Search

Background Adjustment of cardiac dimensions by measures of body size appears intuitively convincing and in patients with aortic stenosis, aortic valve area (AVA) is commonly adjusted by body surface area (BSA). However, there is little evidence to support such an approach. Objective To identify the adequate measure of body size for the adjustment of aortic stenosis severity. Methods Parameters of aortic stenosis severity (jet velocity, mean pressure gradient (MPG) and AVA) and measures of body size (height, weight, BSA and body mass index (BMI)) were analysed in 2843 consecutive patients with aortic stenosis (jet velocity >= 2.5 m/s) and related to outcomes in a second cohort of 1525 patients from the Simvastatin/Ezetimibe in Aortic Stenosis (SEAS) study. Results Whereas jet velocity and MPG were independent of body size, AVA was significantly correlated with height, weight, BSA and BMI (Pearson correlation coefficient (r) 0.319, 0.281, 0.317 and 0.126, respectively, all p

We thank Dr. Rashid and colleagues for their interest in our paper. Similar to other studies, recently reviewed by Rashid et al. [(1)][1] in a meta-analysis, the patients in our study were not systematically readmitted for follow-up, and we obtained documentation of the neurological work-up.

Objective To obtain reference values of aortic valve area (AVA) in a large population and to infer the risk of overestimating aortic stenosis (AS) when focusing on flow-corrected indices of severity. Methods We prospectively measured indices of AS in all consecutive echocardiograms performed in a large referral cardiac imaging laboratory for 1 year. We specifically analysed the distribution of AVA, indexed AVA and velocity ratio (Vratio) in patients with and without AS, the latter defined as the coexistence of valvular outflow obstruction (Vmax ≥2.5 m/s) and morphological findings of valve degeneration. Results 16 156 echocardiograms were analysed, 14 669 of which did not show valvular obstruction (peak jet velocity

Atrial Differences in Endothelial Damage, Leukocyte and Platelet Activation Background Thrombi form mainly in the left rather than the right atria of patients with atrial fibrillation (AF), the reason of this predilection being unknown. Objective The purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation, and tissue factor activity occur in patients with AF. Methods Twenty-two patients (16 men, 6 women; age 56 ± 8 years; 16 paroxysmal AF, 6 persistent AF) with AF undergoing pulmonary vein isolation were investigated. Blood samples from the left and the right atrium were obtained at the start of the procedure. Microparticles (MPs) released by apoptotic/stimulated cells were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase and tissue factor assays and their cellular origin were determined (endothelium, platelet, leukocyte). Platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet P-selectin (CD62P), active glycoprotein IIb/IIIa receptor (PAC-1). Platelet aggregation was evaluated using ADP, TRAP and collagen-induced whole blood aggregometry. Results There were no atrial-specific differences in the levels of total procoagulant MPs, leukocyte-derived-MPs or platelet-derived MPs. Conversely, endothelial-derived MPs and tissue factor activity and collagen-induced platelet aggregation were slightly elevated in the right atrium (P < 0.05). Conclusions Our data show no evidence for increased thrombogenic status in the left atrium that would account for its greater propensity for thrombus formation in patients with AF.

Background: We examined whether undetectable levels of high sensitivity cardiac Troponin (hs cTn) can be used to rule out acute myocardial infarction (AMI) with a single blood draw at presentation to the emergency department (ED). Methods and results: In a prospective multicenter study we used 4 different hs cTn assays (hs cTnT Roche and hs cTnI Siemens hs cTnI Beckman Coulter and hs cTnI Abbott) in consecutive patients presenting with acute chest pain. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available data including serial hs cTnT levels. Mean follow up was 24 months. Among 2072 consecutive patients with available hs cTnT levels 21 had an adjudicated diagnosis of AMI. Among AMI patients 98.2 had initially detectable levels of hs cTnT (sensitivity 98.2 95CI 96.3 99.2 negative predictive value (NPV) 98.6 95CI 97.0 99.3). Undetectable levels of hs cTnT ruled out AMI in 26.5 of patients at presentation. The NPV was similar with the three hs cTnI assays: among 1180 consecutive patients with available hs cTnI (Siemens) the NPV was 98.8; among 1151 consecutive patients with available hs cTnI (Beckman Coulter) the NPV was 99.2; among 1567 consecutive patients with available hs cTnI (Abbott) the NPV was 100.0. The percentage of patients with undetectable levels of hs cTnI was similar among the three hs cTnI assays and ranged from 11.4 to 13.9. Conclusions: Undetectable levels of hs cTn at presentation have a very high NPV and seem to allow the simple and rapid rule out of AMI. This criteria applies to much more patients with hs TnT as compared to the investigated hs cTnI assays. © 2013 Elsevier Ireland Ltd. All rights reserved.

We thank Bartoletti et al for their comments on our novel approach for ablation of persistent atrial fibrillation (AF) targeting selective atrial low-voltage sites.1 Here we provide answers to their comments: 1. Left atrial substrate characterization using bipolar voltage mapping has been mostly performed in sinus rhythm (SR). However, only a single study compared high-density voltage maps of the left atrium during SR in patients (1) without history of AF versus (2) patients with paroxysmal AF versus (3) persistent AF, versus long-persistent AF.2 In this study, the authors report in patients without history of AF, bipolar voltage values during SR that exceed >2.5mV at all left atrial sites.2 In contrast, the bipolar voltages during SR were significantly reduced in patients with history of AF.2 Atrial arrhythmias develop at slow-conduction sites with increased myocardial fibrosis.1 Yet, these regions are not completely fibrotic or electrically silent. To our knowledge, no sharp cutoff value for low voltage has been found that includes all proarrhythmic sites and excludes normal tissue. During substrate mapping of scar-related ventricular tachycardias, the bipolar voltage threshold on …

