Objectives We sought to a) use a novel method of late gadolinium enhancement (LGE) quantification that utilizes normalized intensity measures to confirm the association between LGE extent and atrial fibrillation (AF) recurrence following ablation, and b) examine the presence of interaction and effect modification between LGE and AF persistence. Background Recurrent AF after catheter ablation has been reported to associate with the baseline extent of left atrial (LA) LGE on cardiac magnetic resonance (CMR). Traditional methods for measurement of intensity lack an objective threshold for quantification and interpatient comparisons of LGE. Methods The cohort included 165 participants (60.0±10.2 years, 77% men, 57% persistent AF) that underwent initial AF ablation. The association of baseline LGE extent with AF recurrence was examined using multivariable Cox proportional hazard models. Multiplicative and additive interaction between AF type and LGE extent were examined. Results During 10.2±5.7 months of follow-up, 63 (38.2%) patients experienced AF recurrence. Baseline LGE extent was independently associated with AF recurrence after adjusting for confounders [hazard ratio (HR) 1.5 per 10% increased LGE, P<0.001]. The HR for AF recurrence progressively increased as a function of LGE. The magnitude of association between LGE >35% and AF recurrence was greater among patients with persistent AF (HR 6.5, P=0.001 versus HR 3.6, P=0.001); however, there was no evidence for statistical interaction. Conclusions Regardless of AF persistence at baseline, participants with LGE ≤ 35% have a favorable outcome, whereas those with LGE > 35% have a higher rate of AF recurrence in the first year after ablation. These findings suggest a role for a) patient selection for AF ablation using LGE extent, and b) substrate modification in addition to pulmonary vein isolation in patients with LGE extent exceeding 35% of LA myocardium.

10 seconds (apnea) or a 40% reduction in airflow associated with decreased arterial oxygen saturation of at least 4% (hypopnea) despite persistent ventilatory efforts during sleep. In the Wisconsin Sleep Cohort Study, a population-based study of employed middle-aged adults, 24% of men and 9% of women had sleep-disordered breathing defined by an apnea hypopnea index (AHI), a summary measure of the total number of apnea and hypopnea events per hour of sleep, of five or greater. 1 An AHI of five or greater in combination with self-reported hypersomnolence is indicative of clinically symptomatic sleep apnea syndrome. 2 It is estimated that 4% of middle-aged men and 2% of middle-aged women in the general population meet minimal criteria for sleep apnea syndrome. 1 Several epidemiological studies have shown that sleep apnea syndrome is associated with cardiovascular diseases, such as hypertension, angina, arrhythmias, coronary heart disease, and congestive heart failure. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] In recent community-based studies of sleep-disordered breathing, even mild occult sleep apnea is associated with hypertension, 16,17 excessive daytime somnolence and morning headaches, 18-20 mental and cognitive impairments, 21-24 erectile dysfunction, 25 fibromyalgia, 26 and higher rates of automobile and work-related accidents. 27,28 Many of these sequelae of Objective: To investigate the effects of sleep apnea (SA) on the quality of life (QOL). Design: A prospective study of QOL in patients with and without SA as defined by an apnea-hypopnea index (AHI) >5. Setting: University-based outpatient clinics. Patients: Primary care patients followed in a general internal medicine clinic as well as those referred to a sleep disorders clinic at the University of Wisconsin Hospital and Clinics were consecutively recruited and classified into 3 groups of subjects: (1) patients without SA (AHI<5) (n=46), (2) patients with mild SA (AHI 5-15) (n=16), and (3) patients with moderate to severe SA (AHI>15) (n=21). Interventions: NA Measurements: QOL was assessed with the Medical Outcomes Study SF-36 Health Survey. Health history and demographic data were obtained via structured interview and medical record review. All subjects underwent overnight polysomnography for diagnosis of SA. Results: After controlling for age, gender, body mass index, and number of comorbid conditions, the association between sleep apnea and QOL was significant in the domains of physical functioning and role limitation due to physical health problems (p<0.05) and was borderline in vitality (p<0.1). Patients with both mild and moderately severe SA scored significantly lower (worse) than did patients without SA in physical functioning and in role limitations due to physical-health (82 and 83 vs. 92, respectively). Moderate to severe SA subjects scored significantly lower in vitality than did subjects without SA (51 vs. 64, p<0.05). Subscales analysis revealed that subjects with moderate to severe SA had significantly lower scores that did tho...

