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Objectives: To assess reproducibility of core laboratory performance and impact on sample size calculations.Background: Little information exists about overall reproducibility of core laboratories in contradistinction to performance of individual technicians. Also, qualitative parameters are being adjudicated increasingly as either primary or secondary end-points. The comparative impact of using diverse indexes on sample sizes has not been previously reported.Methods: We compared initial and repeat assessments of five quantitative parameters [e.g., minimum lumen diameter (MLD), ejection fraction (EF), etc.] and six qualitative parameters [e.g., TIMI myocardial perfusion grade (TMPG) or thrombus grade (TTG), etc.], as performed by differing technicians and separated by a year or more. Sample sizes were calculated from these results. TMPG and TTG were also adjudicated by a second core laboratory.Results: MLD and EF were the most reproducible, yielding the smallest sample size calculations, whereas percent diameter stenosis and centerline wall motion require substantially larger trials. Of the qualitative parameters, all except TIMI flow grade gave reproducibility characteristics yielding sample sizes of many 100's of patients. Reproducibility of TMPG and TTG was only moderately good both within and between core laboratories, underscoring an intrinsic difficulty in assessing these.Conclusions: Core laboratories can be shown to provide reproducibility performance that is comparable to performance commonly ascribed to individual technicians. The differences in reproducibility yield huge differences in sample size when comparing quantitative and qualitative parameters. TMPG and TTG are intrinsically difficult to assess and conclusions based on these parameters should arise only from very large trials. [ABSTRACT FROM AUTHOR]

Chronic total coronary occlusions (CTO) occur in up to 50 % of patients with coronary artery disease by angiography. In CTO-patients, clinically significant arrhythmia is potentially important and insufficiently investigated. Therefore, the purpose of the CTO-ARRHYTHMIA study was to investigate the incidence of loop recorder detected clinically significant arrhythmias and the effect on arrhythmias of revascularization by CTO-PCI. The study is an independent sub-study of the NOrdic-Baltic Randomized Registry Study for Evaluation of PCI in Chronic Total Coronary Occlusion (NOBLE-CTO); ClinicalTrials.gov Identifier NCT03392415. NOBLE-CTO prospectively collects procedural data, quality of life measures, echocardiographic and cardiac MRI findings before and after treatment as well as clinical outcomes in all CTO patients that may be treated by PCI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leif Thuesen reports equipment, drugs, or supplies was provided by BIOTRONIK SE und Co KG., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective . Hypertension is a significant health burden. In the last 10 years, renal sympathetic denervation has been tested as a potential treatment option for a select group of patients with treatment-resistant hypertension. The aim of this study was to broadly assess the quality of life in patients undergoing renal sympathetic denervation with two years' follow-up. Materials and methods . Patients with treatment-resistant hypertension being treated by hypertension specialists were eligible for inclusion in this study. Bilateral renal sympathetic denervation was performed with the Symplicity Catheter System. Quality of life was measured using standardised questionnaires (Short Form 36, 15 D and a single-item question) and an open question before denervation, after six months and after two years. Results . A total of 23 patients were included. The typical participant was male, 53 years, had a mean office blood pressure of 162/108 mmHg, body mass index of 32 kg/m 2 , and was prescribed 4.8 blood pressure lowering drug classes. At baseline, both physical and mental aspects of quality of life were affected negatively by the treatment-resistant hypertension. Over time, there were modest improvements in quality of life. The largest improvements were seen at six months. Simultaneously, the mean number of blood pressure lowering drug classes was reduced to 4.2. Conclusion . Following renal sympathetic denervation treatment, some aspects of health related quality of life showed an improved trend during follow-up. The observed improvement may reflect the impact of a reduced number of blood pressure lowering drug classes. Clinical Trial Number registered: NCT01630928.

Objectives. To determine risk factors for radial artery and saphenous vein graft occlusion during long-term follow-up after coronary artery bypass grafting (CABG). Methods: From a cohort of 119 patients who had received a radial artery graft, 76 - of whom 55 also had at least one saphenous vein graft - underwent a preplanned direct angiography and anthropometric, biochemical, and endothelial function assessment 7.6-12.1 (mean 8.9) years after CABG. Comorbidity, medication, and smoking habits were also recorded. The association between these parameters and conduit longevity was analyzed in univariable and multivariable logistic regression models. Results: Radial artery graft occlusions were associated with higher plasma levels of high-sensitive C-reactive protein and patency was best among patients with pharmacologically treated hypertension. The sole independent risk factor identified for saphenous vein graft occlusion was tobacco smoking 8-12 years postoperatively. Conclusion: Our data support the contention that the pathogenesis of radial artery graft failure is distinct from vein graft disease and is related to hypertension status and systemic inflammation. These risk factors are potential targets for preventive measures. Accordingly, the study supports the eventual design of personalized secondary prevention regimens. Clinical registration number: ISRCTN23118170.

Background: While female sex has been associated with worse outcomes following coronary revascularization, previous analyses in left main coronary artery (LMCA) disease have been conflicting. In addition, a signal that increased mortality may be specific to women treated with percutaneous coronary intervention (PCI) requires further investigation., Methods: Nordic-Baltic-British left main revascularization study (NOBLE) was a randomized trial comparing PCI to coronary artery bypass surgery (CABG) in patients with LMCA disease. The primary endpoint was a composite of all-cause mortality, nonprocedural myocardial infarction, repeat revascularization, and stroke (major adverse cardiovascular and cerebrovascular events [MACCE]). We report the 5-year sex-specific outcomes., Results: Of 1184 patients analyzed, 256 (22%) were female and 928 (78%) were male. There were no significant within-sex differences in baseline characteristics, disease location, or complexity between those treated with PCI and those with CABG. The 5-year MACCE rates were 29% and 15% in females and 28% and 20% in males treated with PCI and CABG, respectively. Within both sexes, there was an increased risk of MACCE with PCI compared with CABG, but no difference in all-cause mortality. On multivariate analysis, female sex was not an independent predictor of MACCE., Conclusions: Following the treatment of LMCA disease, long-term outcomes favored CABG over PCI in both sexes. Importantly, there was no difference in all-cause mortality in females or males at 5 ​years., Competing Interests: Dr McEntegart has received consultancy fees from Abbott Vascular and Boston Scientific. Dr Holm has received institutional research grants from 10.13039/501100008877Biosensors, 10.13039/100001316Abbott, 10.13039/100015305Reva Medical, Medis Medical Imaging, and 10.13039/100008497Boston Scientific and speaker fees from Terumo, Abbott, Reva Medical, and Medis Medical Imaging. Dr Oldroyd has received speaker fees from Biosensors and Abbott Vascular. Dr Erglis has received institutional research grants from 10.13039/100011949Abbott Vascular and 10.13039/100008497Boston Scientific and consultancy fees from Abbott Vascular, Biosensors, Boston Scientific, Cordis J&J, and Medtronic. Dr Christiansen has received grants from 10.13039/501100008877Biosensors. None of the other authors have any conflicts of interest., (© 2022 The Authors.)