Background— Complex-fractionated atrial electrograms and atrial fibrosis are associated with maintenance of persistent atrial fibrillation (AF). We hypothesized that pulmonary vein isolation (PVI) plus ablation of selective atrial low-voltage sites may be more successful than PVI only. Methods and Results— A total of 85 consecutive patients with persistent AF underwent high-density atrial voltage mapping, PVI, and ablation at low-voltage areas (LVA70% of AF cycle length on a single electrode (fractionated activity) or multiple electrodes around the circumferential mapping catheter (rotational activity) or discrete rapid local activity (group I). The procedural end point was AF termination. Arrhythmia freedom was compared with a control group (66 patients) undergoing PVI only (group II). PVI alone was performed in 23 of 85 (27%) patients of group I with low amount (P P =0.42). Conclusions— Ablation of sites with distinct activation characteristics within/at borderzones of LVA in addition to PVI is more effective than conventional PVI-only strategy for persistent AF. PVI only seems to be sufficient to treat patients with left atrial low voltage

There is limited data on prognosis after percutaneous coronary intervention (PCI) for coronary chronic total occlusions (CTO) in the era of drug-eluting stents (DES). This study investigates the specific contribution of CTO recanalization to the survival benefit of complete revascularization. Consecutive patients who underwent PCI of a CTO at our center between 01/2005 and 12/2013 were followed for a median of 2.6 years (interquartile range 1.1–3.1 years). All-cause mortality was compared between patients with successful and failed PCI of CTO without and with adjustment for pertinent co-variables by the Cox models. The study comprised 2002 patients with attempted PCI of CTO (mean age 65.2 ± 11 years, 17 % female), 82 % had multivessel disease. The CTO PCI was successful in 1662 (83 %) patients with a DES rate of 94 %. All-cause mortality was significantly lower in patients with successful PCI of CTO compared to failed PCI of CTO (15.3 vs. 25.9 % at 4 years; P

Background Experimental data suggest that use of cryoablation in pulmonary vein isolation (PVI) is associated with less cell damage and less thrombus formation compared to radiofrequency (RF) energy. Objective The purpose of this study was to test the hypothesis that cryoablation significantly reduces markers of cell damage, platelet activation, and inflammation in patients undergoing PVI for treatment of atrial fibrillation (AF). Methods Sixty patients with symptomatic drug-resistant AF (age 56 ± 9 years, 48 males, 38 with paroxysmal AF) were randomly assigned to undergo PVI using either an open irrigated-tip RF catheter or a cryoballoon. Markers of cell damage (high-sensitive troponin T [hs-TnT], microparticles), platelet activation (platelet reactivity by aggregometry, expression of platelet surface proteins P-selectin and activated glycoprotein [GP] IIb/IIIa), and inflammatory response (high-sensitive C-reactive protein [hs-CRP]) were determined before and up to 48 hours after the procedure. Results PVI resulted in a significant rise in hs-TnT, microparticles, markers of platelet activation, and hs-CRP over time, with distinct temporal patterns for each parameter. However, after Bonferroni correction for repeated measurements, no significant differences were noted in these parameters between patients treated with cryoablation or RF energy. Procedural time was significantly shorter in patients treated with cryoballoon (177 ± 30 minutes vs 200 ± 46 minutes, P = .03), with no differences in fluoroscopic time, periprocedural complications, or success rate. Conclusion Cryoablation and RF energy result in a comparable rise of markers of cell damage, platelet activation and inflammatory response. The data do not support the concept of an improved safety profile for cryoablation in PVI.

Bioprosthetic valve replacement is the treatment of choice in older patients with symptomatic severe aortic valve disease. Thrombosis of bioprosthetic valves has been considered a rare complication; however, in the presence of valvular obstruction, therapeutic consequences for the individual patient may be dramatic including repeat valve replacement or thrombolysis. We therefore evaluated oral anticoagulation with phenprocoumon as an alternative treatment for obstructive thrombosis of bioprosthetic valves. Six of 470 patients who had received a single stented bioprosthetic aortic valve from January 2007 through December 2008 at our hospital presented with obstructive bioprosthetic valve thrombosis within 14 months postoperatively. All 6 patients (1% of study population) had received a porcine valve (p = 0.1 vs pericardial), were hemodynamically stable, were in sinus rhythm, and were taking acetylsalicylic acid 100 mg/day. Echocardiography showed an increase in mean pressure gradient early postoperatively from 23.3 ± 4 to 57.0 ± 10 mm Hg (p0.001). Five patients were started on phenprocoumon and followed for 114 ± 54 days, when mean pressure gradient had returned to 23.5 ± 6 mm Hg. No adverse events were observed during that period. One patient presenting with dyspnea and fever underwent emergency repeat valve replacement for suspected endocarditis, with histology showing long-term thrombosis of the explanted valve. In conclusion, oral anticoagulation with phenprocoumon represents a safe and effective treatment in clinically stable patients with obstructive thrombosis of bioprosthetic aortic valves, thus obviating repeat valve surgery or thrombolysis.

Pressure-Guided Cryoballoon Pulmonary Vein Isolation.Background: Pulmonary vein (PV) isolation using a balloon-mounted cryoablation system is a new technology for the percutaneous treatment of atrial fibrillation (AF). Complete PV occlusion during balloon ablation has been shown to predict successful electrical isolation. The aim of this study was to correlate mechanical PV occlusion with changes in a pressure curve recorded at the distal tip of the cryoballoon catheter. Methods and Results: We analyzed 51 PVs in 12 patients (61 ± 6 years old) with paroxysmal AF. At first, PV occlusion via the cryoballoon was documented by changes in the pressure curve. Once the PV is occluded, the pressure curve registered in the vein converts from a left atrial pressure curve to a pulmonary artery pressure curve: the PV wedge curve. Occlusion was then confirmed by transesophageal echocardiography (TEE). Following 2 cryoablation applications, electrical PV isolation was assessed with a circumferential mapping catheter. Under the exclusive guidance of changes in the pressure curve at the tip of the cryoballoon, mechanical occlusion confirmed by TEE was achieved in 47 of 51 PVs (92%). Three PVs required further TEE guidance to achieve occlusion. All 50 occluded veins were electrically isolated after cryoablation. One right inferior vein, which could not be occluded with the balloon, displayed conduction post cryoablation and was isolated by focal ablation. Conclusions: Occlusion and electrical isolation of PVs during cryoballoon ablation can be predicted by the appearance of a PV wedge curve at the tip of the catheter. This new straightforward parameter may facilitate the procedure. (J Cardiovasc Electrophysiol, Vol. 21, pp. 120-125, February 2010)

