The endothelial isoform of nitric-oxide synthase (eNOS), a key determinant of vascular homeostasis, is a calcium/calmodulindependent phosphoprotein regulated by diverse cell surface receptors. Vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) stimulate eNOS activity through Akt/phosphoinositide 3-kinase and calcium-dependent pathways. AMP-activated protein kinase (AMPK) also activates eNOS in endothelial cells; however, the molecular mechanisms linking agonist-mediated AMPK regulation with eNOS activation remain incompletely understood. We studied the role of AMPK in VEGF-and S1P-mediated eNOS activation and found that both agonists led to a striking increase in AMPK phosphorylation in pathways involving the calcium/calmodulin-dependent protein kinase kinase ␤. Treatment with tyrosine kinase inhibitors or the phosphoinositide 3-kinase inhibitor wortmannin demonstrated differential effects of VEGF versus S1P. Small interfering RNA (siRNA)-mediated knockdown of AMPK␣1 or Akt1 impaired the stimulatory effects of both VEGF and S1P on eNOS activation. AMPK␣1 knockdown impaired agonist-mediated Akt phosphorylation, whereas Akt1 knockdown did not affect AMPK activation, thus suggesting that AMPK lies upstream of Akt in the pathway leading from receptor activation to eNOS stimulation. Importantly, we found that siRNA-mediated knockdown of AMPK␣1 abrogates agonist-mediated activation of the small GTPase Rac1. Conversely, siRNA-mediated knockdown of Rac1 decreased the agonist-mediated phosphorylation of AMPK substrates without affecting that of AMPK, implicating Rac1 as a molecular link between AMPK and Akt in agonist-mediated eNOS activation. Finally, siRNA-mediated knockdown of caveolin-1 significantly enhanced AMPK phosphorylation, suggesting that AMPK is negatively regulated by caveolin-1. Taken together, these results suggest that VEGF and S1P differentially regulate AMPK and establish a central role for an agonist-modulated AMPK 3 Rac1 3 Akt axis in the control of eNOS in endothelial cells.

cGMP is involved in numerous vascular signaling pathways, and abnormalities in these pathways have been implicated in the pathophysiology of hypertension, atherosclerosis, and diabetes (1, 2). In endothelial cells, cGMP is synthesized by two distinct guanylate cyclase (GC) 5 isoforms, the nitric oxide (NO)-activated soluble GC (sGC) and the atrial natriuretic peptide (ANP)-activated particulate GC (GC-A) (2-4). NO, produced by endothelial NO synthase (eNOS), plays a crucial role in a variety of vascular responses such as blood pressure control, platelet aggregation, and vascular smooth muscle cell proliferation (5). Activation of eNOS is strongly influenced by a diverse collection of cell surface receptors, including vascular endothelial growth factor (VEGF) receptor (KDR) and sphingosine 1-phosphate (S1P) receptor S1P 1 (Edg-1) (6, 7). ANP is released primarily by cardiac atria in response to atrial stretch; this peptide binds with high affinity to the membrane receptor guanylate cyclase GC-A located in renal cells and in the vasculature (8, 9). Activated GC-A promotes diuresis and inhibits the renin-angiotensin-aldosterone system, thereby controlling salt and water retention and blood pressure (10). Recent studies have revealed ANP to be an endogenous vasoprotective substance as well as a potent pharmacological agent in the treatment of cardiovascular diseases (10 -12). GC-A is abundantly expressed in the vascular endothelium, and binding of ANP to GC-A significantly increases intracellular cGMP levels (13-15).The principal effectors of cGMP in the cardiovascular system include cGMP-gated monovalent cation channels, phosphodiesterases, and cGMP-dependent protein kinases (PKGs) (16,17). Two mammalian PKG genes have been identified, encoding PKG I and PKG II. PKG I is the prevalent PKG isoform expressed in the cardiovascular system (17) and will be referred to here as PKG. Although the functions of PKG have been probed both with PKG knock-out mice and with analyses of cellular substrates phosphorylated by PKG, much remains to be understood about the molecular and cellular significance of PKG signaling in endothelial homeostasis. PKG knock-out mice display decreased life span, impaired vascular smooth * This work was supported in part by Grants HL46457, HL48743, GM36259 (to T. M.), HL32854, and HL70819 (to D. E. G.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

