Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats.

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.

Early invasive strategy in elderly patients with non-ST elevation acute coronary syndrome: comparison with younger patients regarding 30 day and long term outcome.

OBJECTIVES: To evaluate an early invasive strategy in elderly patients with non-ST elevation acute coronary syndrome (ACS). METHODS: All consecutive patients admitted with a diagnosis of non-ST elevation ACS from June 2002 to February 2004 were enrolled in this registry. Clinical outcome was assessed at 30 days and in long term follow up. RESULTS: An early invasive strategy was followed for 439 patients, of whom 159 (36%) were elderly and had a higher clinical risk profile and greater extent of coronary artery disease (CAD) than the younger patients. Coronary revascularisation was conducted in 133 (83%) elderly patients and 239 (85%) younger patients (not significant). At a mean (SD) follow up time of 10.7 (5.2) months overall mortality, cardiac death, and death plus myocardial infarction were significantly higher among elderly patients than among younger patients (9.4% v 2.1%, p < 0.001; 6.8% v 1.8%, p < 0.01; 11.3% v 5%, p = 0.02, respectively). The significant difference in cardiac death between the two groups was related more to elderly patients being treated by coronary artery bypass grafting (19.3% v 4.9%, p = 0.05) than by percutaneous coronary intervention (PCI) (2.9% v 1.1%, p = 0.3). Cox regression analysis showed age, serum creatinine > 115 micromol/l, no previous history of CAD, left ventricular ejection fraction > 45%, and the absence of diabetes to be independent predictors of the occurrence of major adverse cardiac events. CONCLUSIONS: In unselected elderly patients presenting with non-ST elevation ACS an early invasive strategy is feasible and leads to coronary revascularisation in the majority of cases, resulting in encouraging immediate and long term clinical results, particularly among PCI treated patients.

Clinical and angiographic outcomes following elective implantation of the Carbostent in patients at high risk of restenosis and target vessel failure.

The Carbostent is a new balloon-expandable, stainless steel, tubular stent with innovative multicellular design and unique turbostratic carbon coating. The aim of this study was to assess clinical and angiographic outcomes after Carbostent implantation in 112 patients poorly suitable for an effective treatment with stenting because of the high risk of thrombosis, late restenosis, and clinical target vessel failure. The inclusion criteria were age > 75 years, diabetes mellitus, a lesion length > 10 mm, a reference vessel diameter < 3.0 mm, an ostial location of the target lesion, and chronic total occlusion. Overall, a total of 175 stents ranging from 9 to 25 mm in length were placed in 147 lesions. There were no stenting attempt failures. The acute gain after stent implantation was 2.46 +/- 0.51 mm, and the residual stenosis 0 +/- 4%. No stent thrombosis occurred, nor myocardial infarction. The 6-month event-free survival rate was 74% +/- 5%. The 6-month angiographic follow-up showed a late loss of 0.81 +/- 0.88 mm and a binary (> or = 50%) restenosis rate of 25%. The results of this study suggest that the Carbostent may be highly effective in patients at high risk of restenosis and target vessel failure.

Prognostic implications of restrictive left ventricular filling in reperfused anterior acute myocardial infarction.

OBJECTIVES: We sought to assess the relative prognostic role of a restrictive left ventricular (LV) filling pattern after a first anterior acute myocardial infarction (AMI) in patients treated with primary percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: In thrombolized patients, a short Doppler-derived mitral deceleration time (DT) of early filling is a powerful independent predictor of heart failure and death. However, it is still unknown whether the outcome of patients with AMI with a short DT may be improved by a more aggressive treatment. METHODS: In 104 patients, two-dimensional and Doppler echocardiograms were obtained three days after the index AMI. Coronary angiography was performed in all patients one and six months after PTCA. The patients were classified into two groups according to the DT duration: group 1 (n = 34) with DT < or = 130 ms and group 2 (n = 70) with DT >130 ms. All patients were followed-up for a mean (+/- SD) period of 32 +/- 10 months. RESULTS: During the follow-up period, 14 patients (13%) were admitted to the hospital for congestive heart failure, and 9 patients (9%) died. All cardiac deaths (n = 7) occurred in group 1. The survival rate at mean follow-up was 79% in group 1 and 97.2% in group 2 (p = 0.003). Multivariate Cox analysis showed that only age and restrictive filling were independent predictors of event-free survival. Furthermore, when survival with no cardiovascular events was analyzed, a short DT still emerged as the most powerful independent predictor. CONCLUSIONS: Patients with a restrictive LV filling pattern early after anterior AMI have a poor clinical outcome, even if treated with primary PTCA.

