Direct oral anticoagulants in patients with nonvalvular atrial fibrillation and extreme body weight.

BACKGROUND: Limited clinical data exist describing the use of direct oral anticoagulants (DOACs) in patient with extreme body weight. Thus, the International Society of Thrombosis and Haemostasis (ISTH) recommends avoiding DOACs in patients with weight >120 Kg, and on the contrary, no restrictions exist for underweight patients. OBJECTIVE: To evaluate the effects of extreme body weight on DOAC activity and to compare the clinical outcomes of patients with an extreme body weight versus patients with a normal weight (61-119 Kg) treated with DOACs. METHODS: Single tertiary care Italian centre multidisciplinary registry including nonvalvular atrial fibrillation (NVAF) patients treated with DOACs. Based on weight, three subcohorts were defined: (i) underweight patients (≤60 Kg); (ii) patients with a normal weight (61-119 Kg, as control group); and (iii) overweight patients (≥120 Kg). Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. RESULTS: 812 NVAF patients were included, 108 patients weighed ≤60 Kg (13%, underweight), 688 weighed between 61 and 119 Kg (85%, normal weight), and 16 weighed ≥120 Kg (2%, overweight). In particular, among underweight patients, dabigatran was prescribed in 26% patients, apixaban in 27%, rivaroxaban in 28% and edoxaban in 22% ones. Instead, among overweight patients, 44% were treated with dabigatran, 25% with apixaban, 25% with rivaroxaban and 4% with edoxaban. Underweight patients were older, more frequently women, with lower creatinine clearance and a history of previous strokes, resulting in higher CHA2DS2-VASc score than in both remaining groups. Up to 2 years, no statistically significant difference was observed between the three groups of weight for thromboembolic events (P = .765) and for overall bleeding (P = .125), but a trend towards decreased overall bleeding rates was noticed as weight increased (24.1% vs 16.7% vs 12.5%, respectively). CONCLUSION: In this tertiary care centre registry, 15% of patients treated with DOACs presented an extreme weight. Compared to patients with a normal weight, no significant rates of thromboembolic events were observed for underweight or overweight patients. A trend towards decreased overall bleeding frequency as weight increased was highlighted up to 2 years. The present results should be considered as preliminary and hypothesis generating.

Direct oral anticoagulants versus percutaneous left atrial appendage occlusion in atrial fibrillation: 5-year outcomes.

BACKGROUND: LAAO is an emerging option for thromboembolic event prevention in patients with NVAF. We previously reported data on comparison between LAAO and DOAC at two-year follow-up in NVAF patients at HBR (HAS-BLED ≥3). AIMS: Limited data are available on long term follow-up. We aimed to evaluate the efficacy and safety of DOACs versus LAAO indication after 5 years. METHODS: We enrolled 193 HBR treated with LAAO and 189 HBR patients with DOACs. At baseline, LAAO group had higher HAS-BLED (4.2 vs 3.3, p < 0.001) and lower CHADS-VASc (4.3 vs. 4.7, p = 0.005). After 1:1 PSM, 192 patients were included (LAAO n = 96; DOACs n = 96). RESULTS: At 5-year follow-up the rate of the combined safety and effectiveness endpoint (ISTH major bleeding and thromboembolic events) was significantly higher in LAAO group (p = 0.042), driven by a higher number of thromboembolic events (p = 0.047). The rate of ISTH-major bleeding events was similar (p = 0.221). After PSM no significant difference in the primary effectiveness (LAAO 13.3% vs DOACs 9.5%, p = 0.357) and safety endpoint (LAAO 7.5% vs DOACs 7.5%; p = 0.918) were evident. Overall bleeding rate was significantly higher in DOACs group (25.0% vs 13.7%, p = 0.048), while a non-significant higher number of TIA was reported in LAAO group (5.4% vs 1.1%, p = 0.098). All-cause and cardiovascular mortality were higher in LAAO group at both unmatched and matched analysis. CONCLUSION: We confirmed safety and effectiveness of both DOAC and LAAO in NVAF patients at HBR, with no significant differences in thromboembolic events or major bleeding were at 5-year follow-up. The observed increased mortality after LAAO warrants further investigations in RCTs.

Baseline Characteristics and 3-Year Outcome of Nonvalvular Atrial Fibrillation Patients Treated with the Four Direct Oral Anticoagulants (DOACs).

