The gut hormone glucose-dependent insulinotropic polypeptide is downregulated in response to myocardial injury.

BACKGROUND: The gut incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following food intake leading to insulin secretion and glucose lowering. Beyond its metabolic function GIP has been found to exhibit direct cardio- and atheroprotective effects in mice and to be associated with cardiovascular prognosis in patients with myocardial infarction. The aim of this study was to characterize endogenous GIP levels in patients with acute myocardial infarction. METHODS AND RESULTS: Serum concentrations of GIP were assessed in 731 patients who presented with clinical indication of coronary angiography. Circulating GIP levels were significantly lower in patients with STEMI (ST-elevation myocardial infarction; n=100) compared to clinically stable patients without myocardial infarction (n=631) (216.82 pg/mL [Q1-Q3: 52.37-443.07] vs. 271.54 pg/mL [Q1-Q3: 70.12-542.41], p = 0.0266). To characterize endogenous GIP levels in patients with acute myocardial injury we enrolled 18 patients scheduled for cardiac surgery with cardiopulmonary bypass and requirement of extracorporeal circulation as a reproducible condition of myocardial injury. Blood samples were drawn directly before surgery (baseline), upon arrival at the intensive care unit (ICU), 6 h post arrival to the ICU and at the morning of the first and second postoperative days. Mean circulating GIP concentrations decreased in response to surgery from 45.3 ± 22.6 pg/mL at baseline to a minimum of 31.9 ± 19.8 pg/mL at the first postoperative day (p = 0.0384) and rose again at the second postoperative day (52.1 ± 28.0 pg/mL). CONCLUSIONS: Circulating GIP levels are downregulated in patients with myocardial infarction and following cardiac surgery. These results might suggest nutrition-independent regulation of GIP secretion following myocardial injury in humans.

Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study.

BACKGROUND: In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. METHODS: In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. RESULTS: Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/e') which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003). CONCLUSIONS: Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu).

Effects of empagliflozin on erythropoiesis in patients with type 2 diabetes: Data from a randomized, placebo-controlled study.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to significantly reduce hospitalization for heart failure (HHF) and cardiovascular (CV) mortality in various CV outcome trials in patients with and without type 2 diabetes mellitus (T2D). SGLT2 inhibition further increased haemoglobin and haematocrit levels by an as yet unknown mechanism, and this increase has been shown to be an independent predictor of the CV benefit of these agents, for example, in the EMPA-REG OUTCOME trial. The present analysis of the EMPA haemodynamic study examined the early and delayed effects of empagliflozin treatment on haemoglobin and haematocrit levels, in addition to measures of erythropoiesis and iron metabolism, to better understand the underlying mechanisms. In this prospective, placebo-controlled, double-blind, randomized, two-arm parallel, interventional and exploratory study, 44 patients with T2D were randomized into two groups and received empagliflozin 10 mg or placebo for a period of 3 months in addition to their concomitant medication. Blood and urine was collected at baseline, on Day 1, on Day 3 and after 3 months of treatment to investigate effects on haematological variables, erythropoietin concentrations and indices of iron stores. Baseline characteristics were comparable in the empagliflozin (n = 20) and placebo (n = 22) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; Day 1: 48.4 ± 34.7 g/24 h; P < 0.001) as well as urinary volume (baseline: 1740 ± 601 mL/24 h; Day 1: 2112 ± 837 mL/24 h; P = 0.011) already after 1 day and throughout the 3-month study period, while haematocrit and haemoglobin were only increased after 3 months of treatment (haematocrit: baseline: 40.6% ± 4.6%; Month 3: 42.2% ± 4.8%, P < 0.001; haemoglobin: baseline: 136 ± 19 g/L; Month 3: 142 ± 25 g/L; P = 0.008). In addition, after 3 months, empagliflozin further increased red blood cell count (P < 0.001) and transferrin concentrations (P = 0.063) and there was a trend toward increased erythropoietin levels (P = 0.117), while ferritin (P = 0.017), total iron (P = 0.053) and transferrin saturation levels (P = 0.030) decreased. Interestingly, the increase in urinary glucose excretion significantly correlated with the induction of erythropoietin in empagliflozin-treated patients at the 3-month timepoint (Spearman rho 0.64; P = 0.008). Empagliflozin increased haemoglobin concentrations and haematocrit with a delayed time kinetic, which was most likely attributable to increased erythropoiesis with augmented iron utilization and not haemoconcentration. This might be attributable to reduced tubular glucose reabsorption in response to SGLT2 inhibition, possibly resulting in diminished cellular stress as a mechanism for increased renal erythropoietin secretion.

