Three-year clinical outcome in all-comers with "silent" diabetes, prediabetes, or normoglycemia, treated with contemporary coronary drug-eluting stents: From the BIO-RESORT Silent Diabetes study.

BACKGROUND: Patients with coronary disease may have unknown diabetes or prediabetes. We evaluated 3-year outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents (DES) in patients with silent diabetes, prediabetes, and normoglycemia. METHODS: All BIO-RESORT trial (NCT01674803) participants without known diabetes, enrolled at our center, were invited for oral glucose tolerance testing (OGTT) and measurements of fasting plasma glucose and glycated hemoglobin (HbA1c). RESULTS: OGTT detected silent diabetes in 68 (6.9%), prediabetes in 132 (13.4%), and normoglycemia in 788 (79.8%) of all 988 study participants. Follow-up was available in 986 (99.8%) patients. The main endpoint target vessel failure (TVF: cardiac death, target vessel-related myocardial infarction [MI], or target vessel revascularization) differed between groups (14.8, 9.9, and 5.6%; p = .002), driven by MI during the first 48 hr and by cardiac death (p < .001; p = .026). Between 48 hr and 3-years, there was no significant between-group difference in TVF, target vessel MI, and target vessel revascularization. Multivariable analysis demonstrated that silent diabetes was independently associated with TVF (adjusted HR: 2.52, 95%-CI: 1.26-5.03). An alternative diagnostic approach-HbA1c and fasting plasma glucose-detected silent diabetes and prediabetes in 33 (3.3%) and 217 (22.0%) patients, and normoglycemia in 738 (74.7%); TVF rates were 12.1, 7.9, and 6.0% (p = .23). CONCLUSION: In patients without known diabetes, abnormal glucose metabolism by OGTT was independently associated with higher 3-year TVF rates after PCI with contemporary DES. This difference was driven by periprocedural MI and cardiac death. After the first 48 hr, the rates of TVF, target vessel MI, and target vessel revascularization were low and did not differ significantly between metabolic groups.

Serial assessment of endothelial function 1, 6, and 12 months after ST-elevation myocardial infarction.

Knowledge about the changes in endothelial function after ST-elevation myocardial infarction (STEMI) is of substantial interest, but serial data are scarce. The aim of the present study was to noninvasively evaluate whether endothelial function, as assessed shortly after primary percutaneous coronary intervention (PPCI) for STEMI, may improve until 12-month follow-up. This prospective observational cohort study was performed in patients in the RESPONSE randomized trial who participated in a substudy and underwent noninvasive assessment of endothelial function at 1 (baseline), 6, and 12-month follow-up after treatment of a STEMI by PPCI. The reactive hyperemia peripheral artery tonometry (RH-PAT) method was used to assess endothelial function (higher RH-PAT index signifies better function). Of the 70 study participants, who were 57.4 ± 9.7 years of age, 55 (78.6%) were male and 9 (13%) had diabetes. The endothelial function deteriorated significantly during follow-up: the RH-PAT index at baseline, 6, and 12-month follow-up was 1.90 ± 0.58, 1.81 ± 0.57, and 1.69 ± 0.49, respectively (p = 0.04). Although patients were carefully treated in outpatient clinics and adequate pharmacological therapy was prescribed, we noted an increase in total cholesterol (p = 0.001), LDL cholesterol (p = 0.002), HbA1C (p = 0.054), and diastolic blood pressure (p = 0.047) However, multivariate analysis revealed that this increase in cardiovascular risk factors could not explain the observed deterioration in endothelial function. In patients with STEMI, we observed a significant deterioration in endothelial function during 12 months after PPCI that could not be explained by changes in the traditional cardiovascular risk profile.

"Silent" Diabetes and Clinical Outcome After Treatment With Contemporary Drug-Eluting Stents: The BIO-RESORT Silent Diabetes Study.