Background: More extensive ablation strategies for the treatment of atrial fibrillation (AF) have increased success rates but are associated with new and sometimes serious complications. We describe a new complication after extensive radiofrequency (RF) ablation in the left atrium (LA) for persistent AF. Methods and Results: Electroanatomic guided circumferential ablation around both ipsilateral pulmonary veins (PV) was performed with the endpoint of complete conduction block. When necessary, supplementary RF applications were added, including ablation of complex fractionated potentials and/or isolation of other thoracic veins and/or linear left atrial lesions. RF energy was delivered via an irrigated tip catheter with a maximum power of 30–35 W. Four out of 120 patients undergoing extensive RF ablation for persistent AF (including two patients with additional LA substrate modification) developed dyspnea, bilateral pulmonary edema, and signs of a systemic inflammatory response syndrome (SIRS) (rise in body temperature, leukocyte count, and C-reactive protein (CRP levels) 18–48 hours after the procedure. There were no signs of PV stenosis, focal lung injury, left ventricular dysfunction, circulatory failure, or infection. All patients had complete recovery with supportive therapy within 3–4 days after the onset of symptoms. Conclusions: Extensive LA radiofrequency ablation bears the risk of a severe pulmonary edema. Although the precise mechanism is elusive, clinical features point toward a systemic inflammatory response.

The present study tests the consistency of echocardiographic criteria for the grading of aortic valve stenosis.Current guidelines/recommendations define severe stenosis as an aortic valve area (AVA)1 cm2 (or0.6 cm2 adjusted for body surface area), mean pressure gradient (DeltaPm)40 mmHg, or peak flow velocity (Vmax)4 m/s. We tested the consistency of the three criteria for the grading of aortic valve stenosis in 3483 echocardiography studies performed in 2427 patients with normal left ventricular (LV) systolic function and a calculated AVA ofor =2 cm2. We calculated curve fits for the relationship between AVA and DeltaPm using the Gorlin equation and between AVA and Vmax based on the continuity equation for our study population. An AVA of 1.0 cm2 correlated to a DeltaPm of 21 mmHg and a Vmax of 3.3 m/s. Conversely, a DeltaPm of 40 mmHg corresponds to an AVA of 0.75 cm2 and a Vmax of 4.0 m/s to an AVA of 0.82 cm2. Consequently, severe stenosis was diagnosed in 69% of patients based on AVA, 45% on Vmax, and 40% on DeltaPm. Stroke volume was lower in inconsistently graded patients (65 +/- 11 mL vs. consistently graded: 70 +/- 14 mL, P0.001).The criteria for the grading of aortic stenosis are inconsistent in patients with normal systolic LV function. On the basis of AVA, a higher proportion of patients is classified as having severe aortic valve stenosis compared with mean pressure gradient and peak flow velocity. Discrepant grading in these patients may be partly due to reduced stroke volume.

Obstructive thrombosis of bioprosthetic valves is considered rare but may have dramatic consequences for the individual patient including repeat valve replacement, thrombolysis, or long-term anticoagulation. Whether the risk of obstructive thrombosis is dependent on the type of bioprosthesis (porcine versus bovine pericardial) is uncertain.Between 2007 and 2012 a total of 1751 patients received a single stented bioprosthesis in the aortic valve position, 749 (43%) were porcine and 1002 (57%) bovine. During a mean follow-up of 3.4±1.9years, obstructive thrombosis (identified by an increase in mean pressure gradient≥20mm Hg or a decrease in velocity ratio≥0.05 and confirmed by either ECG-gated computer tomography, a return to baseline of stenosis parameters under treatment with a vitamin K antagonist, or histology in case of reoperation) was diagnosed in 17 patients with a porcine (2.3%) and none with a bovine valve (p0.001). The cumulative probability of developing an obstructive thrombosis was significantly higher in patients with a porcine valve (p0.001 log-rank test). Adjusting for differences in baseline variables and stratification by the estimated propensity score showed that strata with a high probability of receiving a bovine valve had the highest number of obstructive thrombosis in porcine valves. These findings were further confirmed in a Poisson model and a competing risk model including all-cause mortality. Treatment of obstructive thrombosis with a vitamin K antagonist was safe and effective in 15/17 patients.The porcine valve type is an independent predictor of obstructive thrombosis in bioprostheses in the aortic position.

Objective Doppler-derived flow velocity measured by transesophageal echocardiography (TEE) may overestimate pulmonary vein stenosis. We hypothesized that combining peak velocity with a stenotic flow pattern improves diagnosis compared with magnetic resonance imaging (MRI). Methods TEE and MRI were performed in 44 patients 19 ± 11 months after radiofrequency catheter ablation. Pulmonary vein stenosis was defined by a peak velocity of 110 cm/s or more plus a stenotic flow pattern (turbulence and reduced flow variation) on TEE and a lumen reduction of more than 50% on MRI. Results In all, 175 pulmonary veins were studied. MRI showed 7 cases of pulmonary vein stenosis that were correctly identified by TEE. In addition, TEE criteria for pulmonary vein stenosis were met in 4 pulmonary veins that did not show obstruction on MRI. In all, 5 pulmonary veins with normal appearance on MRI had peak velocity of 110 cm/s or more with normal flow pattern. Conclusions TEE Doppler measurements can be reliably used to detect or exclude significant pulmonary vein stenosis if the diagnosis is restricted to a combination of elevated peak velocity (≥ 110 cm/s) with turbulence and little flow variation.

