquerre inicia un cert grau de disfunció però abans que aparegui un dany irreversible. La integració de la clínica, l’educació sanitària, l’estratificació del risc quirúrgic, l’anàlisi de l’ecocardiografia i altres tècniques d’imatge, la valoració dels biomarcadors i l’evolució dels mateixos en el temps, així com la realització i correcte interpretació de l’ecocardiografia d’esforç físic són punts bàsics que s’han d’incloure en una programa de maneig de pacients amb estenosi aòrtica severa asimptomàtica en Unitats clíniques especialitzades en malalties valvulars, per tal de realitzar una indicació de recanvi valvular en el moment més oportú pel pacient, així com establir la indicació de la millor tècnica i abordatge per tal de portar a terme el recanvi valvular. En aquesta tesi doctoral s’ha realitzat un estudi prospectiu dels pacients amb EAo severa asimptomàtica atesos en una consulta monogràfica de pacients valvulars de l’Hospital Germans Trias i Pujol amb la finalitat de conèixer les característiques i l’evolució d’aquests pacients en el nostre mitjà i analitzar els diferents factors predictius d’esdeveniments en pacients amb EAo severa asimptomàtica. Hem realitzat un estudi i un seguiment protocol•litzat dels pacients, que ens ha permès obtenir informació de les característiques clíniques d’aquests pacients, de la seva evolució i del seu pronòstic. Així mateix, hem pogut analitzar l’aportació de les diferents tècniques diagnòstiques utilitzades. Així, hem observat com l’ecocardiografia d’esforç és una tècnica que ens ajuda en el maneig dels pacients no tan sols si es realitza en la valoració inicial d’aquests pacients, sinó també quan es repeteix l’estudi al llarg del seguiment. D’altra banda, un enfocament biològic amb l’ús de biomarcadors cardíacs ens ha permès detectar pacients de risc de descompensació, fet que ajuda a un millor maneig dels pacients amb EAo severa asimptomàtica. En la nostre sèrie de pacients amb EAo severa asimptomàtica no només el valor inicial de Troponina T d’ alta sensibilitat (Hs-TnT) comporta un major risc d’esdeveniment a l’any de seguiment sinó que un increment >20% del valor de Hs-TnT als 6 mesos, multiplica per 8 el risc d’esdeveniment a l’any de seguiment, independentment del valor obtingut en l’analítica inicial. Amb la mateixa idea, hem iniciat un estudi que posa els fonaments per seguir una línia d’investigació de l’aportació de la proteòmica en el maneig d’ aquests pacients. Tota l’experiència i informació obtinguda ens permetrà determinar millor el moment per indicar el recanvi valvular dels nostres pacients abans que apareguin canvis irreversibles del ventricle esquerre.
La Estenosis aórtica (EAO) es la valvulopatía más común y que requiere con más frecuencia sustitución valvular aórtica (SVAo) en los países desarrollados. La sustitución valvular tanto sea por técnicas quirúrgicas como percutáneas es el único tratamiento eficaz y este tratamiento está indicado cuando hay síntomas asociados o disfunción ventricular izquierda. En los últimos años, los buenos resultados de la cirugía cardíaca así como los significativos avances en las técnicas percutáneas han hecho que nos planteemos el recambio valvular aórtico en fases más precoces de la enfermedad, cuando el paciente aún está asintomático. Sin embargo, la decisión entre realizar una cirugía precoz versus la estrategia de observar y detectar factores predictivos de eventos (conocida como “watchful waiting strategy”) es una decisión compleja que engloba una valoración global del paciente y sigue siendo un tema no resuelto. Idealmente, la intervención se debe realizar justo cuando el ventrículo izquierdo inicia un cierto grado de disfunción pero antes de que aparezca un daño irreversible. La integración de la clínica, la educación sanitaria, la estratificación del riesgo quirúrgico, el análisis de la ecocardiografía y otras técnicas de imagen, la valoración de los biomarcadores y la evolución de los mismos en el tiempo, así como la realización y correcto interpretación de la ecocardiografía de esfuerzo físico son puntos básicos que deben incluirse en una programa de manejo de pacientes con estenosis aórtica severa asintomática en Unidades Clínicas especializadas en Enfermedades Valvulares, para realizar una indicación de recambio valvular en el momento más oportuno para el paciente, así como establecer la indicación de la mejor técnica y abordaje para llevar a cabo el recambio valvular. En esta tesis doctoral se ha realizado un estudio prospectivo de los pacientes con EAO severa asintomática atendidos en una consulta monográfica de pacientes valvulares del Hospital Germans Trias i Pujol con el fin de conocer las características y la evolución de estos pacientes en el nuestro medio y analizar los diferentes factores predictivos de eventos en pacientes con EAO severa asintomática. Hemos realizado un estudio y un seguimiento protocolizado de los pacientes, que nos ha permitido obtener información de las características clínicas de dichos pacientes, de su evolución y de su pronóstico. Asimismo, hemos podido analizar la aportación de las diferentes técnicas diagnósticas utilizadas. Así, hemos observado como la ecocardiografía de esfuerzo es una técnica que nos ayuda en el manejo de los pacientes no sólo si se realiza en la valoración inicial de estos pacientes, sino también cuando se repite el estudio a lo largo del seguimiento. Por otra parte, un enfoque biológico con el uso de biomarcadores cardíacos nos ha permitido detectar pacientes de riesgo de descompensación, lo que ayuda a un mejor manejo de los pacientes con EAO severa asintomática. En nuestra serie de pacientes con EAO severa asintomática no sólo el valor inicial de Troponina T de alta sensibilidad (Hs-TNT) conlleva un mayor riesgo de evento al año de seguimiento sino que un incremento> 20% del valor de Hs-TNT a los 6 meses, multiplica por 8 el riesgo de evento al año de seguimiento, independientemente del valor obtenido en la analítica inicial. Con la misma idea, hemos iniciado un estudio que pone los cimientos para seguir una línea de investigación de la aportación de la proteómica en el manejo de estos pacientes. Toda la experiencia e información obtenida nos permitirá determinar mejor el momento para indicar el recambio valvular de nuestros pacientes antes de que aparezcan cambios irreversibles del ventrículo izquierdo.
Aortic stenosis (AoS) is the most frequent valve pathology in the developed world and the one that most frequently requires aortic valve replacement (AoVR). Valve replacement, either surgical or percutaneous, is the only effective treatment and is indicated in the presence of associated symptoms or left ventricular dysfunction. In the last years, the good results achieved in heart surgery and the significant advances made in percutaneous techniques have allowed aortic valve replacement to be considered at an earlier stage of the disease, when the patient still has no symptoms. However, early surgery vs. event predictive factor observation and detection (the “watchful waiting” strategy) is a complex decision requiring global patient assessment, and it remains unresolved. Ideally, the surgical procedure should be carried out as soon as the left ventricle begins to present a certain degree of dysfunction, before irreversible damage occurs. Clinical data integration, healthcare education, surgical risk stratification, echocardiography evaluation and analysis of other imaging techniques, biomarker assessment and biomarker evolution with time, and a correct interpretation of physical activity echocardiography are key points to be included in asymptomatic severe aortic stenosis patient management programs in clinical facilities specialized in valve pathologies. This allows valve replacement to be indicated in the most timely fashion possible for the patient, as well as the best technique and approach for valve replacement purposes to be established. As part of this PhD thesis, a prospective study of asymptomatic severe AoS patients from a specialized valve patient consultation at Germans Trias i Pujol Hospital was carried out. The objective was to analyze the characteristics and evolution of these patients in our environment and assess event predictive factors in asymptomatic severe AoS patients. A protocolized patient study and follow-up was performed, which provided significant information on patients’ clinical characteristics, evolution, and prognosis. In addition, the contribution of the various diagnostic techniques used was also analyzed. Physical activity echocardiography proved to be helpful in terms of patient management, not only if carried out at baseline assessment, but also when repeated throughout follow-up. Moreover, a biological approach with the use of cardiac markers allowed decompensation risk patients to be detected, which translated into better asymptomatic severe AoS patient management. In our series of asymptomatic severe AoS patients, not only did high-sensitivity troponin T (Hs-TNT) baseline levels lead to a higher event risk after one-year follow-up, but also >20% increases in Hs-TNT levels after six months multiplied event risk after one-year follow-up by 8, regardless of baseline levels. With the same idea in mind, another study was set up in order to lay the foundations of a new research line on proteomics contribution in the management of these patients. The experience and information gathered will allow the best time for valve replacement indication to be determined before left ventricular irreversible changes occur.

Obiettivo: convalidare l'utilizzo della metodica VH IVUS nella caratterizzazione ex vivo della placca ateromasica carotidea e confrontarne l’accuratezza diagnostica in vivo con quella della Risonanza Magnetica Microscopy (RMM) nella caratterizzazione di placca, allo scopo di identificare l’efficacia e la fattibilità della VH IVUS, considerandola inoltre quale valida alternativa alla stessa RMM. Materiali e metodi: la VH IVUS è stata convalidata mediante caratterizzazione ex vivo di sezioni selezionate di elaborazioni VH di placche carotidee umane utilizzando un’analisi di base pixel-by-pixel. Abbiamo quindi esaminato in vivo 12 pazienti sintomatici mediante RMM e VH, comparativamente Risultati: ex vivo, la sensibilità della VH è stata circa 100,0%, 94,2%, 84,1% e 67,1% nella caratterizzazione rispettivamente del tessuto fibroso, tessuto fibro-lipidico, calcio e necrotico, mentre la specificità è risultata pari a circa il 99,2%, 84,3%, 97,4% e 99,2% , rispettivamente. In vivo, la sensibilità VH è stata 86,1%, 93,7%, 89,3% e 65,4% nel caratterizzare rispettivamente il tessuto fibroso, tessuto fibro-lipidico, calcio e tessuto necrotico, la specificità si è dimostrata pari a circa 84,3%, 97,5%, 99,2% e il 98,1%, rispettivamente. La concordanza tra le due metodiche è stata significativa. Il successo tecnico della procedura di stenting carotideo (CAS) IVUS guidata è stato del 100%. Non abbiamo osservato complicazioni postprocedurali nè restenosi dello stent carotideo durante i 36 mesi di follow-up. Conclusioni: la VH IVUS è una valida alternativa alla RMM nella valutazione in vivo della placca carotidea.
Purpose: to validate the use of Virtual Histology-Intravascular Ultrasound (VH-IVUS) in the ex vivo characterization of carotid plaque and to compare in vivo diagnostic accuracy of VH-IVUS and Microscopy Magnetic Resonance (MMR) in the carotid plaque characterization in order to identify VH IVUS efficacy and feasibility, considering it also as a valid alternative to MMR. Materials and methods: VH was validated by characterization ex vivo of selected cross-sections VH images of human carotid plaque by use of a pixel-by-pixel basis analysis. Subsequently we evaluated in vivo 12 symptomatic patients with MMR and VH, comparatively. Results: ex vivo, VH sensitivity was 100.0 %, 94.2%, 84.1%, and 67.1% in characterizing fibrous tissue, fibro-lipid tissue, calcium and necrosis, respectively; specificity was 99.2%, 84.3%, 97.4%, and 99.2%, respectively. In vivo, VH sensitivity was 86.1%, 93.7%, 89.3% and 65.4%, in characterizing fibrous tissue, fibro-lipid tissue, calcium and necrosis, respectively; specificity was 84.3%, 97.5%, 99.2% and 98.1%, respectively. Concordance between the methods was significant. Technical success of IVUS guided CAS was 100%. We didn’t observe any postprocedural complications and restenosis of carotid stent during 36 months follow up. Conclusions: VH is a valid alternative to MMR in the in vivo assessment of carotid plaque.

