Dissertations / Theses on the topic 'Ischemia – Pathophysiology'

Myocardial stunning is best defined as the persistent, yet reversible, contractile dysfunction that occurs with brief myocardial ischemia / reperfusion (I/R) injury. In contrast, prolonged ischemia results in myocardial infarction that leads to cell death of necrosis of the tissue. The causes of stunning are not fully elucidated, however two major hypotheses currently exist; firstly changes to calcium handling resulting from lowered cellular pH by means of anaerobic respiration, and altered Nair/H)r antiporter kinetics, and secondly, the generation oxygen free radical (OFR) that may occur in a dramatic ‘surge’ at the onset of reperfusion. Treatment of ischemic myocardium with calcium channel blockers and / or OFR scavengers has been successfully shown to prevent stunning in various animal models. Whilst much is known about the physiological and biochemical changes that occur in stunned myocardium, very little is known about events at the molecular level. Since stunning occurs after only brief (15 minutes low-flow in the rabbit model) ischemia and subsequent reperfusion, we hypothesized that these molecular events are not predominated by large changes in protein expression and abundance, yet rather by subtle and / or transient changes to protein post-translational modifications (PTM). Such changes at the protein level are best analysed using the technologies encompassed under the term ‘proteomics’.

Reperfusion injury may mediate renal dysfunction following ischaemia. A murine model was developed to investigate the role of the tissue factor-thrombin-protease activated receptor pathway in renal ischaemia reperfusion injury (IRI). In this model, mice received 25 minutes of ischaemia and subsequent periods of reperfusion. C57BL6, protease activated receptor-1 (PAR-1) knockout mice, and tissue factor (TF) deficient mice were used. Following 24 hours IRI, PAR-1 deficiency resulted in protection against severe renal failure compared to the C57BL6 mice (creatinine, 118.2 ?? 6.3 vs 203 ?? 12 ??mol/l, p<0.001). This was confirmed by lesser tubular injury. By 48 hours IRI, this resulted in a survival benefit (survival, 87.5% vs 0%, p<0.001). Treatment of C57BL6 mice with hirudin, a specific thrombin inhibitor, offered renoprotection at 24 hours IRI (creatinine, 107 ?? 10 ??mol/l, p<0.001), leading to a 60% survival rate at 48 hours IRI (p<0.001). TF deficient mice expressing less than 1% of C57BL6 mouse TF were also protected (creatinine, 113.6 ?? 7 ??mol/l, p<0.001), with a survival benefit of 75% (p<0.001). The PAR-1 knockout, hirudin treated C57BL6 and TF deficient mice had reduced myeloperoxidase activity and tissue neutrophil counts compared to the C57BL6 mice, along with reduced KC and MIP-2 chemokine mRNA and protein expression. Hirudin treatment of PAR-1 knockout mice had no additional benefit over PAR-1 absence alone, suggesting no further contribution by activation of other protease activated receptors (creatinine at 24 hours IRI, 106.5 ?? 10.5 ??mol/l, p>0.05). Furthermore, immunofluoresence staining for fibrin(ogen) showed no difference between C57BL6 and PAR-1 knockout mice, suggesting no major contribution by fibrin in this model. Renal IRI resulted in increased levels of TF mRNA expression in the C57BL6, PAR-1 knockout, and hirudin treated C57BL6 mice compared to normal controls, suggesting that TF mRNA expression was upregulated in this model. This resulted in increased TF functional activity in the C57BL6 and PAR-1 knockout mice, but TF activity was negligible in hirudin treated C57BL6 and TF deficient mice. The data therefore suggests that the TF-thrombin cascade contributes to renal IRI by signalling via PAR-1 that then regulates chemokine gene expression and subsequent neutrophil recruitment.

