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Jan Hansen,1,2,* Jacob Johnsen,1,2,* Jan Møller Nielsen,1,2 Charlotte Brandt Sørensen,1,2 Casper Carlsen Elkjær,1,2 Nichlas Riise Jespersen,1,2 Hans Erik Bøtker1,2 1Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark*These authors contributed equally to this workCorrespondence: Jacob JohnsenDepartment of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, DenmarkTel +45 2674 3580Email jacob.johnsen@clin.au.dkPurpose: The mechanism of cardioprotection by Kv7.1– 5 (KCNQ1-5) channels inhibition by XE991 is unclear. We examined the impact of administration time on the cardioprotective efficacy of XE991, the involvement of key pro-survival kinases, and the importance of the Kv7 subchannels.Methods: Isolated perfused rat hearts were divided into five groups: 1) vehicle, 2) pre-, 3) post- or 4) pre- and post-ischemic administration of XE991 or 5) chromanol 293B (Kv7.1 inhibitor) followed by infarct size quantification. HL-1 cells undergoing simulated ischemia/reperfusion were exposed to either a) vehicle, b) pre-, c) per-, d) post-ischemic administration of XE991 or pre-, per- and post-ischemic administration of e) XE991, f) Chromanol 293B or g) HMR1556 (Kv7.1 inhibitor). HL-1 cell injury was evaluated by propidium iodide/Hoechst staining. Pro-survival kinase activation of Akt, Erk and STAT3 in XE991-mediated HL-1 cell protection was evaluated using phosphokinase inhibitors. Kv7 subtype expression was examined by RT-PCR and qPCR.Results: XE991, but not Chromanol 293B, reduced infarct size and improved hemodynamic recovery in all isolated heart groups. XE991 protected HL-1 cells when administered during simulated ischemia. Minor activation of the survival kinases was observed in cells exposed to XE991 but pharmacological inhibition of kinase activation did not reduce XE991-mediated protection. Kv7 subchannels 1– 5 were all present in rat hearts but predominately Kv7.1 and Kv7.4 were present in HL-1 cells and selective Kv7.1 did not reduce ischemia/reperfusion injury.Conclusion: The cardioprotective efficacy of XE991 seems to depend on its presence during ischemia and early reperfusion and do not rely on RISK (p-Akt and p-Erk) and SAFE (p-STAT3) pathway activation. The protective effect of XE991 seems mainly mediated through the Kv7.4 subchannel.Keywords: cardioprotection, Kv7 channels, myocardial ischemia reperfusion injury, myocardial infarction

Lene Hüche Nielsen,1 Bjarne Linde Nørgaard,2 Hans Henrik Tilsted,3 Niels Peter Sand,4 Jesper Møller Jensen,2 Morten Bøttcher,5 Axel Diederichsen,6 Jess Lambrechtsen,7 Lone Deibjerg Kristensen,8 Hans Mickley,6 Henrik Munkholm,1 Ole Gøtzsche,2 Lars Lyhne Knudsen,5 Hans Erik Bøtker,2 Lars Pedersen,9 Morten Schmidt,2,9 1Department of Cardiology, Lillbaelt Hospital-Vejle, Vejle, Denmark; 2Department of Cardiology Aarhus University Hospital-Skejby, Aarhus, Denmark; 3Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; 4Department of Cardiology, Hospital of Southwestern Denmark-Esbjerg, Esbjerg, Denmark; 5Department of Cardiology, Regional Hospital Herning, Herning, Denmark; 6Department of Cardiology, Odense University Hospital, Odense, Denmark; 7Department of Cardiology, Odense University Hospital-Svendborg, Svendborg, Denmark; 8Department of Cardiology, Regional Hospital Silkeborg, Silkeborg, Denmark; 9Department of Clinical Epidemiology, Aarhus University Hosptial, Aarhus, DenmarkBackground: As a subregistry to the Western Denmark Heart Registry (WDHR), the Western Denmark Cardiac Computed Tomography Registry (WDHR-CCTR) is a clinical database established in 2008 to monitor and improve the quality of cardiac computed tomography (CT) in Western Denmark.Objective: We examined the content, data quality, and research potential of the WDHR-CCTR.Methods: We retrieved 2008–2012 data to examine the 1) content; 2) completeness of procedure registration using the Danish National Patient Registry as reference; 3) completeness of variable registration comparing observed vs expected numbers; and 4) positive predictive values as well as negative predictive values of 19 main patient and procedure variables.Results: By December 31, 2012, almost 22,000 cardiac CTs with up to 40 variables for each procedure have been registered. Of these, 87% were coronary CT angiography performed in patients with symptoms indicative of coronary artery disease. Compared with the Danish National Patient Registry, the overall procedure completeness was 72%. However, an additional medical record review of 282 patients registered in the Danish National Patient Registry, but not in the WDHR-CCTR, showed that coronary CT angiographies accounted for only 23% of all nonregistered cardiac CTs, indicating >90% completeness of coronary CT angiographies in the WDHR-CCTR. The completeness of individual variables varied substantially (range: 0%–100%), but was >85% for more than 70% of all variables. Using medical record review of 250 randomly selected patients as reference standard, the positive predictive value for the 19 variables ranged from 89% to 100% (overall 97%), whereas the negative predictive value ranged from 97% to 100% (overall 99%). Stratification by center status showed consistently high positive and negative predictive values for both university (96%/99%) and nonuniversity centers (97%/99%).Conclusion: WDHR-CCTR provides ongoing prospective registration of all cardiac CTs performed in Western Denmark since 2008. Overall, the registry data have a high degree of completeness and validity, making it a valuable tool for clinical epidemiological research. Keywords: coronary computed tomography angiography, database, epidemiology, registries

