Poor performance of historical prediction models in patients investigated for chest pain: a prospective single centre, head-to-head comparison in a large cohort of patients.

BACKGROUND: An optimal investigation strategy for patients with suspected angina pectoris (AP) remains elusive. Present guidelines use the Duke Clinical Score (DCS) or the Diamond-Forrester (DF) model to compute the likelihood of coronary artery disease (CAD). This prospective study of patients referred to a chest pain clinic compares the relative values of these two historical models and of pain characteristics only to predict the presence of CAD. PATIENTS AND METHODS: Overall, 1376 patients reviewed in a chest pain clinic were assigned to five CAD likelihood groups (<10, 10-29, 30-60, 61-90 and >90%) using DCS and to three CAD likelihood groups (<15, 15-85 and >85%) using the DF model. Patients were diagnosed with CAD when they had either obstructive (>70%) coronary stenoses or a positive functional test. RESULTS: In all, 652 (47%) patients had nonanginal CP, 412 (30%) patients had atypical AP and 312 (23%) had typical AP. Four hundred seventeen (30%) patients were not investigated for CAD because of nonanginal symptoms and/or low CAD probability. The actual CAD prevalence was 21% versus a DCS predicted one of 51% and a DF model predicted one of 38% (P<0.001). Both models had modest predictive abilities with areas under the curve of of 0.695 and 0.693 and did not show useful clinical superiority over a prediction model using pain characteristics only (area under the curve: 0.65). CONCLUSION: CAD prevalence in patients referred for suspected AP is significantly lower than expected by using historical prediction models. The use of risk factors profile and demographics in addition to symptoms characteristics does not improve diagnostic accuracy.

Cardiovascular effects of treatment with taxanes.

Taxanes are cytotoxic drugs that stabilize cellular microtubules and are among the most active of the antineoplastic agents being widely used in the treatment of cancer patients. Furthermore, taxanes comprise a valuable tool in interventional cardiology. Following treatment with taxanes, in many patients, the risk of cardiovascular complications has recently been noted. This review examines the cardiac toxicity of treatment with taxanes and their use in cardiology and analyzes issues in clinical practice.

Pathophysiologic mechanisms of calcific aortic stenosis.

Calcific aortic stenosis (CAS) comprises the leading indication for valve replacement in the Western world. Until recently, progressive calcification was considered to be a passive process. Emerging evidence, however, suggests that degenerative aortic stenosis constitutes an active process involving stimulation of several pathophysiologic pathways such as inflammation and osteogenesis. In addition, CAS and atherosclerosis share common features regarding histopathology of lesions. These novel data raise a new perspective on the prevention and treatment of disease. The current article reviews the most important pathophysiologic mechanisms of senile aortic stenosis.

Evaluation of left ventricular hypertrophy in patients requiring permanent pacing.

OBJECTIVE: Hypertension may lead to left ventricular hypertrophy, fibrosis and degeneration of the conduction system. Our aim was to study the association of hypertrophy with certain arrhythmias such as complete atrioventricular block (AVB) and symptomatic sick sinus syndrome (SSS) that require implantation of permanent pacemaker. METHODS: We studied 130 patients that had been given a pacemaker because of complete AVB, 130 patients that had been given a pacemaker because of symptomatic SSS and 45 patients without cardiac conduction disturbances. In order to estimate left ventricular hypertrophy, indexes of relative wall thickness (RWT) and left ventricular mass (LVM) were evaluated by echocardiography. RESULTS: We observed significant association between complete AVB and abnormal values of echocardiographic indexes. CONCLUSIONS: Our results lend further support to the hypothesis that complete AVB is associated with left ventricular hypertrophy. This hypothesis is enhanced by the observation that the majority of patients with complete AVB were hypertensive.

Survivin overexpression in HCC and liver cirrhosis differentially correlates with p-STAT3 and E-cadherin.

Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of apoptosis and cell proliferation. Overexpression of survivin has been implicated in several human cancers, including human hepatocellular carcinoma (HCC). Although several factors have been shown in vitro to upregulate survivin expression in cancer cells, the in vivo regulators of survivin in human hepato-carcinogenesis are largely unknown. We studied by immunohistochemistry the protein expression of survivin in relation to cyclin D1, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), beta-catenin, E-cadherin and phosphorylated-Akt (p-Akt) in 69 cases of HCC and adjacent liver cirrhosis. Survivin was expressed in 63/69 (91.3%) cases of HCC and in 40/47 (85.1%) cases of liver cirrhosis. Survivin localization in HCC was exclusively nuclear, while intense cytoplasmic and low nuclear expression of survivin was observed in cases of cirrhosis. Survivin expression in HCC correlated significantly with low grade tumors, expression of cyclin D1 and p-STAT3. Expression of survivin in liver cirrhosis correlated with downregulation of E-cadherin expression. There was no significant correlation of survivin with beta-catenin or p-Akt in HCC or liver cirrhosis. In conclusion, we showed an association of nuclear survivin with well differentiated HCC, as well as with the expression of the cell cycle regulator cyclin D1. Activation of STAT3 and loss of E-cadherin but not beta-catenin or Akt pathways seem to be implicated in survivin upregulation in HCC and liver cirrhosis.

Bone regulatory factors NFATc1 and Osterix in human calcific aortic valves.

BACKGROUND: Emerging evidence suggests that calcific aortic valve stenosis constitutes an active process sharing common features with atherosclerosis and bone formation. To further support this hypothesis, we investigated the expression of bone regulatory factors in calcified aortic valves. METHODS-RESULTS: Formalin-fixed, paraffin-embedded tissue samples of human aortic tricuspid valves (n=54) were used from patients undergoing valve replacement for calcific, non-rheumatic aortic stenosis. As controls, fourteen aortic tricuspid valves (n=14) were obtained at autopsy from patients without clinical and morphological aortic valve lesions. Sections from both stenotic and normal aortic valve leaflets were studied immunohistochemically. Interstitial cells in stenotic valves showed intense expression of Sox9, Runx2 and Osterix (Osx) whereas NFATc1 was expressed in interstitial and inflammatory cells. In addition, NFATc1 expression correlated significantly with Osx (r=0.458, p<0.001) and Runx2 (r=0.387, p<0.001). Finally, there was accumulation of activated interstitial cells, T lymphocytes and macrophages as well as intense neoangiogenesis in pathological leaflets. CONCLUSIONS: The presence of NFATc1 and Osx in our material lends further support to the hypothesis that during the process of aortic valve calcification there is expression of osteoblastic phenotypes by valvular cells.

ILK overexpression in human hepatocellular carcinoma and liver cirrhosis correlates with activation of Akt.

Hepatocellular carcinoma (HCC) is one of the most common life-threatening malignancies in the world. The molecular mechanisms leading to the development of HCC are complex and only recently have they begun to be clarified. Integrin linked-kinase (ILK), a multifunctional signaling and scaffold protein of focal adhesion plaques, has been implicated in the pathogenesis of several human malignancies. In the current study the expression of ILK, beta-catenin and E-cadherin and the phosphorylation of Akt were studied by immunohistochemistry in 69 human HCCs and adjacent normal and cirrhotic liver parenchyma. ILK and phosphorylated-Akt (p-Akt) immunostaining was observed in 100 and 79.7% of HCCs, respectively, and their protein levels correlated significantly. Activation of beta-catenin and downregulation of E-cadherin were frequently observed in HCC, but they were not related to ILK expression. A strong correlation between ILK expression and phosphorylation of Akt was also observed in cirrhotic liver. Moreover, downregulation of E-cadherin and membranous beta-catenin were found in cirrhotic tissue suggesting their involvement in the liver tissue remodeling observed in cirrhosis. Our results indicate that ILK overexpression during liver oncogenesis and cirrhosis correlates with activation of Akt but not with other conventional ILK targets.