In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Objective-Left atrial blood stasis is associated with increased risk for left atrial appendage thrombus (LAAT) and stroke in atrial fibrillation (AF). Von Willebrand factor (VWF) is associated with thromboembolism in AF. VWF thrombogenic activity is proportional to multimer size, which is regulated by VWF-cleaving protease (ADAMTS13). Methods and Results-To assess the association between left atrial blood stasis and VWF-ADAMTS13 system, plasma VWF antigen (VWF:Ag), VWF activity (VWF:Act), and ADAMTS13 activity were measured in 414 consecutive patients with nonvalvular AF (age 63Ϯ13 years; 25% women) and in 100 patients (age 64Ϯ14 years; 39% women) with normal sinus rhythm. Key Words: stroke Ⅲ thrombosis Ⅲ von Willebrand factor Ⅲ atrial fibrillation C ardioembolic stroke in the setting of atrial fibrillation (AF) begins with the left atrial appendage thrombus (LAAT) formation. 1-3 The risk for LAAT development and stroke increases with left atrium mechanical function deterioration that is reflected by reduction in left atrial appendage emptying velocity (LAAEV), development of spontaneous echocardiographic contrast (SEC), and progression of left atrial distension. 4 -7 However, the underlying mechanism behind the relationship between AF, atrial stasis, and thrombotic propensity is complex and poorly understood.Von Willebrand factor (VWF) a large plasma glycoprotein that mediates platelet adhesion and aggregation, 8 has been associated with stroke risk in AF. 9 -13 Prior studies comparing VWF levels between AF patients and subjects in normal sinus rhythm (NSR) were limited by small sample size. 14 -16 Assessment of archived plasma samples from Stroke Prevention in Atrial Fibrillation III participants lacked a comparator. 9 -11 Moreover, a prior association between elevated VWF and stroke became nonsignificant after adjustment for other clinical predictors. 11 The association between VWF and AF therefore remains largely unexplored.The thrombogenic potential of VWF is directly proportional to VWF activity (VWF:Act) determined by both plasma concentration and multimer size, 17 which is regulated by VWF-specific protease ADAMTS13. 18 Two patients may have similar plasma VWF content, yet thrombotic propensity will vary considerably depending on the proportion of highmolecular-weight multimer content. This nuance would be missed if mere antigen content was assessed.Atrial distension is associated with overexpression of VWF multimers, 19 and blood stasis has been shown to downregulate ADAMTS13 activity. 20 Previous studies, however, have not systematically accounted for degrees of atrial stasis or measured complete variables within the VWF system. We hypothesized that atrial distension and stasis in AF are associated with the higher VWF and increased proportion of large multimers that lead to the development of LAAT. To address this hypothesis, transesophageal echocardiography (TEE) measures of stasis and LAAT and measures of VWF antigen (VWF:Ag), VWF:Act, and ADAMTS13 activity were compared in consecutive patients wi...

Pulmonary arterial hypertension (PAH) is associated with refractory vasoconstriction and impaired NO-mediated vasodilatation of the pulmonary vasculature. Vascular tone is regulated by light chain (LC) phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosins, which are determined by the activities of MLC kinase and MLC phosphatase. Further, NO mediated vasodilatation requires the expression of a leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of MLC phosphatase. The objective of this study was to define contractile protein expression in the pulmonary arterial vasculature and vascular reactivity in PAH. In severe PAH, compared to controls, relative LZ+MYPT1 expression was decreased (100 ± 14% vs. 60 ± 6%, p<0.05, n=7-8), and NM myosin expression was increased (1 5 ± 4% vs. 53 ± 5% of total myosin, p<0.05, n=4-6). These changes in contractile protein expression should alter vascular reactivity; following activation with Ang II, force activation and relaxation were slowed, and sustained force was increased. Further, the sensitivity to ACh-mediated relaxation was reduced. These results demonstrate that changes in the pulmonary arterial SM contractile protein expression may participate in the molecular mechanism producing both the resting vasoconstriction and the decreased sensitivity to NO-mediated vasodilatation associated with PAH.

BackgroundDiabetes mellitus (DM) patients surviving myocardial infarction (MI) exhibit a substantially higher incidence of subsequent heart failure (HF). Neuregulin (NRG)-1 and erythroblastic leukemia viral oncogene homolog (ErbB) receptors have been shown to play a critical role in maintenance of cardiac function. However, whether myocardial NRG-1/ErbB is altered during post-MI HF associated with DM remains unknown. The aim of this study was to determine the impact of type 1 DM on the myocardial NRG-1/ErbB system following MI in relation to residual left ventricular (LV) function.MethodsType 1 DM was induced in rats via administration of streptozotocin (65 mg/kg, i.p.). Control rats were injected with citrate buffer (vehicle) only. Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left coronary artery. Sham MI rats underwent the same surgical procedure with the exception that the left coronary artery was not ligated. At 4 weeks after surgery, residual in vivo LV function was assessed via echocardiography. Myocardial protein expression of NRG-1β, ErbB2 and ErbB4 receptors, and MDM2 (a downstream signaling pathway induced by NRG-1 that has been implicated in cell survival) was assessed in the remaining, viable LV myocardium by Western blotting. Changes in ErbB receptor localization in the surviving LV myocardium of diabetic and non-diabetic post-MI rats was determined using immunohistochemistry techniques.ResultsAt 4 weeks post-MI, echocardiography revealed that LV fractional shortening (FS) and LV ejection fraction (EF) were significantly lower in the DM + MI group compared to the MI group (LVFS: 17.9 ± 0.7 vs. 25.2 ± 2.2; LVEF: 35.5 ± 1.4 vs. 47.5 ± 3.5, respectively; P < 0.05), indicating an increased functional severity of HF among the DM + MI rats. Up-regulation of NRG-1β and ErbB2 protein expression in the MI group was abrogated in the DM + MI group concurrent with degradation of MDM2, a downstream negative regulator of p53. ErbB2 and ErbB4 receptors re-localized to cardiac myocyte nuclei in failing type 1 diabetic post-MI hearts.ConclusionsType 1 DM prevents compensatory up-regulation of myocardial NRG-1/ErbB after MI coincident with an increased severity of HF.

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