Direct oral anticoagulants (DOACs) represent the cornerstone therapy for cardioembolic events prevention in patients with nonvalvular atrial fibrillation (NVAF). In practice, the choice of one DOAC over another is guided by the decision-making process of the physician, which considers specific patient and drug characteristics. This study aimed to evaluate the clinical features and long-term outcomes of a real-world population treated with DOACs, where the use of the 4 different DOACs is quite equal. We conducted a retrospective observational, single-center, multidisciplinary study enrolling consecutive NVAF patients treated with one of the 4 DOACs. From an initial number of 753 patients, we excluded 72 patients because of loss to follow-up, at the end we enrolled 681:174 (23%) treated with dabigatran, 175 (23%) with apixaban, 190 (25%) with rivaroxaban, and 214 (29%) with edoxaban. Patients treated with apixaban were significantly older, more women represented (p <0.001), and with a higher cardioembolic and bleeding risk (p <0.001). Dabigatran was preferred in patients with liver failure (p = 0.008), whereas Apixaban and Edoxaban were chosen in chronic kidney disease (p = 0.002). At 3-year follow-up, 20 patients (2.7%) experienced a systemic thromboembolic event without significant differences in the 4 DOACs. In the same period, an International Society of Thrombosis and Hemostasis classification major bleeding event occurred in 26 patients (3.6%), more statistically correlated to edoxaban (6.1%) (p = 0.038). Thromboembolic events or major bleeding were higher in the edoxaban group (10%) compared with the others (p = 0.014). In our single-center real-world experience, the choice of the DOAC for a patient with NVAF was tailored to specific clinical features and drug pharmacokinetics of the patient. As a result, a small number of adverse events were observed.

Safety and efficacy of direct oral anticoagulants (DOACs) in very elderly patients (≥85 years old) with non-valvular atrial fibrillation.

BACKGROUND: Limited real-world data are available regarding the comparison about safety and efficacy of DOACs prescription in very elderly patients (≥85 years) with non-valvular atrial fibrillation (NVAF). Concern about the risk of bleeding with anticoagulation in very older patients still represents an important challenge for clinicians. The aim of this study was to evaluate the different prevalence of major bleeding and thromboembolic events between very elderly NVAF patients (≥85 years) compared to those non very elderly (<85 years). METHODS: Single center multidisciplinary registry including NVAF patients treated with DOACs. Primary safety endpoint was 2-year rate of major bleeding. Primary efficacy endpoint was 2-year rate of thromboembolic events. Event-free survival curves among groups were compared using Cox-Mantel Test. RESULTS: 908 NVAF consecutive patients were included, of these, 805 patients were <85 years (89%) and 103 patients were very elderly patients with ≥85 years (11%). Compared to patients <85 years, those very elderly have higher CHA2DS2-VASc Score (P=0.001), higher rate of hypertension (P=0.001), diabetes mellitus (P=0.030), previous bleeding events (P<0.001), previous stroke/TIA/SE (P≤0.001), heart failure (P≤0.001), and lower creatinine clearance (P<0.001). In terms of safety endpoints (overall ISTH-major bleeding) no significative difference between two groups (P=0.952) were observed up to 2-year follow-up. Systemic thromboembolic event (primary efficacy endpoint) was significantly higher in patients with ≥85 years (P=0.027). The incidence of all-cause death was significantly higher in very elderly patients (P<0.001). CONCLUSIONS: This single center registry, showed that the use of DOACs in very elderly NVAF was safe and is a therapeutic option to be pursued for stroke prevention especially for those who are at high risk of ischemic events.

Inappropriate dose of nonvitamin-K antagonist oral anticoagulants: prevalence and impact on clinical outcome in patients with nonvalvular atrial fibrillation.