Urotensin II and its receptor are coexpressed in the heart and up-regulated during cardiac dysfunction. In cultured neonatal cardiomyocytes, we mimicked this up-regulation using an adenovirus to increase expression of the urotensin receptor. In this model system, urotensin II promoted strong hypertrophic growth and phenotypic changes, including cell enlargement and sarcomere reorganization. Urotensin II potently activated the MAPKs, ERK1/2 and p38, and blocking these kinases with PD098059 and SB230580, respectively, significantly inhibited urotensin II-mediated hypertrophy. In contrast, urotensin II did not activate JNK. The activation of ERK1/2 and p38 as well as cellular hypertrophy was independent of protein kinase C, and calcium and phosphoinositide 3-kinase, yet dependent on the capacity of the urotensin receptor to trans-activate the epidermal growth factor receptor. Urotensin II promoted the tyrosine phosphorylation of epidermal growth factor receptors, which was inhibited by the selective epidermal growth factor receptor kinase inhibitor, AG1478. These data indicate that perturbations in cardiac homeostasis, which lead to up-regulation of urotensin II receptors, promote urotensin II-mediated cardiomyocyte hypertrophy via ERK1/2 and p38 signaling pathways in an epidermal growth factor receptor-dependent manner.

• CEACAM2 is a novel platelet immunoreceptor.• CEACAM2 negatively regulates platelet-collagen interactions and thrombus growth and stability in vitro, in vivo and CLEC-2 pathways.Carcinoembryonic antigen-related cell adhesion molecule-2 (CEACAM2) is a cell-surface glycoprotein expressed on blood, epithelial, and vascular cells. CEACAM2 possesses adhesive and signaling properties mediated by immunoreceptor tyrosine-based inhibitory motifs. In this study, we demonstrate that CEACAM2 is expressed on the surface and in intracellular pools of platelets. Functional studies of platelets from Ceacam2) revealed that CEACAM2 serves to negatively regulate collagen glycoprotein VI (platelet) (GPVI)-FcRg-chain and the C-type lectinlike receptor 2 (CLEC-2) signaling. Cc2 2/2 platelets displayed enhanced GPVI and CLEC-2-selective ligands, collagen-related peptide (CRP), collagen, and rhodocytin (Rhod)-mediated platelet aggregation. They also exhibited increased adhesion on type I collagen, and hyperresponsive CRP and CLEC-2-induced a and dense granule release compared with wild-type platelets. Furthermore, using intravital microscopy to ferric chloride (FeCl 3 )-injured mesenteric arterioles and laser-induced injury of cremaster muscle arterioles, we herein show that thrombi formed in Cc2 2/2 mice were larger and more stable than wild-type controls in vivo. Thus, CEACAM2 is a novel platelet immunoreceptor that acts as a negative regulator of platelet GPVI-collagen interactions and of ITAM receptor CLEC-2 pathways. (Blood. 2014;124(15):2431-2441

H ypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, affecting up to one in 500 people (1). HCM is diagnosed by using conventional echocardiographic or cardiac MRI by a maximal left ventricular (LV) wall thickness greater than 15 mm in adults and a z score greater than 2 in children in the absence of other causes for wall thickening (2). Modified criteria are typically used for at-risk relatives (3), and a z score greater than 3 has been suggested for children to better match disease prevalence (4). Sarcomere gene mutations are the most prevalent genetic cause of HCM (5). However, phenotypic expression of overt LV hypertrophy is often delayed until adulthood and penetrance is incomplete. Sarcomere mutation carriers without LV hypertrophy are termed preclinical HCM and are at risk for developing overt

Patient characteristics reflected in CHA2DS2VASc scoring and early institutional experience predict increased complication rates following AF ablation. Despite more patients with higher CHA2DS2VASc scores undergoing AF ablation, complication rates fell over time as institutional experience increased.

BackgroundImpaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH).MethodSeventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15).ResultsLA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both).ConclusionLA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis.Electronic supplementary materialThe online version of this article (10.1186/s12968-017-0420-0) contains supplementary material, which is available to authorized users.

Doxorubicin (DOX) selection of CCRF-CEM leukaemia cell line resulted in multidrug resistance (MDR) CEM/A7R cell line, which overexpresses MDR, 1 coded P-glycoprotein (Pgp). Here, we report for the first time that oncoprotein Cripto, a founding member of epidermal growth factor-Cripto-FRL, 1-Criptic family is overexpressed in the CEM/A7R cells, and anti-Cripto monoclonal antibodies (Mab) inhibited CEM/A7R cell growth both in vitro and in an established xenograft tumour in severe combined immunodeficiency mice. Cripto Mab synergistically enhanced sensitivity of the MDR cells to Pgp substrates epirubicin (EPI), daunorubicin (DAU) and non-Pgp substrates nucleoside analogue cytosine arabinoside (AraC). In particular, the combination of anti-Cripto Mab at less than 50% of inhibition concentrations with noncytotoxic concentrations of EPI or DAU inhibited more than 90% of CEM/A7R cell growth. Cripto Mab slightly inhibited Pgp expression, and had little effect on Pgp function, indicating that a mechanism independent of Pgp was involved in overcoming MDR. We demonstrated that anti-Cripto Mab-induced CEM/A7R cell apoptosis, which was associated with an enhanced activity of the c-Jun N-terminal kinase/stress-activated protein kinase and inhibition of Akt phosphorylation, resulting in an activation of mitochondrial apoptosis pathway as evidenced by dephosphorylation of Bad at Ser136, Bcl-2 at Ser70 and a cleaved caspase-9.