Sitagliptin on carotid intima-media thickness in type 2 diabetes patients receiving primary or secondary prevention of cardiovascular disease: A subgroup analysis of the PROLOGUE study.

BACKGROUND: Whether a dipeptidyl peptidase-4 (DPP-4) inhibitor can attenuate atherosclerosis is still controversial. Some clinical trials reported that DPP-4 inhibitors in diabetes patients without a previous history of cardiovascular (CV) events could reduce carotid intima-media thickness (IMT). However, in the PROLOGUE study, which enrolled diabetes patients both with and without previous CV events, sitagliptin failed to slow the progression of carotid IMT relative to conventional therapy. AIM AND METHODS: We hypothesized that the effect of DPP-4 inhibitors on carotid atherosclerosis might be different between the primary and secondary prevention groups. We performed a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in carotid IMT in subgroups with or without previous CV events. RESULTS: No significant difference in the IMT changes between the treatment groups was found in the secondary prevention subgroup (sitagliptin, N = 102; conventional, 111). However, in the primary prevention subgroup (sitagliptin, 120; conventional, 109), we found significant inhibitory effects of sitagliptin on mean and max internal carotid artery IMT [estimated group difference: -0.096 mm (95% CI -0.175 to -0.018, p = 0.017) and -0.162 mm (95% CI -0.272 to -0.052, p = 0.004), respectively], although there was no significant difference in the common carotid artery IMT. CONCLUSIONS: Our data suggest that there is a favorable effect of DPP-4 inhibitor treatment on carotid atherosclerosis in diabetes patients without previous CV events.

[Coronary Artery Bypass Grafting for In-stent Restenosis Probably Caused by Allergic Response;Report of a Case].

A 58-year-old female presented to our hospital with recurrence of chest pain. She had undergone coronary intervention using biolimus-eluting-stent for total occlusion of the left anterior descending artery(LAD) 3 years before. Since then in-stent restenosis had repeated 4 times in 3 years. In the interim, another everolimus-eluting-stent had been placed on the same lesion. The contact metal allergic patch test revealed the existence of allergic response to nickel and cobalt which were the structural components of these stents. She underwent off-pump coronary artery bypass grafting, and these stents were removed. The invasions of macrophages and eosinophils around the stent-s were pathologically proven. One year after surgery she is doing well without angina or allergic symptom. These observations suggested the allergic reaction of the coronary artery against the stents.

High HDL cholesterol level after treatment with pitavastatin is an important factor for regression in carotid intima-media thickness.

This study is a prospective multicenter study designed to investigate the effects of lipid-lowering therapy with pitavastatin on atherosclerotic plaque in patients with coronary heart disease, and to determine which factor is more closely associated with plaque regression. Participants (n = 63) were treated with pitavastatin for 12 months, and the carotid intima-media thickness (IMT) was measured by ultrasound before and after treatment. Mean IMT slightly but significantly decreased (from 0.99 ± 0.33 to 0.94 ± 0.28 mm for overall, P = 0.01) regardless of the presence of pretreatment with other statins. There were no significant relations with hs-CRP, malondialdehyde-LDL, LDL cholesterol, and smaller LDL cholesterol levels despite their decrease by pitavastatin. Decreases in mean IMT were observed significantly more frequently in subjects with high on-treatment HDL cholesterol levels than with low HDL cholesterol levels (P = 0.017). The change in mean IMT tended to be inversely correlated with increments in HDL cholesterol and apolipoprotein A-I. The IMT regression was more often observed in the absence of diabetes and metabolic syndrome. In conclusion, we demonstrated that treatment with pitavastatin attenuated atherosclerotic plaque. This effect was associated with the level of HDL cholesterol, and was stronger in the absence of diabetes and metabolic syndrome in our ischemic heart disease patients.

Impact of sirolimus-eluting stent fracture on 4-year clinical outcomes.