Background: Drug-eluting stents (DES) reduce target lesion revascularization (TLR) with no effect on mortality or myocardial infarction (MI) compared to bare-metal stents (BMS) in native vessels. Randomized stent studies in saphenous vein grafts (SVG) are few and the reported effects are ambiguous. The Norwegian Coronary Stent Trial study is the first to randomize lesions to percutaneous coronary intervention in native vessels and SVG., Aims: The aim of this study was to compare the rate of mortality, MI, and TLR across stent and vessel types., Methods: In this substudy, 6,087 patients with a single lesion in native vessels and 164 in SVG were followed for 5 years., Results: MI was more frequent in SVG (subdistributional hazard ratio [SHR] 4.95 (3.75-6.54, p < 0.001), but not affected by stent type. In the first 500 days, DES reduced TLR in native vessels (SHR 0.21 (0.15-0.30) p < 0.001) and SVG (SHR 0.18 (0.04-0.80) p = 0.02). Thereafter, DES and BMS were equivalent in native vessels, but DES had a higher TLR rate than BMS in SVG (SHR 3.31 (1.23-8.94) p = 0.02). After 5 years, the TLR rate was still significantly lower for DES in native vessels (3.2% vs. 7.8%, p < 0.001) but not in SVG (21.4% vs. 18. 4%)., Conclusion: In SVG, no difference in TLR between DES and BMS was observed after 5 years in contrast to persistent benefit in native vessels. The high rate of TLR and MI in SVG makes treatment of native vessels a preference whenever feasible and better treatment options for SVG are warranted., (© 2021 S. Karger AG, Basel.)

Data suggest that renal denervation (RDN) in treatment-resistant hypertension (TRHT) is safe in terms of renal function. However, most studies report kidney function as creatinine-based estimated glomerular filtration rate (eGFR), which may be biased by non-renal factors. Damage markers other than albuminuria have never been evaluated after RDN. In this non-randomized RDN trial, we studied changes in kidney function, assessed as measured GFR (mGFR) and various GFR estimates, six months and two years after RDN. We also examined changes in albuminuria and a biomarker of tubular dysfunction. Adult non-diabetic patients with TRHT and eGFR ≥45 ml/min/1.73 m 2 were recruited from hypertension clinics. Before bilateral RDN, mGFR was measured by iohexol clearance. We estimated eGFR from serum creatinine and cystatin C (eGFR crea , eGFR cys, and eGFR creacys ), and albumin-creatinine ratio (ACR) and N-acetyl-β-D-glucosaminidase (NAG)-creatinine ratio (NAG-CR) were measured in spot urines. All measurements were repeated after six and twenty-four months. Twenty patients, mean age 54 (±9) years and baseline mGFR 83 (±20) ml/min/1.73 m 2  underwent RDN. After six months, mGFR fell, eGFR crea remained unchanged, whereas eGFR cys and eGFR creacys increased. At 2 years' follow-up, eGFR creacys was significantly lower than at baseline. mGFR was 78 (±28) ml/min/1.73 m 2 . Change in ambulatory systolic BP predicted change in eGFR crea . Urinary NAG-CR, but not ACR, increased during follow-up. Different GFR assessments gave diverging results after RDN. Therefore, care should be taken to method when evaluating kidney function after RDN. Increases in a tubular dysfunction biomarker suggest that kidney damage may occur. Long-term renal follow-up is needed after RDN., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background & Aims: Denervation of renal sympathetic nerves (RDN) is an invasive endovascular procedure introduced as an antihypertensive treatment with a potential beneficial effect on insulin resistance (IR). We have previously demonstrated a reduction in blood pressure (BP) six months after RDN, but severe hepatic and peripheral IR, assessed by glucose tracer and two step hyperinsulinemic-euglycemic clamp (HEC), did not improve. The aim of the current study was to evaluate IR and adipokines profiles in relation to BP and arterial stiffness changes two years after RDN., Methods: In 20 non-diabetic patients with true treatment-resistant hypertension, ambulatory and office BP were measured after witnessed intake of medications prior to, six and 24 months after RDN. Arterial stiffness index (AASI) was calculated from ambulatory BP. Insulin sensitivity (IS) was assessed using an oral glucose tolerance test (OGTT), the Homeostasis Model Assessment (HOMA-IR), HOMA-Adiponectin Model Assessment (HOMA-AD), the Quantitative Insulin Sensitivity Check Index (QUICKI), the Triglyceride and Glucose Index (TyG) and the Leptin-to-Adiponectin Ratio (LAR). These surrogate indices of IS were compared with tracer/HEC measurements to identify which best correlated in this group of patients., Results: All measured metabolic variables and IS surrogate indices remained essentially unchanged two years after RDN apart from a significant increase in HOMA-AD. OGTT peak at 30 min correlated best with reduction in endogenous glucose release (EGR) during low insulin HEC (r = -0.6, p = 0.01), whereas HOMA-IR correlated best with whole-body glucose disposal (WGD) (r = -0.6, p = 0.01) and glucose infusion rate (r = -0.6, p = 0.01) during high insulin HEC. BP response was unrelated to IS prior to RDN. Nocturnal systolic BP and arterial stiffness before RDN correlated positively with a progression in hepatic IR at six-month follow-up., Conclusion: IR, adiponectin and leptin did not improve two years after RDN. There was no correlation between baseline IS and BP response. Our study does not support the notion of a beneficial metabolic effect of RDN in patients with treatment resistant hypertension., Competing Interests: Conflict of interest No potential conflict of interest was reported by the authors., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objectives: The benefits of coronary artery bypass surgery depend on lasting graft patency. To aid rational graft selection, the relative long-term merits of radial artery and saphenous vein grafts need to be determined by a gold standard method and with minimal clinically driven selection bias. Methods: The patency rates of various conduits were determined by direct angiography in 76 patients from a cohort of 119 undergoing coronary artery bypass grafting 7.6-12.1 (mean 8.9) years before. Results: 14 out of 76 radial artery and 10 out of 61 saphenous vein grafts were occluded (rates 0.18 and 0.16, respectively). Conclusion: The high long-term patency rate of saphenous vein grafts does not support a preferential use of the radial artery as a coronary artery bypass conduit. Clinical registration number: ISRCTN23118170.