BACKGROUND: Limited real-world data are available regarding the outcome of patients treated with inappropriate dose of nonvitamin-K antagonist oral anticoagulants (NOACs). OBJECTIVE: To assess the prevalence and factors associated with inappropriate dose prescription of NOACs and to evaluate adverse events that come from this inappropriate prescription. METHODS: Single-center multidisciplinary registry including nonvalvular atrial fibrillation patients treated with NOACs. Based on guidelines criteria for dose reduction, two subcohorts were defined as treated with appropriate or inappropriate NOACs dose. Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. RESULTS: A total of 760 nonvalvular atrial fibrillation patients were included; 32% patients were treated with dabigatran, 34% with apixaban, 24% with rivaroxaban and 10% with edoxaban. An inappropriate dose was prescribed in 96 patients (12.6%), and in most cases (68%) it was too low. Rivaroxaban (15%) and apixaban (18.5%) were the most frequently prescribed with an inappropriate dose. Patients treated with an inappropriate dose were elderly people, with low-creatinine clearance value, who had experienced previous bleeding and with a high CHADS2 VASc score. In 2 years, a trend for higher numbers of thromboembolic events (5.2 vs. 3.3%, P = 0.348) and less major bleeding (2.1 vs. 4.2%, P = 0.316) has been observed in patients with inappropriate NOACs prescriptions. CONCLUSION: Nearly 13% of patients were treated with an inappropriate dose of NOACs, in this single-center study. A trend for higher numbers of thromboembolic events was observed in these patients. The results should be considered as hypothesis generating.

Comparison of VerifyNow-P2Y12 test and Flow Cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy?

BACKGROUND: Dual anti-platelet therapy with aspirin and a thienopyridine (DAT) is used to prevent stent thrombosis after percutaneous coronary intervention (PCI). Low response to clopidogrel therapy (LR) occurs, but laboratory tests have a controversial role in the identification of this condition. METHODS: We studied LR in patients with stable angina undergoing elective PCI, all on DAT for at least 7 days, by comparing: 1) Flow cytometry (FC) to measure platelet membrane expression of P-selectin (CD62P) and PAC-1 binding following double stimulation with ADP and collagen type I either in the presence of prostaglandin (PG) E1; 2) VerifyNow-P2Y12 test, in which results are reported as absolute P2Y12-Reaction-Units (PRU) or % of inhibition (% inhibition). RESULTS: Thirty controls and 52 patients were analyzed. The median percentage of platelets exhibiting CD62P expression and PAC-1 binding by FC evaluation after stimulation in the presence of PG E1 was 25.4% (IQR: 21.4-33.1%) and 3.5% (1.7-9.4%), respectively. Only 6 patients receiving DAT (11.5%) had both values above the 1st quartile of controls, and were defined as LR. Evaluation of the same patients with the VerifyNow-P2Y12 test revealed that the area under the receiver-operating-characteristic (ROC) curve was 0.94 (95% CI: 0.84-0.98, p < 0.0001) for % inhibition and 0.85 (0.72-0.93, p < 0.005) for PRU. Cut-off values of ≤ 15% inhibition or > 213 PRU gave the maximum accuracy for the detection of patients defined as having LR by FC. CONCLUSION: In conclusion our findings show that a cut-off value of ≤ 15% inhibition or > 213 PRU in the VerifyNow-P2Y12 test may provide the best accuracy for the identification of patients with LR.

Real-world 2-year outcome of atrial fibrillation treatment with dabigatran, apixaban, and rivaroxaban in patients with and without chronic kidney disease.

Patients with non-valvular atrial fibrillation (NVAF) and chronic kidney disease (CKD) are at increased risk of stroke and bleeding. Although direct oral anticoagulant (DOAC) trials excluded patients with severe CKD, a growing portion of CKD patients have been starting DOACs and limited data from real-world outcome in this high-risk setting are available. The INSigHT registry included 632 consecutive NVAF patients that started apixaban (256 patients, 41%), dabigatran (245, 39%) and rivaroxaban (131, 20%) between 2012 and 2015. Based on creatinine clearance, two sub-cohorts were defined: (1) non-CKD group (CrCl 60-89 mL/min, 413 patients) and (2) CKD group (15-59 ml/min, 219). Compared to non-CKD patients, those with CKD, were at higher ischemic (CHA2DS2-VASc 4.5 vs 2.9, p < 0.001) and hemorrhagic risk (HAS-BLED 2.4 vs 1.8, p < 0.001). At 2-year follow-up, the overall ISTH-major bleeding and thromboembolic event rates were 5.2% and 2.3% and no significant difference between non-CKD and CKD patients for both efficacy and safety endpoints were observed. In non-CKD patients, the 2-year ISTH-major bleeding rates were higher in rivaroxaban group (HR 2.9, 95% CI 1.1-7.3; p = 0.047) while dabigatran showed non-significant excess in thromboembolic events (HR 4.3, 95% CI 0.9-20.8; p = 0.068). In CKD patients, a significantly higher rate of thromboembolic events was observed in rivaroxaban (HR 6.3, 95% CI 1.1-38.1; p = 0.044). This real-world, non-insurance database registry shows remarkable 2-year safety and efficacy profile of DOACs even in patients with moderate to severe CKD. Head to head differences between DOACs are exploratory, hypothesis generating and warrant further investigation in larger studies.