Effects of empagliflozin on markers of calcium and phosphate homeostasis in patients with type 2 diabetes - Data from a randomized, placebo-controlled study.

BACKGROUND AND AIM: Sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucose-lowering drugs that increase urinary glucose excretion have been shown to reduce CV events in patients with type 2 diabetes (T2D). Furthermore, several studies have demonstrated that treatment with SGLT2 inhibitors affect calcium and phosphate homeostasis, but the effect of empagliflozin on these biomarkers is hitherto not investigated in detail. Therefore, this analysis of the EMPA hemodynamics study examined effects of empagliflozin on calcium and phosphate homeostasis. METHODS: In this placebo-controlled, randomized, double-blind study patients with T2D were randomized to empagliflozin 10 mg (n = 20) or placebo (n = 22). Biomarkers of calcium and phosphate homeostasis were assessed before, and after 3 days and 3 months of treatment. RESULTS: After 3 days of treatment empagliflozin significantly increased serum levels of phosphate (baseline: 1.10 ± 0.21 mmol/L; day 3: 1.25 ± 0.23 mmol/L; p = 0.036), parathyroid hormone (PTH) (baseline: 57.40 ± 30.49 pg/mL; day 3: 70.23 ± 39.25 pg/mL; p = 0.025), fibroblast growth factor 23 (FGF23) (baseline: 77.92 ± 24.31 pg/mL; day 3: 109.18 ± 58.20 pg/mL; p = 0.001) and decreased 1,25-dihydroxyvitamin D (baseline: 35.01 ± 14.01 ng/L; day 3: 22.09 ± 10.02 mg/L; p < 0.001), while no difference of these parameters was recorded after 3 months of treatment. Empagliflozin had no significant effects on serum calcium and markers of bone resorption (collagen type 1 ß-carboxy-telopeptide = ß-CTX) or formation (osteocalcin) after 3 days and 3 months of treatment. CONCLUSIONS: Empagliflozin treatment of patients with T2D transiently increases serum phosphate, PTH and FGF23, and decreases 1,25-dihydroxyvitamin D. This might reflect a temporal increase of sodium driven phosphate reabsorption in the proximal tubule of the kidney caused by increased sodium availability in response to SGLT2 inhibition.

Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure.

AIMS: In this prospective, placebo-controlled, double-blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF). METHODS AND RESULTS: Patients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP-2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.003]. CONCLUSIONS: In this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.

Effects of empagliflozin on lipoprotein subfractions in patients with type 2 diabetes: data from a randomized, placebo-controlled study.

BACKGROUND AND AIMS: Sodium-glucose cotransporter-2 inhibitors, glucose-lowering drugs that increase urinary glucose excretion, have been shown to reduce CV events in patients with type 2 diabetes (T2D), despite the fact that these agents increase blood levels of the proatherogenic low density lipoprotein cholesterol (LDL-C). It has been hypothesized that hemoconcentration due to osmotic diuresis, effects on calculated LDL particle size, or a modulation of lipoprotein subfractions may play a role in this context but to date the underlying mechanisms remain largely unexplored. Therefore, the present study examined effects of empagliflozin on LDL-C and lipoprotein subfractions including calculated LDL particle size and composition. METHODS: In this placebo-controlled, randomized, double blind study, patients with T2D were randomized to empagliflozin 10 mg (n = 20) or placebo (n = 22). Composition of lipoprotein subfractions was assessed before and after 3 months of treatment. Lipoproteins were separated using a combined ultracentrifugation-precipitation method (ß-quantification). RESULTS: Empagliflozin increased LDL-C after 3 months of treatment (from baseline: 103 ± 36 mg/dL to 112 ± 47 mg/dL; p < 0.001) while no difference was recorded after day 1 or day 3 of treatment. The increase of LDL-C was paralleled by an increase of total cholesterol (baseline: 169 ± 41 mg/dL, 3 months: 185 ± 48 mg/dL; p = 0.001). Analyses of lipoprotein subfractions revealed LDL phospholipids and LDL apolipoprotein B to be increased by empagliflozin after 3 months of treatment while calculated LDL particle size was not affected. In addition empagliflozin increased free fatty acid concentrations. CONCLUSIONS: Empagliflozin treatment of patients with T2D increased LDL-C and LDL apolipoprotein B levels but had no effect on calculated LDL particle size.