Leif Thuesen,1 Lisette Okkels Jensen,2 Hans Henrik Tilsted,3 Michael Mæng,1 Christian Terkelsen,1 Per Thayssen,2 Jan Ravkilde,3 Evald Høj Christiansen,1 Hans Erik Bøtker,1 Morten Madsen,4 Jens F Lassen1 1Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; 2Department of Cardiology, Odense University Hospital, Odense, Denmark; 3Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Skejby, Denmark Aim: To describe a new research tool, designed to reflect routine clinical practice and relying on population-based health care databases to detect clinical events in randomized clinical trials. Background: Randomized clinical trials often focus on short-term efficacy and safety in a controlled environment. Trial follow-up may be linked with study-related investigations and differ from routine clinical practice. Because treatment and control in randomized trials differ from daily practice, trial results may have reduced general applicability and may be of limited value in clinical decision-making. Further, it is economically very costly to conduct randomized clinical trials. Methods and results: Population-based health care databases collect data continuously and prospectively, and make it possible to monitor lifelong outcomes of cardiac interventions in large numbers of patients. This strengthens external validity by eliminating the effects of study-related monitoring or diagnostic tests. Further, follow-up data can be obtained at low expense. Importantly, data sources encompassing a complete population are likely to reflect clinical practice. Because population-based health care databases collect data for quality-control and administrative purposes unrelated to scientific investigations, certain biases, such as nonresponse bias, recall bias, and bias from losses to follow-up, can be avoided. Conclusion: Event detection using population-based health care databases is a new research tool in interventional cardiology that may allow large, low-cost, randomized clinical trials to reflect daily clinical practice, covering a broad range of patients and end points with complete lifelong follow-up. Keywords: clinical study, national registries, event detection, PCI, coronary stents

Henrik Toft Sørensen,1 Tina Christensen,1 Hans Erik Bøtker,2 Christian Fynbo Christiansen,1 Cecilia H Fuglsang,1 Sigrid B Gribsholt,1 Frederik Pagh Bredahl Kristensen,1 Kristina Laugesen,1 Anne Sofie D Laursen,1 Mette Nørgaard,1 Morten Schmidt,1 Nils Skajaa,1 Frederikke S Troelsen,1 Lars Pedersen1 1Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, DenmarkCorrespondence: Henrik Toft Sørensen, Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Olof Palmes Allé 43-45, Aarhus, 8200, Denmark, Tel +45 87 16 82 15, Email hts@clin.au.dkPurpose: Humans are living longer and may develop multiple chronic diseases in later life. The Better Health in Late Life cohort study aims to improve our understanding of the risks and outcomes of multimorbidity in the Danish population.Methods: A randomly-selected sample of Danish residents who were 50– 65 years of age received a questionnaire and an invitation to participate in this study. Respondents completed an online survey between October 2021 and January 2022 which addressed topics that included self-assessed health, mental health, sleep, specific medical conditions, use of painkillers, diet, alcohol consumption, smoking, physical activity, and body composition. This information was linked to the Danish health and social registries (some established in 1943 and onwards) that maintain data on filled prescriptions, hospital records, socioeconomic status, and health care utilization.Results: Responses were received from 115,431 of the 301,244 residents invited to participate (38%). We excluded respondents who answered none of the questions as well as those who provided no information on sex or indicated an age other than 50– 65 years. Of the 114,283 eligible respondents, 54.8% were female, 30.3% were overweight, and 16.7% were obese. Most participants reported a weekly alcohol consumption of less than seven units and 13.3% were current smokers; 5.2% had a history of hospitalization for solid cancer, and 3.0%, 2.3%, 2.0%, and 0.9% reported chronic pulmonary disease, diabetes, stroke, and myocardial infarction, respectively. The most frequently filled prescriptions were for medications used to treat the nervous system and cardiovascular diseases (38.1% and 37.4%, respectively).Keywords: aging, epidemiology, health registries, life course epidemiology, multimorbidity, prospective cohort

Christine Gyldenkerne,1 Kevin Kris Warnakula Olesen,1,2 Morten Madsen,2 Troels Thim,1 Lisette Okkels Jensen,3 Bent Raungaard,4 Henrik Toft Sørensen,2 Hans Erik Bøtker,1 Michael Maeng11Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Cardiology, Odense University Hospital, Odense, Denmark; 4Department of Cardiology, Aalborg University Hospital, Aalborg, DenmarkPurpose: We examined risk of myocardial infarction and all-cause death associated with the extent of coronary artery disease ascertained by coronary angiography in patients with diabetes mellitus. We hypothesized that risks of myocardial infarction and death were associated with extent of coronary artery disease in diabetes patients.Patients and methods: We conducted a cohort study of patients with type 1 and type 2 diabetes, who underwent coronary angiography from 2004 to 2012. Patients were stratified according to extent of coronary artery disease: 0-, 1-, 2- or 3-vessel disease or diffuse vessel disease. Endpoints were myocardial infarction, all-cause death, and major adverse cardiovascular events (MACE), defined as the composite of myocardial infarction, cardiac death, or ischemic stroke. Adjusted incidence and mortality rate ratios (IRRsadj) were calculated using patients with 0-vessel disease as the reference group. Median follow-up was 3 years for a total of 45,164 person-years.Results: The study included 12,594 diabetes patients. Of these, 3,147 (25.0%) had 0-vessel disease, 1,195 (9.5%) had diffuse vessel disease, 3,001 (23.8%) had 1-vessel disease, 2,220 (17.6%) had 2-vessel disease, and 3,031 (24.1%) had 3-vessel disease. The myocardial infarction rate was 0.4 per 100 person-years (95% CI: 0.3–0.5) in patients with 0-vessel disease. Using patients with 0-vessel disease as reference, the risk of myocardial infarction increased according to the number of diseased vessels (diffuse vessel disease: 1.4 per 100 person-years, IRRadj 3.87, 95% CI: 2.41–6.23; 1-vessel disease: 1.9 per 100 person-years, IRRadj 4.99, 95% CI: 3.33–7.46; 2-vessel disease: 2.7 per 100 person-years, IRRadj 7.14, 95% CI: 4.78–10.65; and 3-vessel disease: 4.3 per 100 person-years, IRRadj 11.42, 95% CI: 7.76–16.82; ptrend