Background. The traditional view of aortic valve calcification as a slow, ineluctable event has been recently questioned by evidence showing the importance of a balance between promoting and inhibiting factors, and the relevance of osteogenic cellular-driven processes. The aortic valve leaflets are comprised of a heterogeneous population of interstitial cells (VIC) whose specific contribution to the degenerating valve has not been defined yet. Aim. The major aim is to identify and describe the phenotypic characteristics of a subpopulation of aortic VIC able to acquire a pro-calcific profile when exposed to pathological stimuli (such as endotoxin [LPS] and inorganic phosphate [Pi]). Methods and Results. Explants-derived primary bovine VIC (BVIC) were cloned by a limited dilution technique. Characterization of BVIC clones was performed by morphological and functional as well as immunophenotyping using markers specific for mesenchymal cells, smooth muscle (SM) cell lineage, endothelial cells, hematopoietic cells, and bone formation process. Among the 40 BVIC clones obtained we selected four clones, morphologically representative of the isolated populations, which displayed different growth pattern and immunophenotype. Both uncloned and cloned cell populations grown on plastics did not show a spontaneous tendency for calcification in the standard medium and were, hence, treated with different combinations of LPS (100 ng/ml) and Pi (2.4 mmol/L, final concentration) for 12 days. Uncloned BVIC showed a progressive increase of alkaline phosphatase (ALP) activity after treatment with LPS that resulted in calcium deposition after addition of Pi. Among the clones, only Clone 1 (fibroblast-like phenotype) showed relevant increase in ALP after LPS treatment, which was paralleled by an increased osteocalcin (OC) expression and prevention of smooth muscle (SM) ??actin (SMA) accumulation, as demonstrated by western blotting and cytofluorimetry analysis. The same treatment had no effect on Clone 4 cells that showed a more stable SM cell-like phenotype. Despite ALP activity and OC increase Clone 1 cells did not undergo calcium deposition after treatment with LPS in long-term culture supplemented with Pi. However, mineralization was observed in co-culture of Clone 1 and Clone 4 treated with LPS plus Pi. Moreover, when cells of Clone 1 were grown on type-I collagen sponges and treated with Pi alone or LPS plus Pi for 12 days we observed an extensive mineralization of the collagen-matrix. Instead, only modest calcium deposition was observed in collagen scaffolds seeded with Clone 4 treated in the same way. A high degree of apoptosis was documented in Clone 1 cells seeded in the collagen scaffolds and treated with LPS plus Pi. No apoptotic degeneration was observed in Clone 4 cells. The proteomic analysis of the cytosolic fraction of Clone 1 cells allowed the identification of 34 proteins which levels of expression were modified with the acquisition the pro-calcific profile. Among these proteins we documented a significant decrease in the expression of antioxidant proteins, such as superoxide dismutase [Cu-Zn] and thioredoxin, together with a downregulation in the level of dimethylarginine dimethylaminohydrolase (DDAH), an intracellular enzyme that degrades asymmetric dimethylarginine (ADMA) (a nitric oxide synthase inhibitor [NOS]). In line with these findings we observed that LPS treatment of Clone 1 cells was accompanied by increased reactive oxygen species (ROS) production. Conclusion. The results of this study demonstrate that BVIC clonal subpopulations are endowed with different calcifying potential when stimulated with the same pathogenic factors. In particular, we identified a specific BVIC subset harbouring a fibroblast-like phenotype that express osteogenic markers and promote collagen-matrix calcification in response to endotoxin and elevated phosphate levels.
Introduzione. Tradizionalmente la calcificazione valvolare aortica viene considerata un processo distrofico, ad evoluzione lenta e non modificabile. Tale visione è stata recentemente messa in discussione da evidenze che sottolineano l’importanza, nel corso della calcificazione vascolare, di un bilanciamento fra fattori promuoventi ed inibenti, nonché del ruolo svolto da processi cellulo-mediati. I lembi valvolari aortici sono popolati da cellule interstiziali valvolari (VIC) fenotipicamente eterogenee, il cui contributo specifico nel corso dei processi degenerativi della valvola è solo parzialmente conosciuto. Scopo. Scopo del presente studio è quello di ricercare e caratterizzare una sottopopolazione aortica di VIC in grado di acquisire un fenotipo pro-calcifico in seguito ad esposizione a fattori patogeni (quali endotossina [LPS] e fosfato inorganico [Pi]). Metodi e Risultati. VIC ottenute da espianti di valvole aortiche bovine (BVIC) sono state sottoposte ad un processo di clonazione, mediante tecnica di diluizione limite. I cloni di BVIC sono stati caratterizzati sotto il profilo morfologico ed immunofenotipico mediante l’utilizzo di marcatori tipici per cellule mesenchimali, cellule muscolari lisce (SMC), cellule endoteliali, cellule ematopoietiche e cellule di derivazione ossea. Fra i 40 cloni di BVIC ottenuti sono stati selezionati 4 cloni, morfologicamente rappresentativi delle diverse popolazioni isolate, che mostravano diverse caratteristiche di crescita e di profilo immunofenotipico. Sia la popolazione cellulare di VIC non clonate che i cloni non mostravano la tendenza a fenomeni spontanei di calcificazione in vitro. Le cellule sono state quindi trattate con diverse combinazioni di LPS (100 ng/ml) e Pi (2.4 mmol/L concentrazione finale) per 12 giorni. La popolazione non clonale di BVIC ha mostrato un progressivo incremento nei livelli di espressione della fosfatasi alcalina (ALP) dopo trattamento con LPS, mentre la deposizione di calcio è stata osservata solo nelle cellule trattate con la combinazione di LPS e Pi. Fra i diversi cloni solo il Clone 1 (fenotipo simil-fibroblasto) ha mostrato un significativo incremento nei livelli di espressione dell’ALP. Tale incremento si accompagnava ad un’aumentata espressione di osteocalcina (OC) e ridotto accumulo di ?-actina muscolare liscia (SMA), come documentato da studi in western blotting e citofluorimetria. Il trattamento con LPS non è stato in grado di indurre modifiche simili nel profilo fenotipico del Clone 4 (fenotipo muscolare liscio differenziato). Nonostante il significativo incremento nell’espressione di ALP ed OC, il Clone 1 non ha prodotto fenomeni di calcificazione della matrice dopo trattamento con la combinazione di LPS ed Pi. Tuttavia, aspetti di calcificazione sono stati osservati in esperimenti di co-coltura del Clone 1 e Clone 4, quando trattati con la combinazione di LPS e Pi. Inoltre, dopo semina su spugne di collagene di tipo I, il Clone 1 si è dimostrato in grado di produrre estesi fenomeni di calcificazione della matrice, in seguito a trattamento per 12 giorni con LPS e Pi. Tale combinazione ha indotto solo minimi aspetti di calcificazione nella matrice di collagene popolata dal Clone 4. Fenomeni apoptotici sono stati osservati nel Clone 1 seminato nelle spugne di collagene e trattato con LPS e Pi. Viceversa, nel caso del Clone 4 non sono stati documentati aspetti apoptotici. L’analisi proteomica della frazione citosolica del Clone 1 ha permesso di identificare 34 proteine i cui livelli di espressione si modificano con l’acquisizione del profilo pro-calcifico. Fra queste proteine è stata documentata una significativa riduzione nei livelli di molecole antiossidanti, come la superossido dismutasi [Cu-Zn] e la tioredoxina. Un significativo decremento è stato osservato anche per i livelli di dimetilarginina dimetilaminoidrolase (DDAH), un enzima intracellulare che degrada la dimetilarginina asimmetrica (ADMA) (inibitore dell’ossido nitrico sintetasi [NOS]). In linea con questi dati è stato osservato un aumento della produzione di specie reattive dell’ossigeno (ROS) da parte del Clone 1 trattato con LPS. Conclusioni. I risultati di questo lavoro dimostrano che le popolazioni clonali di BVIC sono dotate di un diverso potenziale pro-calcifico quando stimolate con uno stesso fattore patogeno. In particolare, è stata identificata una specifica sottopopolazione di BVIC, caratterizzata da un profilo fenotipico simil-fibroblasto, che si è dimostrata in grado di esprimere marcatori osteogenici e di calcificare matrice di collagene, in risposta a trattamento con endotossina ed alti livelli di fosfato inorganico.

Background and study aims. While surgery remains the gold standard for the treatment of symptomatic common bile duct stenosis associated with chronic pancreatitis, plastic and self-expandable open mesh stents have been proposed as alternative treatments but are associated with dysfunction mainly due to stent occlusion by clogging or inflammatory tissue hyperplasia. The aim of this study was to evaluate safety and long-term results of partially covered metal stenting in this setting. Patients and methods. Fourteen patients (12 men, 50?3 years) underwent partially covered metal stent insertion for common bile duct stenosis secondary to chronic pancreatitis (12 alcohol-related, 2 idiopathic) previously treated with plastic prostheses. Results. A 40 mm (n=13) or 60 mm (n=1) partially covered metal stent was placed depending on the length of the common bile duct stenosis and the level of the cystic duct bifurcation. Partially covered metal stent placement was technically successful in all but one case. Cholangitis resolved and cholestasis improved in all. During follow-up (median 22 months, range 12-33) seven patients developed dysfunction of the stent and required re-treatment. At 12, 24, and 30 months, the stent patency rate was 100, 40, and 37.5%, respectively. Conclusions. While partially covered metal stenting is safe and effective for immediate treatment of chronic pancreatitis associated common bile duct stenosis and had promising short term results, long-term data show that dysfunction occurs in 50% of cases. In light of the continued interest in non-surgical treatment of this condition, further research is warranted investigating new stent designs for improved long-term patency.

