Effects of remote ischemic conditioning on kidney injury in at-risk patients undergoing elective coronary angiography (PREPARE study): a multicenter, randomized clinical trial.

The ability of remote ischemic preconditioning (RIPC) to prevent contrast-induced nephropathy (CIN) following percutaneous coronary angiography in at-risk patients is controversial. No evidence exists regarding potential RIPC positive effects on renal function and clinical outcomes in the long-term. The PREPARE study was a randomized, prospective, multicenter, and double-blinded trial. A total of 222 patients scheduled for coronary angiography and/or percutaneous transluminal coronary angioplasty with an estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2, or eGFR between 40 and 60 mL/min/1.73 m2 and two further risk factors were allocated to RIPC or control groups. Preventive measures were applied to all patients, including continuous intravenous saline infusion, withdrawal of nephrotoxic drugs, and limited volume of contrast medium. The primary endpoint, namely incidence of CIN, was 3.8% in the control group and 5.1% in the RIPC group (p = 0.74). The secondary endpoints, i.e., changes in serum creatinine and eGFR levels from baseline to 48 hours and from baseline to 12 months following contrast medium exposure, did not differ between both groups. The incidences of all major clinical events at 12 months were similar in both groups. In this population at risk of CIN, preventive strategies were associated with low CIN incidence. RIPC impacted neither the CIN incidence nor both the renal function and clinical outcomes at 1-year follow-up.

ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure.

Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF.

Remote Ischemic Conditioning in a Model of Severe Renal Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) injury is a leading cause of acute renal dysfunction. Remote ischemic conditioning (rIC) is known to protect organs exposed to I/R. We sought to investigate whether rIC would influence renal function recovery in a severe renal I/R injury rat model. Rats were randomly assigned to four experimental groups following median laparotomy and right nephrectomy: Sham (n = 6); 30-min left renal ischemia (RI) only (n = 20); RI + rIC (n = 20) (four 5-min cycles of limb ischemia interspersed with 5-min limb reperfusion during RI); and RI + erythropoietin pretreatment (EPO) (n = 20). Renal function was evaluated by assessing blood urea nitrogen (BUN) and serum creatinine (Cr) levels before surgery and after 1 day of reperfusion. All animals were monitored for 7 days for survival analysis. BUN and Cr baseline levels did not significantly differ between groups. At day 1, BUN and Cr were significantly higher than baseline values in all groups. BUN and Cr levels did not significantly differ at day 1 between RI and RI + rIC (P = 0.68). Conversely, EPO pretreatment injected 60 min before RI was associated with lower BUN and Cr levels compared with RI (P < 0.001 and P = 0.003, respectively) and RI + rIC (P < 0.001 and P = 0.001, respectively). In addition, 7-day survival rates were significantly higher in the Sham group (100%) compared with RI (50%; P = 0.039 vs. Sham) and RI + rIC (45%; P = 0.026 vs. Sham). Conversely, survival rate did not significantly differ between the Sham and RI + EPO groups (70%, P = 0.15). In conclusion, rIC affected neither acute renal dysfunction nor early mortality in a severe I/R renal injury rat model, contrary to EPO pretreatment.

Iron deficiency without anemia is responsible for decreased left ventricular function and reduced mitochondrial complex I activity in a mouse model.

BACKGROUND: Iron deficiency (ID), with or without anemia, is frequent in heart failure patients, and iron supplementation improves patient condition. However, the link between ID (independently of anemia) and cardiac function is poorly understood, but could be explained by an impaired mitochondrial metabolism. Our aim was to explore this hypothesis in a mouse model. METHODS AND RESULTS: We developed a mouse model of ID without anemia, using a blood withdrawal followed by 3-weeks low iron diet. ID was confirmed by low spleen, liver and heart iron contents and the repression of HAMP gene coding for hepcidin. ID was corrected by a single ferric carboxymaltose (FCM) injection (ID + FCM mice). Hemoglobin levels were similar in ID, ID + FCM and control mice. ID mice had impaired physical performances and left ventricular function (echocardiography). Mitochondrial complex I activity of cardiomyocytes was significantly decreased in ID mice, but not complexes II, III and IV activities. ID + FCM mice had improved physical performance, cardiac function and complex I activity compared to ID mice. Using BN-PAGE, we did not observe complex I disassembly, but a reduced quantity of the whole enzyme complex I in ID mice, that was restored in ID + FCM mice. CONCLUSIONS: ID, independently of anemia, is responsible for a decreased left ventricular function, through a reduction in mitochondrial complex I activity, probably secondary to a decrease in complex I quantity. These abnormalities are reversed after iron treatment, and may explain, at least in part, the benefit of iron supplementation in heart failure patients with ID.