Greg Ridgeway,1–3 Mette Nørgaard,4 Thomas Bøjer Rasmussen,4 William D Finkle,3 Lars Pedersen,4 Hans Erik Bøtker,5 Henrik Toft Sørensen4 1Department of Criminology, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Statistics, University of Pennsylvania, Philadelphia, PA, USA; 3Consolidated Research, Inc., Los Angeles, CA, USA; 4Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 5Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark Objective: The aim of this study was to examine hospital performance measures that account more comprehensively for unique mixes of patients’ characteristics. Design: Nationwide cohort registry-based study within a population-based health care system. Participants: In this study, 331,513 patients discharged with a primary cardiovascular diagnosis from 1 of 26 Danish hospitals during 2011–2015 were included. Data covering all Danish hospitals were drawn from the Danish National Patient Registry and the Danish National Health Service Prescription Database. Main outcome measures: Thirty-day post-admission mortality rates, 30-day post-discharge readmission rates, and the associated numbers needed to harm were measured. Methods: For each index hospital, we used a non-parametric logistic regression model to compute propensity scores. Propensity score weighted patients treated at other hospitals collectively resembled patients treated at the index hospital in terms of age, sex, primary discharge diagnosis, diagnosis history, medications, previous cardiac procedures, and comorbidities. Outcomes for the weighted patients treated at other hospitals formed benchmarks for the index hospital. Doubly robust regression formally tested whether the outcomes of patients at the index hospital differed from the outcomes of the patients used to form the benchmarks. For each index hospital, we computed the false discovery rate, ie, the probability of being incorrect if we claimed the hospital differed from its benchmark. Results: Five hospitals exceeded their benchmark for 30-day mortality rates, with the number needed to harm ranging between 55 and 137. Seven hospitals exceeded their benchmark for readmission, with the number needed to harm ranging from 22 to 71. Our benchmarking approach flagged fewer hospitals as outliers compared with conventional regression methods. Conclusion: Conventional methods flag more hospitals as outliers than our benchmarking approach. Our benchmarking approach accounts more thoroughly for differences in hospitals’ patient case mix, reducing the risk of false-positive selection of suspected outliers. A more comprehensive system of hospital performance measurement could be based on this approach. Keywords: performance measurement, propensity score, doubly robust estimation, case mix adjustment, cohort study

Kasper Adelborg,1 Jens Sundbøll,1,2 Morten Schmidt,1,3 Hans Erik Bøtker,2 Noel S Weiss,4 Lars Pedersen,1 Henrik Toft Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Cardiology, Regional Hospital West Jutland, Herning, Denmark; 4Department of Epidemiology, University of Washington, Seattle, WA, USA Background: Histamine H2 receptor activation promotes cardiac fibrosis and apoptosis in mice. However, the potential effectiveness of histamine H2 receptor antagonists (H2RAs) in humans with heart failure is largely unknown. We examined the association between H2RA initiation and all-cause mortality among patients with heart failure. Methods: Using Danish medical registries, we conducted a nationwide population-based active-comparator cohort study of new users of H2RAs and proton pump inhibitors (PPIs) after first-time hospitalization for heart failure during the period 1995−2014. Hazard ratios (HRs) for all-cause mortality and hospitalization due to worsening of heart failure, adjusting for age, sex, and time between heart failure diagnosis and initiation of PPI or H2RA therapy, index year, comorbidity, cardiac surgery, comedications, and socioeconomic status were computed based on Cox regression analysis. Results: Our analysis included 42,902 PPI initiators (median age 78 years, 46% female) and 3,296 H2RA initiators (median age 76 years, 48% female). Mortality risk was lower among H2RA initiators than PPI initiators after 1 year (26% vs 31%) and 5 years (60% vs 66%). In multivariable analyses, the 1-year HR was 0.80 (95% CI, 0.74–0.86) and the 5-year HR was 0.85 (95% CI, 0.80–0.89). These findings were consistent after propensity score matching and for ischemic and nonischemic heart failure, as for sex and age groups. The rate of hospitalization due to worsening of heart failure was lower among H2RA initiators than PPI initiators. Conclusion: In patients with heart failure, H2RA initiation was associated with 15%–20% lower mortality than PPI initiation. Keywords: heart failure, epidemiology, histamine H2 receptor, mortality

Gro Egholm,1,2,* Morten Madsen,2,* Troels Thim,1 Morten Schmidt,2,3 Evald Høj Christiansen,1 Hans Erik Bøtker,1 Michael Maeng1 1Department of Cardiology, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, 3Department of Internal Medicine, Regional Hospital of Randers, Denmark *These authors contributed equally to this work Background: Registry-based monitoring of the safety and efficacy of interventions in patients with ischemic heart disease requires validated algorithms.Objective: We aimed to evaluate algorithms to identify acute myocardial infarction (AMI) in the Danish National Patient Registry following percutaneous coronary intervention (PCI).Methods: Patients enrolled in clinical drug-eluting stent studies at the Department of Cardiology, Aarhus University Hospital, Denmark, from January 2006 to August 2012 were included. These patients were evaluated for ischemic events, including AMI, during follow-up using an end point committee adjudication of AMI as reference standard.Results: Of 5,719 included patients, 285 patients suffered AMI within a mean follow-up time of 3 years after stent implantation. An AMI discharge diagnosis (primary or secondary) from any acute or elective admission had a sensitivity of 95%, a specificity of 93%, and a positive predictive value of 42%. Restriction to acute admissions decreased the sensitivity to 94% but increased the specificity to 98% and the positive predictive value to 73%. Further restriction to include only AMI as primary diagnosis from acute admissions decreased the sensitivity further to 82%, but increased the specificity to 99% and the positive predictive value to 81%. Restriction to patients admitted to hospitals with a coronary angiography catheterization laboratory increased the positive predictive value to 87%.Conclusion: Algorithms utilizing additional information from the Danish National Patient Registry yield different sensitivities, specificities, and predictive values in registry-based detection of AMI following PCI. We were able to identify AMI following PCI with moderate-to-high validity. However, the choice of algorithm will depend on the specific study purpose. Keywords: Danish National Patient Registry, registry, percutaneous coronary intervention, validity, sensitivity, specificity

Morten Krogh Christiansen, Jesper Møller Jensen, Anders Krogh Brøndberg, Hans Erik Bøtker, Henrik Kjærulf JensenDepartment of Cardiology, Aarhus University Hospital, Aarhus, DenmarkBackground: Control of cardiovascular risk factor is important in secondary prevention of coronary artery disease (CAD) but it is unknown whether treatment targets are achieved in young patients. We aimed to examine the prevalence and control of risk factors in this subset of patients.Methods: We performed a cross-sectional, single-center study on patients with documented CAD before age 40. All patients treated between 2002 and 2014 were invited to participate at least 6 months after the last coronary intervention. We included 143 patients and recorded the family history of cardiovascular disease, physical activity level, smoking status, body mass index, waist circumference, blood pressure, cholesterol levels, metabolic status, and current medical therapy. Risk factor control and treatment targets were evaluated according to the shared guidelines from the European Society of Cardiology.Results: The most common insufficiently controlled risk factors were overweight (113 [79.0%]), low-density lipoprotein cholesterol above target (77 [57.9%]), low physical activity level (78 [54.6%]), hypertriglyceridemia (67 [46.9%]), and current smoking (53 [37.1%]). Almost one-half of the patients fulfilled the criteria of metabolic syndrome. The median (interquartile range) number of uncontrolled modifiable risk factors was 2 (2;4) and only seven (4.9%) patients fulfilled all modifiable health measure targets.Conclusion: Among the youngest patients with CAD, there remains a potential to improve the cardiovascular risk profile.Keywords: coronary artery disease, cardiovascular diseases/prevention and control, health behavior, risk factors, young adult, middle aged