Background: Despite the results of some randomized controlled trials in the last 5 years it remains unclear whether revascularization of atherosclerotic renal artery stenosis (ARAS) by means of percutaneous renal angioplasty and stenting (PTRAS) is advantageous over optimal medical therapy. Materials and methods: The METRAS study was designed with the primary objective to determine whether PTRAS is superior or equivalent to optimal medical treatment for preserving glomerular filtration rate (GFR) in the ischemic kidney, as assessed by 99mTc-DTPA renal scintigraphy. Secondary objectives were to establish whether the two treatments are equivalent in lowering blood pressure, preserving overall renal function and regressing target organ damage. Results: At 2 years follow-up compared to the medical treatment in the endovascular group GFR in the ischemic kidney was higher (p=0.027). Moreover, 24 hours DBP was lower in PTRAS group compared to medical therapy at 3 years follow-up (p=0.029). Of note, this difference occurred despite borderline significant (p=0.055) lower need for number of antihypertensive drugs. Both serum creatinine and cystatin-c were lower in PTRAS group compared to medical therapy (p=0.035 and p=0.02, respectively). HBA1c was also lower in PTRAS group compared to medical therapy (p=0.034). Left ventricular mass index, as assessed by echocardiography, was also borderline significant (p=0.058) lower in the PTRAS group. Diastolic dysfunction, as assessed by E/E’ ratio at tissue Doppler, improved in the PTRAS group compared to medical therapy (p=0.011). Conclusions: In the carefully selected patients with atherosclerotic renovascular hypertension of the METRAS study PTRAS on top of optimal medical therapy provided an improvement in GFR in the ischemic kidney and a better DBP control despite a lower need of antihypertensive drugs compared to optimally treated patients receiving medical therapy only.
Background: la stenosi delle arterie renali è una delle cause principali d'insufficienza renale e d’ipertensione arteriosa secondaria. Studi epidemiologici hanno dimostrato che la stenosi dell’arteria renale su base aterosclerotica implica non solo un elevato profilo di rischio cardiovascolare, ma anche un'aumentata incidenza di morbilità e mortalità per stroke, cardiopatia ischemica e arteriopatia periferica. La rivascolarizzazione percutanea con angioplastica transluminale e stenting è divenuta il trattamento di scelta, per lo meno nei pazienti in cui la terapia medica non consente un soddisfacente controllo dei valori pressori e per i quali è presumibile che la rivascolarizzazione possa ritardare o prevenire il declino della funzione renale. La reale utilità di tale costosa procedura rimane, tuttavia, fortemente dibattuta, poiché gli studi clinici prospettici randomizzati di confronto fra trattamento endovascolare e sola terapia medica pubblicati fino ad ora non sono stati conclusivi nel dimostrare una superiorità di un trattamento sull’altro. Materiali e metodi: lo studio METRAS è stato disegnato con l’obiettivo primario di determinare se la rivascolarizzazione sia superiore o equivalente alla sola terapia medica nel preservare la funzione renale nel rene ischemico valutata con la scintigrafia renale al 99mTc-DTPA nei pazienti con stenosi aterosclerotica delle arterie renali. Obiettivi secondari includono il controllo pressorio, la preservazione della funzione renale globale e la regressione del danno d’organo. Risultati: nel gruppo trattato con terapia endovascolare la GFR nel rene ischemico misurata alla scintigrafia è risultata più alta rispetto al gruppo in terapia medica a 2 anni di follow-up (p=0.027). La pressione diastolica nelle 24 ore è risultata inferiore nel gruppo in trattamento endovascolare rispetto al braccio in terapia medica a 3 anni di follow-up (p=0.029) a fronte di un minore utilizzo di farmaci antipertensivi nel braccio endovascolare (p=0.055). I livelli di creatinina, cistatina-c ed emoglobina glicata sono risultati inferiori nei pazienti nel braccio endovascolare rispetto ai pazienti in sola terapia medica (rispettivamente p=0.035, p=0.020, e p=0.034). La massa ventricolare sinistra normalizzata per altezza è risultata inferiore nei pazienti trattati con trattamento endovascolare rispetto ai pazienti in terapia medica, seppur la significatività sia borderline (p=0.058) a fronte di un miglioramento della disfunzione diastolica, espressa come rapporto E/E’, in questo gruppo di pazienti rispetto al braccio in terapia medica (p=0.011). Conclusioni: lo studio METRAS ha dimostrato un miglioramento della GFR nel rene ischemico, un migliore controllo pressorio in termini di pressione diastolica nelle 24 ore ed un minor fabbisogno di farmaci antipertensivi nei pazienti trattati con angioplastica e stenting rispetto al gruppo in sola terapia medica.

Atherosclerosis (also known as Arteriosclerotic Vascular Disease or ASVD) is the condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by Low-density lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL). It is commonly referred to as a hardening or furring of the arteries. It is caused by the formation of multiple plaques within the arteries. Other arteriosclerotic disease is aortic aneurysm usually affecting the abdominal tract of the vessel. The prevalence of abdominal aortic aneurysm (AAA) varies ranging from 4.1% to 11.5% in European men. This disorder is characterized by localized structural deterioration of the aortic wall, leading to progressive dilatation and eventual aortic rupture. Rupture of AAA is responsible for 1.5% of the total mortality in males over 55 years of age. Both disease seem to share common causes in alteration in lipid metabolism and immune response against host and oxidised lipids, leading to a condition of chronic inflammation affecting all the vascular system, especially the big diameter arteries. There are several factors such as smoking, hypertension, hypercholesterolemia and male sex, which are well known risk factors for the development of AAA and carotid stenosis. However, better understanding of molecular mechanisms is an important step toward clarification of the pathophysiology, identification of genetic and molecular biomarkers and development of new therapeutic strategies for AAA and atherosclerosis in general. Gene expression profiling studies by microarray technologies are particularly appropriate to investigate and create working hypotheses to understand the pathophysiology of complex genetic tracts such as arteriosclerotic diseases. Previous microarray studies focused on AAA utilized RNA derived from aortic tissue samples. The use of tissue samples has several disadvantages, including the difficulty of obtaining control samples and bias introduced by use of normal specimens from non-age-matched cadavers, organ-transplant donors or patients with different diseases. Peripheral blood is a complex fluid with a high cellular turnover rate that provides physiological connectivity between tissues. Environmental or disease perturbations in the body may leave molecular signatures detectable by analyzing blood-derived RNA. Most importantly, since blood samples can be obtained readily and with little discomfort to patients, biomarkers derived from blood RNA provide an easier integration to clinical and imaging data for the diagnosis and prognosis of AAA and carotid stenosis. In this study we investigate the gene expression profile of venous whole peripheral blood obtained from AAA patients by using microarray technology to provide insight into systemic pathophysiological processes involved in this disease. Using the data obtained from the microarray analysis from which we detected 91 genes differentially expressed from patients and positive controls, we selected 10 gene belonging to pathways involved in lipid metabolism and immune response to deep our analysis and eventually confirm the microarray data in order to set up new reliable parameters for arteriosclerosis diseases diagnosis and prognosis. The genes we chosen are Lipid Metabolism: 8. Monoglyceride lipase - MGLL - U67963 - 11343 9. Free fatty acid receptor 2 - FFAR2 - AF024690 – 2867 10. Adiponectin receptor 1 - ADIPOR1 - AK001484 – 51094 11. Phospholipase A2, group IB (pancreas) - PLA2G1B - M21054 – 5319 12. Hydroxysteroid (17-beta) dehydrogenase 14 - HSD17B14 - NM_016246 3738 13. Acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain - ACADS Z80345 – 682 14. Low density lipoprotein receptor-related protein 5 - LRP5 - AF077820 - 4041 Immune system: 4. Toll-like receptor adaptor molecule 1 - TICAM1 - AF070530 - 7746 5. Interleukin 1 receptor accessory protein-like 1 - IL1RAPL1 - AJ243874 11141 6. Tumor necrosis factor type 1 receptor-associated protein - TRAP1 NM_016292 – 10131 We designed 10 couples of primers to analyze the expression levels of the genes onto 3 groups of subjects: 1. Control: N=40 2. AAA patients: N=40 3. Patients affected from carotid artery stenosis: N=40 We first analyze the expression levels of the control gene GAPDH of each subject and than we check the expression levels of the all ten genes comparing the resulting CT values with the ones gotten from the housekeeping gene. The result is the so-called ∆CT and we got these values for all the 120 subjects for everyone of the 10 genes in duplicates for a total of 1200 ∆CT values. Than we compare the average ∆CT values of the 80 patients (40 AAA + 40 carotid stenosis) with the control values to get the ∆∆CT values from which calculate the fold number (2-∆∆CT =FOLD) that provides a numeric but qualitative value of the expression level of the target gene that allow to compare the values with others present in literature. Our analysis are only semiquantitative for the moment but we first needed to check the reliability of the experimental approach. For the future studies we are going to use Taqman® probes to rise the specificity and sensitivity of the analysis, introducing a quantitative method using titolation commercial kit that allow to quantify the exact numbers of copies of an m-RNA transcript calculating the exact amount of m-RNA by substituting the CT values in a linear equation. We confirmed the microarray data and extended the results to the carotid stenosis patients. We were able to confirm the genes upregulation and hypothesise that PBMCs could be a suitable base for the detection of novel risk and prognostic indicators for the arteriosclerotic diseases. In fact our aim is to identify new easy-to-detect markers to predict the risk of developing an artery stenosis or most important, an aneurismatic lesion that is symptomless until the very late phases and whose success in treating is proportional to well-timed diagnosis. In the end seems that the right direction to look into are the metabolism of lipids and phospholipids, that are involved in eicosanoids production and degradation (via fatty acid metabolism) and cell signalling in the immune system.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology characterized by inflammation and obliterative fibrosis of the biliary tree. Although the course is highly variable, PSC is often progressive, leading to biliary cirrhosis and its complications. Overall, PSC is a severe disease and median transplant-free survival ranges from 13 years in patients seen at tertiary referral centres to 20 years in a population-based cohort. Liver transplantation is the only life-extending therapeutic intervention for patients with end-stage liver disease. No medical therapy has proven to be effective to halt disease progression. The clinical course of the disease is highly variable among different patients. Identification of prognostic factors is essential for tailoring the follow-up strategies and/or testing new therapeutic modalities in subgroups of PSC patients with poor prognosis. Magnetic resonance cholangiography is recommended as the first diagnostic modality in patients with suspected PSC and its potential role in assessing prognosis is justified by its non-invasive nature, its reproducibility and its adequate performance in assessing biliary alterations in PSC that resulted comparable to that of endoscopic cholangiography. The aim of this thesis was to assess the prognostic value of magnetic resonance imaging in these patients. I thus assessed the prognostic value of two MR risk scores in predicting the risk of adverse outcomes and I evaluated whether the use in combination of MR risk score with liver stiffness may improve risk stratification of these patients. I evaluated the radiological and clinical course of PSC patients with intrahepatic bile ducts cystic dilatations found at magnetic resonance cholangiography and I assessed the prognostic value of this finding. Finally, I assessed the existence of magnetic resonance cholangiography and clinical criteria of improvement after endoscopic treatment for severe strictures. The results of this research demonstrated that two simple MR risk score were associated to the risk of adverse outcomes in PSC patients and that the use in combination of MR risk score without gadolinium-based contrast agent injection with liver stiffness was able to improve risk stratification in these patients. I reported on a subgroup of patients with cystic dilatations of intrahepatic bile ducts and I documented that these patients were characterized by a younger age at PSC diagnosis, a rapid radiological and clinical evolution, and a significantly lower median transplant free survival from PSC diagnosis compared with PSC patients without cystic dilatations. Finally, I documented that some magnetic resonance cholangiography features together with biochemical features, may contribute to identify PSC patients likely to improve after endoscopic treatment for severe strictures of extrahepatic bile ducts. In conclusion, I here provided some evidences in favour of the use of magnetic resonance imaging for prognostic, other than diagnostic, purposes in PSC.