Platelet reactivity in response to loading dose of atorvastatin or rosuvastatin in patients with stable coronary disease before percutaneous coronary intervention: The STATIPLAT randomized study.

BACKGROUND: The acute effects of statin loading dose (LD) on platelet reactivity in patients with chronic stable angina (CSA) are not completely clear. HYPOTHESIS: We hypothesized that LDs of atorvastatin and rosuvastatin have different pharmacodynamic acute effects on platelet aggregability in CSA patients with baseline normal platelet reactivity while on dual antiplatelet therapy (DAPT). METHODS: From September 2011 to February 2014, all consecutive CSA patients on chronic DAPT (aspirin and clopidogrel) were evaluated before elective percutaneous coronary intervention (PCI). An initial assessment of platelet reactivity in response to thrombin receptor agonist, ADP, and ASP (respectively, indicative of the response to clopidogrel and aspirin) was performed with impedance aggregometry. Patients with high platelet reactivity to ADP test (area under the curve >47) were excluded. The remaining patients were randomized into 3 treatment groups: Group A, atorvastatin LD 80 mg; Group B, rosuvastatin LD 40 mg; and Group C, no statin LD (control group). A second assessment of platelet reactivity was performed ≥12 hours after statin LD. RESULTS: 682 patients were screened and 145 were randomized into the 3 groups. At baseline and after statin LD, no significant difference was found in platelet reactivity in response to 3 different agonists between the 3 groups. Subgroup analysis showed that platelet reactivity to ADP test was significantly lower in patients chronically treated with low-dose statins (n = 94) compared with statin-naïve patients (n = 51; 15.32 ± 1.50 vs 18.59 ± 1.30; P = 0.007). CONCLUSIONS: Loading dose of atorvastatin (80 mg) or rosuvastatin (40 mg) did not induce significant variation in platelet reactivity in CSA patients with baseline reduced platelet reactivity as in chronic DAPT. Our data confirm that chronic concomitant treatment with low-dose statins and clopidogrel resulted in significantly lower platelet reactivity compared with clopidogrel alone.

Long-term clinical outcomes of patients with rheumatoid arthritis and concomitant coronary artery disease.

BACKGROUND: Rheumatoid arthritis (RA) is associated with high morbidity and mortality predominately due to increased cardiovascular risk. Few reports are available regarding the management of coronary artery disease (CAD) in RA patients and the long-term clinical outcomes after coronary revascularization. METHODS AND RESULTS: All consecutive patients with RA were identified by retrospective review at a rheumatology tertiary center in Milan, Italy between 2001 and 2013. RA patients affected by significant CAD (RA-CAD+) were prospectively followed for major adverse cardiovascular and cerebrovascular events (MACCE) after percutaneous coronary revascularization (RA-PCI), coronary artery bypass grafting (RA-CABG) or medical therapy (RA-MT). Among 936 patients with RA, the presence of clinically significant CAD was found in 5.6% (53 patients, RA-CAD+). Of these, 32 patients (60%) underwent PCI (RA-PCI), 10 patients (19%) underwent CABG (RA-CABG) and 11 patients (21%) treated with MT (RA-MT). After a mean follow-up of 9±7 years, the rate of MACCE was 56% in RA-PCI patients, 50% in RA-CABG and 27% in RA-MT patients (P=0.184). The high MACCE rate was mainly driven by repeat coronary revascularization (47%) in the RA-PCI group and high rate of strokes (30%) in RA-CABG patients. CONCLUSION: In patients with rheumatoid arthritis and concomitant coronary artery disease (RA-CAD+), we observed at long-term follow-up a high MACCE rate, predominantly in those who underwent coronary revascularization.

Impact and evolution of right ventricular dysfunction after successful MitraClip implantation in patients with functional mitral regurgitation.