OBJECTIVES: This study sought to assess the prevalence and clinical impact of silent diabetes and pre-diabetes in "nondiabetic" percutaneous coronary intervention (PCI) all-comers. BACKGROUND: Patients with undetected and thus untreated (silent) diabetes may have higher event risks after PCI with contemporary drug-eluting stents (DES). METHODS: The BIO-RESORT Silent Diabetes study, performed at Thoraxcentrum Twente, is a substudy of the randomized multicenter BIO-RESORT (BIOdegradable Polymer and DuRable Polymer Drug-eluting Stents in an All COmeRs PopulaTion) trial (NCT01674803). Patients underwent oral glucose tolerance testing (OGTT), and assessment of glycosylated hemoglobin with fasting plasma glucose. Primary endpoint was a composite of cardiac death, target vessel-related myocardial infarction, or target vessel revascularization at 1 year. RESULTS: Of the 988 participants, OGTT detected silent diabetes in 68 (6.9%), pre-diabetes in 133 (13.3%), and normal glucose metabolism in 788 (79.8%). Patients with silent diabetes had higher primary endpoint rates (13.2% vs. 7.6% vs. 4.8%; p < 0.001; silent diabetes vs. normal: hazard ratio: 4.2; 95% confidence interval: 1.9 to 9.2). Differences were driven by myocardial infarction (p < 0.001) which occurred mostly <48 h. Based on glycosylated hemoglobin and fasting plasma glucose, silent diabetes was found in 33 (3.3%) patients, pre-diabetes in 217 (22.0%) patients, and normal glucose metabolism in 738 (74.7%) patients; primary endpoint rates were similar to OGTT-based analyses (12.1% vs. 5.5% vs. 3.1%; p = 0.01). Multivariate analyses demonstrated that abnormal glucose metabolism by either diagnostic approach, present in 330 (33.4%) patients, independently predicted adverse event risk (hazard ratio: 2.2; 95% confidence interval: 1.2 to 4.2). CONCLUSIONS: Abnormal glucose metabolism was detected in 1 of 3 "nondiabetic" PCI patients and was independently associated with up to 4-fold higher event risks. Future intervention trials should determine whether meaningful benefits accrue from routine glycemia testing in such patients.

Prediabetes and its impact on clinical outcome after coronary intervention in a broad patient population.

AIMS: It is unclear whether detection of prediabetes (pre-DM) by routine assessment of glycated haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) among patients undergoing percutaneous coronary intervention (PCI) with contemporary drug-eluting stents (DES) may help identify subjects with increased event risk. We assessed the relation between glycaemia status and one-year outcome after PCI. METHODS AND RESULTS: Glycaemia status was determined in 2,362 non-diabetic BIO-RESORT participants, treated at all four study sites, to identify pre-DM (HbA1c 42-47 mmol/mol; FPG 6.1-6.9 mmol/L) and unknown diabetes mellitus (DM) (HbA1c ≥48 mmol/mol; FPG ≥7.0 mmol/L). Another 624 patients had medically treated DM. The main composite endpoint consisted of death, myocardial infarction, or revascularisation. Glycaemic state was known in 2,986 participants: 324 (11%) patients had pre-DM, 793 (27%) had DM (known or new), and 1,869 (63%) patients had normoglycaemia. Pre-DM and DM patients differed from normoglycaemic patients in cardiovascular risk factors. The composite endpoint occurred in 11.1% in pre-DM, 10.5% in DM, and 5.7% in normoglycaemia (p<0.001). Pre-DM was associated with a twofold higher event risk compared to normoglycaemia (adj. HR 2.0, 95% CI: 1.4-3.0). CONCLUSIONS: Following PCI with contemporary DES, all-comers with pre-DM had significantly higher event risks than normoglycaemic patients. In non-DM patients requiring PCI, routine assessment of HbA1c and FPG appears to be of value to identify subjects with increased event risk.

Endothelial function after ST-elevation myocardial infarction in patients with high levels of high-sensitivity CRP and Lp-PLA2: A substudy of the RESPONSE randomized trial.