Aortic stenosis (AS) has become the most frequent type of valvular heart disease in Europe and North America. As it primarily presents as calcific AS in adults of advanced age (2–7% of the population >65 years), its prevalence is expected to increase further in the future with an aging population. Severe AS is associated with debilitating symptoms (shortness of breath, angina, dizziness, or syncope), and reduced survival if left untreated. According to European Society of Cardiology guidelines, aortic valve replacement (AVR) is the definitive therapy for all patients with symptoms and severe AS, or severe AS with left ventricular systolic dysfunction. However, approximately the 30% of patients referred for AVR are denied surgery because of advanced age, left ventricular dysfunction or comorbidities. Over the last few years, transcatheter aortic valve implantation (TAVI) has been demonstrated to be a feasible and effective therapeutic alternative to traditional AVR for high-risk surgical patients. Clinical trials have shown TAVI to have outcomes similar to surgical AVR up to 2 years after the procedure and excellent outcomes have been confirmed by registry data, with overall survival of 76% at 1 year. TAVI is an invasive technique whose success depends on multidisciplinary team approach, where imaging fulfils a definite part. Pre-procedure imaging is vital to assess the severity of AS, identify eligible candidates, plan the interventional approach, and select the appropriate prosthesis according to the anatomical features. Imaging is pivotal during and after the procedure, guiding prosthesis deployment, providing information regarding valve position, identifying immediate complications, and assessing outcomes. Before TAVI, accurate evaluation of the aortic root dimensions and anatomy is essential for the selection of eligible candidates for the procedure and to ensure the appropriately sized valve prosthesis is chosen. The objective of this thesis is to investigate the incremental value of a multimodality imaging approach to the evaluation of the anatomy of the aortic valve apparatus in TAVI candidates. Chapter 1 illustrates the feasibility and accuracy of 3D transthoracic echocardiography (TTE) compared to 2D TTE and multidetector computed tomography (MDCT) for the measurement of aortic annulus dimensions in the preoperatory evaluation of 100 patients candidates to TAVI. 3D TTE evaluation was feasible in the majority of the patients with low intra and inter observer variability. 3D TTE and MDCT measurements did not differ significantly, with excellent agreement in the selection of cases with too small or too large annulus (recognized exclusion criteria for TAVI) while, as expected due to the oval shape of the aortic annulus, the 2D TTE annulus area, geometrically derived from 2D TTE diameter, was considerably lower in comparison both with 3DTTE and MDCT planimetric surface area. A good agreement in the choice of prosthetic size in cases scheduled for the procedure was found between the 3D TTE and MDCT. Subsequently, even though it’s known that MDCT provides precise information about the annulus anatomy and remains the gold standard for the pre-operative assessment of TAVI candidates, 3D TTE may play a role in those patients that can’t be studied by MDCT for several reasons such as impaired renal function, severe breathlessness, and arrhythmias. 3D TTE does not require breath-old and contrast infusion, may be obtained at the bedside, in more critical cases, and also in the presence of arrhythmias. Chapter 2 shows that cardiac magnetic resonace (CMR), due to its multiplanar reformatting capabilities, allows accurate short-axis visualization of the aortic annulus and precise measurement of the virtual ring corresponding to the site of prosthesis deployment with high reproducibility and accuracy as compared to MDCT. Moreover, it can estimate the coronary ostia height and aortic valve leaflet dimensions that is a key step for patient selection and procedural planning in order to prevent coronary obstruction during TAVI. In Chapter 3 122 aortic patients were studied to evaluate the capability of 3D transesophageal echocardiography (TEE) to estimate preoperatively the distance between the aortic annulus and the left main ostium (AoA-LM), its accuracy in comparison with MDCT-derived measurements, the ability of the 3DTEE-derived measurements in predicting the stent landing zone as defined by the overlap of the prosthesis with mitral leaflet. The results demonstrated that 3D TEE may estimates the AoA-LM distance as an alternative technique to MDCT. Moreover, 3D TEE allows an immediate evaluation of the distance between the mitral leaflet and aortic prosthesis after the implantation. This measurement was feasible in most of the cases (90%) and also accurate. In fact the 3D TEE computed prosthesis was similar to the prosthetic nominal value. Pre and post 3D TEE data concerning the valve and prosthesis morphology and simultaneous real time evaluation of the aortic root including the LM coronary ostium give new insights regarding TAVI and its complications. Chapter 4 suggests that intraoperative 2D and 3D TEE may allow the identification of predictors of significant paravalvular aortic regurgitation (PAR) following successful TAVI. In particular, incomplete device expansion due to aortic valve calcifications is believed to be one of the contributing factors to PAR post-TAVI. In fact, heavily calcified native aortic valves may not allow a perfect apposition of the device along the annulus circumference. Our data, collected in 135 TAVI patients, show that the calcifications of the commissure between the right coronary and non-coronary cusp is related to significant post-procedural PAR. Moreover, the measurement of an “area cover index”, defined as the percentage difference between planimetered aortic annulus area and the nominal prosthesis area, should be considered during patient selection for TAVI. As a low “area cover index” predicts the development of significant post-procedural PAR, this index could be utilized as an additional parameter when choosing the prosthetic size in all those patients with borderline 2D TEE annulus size. Probably a certain degree of prosthetic oversizing is needed in order to minimize the development of significant PAR after the procedure. Chapter 5 shows that, in accordance with previous results, the lack of congruence between prosthesis and annulus size is associated with significant PAR. MDCT is a valuable modality for detecting the mismatch between prosthesis area and aortic annulus area and for predicting PAR. In details, a mismatch of 61.5 mm2 between prosthesis size and aortic annulus area measured by MDCT is a predictor of PAR. In conclusion, advanced cardiac imaging modalities (3D echocardiography, MDCT and MRI), besides standard 2D echocardiography and angiography, play a crucial role in the diagnostic process and management of TAVI patients, allowing proper selection and planning, optimizing the procedure and increasing TAVI success. Echocardiography is the cornerstone of pre-procedure evaluation, complemented by MDCT. Both 3D TTE/TEE and MDCT have a higher predictive value for PAR than 2D echo measurements and have been shown to change valve sizing strategy compared with 2D echo. During TAVI, 2D, and particularly 3D, TEE can be used for guidance and, allowing the visualization of the left main ostium and the measurements of its distance from the annulus, increases the procedure safety. In the future, as patients undergoing TAVI might be younger, CMR might gain significance by the absence of radiation issues.

Le valvulopatie quali stenosi aortica e insufficienza mitralica sono le patologie cardiache maggiormente riscontrate tra la popolazione. Non esiste un trattamento univoco, ma questo dipende dal grado di severità della malattia e dalle caratteristiche fisiologiche del paziente. Ciononostante, la cura migliore continua ad essere la sostituzione o la riparazione della valvola naturale. Nel tempo sono state sviluppate molte tipologie di protesi, differenti per forma, materiale e tecnica chirurgica di impianto. L’affidabilità, l’emocompatibilità in ambiente biologico, l’assenza di reazioni immunitarie dopo l’impianto e la durabilità rappresentano i fattori comuni ad ogni tipo di protesi. La continua ricerca di biomateriali stabili chimicamente, non soggetti a erosione o calcificazione e altamente compatibili con l’organismo umano, hanno favorito la progettazione di protesi all’avanguardia. A differenza delle protesi meccaniche e di quelle biologiche, considerate ormai convenzionali, la ricerca ha promosso lo sviluppo di protesi sutureless con stent auto-espandibile e di protesi percutanee inserite per via transcatetere. Conseguentemente al progresso nel campo protesico, anche le tecniche chirurgiche di impianto o di riparazione delle valvole cardiache hanno subito profondi cambiamenti. La procedura chirurgica tradizionale, a cuore aperto e ad alto rischio operatorio, è stata surclassata dallo sviluppo di tecniche meno invasive, con tempi di degenza minori, in assenza di circolazione extra-corporea e con minori rischi di complicanze per il paziente. L’operazione chirurgica maggiormente in uso è quella transcatetere, utilizzata sia per la sostituzione valvolare aortica che per quella mitralica. Attualmente, per quanto riguarda la valvola mitralica, sono state sviluppate procedure di riparazione, le quali, mediante l’uso della tecnica “edge to edge”, hanno risolto, seppur per un periodo limitato di tempo, il problema dell’insufficienza valvolare.

Carotid stenosis is one of several causes of ischemic stroke and entails a high risk of ischemic stroke recurrence. Removal of a carotid stenosis by carotid endarterectomy results in a risk reduction for ischemic stroke, but the magnitude of risk reduction depends on several factors. If the delay between the last symptom and carotid endarterectomy is less than 2 weeks, the absolute risk reduction is >10%, regardless of age, sex, or if the degree of carotid stenosis is 50–69% or 70–99%. Thus, speed is the key. However, if many patients suffers an ischemic stroke recurrence within the first 2 weeks of the presenting event, an additional benefit is likely be obtained if carotid endarterectomy is performed even earlier than within 2 week after the presenting event. Carotid endarterectomy for asymptomatic carotid stenoses carries a small risk reduction for stroke. Screening for asymptomatic carotid stenosis requires a prevalence of >5% in the examined population, i.e., higher than in the general population; however, directed screening in groups with a prevalence of >5% is beneficial. The aims of this thesis were to investigate the length of the delay to carotid endarterectomy, determine the risk of recurrent stroke before carotid endarterectomy, and determine if a calcification in the area of the carotid arteries seen on dental panoramic radiographs is a valid selection method for directed ultrasound screening to detect asymptomatic carotid stenosis. Consecutive patients with a symptomatic carotid stenosis who underwent a preoperative evaluation aimed at carotid endarterectomy at Umeå Stroke Centre between January 1, 2004–March 31, 2006 (n=275) were collected retrospectively and between August 1, 2007–December 31, 2009 (n=230) prospectively. In addition, 117 consecutive persons, all preliminarily eligible for asymptomatic carotid endarterectomy and with a calcification in the area of the carotid arteries seen on panoramic radiographs, were prospectively examined with carotid ultrasound. The median delay between the presenting event and carotid endarterectomy was 11.7 weeks in the first half year of 2004, dropped to 6.9 weeks in the first quarter year of 2006, and had dropped to 3.6 weeks in the second half year of 2009. The risk of ipsilateral ischemic stroke recurrence was 4.8% within 2 days, 7.9% within 1 week, and 11.2% within 2 weeks of the presenting event. For patients with a stroke or transient ischemic attack as the presenting event, this risk was 6.0% within 2 days, 9.7% within 1 week, and 14.3% within 2 weeks of the presenting event. For the 10 patients with a near-occlusion, the risk of ipsilateral ischemic stroke recurrence was 50% at 4 weeks after the presenting event. Among the 117 persons with a calcification in the area of the carotid arteries seen on panoramic radiographs, eight had a 50–99% carotid stenosis, equalling a prevalence of 6.8% (not statistically significantly over the pre-specified 5% threshold). Among men, the prevalence of 50–99% carotid stenosis was 12.5%, which was statistically significantly over the pre-specified 5% threshold. In conclusion: The delay to carotid endarterectomy was longer than 2 weeks. Additional benefit is likely to be gained by performing carotid endarterectomy within a few days of the presenting event instead of at 2 weeks because many patients suffer a stroke recurrence within a few days; speed is indeed the key. The finding that near-occlusion entails an early high risk of stroke recurrence stands in sharp contrast to previous studies; one possible explaination is that this was a high-risk period missed in previous studies. The incidental finding of a calcification in the area of the carotid arteries on a panoramic radiograph is a valid indication for carotid ultrasound screening in men who are otherwise eligible for asymptomatic carotid endarterectomy.