BACKGROUND: Right ventricular dysfunction (RVdysf) is a predictor of poor outcome in patients with heart failure and valvular disease. The aim of this study was to evaluate the evolution and the impact of RVdysf in patients with moderate-severe functional mitral regurgitation (FMR) successfully treated with MitraClip. METHODS AND RESULTS: From October 2008 to July 2014, 60 consecutive high surgical risk FMR patients were evaluated and stratified into two groups: RVdysf group (TAPSE < 16 mm and/or S'TDI < 10 cm/s, 21 patients) and No-RVdysf group (38 patients). The overall mean age of patients was 73 ± 8 (83% male). Ischemic FMR etiology was present in 67%. Mean LVEF was 30 ± 10%. Overall mean time follow-up was 565 ± 310 days. The only significant difference between the two groups was a greater prevalence of stroke, ICD and use of aldosterone antagonist in RVdysf group. Acute procedural success was achieved in 90% of patients. At 6-month echo-matched analysis significant RV function improvement was observed in patients with baseline RVdysf (TAPSE 15 ± 3.0 vs. 19 ± 4.5, p = 0.007; S'TDI 7 ± 1.2 vs. 11 ± 2.8, p < 0.0001; baseline vs. 6-month, respectively). The mean improvement in the 6-min walking test was significant in both groups (120 and 143 m, RVdysf and No-RVdysf groups, respectively). At Kaplan-Meier analysis, the presence of RVdysf did not affect the outcome in terms of freedom from composite efficacy endpoint. CONCLUSIONS: This study shows that successful MitraClip implantation in patients with FMR and concomitant right ventricular dysfunction yields significant improvement of RV function at mid-term follow-up. Further data on larger population will be required to confirm our observations.

Prognostic role of stress/rest myocardial perfusion scintigraphy in patients with cardiac syndrome x.

AIM: The prognostic utility of myocardial perfusion scintigraphy (MPS) in patients with angiographically normal coronary arteries has not been evaluated yet. Our aim was to determine the prognostic role of positive MPS in patients with angina, positive exercise test and smooth coronary arteries (syndrome X). METHODS: A total of 156 patients with angina, positive exercise test, positive MPS and normal coronary arteries and 172 patients with angina and positive exercise test who had negative MPS were selected for study. The primary endpoint was combined all-cause mortality and hospitalizations for cardiac causes. The secondary endpoint was hospitalization for cardiac causes. RESULTS: Kaplan-Meier analysis showed a greater (p=0.001) incidence of the primary endpoint in patients with positive MPS, compared to those with negative MPS. Additionally, Kaplan-Meier analysis for cardiovascular hospitalization showed a significant difference (p=0.003) between the two groups. Cox regression analysis, adjusted for age, sex, BMI and antianginal therapy confirmed a significant risk increase for patients with positive MPS, with a hazard ratio (HR)=3.20 (CI 95%: 1.14-9.02; p=0.028). Cox analysis for cardiovascular hospitalization also showed a significant risk increase for patients with positive MPS (HR=3.19; CI 95%: 1.13-9.00; p=0.03). Finally, Cox analysis showed that patients with positive MPS tend to have a higher risk to remain symptomatic in the follow-up period (HR=1.614; CI 95%: 0.999-2.607; p=0.51). CONCLUSIONS: This study shows that inducible myocardial hypoperfusion at MPS in patients with syndrome X could discriminate patients with a more severe prognosis, especially in terms of further hospitalization and symptomatic burden.

[Cardiac stem cell therapy for the treatment of chronic stable angina refractory to conventional therapy. State of the art and current clinical experience of the San Raffaele Hospital of Milan, Italy]. / La terapia cellulare cardiaca nel trattamento dei pazienti con angina cronica refrattaria alle terapie convenzionali. Excursus sullo stato dell'arte e descrizione dell'esperienza clinica in corso all'Ospedale San Raffaele di Milano.

BACKGROUND: Cardiac stem cell therapy is a field of scientific research with the goal to translate into clinical benefit the initial findings obtained in basic research laboratories. We have moved into clinical trials in different disease categories: acute myocardial infarction, chronic stable angina refractory to conventional therapy and heart failure. So far we have faced with contradictory results. Some previous studies suggested that bone marrow cell injection may improve myocardial perfusion and left ventricular function in patients with chronic myocardial ischemia. METHODS: In this paper we present a brief review about stem cell use in clinical cardiology and describe our research protocol evaluating the effects of direct intramyocardial injection of autologous bone marrow cells (CD34+ selected cells versus all mononuclear cells) in patients with chronic myocardial ischemia. RESULTS: Preliminary results show that this procedure seems to be safe and generally well tolerated by patients. An improvement in symptoms, in the first 6 months, appears to be achieved in approximately 50% of patients, with concomitant improvement of quantitative scintigraphic stress test imaging. CONCLUSIONS: Before drawing any definitive conclusions, we need to wait for the end of enrollment and unblinding of study randomization.