Cardioprotective Role of Colchicine Against Inflammatory Injury in a Rat Model of Acute Myocardial Infarction.

BACKGROUND: Inflammation plays a crucial role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. A clinical trial has recently reported a smaller infarct size in a cohort of patients with ST-segment elevation myocardial infarction (MI) treated with a short colchicine course. The mechanism underlying colchicine-induced cardioprotection in the early MI phase remains unclear. We hypothesized that a short pretreatment with colchicine could induce acute beneficial effects by protecting the heart against inflammation in myocardial I/R injury. METHODS AND RESULTS: Rats were subjected to 40-minute left anterior descending coronary occlusion, followed by 120-minute reperfusion. Colchicine (0.3 mg/kg) or a vehicle was administered per os 24 hours and immediately before surgery. Infarct size was significantly reduced in the colchicine group (35.6% ± 3.0% vs 46.6% ± 3.3%, P < .05). The beneficial effects of colchicine were associated with an increased systemic interleukin-10 (IL-10) level and decreased cardiac transforming growth factor-ß level. Interleukin-1ß was found to increase in a "time of reperfusion"-dependent manner. Colchicine inhibited messenger RNA expression of caspase-1 and pro-IL-18. Interleukin-1ß injected 10 minutes prior to myocardial ischemia induced greater infarct size (58.0% ± 2.0%, P < .05) as compared to the vehicle. Colchicine combined to IL-1ß injection significantly decreased infarct size (47.1% ± 2.2%, P < .05) as compared to IL-1ß alone, while colchicine alone exhibited a significantly more marked cardioprotective effect than the colchicine-IL-1ß association. CONCLUSION: The cardioprotection induced by a short colchicine pretreatment was associated with an anti-inflammatory effect in the early reperfusion phase in our rat MI model.

Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart.

Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic-however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial IRI.

Influence of stentless versus stented valves on ventricular remodeling assessed at 6 months by magnetic resonance imaging and long-term follow-up.

BACKGROUND: To compare the effect of stented versus stentless bioprostheses on left ventricular remodeling and assess their impact on long-term survival. METHODS: From January 2002 to December 2009, 62 severe aortic stenosis patients without coronary artery disease were randomized for bioprosthetic aortic valve replacement. After randomization, a cross-over was possible based on intraoperative data. Ventricular remodeling was studied by cardiovascular magnetic resonance imaging six months after surgery. Long-term survival was assessed by telephone survey. RESULTS: Thirty-five patients received a porcine Mosaïc® Medtronic bioprosthesis (Stented Group; Medtronic, Minneapolis, MN, USA) inserted using the usual supra-annular technique and 27 received a porcine Freestyle® Medtronic bioprosthesis (Stentless Group) inserted in the subcoronary position. Mean age was 75±3 and 73±4 years in the stentless and stented group, respectively. Nine patients who should have been implanted with a stentless bioprosthesis received a stented bioprosthesis for anatomical reasons. At 6 months, the left ventricular mass (LVM) decreased significantly in both groups (Stentless Group: 214.6±56.1g and 156.3±23g and Stented Group: 237±75.7g and 181±53.3g, respectively after surgery and at 6 months), this decrease was significantly greater in the stentless group (p=0.026). Reserve and coronary flow were increased in both groups at 6 months. Mean follow-up duration was 6.6±3.0 years and 7.2±4.0 years in the stentless and stented group, respectively. The 5-year actuarial survival was 87.5±11.7% and 82.5±17.1% for the stentless and stented group, respectively (p=0.81). CONCLUSION: Porcine stentless prosthesis results in a better LVM regression than a stented valve at 6 months without changing the long-term survival.