Die akustische Rhinometrie ist in der Humanmedizin eine etablierte, nicht-invasive Methode zur Bestimmung von Nasenhöhlenvolumina und definierten Querschnittsflächen in nasalen Atemwegen beim Menschen. Sie basiert auf dem Vergleich beziehungsweise der Analyse der Amplituden von Schallwellen (definiert über die Querschnittsflächen) als Funktion der Zeit (definiert durch den Abstand in die Nasenhöhle), die durch Reflexionen einer Ausgangs-schallwelle in der Nasenhöhle entstehen. Das Ziel dieser Studie war es, erstmals den Nutzen der akustischen Rhinometrie für die klinische Veterinärmedizin bei Hunden zu überprüfen. Die Hauptschwerpunkte lagen in der Quantifizierung des geometrischen Aufbaus der Nasenhöhle von gesunden (n=15) und kranken (n=32) Hunden über die Auswertung der Flächenabstandskurven, der Definition von minimalen Querschnittsflächen (MCA1, MCA2) und Zuordnung zu anatomischen Landmarken auf CT-Schnittbildern. Für die Messungen wurde das Rhinometer SRE 2000 (RhinoMetrics, Dänemark) verwendet. Voruntersuchungen zu Wiederholbarkeit und Genauigkeit der Messmethode erfolgten an zylindrischen Stufenmodellen (n=3). Für jeden Beagle konnte eine deutliche Korrelation der ersten minimalen Querschnittsflächen zur Spitze der Concha nasalis ventralis nachgewiesen werden. Die zweite minimale Querschnittsfläche ließ sich keiner anatomischen Landmarke zuordnen. Es bestand kein statistisch signifikanter Unterschied in Nasenhöhlenvolumina, Auftreten der MCA1 und MCA2 und ihrer entsprechenden Dimension der jeweils rechten und linken Nasenhöhle im Gruppenvergleich. Nach lokaler Applikation von Xylometazolin lag die Größenzunahme des Volumens der rechten Nasen-höhle bei 19,4% [3,9-24,7%] (n=13) und der Linken bei 23,7% [15,4-36,4%] (n=12). Von insgesamt 32 untersuchten Hunden zeigten acht Hunde eindeutig einseitige Veränderungen (25%) in den CT-Schnittbildern. Anhand der Kurvensymmetrie ließ sich die pathologisch veränderte Nasenhöhlenseite nur in vier von acht Fällen zweifellos zuordnen. Besonders bei Erkrankungen mit Rhinorrhoe oder Ansammlungen von Sekret innerhalb der Nasenhöhle kam zu Fehlinterpretationen der Flächenabstandskurven. Oszillationen traten bei 22% der Patienten auf. Die Ergebnisse lassen Rückschlüsse zu, dass sich die akustische Rhinometrie aufgrund einer guten Wiederholbarkeit und einfachen Anwendung für wissenschaftliche Studien eignet, bei denen der Schwerpunkt auf intraindividuellen Vergleichen liegt. Obwohl die Daten objektiv ermittelt werden, ist die Anwendung dieser Methode in der klinischen Veterinärmedizin bei Hunden nur in Kombination mit anderen Untersuchungsmodalitäten sinnvoll. Fehlmessungen treten bereits bei einfach strukturierten Modellen auf; am caninen Patienten nehmen sie durch die ansteigende Diskrepanz zum idealen theoretischen Modell weiter zu. Primäre pathologische Veränderungen in der Nasenhöhlengeometrie werden nicht erkannt oder durch sekundäre Veränderungen maskiert. Verschiedene Krankheitsbilder weisen gleiche oder ähnliche strukturelle Veränderungen in der Nasenhöhle auf und können durch Messungen mit akustischen Schallwellen nicht unterschieden werden. Die Interpretation von Absolutwer-ten ist kritisch. Die Quantifizierung einer intranasalen Stenose ist nicht möglich.

The optimal treatment for patients with stable angina remains controversial. Coronary angioplasty is increasingly performed in stable patients to reduce symptoms. Over the last 20 years there has been an accumulation of data demonstrating that an objective physiological approach to revasularisation is superior to the tradional angiographic approach. Several intra-coronary indices of stenosis severity have been proposed using pressure alone, flow velocity alone or a combination of both pressure and flow velocity. The most clinically used index, Fractional Flow Reserve (FFR) uses pressure alone to estimate the effect of a stenosis on blood flow within the coronary artery. Potent vasodilators are administered during its measurement to ensure the intra-coronary conditions are suitable for pressure to be used as a surrogate for flow. Despite the wealth of evidence supporting its use to guide coronary resvascularisation its adoption is poor. One reason is the need for the potent vasodilators that add time and cost to the procedure, cannot be given to every patient, are associated with side effects and in some regions of the world are simply unavailable. In this series of studies I will use combined pressure and flow velocity measurements to analyse the phasic relations of pressure and flow velocity distal to coronary stenoses. I aim to identify a period in the cardiac cycle that naturally provides the requisite intra-coronary condition for a pressure only index of stenosis severity - stable intra-coronary microvascular resistance. I will then compare the index derived over this period to existing pressure only and flow based indices of stenosis severity. Finally I will perform a detailed analysis of diastole to detemonstrate why this period is suitable by relating wave-mechanics to traditional pressure and flow mechanics.

Renal artery stenosis (RAS) is a potentially curable cause of hypertension and azotemia. Besides intra-arterial renal angiography there are several non-invasive techniques utilized to diagnose patients with suspicion of renal artery stenosis. Removing the stenosis by revascularization to restore unobstructed blood flow to the kidney is known to improve and even cure hypertension/azotemia, but is associated with a significant complication rate.

To visualize renal arteries with x-ray techniques a contrast medium must be used. In a randomized, prospective study the complications of two types of contrast media (CO₂ and ioxaglate) were compared. CO₂ was not associated with acute nephropathy, but induced nausea and had lower attenuation differences compared to Ioxaglate. Acute nephropathy was related to the ioxaglate dose and the risk was evident even at very low doses if the patients were azotemic with creatinine clearance <40 ml/min.

Evaluating patients for clinically relevant renal artery stenosis can be done utilizing several non-invasive techniques. MRA was retrospectively evaluated and shown to be accurate in detecting hemodynamically significant RAS. In a prospective study of 58 patients, evaluated with four methods for renal artery stenosis, it was shown that MRA and CTA were significantly better than ultrasonography and captopril renography in detecting hemodynamically significant RAS. The standard of reference was trans-stenotic pressure gradient measurement, defining a stenosis as significant at a gradient of ≥15 mmHg. The discrepancies were mainly found in the presence of borderline stenosis.

The outcome of percutaneous revascularization procedures showed a technical success rate of 95%, clinical benefit in 63% of treated patients, 30-day mortality 1.5% and major complication rate of 13%. The major complication rate for patients with baseline serum creatinine >300µmol/l was 32%. Our results compare favorably with published studies and guidelines.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A doença cardiovascular compreende uma classe de patologias que envolvem o coração, e vasos sanguíneos, sendo a doença arterial coronária (DAC) a mais comum. O procedimento mais utilizado no tratamento das lesões coronarianas é a angioplastia com implante de stent. Entretanto, o sucesso desse procedimento tem sido comprometido por diversos eventos incluindo a injúria do endotélio, deposição de plaquetas, resposta inflamatória e reestenose. Os stents eluídos com as drogas sirolimus (rapamicina) e paclitaxel têm sido os mais utilizados, uma vez que podem efetivamente reduzir a incidência de reestenose. No entanto, a reestenose ainda permanece entre as causas do insucesso do tratamento coronariano. Considerando que tanto a lesão mecânica (estresse físico) causada pela colocação do stent, quanto o potencial tóxico das drogas utilizadas nos stents poderia ser responsável pela reestenose intra-stent, este estudo teve como objetivo investigar os mecanismos moleculares envolvidos na iniciação e desenvolvimento da reestenose. Citotoxicidade, genotoxicidade e alterações transcricionais (perfil de expressão gênica) possivelmente induzidas pelo sirolimus, paclitaxel, colchicina e estresse mecânico foram avaliados in vitro em células endoteliais (HCAEC) e musculares lisas de artéria coronária humana (HCASMC). Os dados mostraram diminuição da proliferação celular em ambas as linhagens celulares após o tratamento com as três drogas. O sirolimus inibiu o ciclo das HCAEC e HCASMC na fase G1; o paclitaxel apenas da HCASMC na fase G2 e a colchicina, tanto da HCAEC como da HCASMC, respectivamente, nas fases G1 e G2. O efeito citotóxico do paclitaxel e da colchicina foi também constado pelo aumento de células (HCAEC e HCASMC) em apoptose, ao passo que o sirolimus apresentou efeito genotóxico nas células musculares lisas. Os dados da análise de expressão gênica evidenciaram que os genes modulados pelo sirolimus e pelo...
Percutaneous transluminal revascularization of coronary arteries (angioplasty) with bare-metal stents is the most widely used and successful medical intervention for treatment of coronary artery disease (CAD). However, the success of this procedure can be compromised by several events including endothelium injury, platelet deposition, inflammatory response and restenosis. With the advent of drug-eluting stents (DES), incidence of in-stent restenosis has decreased, but is still about 5% to 10%. Thus, this study aimed to investigate the molecular mechanisms underlying the initiation and development of in-stent restenosis. Cytotoxicity, genotoxicity and transcriptional alterations (gene expression profile) possibly induced by sirolimus, paclitaxel, colchicine and also by mechanical stress (cell stretching) were evaluated in human coronary artery endothelial (HCAEC) and coronary artery smooth muscle (HCASMC) cell lines. Acting at different phase of the cell cycle, the three drugs were equally effective for reducing cell proliferation in both cell lines. Nevertheless, while paclitaxel and colchicine induced apoptosis, the main mechanism of cell death induced by sirolimus was necrosis. Similarly, while sirolimus was genotoxic (increase of oxidized pyrimidines) to only smooth muscle cells, colchicine mainly induced oxidative damage in endothelial cells. The transcriptome analyses revealed 82 differentially expressed genes (35 with known biological functions) in the treated groups compared to control. In HCAEC, three genes (TGM3, CTSF and MTSS1L) were differently expressed after sirolimus treatment; two (SLP1 and SLC4A1) after paclitaxel; one (PAQR8) 6 h after mechanical stretching; and 19 (WBE3A, ZBTB7A, CAMK1D, OR5AP2, EME1, C3AR1, VILL, RORC, MPV17L2, CEP350, RTEL1, ATG2A, SLC38A2, SLC25A25, FOXR2,SIGLEC8, CLIC4, ATP2A2 and VPRBP) after 12 h mechanical stretching. In HCASMC, two genes (NDST4 and FZD3) were differently expressed after ...