Direct infarct artery stenting without predilation and no-reflow in patients with acute myocardial infarction.

BACKGROUND: In patients with acute myocardial infarction (AMI), the rate of microvascular embolization and no-reflow promoted by coronary stenting with the use of conventional techniques (CS) appears to be greater than the one that occurs with balloon angioplasty. The minor invasiveness of direct stenting (DS) of the infarct artery without predilation could be expected to reduce embolization in the coronary microvasculature and no-reflow in patients with AMI. METHODS: In a cohort of 423 consecutive patients with AMI who underwent infarct-artery stenting, we compared CS and DS in terms of angiographic no-reflow rate and 1-month clinical outcome. RESULTS: At baseline patients who underwent DS (n = 110) had a better risk profile compared with the use of CS (n = 313). The incidence of angiographic no-reflow was 12% in the CS group and 5.5% in the DS group (P =.040). The 1-month mortality rate was 8% in the CS group and 1% in the DS group (P =.008). The mortality rate was 11% in patients with no-reflow and 5.6% in patients with a normal flow. Multivariate analysis showed that age, preprocedure patent infarct artery, and lesion length were related to the risk of no-reflow. In the subset of patients with a target lesion length

Coronary stenting and platelet glycoprotein IIb/IIIa receptor blockade in acute myocardial infarction.

BACKGROUND: Myocardial reperfusion in patients with acute myocardial infarction may be successfully achieved with primary angioplasty. However, angioplasty, as a primary reperfusion strategy, has limitations such as early recurrent ischemia and late restenosis and reocclusion. To improve the short- and long-term results of primary angioplasty, the use of adjunct strategies has been proposed. METHODS: We reviewed published studies on the effectiveness of primary angioplasty, stenting, and platelet glycoprotein IIb/IIIa receptor blockade and identified the advantages and disadvantages of these interventions in patients with acute myocardial infarction. RESULTS: Recent findings suggest that patients may benefit from stenting of the infarct artery and from the use of more potent antiplatelet agents such as platelet glycoprotein IIb/IIIa receptor inhibitors. In randomized trials that compared primary angioplasty versus primary stenting, stent implantation was associated with a lower rate of death, reinfarction, and especially target vessel revascularization. Platelet glycoprotein IIb/IIIa receptor inhibitors prevented acute ischemic complications after primary angioplasty and primary stenting. In addition to maintaining large vessel patency, these drugs may protect the microvasculature after primary stenting, allowing better functional recovery of the risk area. CONCLUSIONS: Coronary artery stenting in acute myocardial infarction reduces the rate of restenosis and the incidence of problems related to recurrent ischemia. Platelet glycoprotein IIb/IIIa receptor inhibitors may come to play a key role in association with mechanical reperfusion. However, the cost-effectiveness and long-term clinical outcome of this combined pharmacologic/mechanical intervention require further study before this strategy can be recommended for routine use.

Echo-Doppler evaluation of left ventricular diastolic dysfunction during acute myocardial infarction: methodological, clinical and prognostic implications.