BACKGROUND: Although stent fracture (SF) after sirolimus-eluting stent (SES) implantation has been recognized as one of the predisposing factors of in-stent restenosis, it remains uncertain whether SF can increase the risk of major adverse cardiac events (MACE), especially beyond 1 year after SES implantation. The aim of this study was to assess the impact of SF relative to non-SF on 4-year clinical outcomes after treatment with SES of comparable unselected lesions. METHODS AND RESULTS: A total of 874 lesions in 793 patients undergoing SES implantation and subsequent angiography 6 to 9 months after index procedure were analyzed. At 6- to 9-month angiographic follow-up, SF was identified in 70 of 874 lesions (8.0%). In-stent late loss was significantly higher in SF lesions versus non-SF lesions (0.42±0.59 mm versus 0.13±0.49 mm, P<0.001), resulting in a significantly higher in-stent restenosis rate (21.4% versus 4.1%, P<0.001). At 4 years, SF versus non-SF was associated with a significantly higher MACE rate (23.2% versus 12.6%, P=0.014), mainly driven by significantly higher target-lesion revascularization (18.8% versus 10.2%, P=0.029) rate. Adverse effects of SF on clinical outcomes occurred mostly within the first year (17.4% versus 6.6%, P=0.001), with similar MACE rate between 1 and 4 years (5.8% versus 5.9%, P=0.611). No significant differences between SF versus non-SF patients were observed in the cumulative frequency of very late stent thrombosis (2.9% versus 1.4%, P=0.281), death (0% versus 2.1%, P=0.252), or myocardial infarction (5.8% versus 2.9%, P=0.165). CONCLUSIONS: SF of SES was associated with higher MACE rate up to 1 year, mainly driven by higher target-lesion revascularization, whereas no significant association was evident between years 1 and 4.

Subtle myocardial damage associated with diagnostic coronary angiography alone.

AIMS: To evaluate the frequency, predictors and prognostic significance of elevation in cardiac troponin I (cTnI) after coronary angiography (CAG). METHODS AND RESULTS: A series of 296 consecutive patients with normal pre-procedural cTnI levels and undergoing elective CAG at our centre were prospectively analysed. Positive cTnI elevation was defined as >0.06 ng/ml. Positive cTnI elevation was observed in 44 patients (14.8%), but CK-MB was elevated in only four patients (1.3%) after the procedure. The risk of cTnI elevation was independently associated with left ventricular hypertrophy (odds ratio [OR] 5.52; 95% confidence interval [CI], 2.54 to 12.02; P<0.001), inexperienced operator (OR 10.83; 95% CI, 2.47 to 47.43; P=0.002) and the amount of contrast agent (OR 1.12; 95% CI, 1.03 to 1.23; P=0.009 for each 10 ml increase), whereas it was not associated with the severity of coronary artery disease. At one year, however, postprocedural elevation of cTnI was not associated with an increased risk of death (2.3% vs. 0.8%, P=0.384) or myocardial infarction (2.3% vs. 2.0%, P=0.623). CONCLUSIONS: A minor elevation of cTnI is observed commonly after CAG, which might be associated with left ventricular hypertrophy, operator's experience and the amount of contrast used; however, it does not influence 1-year events rates.

Relationship between severity of renal impairment and 2-year outcomes after sirolimus-eluting stent implantation.