Background: It is still uncertain whether coronary bifurcations with lesions involving a large side branch (SB) should be treated by stenting the main vessel and provisional stenting of the SB (simple) or by routine two-stent techniques (complex). We aimed to compare clinical outcome after treatment of lesions in large bifurcations by simple or complex stent implantation., Methods: The study was a randomised, superiority trial. Enrolment required a SB≥2.75 mm, ≥50% diameter stenosis in both vessels, and allowed SB lesion length up to 15 mm. The primary endpoint was a composite of cardiac death, non-procedural myocardial infarction and target lesion revascularisation at 6 months. Two-year clinical follow-up was included in this primary reporting due to lower than expected event rates., Results: A total of 450 patients were assigned to simple stenting (n=221) or complex stenting (n=229) in 14 Nordic and Baltic centres. Two-year follow-up was available in 218 (98.6%) and 228 (99.5%) patients, respectively. The primary endpoint of major adverse cardiac events (MACE) at 6 months was 5.5% vs 2.2% (risk differences 3.2%, 95% CI -0.2 to 6.8, p=0.07) and at 2 years 12.9% vs 8.4% (HR 0.63, 95% CI 0.35 to 1.13, p=0.12) after simple versus complex treatment. In the subgroup treated by newer generation drug-eluting stents, MACE was 12.0% vs 5.6% (HR 0.45, 95% CI 0.17 to 1.17, p=0.10) after simple versus complex treatment., Conclusion: In the treatment of bifurcation lesions involving a large SB with ostial stenosis, routine two-stent techniques did not improve outcome significantly compared with treatment by the simpler main vessel stenting technique after 2 years., Trial Registration Number: NCT01496638., Competing Interests: Competing interests: IK received institutional research grants from Cordis, Abbott and speaker fee from Astra Zeneca. NRH has received institutional research grants from Cordis, Abbott, Terumo, Biosensors, Biotronik, Medis medical imaging, Reva Medical, Boston Scientific, St. Jude Medical and Medtronic and has received speaker fees and personal honorarium from St. Jude Medical, Terumo, Reva Medical and Biotronik. LOJ has received institutional research grants from Terumo, Biosensors and Biotronik. JFL has received institutional research grants from Cordis, Abbott, Terumo, Biosensors, Biotronik, Medis medical imaging, Reva Medical, Boston Scientific, Heartflow, St. Jude Medical and Medtronic and has received speaker fees from Biotronik, Biosensors, Tryton, Boston Scientific, St. Jude Medical, Terumo, Reva medical, Cordis, Astra Zeneca and Abbott. GL has received speaker fees from Astra Zeneca., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sympathetic tone is one of the main determinants of blood pressure (BP) variability and treatment-resistant hypertension. The aim of our study was to assess changes in BP variability after renal denervation (RDN). In addition, on an exploratory basis, we investigated whether baseline BP variability predicted the BP changes after RDN., Methods: We analyzed 24-h BP recordings obtained at baseline and 6 months after RDN in 167 treatment-resistant hypertension patients (40% women; age, 56.7 years; mean 24-h BP, 152/90 mmHg) recruited at 11 expert centers. BP variability was assessed by weighted SD [SD over time weighted for the time interval between consecutive readings (SDiw)], average real variability (ARV), coefficient of variation, and variability independent of the mean (VIM)., Results: Mean office and 24-h BP fell by 15.4/6.6 and 5.5/3.7 mmHg, respectively (P < 0.001). In multivariable-adjusted analyses, systolic/diastolic SDiw and VIM for 24-h SBP/DBP decreased by 1.18/0.63 mmHg (P ≤ 0.01) and 0.86/0.42 mmHg (P ≤ 0.05), respectively, whereas no significant changes in ARV or coefficient of variation occurred. Furthermore, baseline SDiw (P = 0.0006), ARV (P = 0.01), and VIM (P = 0.04) predicted the decrease in 24-h DBP but not 24-h SBP after RDN., Conclusion: RDN was associated with a decrease in BP variability independent of the BP level, suggesting that responders may derive benefits from the reduction in BP variability as well. Furthermore, baseline DBP variability estimates significantly correlated with mean DBP decrease after RDN. If confirmed in younger patients with less arterial damage, in the absence of the confounding effect of drugs and drug adherence, baseline BP variability may prove a good predictor of BP response to RDN.

Background: Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease., Methods: In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651., Findings: Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1·48 (95% CI 1·11-1·96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0066). As-treated estimates were 28% versus 19% (1·55, 1·18-2·04, p=0·0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1·07, 0·67-1·72, p=0·77) for all-cause mortality, 7% versus 2% (2·88, 1·40-5·90, p=0·0040) for non-procedural myocardial infarction, 16% versus 10% (1·50, 1·04-2·17, p=0·032) for any revascularisation, and 5% versus 2% (2·25, 0·93-5·48, p=0·073) for stroke., Interpretation: The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease., Funding: Biosensors, Aarhus University Hospital, and participating sites., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We assessed whether insulin sensitivity improved after renal denervation (RDN) for resistant hypertension. Twenty-three patients underwent a two-step hyperinsulinemic-euglycemic clamp (HEC) with glucose tracer and labeled glucose infusion and oral glucose tolerance test (OGTT) before and 6 months after RDN. Eighteen patients had metabolic syndrome at baseline. Blood pressure declined significantly after RDN, whereas mean (SD) fasting plasma glucose concentration (5.9 ± 0.7 mmol/L), median (minimum-maximum) insulin concentration (254 pmol/L [88-797 pmol/L]), and median C-peptide concentration (2.4 nmol/L [0.9-5.7 nmol/L]) remained unchanged. Endogenous glucose release during HEC was less suppressed after RDN, suggesting a slight decrease in hepatic insulin sensitivity. During high-dose insulin infusion, whole-body glucose disposal was low and remained unchanged after RDN, indicating persistent peripheral insulin resistance (IR). Area under the curve for 0-120 min for glucose and insulin during OGTT, Quantitative Insulin Sensitivity Check Index, Simple Index Assessing Insulin Sensitivity Oral Glucose Tolerance, and HOMA-IR were high, and did not improve after RDN. Despite a significant decrease in blood pressure, neither peripheral nor hepatic insulin sensitivity improved 6 months after RDN treatment in this group of insulin-resistant patients without diabetes and with resistant hypertension, as measured with gold standard methods., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: Randomized trials of coronary bifurcation stenting have shown better outcomes from a simple (provisional) strategy rather than a complex (planned two-stent) strategy in terms of short-term efficacy and safety. Here, we report the 5-year all-cause mortality based on pooled patient-level data from two large bifurcation coronary stenting trials with similar methodology: the Nordic Bifurcation Study (NORDIC I) and the British Bifurcation Coronary Study: old, new, and evolving strategies (BBC ONE)., Methods and Results: Both multicentre randomized trials compared simple (provisional T-stenting) vs. complex (culotte, crush, and T-stenting) techniques, using drug-eluting stents. We analysed all-cause death at 5 years. Data were collected from phone follow-up, hospital records, and national mortality tracking. Follow-up was complete for 890 out of 913 patients (97%). Both Simple and Complex groups were similar in terms of patient and lesion characteristics. Five-year mortality was lower among patients who underwent a simple strategy rather than a complex strategy [17 patients (3.8%) vs. 31 patients (7.0%); P = 0.04]., Conclusion: For coronary bifurcation lesions, a provisional single-stent approach appears to be associated with lower long-term mortality than a systematic dual stenting technique., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Renal sympathetic denervation (RDN) represents a potential treatment option for highly selected patients with resistant arterial hypertension. In this open label study, we aimed to investigate the response of blood pressure (BP) and short-term BP variability (BPV) to RDN 6 months after procedure. We defined treatment-resistant hypertension as office systolic BP>140 mm Hg, despite maximum tolerated doses of ⩾4 antihypertensive drugs, including a diuretic. In addition, daytime systolic ambulatory blood pressure (ABPM) >135 mm Hg was required after witnessed intake of antihypertensive drugs. Bilateral RDN was performed with the Symplicity Catheter System (n=23). The mean systolic office BP and ABPM fell from 162±20 mm Hg to 139±19 mm Hg (P<0.001) and from 154±20 mm Hg to 144±16 mm Hg (P<0.038), respectively. In addition, we observed a significant reduction in diastolic office BP and ABPM. The current study also demonstrated a significant decrease of both systolic and diastolic average real variability, weighted standard deviation (s.d.) as well as conventional s.d. of mean and daytime BP, but not of s.d. of nighttime BP. RDN after witnessed intake of ⩾4 antihypertensive drugs reduced both office BP and ABPM at 6 months in patients with truly resistant hypertension. Also BPV improved, possibly reflecting an additional effect from intervening on the sympathetic nerve system.

