Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition—a magnetic resonance imaging study

Aims Endothelial dysfunction, platelet hyperactivity, and inflammation play a crucial role in atherogenesis. A growing body of evidence suggests that inhibition of the thromboxane A2 (TxA2 or TP) receptor may improve endothelial function and reduce the inflammatory component of atherosclerosis in addition to its demonstrated antiplatelet activity. Consequently, we sought to assess the effect of a novel TP receptor antagonist S18886, on atherosclerotic lesion progression and composition by serial non-invasive magnetic resonance imaging (MRI). Methods and results S18886 was compared with control in an experimental model of established aortic atherosclerosis in New Zealand White rabbits (n=10). The animals underwent MRI of the abdominal aorta at the time of randomization and at the end of treatment. Subsequently, animals were euthanized and specimens were stained for histopathology and immunohistochemistry with anti-α-actin antibodies for vascular smooth muscle cells (VSMC), anti-RAM-11 for macrophages, anti-caspase-3 for apoptotic cells, anti-MMP-1 for metalloproteinases, and anti-endothelin-1 (ET-1) as a marker of endothelial dysfunction. MRI analysis revealed a significant reduction in total vessel area (TVA) and vessel wall area (VWA) in the S18886 group (P<0.05). Immunostaining analysis showed a significant decrease in RAM-11, caspase-3, MMP-1, ET-1 and an increase in α-actin in the treated group (P<0.05 vs. control). Conclusion Inhibition of the TP receptor by S18886 causes a regression of advanced atherosclerotic plaques. In addition, the reduction in the markers for macrophages, apoptotic cells, metalloproteinases, and endothelin-1 and the increase in VSMC, suggests that S18886 may not only halt the progression of atherosclerosis, but also transform lesions towards a more stable phenotype. The possibility of combining antithrombotic and antiatherosclerotic activity by means of the administration of TP inhibitors deserves further investigation in a clinical settin

Incidence, predictors, and evolution of conduction disorders and atrial arrhythmias after contemporary mitral valve repair

Background: Conduction disorders (CD) and atrial arrhythmias (AA) in the postoperative period of cardiac surgery impede prompt clinical recovery and prolong hospitalization. Mitral valve repair (MVR) has become the treatment of choice for patients with significant valvular regurgitation, but information on CD and AA in this population is scarce.Methods: Records of consecutive patients undergoing MVR at a single center were reviewed. Patients with a preoperative pacemaker, CD, prior cardiac surgery or concomitant MVR were excluded. A total of 290 patients were included in the final analysis. Electrocardiograms pre andpost-operatively were analyzed for CD and AA.Results: CD occurred in 69 (23.7%) patients: 47 (16.2%) had first degree atrio-ventricular block (AVB), 10 (3.4%) had Mobitz I, 3 (1.03%) had Mobitz II, and 9 (3.1%) complete AVB. Only 6 (2.0%) patients required pacemakers. Univariate predictors of AVB were age, preexisting right bundle branch block (RBBB), mitral valve ring size, and bypass time. The only multivariate predictors of AVB were bypass time and preexisting RBBB (OR 3.23 and 1.98, respectively). The most common AA was atrial fibrillation 13.1% (38 patients) followed by atrial flutter 2.7% (8 patients). Multivariate predictors of AA were age and left atrial size (OR 1.85 and 4.2, respectively). Length of stay in patients with CD or AA was prolonged 2.2 ± 2 days compared to controls (p &lt; 0.05).Conclusions: In this large sample of patients undergoing MVR, we found that bypass time and preexisting RBBB were independent predictors of CD; age and left atrial size were independent predictors of AA.

