Les malalties cardiovasculars són una de les principals causes de mortalitat als països desenvolupats. La majoria d'elles són degudes a malalties arterials (especialment les coron ries), que vénen causades per l'acumulació de placa. Aquesta patologia estreny el flux sanguini (estenosi) i afecta les propietats elàstiques i bio-mecàniques (arteriosclerosi) de les artèries. En les últimes dècades, l'Ecografia Intra-Coronària (EIC) ha esdevingut una tècnica usual de diagnòstic per la imatge i seguiment de les malalties coronàries. L'EIC està basada en un cateterisme que mostra una seqüència d'imatges corresponents a seccions de l'artèria sota estudi. La inspecció visual de cadascuna d'aquestes imatges proporciona informació sobre el percentatge d'estenosi, mentre que la inspecció de les vistes longitudinals propociona informació sobre les propietats bio-mecàniques, que pot prevenir un desenllaç fatal de la malaltia cardiovascular. Per una banda, la dinàmica arterial (deguda al batec del cor, entre d'altres) és un dels principals artefactes per poder explorar les propietats biomecàniques. Al mateix temps, les mesures manuals d'estenosi requereixen un traçat manual de les vores del vas, tasca feixuga que consumeix molt de temps i que pot patir variabilitat entre observadors.Aquesta tesi proposa vàries eines de processament d'imatge per explorar la dinàmica de les artèries i les seves estructures. Presentem un model físic per extreure, analitzar i corregir la dinàmica rígida transversal dels vasos i per recuperar la fase cardíaca. A més, introduïm un mètode estadístic-determinista per a la detecció automàtica de les vores del vas. En particular, l'enfoquem a segmentar l'adventícia. Un protocol de validació acurat per assegurar una aplicació clínica fiable dels mètodes és un pas crucial en qualsevol proposta d'algorisme. En aquesta tesi tenim especial cura de dissenyar protocols de validació per a cadascuna de les tècniques proposades i contribuïmm a la validació de la dinàmica in vivo amb un indicador objectiu i quantitatiu per mesurar la quantitat de moviment suprimida. / Cardiovascular diseases are a leading cause of death in developed countries. Most of them are caused by arterial (specially coronary) diseases, mainly caused by plaque accumulation. Such pathology narrows blood flow (stenosis) and affects artery bio-mechanical elastic properties (atherosclerosis). In the last decades, IntraVascular UltraSound (IVUS) has become a usual imaging technique for the diagnosis and follow up of arterial diseases. IVUS is a catheter-based imaging technique which shows a sequence of cross sections of the artery under study. Inspection of a single image gives information about the percentage of stenosis. Meanwhile, inspection of longitudinal views provides information about artery bio-mechanical properties, which can prevent a fatal outcome of the cardiovascular disease. On one hand, dynamics of arteries (due to heart pumping among others) is a major artifact for exploring tissue bio-mechanical properties. On the other one, manual stenosis measurements require a manual tracing of vessel borders, which is a time-consuming task and might suffer from inter-observer variations.This PhD thesis proposes several image processing tools for exploring vessel dynamics and structures. We present a physics-based model to extract, analyze and correct vessel in-plane rigid dynamics and to retrieve cardiac phase. Furthermore, we introduce a deterministic-statistical method for automatic vessel borders detection. In particular, we address adventitia layer segmentation. An accurate validation protocol to ensure reliable clinical applicability of the methods is a crucial step in any proposal of an algorithm. In this thesis we take special care in designing a validation protocol for each approach proposed and we contribute to the in vivo dynamics validation with a quantitative and objective score to measure the amount of motion suppressed.