Central Role of P2Y6 UDP Receptor in Arteriolar Myogenic Tone.

OBJECTIVE: Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT. APPROACH AND RESULTS: We measured MT and the associated pathway in mouse mesenteric resistance arteries using arteriography for small arteries and molecular biology. Of the P2 receptors in mouse mesenteric resistance arteries, mRNA expression of P2X1 and P2Y6 was dominant. P2Y6 fully sustained UDP/UTP-induced contraction (abrogated in P2ry6(-/-) arteries). Preventing nucleotide hydrolysis with the ectonucleotidase inhibitor ARL67156 enhanced pressure-induced MT by 20%, whereas P2Y6 receptor blockade blunted MT in mouse mesenteric resistance arteries and human subcutaneous arteries. Despite normal hemodynamic parameters, P2ry6(-/-) mice were protected against MT elevation in myocardial infarction-induced heart failure. Although both P2Y6 and P2Y2 receptors contributed to calcium mobilization, P2Y6 activation was mandatory for RhoA-GTP binding, myosin light chain, P42-P44, and c-Jun N-terminal kinase phosphorylation in arterial smooth muscle cells. In accordance with the opening of a nucleotide conduit in pressurized arteries, MT was altered by hemichannel pharmacological inhibitors and impaired in Cx43(+/-) and P2rx7(-/-) mesenteric resistance arteries. CONCLUSIONS: Signaling through P2 nucleotide receptors contributes to MT. This mechanism encompasses the release of nucleotides coupled to specific autocrine/paracrine activation of the uracil nucleotide P2Y6 receptor and may contribute to impaired tissue perfusion in cardiovascular diseases.

Remote ischemic preconditioning in aortic valve surgery: Results of a randomized controlled study.

BACKGROUND: Although remote ischemic preconditioning (RIPC) has emerged as an attractive strategy to reduce cardiac injury in patients undergoing diverse cardiac surgical procedures, it is unclear whether RIPC has protective effects in patients undergoing aortic valve replacement surgery without coronary artery bypass grafting (CABG). METHODS: Hence, 100 adult patients undergoing elective aortic valve replacement for aortic valve stenosis, without combined surgery with CABG, were prospectively randomly assigned in a 1:1 ratio to either the RIPC group or the control group. The RIPC group underwent three cycles of 5-min inflation to 200mmHg and 5-min deflation of an automated upper-arm cuff inflator after induction of anesthesia. The control group had a deflated cuff placed on upper arm for 30min. The primary endpoint was 72-h area under curve (AUC) for troponin I (cTnI). Secondary endpoints were 72-h AUC for creatine kinase-MB isoenzyme (CK-MB) release, incidence of acute kidney injury, extubation time, length of stay in intensive care unit, and simplified acute physiology score (SAPS II). RESULTS: There were no significant differences in cTnI AUC [195±190 arbitrary units (a.u.) in RIPC group vs. 169±117 a.u. in the control group; p=0.41] and CK-MB AUC between groups. None of the other secondary endpoints differed between groups. Acute kidney injury occurred in 12 patients (24.5%) in the control group and in 13 (26.0%) in the RIPC group (p=0.86). CONCLUSIONS: RIPC did not exhibit significant cardiac or kidney protective effects in patients undergoing aortic valve replacement surgery without CABG.

Predictive Factors of Pericardial Effusion After a First Acute Myocardial Infarction and Successful Reperfusion.

