The precise molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. Toll-like receptor-4 (TLR-4) engages lipopolysaccharide (LPS) and activates signaling pathways leading to the expression of proinflammatory cytokines implicated in myocardial dysfunction. We determined whether TLR-4 was necessary for LPS-induced myocardial dysfunction in vivo. The effects of LPS on left ventricular (LV) function were studied in mice with defective TLR-4 signaling (C3H/HeJ, TLR-4 deficient) and wild-type mice (C3HeB/FeJ). Mice (n = 5/group) were injected with LPS or diluent, and LV function was examined by using two-dimensional echocardiography and conductance catheters. LPS significantly decreased all indexes of LV function in wild-type mice when compared with controls; LV function was not depressed in the LPS-treated TLR-4-deficient mice relative to controls. LPS increased myocardial nitric oxide synthase-2 expression and cGMP only in wild-type mice. This study suggests that TLR-4 mediates the LV dysfunction that occurs in LPS-induced shock. Therefore, TLR-4 might be a therapeutic target for attenuating the effects of LPS on the heart.

Background-The molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. CD14mediates the inflammatory response to lipopolysaccharide (LPS) in various organs including the heart. In this study we investigated the role of CD14 in LPS-induced myocardial dysfunction in vivo. Methods and Results-Wild-type and CD14-deficient (CD14-D) mice were challenged with Escherichia coli LPS.Myocardial tumor necrosis factor, interleukin-1␤ (IL-1␤), and NOS2 induction was measured before and 6 hours after LPS challenge. Echocardiographic parameters of left ventricular function were measured before and 6 hours after LPS administration. LPS challenge induced a significant increase in myocardial tumor necrosis factor and IL-1␤ mRNA and protein expression in wild-type mice. In contrast, mRNA and protein levels for TNF and IL-1␤ were significantly blunted in CD14-D mice. An increase in NOS2 protein was noted within 6 hours of LPS provocation only in the hearts of wild-type mice. This was associated with an increase in ventricular cGMP levels. Activation of nuclear factor-B was observed within 30 minutes of LPS in the hearts of wild-type mice but not in CD14-D mice. In wild-type mice, LPS significantly decreased left ventricular fractional shortening, velocity of circumferential shortening, and dP/dt max . LPS-treated CD14-D mice maintained normal cardiac function. Conclusions-These results suggest that CD14 is important in mediating the proinflammatory response induced by LPS in the heart and that CD14 is necessary for the development of left ventricular dysfunction during LPS-induced shock in vivo.

Background-Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor B (NF-B) and given that NF-B mediates cytoprotective responses, we asked whether NF-B activation conferred cytoprotective responses in acute myocardial ischemia/infarction. Methods and Results-We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IB␣ protein (IB␣⌬N) that prevents nuclear translocation of NF-B in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was Ϸ50% greater (PϽ0.02) in the IB␣⌬N mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (PϽ0.008) in the IB␣⌬N mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the IB␣⌬N mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity. Conclusions-Transgenic

Despite the many advances in cardiovascular medicine, decisions concerning the diagnosis, prevention, and treatment of left ventricular (LV) thrombus often remain challenging. There are only limited organizational guideline recommendations with regard to LV thrombus. Furthermore, management issues in current practice are increasingly complex, including concerns about adding oral anticoagulant therapy to dual antiplatelet therapy, the availability of direct oral anticoagulants as a potential alternative option to traditional vitamin K antagonists, and the use of diagnostic modalities such as cardiac magnetic resonance imaging, which has greater sensitivity for LV thrombus detection than echocardiography. Therefore, this American Heart Association scientific statement was commissioned with the goals of addressing 8 key clinical management questions related to LV thrombus, including the prevention and treatment after myocardial infarction, prevention and treatment in dilated cardiomyopathy, management of mural (laminated) thrombus, imaging of LV thrombus, direct oral anticoagulants as an alternative to warfarin, treatments other than oral anticoagulants for LV thrombus (eg, dual antiplatelet therapy, fibrinolysis, surgical excision), and the approach to persistent LV thrombus despite anticoagulation therapy. Practical management suggestions in the form of text, tables, and flow diagrams based on careful and critical review of actual study data as formulated by this multidisciplinary writing committee are given.