Left ventricular (LV) diastolic dysfunction has been reported in the subacute and late phase after myocardial infarction and it is becoming increasingly clear that abnormalities of diastolic function during acute myocardial infarction (AMI) have a major role in affecting the prognosis. However, until recent years the study of patients with diastolic dysfunction has suffered from the substantial difficulties inherent in diagnosing, measuring, quantitating and in following it over time. Moreover, the complexity of events encompassed by diastole, which are often difficult to control in the clinical arena, and the lack of data available to guide therapy, have hampered the widespread application of diastology in the clinical setting of AMI. The advent of Doppler echocardiography and its complementary techniques have provided a bedside tool which yields reliable and useful measures of diastolic performance during AMI, placing such an assessment well within the grasp of every clinical echocardiographic laboratory. Determination of the pattern of LV filling by Doppler echocardiography provides important information about LV diastolic function in AMI patients. Clinical data gathered so far demonstrate that Doppler-derived LV filling, specifically the restrictive filling pattern, is a powerful independent predictor of late LV dilation and, most importantly, of cardiac death in patients with AMI and clearly indicate the need for evaluating and monitoring LV diastolic function in these patients. Large scale studies, utilizing simple and easy to measure Doppler indexes of LV filling are needed to assess the efficacy of medical therapy in patients with acute LV diastolic dysfunction during AMI.

Sex-based differences in clinical and angiographic outcomes after primary angioplasty or stenting for acute myocardial infarction.

A paucity of data exists on the importance of gender in contributing to the mortality rate after primary angioplasty, although it is has been shown that women with acute myocardial infarction (AMI) are less likely than men to undergo reperfusion treatments. This study analyzes gender-related differences in 6-month clinical and angiographic outcomes in nonselected patients with AMI who underwent primary angioplasty or stenting. We compared clinical and angiographic outcomes of 230 women and 789 men who underwent primary angioplasty or stenting from January 1995 to August 1999. The women were older than the men, and had a greater incidence of diabetes and cardiogenic shock. The 6-month mortality rate was 12% in women and 7% in men (p = 0.028). Nonfatal reinfarction occurred in 3% of the women and in 1% of the men (p = 0.010). There were no differences in repeat target vessel revascularization rates. After multivariate analysis, gender did not emerge as a significant variable in relation to 6-month mortality or to the combined end point of death, reinfarction, and repeat target vessel revascularization. Both women and men with stented infarct arteries had lower restenosis rates (29% and 26%, respectively) than patients without stents (52% and 39%, repectively). The results of outcome analysis in nonselected patients suggest that sex is not an independent predictor of mortality after primary angioplasty for AMI, and that the benefit of primary stenting is similar in men and women.

A randomized study of intravenous magnesium in acute myocardial infarction treated with direct coronary angioplasty.

BACKGROUND: Notwithstanding the negative result of the International Study of Infarct Survival-4 (ISIS-4), the controversy about the role of magnesium in acute myocardial infarction is still open because, according to experimental data, magnesium could decrease myocardial damage and mortality only if infusion is started before reperfusion. This randomized placebo-controlled trial was designed to evaluate the effect of intravenous magnesium, delivered before, during, and after direct coronary angioplasty, in patients with acute myocardial infarction. METHODS: One-hundred fifty patients were randomized to intravenous magnesium sulfate or placebo. The primary end point was an infarct zone wall motion score index at 30 days, as a measure of infarct size. The secondary end points included creatine kinase peak, ventricular fibrillation/tachycardia within the first 24 hours, death and congestive heart failure within the 30-day follow-up, and 30-day left ventricular ejection fraction. Analysis was by intention to treat. RESULTS: There were no significant differences between the magnesium and placebo groups in the 30-day infarct zone wall motion score index (1.93 +/- 0.61 vs 1.85 +/- 0.51, P =.39), ventricular arrhythmias (24% vs 15%, P =.15), death (0 vs 1%, P =.32), heart failure (8% vs 7%, P =.75), and 30-day left ventricular ejection fraction (49% +/- 11% vs 50% +/- 9%, P = 0.55). There was a trend toward a higher creatine kinase peak in the magnesium group (3059 +/- 2359 vs 2404 +/- 1673,P =.052). CONCLUSIONS: Intravenous magnesium delivered before, during, and after reperfusion did not decrease myocardial damage and did not improve the short-term clinical outcome in patients with acute myocardial infarction treated with direct angioplasty.