Orientador: Daisy Maria Fávero Salvadori
Coorientador: Glenda Nicioli da Silva
Banca: Ana Lucia dos Anjos Ferreira
Banca: Maria Aparecida Custódio Domingues
Banca: Daniel Araki Ribeiro
Banca: Verônica Elisa Pimenta Vicentini
Resumo: A doença cardiovascular compreende uma classe de patologias que envolvem o coração, e vasos sanguíneos, sendo a doença arterial coronária (DAC) a mais comum. O procedimento mais utilizado no tratamento das lesões coronarianas é a angioplastia com implante de stent. Entretanto, o sucesso desse procedimento tem sido comprometido por diversos eventos incluindo a injúria do endotélio, deposição de plaquetas, resposta inflamatória e reestenose. Os stents eluídos com as drogas sirolimus (rapamicina) e paclitaxel têm sido os mais utilizados, uma vez que podem efetivamente reduzir a incidência de reestenose. No entanto, a reestenose ainda permanece entre as causas do insucesso do tratamento coronariano. Considerando que tanto a lesão mecânica (estresse físico) causada pela colocação do stent, quanto o potencial tóxico das drogas utilizadas nos stents poderia ser responsável pela reestenose intra-stent, este estudo teve como objetivo investigar os mecanismos moleculares envolvidos na iniciação e desenvolvimento da reestenose. Citotoxicidade, genotoxicidade e alterações transcricionais (perfil de expressão gênica) possivelmente induzidas pelo sirolimus, paclitaxel, colchicina e estresse mecânico foram avaliados in vitro em células endoteliais (HCAEC) e musculares lisas de artéria coronária humana (HCASMC). Os dados mostraram diminuição da proliferação celular em ambas as linhagens celulares após o tratamento com as três drogas. O sirolimus inibiu o ciclo das HCAEC e HCASMC na fase G1; o paclitaxel apenas da HCASMC na fase G2 e a colchicina, tanto da HCAEC como da HCASMC, respectivamente, nas fases G1 e G2. O efeito citotóxico do paclitaxel e da colchicina foi também constado pelo aumento de células (HCAEC e HCASMC) em apoptose, ao passo que o sirolimus apresentou efeito genotóxico nas células musculares lisas. Os dados da análise de expressão gênica evidenciaram que os genes modulados pelo sirolimus e pelo...
Abstract: Percutaneous transluminal revascularization of coronary arteries (angioplasty) with bare-metal stents is the most widely used and successful medical intervention for treatment of coronary artery disease (CAD). However, the success of this procedure can be compromised by several events including endothelium injury, platelet deposition, inflammatory response and restenosis. With the advent of drug-eluting stents (DES), incidence of in-stent restenosis has decreased, but is still about 5% to 10%. Thus, this study aimed to investigate the molecular mechanisms underlying the initiation and development of in-stent restenosis. Cytotoxicity, genotoxicity and transcriptional alterations (gene expression profile) possibly induced by sirolimus, paclitaxel, colchicine and also by mechanical stress (cell stretching) were evaluated in human coronary artery endothelial (HCAEC) and coronary artery smooth muscle (HCASMC) cell lines. Acting at different phase of the cell cycle, the three drugs were equally effective for reducing cell proliferation in both cell lines. Nevertheless, while paclitaxel and colchicine induced apoptosis, the main mechanism of cell death induced by sirolimus was necrosis. Similarly, while sirolimus was genotoxic (increase of oxidized pyrimidines) to only smooth muscle cells, colchicine mainly induced oxidative damage in endothelial cells. The transcriptome analyses revealed 82 differentially expressed genes (35 with known biological functions) in the treated groups compared to control. In HCAEC, three genes (TGM3, CTSF and MTSS1L) were differently expressed after sirolimus treatment; two (SLP1 and SLC4A1) after paclitaxel; one (PAQR8) 6 h after mechanical stretching; and 19 (WBE3A, ZBTB7A, CAMK1D, OR5AP2, EME1, C3AR1, VILL, RORC, MPV17L2, CEP350, RTEL1, ATG2A, SLC38A2, SLC25A25, FOXR2,SIGLEC8, CLIC4, ATP2A2 and VPRBP) after 12 h mechanical stretching. In HCASMC, two genes (NDST4 and FZD3) were differently expressed after ...
Doutor

Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion.

The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group.

Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication.

In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated.

In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.

BACKGROUND Aortic stenosis is a common and potentially fatal condition in which fibro-calcific changes within the valve leaflets lead to the obstruction of blood flow. Severe symptomatic stenosis is an indication for aortic valve replacement and timely referral is essential to prevent adverse clinical events. Calcification is believed to represent the central process driving disease progression. 18F-Fluoride positron emission tomography computed tomography (PET-CT) and CT aortic valve calcium scoring (CT-AVC) quantify calcification activity and burden respectively. The overarching aim of this thesis was to evaluate the applications of these techniques to the study and management of aortic stenosis. METHODS AND RESULTS REPRODUCIBILITY The scan-rescan reproducibility of 18F-fluoride PET-CT and CT-AVC were investigated in 15 patients with mild, moderate and severe aortic stenosis who underwent repeated 18F-fluoride PET-CT scans 3.9±3.3 weeks apart. Modified techniques enhanced image quality and facilitated clear localization of calcification activity. Percentage error was reduced from ±63% to ±10% (tissue-to-background ratio most-diseased segment (MDS) mean of 1.55, bias -0.05, limits of agreement - 0·20 to +0·11). Excellent scan-rescan reproducibility was also observed for CT-AVC scoring (mean of differences 2% [limits of agreement, 16 to -12%]). AORTIC VALVE CALCIUM SCORE: SINGLE CENTRE STUDY Sex-specific CT-AVC thresholds (2065 in men and 1271 in women) have been proposed as a flow-independent technique for diagnosing severe aortic stenosis. In a prospective cohort study, the impact of CT-AVC scores upon echocardiographic measures of severity, disease progression and aortic valve replacement (AVR)/death were examined. Volunteers (20 controls, 20 with aortic sclerosis, 25 with mild, 33 with moderate and 23 with severe aortic stenosis) underwent CT-AVC and echocardiography at baseline and again at either 1 or 2-year time-points. Women required less calcification than men for the same degree of stenosis (p < 0.001). Baseline CT-AVC measurements appeared to provide the best prediction of subsequent disease progression. After adjustment for age, sex, peak aortic jet velocity (Vmax) ≥ 4m/s and aortic valve area (AVA) < 1 cm2, the published CT-AVC thresholds were the only independent predictor of AVR/death (hazard ratio = 6.39, 95% confidence intervals, 2.90-14.05, p < 0.001). AORTIC VALVE CALCIUM SCORE: MULTICENTRE STUDY CT-AVC thresholds were next examined in an international multicenter registry incorporating a wide range of patient populations, scanner vendors and analysis platforms. Eight centres contributed data from 918 patients (age 77±10, 60% male, Vmax 3.88±0.90 m/s) who had undergone ECG-gated CT within 3 months of echocardiography. Of these 708 (77%) had concordant echocardiographic assessments, in whom our own optimum sex-specific CT-AVC thresholds (women 1377, men 2062 AU) were nearly identical to those previously published. These thresholds provided excellent discrimination for severe stenosis (c-statistic: women 0.92, men 0.88) and independently predicted AVR and death after adjustment for age, sex, Vmax ≥4 m/s and AVA < 1 cm2 (hazards ratio, 3.02 [95% confidence intervals, 1.83-4.99], p < 0.001). In patients with discordant echocardiographic assessments (n=210), CT-AVC thresholds predicted an adverse prognosis. BICUSPID AORTIC VALVES Within the multicentre study, higher continuity-derived estimates of aortic valve area were observed in patients with bicuspid valves (n=68, 1.07±0.35 cm) compared to those with tri-leaflet valves (0.89±0.36 cm p < 0.001,). This was despite no differences in measurements of Vmax (p=0.152), or CT-AVC scores (p=0.313). The accuracy of AVA measurments in bicuspid valves was therefore tested against alternative markers of disease severity. AVA measurements in bicuspid valves demonstrated extremely weak associations with CT-AVC scores (r2=0.08, p=0.02) and failed to correlate with downstream markers of disease severity in the valve and myocardium and against clinical outcomes. AVA measurements in bicuspid patients also failed to independently predict AVR/death after adjustment for Vmax ≥4 m/s, age and gender. In this population CT-AVC thresholds (women 1377, men 2062 AU) again provided excellent discrimination for severe stenosis. CONCLUSIONS Optimised 18F-fluoride PET-CT scans quantify and localise calcification activity, consolidating its potential as a biomarker or end-point in clinical trials of novel therapies. CT calcium scoring of aortic valves is a reproducible technique, which provides diagnostic clarity in addition to powerful prediction of disease progression and adverse clinical events.

OBJECTIVES The aim of this analysis was to assess the 7-year long-term safety and effectiveness of a randomized comparison of percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) versus minimally invasive direct coronary artery bypass (MIDCAB) surgery for the treatment of isolated proximal left anterior descending lesions. BACKGROUND Long-term follow-up data comparing PCI by SES and MIDCAB surgery for isolated proximal left anterior descending lesions are sparse. METHODS Patients were randomized either to PCI with SES (n ¼ 65) or MIDCAB (n ¼ 65). Follow-up data were obtained after 7 years with respect to the primary composite endpoint of death, myocardial infarction, and target vessel revas- cularization. Angina was assessed by the Canadian Cardiovascular Society classification and quality of life with Short Form 36 and MacNew quality of life questionnaires. RESULTS Follow-up was conducted in 129 patients at a median time of 7.3 years (interquartile range: 5.7, 8.3). There were no significant differences in the incidence of the primary composite endpoint between groups (22% PCI vs. 12% MIDCAB; p ¼ 0.17) or the endpoints death (14% vs. 17%; p ¼ 0.81) and myocardial infarction (6% vs. 9%, p ¼ 0.74). However, the target vessel revascularization rate was higher in the PCI group (20% vs. 1.5%; p < 0.001). Clinical symptoms and quality of life improved significantly from baseline with both interventions and were similar in magnitude between groups. CONCLUSIONS At 7-year follow-up, PCI by SES and MIDCAB in isolated proximal left anterior descending lesions yielded similar long-term outcomes regarding the primary composite clinical endpoint and quality of life. Target vessel revascularization was more frequent in the PCI group. (Randomied Comparison of Minimally Invasive Direct Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention With Drug-Eluting Stents in Patients With Proximal Stenosis of the Left Anterior Descending Coronary Artery; NCT00299429) (J Am Coll Cardiol Intv 2014;-:-–-) © 2014 by the American College of Cardiology Foundation.