To elucidate a possible explanation for a relatively low bioavailability, the hydrolysis of frusemide in gastrointestinal juices was studied in vitro at concentrations likely to be present in vivo. Between 1.0 and 4.4% of the frusemide molecules were hydrolyzed to 4- chloro-N-furfuryl-5-sulphamoyl-antranilic acid (CSA) after 1 h at 37 degrees C in gastric juices. The rate of hydrolysis was inversely connected to pH. No fall in frusemide concentration was observed and no CSA was found in duodenal juices after 4 h at 37 degrees C. In three buffer solutions with the same pH as three gastric juices frusemide was hydrolyzed to CSA at a lower rate than in the gastric juices (pH 1.2, P less than 0.15;pH 1.4, P less than 0.001; pH 1.6, P less than 0.001). The solubility of frusemide was significantly higher in gastric juice from two fasting subjects (83-104 mg l-1) than in buffer solutions with the same pH (52-58 mg 1-1). The solubility of frusemide was significantly increased (by 40-50%) in gastric juice obtained after pentagastrin stimulation compared with its solubility in the mixed gastric secretion obtained after fasting. The binding of frusemide to macromolecules was 28.0 +/- 9.7% in ventricular secretion after fasting while it was 1.4 +/- 2.6% in the fluid obtained after pentagastrin stimulation. It is concluded that a hydrolysis of frusemide in the stomach prior to absorption cannot explain the relatively low bioavailability of the drug observed after oral intake. [ABSTRACT FROM AUTHOR]

Kevin Kris Warnakula Olesen,1,2 Christine Gyldenkerne,1 Morten Madsen,2 Troels Thim,1 Lisette Okkels Jensen,3 Bent Raungaard,4 Henrik Toft Sørensen,2 Hans Erik Bøtker,1 Michael Maeng11Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Cardiology, Odense University Hospital, Odense, Denmark; 4Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark We thank Xu et al for their interest in our study.1 First, we unfortunately did not have access to LDL measurements which we acknowledge potentially could have provided valuable information. We found that statin treatment increased with the extent of coronary artery disease (CAD) which may lead to underestimation of the actual effect of CAD extent. This is in response to the Letter to the Editor

Karin Biering,1 Hans Erik Bøtker,2 Troels Niemann,3 Niels Henrik Hjollund4,51Department of Occupational Medicine, Regional Hospital West Jutland, Herning, 2Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, 3Department of Cardiology, Regional Hospital West Jutland, Herning, 4WestChronic, Regional Hospital West Jutland, Herning, 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, DenmarkObjective: A relation may exist between self-reported health and adverse events in coronary heart disease. Previous studies have been vulnerable to possible selection bias. In the study reported here, we examined the association between self-rated health and adverse events in terms of cardiac events, cardiac readmissions, and all-cause mortality in a complete cohort of patients treated with percutaneous coronary intervention (PCI).Study design and setting: A cohort of patients with coronary heart disease treated with PCI was followed up with questionnaires 4 weeks after PCI to measure self-rated health and in registers to identify adverse events. Of 1,752 eligible patients under 67 years, 26 died during the first 4 weeks. A total of 224 patients were excluded from the analysis because they were readmitted with a cardiac diagnosis before answering the first questionnaire. We received complete SF-12 Health Survey component summaries from 984 of the remaining 1,502 patients. We used multiple imputation to establish a complete cohort, including nonrespondents.Results: During follow-up, 83 patients died, 220 patients experienced a new cardiac event, and 526 patients experienced a hospital readmission related to coronary heart disease. Poor self-rated health was related to cardiac events, cardiac readmission, and all-cause mortality. The associations were stronger for all-cause mortality than for events and readmissions. Physical health was more important than mental health, but both revealed an exposure–response pattern.Conclusion: Poor self-reported health within 4 weeks of PCI was associated with adverse outcomes during up to 5 years’ follow-up.Keywords: coronary heart disease, patient-reported outcomes, SF-12 adverse events, mortality, multiple imputation

The aim of the present study was to evaluate angiographic late luminal loss after the implantation of sirolimus-eluting Cypher stents and paclitaxel-eluting Taxus stents in patients with diabetes. The study was a Danish multicenter, open-label, randomized trial. One hundred fifty-three patients with diabetes with coronary artery disease were randomized to Cypher (n = 76) or Taxus (n = 77) stent implantation. All patients were followed for 8 months. The primary end point was 8-month angiographic in-stent late luminal loss. This primary end point was reduced in the Cypher group compared with the Taxus group (0.23 +/- 0.54 vs 0.44 +/- 0.52 mm, p = 0.025). Angiographic in-segment restenosis at 8-month follow-up, a secondary end point, was present in 16 patients (Cypher, n = 6; Taxus, n = 10; p = 0.24). Target lesion revascularization was performed in 5 patients (6.5%) and 9 patients (11.8%) in the Cypher and Taxus groups, respectively (p = 0.25). Definite stent thrombosis was observed in 2 patients (in the Taxus group), no patients had probable stent thrombosis, and 1 patient in each group had possible stent thrombosis. Major adverse cardiac events (cardiac death, myocardial infarction, definite stent thrombosis, or target lesion revascularization) were observed in 17 patients (Cypher, n = 6; Taxus, n = 11; p = 0.19). In conclusion, angiographic in-stent late luminal loss is significantly reduced in patients with diabetes by use of the sirolimus-eluting Cypher stent compared with the paclitaxel-eluting Taxus stent. [ABSTRACT FROM AUTHOR]

