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We thank Drs Bisleri and Hernandez-Vaquero and their colleagues for their interest in our study. 1We agree with Drs Bisleri and Muneretto that our study was not designed to determine the effect of endoscopic vein harvesting (EVH) on vein graft failure (VGF).As with any observational analysis of an assignable intervention, these results should be interpreted with care because of potential residual confounding.We first reported a possible association between EVH and adverse VGF and clinical outcomes in 2009. 2 Since then, other, equally confounded, observational studies have provided conflicting results. 3,4A recent publication from the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) trial suggests that the risk associated with EVH was not explained by the device type. 5We completely agree that understanding the true impact of EVH on graft patency and clinical outcomes will require an adequately sized randomized trial with appropriate outcomes.To this end, we await the results of the ongoing Randomized Endo-Vein Graft Prospective (REGROUP) trial (http://www.clinicaltrials.gov;identifier NCT01850082).With 1150 patients and a primary outcome of death, myocardial infarction, or repeat revascularization, the REGROUP trial should shed some light on the EVH-related safety concerns raised by observational studies.Although our model fit our data well (Hosmer-Lemeshow P value=0.85),we also agree with Dr Hernandez-Vaquero and colleagues in their assessment of the modest discriminatory power of our model.It is likely that VGF has multiple heterogeneous causes.In PREVENT IV, we measured VGF during systematic angiographic follow-up in all patients between 12 and 18 months after coronary artery bypass graft surgery.Most previous studies investigating predictors of VGF have used clinically driven angiographic follow-up. 6It may be that factors associated with clinically driven VGF are different than factors associated with VGF overall.Despite access to detailed clinical and procedural factors in PREVENT IV, as well as systematic angiographic follow-up, the low c statistic of our model highlights the difficulty in predicting VGF with currently available variables and the need for further investigation in this area.
ADP responses underlie therapeutic approaches to many cardiovascular diseases, and ADP receptor antagonists are in widespread clinical use. The role of ADP in platelet biology has been extensively studied, yet ADP signaling pathways in endothelial cells remain incompletely understood. We found that ADP promoted phosphorylation of the endothelial isoform of nitric-oxide synthase (eNOS) at Ser(1179) and Ser(635) and dephosphorylation at Ser(116) in cultured endothelial cells. Although eNOS activity was stimulated by both ADP and ATP, only ADP signaling was significantly inhibited by the P2Y(1) receptor antagonist MRS 2179 or by knockdown of P2Y(1) using small interfering RNA (siRNA). ADP activated the small GTPase Rac1 and promoted endothelial cell migration. siRNA-mediated knockdown of Rac1 blocked ADP-dependent eNOS Ser(1179) and Ser(635) phosphorylation, as well as eNOS activation. We analyzed pathways known to regulate eNOS, including phosphoinositide 3-kinase/Akt, ERK1/2, Src, and calcium/calmodulin-dependent kinase kinase-beta (CaMKKbeta) using the inhibitors wortmannin, PD98059, PP2, and STO-609, respectively. None of these inhibitors altered ADP-modulated eNOS phosphorylation. In contrast, siRNA-mediated knockdown of AMP-activated protein kinase (AMPK) inhibited ADP-dependent eNOS Ser(635) phosphorylation and eNOS activity but did not affect eNOS Ser(1179) phosphorylation. Importantly, the AMPK enzyme inhibitor compound C had no effect on ADP-stimulated eNOS activity, despite completely blocking AMPK activity. CaMKKbeta knockdown suppressed ADP-stimulated eNOS activity, yet inhibition of CaMKKbeta kinase activity using STO-609 failed to affect eNOS activation by ADP. These data suggest that the expression, but not the kinase activity, of AMPK and CaMKKbeta is necessary for ADP signaling to eNOS.
A 69-year-old man underwent coronary angiography 7 years after coronary artery bypass. Saphenous vein graft spasm was observed during contrast injection, resulting in ventricular fibrillation. Angiography 6 years later showed graft patency. Vein graft spasm after coronary artery bypass grafting is rarely described. Further investigation is needed regarding incidence, mechanism, and clinical outcomes. (Level of Difficulty: Beginner.)
Introduction: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction. Migraine headache has been reported to be common among patients with SCAD, but the degree of migraine-related disability has not been quantified. Methods: Clinical data and headache variables were obtained from the baseline assessment of the prospective, multicenter iSCAD Registry. Migraine-related disability was quantified using the self-reported Migraine Disability Assessment (MIDAS). Demographic, clinical, psychosocial, and medical characteristics from data entry forms were compared between patients with and without migraine. Results: Of the 773 patients with available data, 46% reported previous or current migraines. Those with migraines were more likely to be women (96.9% vs 90.3%, p = 0.0003). The presence of underlying carotid fibromuscular dysplasia was associated with migraine (35% vs 27%, p = 0.0175). There was not a significant association with carotid artery dissection and migraine. Current migraine frequency was less than monthly (58%), monthly (24%), weekly (16%), and daily (3%). Triptan use was reported in 32.5% of patients, and 17.5% used daily migraine prophylactic medications. Using the MIDAS to quantify disability related to migraine, 60.2% reported little or no disability, 14.4% mild, 12.7% moderate, and 12.7% severe. The mean MIDAS score was 9.9 (mild to moderate disability). Patients with SCAD had higher rates of depression and anxiety (28.2% vs 17.7% [ p = 0.0004] and 35.3% vs 26.7% [ p = 0.0099], respectively). Conclusions: Migraines are common, frequent, and a source of disability in patients with SCAD. The association between female sex, anxiety, and depression may provide some insight for potential treatment modalities.
