Background-The time course of neointimal formation after stent implantation has not been studied extensively by angioscopy in the drug-eluting stent era. Methods and Results-Serial angioscopic findings at first follow-up (3.6Ϯ1.1 months), second follow-up (10.5Ϯ1.6 months), and third follow-up (21.2Ϯ2.2 months) after stent implantation were compared between sirolimus-eluting stents (SES, nϭ17) and bare-metal stents (BMS, nϭ11). Neointimal coverage, thrombus, and presence of yellow plaques underneath the stents were assessed. Neointimal coverage was graded as follows: grade 0, stent struts were fully visible; grade 1, struts bulged into the lumen, although they were covered; grade 2, struts were embedded by the neointima but were seen translucently; or grade 3, struts were fully embedded and invisible. Neointimal coverage was remarkably different between SES and BMS at each follow-up point. Neointimal coverage grade was 1.1Ϯ0.5 in SES versus 2.9Ϯ0.3 in BMS at the first follow-up (PϽ0.0001), 1.1Ϯ0.5 in SES versus 3.0Ϯ0.0 in BMS (PϽ0.0001) at the second follow-up, and 1.3Ϯ0.5 in SES versus 3.0Ϯ0.0 in BMS at the third follow-up (Pϭ0.0009). No significant serial changes in coverage grade were noted in the BMS group, whereas coverage grade slightly but significantly increased at the third follow-up in the SES group (PϽ0.05). Thrombi were detected in 4 SES: a red thrombus was seen from the first to the third follow-up in 2; another was detected only at the third follow-up; and the fourth was seen at the first follow-up but disappeared at the second follow-up, associated with a new white thrombus despite dual antiplatelet therapy. Yellow plaques had disappeared by the time of the second follow-up in BMS. In contrast, yellow plaques were exposed in 71% of SES at the first follow-up and remained exposed until the third follow-up. Neointimal coverage grades correlated with thrombi (Pϭ0.002) and with yellow plaques (PϽ0.0001). Conclusions-Serial angioscopic findings up to 2 years after SES implantation were markedly different from those after BMS. Neointimal coverage was completed by 3 to 6 months in BMS. In contrast, SES demonstrated the presence of thrombi and yellow plaques even as much as 2 years after implantation. (Circulation. 2007;116:910-916.)

Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-β/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy.

Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is characterized by cardiac conduction abnormalities and left ventricular systolic dysfunction predisposing to heart failure. Previous cardiac transcriptional profiling of LmnaH222P/H222P mouse, a small animal model of LMNA cardiomyopathy, suggested decreased WNT/β-catenin signalling. We confirmed decreased WNT/β-catenin signalling in the hearts of these mice by demonstrating decreased β-catenin and WNT proteins. This was correlated with increased expression of soluble Frizzled-related proteins that modulate the WNT/β-catenin signalling pathway. Hearts of LmnaH222P/H222P mice also demonstrated lowered expression of the gap junction connexin 43. Activation of WNT/β-catenin activity with 6-bromoindirubin-3'-oxime improved cardiac contractility and ameliorated intraventricular conduction defects in LmnaH222P/H222P mice, which was associated with increased expression of myocardial connexin 43. These results indicate that decreased WNT/β-catenin contributes to the pathophysiology of LMNA cardiomyopathy and that drugs activating β-catenin may be beneficial in affected individuals.

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Aims General obesity, measured by the body mass index (BMI), and abdominal adiposity, measured as waist circumference (WC) and waist-to-hip ratio (WHR), are associated with heart failure and cardiovascular events. However, the relationship of general and abdominal obesity with subclinical left ventricular (LV) dysfunction is unknown. We assessed the association of general and abdominal obesity with subclinical LV systolic dysfunction in a population-based elderly cohort. Methods and Results Participants from the Cardiovascular Abnormalities and Brain lesions study underwent measurement of BMI, WC, and WHR. LV systolic function was assessed by two-dimensional echocardiographic LV ejection fraction (LVEF) and speckle-tracking global longitudinal strain (GLS). The study population included 729 participants (mean age 71±9 years, 60% women). In multivariate analysis, higher BMI (but not WC and WHR) was associated with higher LVEF (β=0.11, p=0.003). Higher WC (β=0.08, p=0.038) and higher WHR (β=0.15, p<0.001) were associated with lower GLS, whereas BMI was not (p=0.720). Compared with normal WHR, high WHR was associated with lower GLS in all BMI categories (normal, overweight, and obese), and was associated with subclinical LV dysfunction by GLS both in participants without (adjusted OR=2.0, 95% CI=1.1-3.6, p=0.020) and with general obesity (adjusted OR=5.4, 95% CI=1.1-25.9, p=0.034). WHR was incremental to BMI and risk factors in predicting LV dysfunction. Conclusion Abdominal adiposity was independently associated with subclinical LV systolic dysfunction by GLS in all BMI categories. BMI was not associated with LV dysfunction. Increased abdominal adiposity may be a risk factor for LV dysfunction regardless of the presence of general obesity.