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca 2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal., Competing Interests: Declaration of competing interest PF is the founder and CEO of Pharmahungary Group, a group of R&D companies. AMS is an adviser to Forcefield Therapeutics and CYTE – Global Network for Clinical Research and sits on the Board of Heqet Therapeutics. CM served as an advisor to Amgen, Boehringer Ingelheim, Bristol Myers Squibb, NovoNordisk and Servier and received speaker honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Berlin Chemie, Novartis and NovoNordisk. No other author had an interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background Estimated pulse wave velocity (ePWV) calculated by equations using age and blood pressure has been suggested as a new marker of mortality and cardiovascular risk. However, the prognostic potential of ePWV during long-term follow-up in patients with symptoms of stable angina remains unknown. Methods and Results In this study, ePWV was calculated in 25 066 patients without diabetes, previous myocardial infarction (MI), stroke, heart failure, or valvular disease (mean age 63.7±10.5 years, 58% male) with stable angina pectoris undergoing elective coronary angiography during 2003 to 2016. Multivariable Cox models were used to assess the association with incident all-cause mortality, MI, and stroke. Discrimination was assessed using Harrell´s C-index. During a median follow-up period of 8.5 years (interquartile range 5.5-11.3 years), 779 strokes, 1233 MIs, and 4112 deaths were recorded. ePWV was associated with all-cause mortality (hazard ratio [HR] per 1 m/s, 1.13; 95% CI, 1.05-1.21) and MI (HR per 1 m/s 1.23, 95% CI, 1.09-1.39) after adjusting for age, systolic blood pressure, body mass index, smoking, estimated glomerular filtration rate, Charlson Comorbidity Index score, antihypertensive treatment, statins, aspirin, and number of diseased coronary arteries. Compared with traditional risk factors, the adjusted model with ePWV was associated with a minor but likely not clinically relevant increase in discrimination for mortality, 76.63% with ePWV versus 76.56% without ePWV, P <0.05. Conclusions In patients with stable angina pectoris, ePWV was associated with all-cause mortality and MI beyond traditional risk factors. However, the added prediction of mortality was not improved to a clinically relevant extent.

Objective: Investigating the cardiovascular system is challenging due to its complex regulation by humoral and neuronal factors. Despite this complexity, many existing research methods are limited to the assessment of a few parameters leading to an incomplete characterization of cardiovascular function. Thus, we aim to establish a murine in vivo model for integrated assessment of the cardiovascular system under conditions of controlled heart rate. Utilizing this model, we assessed blood pressure, cardiac output, stroke volume, total peripheral resistance, and electrocardiogram (ECG)., Hypothesis: We hypothesize that (i) our in vivo model can be utilized to investigate cardiac and vascular responses to pharmacological intervention with the α 1 -agonist phenylephrine, and (ii) we can study cardiovascular function during artificial pacing of the heart, modulating cardiac function without a direct vascular effect., Methods: We included 12 mice that were randomly assigned to either vehicle or phenylephrine intervention through intraperitoneal administration. Mice were anesthetized with isoflurane and intubated endotracheally for mechanical ventilation. We measured blood pressure via a solid-state catheter in the aortic arch, blood flow via a probe on the ascending aorta, and ECG from needle electrodes on the extremities. Right atrium was electrically paced at a frequency ranging from 10 to 11.3 Hz before and after either vehicle or phenylephrine administration., Results: Phenylephrine significantly increased blood pressure, stroke volume, and total peripheral resistance compared to the vehicle group. Moreover, heart rate was significantly decreased following phenylephrine administration. Pacing significantly decreased stroke volume and cardiac output both prior to and after drug administration. However, phenylephrine-induced changes in blood pressure and total peripheral resistance were maintained with increasing pacing frequencies compared to the vehicle group. Total peripheral resistance was not significantly altered with increasing pacing frequencies suggesting that the effect of phenylephrine is primarily of vascular origin., Conclusion: In conclusion, this in vivo murine model is capable of distinguishing between changes in peripheral vascular and cardiac functions. This study underlines the primary effect of phenylephrine on vascular function with secondary changes to cardiac function. Hence, this in vivo model is useful for the integrated assessment of the cardiovascular system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rajanathan, Pedersen, Thomsen, Botker and Matchkov.)

Background Coronary CT angiography with noninvasive fractional flow reserve (FFR) predicts lesion-specific ischemia when compared with invasive FFR. The longer term prognostic value of CT-derived FFR (FFR CT ) is unknown. Purpose To determine the prognostic value of FFR CT when compared with coronary CT angiography and describe the relationship of the numeric value of FFR CT with outcomes. Materials and Methods This prospective subanalysis of the NXT study (Clinicaltrials.gov: NCT01757678) evaluated participants suspected of having stable coronary artery disease who were referred for invasive angiography and who underwent FFR, coronary CT angiography, and FFR CT . The incidence of the composite primary end point of death, myocardial infarction, and any revascularization and the composite secondary end point of major adverse cardiac events (MACE: cardiac death, myocardial infarction, unplanned revascularization) were compared for an FFR CT of 0.8 or less versus stenosis of 50% or greater on coronary CT angiograms, with treating physicians blinded to the FFR CT result. Results Long-term outcomes were obtained in 206 individuals (age, 64 years ± 9.5), including 64% men. At median follow-up of 4.7 years, there were no cardiac deaths or myocardial infarctions in participants with normal FFR CT . The incidence of the primary end point was more frequent in participants with positive FFR CT compared with clinically significant stenosis at coronary CT angiography (73.4% [80 of 109] vs 48.7% [91 of 187], respectively; P < .001), with the majority of outcomes being planned revascularization. Corresponding hazard ratios (HRs) were 9.2 (95% confidence interval [CI]: 5.1, 17; P < .001) for FFR CT and 5.9 (95% CI: 1.5, 24; P = .01) for coronary CT angiography. FFR CT was a superior predictor compared with coronary CT angiography for primary end point (C-index FFR CT , 0.76 vs coronary CT angiography, 0.54; P < .001) and MACE (FFR CT , 0.71 vs coronary CT angiography, 0.52; P = .001). Frequency of MACE was higher in participants with positive FFR CT compared with coronary CT angiography (15.6% [17 of 109] vs 10.2% [19 of 187], respectively; P = .02), driven by unplanned revascularization. MACE HR was 5.5 (95% CI: 1.6, 19; P = .006) for FFR CT and 2.0 ( 95% CI: 0.3, 14; P = .46) for coronary CT angiography. Each 0.05-unit FFR CT reduction was independently associated with greater incidence of primary end point (HR, 1.7; 95% CI: 1.4, 1.9; P < .001) and MACE (HR, 1.4; 95% CI: 1.1, 1.8; P < .001). Conclusion In stable patients referred for invasive angiography, a CT-derived fractional flow reserve (FFR CT ) value of 0.8 or less was a predictor of long-term outcomes driven by planned and unplanned revascularization and was superior to clinically significant stenosis on coronary CT angiograms. Additionally, the numeric value of FFR CT was an independent predictor of outcomes. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Dennie and Rubens in this issue.

Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: We aimed to investigate if lesion-specific ischaemia by invasive fractional flow reserve (FFR) can be predicted by an integrated machine learning (ML) ischaemia risk score from quantitative plaque measures from coronary computed tomography angiography (CTA)., Methods: In a multicentre trial of 254 patients, CTA and invasive coronary angiography were performed, with FFR in 484 vessels. CTA data sets were analysed by semi-automated software to quantify stenosis and non-calcified (NCP), low-density NCP (LD-NCP, < 30 HU), calcified and total plaque volumes, contrast density difference (CDD, maximum difference in luminal attenuation per unit area) and plaque length. ML integration included automated feature selection and model building from quantitative CTA with a boosted ensemble algorithm, and tenfold stratified cross-validation., Results: Eighty patients had ischaemia by FFR (FFR ≤ 0.80) in 100 vessels. Information gain for predicting ischaemia was highest for CDD (0.172), followed by LD-NCP (0.125), NCP (0.097), and total plaque volumes (0.092). ML exhibited higher area-under-the-curve (0.84) than individual CTA measures, including stenosis (0.76), LD-NCP volume (0.77), total plaque volume (0.74) and pre-test likelihood of coronary artery disease (CAD) (0.63); p < 0.006., Conclusions: Integrated ML ischaemia risk score improved the prediction of lesion-specific ischaemia by invasive FFR, over stenosis, plaque measures and pre-test likelihood of CAD., Key Points: • Integrated ischaemia risk score improved prediction of ischaemia over quantitative plaque measures • Integrated ischaemia risk score showed higher prediction of ischaemia than standard approach • Contrast density difference had the highest information gain to identify lesion-specific ischaemia.

Objective: Diagnosing coronary artery disease (CAD) continues to require substantial healthcare resources. Acoustic analysis of transcutaneous heart sounds of cardiac movement and intracoronary turbulence due to obstructive coronary disease could potentially change this. The aim of this study was thus to test the diagnostic accuracy of a new portable acoustic device for detection of CAD., Methods: We included 1675 patients consecutively with low to intermediate likelihood of CAD who had been referred for cardiac CT angiography. If significant obstruction was suspected in any coronary segment, patients were referred to invasive angiography and fractional flow reserve (FFR) assessment. Heart sound analysis was performed in all patients. A predefined acoustic CAD-score algorithm was evaluated; subsequently, we developed and validated an updated CAD-score algorithm that included both acoustic features and clinical risk factors. Low risk is indicated by a CAD-score value ≤20., Results: Haemodynamically significant CAD assessed from FFR was present in 145 (10.0%) patients. In the entire cohort, the predefined CAD-score had a sensitivity of 63% and a specificity of 44%. In total, 50% had an updated CAD-score value ≤20. At this cut-off, sensitivity was 81% (95% CI 73% to 87%), specificity 53% (95% CI 50% to 56%), positive predictive value 16% (95% CI 13% to 18%) and negative predictive value 96% (95% CI 95% to 98%) for diagnosing haemodynamically significant CAD., Conclusion: Sound-based detection of CAD enables risk stratification superior to clinical risk scores. With a negative predictive value of 96%, this new acoustic rule-out system could potentially supplement clinical assessment to guide decisions on the need for further diagnostic investigation., Trial Registration Number: ClinicalTrials.gov identifier NCT02264717; Results., Competing Interests: Competing interests: The current research is financed partly by Acarix A/S by an unrestricted grant. SES is a minor shareholder and part-time consultant in Acarix A/S. BSL is an industrial student at Acarix A/S. MB is part of the Acarix A/S advisory board. MB and SW received an unrestricted institutional research grant from Acarix A/S., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Surgery may necessitate interruption of dual antiplatelet therapy (DAPT) within the first year after coronary drug-eluting stent (DES) implantation. We conducted a population-based cohort study to assess the rate of surgery within the first year after DES implantation, surgery-associated major adverse cardiac events (MACE), reoperation for bleeding within 30 days after surgery, and two nested case-control analyses to explore any association between preoperative antiplatelet therapy, MACE, and reoperation for bleeding. In the cohort of 22,654 patients treated with DES, 1,944 patients (8.6 %) underwent moderate- to high-risk surgery within 12 months. Of these, 62 (3.2 %) experienced MACE and 54 (2.8 %) needed reoperation for bleeding within 30 days. In the nested case-control analyses of 458 cases and controls, where 70 % (n=324) had a first generation DES, absence of preoperative antiplatelet therapy was associated with an increased MACE rate (OR 2.36, 95 % CI 1.02-5.48) compared to single antiplatelet therapy (SAPT) or DAPT. Preoperative SAPT versus DAPT showed no difference in MACE rates (OR 0.85, 95 % CI 0.30-2.40). Surgery within the first month was associated with increased MACE rate (OR 4.67, 95 % CI 2.22-9.83) compared to surgery 2-12 months after DES implantation. Absence of preoperative antiplatelet therapy did not reduce reoperation for bleeding as compared to patients on SAPT or DAPT (OR 1.32, 95 % CI 0.56-3.12). In conclusion, absence of preoperative antiplatelet therapy and surgery within the first month after DES implantation were associated with increased MACE rates.