Peptide YY (PYY) Is Associated with Cardiovascular Risk in Patients with Acute Myocardial Infarction.

AIMS: Recent studies have found circulating concentrations of the gastrointestinal hormone GLP-1 to be an excellent predictor of cardiovascular risk in patients with myocardial infarction. This illustrates a yet not appreciated crosstalk between the gastrointestinal and cardiovascular systems, which requires further investigation. The gut-derived hormone Peptide YY (PYY) is secreted from the same intestinal L-cells as GLP-1. Relevance of PYY in the context of cardiovascular disease has not been explored. In this study, we aimed to investigate PYY serum concentrations in patients with acute myocardial infarction and to evaluate their association with cardiovascular events. MATERIAL AND METHODS: PYY levels were assessed in 834 patients presenting with acute myocardial infarction (553 Non-ST-Elevation Myocardial Infarction (NSTEMI) and 281 ST-Elevation Myocardial Infarction (STEMI)) at the time of hospital admission. The composite outcomes of first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke (3-P-MACE), and all-cause mortality were assessed with a median follow-up of 338 days. RESULTS: PYY levels were significantly associated with age and cardiovascular risk factors, including hypertension, diabetes, and kidney function in addition to biomarkers of heart failure (NT-pro BNP) and inflammation (hs-CRP). Further, PYY was significantly associated with 3-P-MACE (HR: 1.7; 95% CI: 1-2.97; p = 0.0495) and all-cause mortality (HR: 2.69; 95% CI: 1.61-4.47; p = 0.0001) by univariable Cox regression analyses, which was however lost after adjusting for multiple confounders. CONCLUSIONS: PYY levels are associated with parameters of cardiovascular risk as well as cardiovascular events and mortality in patients presenting with acute myocardial infarction. However, this significant association is lost after adjustment for further confounders.

The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE-/- mice by blocking monocyte/macrophage activation.

OBJECTIVE: The incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by the gut after food intake leading to pancreatic insulin secretion and glucose lowering. Beyond its role in glucose control, GLP-1 was found in mice and men to beneficially modulate the process of atherosclerosis, which has been linked to improved cardiovascular outcome of patients with diabetes at high cardiovascular risk treated with GLP-1 receptor agonists. However, little is known on the role of the other main incretin in the cardiovascular system. The aim of this study was to characterize GIP in atherosclerotic cardiovascular disease. METHODS AND RESULTS: Serum concentrations of GIP were assessed in 731 patients who presented for elective coronary angiography at the University Hospital Aachen. While GIP concentrations were not associated with coronary artery disease (CAD), we found 97 patients with PAD (peripheral artery disease) vs. 634 without PAD to have higher circulating GIP levels (413.0 ± 315.3 vs. 332.7 ± 292.5 pg/mL, p = 0.0165). GIP levels were independently related to PAD after multivariable adjustment for CAD, age, sex, BMI, hypertension, diabetes, CRP, WBC, and smoking. To investigate the functional relevance of elevated GIP levels in human atherosclerotic disease, we overexpressed GIP (1-42) in ApoE-/- mice fed a Western diet for 12 weeks using an adeno-associated viral vector system. GIP overexpression led to reduced atherosclerotic plaque macrophage infiltration and increased collagen content compared to control (LacZ) with no change in overall lesion size, suggesting improved plaque stability. Mechanistically, we found GIP treatment to reduce MCP-1-induced monocyte migration under In vitro conditions. Additionally, GIP prevented proinflammatory macrophage activation leading to reduced LPS-induced IL-6 secretion and inhibition of MMP-9 activity, which was attributable to GIP dependent inhibition of NfκB, JNK-, ERK, and p38 in endotoxin activated macrophages. CONCLUSION: Elevated concentrations of the incretin hormone GIP are found in patients with atherosclerotic cardiovascular disease, while GIP treatment attenuates atherosclerotic plaque inflammation in mice and abrogates inflammatory macrophage activation in vitro. These observations identified GIP as a counterregulatory vasoprotective peptide, which might open new therapeutic avenues for the treatment of patients with high cardiovascular risk.