BACKGROUND: The presence of chronic kidney disease (CKD) is associated with an increased risk of restenosis and major adverse cardiac events (MACEs) after coronary interventions, especially in patients on hemodialysis (HD). The aim of this study was to assess the impact of varying degrees of renal impairment on angiographic and 2-year clinical outcomes after treatment with sirolimus-eluting stents (SESs). METHODS: A total of 675 lesions of 593 patients treated with SES were analyzed. Patients were classified into 3 groups: 34 patients on HD; 337 patients with estimated glomerular filtration rate > or =60 mL min(-1) 1.73 m(-2) (non-CKD group); and 222 patients who had lower estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2) without HD dependency (CKD group). RESULTS: At angiographic follow-up (201 +/- 73 days), in-segment late loss was markedly higher in the HD group versus the non-CKD and CKD groups (0.68 +/- 1.06 vs 0.11 +/- 0.45 and 0.15 +/- 0.50 mm, respectively, P < .001), resulting in a significantly higher in-segment restenosis rate (40.0% vs 10.4% and 11.5%, respectively, P < .001). At 2 years, HD vs non-CKD and CKD was associated with a significantly higher MACE rate (35.3% vs 10.4% and 12.6%, respectively, P < .001), mainly driven by significantly higher mortality (11.8% vs 0.6% and 2.3%, respectively, P < .001) and target-lesion revascularization (23.5% vs 9.2% and 8.1%, respectively, P = .016) rates. Multivariable analysis revealed that HD was the independent predictor of 2-year MACE (hazard ratio 4.70, 95% CI 2.40-9.20, P < .001). CONCLUSIONS: Although angiographic and clinical outcomes after SES implantation were similarly favorable in non-HD-dependent CKD patients, regardless of renal function, in patients with end-stage CKD requiring HD, frequencies of restenosis and 2-year MACE were markedly higher than in non-HD-dependent patients.

Safety and efficacy of 2.5-mm sirolimus-eluting stent implantation at lower deployment pressures in very small vessels (<2.5 mm).

OBJECTIVES: Percutaneous coronary interventions for very small vessels are common in clinical practice despite an unavailability of the 2.25-mm sirolimus-eluting stent (SES) in some countries. We sought to evaluate the clinical and angiographic outcomes of 2.5-mm SES implantation at lower deployment pressures in very small coronary arteries. METHODS: Between June 2004 and March 2007, a total of 244 patients underwent percutaneous coronary interventions in vessels with reference diameters less than 2.5 mm at our centers: outcomes in 126 consecutive patients undergoing 2.5-mm SES implantation at lower deployment pressures (< or =10 atmospheres) with predilatation and postdilatation were compared with those in 118 patients who received bare-metal stents (BMS). RESULTS: In the SES group, rates of predilatation and postdilatation were 73.8 and 81% respectively, and mean deployment pressure was 8.3+/-1.2 atmospheres. At follow-up, in-segment late loss was markedly lower in SES versus BMS (0.21+/-0.41 vs. 0.48+/-0.63 mm, P=0.001), resulting in significantly lower rates of restenosis (14.7 vs. 37.5%, P<0.001). At 1 year, SES versus BMS use was associated with similar rates of stent thrombosis (0.8 vs. 0.8%, P>0.999), but significantly lower rates of major adverse cardiac events (MACE) (11.9 vs. 27.1%, P=0.003), mainly driven by a significantly lower need for target-lesion revascularization (9.5 vs. 26.3%, P=0.001). Multivariable analysis identified the SES use as independently associated with a reduced 1-year MACE risk (hazard ratio: 0.32; 95% confidence interval: 0.15-0.66; P=0.002). CONCLUSION: Implantation of 2.5-mm SES in vessels with reference diameters less than 2.5 mm using lower deployment pressures and predilatation and postdilatation may lead to reduced risks of restenosis and MACE without an increased risk of stent thrombosis up to 1 year.

Frequency, predictors and outcome of stent fracture after sirolimus-eluting stent implantation.

BACKGROUND: Recently, stent fracture (SF) of sirolimus-eluting stents (SES) has been shown to be associated with an increased risk of in-stent restenosis. We sought to evaluate the incidence, predictors and clinical outcome of SF after SES implantation in comparable unselected lesions. METHODS: A total of 430 lesions of 382 patients treated with SES were analyzed. SF was defined as single or multiple stent strut fracture as well as complete separation of stent segments. RESULTS: At follow-up, SF was identified in 33 of 430 lesions (7.7%). In lesions with SF, the in-stent restenosis was observed more frequently than non-SF lesions (15.2% vs. 4.0%, P=0.004). At 450 days, however, the cumulative rate of major cardiac events was not significantly different between lesions with and without SF (9.1% vs. 7.1%, P=0.722). The risk of SF was independently associated with total stent length (OR 2.22; 95% CI, 1.25 to 3.95; P=0.007), the change in the angulation of the lesion after stenting (OR 1.55; 95% CI, 1.07 to 2.25; P=0.020), and the right coronary artery lesions (OR 3.26; 95% CI, 1.18 to 8.96; P=0.022). CONCLUSIONS: The occurrence of SF after SES implantation, was found to be relatively common in the particular population, however, did not lead to an increased risk of adverse cardiac events at 450 days, despite a higher incidence of in-stent restenosis.