Background: There is no study focusing on changes of coronary atherosclerosis during dual hypolipidemic therapy with statin and ezetimibe. Methods: 107 patients with stable angina were enrolled and the final analysis was performed in 89 patients. Randomization was 1:1 to the group A (atorvastatin 80mg and ezetimibe 10mg) and to the standard group S. Treatment period was 12 months. Results: Changes of percent atheroma volume (PAV) were -0,4% in group A and + 1,4% in group S, p=0,014. Combine atherosclerosis regression (increase of lumen volume together with decrease of PAV) was found more frequent in group A (40,5%) than the group S (14,9%), p=0,007. The target LDLc level < 2mmol/l, presence of at least four of five atherosclerotic risk factors, and decrease of VCAM level were independent predictors for plaque regression. There were no significant differences in plaque composition between the two groups over the duration of the study. However during analysis the two groups together, fibrous and fibro-fatty tissues decreased and dense calcification and necrotic core increased during follow-up. Conclusion: The dual hypolipidemic therapy starts atherosclerosis regression. Despite significant decrease of lipid levels the continuous plaque shift from fibro and fibro-fatty to necrotic with calcification...

Background: There is no study focusing on changes of coronary atherosclerosis during dual hypolipidemic therapy with statin and ezetimibe. Methods: 107 patients with stable angina were enrolled and the final analysis was performed in 89 patients. Randomization was 1:1 to the group A (atorvastatin 80mg and ezetimibe 10mg) and to the standard group S. Treatment period was 12 months. Results: Changes of percent atheroma volume (PAV) were -0,4% in group A and + 1,4% in group S, p=0,014. Combine atherosclerosis regression (increase of lumen volume together with decrease of PAV) was found more frequent in group A (40,5%) than the group S (14,9%), p=0,007. The target LDLc level < 2mmol/l, presence of at least four of five atherosclerotic risk factors, and decrease of VCAM level were independent predictors for plaque regression. There were no significant differences in plaque composition between the two groups over the duration of the study. However during analysis the two groups together, fibrous and fibro-fatty tissues decreased and dense calcification and necrotic core increased during follow-up. Conclusion: The dual hypolipidemic therapy starts atherosclerosis regression. Despite significant decrease of lipid levels the continuous plaque shift from fibro and fibro-fatty to necrotic with calcification...

The application of high frequency ultrasound is the key to higher resolution intravascular ultrasound (IVUS) images. The need to further improve the IVUS spatial resolution may drive the transducer center frequency even higher than the current 40 MHz range. However, increasing the center frequency may be challenging as it leads to stronger scattering echoes from blood. The high level of blood scattering echoes may obscure the arterial lumen and make image interpretation difficult. Blood backscatter levels increase with transmission center frequency at a much greater rate compared to arterial tissue. These different frequency dependencies provide a potential method to distinguish blood from tissues by means of multi-frequency processing techniques. To obtain a good blood-tissue contrast with sufficient signal-to-noise ratio, a system with a wider bandwidth is highly desirable. The method described in this paper is based on the ratio of the received signal power between the high (60 MHz) and low (25 MHz) frequency ranges from a novel 40 MHz wideband IVUS catheter. In this paper we will present our in vitro experiment work on porcine blood and a tissue-mimicking arterial wall. Results of multi-frequency processing indicate that blood, at higher frequencies, has a greater backscatter power that is 8X greater than arterial tissue, suggesting this technique will provide a greater contrast between the blood-wall lumen boundary for coronary imaging.

Rupture of atherosclerotic plaque is closely related to plaque composition. Currently, plaque composition cannot be clinically characterized by any imaging modality. The objective of this dissertation is to use a recently developed imaging modality – ultrasound-guided intravascular photoacoustic (IVPA) imaging – to detect the distribution of two critical components in atherosclerotic plaques: lipid and phagocytically active macrophages. Under the guidance of intravascular ultrasound imaging, spectroscopic IVPA imaging is capable of detecting the spatially resolving optical absorption property inside a vessel wall. In this study, contrast in spectroscopic IVPA imaging was provided by either the endogenous optical property of lipid or optically absorbing contrast agent such as gold nanoparticles (Au NPs). Using a rabbit model of atherosclerosis, this dissertation demonstrated that ultrasound guided spectroscopic IVPA imaging could simultaneously image lipid deposits as well as macrophages labeled in vivo with Au NPs. Information of macrophage activity around lipid rich plaques may help to identify rupture-prone or vulnerable plaques. The results show that ultrasound guided IVPA imaging is promising for detecting plaque composition in vivo. Clinical use of ultrasound guided IVPA imaging may significantly improve the accuracy of diagnosis and lead to more effective treatments of atherosclerosis. / text