Acute and long-term results of bifurcation stenting (from the Coroflex Registry).

Angioplasty of bifurcation lesions represents a continuing challenge. A total of 421 consecutive patients were prospectively followed in a registry on bifurcation stenting with a high-end bare metal stent (Coroflex, BBraun, Berlin, Germany), allowing side branch percutaneous transluminal coronary angioplasty through the stent struts without distraction of the main vessel stent from the vessel wall or other distortions. This approach obviated the 2-wire technique and kissing balloons. Detailed data, including lesion location, stenosis morphology, procedural success, and hospital and follow-up major adverse cardiac events (MACEs; acute myocardial infarction, death, revascularization, hospitalization due to angina), were collected from 6 European centers. Of the patients, 60% had stable angina, 23% had unstable angina pectoris/non-ST-elevation myocardial infarction, and 17% had ST-elevation myocardial infarction. In 17% of patients, the main vessel alone was stented; in 71%, stenting of the main vessel was complemented by side branch percutaneous transluminal coronary angioplasty. Technical success (residual stenosis <50%) in the 2 branches was achieved in 90% (main vessel in 99%). The rate of MACEs at discharge was 2%. After 6 months, 17% of patients had undergone target lesion revascularization or coronary artery bypass grafting. The total 6-month MACE rate was 22%. In conclusion, successful bifurcation stenting with a low MACE rate is possible in most patients using a simplified approach with a dedicated high-end bare metal stent.

Magnetic resonance to assess the aortic valve area in aortic stenosis: how does it compare to current diagnostic standards?

OBJECTIVES: The purpose of the present study was to evaluate whether magnetic resonance (MR) planimetry of the aortic valve area (AVA) may prove to be a reliable, non-invasive diagnostic tool in the assessment of aortic valve stenosis, and how the results compare with current diagnostic standards. BACKGROUND: Current standard techniques for assessing the severity of aortic stenosis include transthoracic and transesophageal echocardiography (TEE) as well as transvalvular pressure measurements during cardiac catheterization. METHODS: Forty consecutive patients underwent cardiac catheterization, TEE, and MR. The AVA was estimated by direct planimetry (MR, TEE) or calculated indirectly via the peak systolic transvalvular gradient (catheter). Pressure gradients from cardiac catheterization and Doppler echocardiography were also compared. RESULTS: By MR, the mean AVA(max) was 0.91 +/- 0.25 cm(2); by TEE, AVA(max) was 0.89 +/- 0.28 cm(2); and by catheter, the AVA was calculated as 0.64 +/- 0.26 cm(2). Mean absolute differences in AVA were 0.02 cm(2) for MR versus TEE, 0.27 cm(2) for MR versus catheter, and 0.25 cm(2) for TEE versus catheter. Correlations for AVA(max) were r = 0.96 between MR and TEE, r = 0.47 between TEE and catheter, and r = 0.44 between MR and catheter. The correlation between Doppler and catheter gradients was r = 0.71. CONCLUSIONS: Magnetic resonance planimetry of the AVA correlates well with TEE and less well with the catheter-derived AVA. Invasive and Doppler pressure correlated less well than those obtained from planimetric techniques. Magnetic resonance planimetry of the AVA may provide an accurate, non-invasive, well-tolerated alternative to invasive techniques and transthoracic echocardiography in the assessment of aortic stenosis.