Objectives: Patients previously treated with coronary stents may suffer an acute coronary syndrome (ACS) without any evidence of thrombus formation on coronary angiography (CAG). This may be due to partial, nonocclusive stent thrombosis with microembolization. In this paper, we illustrate possible mechanisms both with optical coherence tomography (OCT) and histology., Design: We present two cases with ACS from very late stent thrombosis who have been previously treated with first-generation drug-eluting stents (DES)., Results: The first patient had ACS 15 months after DES implantation. The angiogram (CAG) was near normal with slight peri-stent contrast staining. OCT revealed abnormalities including thrombus not visible on CAG. These are findings that may explain the ACS. The second patient had subclinical episodes with chest pain after DES implantation. The patient died from stent thrombosis in a DES. Postmortem histological examination of the coronary arteries revealed stent struts with little or no neointimal coverage, persistent peri-strut fibrin deposition, inflammatory cells, malapposition, and small luminal platelet-rich thrombi. Old spotty myocardial infarctions were found in the supplied territory possibly caused by earlier episodes of embolizing thrombus., Conclusions: In patients with previous implanted DES presenting with ACS, OCT may detect abnormalities and thrombus formation not visible on CAG. Such findings may impact the treatment strategy in these patients.

Objectives: The aim of the study was to compare long-term follow-up results of crush versus culotte stent techniques in coronary bifurcation lesions., Background: The randomized Nordic Stent Technique Study showed similar 6-month clinical and 8-month angiographic results with the crush and culotte stent techniques of de novo coronary artery bifurcation lesions using sirolimus-eluting stents. Here, we report the 36-month efficacy and safety of the Nordic Stent Technique Study., Methods: A total of 424 patients with a bifurcation lesion were randomized to stenting of both main vessel and side branch with the crush or the culotte technique and followed for 36 months. Major adverse cardiac events-the composite of cardiac death, myocardial infarction, stent thrombosis, or target vessel revascularization-were the primary endpoint., Results: Follow-up was complete for all patients. At 36 months, the rates of the primary endpoint were 20.6% versus 16.7% (p = 0.32), index lesion restenosis 11.5% versus 6.5% (p = 0.09), and definite stent thrombosis 1.4% versus 4.7% (p = 0.09) in the crush and the culotte groups, respectively., Conclusions: At 36-month follow-up, the clinical outcomes were similar for patients with coronary bifurcation lesions treated with the culotte or the crush stent technique. (Nordic Bifurcation Study. How to Use Drug Eluting Stents [DES] in Bifurcation Lesions? NCT00376571)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to report the 5-year follow-up results of the Nordic Bifurcation Study., Background: Randomized clinical trials with short-term follow-up have indicated that coronary bifurcation lesions may be optimally treated using the optional side branch stenting strategy., Methods: A total of 413 patients with a coronary bifurcation lesion were randomly assigned to a simple stenting strategy of main vessel (MV) and optional stenting of side branch (SB) or to a complex stenting strategy, namely, stenting of both MV and SB., Results: Five-year clinical follow-up data were available for 404 (98%) patients. The combined safety and efficacy endpoint of cardiac death, non-procedure-related myocardial infarction, and target vessel revascularization were seen in 15.8% in the optional SB stenting group as compared to 21.8% in the MV and SB stenting group (p = 0.15). All-cause death was seen in 5.9% versus 10.4% (p = 0.16) and non-procedure-related myocardial infarction in 4% versus 7.9% (p = 0.09) in the optional SB stenting group versus the MV and SB stenting group, respectively. The rates of target vessel revascularization were 13.4% versus 18.3% (p = 0.14) and the rates of definite stent thrombosis were 3% versus 1.5% (p = 0.31) in the optional SB stenting group versus the MV and SB stenting group, respectively., Conclusions: At 5-year follow-up in the Nordic Bifurcation Study, the clinical outcomes after simple optional side branch stenting remained at least equal to the more complex strategy of planned stenting of both the main vessel and the side branch., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The substudy was performed to evaluate the acute and eight-month follow-up effect of final kissing balloon dilatation (FKBD) on fractional flow reserve (FFR) in the side branch (SB) after main vessel (MV) stenting., Methods and Results: We included 75 patients in the Nordic-Baltic Bifurcation Study III FFR substudy: 42 in the FKBD group and 33 in the no-FKBD group. Complete angiographic and FFR eight-month follow-up was obtained in 25 (60%) patients in the FKBD group and 21 (63%) patients in the no-FKBD group. In the FKBD group the post-PCI mean SB FFR was significantly higher compared to the no-FKBD group (0.92 vs. 0.85, respectively; p=0.011). No significant difference in FFR value between treatments was detected at eight-month follow-up (0.91 vs. 0.87; p=0.19). There were no significant changes in mean SB FFR during the follow-up period (0.92 vs. 0.91; p=0.80) in the FKBD group and (0.87 vs. 0.87; p=0.91) in the no-FKBD group., Conclusions: FKBD in simple stenting of bifurcation lesions improved acute functional outcome in SB compared to leaving the SB jailed. No significant difference was detected at follow-up. In both groups there was no significant functional late loss during follow-up. Thus, both strategies were equally effective in ensuring that side branch jailing would not cause ischaemia in the long term.

Background: Short-term results are presented from our first year of experience with transcatheter aortic-valve implantation [corrected] (TAVI) at the University Hospital of North Norway., Materials and Methods: TAVI was used to treat 25 patients with aortic stenosis [corrected] from September 2008 to August 2009. 25 patients operated with conventional aortic valve replacement (AVR) served as controls., Results: The TAVI group had a significantly higher EuroSCORE (p < 0.001) than the AVR group. No patients in the TAVI group were treated in the intensive care unit while those in the AVR group received 38 days of intensive care in total. The TAVI group had shorter operating times (p < 0.001), larger mean valve sizes (p < 0.001) and significantly fewer postoperative transfusions (p < 0.001) than the ACR group. Peri-operative stroke and myocardial infarction did not occur in the TAVI group while there was one incidence of stroke and one myocardial infarction in the AVR group. The postoperative transvalvular mean gradient decreased in both groups (p < 0.001) and was significantly lower in the TAVI group (p = 0.001). The NYHA class improved significantly in the TAVI group (p < 0.001). No patients needed implantation of a permanent pacemaker. 30-day mortality was four patients in the AVR group and one patient in the TAVI group. After discharge one patient died in each group., Interpretation: TAVI is safe and effective for selected patients with aortic stenosis [corrected] who are assessed as high risk for AVR. Long-term results are needed and will be decisive for use of this approach in the future.