Le present travail s'inscrit dans le cadre general des etudes consacrees a la protection pharmacologique du tissu cardiaque reperfuse apres une periode d'ischemie de courte duree. Les differentes etudes experimentales qui le constituent sont realisees sur un modele d'ischemie myocardique sur le cur isole et perfuse de rat, et prennent en compte une appreciation fonctionnelle, ultrastructurale et metabolique des effets du cycle ischemie-reperfusion. Une etude clinique, s'inscrivant dans une thematique voisine, complete l'ensemble. Dans la premiere partie de ce travail, nous avons mis en evidence l'implication des radicaux libres de l'oxygene, via la reaction de fenton, dans le developpement des lesions d'ischemie-reperfusion. Nous avons montre qu'une surcharge myocardique en fer augmentait la susceptibilite du tissu cardiaque vis a vis d'un cycle d'ischemie-reperfusion. En revanche, nous avons observe un effet benefique de la surcharge en fer sur l'incidence des troubles du rythme a la reperfusion. Enfin, nous avons montre qu'un traitement par des antioxydants et plus particulierement par l'euk8, molecule presentant in vitro une forte activite de type sod et catalase, entrainait une importante diminution des alterations fonctionnelles et ultrastructurales des curs surcharges en fer a la reperfusion. Dans la seconde partie, nous avons etudie le role des oligoelements (zn, cu, se et mn), cofacteurs d'enzymes de defense antiradicalaire, dans le developpement des lesions cellulaires associees a la reperfusion post-ischemique. Nous avons d'une part mis en evidence une plus grande vulnerabilite du tissu cardiaque dans les monocarences en oligoelements et plus particulierement dans les carences en selenium ou en cuivre. D'autre part, nous avons montre qu'un apport nutritionnel simultane en ces divers oligoelements augmentait l'activite des enzymes antioxydantes, limitant ainsi les consequences fonctionnelles et structurales de l'ischemie et de la reperfusion. Enfin, une troisieme partie consacree a l'etude de l'existence d'un stress radicalaire chez des patients presentant un infarctus du myocarde traite par thrombolyse, a permis de montrer 1) que les dosages plasmatiques des mda et de la gpx constituent un bon reflet de la production radicalaire apres traitement thrombolytique, et 2) que les systemes antioxydants physiologiques apparaissent modifies chez ces patients

Includes bibliographical references (leaves 292-352) Determines the role of matrix metalloproteinases, MMP-2 and MMP-9 in reperfusion injury following skeletal muscle ischaemia; and, whether inhibition of MMPs by doxycycline protects against tissue damage.

Las alteraciones mitocondriales están vinculadas a la mayor vulnerabilidad de padecer enfermedades durante el envejecimiento. La edad avanzada es un factor determinante de la incidencia y gravedad de la cardiopatía isquémica. Estudios preclínicos sugieren la existencia de un daño celular intrínseco, por mecanismos no del todo establecidos, que contribuye a un incremento de la susceptibilidad del miocardio senescente al daño isquémico. Esta tesis investiga el papel de la comunicación mitocondria-retículo sarcoplásmico (RS) en el deterioro funcional de los cardiomiocitos durante el envejecimiento. El estudio ecocardiográfico ha demostrado que la función cardiaca en el reposo se mantiene preservada en los animales viejos. No se han observado cambios debidos a la edad en el potencial de membrana mitocondrial ni en el consumo de oxígeno en condiciones de reposo en mitocondrias aisladas de corazones de ratón. El consumo de oxígeno inducido por ADP ha revelado que las mitocondrias interfibrilares de corazones viejos no alcanzan el nivel respiratorio máximo. Análisis proteómicos de segunda generación han demostrado un aumento de la oxidación de proteínas mitocondriales relacionado con el envejecimiento. Esta tesis ha investigado el posible efecto de la edad sobre la capacidad de las mitocondrias para captar calcio. En cardiomiocitos la captación mitocondrial del calcio procedente del RS se ha visto reducida de forma significativa en el envejecimiento. Esta disminución de la captación de calcio mitocondrial se asoció a una reducida capacidad de regeneración de NAD(P)H y a un incremento de la producción de ROS mitocondriales en cardiomiocitos viejos. Ensayos de inmunofluorescencia y de ligación por proximidad han revelado una comunicación defectuosa entre la mitocondria y el RS en cardiomiocitos de corazones senescentes. La desestructuración de las uniones entre el RS y la mitocondria con colchicina fue capaz de reproducir el efecto de la edad sobre las alteraciones en el manejo/transferencia de calcio entre ambos orgánulos en cardiomiocitos jóvenes. La segunda parte de este trabajo investiga el impacto potencial de las alteraciones mitocondriales sobre los efectos adversos del envejecimiento