Diagnostic utility of new immunoassays for the cardiac markers cTnI, myoglobin and CK-MB mass.

OBJECTIVES: We investigated the diagnostic value of a new system, the Innotrac Aio! immunoassays for troponin, myoglobin and CK-MB, in 270 samples from patients with ACS, after bypass surgery (CABG) or with stable heart failure in comparison to the respective Roche assays. RESULTS: The values of the cardiac markers assessed by the respective assays correlated (cTnT/cTnI Rho = 0.94, myoglobin Rho = 0.87, CK-MB Rho = 0.84). If values were dichotomised, we found a high concordance of test positive and negative classified patients by troponins with the respective assays. CONCLUSION: There is strong evidence that the Innotrac Aio! system for cTnI measurement can be used reliably.

N-terminal B-type natriuretic peptide predicts extent of coronary artery disease and ischemia in patients with stable angina pectoris.

BACKGROUND: B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are elevated in patients with acute coronary syndromes and are closely linked to prognosis. Because there is only a small amount of data available concerning NT-proBNP in patients with stable angina pectoris, we aimed to determine whether NT-proBNP is of additional diagnostic value in these patients. METHODS AND RESULTS: Ninety-four patients with stable angina pectoris were prospectively included. All patients underwent exercise testing and coronary angiography, and 91 patients received thallium-201 single-photon emission computed tomography myocardial scintigraphy. NT-proBNP was analyzed at rest and after exercise testing. NT-proBNP was elevated in patients with inducible myocardial ischemia shown by single-photon emission computed tomography (396 +/- 80 pg/mL vs 160 +/- 101 pg/mL; P <.01) closely linked to the extent of coronary artery disease (CAD) (no CAD, 148 +/- 29 pg/mL; 1- or 2-vessel disease, 269 +/- 50 pg/mL; 3-vessel disease 624 +/- 186 pg/mL; P <.01). In a multivariate analysis, NT-proBNP was an independent predictor for CAD. The area under the curve of the receiver operating characteristic curve was 0.72 for NT-proBNP to predict CAD. Using an optimized cut off level of 214 pg/mL, CAD can be predicted with high accuracy. The total test efficiency of exercise testing can be improved from 1.46 to 1.52 when combined with NT-proBNP measurement. CONCLUSION: NT-proBNP is elevated in patients with stable angina pectoris and has a close correlation to disease severity. Combining the measurement of NT-proBNP with exercise testing, the test accuracy for predicting severe CAD can be improved. Our data show an incremental value of NT-proBNP in the diagnostic process of stable angina pectoris.

Relation of N-terminal pro-B-type natriuretic peptide to severity of valvular aortic stenosis.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been shown to be a reliable biochemical marker for left ventricular wall stress and is increased in patients with aortic stenosis (AS). We evaluated the role of NT pro-BNP as a biochemical marker in the diagnosis of AS and whether it contributes to the optimal timing for aortic valve replacement (AVR). Included in this study were 146 patients who had AS, 31 who underwent AVR, and 32 who had "normal valve function" (controls). Increased NT pro-BNP was closely linked to severity of AS (mild AS 612 +/- 151 pg/ml, moderate AS 1,441 +/- 32 pg/ml, severe AS 2,579 +/- 13 pg/ml, AVR 593 +/- 148 pg/ml, controls 140 +/- 27 pg/ml; p <0,01) and to New York Heart Association functional class (class I 601 +/- 116 pg/ml, class II 1,119 +/- 216 pg/ml, class III 1,998 +/- 459 pg/ml, class IV 5,107 +/- 1,512 pg/ml; p <0.01). Area under the receiver-operating characteristic curve for NT pro-BNP as a predictor for AVR was 0.73. Using an optimized cutoff of 550 pg/ml for NT-proBNP, the positive predictive value was 85%. Thus, NT pro-BNP is linked to severity of AS and New York Heart Association class and is an indication for AVR. Therefore, it is a useful biochemical marker to evaluate severity of AS, monitor disease progression at an early stage, and decide on the optimal time for AVR.