Background: Controversy persists regarding the correct strategy for bifurcation lesions. Therefore, we combined the patient-level data from 2 large trials with similar methodology: the NORDIC Bifurcation Study (NORDIC I) and the British Bifurcation Coronary Study (BBC ONE)., Methods and Results: Both randomized trials compared simple (provisional T-stenting) versus complex techniques, using drug-eluting stents. In the simple group (n=457), 129 patients had final kissing balloon dilatation in addition to main vessel stenting, and 16 had T-stenting. In the complex group (n=456), 272 underwent crush, 118 culotte, and 59 T-stenting techniques. A composite end point at 9 months of all-cause death, myocardial infarction, and target vessel revascularization occurred in 10.1% of the simple versus 17.3% of the complex group (hazard ratio 1.84 [95% confidence interval 1.28 to 2.66], P=0.001). Procedure duration, contrast, and x-ray dose favored the simple approach. Subgroup analysis revealed similar composite end point results for true bifurcations (n=657, simple 9.2% versus complex 17.3%; hazard ratio 1.90 [95% confidence interval 1.22 to 2.94], P=0.004), wide-angled bifurcations >60 to 70° (n=217, simple 9.6% versus complex 15.7%; hazard ratio 1.67 [ 95% confidence interval 0.78 to 3.62], P=0.186), large (≥2.75 mm) diameter side branches (n=281, simple 10.4% versus complex 20.7%; hazard ratio 2.42 [ 95% confidence interval 1.22 to 4.80], P=0.011), longer length (>5 mm) ostial side branch lesions (n=464, simple 12.1% versus complex 19.1%; hazard ratio 1.71 [95% confidence interval 1.05 to 2.77], P=0.029), or equivalent sized vessels (side branch <0.25 mm smaller than main vessel) (n=108, simple 12.0% versus complex 15.5%; hazard ratio 1.35 [95% confidence interval 0.48 to 3.70], P=0.57)., Conclusions: For bifurcation lesions, a provisional single-stent approach is superior to systematic dual stenting techniques in terms of safety and efficacy. A complex approach does not appear to be beneficial in more anatomically complicated lesions.

Background: Whether myocardial perfusion grade (MPG) following late recanalization of infarct-related arteries (IRAs) predicts left ventricular (LV) function recovery beyond the acute phase of myocardial infarction (MI) is unknown., Methods and Results: The Total Occlusion Study of Canada-2 enrolled stable patients with a persistently occluded IRA beyond 24 hours and up to 28 days post-MI. We studied the relationship between the initial MPG and changes in LV function and volume as well as the change in MPG from immediate post-percutaneous coronary intervention (PCI) to 1 year in 139 PCI patients with thrombolysis in myocardial infarction grade 3 epicardial flow post-PCI and with paired values grouped into impaired or good MPG groups (MPG 0/1 or MPG 2/3). MPG 0/1 patients were more likely to have received thrombolytic therapy and to have a left anterior descending IRA. They had lower blood pressure and LV ejection fraction (LVEF) and a higher heart rate and systolic sphericity index at baseline. Changes in the MPG 0/1 and MPG 2/3 groups from baseline to 1 year were LVEF, 3.3±9.0% and 4.8±8.9% (P=0.42); LV end-systolic volume index (LVESVI), -1.1±9.2 and -4.7±12.3 mL/m(2) (P=0.25); LV end-diastolic volume index (LVEDVI), 0.08±19.1 and -2.4±22.2 mL/m(2) (P=0.67); and SDs/chord for infarct zone wall motion index (WMI), 0.38±0.70 and 0.84±1.11 (P=0.01). By covariate-adjusted analysis, post-PCI MPG 0/1 predicted lower WMI (P<0.001), lower LVEF (P<0.001), and higher LVESVI (P<0.01) but not LVEDVI at 1 year. Of the MPG 0/1 patients, 60% were MPG 2 or 3 at 1 year., Conclusions: Preserved MPG is present in a high proportion of patients following late PCI of occluded IRAs post-MI. Poor MPG post-PCI frequently improves MPG over 1 year. MPG graded after IRA recanalization undertaken days to weeks post MI is associated with LV recovery, indicating that MPG determined in the subacute post-MI period remains a marker of viability., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00025766.

Unlabelled: The radial artery is resistant to atherosclerotic degeneration and therefore appears more attractive for coronary artery bypass grafting than the saphenous vein. However, the patency of radial artery grafts varies widely among studies. Therefore, before deciding whether to adopt this as the conduit of choice second to internal mammary artery grafts, we have prospectively monitored our first cohort of patients with radial-to-coronary bypasses., Design: Angiographic and clinical outcome parameters were registered for the 119 patients receiving radial artery grafts at our institution during April 4, 2001 to October 7, 2003., Results: Reangiography of 102 patients (86%) showed that after two to three years, 79% of the radial artery and 87% of the saphenous vein grafts remained patent. Radial artery harvesting was well tolerated. Patency of radial artery grafts was correlated to diabetes mellitus (detrimental), gender (women had higher occlusion rates), and use of angiotensin inhibiting medication (beneficial)., Conclusions: The pre-study assumption that radial artery grafts would out-perform those of saphenous vein at mid-term is not borne out. The propensity of radial artery graft failure in diabetics and the higher patency associated with angiotensin inhibition might both relate to endothelial modulation of the muscular tone of the graft.

Background: In a number of coronary bifurcation lesions, both the main vessel and the side branch need stent coverage. Using sirolimus eluting stents, we compared 2 dedicated bifurcation stent techniques, the crush and the culotte techniques in a randomized trial with separate clinical and angiographic end-points., Methods and Results: A total of 424 patients with a bifurcation lesion were randomized to crush (n=209) and culotte (n=215) stenting. The primary end point was major adverse cardiac events; cardiac death, myocardial infarction, target vessel revascularization, or stent thrombosis after 6 months. At 6 months there were no significant differences in major adverse cardiac event rates between the groups; crush 4.3%, culotte 3.7% (P=0.87). Procedure and fluoroscopy times and contrast volumes were similar in the 2 groups. The rates of procedure-related increase in biomarkers of myocardial injury were 15.5% in crush versus 8.8% in culotte group (P=0.08). A total of 324 patients had a quantitative coronary assessment at the index procedure and after 8 months. The angiographic end-points of in-segment and in-stent restenosis of main vessel and/or side branch after 8 months were found in 12.1% versus 6.6% (P=0.10) and in 10.5% versus 4.5% (P=0.046) in the crush and culotte groups, respectively., Conclusions: Both the crush and the culotte bifurcation stenting techniques were associated with similar and excellent clinical and angiographic results. Angiographically, there was a trend toward less in-segment restenosis and significantly reduced in-stent restenosis following culotte stenting.