en el daño por isquemia y reperfusión (IR). Los corazones aislados y perfundidos de ratones viejos sometidos a IR desarrollaron mayor rotura sarcolemal y tamaño de infarto, junto con un retraso significativo del desarrollo del rigor isquémico. Los cardiomiocitos viejos sometidos a isquemia, desarrollaron una caída más rápida del potencial de membrana mitocondrial (ΔΨm) junto con un retraso paradójico en la aparición del rigor. La tasa de recuperación transitoria del ΔΨm durante los primeros minutos de isquemia, debida a la actividad reversa de la FoF1-ATPsintasa, se encontró significativamente disminuida en cardiomiocitos viejos. El análisis proteómico ha demostrado un aumento de la oxidación de diferentes subunidades de la FoF1-ATPsintasa asociado al envejecimiento. La alteración del ΔΨm observado en los cardiomiocitos viejos se asoció a una menor captación de calcio mitocondrial durante la IR. A pesar de esto, el desarrollo de permeabilidad transitoria (mPT) fue mayor en los cardiomiocitos senescentes y este efecto se correlacionó con una mayor hipercontractura y muerte celular en reperfusión. Por lo tanto, el desarrollo de una comunicación defectuosa entre el RS y la mitocondria durante el envejecimiento produce un intercambio ineficiente de calcio entre ambos orgánulos, que contribuye al desajuste en la demanda/aporte de energía y a un aumento consiguiente del estrés oxidativo. La oxidación de la FoF1-ATPsintasa se asocia a una alteración de su funcionamiento y a un incremento de la sensibilidad de la mitocondria para desarrollar mPT. Debido al modelo recientemente propuesto según el cual la FoF1-ATPsintasa forma parte del mPTP, es posible especular que la oxidación de esta enzima está asociada al aumento del daño por IR en el miocardio senescente.
Mitochondrial alterations are critically involved in the increased vulnerability to disease during aging. On the other hand, aging is a major determinant of the incidence and severity of ischemic heart disease. Preclinical information suggests the existence of intrinsic cellular alterations that contribute to ischemic susceptibility in senescent myocardium, by mechanisms not well established. The first part of this thesis investigates the contribution of mitochondria-sarcoplasmic reticulum (SR) communication in the functional decline of cardiomyocyte during aging. Echochardiographic analysis of aging mice (>20 months) showed a rather preserved cardiac contractile function in resting conditions respect to young mice (5-6 months). ATP/phosphocreatine were preserved in hearts from old mice as quantified by RMN spectroscopy. In isolated mitochondria from young and old mouse hearts, mitochondrial membrane potential and resting O2 consumption were similar in both groups. However, stimulation of O2 consumption after the addition of ADP resulted in a partial failure of interfibrillar mitochondria from aged hearts to achieve maximal respiratory rate. Second generation proteomics disclosed an increase of mitochondrial protein oxidation in advanced age. Because both energy production and oxidative status are regulated by mitochondrial calcium, this work further investigated the effect of age on mitochondrial calcium uptake. While no age-dependent differences were found in calcium uptake kinetics in isolated mitochondria, in which the contribution of other organelles and sarcolemma is absent, mitochondrial calcium uptake secondary to SR calcium release was significantly reduced in cardiomyocytes from old hearts. Reduced mitochondrial calcium uptake in aging cardiomyocytes was associated with decreased NAD(P)H regeneration and a concomitant increase of mitochondrial ROS production manifested only when cells were exposed to high frequency electrical stimulation. Immunofluorescence and proximity ligation assay identified defective communication between mitochondria and SR in cardiomyocytes from aged hearts. Functional analysis of calcium handling in fluo-4 loaded cardiomyocytes disclosed an altered pattern of RyR gating properties. The observed defects in SR calcium transfer and in calcium handling could be reproduced in young cardiomyocytes after interorganelle disruption with colchicine, at concentrations that had no significant effect in aged cardiomyocytes or isolated mitochondria. The second part of this work investigates the potential impact of the altered mitochondrial function in the adverse effect of aging on myocardial ischemia and reperfusion (IR) injury. Isolated perfused hearts from old mice submitted to transient IR displayed an increase in hypercontracture, sarcolemmal rupture and infarct size, as compared to hearts from young mice, despite a paradoxical delay ischemic rigor contracture onset. In isolated cardiomyocytes from aging hearts submitted to IR there was a faster decline of mitochondrial membrane potential (ΔΨm) in comparison