BACKGROUND: The combination of high levels of high-sensitive C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase-A2 (Lp-PLA2) was recently shown to correlate with increased cardiovascular risk. Endothelial dysfunction is also known to be a risk factor for cardiovascular events. AIM: To test among patients with previous ST-elevation myocardial infarction (STEMI) the hypothesis that high levels of both hs-CRP and Lp-PLA2 may be associated with impaired endothelium-dependent vasodilatation. METHODS: In this substudy of the RESPONSE randomized trial, we used reactive hyperemia peripheral artery tonometry (RH-PAT) 4 to 6weeks after STEMI and primary percutaneous coronary intervention (PPCI) to non-invasively assess endothelial function (RH-PAT index <1.67 identified endothelial dysfunction). Reliable measurements of RH-PAT, hs-CRP, and Lp-PLA2 were obtained in 68 patients, who were classified as high-risk if levels of both hs-CRP and Lp-PLA2 were in the upper tertile (≥3.84mg/L and >239µg/L, respectively). RESULTS: Patients were 57.4±9.7years and 53 (77.9%) were men. 11 (16%) patients were classified as high-risk and 57 (84%) as low-to-intermediate-risk. The RH-PAT index was 1.68±0.22 in high-risk and 1.95±0.63 in low-to-intermediate-risk patients (p=0.17). Endothelial dysfunction was present in 8 (72.7%) high-risk and 26 (45.6%) low-to-intermediate-risk patients (p=0.09). Framingham risk score, NT-proBNP and fibrinogen levels were higher in high-risk patients (p≤0.03). CONCLUSION: In this population of patients with recent STEMI and PPCI, we observed between patients with high hs-CRP and Lp-PLA levels and all other patients no more than numerical differences in endothelial function that did not reach a statistical significance. Nevertheless, further research in larger study populations may be warranted.

Disfunción endotelial tras infarto de miocardio con elevación del segmento ST y evolución a largo plazo: un estudio con tonometría arterial periférica e hiperemia reactiva / Endothelial dysfunction after ST-segment elevation myocardial infarction and long-term outcome: a study with reactive hyperemia peripheral artery tonometry

Introducción y objetivos: Escasean datos a largo plazo sobre la relación entre disfunción endotelial tras infarto agudo de miocardio con elevación del segmento ST y futuros eventos clínicos adversos. El objetivo de este estudio es evaluar de manera no invasiva si la disfunción endotelial 4-6 semanas tras una intervención coronaria percutánea primaria por infarto agudo de miocardio con elevación del segmento ST predice la aparición futura de eventos clínicos. Métodos: Este estudio prospectivo de cohortes se llevó a cabo en 70 pacientes del ensayo aleatorizado RESPONSE, a los que se evaluó de manera no invasiva la función endotelial 4–6 semanas después de la intervención coronaria percutánea primaria. Se determinó la función endotelial por el método de tonometría arterial periférica con hiperemia reactiva; la disfunción endotelial se identificó por un índice < 1,67. Resultados: El índice de tonometría arterial periférica con hiperemia reactiva fue en promedio 1,90 ± 0,58. Un total de 35 (50%) pacientes presentaban disfunción endotelial y 35 (50%) tenían función endotelial normal. Las «complicaciones» periintervención (como shock cardiogénico o bloqueo auriculoventricular completo) fueron más frecuentes entre los pacientes con disfunción endotelial que entre quienes no la presentaban (el 25,7 frente al 2,9%; p < 0,01). Durante un seguimiento medio de 4,0 ± 1,7 años, 20 pacientes (28,6%) presentaron eventos adversos cardiovasculares mayores: se produjeron eventos de este tipo en 9 pacientes (25,7%) con disfunción endotelial y 11 (31,5%) con función endotelial normal (p = 0,52). Se observó asociación entre la prevalencia basal de diabetes mellitus y la aparición de eventos adversos cardiovasculares mayores durante el seguimiento (análisis univariable, hazard ratio = 2,8; intervalo de confianza del 95%, 1,0-7,8; p < 0,05) e incluso en los análisis multivariable el riesgo parecía aumentar, aunque sin alcanzar significación estadística (análisis multivariable, hazard ratio = 2,5; intervalo de confianza del 95%, 0,8-7,5). Conclusiones: En esta serie de pacientes que habían sobrevivido a un infarto agudo de miocardio con elevación del segmento ST, la disfunción endotelial evaluada mediante tonometría arterial periférica con hiperemia reactiva 4-6 semanas tras el infarto de miocardio, no predijo los eventos clínicos futuros en una media de seguimiento de 4 años (AU)