The aim of the study was to identify the determinants of pericardial effusion (PE) after a first myocardial infarction (MI). Cardiac magnetic resonance enables early analysis of multiple post-MI parameters; 193 patients with a first ST-elevation MI admitted to the Angers University Hospital (France) were enrolled prospectively. Cardiac magnetic resonance was performed at baseline (median of 5 days [4 to 7]) and repeated at a 3-month follow-up to investigate left ventricular (LV) volumes, LV ejection fraction, infarct size, microvascular obstruction (MVO), systolic wall stress (SWS), and PE presence and extent. A 1-year follow-up was also performed. Overall, 113 patients (58.5%) showed a PE with a median size of 31.6 ± 24.0 ml in the event that a PE was present. Patients with PE typically presented larger initial infarct sizes and LV volumes, and higher SWS, with more depressed LV ejection fraction and more frequent MVO and pleural effusions. Patients with PE exhibited higher rates of heart failure during hospitalization. At follow-up, there was no relevant PE, with no pericardiocentesis required. The multivariate analysis revealed SWS (odds ratio [OR] 1.092 [95% CI 1.007 to 1.184], p = 0.042), infarct size (OR 1.048 [95% CI 1.014 to 1.083], p = 0.003), and MVO extent (OR 1.274 [95% CI 1.028 to 1.579], p = 0.018) to be independent predictors for PE presence and volume. One patient died of LV free wall rupture during initial hospitalization, with only "small" PE found. In conclusion, infarct size, MVO, and SWS were independently related to PE presence and volume. Post-MI PE was found in 58.5% of cases, being regressive at follow-up. Among these patients with early reperfusion and optimal medical therapy, PE volume did not seem to be related to future clinical events.

Remote ischemic conditioning: Current clinical perspectives.

Remote ischemic conditioning (RIC) constitutes a promising method in which a tissue or organ is exposed to intermittent ischemia/reperfusion periods enabling it to provide protection to a distant target organ. RIC has been tested in various clinical settings through its simple application by means of intermittent inflation of a blood pressure cuff placed on a limb, primarily evaluating its potential abilities to decrease myocardial injury biomarkers. Its use on other organs, such as the kidneys or brain, has recently been a topic of research. To date, no study has yet been powerful enough to reach a conclusion on the potential benefit of RIC on clinical outcomes. The future role of RIC in the clinical arena could be clarified by the large phase III trials currently underway targeting major outcomes as primary endpoints.

Remote ischemic conditioning and cardioprotection: a systematic review and meta-analysis of randomized clinical trials.

Remote ischemic conditioning (RIC) represents an innovative cardioprotective method that has been investigated in numerous clinical studies providing miscellaneous results. This systematic review and meta-analysis sought to assess RIC-induced effects on myocardial injury biomarkers and clinical outcomes in clinical situations at risk of myocardial ischemia/reperfusion damage. PubMed and Cochrane databases were searched for randomized clinical trials testing any RIC protocol versus a control in a situation or procedure at risk of cardiac ischemia/reperfusion damage, including coronary angioplasty and cardiac or major vascular surgery. Data were collected from publications reporting biological markers of myocardial injury or clinical events, including major adverse cardiovascular and cerebral events (MACCE), all-cause mortality, myocardial infarction incidence, and repeat revascularization. Standardized mean difference (SMD) (continuous outcomes) and odds ratios (OR) (dichotomous outcomes) were compared between groups. Heterogeneity was investigated by means of meta-analysis regression. A total of 53 articles (44 studies) were identified by the search, with 5,317 patients included in the systematic meta-analysis. RIC significantly reduced troponin area under curve (AUC) (SMD -0.27, 95% confidence interval (CI): [-0.36, -0.18]; p < 0.01) and troponin peak (SMD: -0.22, 95% CI: [-0.30, -0.15]; p < 0.01). The same reduction was observed with creatine kinase MB (CK-MB) AUC and peak. Long-term MACCE and all-cause mortality were significantly lower in the RIC group (OR: 0.42, 95% CI [0.28, 0.64]; p < 0.01 vs. OR: 0.27, 95% CI [0.13, 0.58]; p < 0.01, respectively), as was myocardial infarction incidence (OR: 0.54, 95% CI [0.40, 0.73]; p < 0.01). We observed no difference regarding repeat revascularization. RIC appears to be an effective method for reducing ischemia/reperfusion myocardial injury, and our findings suggest that it may reduce long-term clinical events.

Safety and clinical outcome of erythropoiesis-stimulating agents in patients with ST-elevation myocardial infarction: a meta-analysis of individual patient data.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events. METHODS: A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with ≥30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality. RESULTS: Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (±131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06). CONCLUSIONS: Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients.

RISK and SAFE signaling pathway involvement in apolipoprotein A-I-induced cardioprotection.