Transcatheter closure of atrial septal defect and patent foramen ovale in adult patients using the Amplatzer occlusion device: no evidence for thrombus deposition with antiplatelet agents.

Transcatheter closure of atrial septal defect (ASD) and patent foramen ovale (PFO) using the Amplatzer septal occluder (AGA Medical, Minneapolis, Minn) is an alternative to surgical closure. There are only limited data on the thrombogenic potential of the device. Thirty-seven patients (14 men, 23 women) underwent device closure of their ASD (n = 21) or PFO (n = 16) at a mean age of 47 +/- 14 years (range, 18-72). The device was successfully deployed in all patients. Thirty-three of 37 patients received antiplatelet therapy with clopidogrel bisulfate and aspirin for a total of 6 months. Four patients in atrial fibrillation were also anticoagulated (international normalized ratio 2.0 to 3.0). No thrombus was detected in any patient on either side of the device by transthoracic and transesophageal echocardiography and there were no cases of symptomatic thromboembolism. Right-to-left interatrial shunting was diagnosed by contrast transesophageal echocardiography with the Valsalva's maneuver. At 1-month follow-up, minimal right-to-left shunting was detected in 6 patients (2 PFO, 4 ASD). Two patients (PFO) had minimal shunting at 1 month but not at 6 months. In 3 patients (ASD), inducible right-to-left shunting persisted at 6 months. In conclusion, our results obtained from a modest number of patients indicate that antiplatelet therapy is safe and effective in preventing thrombus formation on the septal occluder surface.

Peptide-treated stent graft for the treatment of saphenous vein graft lesions: first clinical results.

UNLABELLED: Percutaneous interventions of degenerated saphenous vein grafts (SVG) are associated with high rates of distal embolic events and in-stent restenosis. A novel ePTFE-covered stent graft has been developed to improve outcomes for these difficult lesions. The stent graft has been treated with a 15-amino acid, cell adhesion peptide (P-15) to promote endothelialization on the inner surface post-implantation. Patients with de novo lesions in SVGs were treated with a peptide-coated ePTFE stent graft. Follow-up data was collected at 30 days, 3 and 6 months. An angiographic core lab analyzed an angiographic follow-up at 6 months. RESULTS: Procedural success was achieved in all cases. No device-related major adverse cardiac events occurred in-hospital, at 30 days, or at 3 months, despite the lack of distal protection. Six-month restenosis rates were 21%, and were comparable to similar devices. CONCLUSIONS: The peptide-treated stent graft appears to be a safe and effective treatment for SVG lesions, and has the potential to reduce complications without the use of adjunct distal protection in this patient population.

Rapid effect of single-dose rosiglitazone treatment on endothelial function in healthy men with normal glucose tolerance: data from a randomised, placebo-controlled, double-blind study.

Antidiabetic thiazolidinediones (TZDs) improve endothelial function in patients with or without type 2 diabetes. The present randomised, placebo-controlled, double-blind study examined the time course of a single dose of rosiglitazone on flow-mediated endothelium-dependent vasodilation (FMD), metabolic parameters, and its effect on inflammatory markers in non-diabetic men. Forty non-obese, healthy men with normal glucose tolerance were randomised to a single dose of rosiglitazone (8 mg) or placebo, and FMD was assessed at baseline as well as after 6 h and 24 h. Rosiglitazone did not significantly affect blood glucose and insulin levels or lipid parameters after 6 and 24 h compared with placebo. Treatment with rosiglitazone significantly increased FMD after 6 h from 4.3% (3.3; 4.9) to 7.6% (5.6; 9.2) (p<0.0001 vs. baseline) resulting in a highly significant effect compared with placebo (p<0.0001 for difference between groups). After 24 h FMD was still significantly higher in the rosiglitazone group compared with baseline (p=0.001), but the effect was no longer statistically significant versus placebo (p=0.171). Our study shows a very rapid effect of single dose rosiglitazone treatment on endothelial function in non-diabetic healthy men, underscoring the hypothesis that TZDs may exhibit direct effect in the vasculature independent of their metabolic action.