Objective: To evaluate the distribution and determinants of myocardial perfusion grade (MPG) following late recanalization of persistently occluded infarct-related arteries (IRA)., Background: MPG reflects microvascular integrity. It is an independent prognostic factor following myocardial infarction, but has been studied mainly in the setting of early reperfusion. The occluded artery trial (OAT) enrolled stable patients with persistently occluded IRAs beyond 24 hr and up to 28 days post-MI., Methods: Myocardial blush was assessed using TIMI MPG grading in 261 patients with TIMI 3 epicardial flow following IRA PCI. Patients demonstrating impaired (0-1) versus preserved (2-3) MPG were compared with regard to baseline clinical and pre-PCI angiographic characteristics., Results: Impaired MPG was observed in 60 of 261 patients (23%). By univariate analysis, impaired MPG was associated with failed fibrinolytic therapy, higher heart rate, lower systolic blood pressure, lower ejection fraction, LAD occlusion, absence of collaterals (P < 0.01) and ST elevation MI, lower diastolic blood pressure, and higher systolic sphericity index (P < 0.05). By multivariable analysis, higher heart rate, LAD occlusion, absence of collaterals and higher systolic sphericity index (P < 0.01), and lower systolic blood pressure (P < 0.05) were independently associated with impaired MPG., Conclusion: Preserved microvascular integrity was present in a high proportion of patients following late recanalization of occluded IRAs post-MI. Presence of collaterals was independently associated with preserved MPG and likely accounted for the high frequency of preserved myocardial perfusion in this clinical setting. Impaired MPG was associated with baseline clinical and angiographic features consistent with larger infarct size., ((c) 2008 Wiley-Liss, Inc.)

Aims: The risk of stent thrombosis has been reported to increase with percutaneous coronary intervention (PCI) complexity. The present study reports the pre-specified secondary endpoint of a 14-month stent thrombosis and major adverse cardiac events in patients stented with a simple versus a complex bifurcation technique using sirolimus eluting stents (SES)., Methods and Results: A total of 413 patients with a coronary bifurcation lesion were randomised to a simple treatment strategy; stenting of main vessel and optional stenting of side branch (MV group), or to a complex stenting strategy; stenting of both main vessel and side branch (MV+SB group). Mortality data were available in all patients and 14-month clinical follow-up data in 395 (96%) of the patients. After 14 months, the rates of definite, probable and possible stent thrombosis (ARC criteria) were 1.0% vs. 0.5%, 1.0% vs. 0% and 0.5% vs. 0% (ns) in the MV and in the MV+SB groups, respectively. Rates of MACE were 9.5% in the MV group and 8.2% in the MV+SB group (ns). Total death was seen in 2.4% vs. 1.0% and non-PCI related myocardial infarction in 2.0% vs. 1.0% in the MV and the MV+SB groups, respectively., Conclusions: After 14 months, two months after recommended cessation of dual antiplatelet therapy, the rates of stent thrombosis and major adverse cardiac events were low and independent of treatment complexity in patients treated with SES for coronary artery bifurcation lesions.

Objectives: Angiography by selective catheterization is the standard method for coronary artery imaging but carries a risk of rare, but serious complications. We investigated whether 16-slice multidetector spiral computed tomography (MDCT) could substitute for selective angiography for evaluation of coronary artery disease in surgically revascularized patients., Design: In a setting closely resembling routine clinical practice, 45 patients who had been operated with coronary artery bypass grafting 508-1135 (mean 811) days before were examined with MDCT and conventional selective angiography on the same day. The interpreters were blinded to the results of the parallel imaging modality., Results: Significant pathology (stenosis >/=50% or occlusion) in the larger coronary artery segments was detected by MDCT with a sensitivity of 70-98% (mean 87%) and a specificity of 0-37% (mean 21%). MDCT failed to identify three of ten left main stem stenoses., Conclusion: Sixteen-slice MDCT cannot routinely replace selective angiography for evaluation of coronary artery disease.

Aims: Different distal protections devices have been developed to prevent embolisation during percutaneous coronary intervention (PCI) in atherosclerotic saphenous vein grafts (SVG). The purpose of this descriptive study was to characterise the composition of material captured by embolic protection device from saphenous vein graft interventions by light and electron microscopy, to determine the age of the thrombotic component and to relate the pathological findings to the clinical condition, lesion characteristics and to the use of conventional or membrane covered self-expanding stents during the intervention., Methods and Results: Forty consecutive patients treated with the FilterWire EX (Boston Scientific) during 42 SVG interventions were included. Plaque was found in 4.8%, thrombus in 16.7%, both plaque and thrombus in 69.0% of the filter bags, and 9.5% were empty. In 93% of the thrombus containing samples we found platelet aggregates that were formed within the last 10-15 minutes before fixation. This indicated platelet stimulation and aggregation during the PCI procedures. No relation was found between the composition of filter wire material and clinical condition, coronary lesion characteristics or the use of membrane covered self-expanding stents (Symbiot(R))., Conclusion: The present study on material captured by embolic protein device after SVG interventions generated the hypothesis that these interventions were associated with acute platelet activation. In consequence, the use of glycoprotein IIb/IIIa inhibitors might be reconsidered in distal protected SVG interventions.

Objectives: Angiography by selective catheterization is the reference standard for coronary bypass graft patency assessment but carries a risk of serious complications. We have investigated whether 16-slice multidetector spiral computed tomography (MDCT) can substitute for selective angiography., Design: Two to three years after coronary artery bypass grafting, 45 patients with a total of 156 bypasses (100 single and 28 sequential grafts) were examined with both MDCT and conventional selective angiography on the same day. The bypasses were classified as patent, stenotic or occluded., Results: The likelihood ratio for MDCT-detected occlusion was 40, reflecting a fairly high combined sensitivity and specificity. However, 24% of the distal anastomoses could not be evaluated by MDCT, mainly because of respiratory movements, artifacts due to metal clips, and small vessel dimensions. Moreover, seven out of 117 bypasses (6%) deemed evaluable by MDCT were wrongly classified by this method., Conclusions: At present, 16-slice MDCT cannot replace selective angiography for assessment of coronary bypass graft patency since 24% of bypasses could not be evaluated by this method, and an error rate of 6% is unacceptable.

This paper is a short review of thrombolytic treatment of ST-segment elevation myocardial infarction with particular focus on pre-hospital thrombolysis. The paper is based on international publications within the field as well as on the authors' own experience. The effect of thrombolytic therapy following acute myocardial infarction is well documented, and a major advantage with this treatment is its ease of administration. Mechanical opening of acutely occluded coronary arteries by percutaneous coronary interventions (PCI) is, however, an alternative to thrombolytic therapy. Meta-analyses have demonstrated better outcome of PCI compared to thrombolytic therapy in patients with acute myocardial infarction admitted to invasive centres or being transported to such centres within a certain time frame. It is obvious, however, that the geographical conditions in Norway may limit the possibility for taking all patients to an invasive centre in acceptable time. In the absence of contraindications and if primary PCI cannot be performed within 90 min by an experienced team, pharmacological reperfusion should be initiated as soon as possible. In patients presenting late (6-12 h after symptom onset) PCI should always be considered due to less efficient thrombolysis in patients treated more than 6 h after symptom onset. A combined pre-hospital pharmacological and mechanical reperfusion strategy might prove to be beneficial and is currently under investigation. The time factor is essential for any method of revascularization, hence the possibility of offering pre-hospital thrombolytic therapy throughout Norway must be further developed.