Beneficial electrophysiological effects of trimetazidine in patients with postischemic chronic heart failure.

The aim of the study was to assess whether trimetazidine (TMZ) could affect dispersion of atrial depolarization and ventricular repolarization. Corrected QT interval (QTc), QTc dispersion (QTc-d), Tpeak-Tend, and Tpeak-Tend dispersion (Tpeak-Tend-d) were measured in 30 patients with chronic heart failure (CHF) before and 6 months after randomization to conventional therapy plus TMZ (17 patients) or conventional therapy alone (13 patients). After 6 months, QTc was significantly reduced in both groups, whereas QT-peak was increased only in control group. Tpeak-Tend-d decreased (from 63.53 +/- 24.73 to 42.35 +/- 21.07 milliseconds, P = .006) only in TMZ group. When subgrouped according to CHF etiology, only ischemic patients on TMZ showed Tpeak-Tend-d reduction (65.00 +/- 27.14 vs 36.67 +/- 11.55 milliseconds, P = .001 in ischemic patients; 60.00 +/- 20.00 vs 56.00 +/- 33.86 milliseconds, P = NS, in nonischemic). These electrophysiological properties indicate an undiscovered mechanism of action of TMZ, which could be useful in conditions at risk of major arrhythmias.

Long-term follow-up (four years) of unprotected left main coronary artery disease treated with paclitaxel-eluting stents (from the TRUE Registry).

AIMS: Limited data are available on the long-term outcome following PCI with paclitaxel-eluting stent (PES) implantation in patients with unprotected left main coronary artery (LMCA). The objective of this study was to evaluate "real world" long-term outcome following paclitaxel-eluting stent (PES) implantation for unprotected LMCA disease in patients enrolled in the TRUE registry. METHODS AND RESULTS: From March 2003 to October 2004, 93 consecutive patients (81.7% male) underwent PCI for unprotected LMCA disease. Surveillance angiography was performed at 6.8+/-3.3 months follow-up. The target lesion involved the distal LMCA in 68 (73.1%) patients. Double stenting techniques were performed in 46 (67.6%) distal LMCA, of these 50% were stented using the Crush technique. Clinical follow-up was complete in all patients with 85.8% angiographic follow-up rate. In-segment restenosis occurred in 16 (20.3%) patients and was focal in 72.4% of cases and significantly higher in patients with distal LMCA (36.8% vs. 13.6%, p<0.04). At a median follow-up of 1,450 days (IQR 1281-1595), the overall incidence of MACE was 35.5% and the TLR rate was 25.8% and significantly higher in patients with bifurcation stenting (32.3% vs. 8%, p<0.02). The estimated cardiac survival rate at one and four years was 96.7% and 93.3%, respectively. Total mortality rate was 14.1% and cardiac was 6.5%. There was one (1.1%) definite stent thrombosis (ST) and one (1.1%) probable ST. CONCLUSIONS: Treatment of unprotected LMCA disease with PES, after four years follow-up, appears to be safe and effective with a low rate of cardiac mortality and overall risk of ST. The need for target lesion revascularisation in 25.8% of patients highlights the need for more effective PCI especially in patients with distal LMCA disease.

Effects of metabolic approach in diabetic patients with coronary artery disease.