Introduction and objectives: Long-term data on the relationship between endothelial dysfunction after ST-segment elevation myocardial infarction and future adverse clinical events are scarce. The aim of this study was to noninvasively assess whether endothelial dysfunction 4 weeks to 6 weeks after primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction predicts future clinical events. Methods: This prospective cohort study was performed in 70 patients of the RESPONSE randomized trial, who underwent noninvasive assessment of endothelial function 4 weeks to 6 weeks after primary percutaneous coronary intervention. Endothelial function was measured by the reactive hyperemia peripheral artery tonometry method; an index < 1.67 identified endothelial dysfunction. Results: The reactive hyperemia peripheral artery tonometry index measured on average 1.90 ± 0.58. A total of 35 (50%) patients had endothelial dysfunction and 35 (50%) patients had normal endothelial function. Periprocedural «complications» (eg, cardiogenic shock, total atrioventricular block) were more common in patients with endothelial dysfunction than in those without (25.7% vs 2.9%; P < .01). During 4.0 ± 1.7 years of follow-up, 20 (28.6%) patients had major adverse cardiovascular events: events occurred in 9 (25.7%) patients with endothelial dysfunction and in 11 (31.5%) patients with normal endothelial function (P = .52). There was an association between the prevalence of diabetes mellitus at baseline and the occurrence of major adverse cardiovascular events during follow-up (univariate analysis: hazard ratio = 2.8; 95% confidence interval, 1.0-7.8; P < .05), and even in multivariate analyses the risk appeared to be increased, although not significantly (multivariate analysis: hazard ratio = 2.5; 95% confidence interval, 0.8-7.5). Conclusions: In this series of patients who survived an ST-segment elevation myocardial infarction, endothelial dysfunction, as assessed by reactive hyperemia peripheral artery tonometry 4 weeks to 6 weeks after myocardial infarction, did not predict future clinical events during a mean follow-up of 4 years (AU)

Endothelial Dysfunction After ST-segment Elevation Myocardial Infarction and Long-term Outcome: A Study With Reactive Hyperemia Peripheral Artery Tonometry.

INTRODUCTION AND OBJECTIVES: Long-term data on the relationship between endothelial dysfunction after ST-segment elevation myocardial infarction and future adverse clinical events are scarce. The aim of this study was to noninvasively assess whether endothelial dysfunction 4 weeks to 6 weeks after primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction predicts future clinical events. METHODS: This prospective cohort study was performed in 70 patients of the RESPONSE randomized trial, who underwent noninvasive assessment of endothelial function 4 weeks to 6 weeks after primary percutaneous coronary intervention. Endothelial function was measured by the reactive hyperemia peripheral artery tonometry method; an index<1.67 identified endothelial dysfunction. RESULTS: The reactive hyperemia peripheral artery tonometry index measured on average 1.90±0.58. A total of 35 (50%) patients had endothelial dysfunction and 35 (50%) patients had normal endothelial function. Periprocedural "complications" (eg, cardiogenic shock, total atrioventricular block) were more common in patients with endothelial dysfunction than in those without (25.7% vs 2.9%; P<.01). During 4.0±1.7 years of follow-up, 20 (28.6%) patients had major adverse cardiovascular events: events occurred in 9 (25.7%) patients with endothelial dysfunction and in 11 (31.5%) patients with normal endothelial function (P=.52). There was an association between the prevalence of diabetes mellitus at baseline and the occurrence of major adverse cardiovascular events during follow-up (univariate analysis: hazard ratio=2.8; 95% confidence interval, 1.0-7.8; P<.05), and even in multivariate analyses the risk appeared to be increased, although not significantly (multivariate analysis: hazard ratio=2.5; 95% confidence interval, 0.8-7.5). CONCLUSIONS: In this series of patients who survived an ST-segment elevation myocardial infarction, endothelial dysfunction, as assessed by reactive hyperemia peripheral artery tonometry 4 weeks to 6 weeks after myocardial infarction, did not predict future clinical events during a mean follow-up of 4 years.

Assessment of the relation between initial culprit vessel patency in acute ST-elevation myocardial infarction and endothelial function.

AIMS: To assess whether better endothelial function increases the likelihood of patients with acute ST-elevation myocardial infarction (STEMI) having initially patent culprit vessels. Clinical data on the relation between endothelial function and culprit vessel patency in STEMI patients are scarce. METHODS AND RESULTS: In this prospective cohort study in 71 patients with STEMI, endothelial function was non-invasively assessed by use of the reactive hyperaemia peripheral artery tonometry (RH-PAT) method at four to six weeks after the primary percutaneous coronary intervention (PPCI). The RH-PAT index measured on average 1.90±0.58. In patients with patent culprit vessels before PPCI (n=33, 46.5%), endothelial function was significantly better than in patients with occluded vessels (n=38, 53.5%) (RH-PAT index 2.08±0.34 vs. 1.75±0.35; p<0.007). Compared to patients with normal endothelial function, the patients with severe endothelial dysfunction had a fivefold higher risk of presenting with an occluded culprit vessel (OR 5.1, 95% CI: 1.8-14.2). Logistic regression analysis revealed that this relation between endothelial function and vessel patency became even stronger after adjustment for potential confounders (adjusted OR 7.1, 95% CI: 2.1-23.6). CONCLUSIONS: In this series of patients with acute STEMI, better endothelial function was independently associated with a higher likelihood of presenting with an initially patent culprit vessel.