UNLABELLED: Recent findings indicate that apolipoprotein A-I (ApoA-I) may be a protective humoral mediator involved in remote ischemic preconditioning (RIPC). This study sought to determine if ApoA-I mediates its protective effects via the RISK and SAFE signaling pathways implicated in RIPC. Wistar rats were allocated to one of the following groups. CONTROL: rats were subjected to myocardial ischemia/reperfusion (I/R) without any further intervention; RIPC: four cycles of limb I/R were applied prior to myocardial ischemia; ApoA-I: 10 mg/Kg of ApoA-I were intravenously injected prior to myocardial ischemia; ApoA-I + inhibitor: pharmacological inhibitors of RISK/SAFE pro-survival kinase (Akt, ERK1/2 and STAT-3) were administered prior to ApoA-I injection. Infarct size was significantly reduced in the RIPC group compared to CONTROL. Similarly, ApoA-I injection efficiently protected the heart, recapitulating RIPC-induced cardioprotection. The ApoA-I protective effect was associated with Akt and GSK-3ß phosphorylation and substantially inhibited by pretreatment with Akt and ERK1/2 inhibitors. Pretreatment with ApoA-I in a rat model of I/R recapitulates RIPC-induced cardioprotection and shares some similar molecular mechanisms with those of RIPC-involved protection of the heart.

What is the role of erythropoietin in acute myocardial infarct? Bridging the gap between experimental models and clinical trials.

Erythropoietin (EPO) is the main hormone that regulates erythropoiesis. Beyond its well-known hematopoietic action, EPO has diverse cellular effects in non-hematopoietic tissues. It has been shown to inhibit apoptosis by activating pro-survival pathways in the myocardium, to mobilize endothelial progenitor cells and to inhibit migration of inflammatory cells. EPO has also been shown to have potent pro-angiogenic properties. Numerous experimental data support the cardioprotective effects of EPO in animal models of acute myocardial infarct (AMI). However, these findings are not supported by recent clinical trials designed to investigate the safety and efficacy of EPO in patients with AMI. In this article, we begin by providing a comprehensive review of the cardioprotective effects of EPO in experimental animal models and the molecular mechanisms underlying these effects. We then discuss the EPO data obtained through clinical trials. We compare similarities and differences between the animal and human studies as well as between the different clinical studies in terms of sample size and study design including the dose, the route and the timing of administration as well as confounding factors such as comorbidities and concomitant treatments. Finally, we question the gap between the experimental and the translational clinical data and propose further developments to address these discrepancies and clearly evaluate the role of EPO in the clinical setting of MI.

Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum.

OBJECTIVES: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and calcification in the cutaneous, ophthalmologic, and vascular tissues. Cardiovascular manifestations such as peripheral arterial disease (PAD) are frequent in PXE. Because of the changes in the elastic properties and medial calcification of the arterial wall in PXE, the impact of the arterial remodeling on the ankle brachial index (ABI), a well-established diagnostic method for the detection and follow-up of PAD, remains to be determined in this disease. METHODS: This was a cross-sectional, comparative, open study, which took place at the PXE Consultation Center, University Hospital of Angers. The subjects were 53 patients (mean age, 49 ± 14 years; 35 females) with PXE clinically proven on the basis of established criteria (skin changes, angioid streaks, and skin biopsy). The ABI at rest, symptoms of intermittent claudication (IC), carotid intima-media thickness (IMT), carotid-femoral pulse wave velocity (c-f PWV), compliance (CC), and ß stiffness index were measured in a single-center cohort. RESULTS: Forty-five percent of the PXE patients had an ABI ≤0.90, but only one patient had an ABI >1.40. IC was found in 23% of the patients with an ABI ≤0.90. There were no significant differences between the patients with a low and normal ABI in terms of IMT (P = .566) or ß stiffness index (P = .194), but differences were significant for c-f PWV (P = .010) and CC (P = .011). Adjusted multivariate linear regression for the Framingham-Laurier score showed that patients with a low ABI had less compliant carotid arteries (B = 0.318, P = .039). CONCLUSIONS: PAD detected by a low ABI is very frequent in PXE, although with limited prevalence of symptomatic claudication. Unexpectedly, ABI was low in such calcifying PAD and associated with lower CC, independently of atherosclerosis risk factors. These findings demonstrate that PXE represents a unique monogenic model of PAD in which the specific arterial wall remodeling could change the diagnostic value of the ABI to detect PAD.

Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3ß signaling.

Recent studies reported cardioprotective effects of erythropoietin (EPO) against ischemia-reperfusion (I/R) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been reported to be impaired in diabetes and insulin resistance syndrome, we examined whether EPO-induced cardioprotection was maintained in rat models of type 1 diabetes and insulin resistance syndrome. Isolated hearts were obtained from three rat cohorts: healthy controls, streptozotocin (STZ)-induced diabetes, and high-fat diet (HFD)-induced insulin resistance syndrome. All hearts underwent 25 min ischemia and 30 min or 120 min reperfusion. They were assigned to receive either no intervention or a single dose of EPO at the onset of reperfusion. In hearts from healthy controls, EPO decreased infarct size (14.36 ± 0.60 and 36.22 ± 4.20% of left ventricle in EPO-treated and untreated hearts, respectively, p < 0.05) and increased phosphorylated forms of Akt, ERK1/2, and their downstream target GSK-3ß. In hearts from STZ-induced diabetic rats, EPO did not decrease infarct size (32.05 ± 2.38 and 31.88 ± 1.87% in EPO-treated and untreated diabetic rat hearts, respectively, NS) nor did it increase phosphorylation of Akt, ERK1/2, and GSK-3ß. In contrast, in hearts from HFD-induced insulin resistance rats, EPO decreased infarct size (18.66 ± 1.99 and 34.62 ± 3.41% in EPO-treated and untreated HFD rat hearts, respectively, p < 0.05) and increased phosphorylation of Akt, ERK1/2, and GSK-3ß. Administration of GSK-3ß inhibitor SB216763 was cardioprotective in healthy and diabetic hearts. STZ-induced diabetes abolished EPO-induced cardioprotection against I/R injury through a disruption of upstream signaling of GSK-3ß. In conclusion, direct inhibition of GSK-3ß may provide an alternative strategy to protect diabetic hearts against I/R injury.

Speckle tracking imaging improves in vivo assessment of EPO-induced myocardial salvage early after ischemia-reperfusion in rats.

A noninvasive assessment of infarct size and transmural extension of myocardial infarction (TEMI) is fundamental in experimental models of ischemia-reperfusion. Conventional echocardiography parameters are limited in this purpose. This study was designed to examine whether speckle tracking imaging can be used in a rat model of ischemia-reperfusion to accurately detect the reduction of infarct size and TEMI induced by erythropoietin (EPO) as early as 24 h after reperfusion. Rats were randomly assigned to one of three groups: myocardial infarction (MI)-control group, 45 min ischemia followed by 24 h of reperfusion; MI-EPO group, similar surgery with a single bolus of EPO administered at the onset of reperfusion; and sham-operated group. Short-axis two-dimensional echocardiography was performed after reperfusion. Global radial (GS(r)) and circumferential (GS(cir)) strains were compared with infarct size and TEMI assessed after triphenyltetrazolium chloride staining. As a result, ejection fraction, shortening fraction, GS(r), and GS(cir) significantly correlated to infarct size, whereas only GS(r) and GS(cir) significantly correlated to TEMI. EPO significantly decreased infarct size (30.8 + or - 3.5 vs. 56.2 + or - 5.7% in MI-control, P < 0.001) and TEMI (0.37 + or - 0.05 vs. 0.77 + or - 0.05 in MI-control, P < 0.001). None of the conventional echocardiography parameters was significantly different between the MI-EPO and MI-control groups, whereas GS(r) was significantly higher in the MI-EPO group (29.1 + or - 4.7 vs. 16.4 + or - 3.3% in MI-control; P < 0.05). Furthermore, GS(cir) and GS(r) appeared to be the best parameters to identify a TEMI >0.75 24 h after reperfusion. In conclusion, these findings demonstrate the usefulness of speckle tracking imaging in the early evaluation of a cardioprotective strategy in a rat model of ischemia-reperfusion.