To evaluate the usefulness of velocity ratio (VR) in patients with low gradient severe aortic stenosis (LGSAS) and preserved EF.LGSAS despite preserved EF represents a clinically challenging entity. Reliance on mean pressure gradient (MPG) may underestimate stenosis severity as has been reported in the context of paradoxical low flow, LGSAS. On the other hand, grading of stenosis severity by aortic valve area (AVA) may overrate stenosis severity due to erroneous underestimation of LV outflow tract (LVOT) diameter, small body size or inconsistencies in cut-off values for severe stenosis. We hypothesised that VR may have conceptual advantages over MPG and AVA, predict clinical outcomes and thereby be useful in the management of patients with LGSAS.Patients from the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study with an AVA1.0 cm(2), MPG≤40 mm Hg and EF≥55% and asymptomatic at baseline were stratified according to VR with a cut-off value of 0.25. Outcomes were evaluated according to aortic valve-related events and cardiovascular death.Of 435 patients with LGSAS, 197 (45%) had VR0.25 suggesting severe and 238 (55%) had VR≥0.25 suggesting non-severe stenosis. Aortic valve-related events (mean follow-up 42±14 months) were more frequent in patients with VR0.25 (57% vs 41%; p0.001) as was cardiovascular death within the first 24 months (p0.05). In multivariable Cox regression analysis, MPG was the strongest independent predictor of aortic valve events (p0.001) followed by VR (p0.02). Adjusting AVA by VR increased predictive accuracy for aortic valve events (area under the receiver operating curve 0.62 (95% CI 0.57 to 0.67) vs 0.56 (95% CI 0.51 to 0.61) for AVA, p=0.02) with net reclassification improvement calculated at 0.36 (95% CI 0.17 to 0.54, p0.001). VR did not improve the prediction of clinical events by MPG.In the difficult setting of LGSAS, VR shows a strong association with valve-related events and-although not outperforming MPG-may be particularly useful in guiding clinical management.NCT00092677.

Objectives. We investigated the influence of lipoprotein(a) [Lp(a)] serum levels on different endothelium-dependent vasodilator stimuli representing different mechanisms of endothelium-dependent vasodilation. Background. Lp(a) is an independent predictor for the development and progression of coronary artery disease. Impairment of endothelium-dependent vasodilation of epicardial arteries has been shown in patients with high levels of Lp(a). Methods. In 108 patients with angiographically normal or minimally diseased coronary vessels, vasomotor responses to acetylcholine, cold pressor testing, increased blood flow and nitroglycerin were assessed. Results. Lp(a) levels ≥30 mg/dl were associated with significant dose-dependent enhancement of the vasoconstrictor response to acetylcholine [receptor-mediated vasodilation, p = 0.002; acetylcholine 10−6mol/liter, −29 ± 21% vasoconstriction with Lp(a) levels ≥30 mg/dl vs. −5.6 ± 25% with Lp(a) levels

Increased life expectancy has led to a higher prevalence of calcific aortic valve disease. Both ends of the disease spectrum-sclerosis of the aortic valve without hemodynamic obstruction and the late stage of aortic valve stenosis (AS)-have been associated with increased morbidity and mortality. This raises the question of the prognostic contribution of atherosclerotic diseases and other comorbidities as opposed to the hemodynamic effect of obstructive AS. Hence, the evaluation of asymptomatic patients with mild or moderate AS without comorbidities is of major interest. In the Simvastatin and Ezetimibe in Aortic Stenosis study, with the exception of hypertension, comorbidities were excluded, thus allowing an analysis of the effect of pure AS as well as the effect of hypertension on the progression and outcome of AS. We discuss the results that emerged from this large European prospective study and relate these to the published literature.

Thrombi form mainly in the left rather than the right atria of patients with atrial fibrillation (AF), the reason of this predilection being unknown.The purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation, and tissue factor activity occur in patients with AF.Twenty-two patients (16 men, 6 women; age 56 ± 8 years; 16 paroxysmal AF, 6 persistent AF) with AF undergoing pulmonary vein isolation were investigated. Blood samples from the left and the right atrium were obtained at the start of the procedure. Microparticles (MPs) released by apoptotic/stimulated cells were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase and tissue factor assays and their cellular origin were determined (endothelium, platelet, leukocyte). Platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet P-selectin (CD62P), active glycoprotein IIb/IIIa receptor (PAC-1). Platelet aggregation was evaluated using ADP, TRAP and collagen-induced whole blood aggregometry.There were no atrial-specific differences in the levels of total procoagulant MPs, leukocyte-derived-MPs or platelet-derived MPs. Conversely, endothelial-derived MPs and tissue factor activity and collagen-induced platelet aggregation were slightly elevated in the right atrium (P0.05).Our data show no evidence for increased thrombogenic status in the left atrium that would account for its greater propensity for thrombus formation in patients with AF.

BACKGROUND Current guidelines require a change (rise and/or fall) in levels of cardiac troponin (cTn) for the diagnosis of acute myocardial infarction (AMI). It is unknown whether absolute or relative changes provide higher accuracy when using high sensitivity cTnI assays. METHODS In a prospective international multicentre study we assessed the diagnostic accuracy of early absolute and relative changes in cTnI measured with two novel pre commercial high sensitivity assays (Siemens and Beckman Coulter) in 943 unselected patients presenting to the ED with suspected AMI. The final diagnosis of AMI was adjudicated using all available data including serial hs cTnT levels by two independent cardiologists. RESULTS The diagnostic accuracy of absolute changes in the diagnosis of AMI as quantified by the area under the receiver operating characteristics curve (AUC) was very high (e.g. at 2h Siemens high sensitivity cTnI AUC 0.93 95Cl 0.90 0.96; Beckman Coulter high sensitivity cTnI AUC 0.93 95Cl 0.90 0.96) and superior to relative changes at all time points (p

Background Smoking is a primary risk factor for coronary and peripheral vascular disease. Because the endothelium is a principal target for the effects of risk factors early in the pathogenesis of atherosclerosis, we investigated whether long-term smoking is associated with impaired endothelial vasodilator function of epicardial conductance vessels regardless of the presence or absence of atherosclerotic lesions. Methods and Results Using quantitative coronary angiography, we measured epicardial artery diameter at baseline, after maximal increases in coronary blood flow that caused flow-mediated dilation (which is strictly endothelium dependent), and after intracoronary injection of nitroglycerin (an endothelium-independent dilator) in 96 patients. Endothelium-dependent, flow-mediated dilation was significantly ( P P P P r =−.82, P P Conclusions Long-term cigarette smoking is associated with impaired endothelium-dependent coronary vasodilation regardless of the presence or absence of coronary atherosclerotic lesions.