Recent studies have identified the importance of proinflammatory mediators in regulating cardiac structure in health and disease. Recent studies suggest that cytokines that are expressed within the myocardium in response to a environmental injury, namely tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1) and the interleukin-6 (IL-6) family of cytokines play an important role in initiating and integrating homeostatic responses within the heart. However, these "stress-activated" cytokines all have the potential to produce cardiac decompensation when expressed at sufficiently high concentrations. Indeed, there is now a growing appreciation that these molecules may play an important role in mediating disease progression in the failing heart. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in pre-clinical and clinical heart failure models culminated in a series of multicenter clinical trials that utilized "targeted" approaches to neutralize tumor necrosis factor (TNF) in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.

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Background Increased arterial stiffness has been shown to be associated with aging and cardiovascular risk factors. Speckle-tracking algorithms are being used to measure myocardial strain. We evaluated if speckle-tracking could be used to measure carotid arterial wall strain (CAS) reproducibly in healthy volunteers and then examined if CAS was lesser in individuals with diabetes. Methods Bilateral electrocardiography-gated ultrasound scans of the distal common carotid arteries [D-CCA] (3 cardiac cycles, 14 MHz linear probe, mean 78.7 [Standard deviation (SD) 8.9]) frames per second were performed twice (2–4 days apart) on 10 healthy volunteers to test repeatability. Differences in CAS between healthy (n=20) and diabetic subjects (n=21) were examined. Peak CAS was measured in each of 6 equal segments and averages of all segments (i.e., global average), of the 3 nearest the probe, and of the 3 farthest from the probe (i.e., far wall average) were obtained. Results Global CAS (intraclass correlation coefficient [ICC]=0.40) and far wall average (ICC=0.63) had the greatest test-retest reliability. The global and far wall averaged CAS were lower in diabetics (4.29% [Standard Error (SE) 0.27%]; 4.30% [SE 0.44%], respectively) than in controls (5.48% [SE 0.29%], p=0.001; 5.58% [SE 0.44%], p=0.003, respectively). This difference persisted after adjustment for age, gender, race, and hemodynamic parameters. Conclusions Speckle-tracking for measuring carotid arterial wall strain is feasible and modestly reliable. Diabetic subjects had a lower carotid arterial wall strain obtained with speckle-tracking when compared with healthy controls.

Clinical decision support systems (CDSSs) have the potential to save lives and reduce unnecessary costs through early detection and frequent monitoring of both traditional risk factors and novel biomarkers for cardiovascular disease (CVD). However, the widespread adoption of CDSSs for the identification of heart diseases has been limited, likely due to the poor interpretability of clinically relevant results and the lack of seamless integration between measurements and disease predictions. In this paper we present the Cardiac ScoreCard—a multivariate index assay system with the potential to assist in the diagnosis and prognosis of a spectrum of CVD. The Cardiac ScoreCard system is based on lasso logistic regression techniques which utilize both patient demographics and novel biomarker data for the prediction of heart failure (HF) and cardiac wellness. Lasso logistic regression models were trained on a merged clinical dataset comprising 579 patients with 6 traditional risk factors and 14 biomarker measurements. The prediction performance of the Cardiac ScoreCard was assessed with 5-fold cross-validation and compared with reference methods. The experimental results reveal that the ScoreCard models improved performance in discriminating disease versus non-case (AUC = 0.8403 and 0.9412 for cardiac wellness and HF, respectively), and the models exhibit good calibration. Clinical insights to the prediction of HF and cardiac wellness are provided in the form of logistic regression coefficients which suggest that augmenting the traditional risk factors with a multimarker panel spanning a diverse cardiovascular pathophysiology provides improved performance over reference methods. Additionally, a framework is provided for seamless integration with biomarker measurements from point-of-care medical microdevices, and a lasso-based feature selection process is described for the down-selection of biomarkers in multimarker panels.