with young ones, but ischemic rigor shortening was also delayed. Transient recovery of ΔΨm observed during ischemia, secondary to the reversal of mitochondrial FoF1-ATPsynthase to ATPase mode, was markedly reduced in aging cardiomyocytes. Proteomic analysis demonstrated an increased oxidation of different subunits of FoF1-ATPsynthase. Altered bionergetics in aging cells was associated with reduced mitochondrial calcium uptake and more severe cytosolic calcium overload during both ischemia and reperfusion. Despite attenuated mitochondrial calcium overload, the occurrence of mitochondrial permeability transition pore (mPTP) opening, hypercontracture and cell death were increased during reperfusion in cardiomyocytes from old mice. In vitro studies demonstrated a significantly reduced calcium retention capacity in interfibrillar mitochondria from aging hearts. Thus, defective SR-mitochondria communication underlies inefficient interorganelle calcium exchange that contributes to energy demand/supply mismatch and oxidative stress in the aged heart. This may spread on an altered FoF1-ATPsynthase and increased sensitivity of mitochondria to undergo mPTP opening as important determinants of the reduced tolerance to ischemia-reperfusion in senescent myocardium. Because ATPsynthase has been proposed to conform mPTP, it is tempting to hypothesize that oxidation of ATPsynthase underlie both phenomena.

博士
國立臺灣大學
生理學研究所
92
Ischemia-reperfusion injury occurrs when the reoxygenated blood is introduced into anoxic tissue, and that cause multiple organs dysfunction. Our studies aim to understand the pathophysiology and to the way to minimize the ischemia-reperfusion injury. Recently, investigators found that heme oxygenase-1, a key enzyme in heme metabolism, was highly expressed when cells were experiencing stress, and the expression was supposed to be cell-protective. To clarify the mechanism of preconditioning, we used the liver ischemia-reperfusion model to testify the role that heme oxygenase-1 plays in two kinds of preconditioning, hypoxic and remote preconditioning. Besides, to understand the pathophysiology of ischemia-reperfusion injury on remote organs, we used the intestinal ischemia-reperfusion injury to testify the associated changes of renal nerve activity and renal function. In the first experiment, we proposed that hypoxic preconditioning (HP) confers cytoprotection against ischemia-reperfusion injury, and this effect is in part due to the induction of heme oxygenase-1. This experiment evaluates liver cell damage after ischemia-reperfusion injury in HP rats. HP rats were prepared by exposure (15hours day-1) to an altitude chamber (5500m) for 2 weeks. Partial hepatic ischemia was produced in the left lobes for 45 minutes followed by 180 minutes of reperfusion. Zinc-protoporphyrin IX(ZnPP), a specific inhibitor of HO enzymatic activity, was subcutaneously injected 1 hour before the I/R injury in separate groups of sea-level （SL）control and HP rat. Serum alanine transaminase (ALT) levels, liver HO-1 mRNA and protein, and HO enzymatic activity were measured. Our results showed that heme oxygenase-1 (HO-1) was induced in the livers of rats exposed to HP. The levels of HO-1 mRNA and protein were obviously over-expressed after two weeks of hypoxic preconditioning. HP diminished the elevation of serum ALT levels after I/R injury （83.7±4.9 U L-1）when compared with SL controls （280.8±19.4 U L-1） and HP+ ZnPP pre-treated groups（151.3±4.4 U L-1）. The heme oxygenase activity in treated rats also correlated these results（237.9±19.8 pmol mg-1 protein hr-1 for the HP group, 164.3±12.7 pmol mg-1 protein hr-1 for the HP+ ZnPP, and 182.6±8.9 pmol mg-1 protein hr-1 for the SL controls. Our data showed that (a）The induction of HO-1 in HP indicates that it may participate in the cellular response to hypoxia；（b） hypoxic preconditioning protects the liver from ischemia-reperfusion injury；（c） the protective effects induced by hypoxic preconditioning are reduced by inhibiting HO-1 enzyme activity with pretreated ZnPP, suggesting that the effects are mediated by HO-1. In the next experiment, again we proposed that remote preconditioning (RP) confers cytoprotection against ischemia-reperfusion injury, and this effect is in part due to the induction of heme oxygenase-1. This experiment evaluates liver cell damage after ischemia-reperfusion injury in RP rats. The remote preconditioning was produced by four cycles of 10 minutes’ ischemia-reperfusion of the hind limb of rats. Partial hepatic ischemia was produced in the left lobes for 45 minutes followed by 180 minutes of reperfusion. Zinc-protoporphyrin IX(ZnPP), a specific inhibitor of HO enzymatic activity, was subcutaneously injected 1 hour before the ischemia-reperfusion injury in separate groups of control and RP rat. Serum alanine transaminase (ALT) levels, liver HO-1 