Indiana University-Purdue University Indianapolis (IUPUI) / Metabolic syndrome (MetS) affects 1/3 of all Americans and is the clustering of three or more of the following cardiometabolic risk factors: obesity, hypertension, dyslipidemia, glucose intolerance, and insulin resistance. MetS drastically increases the incidence of coronary artery disease (CAD), which is the leading cause of mortality globally. A cornerstone of CAD is arterial remodeling associated with coronary smooth muscle (CSM) cytodifferentiation from a contractile phenotype to proliferative and osteogenic phenotypes. This cytodifferentiation is tightly coupled to changes in intracellular Ca2+ handling that regulate several key cellular functions, including contraction, transcription, proliferation, and migration. Our group has recently elucidated the time course of Ca2+ dysregulation during MetS-induced CAD development. Ca2+ transport mechanisms, including voltage-gated calcium channels, sarcoplasmic reticulum (SR) Ca2+ store, and sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), are enhanced in early, mild disease and diminished in late, severe disease in the Ossabaw miniature swine. Using this well-characterized large animal model, I tested the hypothesis that this Ca2+ dysregulation pattern occurs in multiple etiologies of CAD, including diabetes and aging. The fluorescent intracellular Ca2+ ([Ca2+]i) indicator fura-2 was utilized to measure [Ca2+]i handling in CSM from lean and diseased swine. I found that [Ca2+]i handling is enhanced in mild disease with minimal CSM phenotypic switching and diminished in severe disease with greater phenotypic switching, regardless of CAD etiology. We are confident of the translatability of this research, as the Ca2+ influx, SR Ca2+ store, and SERCA functional changes in CSM of humans with CAD are similar to those found in Ossabaw swine with MetS. Single-cell RNA sequencing revealed that CSM cells from an organ culture model of CAD exhibited many different phenotypes, indicating that phenotypic modulation is not a discreet event, but a continuum. Transcriptomic analysis revealed differential expression of many genes that are involved in the osteogenic signaling pathway and in cellular inflammatory responses across phenotypes. These genes may be another regulatory mechanism common to the different CAD etiologies. This study is the first to show that CSM Ca2+ dysregulation is common among different CAD etiologies in a clinically relevant animal model.

No description available.

Although the drug-eluting stent (DES) has dramatically reduced the rate of coronary restenosis, it still occurs in up to 20% of patients with a DES. Monitoring drug delivery could be one way to decrease restenosis rates. We demonstrate real-time photoacoustic imaging and spectroscopy (PAIS) using a wavelength-tunable visible laser and clinical ultrasound scanner to track cardiac drug delivery. The photoacoustic signal was initially calibrated using porcine myocardial samples soaked with a known concentration of a drug surrogate (Dil). Next, an in situ coronary artery was perfused with DiI for 20 min and imaged to monitor dye transport in the tissue. Finally, a partially DiI-coated stent was inserted into the porcine brachiocephalic trunk for imaging. The photoacoustic signal was proportional to the DiI concentration between 2.4 and 120 mu g/ml, and the dye was detected over 1.5 mm from the targeted coronary vessel. Photoacoustic imaging was also able to differentiate the DiI-coated portion of the stent from the uncoated region. These results suggest that PAIS can track drug delivery to cardiac tissue and detect drugs loaded onto a stent with sub-mm precision. Future work using PAIS may help improve DES design and reduce the probability of restenosis. (C) 2017 Society of Photo-Optical Instrumentation Engineers (SPIE)