Aims In aortic valve stenosis (AS), having a small aortic root may influence both the assessment of AS severity and the treatment strategy. The aim was to test the prognostic implications of having a small aortic root in AS within a large prospective study. Methods and results We used data from 4.3-year follow-up of 1560 patients with asymptomatic, initially mostly moderate AS enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study. A small aortic root was defined as inner aortic sinotubular junction diameter indexed for body height

Response to Letters Regarding Article, "Outcome of Patients With Low-Gradient "Severe" Aortic Stenosis and Preserved Ejection Fraction"

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area 2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area 2 and mean gradient ≤40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm 2 ; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P P =0.37; major cardiovascular events, 50.9% versus 48.5%, P =0.58; cardiovascular death, 7.8% versus 4.9%, P =0.19). Low-gradient severe stenosis patients with reduced stroke volume index (≤35 mL/m 2 ; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P =0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

On echocardiography approximately one-third of patients with severe aortic valve stenosis based on aortic valve area (AVA1.0 cm(2)) demonstrate a non-severe mean pressure gradient (DeltaPm;or =40 mm Hg) despite apparently normal left ventricular function. It has been suggested that inconsistent echocardiographic grading may be due to 'paradoxical' low stroke volume. However, the correct echocardiographic assessment of stroke volume hinges on the often problematic measurement of the left ventricular outflow tract (LVOT) diameter.To investigate whether inconsistent grading and reduced stroke volume persist when the quantification of aortic valve stenosis is based on cardiac catheterisation which is independent of LVOT measurements.333 consecutive patients underwent cardiac catheterisation within 30 days after their index echocardiography showing an AVAor =2 cm(2) and shortening fractionor =30%. On invasive testing 85 patients (26%) demonstrated inconsistent (AVA1 cm(2) and DeltaPmor =40 mm Hg) and 153 (46%) consistent grading (AVA1 cm(2) and DeltaPm40 mm Hg) with the remainder (28%) presenting with a calculated AVAor =1 cm(2). Inconsistently graded patients were older (71 vs 67 years, p0.006) with no differences in sex or body surface area between groups. Stroke volume and stroke volume index were significantly lower in inconsistently graded patients (63+/-14 vs 73+/-18 ml and 35+/-7 vs 39+/-7 ml/m(2), respectively, both p0.001). However, 41/85 (48%) of inconsistently graded patients had a normal stroke volume index35 ml/m(2).In the framework of current guidelines inconsistent grading of aortic valve stenosis is common, extends to cardiac catheterisation and is only partially explained by low stroke volume despite apparently normal left ventricular systolic function.

Background: Pulmonary vein (PV) isolation using a balloon-mounted cryoablation system is a new technology for the percutaneous treatment of atrial fibrillation (AF). Transesophageal echocardiography (TEE) allows real-time visualization of cryoballoon positioning and successful vein occlusion via color Doppler. We hypothesized that PV mechanical occlusion monitored with TEE could predict effective electrical isolation. Methods: We studied 124 PVs in 30 patients. Under continuous TEE assessment, a cryoballoon was placed in the antrum of each PV aiming for complete PV occlusion as documented by color Doppler. At the end of the procedure, PV electrical isolation was evaluated using a circumferential mapping catheter. Results: Of the 124 PVs studied, 123 (99.2%) could be visualized by TEE: the antrum was completely visualized in 80 of them (64.5%), partially in 36 (29.0%), and only disappearance of proximal flow could be observed in the remaining 7 PVs (5.7%). Vein occlusion could be achieved in 111 of the 123 (90.2%) visualized PVs. Postinterventional mapping demonstrated electrical isolation in 109 of 111 occluded PVs (positive predictive value 98.2%) and only in 1 of 12 nonoccluded PVs (negative predictive value 91.7%, P < 0.001). After a mean follow-up of 7.4 ± 3.7 months, 73.3% of patients remained in sinus rhythm without antiarrhythmic drugs. Conclusion: Color Doppler documented PV occlusion during cryoballoon ablation can predict effective electrical isolation.

Aims An increasing body of evidence has demonstrated the essential role of inflammation in the genesis and maintenance of atrial fibrillation (AF). The aim of the present study was to investigate whether success or failure of electrical pulmonary vein isolation (PVI) in patients with AF is related with the presence of a pre-ablative inflammatory state as determined by known clinical parameters and conventional markers of inflammation including high-sensitivity C-reactive protein, white blood cell (WBC) count, and fibrinogen. Methods and results Seventy-two patients with paroxysmal (64%) or persistent AF (36%) underwent successful electrical PVI. The mean duration of arrhythmia was 5.5 ± 2.9 years. After a mean follow-up period of 12.5 ± 5.7 months, 44 patients (61%) were in sinus rhythm. In univariate Cox proportional hazard regression analysis, hypertension, body mass index (BMI), left ventricular ejection fraction, left ventricular end-diastolic diameter, left atrial diameter (LAD), WBC count, and high-sensitivity C-reactive protein were significantly associated with AF recurrence ( P < 0.05). In multivariate Cox proportional hazard regression analysis, hypertension [hazard ratio (HR) 3.127; 95% confidence interval (CI) 1.269–7.706, P = 0.013], LAD (HR 1.077; 95% CI 1.014–1.144, P = 0.015), and WBC count (HR 1.423; 95% CI 1.067–1.897, P = 0.016) were independent pre-ablative predictors of AF recurrence following PVI. Conclusion Conventional markers of the inflammatory cascade such as WBC count and high-sensitivity C-reactive protein as well as elements of the metabolic syndrome such as hypertension and increased BMI were significantly associated with AF recurrence. The impact of a pre-ablative inflammatory state in the overall success rate of PVI needs further elucidation.