Aims: Atherosclerosis accelerates with increasing age; however, young women presenting with acute coronary syndromes (ACS) have adverse outcomes compared to men despite less obstructive coronary artery disease. We sought to evaluate the in vivo plaque characteristics and composition of untreated non-culprit lesions (NCL) at two ages (<65 years old and ≥65 years old) in patients with ACS and examine the effect of sex in both groups., Methods and Results: Untreated NCLs from 697 patients with ACS were imaged with greyscale and radiofrequency intravascular ultrasound. NCL plaque morphology, burden, composition, and major adverse cardiac events (MACE) were analysed in both age groups, and a posterior sex-based sub-analysis was performed. Plaques from patients ≥65 (n=974) vs. <65 (n=2,275) years old were longer (median 12.62 mm vs. 10.75 mm, p=0.008) and had greater plaque burden (48.2% vs. 47.5%, p=0.001), necrotic core (12.5% vs. 11.0%, p=0.001) and dense calcium (5.7% vs. 4.0%, p<0.0001). Men <65 years old also had a greater number of fibroatheromas (3.0 vs. 2.0, p=0.007) and NCLs per patient (5.0 vs. 4.0, p=0.004) with larger plaque volumes (47.7% vs. 46.8%, p=0.04), and fewer fibrotic plaques (2.2% vs. 4.4%, p=0.03) than women in the same age group. These sex differences were not observed in patients ≥65 years old. The incidence of MACE during median 3.4 year follow-up did not significantly differ according to age in this study., Conclusions: The current study confirms in vivo that, with aging, plaque burden, necrotic core and calcium content increase significantly. Moreover, gender-specific differences in the extent and composition of coronary plaque are present in patients <65 years (but not ≥65 years) of age, which suggest differential sex-related effects on atherosclerosis development and progression.

Objectives: The aim of this study was to assess whether residual nonculprit (NC) lesions, defined as visual diameter stenosis ≥ 30% after successful percutaneous coronary intervention, affect the rate of future events in patients with acute coronary syndromes., Background: In patients with acute coronary syndromes, approximately one-half of recurrent events after percutaneous coronary intervention arise from untreated lesions., Methods: Patients enrolled in PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) were divided into 3 groups: those with no NC lesions, 1 NC lesion, or ≥ 2 NC lesions. Time to events for major adverse cardiac events was estimated up to 3 years., Results: Among 697 patients, 13.3% had no NC lesions, 19.7% had 1 NC lesion, and 67.0% had ≥ 2 NC lesions. The median diameter stenoses of the NC lesions in the latter 2 groups were 36.7% (interquartile range: 31.0% to 43.4%) and 37.4% (interquartile range: 32.0% to 46.5%), respectively (p = 0.22). At least 1 thin-cap fibroatheroma was present in one-half the patients in each group. At 3 years, the incidence of major adverse cardiac events was 8.5%, 15.2%, and 24.3%, respectively (p = 0.0009). NC lesion-related events occurred in 0%, 5.0%, and 15.9% of patients, respectively (p < 0.0001). Of 105 NC lesion-related clinical events occurring during follow-up, 73 (69.5%) originated from angiographically evident baseline NC lesions (of which 36 had diameter stenosis >50%), while the other 32 arose from normal or near normal segments., Conclusions: Residual NC lesions are common after percutaneous coronary intervention for acute coronary syndromes and portend a higher rate of recurrent ischemic events within 3 years, especially when angiographically more severe. Conversely, the absence of NC lesions by angiography is highly predictive of freedom from events not related to the originally treated culprit lesion(s)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent implantation due to neointimal hyperplasia (NIH). The aim of this study was to use quantitative coronary angiography (QCA) and volumetric intravascular ultrasound (IVUS) to evaluate the effects of the sirolimus-eluting Cypher® stent (SES) and the zotarolimus-eluting Endeavor® stent (ZES) on angiographic late lumen loss and intima hyperplasia in diabetic patients., Methods and Results: In the DiabeDES III trial, 127 patients were randomised to SES or ZES stent implantation. Angiographic 10-month follow-up data were available in 105 patients, including 48 SES and 57 ZES treated patients. Angiographic endpoints were in-stent late lumen loss and minimal lumen diameter. IVUS endpoints included NIH volume and in-stent percent volume obstruction. Baseline clinical characteristics and lesion parameters were similar in the two groups. At 10-month follow-up, angiographic in-stent late lumen loss (0.14±0.37 mm vs. 0.74±0.45 mm, p<0.001) was reduced and minimum lumen diameter was higher (2.36±0.53 mm vs. 1.96±0.65, p<0.001) in the SES group as compared to the ZES group. As compared to the ZES group, NIH volume was significantly reduced in the SES group (median [interquartile range]: 0.0 mm3 [0.0 to 1.2] vs. 16.5 mm3 [6.2 to 31.1], p<0.001). In-stent% volume obstruction was significantly reduced in SES as compared to ZES (median [interquartile range]: 0.0% [0.0-0.7] vs. 13.0% [6.7-20.8], p<0.001)., Conclusions: In diabetic patients, the SES reduced angiographic late lumen loss and inhibited NIH more effectively than ZES.

Aims: Collateral flow may influence long-term results after percutaneous coronary intervention (PCI) because of haemodynamic forces compete with the antegrade flow through the dilated lesion. The aim of the study was to assess the influence of recruitable collateral blood flow on restenosis in patients undergoing PCI with bare metal stents and using optimal antithrombotic treatment., Methods and Results: In 95 patients, 95 de novo lesions were treated with PCI and a bare metal stent. Fractional flow reserve (FFR) at maximum hyperaemia induced by intravenous adenosine was determined. The pressure-derived collateral flow index (CFI) was determined as (P(w)-P(cvp))/(P(a)-P(cvp)), where P(w) represents coronary wedge pressure, P(cvp) central venous pressure, and P(a) mean aortic blood pressure. Both were measured during transient coronary occlusion by a balloon inflation of 30 s. Pre-interventional FFR (0.65 +/- 0.20) correlated inversely with the CFI (0.18 +/- 0.11), r =- 0.356, P < 0.001. After 9 months, binary angiographic restenosis (>/=50% diameter stenosis) was seen in 29.1%. Compared to patients with poorly developed collaterals (CFI < 0.25), patients with well-developed collaterals (CFI >/= 0.25) had a lower pre-interventional FFR (0.50 +/- 0.14 vs. 0.72 +/- 0.18, P < 0.001), a higher CFI (0.33 +/- 0.08 vs. 0.13 +/- 0.07, P < 0.001), and a higher binary restenosis rate (54.2% vs. 19.4, P = 0.003). CFI*100 was an independent predictor of restenosis after 9 months (odds ratio 1.07, 95% CI 1.02-1.12, P = 0.016)., Conclusion: Recruitable collateral blood flow measured during balloon inflation predicts angiographic instent restenosis in PCI patients treated with bare metal stents.