Circulating endothelial progenitor cells predict angiographic and intravascular ultrasound outcome following percutaneous coronary interventions in the HEALING-II trial: evaluation of an endothelial progenitor cell capturing stent.

AIMS: In contrast to the cytostatic and cytotoxic pharmacotherapy of drug eluting stents, approaches to stimulate the arterial healing response by accelerating re-endothelialisation may be an attractive alternative to prevent post-stenting neointimal formation and thrombosis. The study sought to evaluate whether stainless steel stents able to sequester endothelial progenitor cells (EPCs) to the stent surface to promote the endogenous arterial healing, can prevent in-stent restenosis and stent thrombosis. METHODS AND RESULTS: The HEALING-II study was a multicentre, prospective registry study, including 63 patients treated with the implantation of a Genous EPC capture stent. The primary safety endpoint was Major Adverse Cardiac Events (MACE) at 30 days, whereas the primary efficacy endpoint was percent in-stent volume obstruction at 6 months by intravascular ultrasound (IVUS). The 9 month composite MACE rate was 7.9%, whereas 6.3% clinically justified target lesion revascularisations were observed. Although patients received one month of clopidogrel, no angiographic stent thrombosis occurred. In-stent late luminal loss was 0.78+/-0.39 mm and percent in-stent volume obstruction was 22.9+/-13.7% (mean+/-sd). Patients with normal EPC titers at 6 months FU responded favourably to the EPC capturing stent (late luminal loss 0.53+/-0.06) as opposed to patients with low EPC titers (late luminal loss 1.01+/-0.07). These low circulating EPC titers were generally associated with the lack of HMG-Co-A reductase inhibitors ('statins') at the time of stent implantation and diabetes mellitus. CONCLUSIONS: The HEALING-II study suggests that the EPC capture coronary stents are safe and effective for the treatment of de novo coronary artery disease in patients with normal EPC levels.

Accelerated vascular repair following percutaneous coronary intervention by capture of endothelial progenitor cells promotes regression of neointimal growth at long term follow-up: final results of the Healing II trial using an endothelial progenitor cell capturing stent (Genous R stent).

AIMS: The study sought to define the long-term angiographic and clinical outcome of a bio-engineered stent, able to sequester endothelial progenitor cells (EPC) to the stent to promote the post-stenting vascular repair response. METHODS AND RESULTS: The HEALING-II was a multicentre, prospective registry, including 63 patients treated with the implantation of a Genous EPC capture stent. Serial quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) analysis was performed at 6 and 18 month. The 18 month composite MACE rate was 7.9%, whereas 6.3% clinically justified target lesion revascularisations were observed. Although patients received one month of clopidogrel, no (sub)acute or late angiographic stent thrombosis occurred. At 6 month follow-up, in-stent late luminal loss was 0.78+/-0.39 mm and percent in-stent volume obstruction was 22.9+/-13.7% (mean+/-sd). Serial angiographic and IVUS analyses were available in 30 event-free patients at post-procedure, 6 months and 18 months. From 6 months to 18 months follow-up, a significant late regression of neointimal hyperplasia was observed on QCA (late luminal loss 0.59+/-0.31, 24.4% reduction or 16.9% by matched serial analysis) and IVUS (percent in-stent volume obstruction 20.3+/-14.3%, 11.4% reduction or 9.6% by matched serial analysis). The relative increase in circulating EPC titers at long-term follow-up correlated with neointimal compaction in individual patients, suggestive of an EPC-mediated vascular repair response. CONCLUSIONS: The HEALING II study suggests that the EPC capture stent, aimed to stimulate the coronary vascular repair response, significantly promotes late regression of neointimal hyperplasia up to 18 months after stent implantation.