In their letter regarding our article,1 Drs Kriatselis and Roser suggest that large isolation during circumferential ablation can only be proved using 2 circumferential mapping catheters, 1 in each ipsilateral …

Background— Pulmonary vein (PV) isolation is a promising new treatment for atrial fibrillation (AF). We hypothesized that isolation of large areas around both ipsilateral PVs with verification of conduction block is more effective than the isolation of each individual PV. Methods and Results— A total of 110 patients, 67 with paroxysmal AF and 43 with persistent AF, were randomly assigned to undergo either isolation of each individual PV or isolation of large areas around both ipsilateral PVs. The isolation of each individual PV was an electrophysiologically guided, ostial segmental ablation with a 64-pole basket catheter or a 20-pole circular mapping catheter (group I). Isolation of large areas was performed around the 2 ipsilateral veins with a nonfluoroscopic navigation system and a circular 20-pole mapping catheter for verification of conduction block (group II). In both groups, an irrigated-tip ablation catheter (25 to 35 W) was used to achieve complete isolation. Procedure and ablation times were longer in group II, whereas fluoroscopic time was significantly shorter ( P ≤0.001). After a follow-up period of 15±4 months, 27 patients in group I (49%) and 37 patients in group II (67%) remained free of symptoms of AF and had no AF or atrial flutter during repetitive Holter monitoring without antiarrhythmic drug treatment after a single procedure ( P ≤0.05). Conclusions— The rate of success was significantly higher and fluoroscopy times were significantly lower in the group with large isolation areas around both ipsilateral PVs than in those who underwent individual PV isolation.

The ischemic preconditioning biological phenomenon has been explored to identify putative pharmacologic agents to mimic this cytoprotective program against cellular ischemic injury. Diazoxide administration confers this cytoprotection, however, whether this is via direct activation of the putative mitochondrial K(ATP) (mK(ATP)) channel which was originally proposed has been questioned. Here, we present data supporting an alternate hypothesis evoking mitochondrial respiratory inhibition rather than mK(ATP) channel activation, as a mediating event in the diazoxide-activated cytoprotective program. Mitochondrial respiration and reactive oxygen species (ROS) production was measured in digitonin-permeabilized C2C12 myotubes, allowing for the modulation of mK(ATP) conductance by changing the potassium concentration of the medium (0-130 mM). Diazoxide dose-dependently attenuated succinate-supported respiration, an effect that was independent of mK(ATP) channel conductance. Similarly, 5-hydroxydecanoate (5-HD), a putative mK(ATP) channel blocker, released diazoxide-induced respiratory inhibition independently of potassium concentration. Since diazoxide-induced cytoprotection and respiratory inhibition are both integrally linked to ROS generation we repeated above experiments following ROS generation using DCF fluorescence. Cytoprotective doses of diazoxide increased ROS generation independently of potassium concentration and 5-HD inhibited ROS production under the same conditions. Collectively these data support the hypothesis that diazoxide-mediated cytoprotection is independent of the conductance of the mK(ATP) channel and rather implicate mitochondrial respiratory inhibition-triggered ROS signaling.

Modest cardiac-overexpression of constitutively active PKCepsilon (aPKCepsilon) in transgenic mice evokes cardioprotection against ischemia. As aPKCepsilon interacts with mitochondrial respiratory-chain proteins we hypothesized that aPKCepsilon modulates respiration to induce cardioprotection. Using isolated cardiac mitochondria wild-type and aPKCepsilon mice display similar basal mitochondrial respiration, rate of ATP synthesis and adenosine nucleotide translocase (ANT) functional content. Conversely, the aPKCepsilon mitochondria exhibit modest hyperpolarization of their inner mitochondrial membrane potential (DeltaPsi(m)) compared to wild-type mitochondrial by flow cytometry. To assess whether this hyperpolarization engenders resilience to simulated ischemia, anoxia-reoxygenation experiments were performed. Mitochondria were exposed to 45 min anoxia followed by reoxygenation. At reoxygenation, aPKCepsilon mitochondria recovered ADP-dependent respiration to 44 +/- 3% of baseline compared to 28 +/- 2% in WT controls (P = 0.03) in parallel with enhanced ATP synthesis. This preservation in oxidative phosphorylation is coupled to greater ANT functional content [42%concentration of atractyloside for inhibition in the aPKCepsilon mitochondria vs. WT control (P0.0001)], retention of mitochondrial cytochrome c and conservation of DeltaPsi(m). These data demonstrate that mitochondria from PKCepsilon activated mice are intrinsically resilient to anoxia-reoxygenation compared to WT controls. This resilience is in part due to enhanced recovery of oxidative phosphorylation coupled to maintained ANT activity. As maintenance of ATP is a prerequisite for cellular viability we conclude that PKCepsilon activation augmented mitochondrial respiratory capacity in response to anoxia-reoxygenation may contribute to the PKCepsilon cardioprotective program.

Ischemic preconditioning is a powerful biologic phenomenon that activates innate cell survival programs to protect the heart from ischemic injury. The preponderance of research into classical ischemic preconditioning has focused on signaling pathways orchestrating cardioprotection. Conceptually classified into triggers, mediators and end effectors of preconditioning multiple distinct signaling pathways appear to 'converge' on the mitochondria possibly via activation of the mitochondrial ATP-sensitive potassium (mK(ATP)) channel. The mechanisms by which mK(ATP) channel activation induces preconditioning are incompletely elucidated but include perturbations of mitochondrial architecture and function. Since evidence invoking the mK(ATP) channel has almost exclusively been based on studies using diazoxide and 5-hydroxydecanote the finding that these two compounds have mitochondrial effects independent of the mK(ATP) channel has initiated a controversy regarding the exclusivity of this particular channel in preconditioning. A concerted effort to characterize the mitochondrial phenotype is important to advance our understanding of the mechanistic events that underlie the robust cardioprotective phenotype unmasked by preconditioning. The purpose of this review is to collate the information available on mitochondrial biology associated with classical preconditioning, to delineate the distinct temporal presentation of these mitochondrial perturbations, to reassess the role of the mitochondrial K(ATP) channel and to propose a working model integrating the mitochondrial adaptations into the biology driving this cyto-protective phenotype.