Is it possible to predict which patients need distal protection during primary angioplasty?

BACKGROUND: Although the benefit of distal protection (DP) during primary percutaneous coronary intervention (PCI) remains questionable, there appears to be efficacy in some clinical situations. We sought to identify in patients with ST-segment elevation acute myocardial infarction (STEMI) which clinical and angiographic characteristics might indicate the patient who will benefit from the use of a DP device. METHODS: A series of 103 consecutive patients with STEMI undergoing primary PCI using DP were compared with 98 consecutive patients treated by primary PCI alone. RESULTS: The overall rates of thromboembolic complications and achievement of optimal reperfusion (myocardial blush grade >/=2 and ST-segment resolution >/=70%), and infarct size, were similar between the 2 groups. However, DP use was associated with higher rates of optimal reperfusion in patients with right coronary artery (RCA) lesions (OR 2.45; 95% CI, 1.07 to 5.59; P=0.034), thrombus score >/=4 (OR 2.64; 95% CI, 1.07 to 6.50; P=0.034) or infarct-related artery (IRA) of >/=3.5 mm in diameter (OR 4.09; 95% CI, 1.02 to 16.40; P=0.047). In this population (RCA location, thrombus score >/=4, or IRA >/=3.5 mm), DP use reduced the risk of thromboembolic complications (64%, P=0.012, 45%, P=0.035 and 54%, P=0.050, respectively), resulting in a smaller infarct size (8.0+/-5.1 vs. 11.7+/-7.5, P=0.028, 13.1+/-8.8 vs. 17.4+/-10.0, P=0.026 and 15.5+/-10.8 vs. 22.1+/-10.1, P=0.042, respectively). CONCLUSIONS: The use of a DP during primary PCI may lead to a reduction of thromboembolic complications, subsequent higher rates of optimal reperfusion and reduced infarct size in patients with RCA culprit lesions, a large thrombus, or large IRA.

Growth hormone-releasing peptide can improve left ventricular dysfunction and attenuate dilation in dilated cardiomyopathic hamsters.

OBJECTIVE: The mammalian heart contains specific growth hormone-releasing peptide (GHRP) binding sites whose physiological significance is unknown. We sought to compare the effects of GHRP and GH on progressive left ventricular (LV) dysfunction in the TO-2 hamster model of dilated cardiomyopathy. METHODS: TO-2 hamsters (8 weeks old) were injected with GHRP-6 (100 microg/kg day), GH (2 mg/kg day), or saline for 4 weeks; F1B hamsters served as controls. LV functional and structural changes were evaluated by echocardiography and pathology. RESULTS: The increase in body weight of GH-treated TO-2 hamsters was greater than that of animals in the other two groups. Plasma GH and insulin-like growth factor-1 (IGF-1) concentrations were not increased by GHRP-6. LV fractional shortening (LVFS) decreased from 42.0+/-2.6% to 25.4+/-1.8% and the LV end-diastolic dimension (LVDd) increased from 4.0+/-0.1 to 5.0+/-0.1 mm in untreated TO-2 hamsters between 8 and 12 weeks. LVFS was substantially improved by treatment with GHRP-6 (33.4+/-2.0%) or GH (32.0+/-2.1%). The LVDd was significantly smaller in animals treated with GHRP-6 than in those treated with GH. The cross-sectional LV myocyte area and the amount of atrial natriuretic peptide mRNA in the LV were increased by GH but not by GHRP-6. Treatment woth GH at a lower dose (0.2 mg/(kg day)) exerted minimal cardiac and systematic growth effects without improving LV function. CONCLUSION: GHRP can ameliorate the development of progressive LV dysfunction independently of the GH-IGF-1 axis, suggesting a potential new approach to the heart failure.