Background: Reduced myocardial function after hypothermia may be metabolic in origin, but the relationship between myocardial metabolism and the various components of hypothermia-mediated dysfunction has not been thoroughly investigated., Methods: In the present study we measured myocardial uptake and oxidation of glucose and oleate in mongrel dogs undergoing cooling to 25 degrees C followed by rewarming to 37 degrees C, using radiolabeled substrates., Results: Segment work index declined from 39.3 +/- 5.1 to 15.1 +/- 2.4 mm Hg in response to cooling from 37 degrees to 25 degrees C and did not recover completely on rewarming (27.2 +/- 4.2 mm Hg, p < 0.05). Oleate uptake declined from 3,251 +/- 619 to 1,043 +/- 356 nmol.min-1.100 g-1 (p < 0.05) when the dogs were cooled from 37 degrees to 25 degrees C. Simultaneously, oxidation rate fell from 1,089 +/- 158 to 354 +/- 83 nmol.min-1.100 g-1 (p < 0.05). On rewarming, oleate uptake was restored to prehypothermic values, whereas its rate of oxidation remained depressed (480 +/- 129 nmol.min-1.100 g-1; p < 0.05). Uptake and oxidation of glucose also declined significantly during cooling. However, both uptake and oxidation of glucose recovered fully on rewarming., Conclusions: The results of the present study demonstrate a reduced capacity to oxidize fatty acids by the myocardium during rewarming after hypothermia.

In the present study we examined the impact of glycolysis and glucose oxidation on myocardial calcium control and mechanical function of fatty acid-perfused rat hearts subjected to hypothermia rewarming. One group (control) was given glucose (11.1 mM) and palmitate (1.2 mM) as energy substrates. In a second group glycolysis was inhibited by iodoacetate (IAA, 100 microM) and replacement of glucose with pyruvate (5 mM), whereas in the third group glucose oxidation was stimulated by administration of dichloroacetate (DCA, 1 mM) and insulin (500 microU/ml). All groups showed a rise in myocardial calcium ([Ca]total in response to hypothermia (10 degrees C). However, [Ca]total was significantly lower both in IAA- and DCA-treated hearts, as compared to controls (2.20 +/- 0.22 and 2.94 +/- 0.20 v 3.83 +/- 0.29 nmol/mg dry wt., P < 0.025). The reduced calcium load in the treated hearts was correlated with higher levels of high energy phosphates. Following rewarming control and DCA-treated hearts still showed elevated [Ca]total, whereas IAA-treated hearts [Ca]total was not different from the pre-hypothermic value. All groups showed a reduction in cardiac output following rewarming. Furthermore, the control group, in contrast to both IAA- and DCA-treated hearts, showed a significant reduction in systolic pressure. These results show that hypothermia-induced calcium uptake in glucose and fatty acid-perfused rat hearts was reduced by two different metabolic approaches: (1) inhibition of glycolysis by IAA while simultaneously by-passing the glycolytic pathway by exogenous pyruvate: and (2) stimulation of glucose oxidation by DCA. Thus, glycolytic ATP is not an essential regulator of sarcolemmal calcium transport under the present experimental conditions. Instead, we suggest that a change in oxidative substrate utilization in favour of carbohydrates may improve myocardial calcium homeostasis during hypothermia and rewarming.

Background: Although long-chain fatty acids are a major energy substrate utilized by the myocardium, changes in the substrate balance toward a predominating fatty acid utilization could jeopardize the myocardium during cardiac operative procedures., Methods: In the present study myocardial substrate utilization was examined during warm continuous blood cardioplegia (4 hours, 37 degrees C), using pigs undergoing cardiopulmonary bypass. Hearts were perfused antegradely in a closed extracorporeal circuit in which cardioplegic donor blood (hematocrit, 22%) containing 14C-glucose and 3H-oleate was delivered to the heart. Arterial and coronary sinus blood samples were taken at intervals for determination of plasma concentrations of energy substrates, as well as glucose and oleate oxidation rates (14CO2 and 3HOH production)., Results: The concentration of fatty acids in the cardioplegic perfusate did not change significantly during the cardiac arrest period. The mean concentration of glucose showed a 30% decline (not significant), whereas the lactate concentration increased from a starting value of 3.12 +/- 0.27 to 6.31 +/- 0.72 mmol/L at the end (mean +/- standard error of the mean; n = 8; p < 0.05). Only fatty acid levels showed a significant (positive) arterial-coronary sinus difference. Myocardial oxidation of oleate varied between 302 +/- 71 and 650 +/- 66 nmol.min-1.heart-1, whereas the range of variation for glucose oxidation was 144 +/- 64 to 355 +/- 107 nmol.min-1.heart-1. However, the changes in fatty acid levels and glucose oxidation rates during the cardiac arrest period were not statistically significant. We calculated that overall glucose oxidation accounted for less than 5% of the total aerobic energy production., Conclusions: The present results demonstrate overreliance on fatty acids as a source of energy during warm continuous blood cardioplegia, consistent with a condition of myocardial insulin resistance.

Although hypothermia is regarded as providing protection of the myocardium during cardiac operations, rapid cooling of the myocardium in the nonarrested state may have detrimental effects on the function of the myocardial cell membrane as a permeability barrier. We therefore measured total cellular calcium in isolated working rat hearts, receiving either glucose (11.1 mmol/L) or glucose plus palmitate (1.2 mmol/L), before, during, and after a 40-minute hypothermic arrest (10 degrees C, Langendorff perfusion). In both groups a rise in total cellular calcium, measured by 45Ca2+ technique, was observed during hypothermia, followed by a decline on rewarming. However, the rise in total cellular calcium during hypothermia was significantly (p < 0.05) higher in hearts perfused with palmitate (from 1.0 +/- 0.2 to 3.5 +/- 0.2 nmol/mg dry weight) compared with that in glucose-perfused hearts (from 1.1 +/- 0.13 to 2.6 +/- 0.2 nmol/mg dry weight). Palmitate-perfused, but not glucose-perfused, hearts showed arrhythmias and delayed pressure development 1 to 2 minutes after rewarming. In addition cardiac output of these hearts was significantly lower (p < 0.025) than that of glucose-perfused hearts 5 to 10 minutes after rewarming. These data show that hypothermia per se causes a net calcium uptake in isolated rat hearts and that this effect is aggravated by high concentrations of fatty acids. Thus the impaired recovery of myocardial function in palmitate-perfused hearts can possibly be related to a distorted calcium handling.