Ischaemic heart disease remains the single leading cause of death throughout the world. Rupture of an advanced atheromatous coronary plaque precipitates the majority of these clinical events, resulting in thrombosis and myocardial infarction. Post-mortem studies have identified thin-cap fibroatheroma (TCFA) as the plaque subtype most prone to rupture with prospective virtual-histology intravascular ultrasound (VH-IVUS) studies linking VH-TCFA to future adverse clinical events. VH-TCFA are however common along the coronary tree with the majority remaining clinically silent, suggesting that factors other than plaque phenotype play an important role in determining rupture and future plaque behaviour. Rupture is thought to occur when the structural stress within the plaque exceeds the material strength of the overlying fibrous cap. Previous histological work has demonstrated that ruptured plaques are associated with higher stress compared to non-ruptured controls, with in vivo VH-IVUS studies linking higher plaque structural stress (PSS) with the presentation of acute coronary syndrome. Wall shear stress (WSS) on the other hand has been implicated in early plaque development and plaque growth suggesting that both PSS and WSS can influence future plaque behaviour. The work presented in this thesis is associated with a number of novel findings. First, it is the only work to demonstrate that in vivo PSS is higher in coronary atherosclerotic plaques with rupture vs. no rupture across a range of plaque subtypes and irrespective of whether analysis of the entire plaque or of regions close to the minimal luminal area is performed. Second, it shows that the pattern and extent of plaque progression and regression defined as an increase and decrease in plaque area, respectively, are associated with specific biomechanical environments at baseline, in the only study that examines the role of both PSS and WSS in this process. More specifically, high PSS is associated with changes consistent with increased vulnerability both in areas of progression and regression. On the other hand, lower WSS at baseline is associated with greater increases in plaque area and burden in areas that progress and with smaller decreases in areas that regress largely due to changes in fibrous tissue. Although the role of WSS in determining future plaque behaviour has been previously examined, this is the first time that this is assessed specifically in areas of progression and regression, particularly important in view of the dynamic nature of atherosclerotic plaques. More importantly, the work presented in this thesis demonstrates that the interplay of these biomechanical forces is associated with specific patterns of plaque progression and regression despite the fact that PSS and WSS are independent of each other. This has never been previously demonstrated and further suggests that incorporation of biomechanical analysis can play role in the identification of plaques that lead to future clinical events. Finally, the ability of PSS to identify plaques that lead to adverse clinical events was assessed through a propensity core matched analysis of the PROSPECT (A Prospective Natural-History Study of Coronary Atherosclerosis) study. The analysis presented here is the largest, most extensive and thus most significant work to ever examine this with results suggesting that incorporation of PSS and associated parameters can improve the capability of VH-IVUS to identify plaques that lead to such events. In summary, the results of this thesis suggest that coronary PSS plays an important role in the pathophysiology of plaque rupture, and that its incorporation in routine plaque assessment may improve our current ability to identifying coronary plaques that lead to future adverse clinical events. The interplay between PSS and WSS may also affect future plaque behaviour and in particular progression and regression. Prospective studies are now required to fully evaluate the role of these biomechanical forces in plaque development, and whether their incorporation in plaque evaluation can be of clinical significance.