The pivotal therapeutic role of myocardial metabolic modulation in ischemic heart disease (IHD) is increasingly recognized. Among the others, inhibitors of free fatty acids (FFA) oxidation have been consistently shown to play an important role in the therapeutic strategy of IHD patients. Additionally, abnormalities of glucose homeostasis are consistently present in patients with IHD, definitely contributing to the progression of the primary disease. If not adequately treated, in most patients glucose metabolism abnormalities will heavily contribute to the occurrence of complications, of whom severe left ventricular dysfunction is at present one of the most frequent and insidious. Apart from a meticulous metabolic control of frank diabetes, special attention should be also paid to insulin resistance, a condition that is generally underdiagnosed as a distinct clinical entity. An important metabolic alteration in diabetic patients is the increase in free fatty acid concentrations and the increased muscular and myocardial free fatty acid uptake and oxidation. The increased uptake and utilization of free fatty acid and the reduced utilization of glucose as source of energy during stress and ischemia are responsible for the increased susceptibility of the diabetic heart to myocardial ischemia and to a greater decrease of myocardial performance for a given amount of ischemia compared to non diabetic hearts. In order to shift cardiac metabolism from FFA to preferential glucose utilization, the use of FFA inhibitors has been advocated. Among FFA inhibitors etomoxir, perhexiline, oxfenicine and trimetazidine have been evaluated. Among them, trimetazidine, specifically a 3-ketoacyl coenzyme A thiolase inhibitor, has been shown to improve overall glucose metabolism in IHD patients with diabetes and left ventricular dysfunction. The observed combined beneficial effects of FFA inhibitors on myocardial ischemia, left ventricular function and glucose metabolism, represent an additional advantage of these drugs, especially when myocardial and glucose metabolism abnormalities coexist. In this paper, the recent literature on the beneficial therapeutic effects of FFA oxidation inhibitors on myocardial ischemia, left ventricular dysfunction and glucose metabolism in patients with ischemic heart disease and abnormalities of carbohydrate metabolism is reviewed and discussed.

Multifocal, persistent cardiac uptake of [18-F]-fluoro-deoxy-glucose detected by positron emission tomography in patients with acute myocardial infarction.

BACKGROUND: Inflammation appears to be important in the pathogenesis of acute myocardial infarction (AMI). METHODS AND RESULTS: Cardiac [18-F]-fluoro-deoxy-glucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT)-scan was investigated in 12 fasting patients with first AMI (FAMI) single-vessel disease after successful primary percutaneous coronary intervention and at 9 weeks follow-up, and in 12 controls. The average FDG uptake (aFDGu) of the 28 left ventricular (LV) wall segments defined on the PET/CT images of the 12 FAMI patients was 1.28+/-0.57-fold higher than the activity present in the LV cavity. By contrast, the aFDGu of the 12 controls was 0.70+/-22 (p<0.001). The segmental aFDGu in the FAMI was multifocal in both the culprit and non-culprit segments; it was less than LV cavity activity in 38%, 1-2-fold greater in 51.8% and more than 2-fold greater in 10.2%. At follow-up, aFDGu was significantly increased in both culprit and non-culprit segments (1.69+/-1.15, p<0.001). Statistically significant differences between FAMI and controls patients were only found for interleukin-6 plasma levels on admission (11.3+/-7.7 pg/ml vs 2.2+/-1.3 pg/ml; p<0.004). CONCLUSION: Multifocal, non-infarct related, cardiac-FDG-uptake occurred immediately after AMI and persisted at follow-up. The cause of these striking and consistent findings is still speculative.

Clinical and angiographic follow-up of small vessel lesions treated with paclitaxel-eluting stents (from the TRUE Registry).

Several randomized trials have shown that sirolimus-eluting stents and paclitaxel-eluting stents (PES) are effective in reducing restenosis in respect to bare-metal stents, including the subset of small vessels. The objective of this study was to evaluate "real world" angiographic and clinical outcomes of a large series of patients enrolled in the TRUE registry and treated with PES for both small vessel and very small vessel lesions. A consecutive series of 675 patients (926 lesions) with reference vessel diameter <2.75 mm measured by quantitative coronary angiography analysis were analyzed. The primary end point was the rate of angiographic in-stent restenosis and 1-year major adverse cardiac events. In this study 390 lesions were identified as small vessel (reference vessel diameter >or=2.25 and <2.75 mm) and 536 lesions as very small vessel (reference vessel diameter <2.25 mm). Overall in-stent restenosis was 15.5% (n = 96). Compared with small vessel, the very small vessel lesions had more in-stent restenosis (21.7% vs 11.4%, p <0.001) and in-segment restenosis (29.3% vs 22.5%, p = 0.055). The majority of the restenotic lesions (n = 125) were focal (57%, n = 71). At 1 year, cardiac death was 1.6% (n = 11), acute myocardial infarction 0.5% (n = 4.), and the target lesion revascularization 12.8% (n = 86). Cumulative major adverse cardiac events rate was 17.3% (n = 119). The rate of definite and probable stent thrombosis was 0.9% (n = 8). In conclusion, in comparison with historical bare-metal stent controls, this large series of small vessel lesions treated with PES confirms previous results reporting the efficacy of PES in small vessels. The rate of subacute and late stent thrombosis was low in this subgroup of patients.