Pharmacological uncoupling of mitochondrial oxidation from phosphorylation promotes preconditioning-like cardioprotection in the isolated rat heart. We hypothesized that modest mitochondrial uncoupling may be a critical cellular event in orchestrating preconditioning. Human-derived Girardi cells and murine C2C12 skeletal myotubes were preconditioned using simulated ischemia, adenosine, and diazoxide. Cell viability after 6 hours of simulated ischemia was measured using lactate dehydrogenase release and propidium iodide uptake. Mitochondrial inner membrane potential (ΔΨm) was investigated by flow cytometry, cellular ATP by recombinant firefly-luciferase bioluminescence, and cellular oxygen consumption using oximetry. Preconditioning enhanced cell viability with attenuation of lactate dehydrogenase release (≥30%, P P P 6 cells, simulated ischemia 3.1±0.1, adenosine 3.1±0.3, diazoxide 2.6±0.2, P ATP -channel antagonist 5-hydroxydecanoate. The uncoupled phenotype in response to preconditioning was similarly observed in C2C12 myotubes. The present study suggests that modest mitochondrial uncoupling represents a unifying cellular response which may be important in directing preconditioning-mediated cytoprotection.

Background: Recent studies have postulated that mitochondrial ATP-sensitive potassium (mitoKATP) channel activation may modulate mitochondrial function with the resultant induction of a preconditioning phenotype in the heart. We hypothesized that the modulation of mitochondrial homeostasis might confer preconditioning-like cardioprotection. Methods: We used a model of regional ischemia in Langendorff-perfused isolated rat hearts. Short-term administration of 2,4-dinitrophenol (DNP), an uncoupler of oxidative phosphorylation and cyclosporin A (CSA), an inhibitor of mitochondrial respiration, was used in an attempt to elicit preconditioning-like cardioprotection. The anti-ischemic drug trimetazidine, known to attenuate CSA-induced disruption in mitochondrial function, and the mitoKATP channel blocker 5-hydroxydecanoic acid (5-HD) were used to inhibit the effects of DNP and CSA. Finally, we studied the effect of trimetazidine on adenosine-induced and ischemic preconditioning. Risk zone and infarct size were measured and expressed as a percentage of the risk zone (I/R ratio). Results: DNP, CSA and adenosine pretreatment reduced infarct size (I/R ratio: DNP 9.0±2.4%, CSA 12.5±1.4%, adenosine 11.9±3.6%, all P

Background The release of endothelium-derived relaxing factors has been shown experimentally to be of pivotal importance for the maintenance of coronary blood flow during increased demand. In humans with coronary atherosclerosis, endothelial vasodilator dysfunction is not confined only to epicardial conductance vessels but may also extend into the coronary microcirculation. We therefore tested the hypothesis that endothelial vasodilator dysfunction of the coronary resistance vasculature is associated with myocardial ischemia during exercise in patients without hemodynamically significant epicardial artery stenoses. Methods and Results Coronary vasodilator function was assessed by subselective infusion of the endothelium-dependent dilator acetylcholine (0.036 to 3.6 μg/mL) and the endothelium-independent dilator papaverine (7 mg). Coronary blood flow responses were evaluated by intracoronary Doppler flow velocity recordings and quantitative angiography. Exercise-induced myocardial perfusion was determined by 201 Tl single photon emission computed tomographic imaging. Thirteen patients had exercise-induced myocardial perfusion defects suggestive of myocardial ischemia, whereas 14 patients had normal thallium imaging during exercise. In patients with exercise-induced thallium perfusion defects, coronary blood flow responses to acetylcholine were significantly ( P P Conclusions Impaired endothelium-dependent vasodilation of the coronary microcirculation is associated with exercise-induced myocardial ischemia in patients without hemodynamically significant epicardial artery lesions. Endothelial vasodilator dysfunction extending into the coronary microcirculation may thus contribute to the ischemic manifestations of coronary artery disease during times of increased myocardial demand.

We present a 74-year-old patient who underwent aortic valve replacement with a porcine bioprosthesis (St Jude Medical Epic 23 mm) because of severe aortic stenosis. On a routine visit 1-year postoperatively, the patient reported mild symptoms of angina (CCS 2). Doppler echocardiography demonstrated a mean gradient of 62 mmHg. Transoesophageal …

Background In atrial fibrillation (AF), the reasons why most of the thrombi form in the left atrium are mainly unknown. In the vasculature, endothelial damage together with platelet activation and inflammation contribute to initiation of blood coagulation and thrombus growth. Objective The purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation occur in patients with AF. Methods Twenty patients (15 men, 5 women; age 55 ± 8 years, 15 paroxystic AF, 5 persistent AF) with AF undergoing ablation were investigated. Blood samples from the left and right atrium were obtained at the start of the procedure. Procoagulant microparticles (MPs), reliable markers of vascular damage were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase assay and their cellular origin were determined (endothelium, platelet, leukocyte). In addition, platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet Pselectin (CD62P), active glycoprotein IIbIIIa receptor (PAC-1). Platelet aggregation was evaluated using Arachidonic acid (AA), ADP, TRAP and collageninduced whole blood aggregometry. Results No atrial-specific differences in the levels of total procoagulant MP, leukocyte-derived-MP and platelet-derived MP could be evidenced. Conversely, endothelial-derived MPs (CD105+) were slightly elevated in the right atrium (RA 0.96 ± 0.53 vs. LA 0.80 ± 0.45 nm PhtdSer Eq.; p = 0.041). Likewise, collagen-induced platelet aggregation was evidenced in the right atrium (Collagen 1 mg/l RA: 48 ± 33% vs LA 37 ± 29%; p 0.035; collagen 2,5 mg/l RA: 76 ± 25% vs LA: 60 ± 29%; p = 0.001). Conclusions In patients with AF, endothelial damage and collageninduced platelet aggregation appear slightly more pronounced in the right atrium. Our data did not substantiate the view that chamber specific enhanced thrombogenic status could be a reliable explanation for the increased propensity for thrombus formation observed in the left atrium in AF patients.