Open or percutaneous revascularization for chronic splanchnic syndrome.

BACKGROUND: Treatment of chronic splanchnic syndrome remains controversial. In the past 10 years, endovascular repair (ER) has replaced open repair (OR) to some extent. This evidence summary reviews the available evidence for ER or OR of chronic splanchnic syndrome. METHODS: A systematic literature search of MEDLINE database was performed to identify all studies that evaluated treatment of chronic splanchnic syndrome between 1988 and 2009. RESULTS: The best available evidence consists of prospectively accumulated but retrospectively analyzed data with a high risk for confounding. Only a few of these studies incorporated functional tests to assess splanchnic ischemia before or after treatment. ER has the advantage of low short-term morbidity but the disadvantage of decreased long-term primary patency compared with OR. ER and OR have similar rates of secondary patency, although the reintervention rate after ER is higher. CONCLUSION: ER appears to be preferential in the treatment of elderly patients and in patients with comorbidity, severe cachexia, or hostile abdomen. Long-term results after OR are excellent. OR can still be proposed as the preferred option for relatively young and fit patients.

Transient postprandial ischemia is associated with increased intestinal fatty acid binding protein in patients with chronic gastrointestinal ischemia.

BACKGROUND: Chronic gastrointestinal ischemia (CGI) is still a difficult diagnosis to make. Currently, the only diagnostic with an acceptable sensitivity for actual mucosal ischemia is gastrointestinal tonometry. However, tonometry is a cumbersome and invasive diagnostic test. We are in need of a more simple, noninvasive test for diagnosing mucosal ischemia. A sensitive and early serum marker could be of great use in this setting. The aim of this study was to evaluate the use of promising serum markers for mucosal ischemia [intestinal fatty acid binding protein (I-FABP), D-lactate, and lipopolysaccharide] and compared findings with corresponding gastrointestinal tonometry measurements. METHODS: Patients referred for evaluation of CGI were included. All patients had visualization of abdominal arteries and gastrointestinal tonometry. Before, during, and after tonometry blood samples were drawn for measurements of serum markers. RESULTS: Forty-nine patients were eligible for evaluation. CGI was diagnosed in 24 (49%) patients. The baseline measurements showed a significant increase in I-FABP before exercise tonometry in the abnormal-response groups compared with the normal-response group, respectively, 0.45 and 1.3 microg/l (P=0.04). An abnormal response on meal tonometry was associated with increased I-FABP levels, 1, 2, and 4 h after tonometry, compared with the patients with a normal response, respectively, 1.26, 1.11, and 0.58 microg/l (P=0.048, 0.01, and 0.03). The measurements of D-lactate and lipopolysaccharide were undetectable, or low, at all different points of time. CONCLUSION: Transient postprandial mucosal ischemia, as detected with gastrointestinal tonometry, is associated with increased I-FABP levels, indicating epithelial damage. Late markers for mucosal ischemia remained negative.

Influence of the Ginkgo extract EGb 761 on rat liver cytochrome P450 and steroid metabolism and excretion in rats and man.

Extracts from leaves of Ginkgo biloba L. are among the most used herbal medicinal products worldwide. Based on in-vitro tests and studies in rats, concern has been expressed that intake of Ginkgo extracts may affect hepatic metabolism of xenobiotics and cause drug interactions, although no evidence for modulation of cytochrome P450 (CYP450) enzyme activity was obtained in human trials. Because of these contradictory findings, we investigated the effects of the standardised extract EGb 761 on hepatic CYP450 in rats. EGb 761 (100 mg kg-1 daily, p.o., for 4 days) strongly increased liver CYP450 content and altered the ex-vivo biotransformation of androstendione, as well as metabolism of endogenous steroids. However, in human subjects no effect on the urinary steroid profile was observed after intake of EGb 761 for 28 days (240 mg daily). These results indicate that the effects of EGb 761 on drug metabolising enzymes are specific for rats and may not be extrapolated to man.