Primary stenting in nonselected patients with acute myocardial infarction: the Multilink Duet in Acute Myocardial Infarction (MIAMI) trial.

Most randomized trials comparing primary stenting with primary coronary angioplasty (PTCA) excluded patients at high risk from enrollment, thus arising the important question about the generalizability of the randomized trial results to all patients with AMI. The aim of this study was to assess the feasibility and effectiveness of a primary infarct-related artery (IRA) stenting strategy using a second-generation tubular stent in nonselected patients with acute myocardial infarction (AMI). All patients with AMI were considered eligible for primary IRA stenting. No restriction was made based on age or clinical status on presentation, or coronary anatomy, except in cases of a reference IRA diameter < 2.5 mm. The primary endpoint of the study was clinical target vessel failure defined as death, reinfarction, or repeat TVR due to restenosis or reocclusion of the IRA. Between June 1998 and March 1999, 201 consecutive patients with AMI underwent mechanical recanalization of the IRA. The mean age was 64 +/- 12, and 16% of patients were aged 75 years or over. The incidence of shock was 9%. Primary IRA stenting was performed in 89% of the patients. Patients who underwent PTCA alone had a smaller IRA diameter as compared to patients with a stented IRA (2.48 +/- 0.46 mm vs. 3.15 +/- 0.37 mm; P < 0.001). There were no stent deployment failures. The 6-month primary endpoint rate was 15% (2 deaths, 27 repeat TVR, 0 reinfarctions), while the 6-month angiographic restenosis rate was 22%. Primary IRA stenting in nonselected patients with AMI is highly feasible and associated with favorable clinical and angiographic outcomes. Cathet. Cardiovasc. Intervent. 51:273-279, 2000.

Prognostic implications of Tc-99m sestamibi viability imaging and subsequent therapeutic strategy in patients with chronic coronary artery disease and left ventricular dysfunction.

OBJECTIVES: The aim of the study was to verify the prognostic implications of viability detection using baseline-nitrate sestamibi imaging in patients with left ventricular (LV) dysfunction due to chronic coronary artery disease (CAD) submitted to different therapeutic strategies. BACKGROUND: The prognostic meaning of preserved viability in these patients is still debated. Sestamibi is increasingly used for myocardial perfusion scintigraphy and is being accepted also as viability tracer, but no data are available about the relationship between viability in sestamibi imaging, subsequent treatment, and patient's outcome. METHODS: Follow-up data were collected in 105 CAD patients with LV dysfunction who had undergone baseline-nitrate sestamibi perfusion imaging for viability assessment and had been later treated medically (group 1), or submitted to revascularization, which was either complete (group 2A) or incomplete (group 2B). RESULTS: Eighteen hard events (cardiac death or nonfatal myocardial infarction) were registered during the follow-up. A significantly worse event-free survival curve was observed in the patients of group 1 (p < 0.0002) and group 2B (p < 0.03) compared to those of group 2A. Using a Cox proportional hazard model, the most powerful prognostic predictors of events were the number of nonrevascularized asynergic segments with viability in sestamibi imaging (p < 0.003, risk ratio [RR] = 1.4), and the severity of CAD (p < 0.02, RR = 1.28). CONCLUSIONS: Viability detection in sestamibi imaging has important prognostic implications in CAD patients with LV dysfunction. Patients with preserved viability kept on medical therapy or submitted to incomplete revascularization represent high-risk groups.

The role of myocardial viability in deriving benefit from reestablishing infarct-related artery flow after acute myocardial infarction.