protein, and HO enzymatic activity were measured. Our results showed that heme oxygenase-1 (HO-1) was induced in the livers of rats exposed to RP (2793.6± 422.7 V.S. 1614.7±454.2 unit). RP diminished the elevation of serum ALT levels after I/R injury （346.5± 251.4 U L-1）when compared with controls （1188.3±559U L-1） and RP+ ZnPP pre-treated groups（1578± 692.3U L-1）. The heme oxygenase activity in treated rats also correlated these results（286.8±34.3 pmol mg-1 protein hr-1 for the RP group, 156.3±27.5 pmol mg-1 protein hr-1 for the RP+ ZnPP pre-treated group, and 170.6±19.4pmol mg-1 protein hr-1 for the control group, 144.8± 7.8pmol mg-1 protein hr-1 for the control+ ZnPP pre-treated group）. Our data showed that (a）remote preconditioning produced by repeated limb ischemia-reperfusion could induce hepatic HO-1 expression；（b） remote preconditioning protects the liver from ischemia-reperfusion injury；（c） the protective effects induced by remote preconditioning are reduced by inhibiting HO-1 enzyme activity with pretreated ZnPP, suggesting that the effects are mediated by HO-1. The above two in vivo experiments showed that HO-1 plays important roles in both the mechanisms of hypoxic and remote preconditioning. Previous study showed that a neurogenic pathway was involved in the mechanism of remote intestinal preconditioning. We proposed that remote organs injury induced by the intestinal reperfusion injury might be related to neurogenic mechanisms. To clarify this problem, we used the intestinal ischemia-reperfusion injury model to testify the impact of the injury upon renal nerve activity and associated renal dysfunction. Our results showed that the efferent renal nerve activity (ERNA) was only 14.3±6.6% lower than basline value after 120 minutes’ ischemia, but elevated to 100.4±29.4% higher when the reperfusion began. The ERNA remained 94.3±21.65% higher than baseline even after 60 minutes’ reperfusion. In the fluid expansion group, the ERNA also was 21.4±2.4% lower than the baseline, but still elevated to 29.3±5.2% higher even the hypotension were corrected by fluid expansion in the reperfusion injury. There was only mild change of afferent renal nerve activity (ARNA) in ischemia period. When the reperfusion period began, the ARNA was obviously depressed (37.5±5.8% lower than baseline) 。After 60 minutes’ reperfusion, the ARNA was still 45.7±8.1% lower than baseline. The fluid expansion did not change the depressed ARNA in reperfusion period. We also detected the levels of calcitonin-gene related pepetide (CGRP) in portal vein and intestinal tissue were higher than baseline values after 60 minutes’ reperfusion. (in portal vein: 92.2±4.4 pg/ml v.s 57.8±0.6 pg/ml, and in intestine: 655.8±115.9pg/mlv.s 60.5±9.4pg/ml), which implicated that CGRP was released into intestinal and portal vein from enteric nervous system in the reperfusion period. Fluid expansion not only lessens the hemodynamic changes and hemoconcentration occurring in reperfusion period, it also lessens the release of CGR, though the CGRP level was still higher than baseline value in reperfusion period. The level of another capsaicin-sensitive neuropeptide, substance P, was not found to be affected by this experiment model. Te result showed that ERNA increased after intestinal ischemia-reperfusion injury and the increased ERNA could reduce renal blood flow. To clarify the increased ERNA was due to baroreflex, another group of rats received fluid expansion before reperfusion began to correct the hemoconcentration and restore the renal blood flow. The amplitude of increased ERNA was lessen by fluid expansion, but was still higher than baseline, indicating the baroreflex could be totally responsible for the rise of ERNA in this model. Besides, a sensory impairment not related to baroreflex was recognized in intestinal ischemia-reperfusion injury for the depressed ARNA was not altered by fluid expansion. Through the inhibitory reno-renal reflex, the depressed ARNA could increased the contralateral ERNA. At the same time, the released CGRP in intestinal ischemia-reperfusion injury might directly stimulate the increase of ERNA. Our results indicated that intestinal ischemia-reperfusion injury causes a disturbance of renal nerve activity. The increased ERNA are related in part to hypotension and released CGRP in reperfusion period acting by a baroreflex way. Besides, the depressed ARNA leads to the loss of inhibitory action on contralateral ERNA, which further impairs the homeostasis of renal circulation and renal tubular function. To sum up, both the hypoxic and remote preconditioning effectively reduce the hepatic ischemia-reperfusion injury, partly due to the induction of heme oxygenase-1. The renal dysfunction in intestinal ischemia-reperfusion injury is in part due to an impairment of renal nerve activity induced in this injury model.