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Cardiac rehabilitation program (CRP) is a recognized non-pharmacological modality to decrease mortality after acute myocardial infarction (AMI) events. We aimed to evaluate the effect of CRP on the cardiac physiology in patients post myocardial infarction (MI). Online database search of PubMed, MEDLINE, EMBASE, SCOPUS, COCHRANE, and GOOGLE SCHOLAR were performed ( -Mar 2016; key bibliographies were reviewed. Studies comparing post MI patients who were enrolled in a CRP to those who were not, were included. Standardized mean difference (SMD) with the corresponding 95% confidence intervals (CI) by random and fixed effects models of pooled data were calculated. Study quality was assessed using CONSORT criteria. Outcomes of interest measured included resting and maximum heart rate (HR), peak VO 2 , ejection fraction (EF%), wall motion score index (WMSI), left ventricular end diastolic volume (LVEDV) in cardiac rehabilitation patients versus control. Search strategy yielded 147 studies, 23 studies fulfilled the selection criteria, 19 of which were RCTs. These included a total of 1,683 patients; 827 were enrolled in a CRP while 855 did not receive the intervention. Median age was 58 years. There was no significant difference between the two groups in terms of age, comorbidities, severity of CAD, baseline EF or HR. Meta-analysis of data included demonstrated that CRP patients had lower post-intervention resting HR than non-CRP patients (SMD: −0.59; 95% CI: −0.73 to −0.46, fixed effect model P<0.05). EF% was significantly improved after CRP compared to control (SMD: 0.21; 95% CI: 0.02 to 0.40, P=0.03). Peak VO 2 was significantly improved by CRP (SMD: 1.00; 95% CI: 0.56 to 1.45; P<0.0001). LVEDV was significantly less in CRP patients (SMD: −0.31; 95% CI: −0.59 to −0.02, fixed effect model P<0.05). WMSI was significantly less in CRP patients (SMD: −0.41; 95% CI: −0.78 to −0.05, P=0.024). CRP improves cardiac function in post MI patients. This may explain the reported improvement of functionality and mortality among those patients. Further randomized trials may help evaluate the longterm benefits of CRP.

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For patients with atrial fibrillation (AF) and acute coronary syndrome (ACS), it is often challenging to find the optimal balance between the risk for ischemic and hemorrhagic complication when using both antiplatelet therapy and oral anticoagulation (OAC) with vitamin K antagonist (VKA) or direct oral anticoagulants (DOACs). Current guidelines recommended: (I) double therapy with a P2Y12 inhibitor and dose adjusted VKA is reasonable post-stenting; (II) double therapy with clopidogrel and low-dose rivaroxaban (15 mg daily) may be reasonable post-stenting; (III) double therapy with a P2Y12 inhibitor and dabigatran 150 mg twice daily is reasonable post-stenting. In the AUGUSTUS trial, most patients were given clopidogrel as part a DAPT regimen, however prasugrel and ticagrelor use allowed albeit in a small percentage of the trial population, underestimating its effect. Ticagrelor and prasugrel are known to have a stronger antiplatelet effect compared to clopidogrel, however randomized studies have not been adequately powered to date allowing comparisons between ticagrelor, prasugrel and clopidogrel together in the setting of anticoagulation for the treatment of patients with ACS and AF. Careful consideration should be given to this scenario to avoid falling into the concept of sacrificing efficacy for safety.

: Implantable cardioverter-defibrillator (ICD) therapy is indicated for patients at risk for sudden cardiac death due to ventricular tachyarrhythmia. The most commonly used risk stratification algorithms use left ventricular ejection fraction (LVEF) to determine which patients qualify for ICD therapy, even though LVEF is a better marker of total mortality than ventricular tachyarrhythmias mortality. This review evaluates imaging tools and novel biomarkers proposed for better risk stratifying arrhythmic substrate, thereby identifying optimal ICD therapy candidates.