Early, sustained patency of the infarct-related artery (IRA) induces myocardial salvage, which preserves left ventricular (LV) function and mediates better long-term outcome. However, the time course and the mechanisms of muscle recovery after myocardial infarction are not completely understood. A large body of evidence suggests that most of the improvement occurs during the hospital phase and is related to early and sustained thrombolysis in myocardial infarction 3 flow in the IRA. Nevertheless, the relationship between IRA status and regional and global LV mechanics in the chronic phase of the disease remains controversial. Some late recovery may occur, either spontaneously or after revascularization, even in the absence of documented myocardial ischemia. The interplay between vessel patency, coronary flow grade and severity of the residual stenosis, and the presence of stunned or hibernating myocardium in the area at jeopardy may explain this delayed improvement. Although there seems to be a limited time window in which myocardium can be salvaged, timely testing for viability, particularly in patients with poor LV function, is justified even in a later phase of the disease to challenge potential cardiac recovery.

Clinical and angiographic outcome after coronary arterial stenting with the carbostent.

The Carbostent is a new balloon-expandable, stainless steel, tubular stent with innovative multicellular design and unique turbastratic carbon coating (Carbofilm). This open nonrandomized 2-center study assesses the immediate and long-term clinical and angiographic outcomes after Carbostent implantation in patients with native coronary artery disease. The Carbostent was implanted in 112 patients with 132 de novo lesions. Most patients (55%) had unstable angina, and 38% of lesions were type B2-C. The mean lesion length was 12.5 +/- 7.0 mm, and 29% of lesions were > 15 mm in length. No stent deployment failure occurred, as well as acute or sub-acute stent thrombosis. The 6-month event-free survival was 84 +/- 4%. One patient with a stented right coronary artery and no restenosis at the angiographic follow-up died after 6 months of fatal infarction due to abrupt closure of a nontarget vessel. In-hospital non-Q-wave myocardial infarction occurred in 1 patient, and 11 patients had repeat target lesion revascularization (target lesion revascularization rate 10%). The 6-month angiographic follow-up was obtained in 108 patients (96%) (127 lesions). Angiographic restenosis rate was 11%. The loss index was 0.29 +/- 0.28. The results of this study indicate a potential benefit of Carbostent for the prevention of stent thrombosis and restenosis in these relatively high-risk patients. A larger trial is being planned to confirm these promising results.

Early dobutamine echocardiography predicts improvement in regional and global left ventricular function after reperfused acute myocardial infarction without residual stenosis of the infarct-related artery.

BACKGROUND: The accuracy of dobutamine echocardiography (DE) early after reperfused acute myocardial infarction (AMI) without residual stenosis of the infarct-related artery is unknown. The objective of this study was to assess whether in reperfused AMI DE can predict early as well as late regional and global spontaneous functional recovery. METHODS: DE was performed in 157 patients (61 +/- 11 years; 33 women) 3 days after AMI treated with successful direct percutaneous transluminal coronary angioplasty (Thrombolysis in Myocardial Infarction flow grade 3, residual stenosis <30%). All patients underwent 2-dimensional echocardiography and coronary angiography at 1 month and 145 (92%) at 6 months. RESULTS: Patency and restenosis rate were similar between those who did and did not respond to DE. DE showed a high accuracy in predicting both early and late regional functional recovery (86% and 81%, respectively). DE accuracy in predicting early and late reversible dysfunction was also high on a patient-by-patient analysis (89% and 87%). In DE responders left ventricular ejection fraction increased from 44% +/- 9% at baseline to 57% +/- 9% at 6 months (P <.00005), whereas only a slight, although significant improvement was found in nonresponders (from 40% +/- 10% to 44% +/- 12%; P =.03). A significant correlation was found between the number of dobutamine-responder segments and the magnitude of their functional improvement at peak dobutamine and changes in ejection fraction (r =.72; P <.000001; r =.68, P <.000001, respectively). CONCLUSIONS: These data indicate that in patients with AMI in whom anterograde flow is fully restored without residual stenosis, DE can predict the recovery of regional function and whether a relevant change in ejection fraction will occur at early and late follow-up.