Stent design and technological modifications to allow for anti-proliferative drug elution influence restenosis rates following percutaneous coronary intervention (PCI). The main aim of this study was to investigate whether peri-procedural administration of corticosteroids or the use of thinner strut cobalt alloy stents would reduce rates of binary angiographic restenosis (BAR) after PCI. In addition, the role of the acute phase highly sensitive C-Reactive protein (hs-CRP) in restenosis in bare metal stents (BMS) was also investigated. This was a two centre, mixed single and double blinded, randomised controlled trial using a factorial design. The use of prednisolone was compared against placebo, starting at least six hours pre-PCI and continued for 28 days post-PCI. Additionally, cobalt chromium (CoCr) stents were compared to stainless steel (SS) alloy stents, in patients admitted for PCI. The primary end-point was BAR at six months. Three hundred and fifteen (359 lesions) were randomly assigned to either placebo (n=145) or prednisolone (n=170) and SS (n=160) or CoCr (n=160). The majority (58%) presented with an acute coronary syndrome (ACS), 11% had diabetes and 287 (91%) completed angiographic follow up. The primary endpoint, binary angiographic restenosis, occurred in 26 cases in the placebo group (19.7%) versus 31 cases in the prednisolone group (20.0%) respectively, p=1.00. For the comparison between SS and CoCr stents, BAR occurred in 32 patients (21.6%) versus 25 patients (18.0%) respectively, p=0.46. Hs-CRP was monitored at 5 points during the trial. The pre-PCI hs-CRP measurement was ≤5mg/l in 213 patients (71%) of whom only 28 (13%) had a raised CRP at day 7. There was some evidence of prednisolone suppressing hs-CRP response at day 7 (-5.98 mg/L, 95%CI: -8.35 to -3.61, p < 0.001). There was no correlation between lowering hs-CRP and stenosis diameter at follow-up. This study showed that treating patients with a moderately high dose of prednisolone to cover most of the period of inflammation associated with restenosis in BMS did not reduce the incidence of BAR. There was also no significant reduction in six month BMS restenosis rates with stents composed of CoCr alloy compared to SS alloy and no observed relationship to hs-CRP.

The incidence of lumbar spinal stenosis (LSS) is steadily rising, mostly because of a noticeably older age structure. In Sweden, LSS surgery has increased continuously over the years and is presently the most common argument to undergo spine surgery. The purpose of the surgery is to decompress the neural elements in the stenotic spinal canal. To avoid instability, there has been a tradition to do the decompression with a complementary fusion, especially if degenerative spondylolisthesis is present preoperatively. The overall aims of this thesis were to evaluate which method of surgery that generally can be considered to give sufficiently good clinical results with least cost to society and risk of complications and to determine whether there is a difference in outcome between smokers and non-smokers. The Swespine Register was used to collect data on clinical outcome after LSS surgery. In two of the studies, large cohorts were observed prospectively with follow-up after 2 years. Data were analysed in a multivariate model and logistic regression. In a randomised controlled trial (RCT, the Swedish Spinal Stenosis Study), 233 patients were randomised to either decompression with fusion or decompression alone and then followed for 2 years. The consequence of preoperative degenerative spondylolisthesis on the results was analysed and a health economic evaluation performed. The three-dimensional CT technique was used in a radiologic biomechanical pilot study to evaluate the stabilising role of the segmental midline structures in LSS with preoperative degenerative spondylolisthesis by comparing laminectomy with bilateral laminotomies. Smokers, in comparison with non-smokers, showed less improvement after surgery for LSS. Decompression with fusion did not lead to better results compared with decompression alone, no matter if degenerative spondylolisthesis was present preoperatively or not; nor was decompression with fusion found to be more cost-effective than decomression alone. The instability caused by a decompression proved to be minimal and removal of the midline structures by laminectomy did not result in increased instability compared with the preservation of these structures by bilateral laminotomies. In LSS surgery, decompression without fusion should generally be the treatment of choice, regardless of whether preoperative degenerative spondylolisthesis is present or not. Special efforts should be targeted towards smoking cessation prior to surgery.

Upper airway stenosis has a significant impact on the quality of life and sometimes on life itself. The incidence of this condition is likely to be increasing as survival rates following periods of ventilation on Intensive Care Units (ICUs) improve (1, 2). Paediatric laryngotracheal stenosis is a well researched discipline and treatment includes airway augmentation with rib grafts and tracheal or cricotracheal resection with end-to-end anastomosis. At the start of my research, in 2005, adult laryngotracheal stenosis was poorly researched and the treatment options were tracheostomy, tracheal resection or cricotracheal resection, each with associated morbidity and mortality. This thesis investigates the aetiology, incidence, screening and alternative treatment options, which include endoscopic techniques, for the management of acquired adult benign laryngotracheal stenosis. The commonest causes for this condition are ventilation on intensive care units and inflammatory disorders such as Wegener's granulomatosis, idiopathic subglottic stenosis and sarcoidosis. In January 2004 a prospective database was set up in the busiest airway reconstruction unit in the United Kingdom. Data was collected on all new adult patients with upper airways stenosis. At the completion of this research in January 2010, 400 patients had been entered on this database. Due to the rarity of this condition, it was not possible to design randomised trials to compare different treatment options. This thesis is an integrated series of prospective cohort studies, with the aim of developing a greater understanding of adult airway stenosis, with a particular emphasis on minimally invasive endoscopic techniques. This research has shown that 72% of patients with post-intubation airway stenosis can be treated with these minimally invasive endoscopic techniques. Effective new treatments have been devised for the management of inflammatory stenoses when the results of previous treatments had not been effective. New tools for assessing the airway and outcome measures have also been proposed.

Introduction: Key trials and a Cochrane systematic review in asymptomatic carotid stenosis have highlighted the need to identify a high-risk subgroup of patients with carotid stenosis who may benefit from intervention. Traditionally, this risk stratification has considered structural imaging and clinical factors. However, using only these approaches, still a significant number of patients are missed. Biological attributes are acknowledged as key determinants of thrombo-embolic events. Functional and hybrid structural-functional imaging, and circulating biomarkers allow exploration of plaque biology non-invasively, in vivo. The importance of innate immunity in atherosclerosis is now established, with a recent interest in macrophage phenotypic polarisation in atherosclerosis supported by in vitro and experimental data, with the hypothesis of an M1 macrophage predominance associated with unstable plaques. The emergence of systems biology has been seen to facilitate understanding of biological pathways and generate hypotheses, although the utility of this approach for the examination of human atherosclerosis tissue has not been fully explored. Aims: (i) To employ functional imaging to probe carotid atherosclerosis in vivo; (ii) to assess the plaque microenvironment in determination of the balance of macrophage populations in unstable compared with stable atherosclerosis; (iii) to investigate whether late phase (LP-) contrast enhanced ultrasound (CEUS) reflects plaque biological features; (iv) to examine the utility of systems biology techniques in distinguishing symptomatic from asymptomatic carotid atherosclerosis tissue, and in hypothesis generation; and (v) to evaluate a putative biomarker for carotid atherosclerosis and plaque vulnerability. Methods: Patients with carotid stenosis, both symptomatic and asymptomatic, have undergone systematic collection of data, fresh carotid endarterectomy (CEA) specimens, and plasma. Thirty-two patients with 36 carotid stenoses underwent 11C-PK11195 PET/CT. Thirty-seven patients had dynamic (D-) and LP-CEUS carotid imaging. CEA specimens were assessed by immunohistochemical techniques, as well as atheroma cell culture with supernatant multi-analyte profiling (MAP). MAP data was subject to Ingenuity Pathway Analysis. CEA specimens were further examined using systems biology methodologies: transcriptomics with Affymetrix Human Exon 1.0 ST arrays; proteomics and lipidomics by liquid chromatography (LC) coupled to tandem triple quadrupole mass spectrometry (MS); and metabolite profiling by nuclear magnetic resonance and LC-MS. Furthermore, venous and arterial plasma was quantified for the lysozyme, a putative biomarker in carotid atherosclerosis. Results: 11C-PK11195 PET allowed the non-invasive quantification of intraplaque inflammation in patients with carotid stenoses and, when combined with CTA, provided an integrated assessment of plaque structure, composition and biological activity. 11C-PK11195 PET/CT distinguished between recently symptomatic vulnerable plaques and asymptomatic plaques with a high positive predictive value. D-CEUS and LP-CEUS (at a cut-off of zero) was able to distinguish symptomatic and asymptomatic plaques. Atheroma cell culture and supernatant MAP revealed that symptomatic human atherosclerotic carotid disease is associated with a cytokine and chemokine pattern consistent with the predominance of pro-inflammatory M1-type macrophage polarisation. Furthermore, IFNγ signatures are observed, including the novel finding of CCL20 with its significant elevation in symptomatic atherosclerosis. MAP of supernatants from patients who had undergone ipsilateral carotid LP-CEUS revealed significantly higher levels of IL6, MMP1 and MMP3, as well as greater CD68 and CD31 immunopositivity, in those with high (≥0) compared with low (<0) LP-CEUS signal. This suggests that LP-CEUS was able to reflect plaque biology. Transcriptomic analysis was able to clearly separate stenosing plaque and intimal thickening, as well as unstable and stable atherosclerosis, finding differential expression and alternative splicing of interferon regulatory factor 5 between stenosing plaque and intimal thickening. Proteomic analysis of the salt extract fraction from carotid atherosclerotic plaques identified 2,470 proteins implicated in 33 bio-molecular functions and having their origins previously described in 14 different cellular compartments. There were 159 proteins which, based upon the number of assigned spectra, were significantly different between symptomatic and asymptomatic atherosclerosis. Through lipidomic analysis, 150 lipid species from 9 different classes were identified, of which 24 were exclusive to atherosclerotic plaques. A comparison of 28 carotid endarterectomy specimens revealed differential lipid signatures of symptomatic compared with asymptomatic lesions, as well as stable and unstable plaque areas. Similarly, LC-MS metabolite profiling of organic plaque extract was able to separate symptomatic from asymptomatic atherosclerosis. Arterial and venous plasma lysozyme levels were seen to distinguish individuals with carotid atherosclerosis from matched control subjects. Furthermore, arterial plasma lysozyme levels were significantly higher in patients with symptomatic than asymptomatic carotid stenosis. Conclusions: These findings support the use of hybrid structural-functional imaging, and the utility and use of a systems biology approach in identifying significantly different and biologically relevant variations in atherosclerosis tissue, and in hypothesis generation for further study. The data presented concurs with recent reports in the literature linking the lipidic/organic component of atherosclerosis with the generation of a pro-inflammatory plaque microenvironment prone to lesion development, instability and the complications thereof. The importance of innate immunity has been highlighted with the demonstration of a predominance of M1 macrophage polarisation and evidence of Th17/IL17 signalling in unstable atherosclerosis. It is hoped that this work will contribute to the ongoing refinement of multi-factorial risk stratification in carotid atherosclerosis.