Background New transvenous devices using cryoenergy have been recently introduced to perform pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF). Experimental data suggested that cryoenergy (CRYO) produced less endothelial disruption and platelet activation than radiofrequency energy (RF) offering safety benefits. We aimed to compare both systems with regards to safety in patients by measuring for the first time sensitive laboratory markers of cell damage. platelet activation and inflammation after a PVI using either one of those energies. Methods Sixty patients with symptomatic drug-resistant AF referred for PVI (56 ± 9 years of age, 48 males. 38 with paroxysmal and 22 with persistent AF) were randomly assigned to undergo the ablation procedure using either an open irrigated tip RF catheter (Thermocool®. Biosense Webster) or a cryoballoon catheter (Arctic front®. Medtronic). Systemic markers of cell damage (procoagulant microparticles [MPs of various cellular origin], troponin T, CK and CK-MB). platelet activation (ADP-induced light transmittance aggregation [LTA], expression of the platelet surface proteins P-selectin [pSEL] and activated GPIIb/IIIa [PAC-1]) and inflammatory response (hs-CRP) were determined frequently before and 4, 24 and 48 hours after the procedure. Results Procedure time was significantly shorter in patients treated with the cryoballoon (177 ± 30 min versus 200 ± 46 min. p = 0.028), but there were no differences in fluoroscopic time, clinical event rate and success rate. Post-procedural increases of MPs Troponin T and hs-CRP were observed but there were no consistent differences in parameters used for comparative laboratory safety assessment of the ablation systems using either cryoenergy or radiofrequency energy. Conclusions Neither systematic sensitive markers of cell damage, of platelet activation nor of inflammatory response could detect any difference in the safety profile between cryoenergy and RF energy used for transseptal PVI in patients with AF.

Background In atrial fibrillation (AF), the reasons why most of the thrombi form in the left atrium are mainly unknown. In the vasculature, endothelial damage together with platelet activation and inflammation contribute to initiation of blood coagulation and thrombus growth. Objective The purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation occur in patients with AF. Methods Twenty patients (15 men, 5 women; age 55 ± 8 years, 15 paroxystic AF, 5 persistent AF) with AF undergoing ablation were investigated. Blood samples from the left and right atrium were obtained at the start of the procedure. Procoagulant microparticles (MPs), reliable markers of vascular damage were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase assay and their cellular origin were determined (endothelium, platelet, leukocyte). In addition, platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet Pselectin (CD62P), active glycoprotein IIbIIIa receptor (PAC-1). Platelet aggregation was evaluated using Arachidonic acid (AA), ADP, TRAP and collageninduced whole blood aggregometry. Results No atrial-specific differences in the levels of total procoagulant MP, leukocyte-derived-MP and platelet-derived MP could be evidenced. Conversely, endothelial-derived MPs (CD105+) were slightly elevated in the right atrium (RA 0.96 ± 0.53 vs. LA 0.80 ± 0.45 nm PhtdSer Eq.; p = 0.041). Likewise, collagen-induced platelet aggregation was evidenced in the right atrium (Collagen 1 mg/l RA: 48 ± 33% vs LA 37 ± 29%; p 0.035; collagen 2,5 mg/l RA: 76 ± 25% vs LA: 60 ± 29%; p = 0.001). Conclusions In patients with AF, endothelial damage and collageninduced platelet aggregation appear slightly more pronounced in the right atrium. Our data did not substantiate the view that chamber specific enhanced thrombogenic status could be a reliable explanation for the increased propensity for thrombus formation observed in the left atrium in AF patients.

Morphine mimics the cardioprotective effect of ischemic preconditioning (PC) through a mechanism sensitive to glibenclamide and therefore mediated via opening of KATP channels [1,2]. Furthermore, the PCmimetic effect involves the mitochondrial KATP channels as now demonstrated in human heart muscle [3]. Of the three classes of opioid receptors: μ, δ and κ receptors, ischemic preconditioning is mediated by the δ receptor, with further evidence for the role of the δ1 subtype [3–5]. On the other hand stimulation of the κ receptors may provoke an “anti-preconditioned state” in the isolated rat heart [5]. Opioid receptor stimulation by drugs such as morphine is, however, associated with pain relief and central depressive effects. Presently there are two outstanding problems. First, are there other opioid-like agents that have less of a central effect than morphine yet also give PC? Second, does opioid PC lead to better functional recovery, rather than to a reduction in infarct size, the classic end point used in previous studies. Functional recovery may be more relevant for those undergoing thrombolytic reperfusion or recovery from bypass grafting. We here report opioid-induced preconditioning by SB 235863A, a novel δ1 selective opioid that is structurally a derivative of morphine. At a concentration of 100 nM, it displaces almost 100% of DADLE ({D-ala; D-leu} encephalin, a δ selective opioid) from the opioid receptors (unpublished data, SmithKline Beecham). It has much less effect against pain than morphine in laboratory conditions, and may therefore differ in its central effects. Other agents used were as follows (for references, see [5]). The opioid DADLE ({D-ala; D-leu} encephalin) is a δ selective peptide that activates both the δ1 and δ2 receptors. Naltriben (NTB) is a highly selective δ2 opioid receptor antagonist. 7-benzylidenenaltrexone (BNTX) is a highly selective δ1 opioid receptor antagonist. 5-Hydroxydecanoate (5-HD) blocks the mitochondrial ATP sensitive potassium channel. 5-HD and DADLE were obtained from Research Biochemicals International. SB235863A, BNTX and NTB were obtained from SmithKline Beecham. All drugs were dissolved in Krebs-Henseleit buffer. For these experiments, methods were as before [5] except that post-ischemic recovery of contractile function was used as a surrogate end point for preconditioning [6]. The protocols are shown in Figure 1. Control hearts had a functional recovery after 30 min of ischemia of 21.5 ± 3.8% (Table 1). Ischemic preconditioning increased functional recovery significantly to 75.3 ± 3.6% (p < 0.001). The functional recovery in all the SB235863A groups was better than in the control group (recovery with 100 nM SB235863A was 54.5 ± 3.7%), but the same degree of protection was not found as found with ischemic preconditioning. One cycle of 5 minutes SB235863A perfusion was as effective as two cycles. There was no difference between the groups pre-treated with 1 nM or with 100 nM SB235863A. 5-HD reduced the improved functional recovery achieved by the SB235863A group back to control group values (19.6 ± 3.4%). With DADLE perfusion, the functional recovery was 66.8 ± 5.5%; this mimicked the benefits of ischemic preconditioning. As expected, NTB, the highly selective δ2 opioid receptor antagonist, did not influence the protection seen in the DADLE pretreated group (functional recovery remained at 67.9 ± 3.1%). BNTX limited the protection of DADLE perfused hearts to control values (23.8 ± 3.5%).