Stenting for in-stent restenosis.

Intravascular ultrasound studies have shown that additional stent implantation is the only percutaneous technique that allows for recovery of all the lumen area of the original implantation procedure. Despite this theoretical advantage, information on systematic additional stent implantation is still forthcoming, especially concerning the impact of new stent designs. This prospective study evaluated the efficacy of routine additional stent implantation for treatment of in-stent restenosis in 68 consecutive patients. Repeat stenting was successful in all cases, and second-generation tubular stents were used in 84% of patients. The mean additional stent length was 19.2 +/- 9.4 mm, and 15% of patients had multiple stent implantation. The postprocedure minimum lumen diameter was 3.11 +/- 0.41 mm, and the percentage residual stenosis was 2% +/- 7%. At a mean clinical follow-up of 10 +/- 8 months (follow-up rate 100%), the incidence of major adverse events was 21% (1 death, 13 target vessel revascularizations). Overall, angiographic restenosis rate was 32% (angiographic follow-up rate 79%). By multivariate analysis, the only predictors of recurrence after additional stenting were unstable angina at the second procedure (OR 8.70, 95% CI 1.50-50.33, P = 0.019), and early clinical recurrence after the first stent procedure (OR 4.83, 95% CI 1.13-20.71, P = 0.038). Additional stenting is a safe and effective treatment modality for the majority of patients with in-stent restenosis. Alternative treatments should be considered only for patients with in-stent restenosis presenting as unstable angina or early recurrence after a first stent procedure.

Efficacy of a "stent-like" PTCA strategy in current clinical practice.

Retrospective analysis within the BENESTENT-l trial has shown that patients having a "stent-like" result after standard PTCA had angiographic and clinical outcomes similar to those of patients receiving a stent. The objective of this study is to assess the efficacy of a "stent-like" PTCA strategy in native coronary arteries in non-selected patients. From our data base, 503 consecutive patients who underwent successful PTCA or stent supported PTCA were stratified according to a target lesion length < 15 mm, a reference vessel diameter > or = 2.5 mm, and a postprocedural residual stenosis < 30%. After stratification, 132 patients with "stent-like" PTCA, and 88 with single stent implantation were compared on two-year clinical outcomes. Two-year event-free survival rate was 70% in the "stent-like" PTCA group, and 83% in the stent group (p = 0.022). Stent-like PTCA is associated with a higher restenosis rate and higher adverse events rate as compared to single stent supported PTCA, whatever the indication for stenting.

Primary coronary infarct artery stenting in acute myocardial infarction.

Completed and ongoing randomized trials have provided results that favor primary infarct-related artery (IRA) stenting as opposed to primary percutaneous transluminal coronary angioplasty, but the applicability of the trial results to all patients with acute myocardial infarction (AMI) has not yet been investigated. This study sought to determine the applicability of an unconditional IRA stenting strategy in nonselected patients with AMI. After successful mechanical recanalization of the IRA, all patients with AMI and a reference diameter > or =2.5 mm were considered eligible for primary IRA stenting without any restriction regarding age or clinical status on presentation. The primary end point of the study was a composite end point defined as death, reinfarction, or repeat target lesion revascularization. Primary IRA stenting was successfully performed in 161 of 190 consecutive patients with AMI (85%), and of 162 (99%) considered suitable for stenting. Patients with nonstented IRA had a reference IRA diameter smaller than patients with a stent (2.71+/-0.48 vs 3.20+/-0.41 mm, p <0.001). Overall, the 6-month mortality was 5%. Mortality was 2% for patients without, and 32% for patients with cardiogenic shock. The incidences of reinfarction and of repeat target lesion revascularization were 1% and 12%, respectively. The 6-month angiographic follow-up showed an IRA patency rate of 94% and a restenosis rate of 26%. The results of this study strengthen the hypothesis that unconditional primary IRA stenting is highly feasible, and may actually improve the outcome of patients with AMI.