Promising efficacy of primary gradual and prolonged balloon angioplasty in small coronary arteries: a randomized comparison with cutting balloon angioplasty and conventional balloon angioplasty.

BACKGROUND: Small vessel size represents a critical risk factor for an adverse outcome after both conventional balloon angioplasty (POBA) and stenting. Gradual and prolonged balloon angioplasty (GPBA) has been shown to cause less arterial trauma, which results in higher procedural success rates and fewer in-hospital complications than POBA. The aim of this study was to assess the clinical and angiographic benefits of primary GPBA with a perfusion balloon in small coronary arteries, as compared with cutting balloon angioplasty (CBA) and POBA. METHODS: A total of 263 patients with symptoms and reference diameters <3.0 mm were randomly assigned to undergo GPBA (n = 85), CBA (n = 88), or POBA (n = 90). The cumulative inflation time must be >10 minutes in GPBA. Crossover to stent was allowed for inadequate results. Follow-up angiography was performed after 6 months. The primary end point was angiographic restenosis at follow-up. RESULTS: Compared with POBA, GPBA resulted in a lower final residual diameter stenosis (27.3% vs 34.2%, P =.01) and decreased the need for stent placement (8.0% vs 22.2%, P =.031). At follow-up, the restenosis rates were lower with GPBA (31.3%, P =.034) and CBA (32.9%, P =.059) than POBA (50.6%). Target lesion revascularization was less frequently needed with GPBA (20.5%, P =.043) and CBA (20.0%, P =.033) than POBA (37.6%). Additionally, the event-free survival rate was higher with GPBA (77.1%, P =.033) and CBA (76.4%, P =.047) than POBA (58.8%). CONCLUSIONS: In small coronary arteries, both GPBA and CBA resulted in favorable angiographic and clinical outcomes. With a lower restenosis rate and target lesion revascularization rate, GPBA may be a superior strategy for small vessels compared with POBA.

Developmental changes of Ca(2+) handling in mouse ventricular cells from early embryo to adulthood.

Transplant of immature cardiomyocytes is recently attracting a great deal of interest as a new experimental strategy for the treatment of failing hearts. Full understanding of normal cardiomyogenesis is essential to make this regenerative therapy feasible. We analyzed the molecular and functional changes of Ca(2+) handling proteins during development of the mouse heart from early embryo at 9.5 days postcoitum (dpc) through adulthood. From the early to the late (18 dpc) embryonic stage, mRNAs estimated by the real time PCR for ryanodine receptor (type 2, RyR2), sarcoplasmic reticulum (SR) Ca(2+) pump (type 2, SERCA2) and phospholamban (PLB) increased by 3-15 fold in the values normalized to GAPDH mRNA, although Na(+)/Ca(2+) exchanger (type 1, NCX1) mRNA was unchanged. After birth, there was a further increase in the mRNAs for RyR2, SERCA2 and PLB by 18-33 fold, but a 50% decrease in NCX1 mRNA. The protein levels of RyR2, SERCA2, PLB and NCX1, which were normalized to total protein, showed qualitatively parallel developmental changes. L-type Ca(2+) channel currents (I(Ca-L)) were increased during the development (1.3-fold at 18 dpc, 2.2-fold at adult stage, vs. 9.5 dpc). At 9.5 dpc, the Ca(2+) transient was, unlike adulthood, unaffected by the SR blockers, ryanodine (5 microM) and thapsigargin (2 microM), and also by a blocker of the Ca(2+) entry via Na(+)/Ca(2+) exchanger, KB-R 7943 (1 microM). The Ca(2+) transient was abolished after application of nisoldipine (5 microM). These results indicate that activator Ca(2+) for contraction in the early embryonic stage depends almost entirely on I(Ca-L).