Low back pain is the leading cause of disease burden globally, impacting over half a billion people. Low back pain is a broad classification of a condition which includes multiple clinical presentations, such as spondylosis, discogenic pain, muscle and ligament injuries, and lumbar spinal stenosis (LSS). This thesis has focused on LSS, which itself is a leading cause of pain, disability, and reduced quality of life among older adults. Eight chapters are included in this thesis that aims to improve the management of LSS. Chapter One was an introduction to LSS, its diagnosis, prevalence, and current management. Chapter Two outlined the largest known cohort study of emergency department attendance and hospital admission for low back pain conditions (e.g., LSS, disc protrusion) in New South Wales, Australia, between 2005 and 2014. This cohort study found that attendance to emergency departments and hospital admissions increased over the 10-years of the study, possibly due to the ageing Australian population, given an increase in the mean age of the people who presented over the study period. The study also found that people who were from lower socioeconomic backgrounds or who were managed under a worker’s compensation scheme had lower odds of being admitted to hospital following their presentation to the emergency department with a low back pain condition. Having demonstrated that both the attendance rates to hospital emergency departments and the mean age of the population presenting for low back pain had increased in recent years, more information on currently endorsed treatments for LSS, the most common lumbar pain presentation among older people, was sought. Chapter Three was a systematic review of international LSS clinical practice guidelines that examined the quality of the guidelines themselves, and the evidence supporting their treatment recommendations. Chapter Three found that around three-quarters of the recommendations presented in international practice guidelines for LSS were based on poor-quality evidence. There were no recommendations in the guidelines based on high-quality evidence. This study also identified that overall, guidelines made more recommendations in favour of surgery and injections than for medications and other non-surgical treatments, despite the evidence for both interventions being comparable. The absence of good evidence to support treatments for LSS highlighted the need for more high-quality studies to be conducted on LSS. To assist with increasing the number of high-quality studies conducted on LSS, a series of studies were planned to help inform the design of future studies. Initially, two systematic reviews were planned on key aspects of study design. The first review in Chapter Four was on the measurement properties of outcome measures and the second, presented in Chapter Five, on placebo-controlled trials of surgery for musculoskeletal conditions, including spinal conditions. Although the choice of appropriate outcome measures should be at the centre of trial design, their measurement properties are often overlooked. The review on outcome measures outlined in Chapter Four aimed to identify the walking test(s) with the best measurement properties in people with LSS. Walking tests were selected as the outcome of priority, as people living with LSS often nominate walking ability as the most important part of their condition that they want improved. A systematic review and meta-analysis were therefore conducted on the measurement properties used to assess LSS. This study found that there was a limited number of studies assessing the key measurement properties of validity, reliability, and responsiveness. Of the data that were available, the self-paced walking test and walking item of the Oswestry Disability Index were recommended to be used together before and after any intervention for LSS. Next, the review on placebo-controlled trials of surgery for musculoskeletal conditions was completed as presented in Chapter Five. The rationale for this review was based upon the findings of Chapter Three confirming the lack of studies utilising high-quality methods including randomisation, placebo-controls, and adequate blinding. It is well known that randomised, placebo-controlled trials are the gold standard for determining the efficacy of interventions, because of their ability to account for placebo and other non-specific effects. A systematic review was conducted in Chapter Five to investigate the number and quality of existing randomised placebo-controlled trials of surgical management of musculoskeletal conditions. Whilst the study found that no randomised placebo-controlled trials had been completed on LSS, 18 trials had been completed on other musculoskeletal conditions (e.g., vertebroplasty for vertebral compression fractures). Chapter Five found a rapid increase in the number of placebo-controlled trials of musculoskeletal conditions, from 2 trials before the year 2000 to 20 trials between 2001 and 2020. The study also found that the majority of trials (59%) used a high-fidelity placebo control, which was the degree in which the placebo procedure mimicked all but the ‘active’ component of the surgical procedure being assessed. Minimal fidelity placebo controls were those that had only minimal resemblance to the surgical procedure, such as using a skin incision only, when assessing meniscal repair. The vast use of high-fidelity placebo surgery suggests an increased focus on accounting for non-specific effects and maximising blinding of patients in placebo trials of musculoskeletal surgery. Considering the level of fidelity and other methodological aspects of placebo-controlled trials of surgery can help to improve their feasibility and impact on policy and practice. Following decisions on level of treatment fidelity, another important aspect to trial design in placebo-trials included engaging key stakeholders in the design process, as discussed by Beard et al (2020) in their Lancet paper on consideration and methods of placebo studies. In Chapter Six, LSS patients considered eligible for spine surgery were surveyed to determine their opinions, including barriers to participation in a placebo-controlled surgical trial. The study suggested that a placebo-controlled trial was feasible, with just under 1 in 5 eligible patients with LSS stating that they would consider participation in a placebo-surgical trial of LSS. Following the engagement of LSS patients, spinal surgeons were then consulted in Chapter Seven, to better understand how they viewed the current evidence supporting LSS. Surgeons were also asked what change they expected following spine surgery, including on neurogenic claudication following lumbar decompression. The key findings in Chapter Seven were that spine surgeons expected a mean improvement in neurogenic claudication by 3 months post-surgery of 86% (median: 87%, interquartile range (IQR): 80%, 91%), using a +/- 100% change scale. The majority of surgeons also rated the quality of evidence for lumbar decompression procedures, including decompression alone, decompression with fusion, and interspinous spacer, as low to moderate, supporting the need for future studies. The combined results of Chapter Six and Seven then helped inform the first randomised placebo-controlled trial of decompression for LSS, which has its protocol outlined in Appendix One.

Im Rahmen der vorliegenden Arbeit ist ein neues bronchoskopisches Verfahren entwickelt und getestet worden, mit dem eine Längs- und Querschnittsvermessung zentraler Atemwegesstenosen in Echtzeit ermöglicht wird und anschließend eine 3D-Rekonstruktion des untersuchten Abschnitts dargestellt werden kann. Für die Querschnittsflächenbestimmung wird durch den Arbeitskanal des Bronchoskops eine Lasersonde eingeführt und ein Laserlichtring auf die Trachealwand projiziert. Die Abbildung des Lichtrings wird im bronchoskopischen Bild noch während der Untersuchung mit Hilfe einer speziell im Rahmen dieser Arbeit entwickelten Software Endo3D segmentiert und vermessen. Durch Speichern aufeinanderfolgender Querschnittsflächen kann ein 3D-Datensatz erstellt, visualisiert und das Volumen berechnet werden. Experimentell wurde die Methode an Kunststoffmodellen mit bekannten Maßen und Präparaten aus Schweineluftröhren getestet. Die Referenzwerte für die Volumen der Schweineluftröhren wurden durch Wasservolumetrie bestimmt. Klinisch wurde die Methode in einer Pilotstudie getestet. Bei 10 Patienten wurden Querschnitte und Volumen unterschiedlich langer Trachealabschnitte vermessen. Als Vergleichsmethode wurde jeweils eine CT durchgeführt. Die Ergebnisse im experimentellen Teil zeigten bei sehr guter Reproduzierbarkeit eine gute Korrelation zwischen den bronchoskopisch gemessenen Werten und den realen bzw. Referenzwerten. Die Korrelation der klinischen Ergebnisse erwies sich als befriedigend ohne Hinweis auf einen systematischen Fehler. Ein kleiner systematischer Messfehler im experimentellen Teil zeigte sich als irrelevant für die Klinik. Die hier vorgestellte Methode ermöglicht untersucherunabhängige Verlaufsbeschreibungen von Stenosen und erlaubt die Schaffung einer einheitlichen Klassifikation. Darüber hinaus ist damit zukünftig eine individualisierten Stentimplantation sowie Tumorvolumenberechnungen denkbar.
In this paper a new bronchoscopic method was developed and tested, that performs measuring both cross-sectional areas and length of central airway stenoses in real-time. Furthemore this method enables to represent a three-dimensional reconstruction of the airway section that was analysed. To measure th cross-section area, a laser probe inserted into the operating channel of a bronchoscope projects a ring of light onto the trachal wall and marks the cross-sectional area. A new software especially developed for this method makes it possible to identify the projected ring of light and measures the cross-sectional area after applying lens distortion correction algorithms. By saving a succession of cross-sections 3D-data is provided for visualizing and volume calculation. The measuring accurracy was first tested employing plastic tubes with known diameters and 17 models of porcine trachea. The cilinical evaluation was realized in a pilot study. Sections of different length of tracheas of 10 patients were analysed by both the new method and by CT. The results of the experimental part showed good correlation between the reference methods and a very good reliability. The correlation between CT and bronchoscopic measuring results was slightly less good than the experimental correlation, but they showed no systematic measuring error. A little systematic error in the experimental evaluation prooved to be irrelevant for clinical results. The new method enabels objective description of stenoses and makes it possible to develop a standardized classification. In future indvidual stent construcions or calculation of tumor volumes are conceivable.

We hypothesised that (a) risk factors for atherosclerosis would predict, and (b) lipid lowering therapy would retard, disease progression and clinical outcome in patients with calcific aortic stenosis. Objectives: In patients with aortic stenosis, (i) to compare the magnitude and reproducibility of measures of valvular stenosis and calcification, (ii) to determine the effect of intensive lipid lowering therapy on disease progression and clinical outcome, and (iii) to describe predictors of disease progression and clinical outcome. Methods: In the Scottish Aortic stenosis and Lipid lowering Therapy, Impact on Regression (SALTIRE) trial, 155 patients aged 68±11 years (range 34-85) with aortic valve stenosis underwent helical computed tomography and Doppler echocardiography. In a double blind randomised controlled trial, 77 patients were assigned to atorvastatin 80 mg daily and 78 to matched placebo over a medium period of 25 months. Of the 155 patients, 102 had detectable coronary artery calcification on computed tomography with 48 of these patients being randomised to atorvastatin and 54 to placebo. Conclusions: Calcification of the aortic valve is closely associated with the severity of aortic stenosis with heavy calcification suggesting the presence of severe aortic stenosis that requires urgent cardiological assessment. In contrast to observational studies, intensive lipid-lowering therapy does not halt the progression or induce regression of aortic stenosis or coronary artery calcification. Long-term, large-scale, randomised, controlled trials are needed to establish the role of statin therapy in patients with calcific aortic stenosis. The major predictors of disease progression and clinical outcome remain baseline measures of disease severity; namely aortic-jet velocity, aortic valve calcification and serum BNP concentration. With the exception of hypertension the presence of atherosclerotic risk factors and vascular disease are not predictive. Our findings suggest that atherogenesis does not provide a major contribution to the progression of aortic stenosis.