Fundamentos: Ensaios prévios reunindo pacientes em series consecutivas ou randomicas sem cegamento evidenciaram beneficio da adição do cilostozol à terapia antiplaquetária em diabéticos submetidos ao implante de stents coronários farmacológicos com redução nas taxas de reestenose binária, perda tardia intra-stent e revascularização tardia da lesão alvo. Objetivos: O objetivo primário deste estudo foi verificar se a adição do cilostazol à dupla terapia antiplaquetária, proporcionaria uma redução adicional da hiperplasia intimal em diabéticos após o implante de stent farmacológico, mensurada por meio do cálculo do volume de obstrução pelo ultrassom intracoronário 9 meses após o procedimento índice. Os objetivos secundários foram aferir a angiografia quantitativa do vaso alvo e ocorrência de eventos cardíacos adversos graves (óbito, infarto do miocárdio não fatal e necessidade de nova revascularização da lesão-alvo) aos 30 dias, 9 meses e 1 ano. Casuística e métodos: Estudo prospectivo, unicêntrico, randomizado, duplo cego, reunindo 133 pacientes diabéticos, comparando pacientes que receberam cilostazol (Grupo 1, n= 65 ) versus placebo (Grupo 2, n= 68), submetidos a implante de stent coronário com liberação de zotarolimus em artéria coronária nativa com estenose maior ou igual a 50% e diâmetro de referência igual ou superior a 2,0 mm (avaliação visual), com reestudo angiográfico e análise ultrassonográfica aos 9 meses. Resultados: Os 2 grupos foram similares nas características clínicas, angiográficas e técnicas, exceto na evidencia de maior incidência de hipertensão arterial no grupo 2 (81,5% vs 94,1%, p=0,026) assim como nos diâmetros dos stents coronários utilizados, significativamente menores no grupo 1 (2,78 mm vs 2,96 mm, p<0,001). O calculo do volume de obstrução intimal por meio do ultrassom intracoronário aos 9 meses foi similar entre os grupos (33,2% vs 35,1%, p=0,069), assim como as taxas de eventos cardíacos adversos graves (12,3% vs 8,8%, p= 0,811), trombose de stent (1,5% versus 0,75%, p= 0,237), reestenose binária intra-sent (9,8% vs 6,8%, p= 0,988), perda tardia intra-stent (0,60 vs 0,64, p=0,300) e no segmento ( 0,57 vs 0,58, p= 0,387). Conclusões: A adição do cilostazol à dupla terapia antiplaquetária com ácido acetilsalicílico e clopidogrel em pacientes diabéticos submetidos à implante de stent com zotarolimus, não reduziu eventos cardíacos adversos graves ou o porcentual de hiperplasia intimal intra-stent mensurado pela análise volumétrica do ultrassom intracoronário. / Background: Previous trials with assembled patients in consecutive or random series without blindness offered evidence of the benefit adding cilostazol to the antiplatelet therapy in diabetic patients undergoing drug-eluting stents coronary implantation, with reduction in binary restenosis rates, in-stent late loss and late target lesion revascularization. Objectives: The primary objective of this study was to determine whether the addition of cilostazol to the dual antiplatelet therapy would provide an additional intimal hyperplasia reduction in diabetic patients after drug-eluting stents implantation, measured by calculating the obstruction volume through the intravascular ultrasound 9 months after the index procedure. Secondary objectives were to assess the target vessel quantitative angiography and the occurrence of serious adverse cardiac events (death, nonfatal myocardial infarction and need for a target lesion revascularization) at 30 days, 9 months and 1 year. Methods: Prospective, single center, randomized, double blinded study, gathering 133 diabetic patients, comparing who received cilostazol (Group 1, n= 65) versus placebo (Group 2, n= 68), undergoing coronary stenting, with the releasing of zotarolimus in a native coronary artery with stenosis greater than or equal to 50% and reference diameter equal to or greater than 2.0 mm (visual assessment) with the intravascularultrasound and angiographic restudy at 9 months. Results: Both groups were similar in clinical, angiographic and technical characteristics, except for a higher incidence of arterial hypertension in group 2 (81,5% vs 94,1%, p=0,026) as well as significantly lower coronary stents diameters in group 1 (2,78 mm vs 2,96 mm, p<0,001). The intimal obstruction volume calculated by the intravascularultrasound at 9 months was similar between the groups (33,2% vs 35,1%, p=0,069), as well as the rates of major adverse cardiac events (12,3% vs 8,8%, p= 0,811), stent thrombosis (1,5% versus 0,75%, p= 0,237), in-stent binary restenosis (9,8% vs 6,8%, p= 0,988), in stent late loss (0,60 vs 0,64, p=0,300) and at the segment ( 0,57 vs 0,58, p= 0,387). Conclusions: The addition of cilostazol to the dual antiplatelet therapy with acetylsalicylate acid and clopidogrel, in diabetic patients undergoing stent implantation with zotarolimus did not reduce major adverse cardiac events nor the percentage of intra-stent intimal hyperplasia measured by the intravascularultrasound volumetric analysis.