Sudden cardiac death and pump failure death prediction in chronic heart failure by combining ECG and clinical markers in an integrated risk model

BACKGROUND: Sudden cardiac death (SCD) and pump failure death (PFD) are common endpoints in chronic heart failure (CHF) patients, but prevention strategies are different. Currently used tools to specifically predict these endpoints are limited. We developed risk models to specifically assess SCD and PFD risk in CHF by combining ECG markers and clinical variables. METHODS: The relation of clinical and ECG markers with SCD and PFD risk was assessed in 597 patients enrolled in the MUSIC (MUerte Súbita en Insuficiencia Cardiaca) study. ECG indices included: turbulence slope (TS), reflecting autonomic dysfunction; T-wave alternans (TWA), reflecting ventricular repolarization instability; and T-peak-to-end restitution (ΔαTpe) and T-wave morphology restitution (TMR), both reflecting changes in dispersion of repolarization due to heart rate changes. Standard clinical indices were also included. RESULTS: The indices with the greatest SCD prognostic impact were gender, New York Heart Association (NYHA) class, left ventricular ejection fraction, TWA, ΔαTpe and TMR. For PFD, the indices were diabetes, NYHA class, ΔαTpe and TS. Using a model with only clinical variables, the hazard ratios (HRs) for SCD and PFD for patients in the high-risk group (fifth quintile of risk score) with respect to patients in the low-risk group (first and second quintiles of risk score) were both greater than 4. HRs for SCD and PFD increased to 9 and 11 when using a model including only ECG markers, and to 14 and 13, when combining clinical and ECG markers. CONCLUSION: The inclusion of ECG markers capturing complementary pro-arrhythmic and pump failure mechanisms into risk models based only on standard clinical variables substantially improves prediction of SCD and PFD in CHF patients

Differential clinical characteristics and prognosis of intraventricular conduction defects in patients with chronic heart failure

Intraventricular conduction defects (IVCDs) can impair prognosis of heart failure (HF), but their specific impact is not well established. This study aimed to analyse the clinical profile and outcomes of HF patients with LBBB, right bundle branch block (RBBB), left anterior fascicular block (LAFB), and no IVCDs. Clinical variables and outcomes after a median follow-up of 21 months were analysed in 1762 patients with chronic HF and LBBB (n = 532), RBBB (n = 134), LAFB (n = 154), and no IVCDs (n = 942). LBBB was associated with more marked LV dilation, depressed LVEF, and mitral valve regurgitation. Patients with RBBB presented overt signs of congestive HF and depressed right ventricular motion. The LAFB group presented intermediate clinical characteristics, and patients with no IVCDs were more often women with less enlarged left ventricles and less depressed LVEF. Death occurred in 332 patients (interannual mortality = 10.8%): cardiovascular in 257, extravascular in 61, and of unknown origin in 14 patients. Cardiac death occurred in 230 (pump failure in 171 and sudden death in 59). An adjusted Cox model showed higher risk of cardiac death and pump failure death in the LBBB and RBBB than in the LAFB and the no IVCD groups. LBBB and RBBB are associated with different clinical profiles and both are independent predictors of increased risk of cardiac death in patients with HF. A more favourable prognosis was observed in patients with LAFB and in those free of IVCDs. Further research in HF patients with RBBB is warranted

Atherothrombosis: the role of tissue factor

Atherothrombosis, defined as atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes and cardiovascular deaths. It is the leading cause of morbidity and mortality in the industrialized world. Plaque composition, rather than luminal stenosis, is recognized as the major determinant of this disease. Since tissue factor is found within atheroma and also in the bloodstream of atherosclerotic patients, it likely plays a key role in determining both plaque and blood thrombogenicity. Ongoing clinical and preclinical studies are evaluating the therapeutic possibilities of specific inhibition of the tissue factor pathway. Here, we will review the role of tissue factor in atherothrombosis

Atherothrombosis: A widespread disease with unpredictable and life-threatening consequences

Atherothrombosis, characterised by atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes (ACS) and cardiovascular death. It is the leading cause of mortality in the industrialised world. Atherosclerosis is a diffuse process that starts early in childhood and progresses asymptomatically through adult life. Later in life, it is clinically manifested as coronary artery disease, stroke, transient ischaemic attack, and peripheral arterial disease. From the clinical point of view, we should envision this disease as a single pathologic entity that affects different vascular territories. Available antithrombotic therapy is very safe and efficient but the morbidity and mortality due to atherothrombosis is still unacceptably high. Recent evidence suggests that inhibition of tissue factor or elements in the tissue factor pathway (i.e., factors VIIa and Xa, or thrombin) has the potential to further improve outcomes in atherothrombosis. Here, we will review the most important concepts and advances in the pathogenesis, prevention, and antithrombotic treatment of this widespread disease