A phospholipase C specific for choline and ethanolamine acyl and plasmalogen glycerophospholipids (PC-PLC) has been described in myocardial tissue. In the present study we investigated whether an endogenous PC-PLC is activated in hypoxic, substrate-free incubations of rat ventricular myocytes. The phosphatidylcholine pool of the myocytes was prelabelled with [14C]choline during a 4-h preincubation (pulse) period. The myocytes were subsequently washed and incubated for another 2 h (chase period) in normoxic, hypoxic, or hypoxic buffer supplemented with PC-PLC from Bacillus cereus. We hypothesized that an increase in the total (intracellular plus extracellular) content of [14C]phosphocholine (one of the products resulting from PC-PLC action on phosphatidylcholine) throughout the chase period would indicate PC-PLC activity. Instead, an apparent decrease was observed for this parameter in all myocyte groups (17-29%), even in the one exposed to exogenous PC-PLC. However, 60 min after the start of the chase period, the level of total [14C]phosphocholine was higher in hypoxic (p = 0.022) and hypoxic + PC-PLC exposed (p = 0.013) myocytes compared with normoxic controls. The total content of [14C]choline increased significantly (p < 0.017) in all myocyte groups during the incubation period (98-153%) as a result of an increment of this metabolite in the buffer. Furthermore, the values measured in hypoxic and hypoxic + PC-PLC exposed myocytes during the first hour of the chase period were significantly (p < 0.017) higher than the corresponding values in normoxic myocytes. The present results do not allow firm conclusions regarding endogenous PC-PLC activation in energy-depleted rat cardiac myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatty acid and glucose oxidation rates were measured in isolated rat hearts undergoing hypothermia and rewarming. The hearts were perfused in the Langendorff mode with Krebs-Henseleit bicarbonate buffer containing 11.1 mM glucose plus 0.6 mM albumin-bound oleic acid as energy substrates. The hearts were stabilized at 37 degrees C and thereafter cooled progressively to 15 degrees C over a period of 60 min. The hearts were kept at this temperature for 10 min and then rewarmed to 37 degrees C during the next 30 min. Control hearts were perfused at 37 degrees C throughout the whole perfusion period. Trace amounts of [14C]glucose or [14C]oleic acid were included in the perfusate, and the rate of substrate oxidation was determined on the basis of the radioactive CO2 production. In normothermic hearts steady state oxidation rates of glucose and oleate were found to be 0.17 +/- 0.01 and 0.51 +/- 0.07 mumol min-1 g-1 dry wt, respectively (mean +/- SEM). In response to hypothermia (15 degrees C) glucose oxidation was reduced by 76% (from 0.17 +/- 0.01 to 0.04 +/- 0.01 mumol min-1 g-1 dry wt) and oleate oxidation by 47% (from 0.51 +/- 0.07 to 0.27 +/- 0.02 mumol min-1 g-1 dry wt). Upon rewarming glucose and fatty acid oxidation rates returned to essentially the same values (0.12 +/- 0.02 and 0.45 +/- 0.04 mumol min-1 g-1 dry wt) as those observed under steady state normothermic conditions. The molar ratio between glucose and fatty acid oxidation was, however, significantly (P < 0.05) lower in hypothermic than in normothermic hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial cell vulnerability to phospholipase C (PC-PLC) attack was investigated in three different preparations of rat myocardial cells: triacylglycerol (TG)-loaded, hypothermic/rewarmed and energy depleted myocytes. The attack by PC-PLC was evaluated as PC-PLC induced glycerol output due to the combined action of phospholipase C and intracellular lipases. PC-PLC induced glycerol output was significantly higher (p < 0.05) in all three myocyte preparations, compared to their respective controls. Cell morphology (% rod shaped myocytes) of TG-loaded or hypothermic/rewarmed myocytes was not different from their controls, whereas energy depleted myocytes almost exclusively were rounded up, due to hypercontraction of the myofilaments. Hypothermic/rewarmed and energy depleted myocytes showed a significantly higher release of lactate dehydrogenase (LDH), compared to their controls although the difference was much more pronounced in the latter. Finally, the cellular contents of ATP were maintained both in TG-loaded and hypothermic rewarmed myocytes, while energy depleted myocytes contained only about 25% of the normal ATP level. These results demonstrate that attack from exogenously added phospholipases can occur, not only in seriously damaged cardiac myocytes, but in myocytes with a more subtle damage as well.

The combined action of phosphatidylcholine preferring phospholipase C (PC-PLC) and intracellular lipases has recently been shown to cause glycerol output in energy deprived rat cardiomyocytes. In the present study we examined the effect of hypothermia and rewarming on PC-PLC evoked glycerol output in freshly isolated, calcium-tolerant myocytes. The cells were preincubated for 60 min at hypothermic (5 degrees C) or normothermic (37 degrees C) conditions in Krebs-Henseleit bicarbonate buffer (pH 7.4) supplemented with 1 mM DL-carnitine, 1% B.S.A. and 5 mM glucose. Addition of PC-PLC resulted in a significantly higher (P less than 0.05) output of glycerol in myocytes undergoing rewarming than in myocytes kept constantly at 5 degrees C or 37 degrees C. The values obtained for PC-PLC induced glycerol output (difference in glycerol output between incubations with and without PC-PLC) were 6.77 +/- 2.6 (37 degrees C), 4.54 +/- 1.7 (5 degrees C) and 22.85 +/- 5.9 (5-37 degrees C) nmol/10(6) cells.h. Rewarming in addition caused a significantly higher (P less than 0.05) leakage of lactate dehydrogenase (LDH) from the rewarmed cells as compared to cells at constant temperatures (5 degrees C or 37 degrees C). However, there was no additional effect of PC-PLC on LDH leakage. The elevated PC-PLC induced glycerol output in rewarmed myocytes was not related to a fall in the percentage of rod-shaped cells or a reduced cellular content of ATP, since no differences could be detected between the various myocyte preparations with respect to these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

The phospholipid bilayer of the plasma membrane plays an important role in forming a functional barrier against leakage of ions and other cell constituents. We have examined the effect of an exogenously added phospholipase C (PLC) on phospholipid degradation in isolated rat myocardial cells subjected to hypothermia (5 degrees C) and hypothermia followed by rewarming to 37 degrees C. The activity of PLC was measured as glycerol output to the incubation medium since the combined action of PLC and endogenous lipases will result in glycerol production. Addition of PLC resulted in a significantly higher output of glycerol in rewarmed myocytes than in myocytes kept constantly at 5 degrees C and 37 degrees C. Rewarmed cells also showed the highest leakage of lactate dehydrogenase (LDH), but there was no additional effect of PLC on LDH leakage. Normal levels of cellular ATP were maintained in all myocyte groups. These results show that rewarming from hypothermia may cause structural derangements in the phospholipid bilayer of the sarcolemma which in turn could favor attack by endogenous phospholipases.

A radioimmunoassay for myeloperoxidase was established with the use of affinity-purified anti-(human myeloperoxidase) immunoglobulins. By the use of ion-exchange followed by immunoaffinity chromatography a preparation of immunoreactive, catalytically active myeloperoxidase was obtained from fresh human plasma. In non-denaturing gel electrophoresis, the plasma preparation showed about four catalytically active components of mobility very similar to that of the granulocyte enzyme. SDS/polyacrylamide-gel electrophoresis combined with protein blotting showed that the two polypeptides of strongest antigenicity in the plasma preparation corresponded in Mr to the large and the small subunits of the granulocyte enzyme. In addition, the plasma preparation contained a higher-Mr immunoreactive polypeptide, possibly a precursor form of the enzyme, together with another of Mr similar to that of the large subunit of eosinophil peroxidase.