Objective: We sought to evaluate the effects of captopril on glucose-related metabolism during hypothermic cardioplegic storage and subsequent reperfusion., Methods: We compared hearts from control pigs with hearts from pigs treated with increasing oral doses of captopril for 3 weeks (12.5-150 mg daily), an intravenous bolus (25 mg) before operation, and captopril-containing cardioplegic solution (1 mg/L). The hearts were excised after infusion of cold crystalloid cardioplegic solution and stored in saline solution (4 degrees C-6 degrees C). In one series we studied myocardial blood flow and arteriovenous differences in oxygen, glucose, lactate, glutamate, and alanine during 60 minutes of postcardioplegic blood reperfusion. In this series captopril-treated hearts were reperfused with captopril-containing blood (1 mg/L). In another series we obtained biopsy specimens from the left ventricle throughout 30 hours of hypothermic cardioplegic storage and monitored tissue content of energy-rich phosphates, glycogen, glutamate, and alanine., Results: Captopril increased glutamate and alanine release 11- to 17-fold at the start of reperfusion (P <.001). Furthermore, captopril increased myocardial oxygen and glucose uptake during reperfusion (P <.001 for both), whereas lactate release and myocardial blood flow were unaffected by captopril. At the start of reperfusion, there was a positive correlation between glutamate release and glucose uptake in captopril-treated hearts (r = 0.66, P =.05). We found no statistically significant differences between captopril and control hearts in tissue content of adenosine triphosphate, glycogen, glutamate, alanine, or lactate during 30 hours of cardioplegic storage., Conclusions: The metabolic effects of captopril are strictly related to reperfusion, during which oxidative metabolism of glucose is improved. The captopril-induced increase in glutamate and alanine release at the start of reperfusion after cardioplegic storage may reflect a switch in metabolism of glucose-related amino acids.

Background: Impaired vasodilatation capacity in patients with angina pectoris and a normal coronary arteriogram (syndrome X [SX]) has been reported. Most studies report on the response in epicardial vessels. This does not necessarily reflect compromised myocardial microcirculation. Lack of the NO precursor L-arginine has been suggested as a possible cause., Methods and Results: Myocardial blood flow (MBF) was measured, using PET, at rest (MBF-rest) and during intravenous dipyridamole (MBF-DIP) in 25 women (mean age 53+/-7 years) with SX. Thirty healthy volunteers served as controls. One group (A) consisted of 15 age-matched female volunteers (54+/-10 years). The other control group consisted of 15 young healthy women (B; 24+/-5 years). In 12 SX patients, MBF-rest and MBF during cold pressor testing were also measured after infusion of L-arginine (6.7 g/min for 45 minutes). The increase in MBF after cold pressor testing was similar in the SX group compared with controls. L-arginine did not affect MBF-rest (0.83+/-0.14 versus 0.89+/-0.13 mL. g-1. min-1) or MBF after cold pressor test (0.95+/-0.10 versus 1. 03+/-0.17 mL. g-1min-1). In contrast, the hyperemic response to DIP was blunted compared with the group A controls (1.68+/-0.49 versus 2. 34+/-0.45 mL. g-1. min-1, P<0.05); this resulted in a significant reduction of the coronary flow reserve in SX patients relative to controls (2.03+/-0.53 versus 2.96+/-0.63 mL. g-1. min-1, P<0.01)., Conclusions: In patients with SX, the microcirculatory response to cold, reflecting the endothelium function, is normal and unaltered by intravenous L-arginine. This suggests preserved microcirculatory endothelial function. However, a markedly attenuated hyperemic flow and flow reserve after DIP suggest a dysfunction of the adenosine-mediated endothelium-independent vasodilatation at the microcirculatory level in these patients.

Insulin resistance is common in patients with angina pectoris, a positive exercise electrocardiogram, and normal coronary angiograms (syndrome X). It is still not known whether insulin resistance affects the cardiac muscle itself and, if so, whether insulin resistance involves myocardial hemodynamics and energy metabolism. We investigated hemodynamics as well as metabolite exchanges across the heart and the forearm in eight patients with syndrome X and eight control subjects during a baseline period after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Myocardial hemodynamics and metabolism were studied at rest, during pace stress, and in the recovery period after pacing. Neither coronary sinus blood flow nor forearm blood flow differed between the groups before and during the clamp. Whole body insulin-stimulated glucose uptake was decreased in the patients (15.6+/-2.1 vs. 23.1+/-2.0 micromol x kg-1 x min-1). Insulin-stimulated glucose uptake in the forearm and the cardiac muscle was equally reduced in the patients (46+/-5 and 48+/-5%). Myocardial glucose uptake correlated with total arterial delivery in the control subjects (r = 0.63, P < 0.01), but not in patients (r = 0.22, P = 0.13). Carbohydrate and lipid oxidation was similar in the two groups at rest, and changes during the clamp were not different in control subjects and patients either at rest, during pacing, or in the recovery period. Patients with syndrome X exhibit myocardial insulin resistance, but cardiac energy metabolism remains unaffected. In patients with syndrome X, insulin-stimulated glucose uptake is independent from myocardial blood flow.

We wished to study the effects of intravenous glucose/ insulin infusion to brain-dead pigs on the hepatic glycogen content. Four groups of 40-kg pigs were studied: brain-dead and control pigs given isotonic saline or glucose/insulin (7.5 mg glucose/kg/min, 1.25 mU insulin/kg/ min) (n = 5 to 10 in each group). Brain death was induced by inflating a balloon placed in the epidural space. In brain-dead pigs given saline, liver glycogen decreased from 45 +/- 11 mmol/g DNA (mean +/- SEM) to 7 +/- 3 mmol/ g DNA after 6 hours. Thereafter, it increased to 28 +/- 9 mmol/g DNA after 9 hours (P = .05 compared with the 6-hour measurement). These changes were accompanied by transient increases in plasma adrenaline, glucose, free fatty acids (FFA), and glucagon. Following glucose/ insulin infusion, hepatic glycogen increased steadily and was approximately double after 12 hours (P < .01) in both brain-dead and in non-brain-dead pigs. In brain-dead pigs, the increases in the aforementioned blood measurements were smaller following glucose/insulin infusion than following saline infusion. However, studies of longer duration will be needed to examine these effects on a time scale that is relevant to human organ donors. In conclusion, the decrease in hepatic glycogen content after brain death could be prevented by intravenous glucose/insulin infusion probably because of a reduction of the adrenaline response to the induction of brain death.