Includes bibliographical references (leaves 292-352)
xvi, 352 leaves
Determines the role of matrix metalloproteinases, MMP-2 and MMP-9 in reperfusion injury following skeletal muscle ischaemia; and, whether inhibition of MMPs by doxycycline protects against tissue damage.
Thesis (M.D.) -- University of Adelaide, Dept. of Surgery, 2002

Research Doctorate - Doctor of Philosophy (PhD)
Background: Ischemic stroke is the leading cause of adult disability in the developed world. When a blood vessel within the brain becomes occluded, there is a volume of tissue which immediately dies, the ischemic core, and a volume of tissue which is hypo-perfused and will die within hours if the occlusion is not removed, the ischemic penumbra. Salvage of the ischemic penumbra by reperfusion can be achieved with intravenous thrombolysis which activates the bodies’ anti-clotting system to dissolve a thrombus, or mechanical removal of the clot with thrombectomy. Computed tomography perfusion (CTP) is a clinically available brain imaging technique which not only assists with positively confirming the diagnosis of acute ischemic stroke, but also assists reperfusion therapy decision making in clinical practice by providing information about brain tissue viability (salvageable versus non-salvageable tissue). The volume of the ischemic core has been shown to be related to patient outcomes, and the volume of the penumbra has also been shown to relate to treatment response potential. However, the measurement of penumbra and infarct core with CTP can be varied due to different structural tissue compartments of the brain (grey matter and white matter) and different algorithms applied to post-processing of raw imaging (standard singular value deconvolution (sSVD) and standard singular value deconvolution with delay and dispersion correction(ddSVD). This thesis incorporated a series of studies, aimed to increase the precision and accuracy of the tissue pathophysiology measures in acute ischemic stroke with CTP and relate the relevant measurement of ischemic penumbra and infarct core to patient outcomes. Methods: This thesis included acute ischemic stroke patients from two data sets: (1) A previously collected data set of acute ischemic stroke patients admitted to the John Hunter Hospital within 6 hours of symptom onset, underwent baseline MRI within 1 hour of the initial CTP, and follow-up MRI at 24-hour. (2) Acute ischemic strokes patients recruited into the INternational Stroke Perfusion Imaging REgistry (INSPIRE). National Institutes of Health Stroke Scale (NIHSS) was performed at baseline and 24-hour to assess the stroke severity. A modified Rankin Score (mRS) was performed at day-90 post-stroke to evaluate patient outcomes. All perfusion imaging were post-processing with MIStar (Apollo Medical Imaging Technology, Melbourne, Australia) using sSVD and/or ddSVD as post-processing algorithms. Results: The first study in this thesis derived the optimal threshold of penumbra and infarct core for gray matter and white matter. This study demonstrated that separated tissue-specific thresholds for gray matter and white matter increased volumetric agreement with acute diffusion-weighted imaging. Gray matter had considerably higher infarct core thresholds than white matter. Furthermore, a single threshold, delay time (DT) >3seconds from ddSVD accurately defined penumbra in gray matter and white matter, as well as mixed measures of gray matter and white matter. The following three studies in this thesis aimed to relate the relevant measurement of penumbra and infarct core to patient outcomes. This thesis demonstrated that in acute ischemic stroke patients who received alteplase, after correcting for baseline infarct core volume, for each percentage of penumbral volumes that was salvaged, the odds of a patient having an excellent clinical outcome increased by 7.4%. Furthermore, the perfusion imaging mismatch classification with DT was the optimal mismatch criteria as a patient selection tool for reperfusion therapy, in large vessel occlusion patients who receive intravenous thrombolysis only and patients who receive endovascular thrombectomy. Lastly, this