Prognostic value of adenosine stress cardiovascular magnetic resonance in patients with low-risk chest pain

<p>Abstract</p> <p>Background</p> <p>Approximately 5% of patients with an acute coronary syndrome are discharged from the emergency room with an erroneous diagnosis of non-cardiac chest pain. Highly accurate non-invasive stress imaging is valuable for assessment of low-risk chest pain patients to prevent these errors. Adenosine stress cardiovascular magnetic resonance (AS-CMR) is an imaging modality with increasing application. The goal of this study was to evaluate the negative prognostic value of AS-CMR among low-risk acute chest pain patients.</p> <p>Methods</p> <p>We studied 103 patients, mean 56.7 ± 12.3 years of age, with chest pain and no electrocardiographic evidence of ischemia and negative cardiac biomarkers of necrosis, who were admitted to the Cardiac Decision Unit of our institution. All patients underwent AS-CMR. A negative AS-CMR was defined as absence of all the following: regional wall motion abnormalities at rest; perfusion defects during stress (adenosine) and rest; and myocardial scar on late gadolinium enhancement images. The patients were followed for a mean of 277 (range 161-462) days. The primary end point was defined as the combination of cardiac death, nonfatal acute myocardial infarction, re-hospitalization for chest pain, obstructive coronary artery disease (>50% coronary stenosis on invasive angiography) and coronary revascularization.</p> <p>Results</p> <p>In 14 patients (13.6%), AS-CMR was positive. The remaining 89 patients (86.4%), who had negative AS-CMR, were discharged. No patient with negative AS-CMR reached the primary end-point during follow-up. The negative predictive value of AS-CMR was 100%.</p> <p>Conclusion</p> <p>AS-CMR holds promise as a useful tool to rule out significant coronary artery disease in patients with low-risk chest pain. Patients with negative AS-CMR have an excellent short and mid-term prognosis.</p

PAK4 signaling in development and cancer

Our understanding of cancer biology has been evolving rapidly shaped by groundbreaking discoveries. We now understand that cancer is not one disease but many, and that tumors are not foreign objects in the human body but rather the result of changes in the previously normal tissues and organs. Thus, in order to ask fundamental questions and dissect the complexity of cancer it is essential to grasp how the healthy organs develop and function and the cellular and molecular mechanisms involved. The serine/threonine PAKs are signaling hubs with proven roles in development and disease. Specifically, they are important to several hallmarks of cancer. Thus, the family in general, and PAK4 in particular, is increasingly attracting the interest of the scientific community. In this thesis I have explored the role of PAK4 in normal organ development and cancer. Novel mouse models with PAK4 depletion in the mammary gland and in the pancreas have been established and characterized in Paper I and Paper II. The absence of major tissue abnormalities upon PAK4 depletion in the mammary epithelium allowed me to use this model to study the role of PAK4 in tumorigenesis in vivo, in Paper III, and a counterpart mouse model with PAK4 overexpression in the mammary epithelium was also generated. These complementary in vivo setups showed that PAK4-overexpressing mammary glands occasionally developed mammary tumors while PAK4 abrogation impaired PyMT-driven mammary tumorigenesis. Extensive in vitro experiments, using state of the art techniques, then supported a model in which PAK4 confers selective advantages to cancer cells by overcoming the senescence barrier. This, in turn, constitutes a selective vulnerability of cancer cells that become susceptible to a senescence-like response upon PAK4 inhibition. The data presented also demonstrates a crosstalk between PAK4 and NF-κB signaling, and a direct interaction and phosphorylation site within the REL-homology domain of RELB is found to be relevant for tuning RELB-mediated transcription and cancer cell proliferation via C/EBPβ. Importantly, these findings were largely supported by correlations in clinical data and validated ex vivo in patient-derived cells, thus highlighting PAK4 as an attractive therapeutic opportunity in cancer. Therefore, this thesis contributes to a better understanding of the mechanisms that govern breast tumorigenesis, with hopes that such knowledge will prove relevant in cancer prognosis and treatment

Adenosine magnetic resonance imaging versus dobutamine stress echocardiography in patients with low probability for coronary artery disease

Accurate assessment of patients with chest pain without electrocardiographic changes or elevation of serum cardiac enzymes is challenging. There is increased interest in the role of dobutamine stress echocardiography (DSE) and adenosine magnetic resonance imaging (AMRI) performed in the chest pain unit as a diagnostic method to rule out Coronary Artery Disease (CAD) as the cause of the chest pain in this population