thesis also found that patients with larger baseline CTP infarct core (>30mL) and “proximal” large vessel occlusion, with poorer collaterals clearly benefited from complete reperfusion after endovascular thrombectomy compared to complete reperfusion after intravenous thrombolysis alone. However, more “distal” large vessel occlusion patients with smaller baseline infarct cores and better collaterals, did not have additional benefit from complete reperfusion after endovascular thrombectomy compared with intravenous thrombolysis alone. Conclusion: The findings of this thesis supported that CTP was able to accuratly and precicely define acute ischemic tissue pathophysiology. Moreover, the accurate measures of brain tissue viability were directly related to patient clinical outcome regardless of the type of treatment received (intravenous thrombolysis or thrombectomy), and the likelihood of the success of reperfusion therapy. Importantly, the relationship between the baseline tissue pathophysiology of the ischemic core and penumbra to patient outcomes was seen to be significantly different depending on treatment type.

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2016
Ischemic mitral regurgitation (IMR) is a frequent and serious complication of coronary artery disease, associated with considerable increases in mortality and morbidity for the patient. While the benefits of simultaneous revascularization and mitral valve surgery are uncontested in moderate to severe cases, the ideal surgical approach to the valve is yet to be established. Mitral valve repair (MVr) has shown benefits over replacement (MVR) in nonischemic primary mitral regurgitation, but its superiority in the treatment of IMR has not been replicated. New randomized trials suggest it may be in fact non-superior, due to significantly greater reoperation rates amidst similar mortality in the long run. Such discrepant outcomes likely stem from the distinct pathophysiology of IMR. Unlike its etiologically degenerative counterparts, IMR does not derive from direct damage to the valve leaflets, but rather from dysfunction of its sub-valvular apparatus and the left ventricular wall, in the context of acute or chronic ischaemia. Echocardiographic data points to remodelling of the left ventricle, with subsequent papillary muscle displacement, increased leaflet tethering and inefficient coaptation, as the main responsible mechanism for ischemic mitral regurgitation. The purpose of this article is to review the currently available data, in an attempt to better understand IMR’s unique pathophysiology and compare the different outcomes for mitral valve repair and replacement.
A Regurgitação Mitral Isquémica (RMI) é uma complicação frequente e importante de doença arterial coronária, estando associada a aumentos consideráveis da mortalidade e morbilidade dos doentes. Apesar dos incontestados benefícios da revascularização e cirurgia valvular em simultâneo, a abordagem ideal à válvula não é ainda, nestes casos, consensual. Apesar das demonstradas vantagens da valvuloplastia mitral face à substituição em doentes com insuficiência mitral não-isquémica, estas não se verificam em doentes com RMI. Estudos randomizados recentes sugerem a não-superioridade da plastia face à substituição, devido a maiores taxas de reoperação, apesar de taxas de mortalidade semelhantes a longo-prazo. Esta discrepância poderá resultar da fisiopatologia distinta da RMI. Ao contrário dos seus congéneres de etiologia degenerativa, a RMI não deriva do dano directo aos folhetos mitrais, mas antes da disfunção do aparelho sub-valvular e do ventrículo esquerdo, em contexto isquémico, seja este agudo ou crónico. Estudos ecográficos sugerem que a distorção do ventrículo esquerdo, com subsequente deslocação dos músculos papilares, aumento das forças de ancoragem dos folhetos e coaptação ineficiente dos mesmos, são os grandes responsáveis pela RMI. Este artigo tem como propósito fazer uma revisão dos estudos presentemente disponíveis, de forma a sumarizar o entendimento corrente da fisiopatologia da RMI e a comparar os diferentes outcomes da valvuloplastia e substituição valvular.