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Abstract Background Cardiogenic shock (CS) occurs in 5–10% of patients with acute myocardial infarction (AMI), and the condition is associated with a 30-day mortality rate of up to 50%. Most of the AMI patients are in SCAI SHOCK stage B upon hospital arrival, but some of these patients will progression through the stages to overt shock (SCAI C-E). Around one third of patients who develop CS are not in shock at the time of hospital admission. Pro-B-type natriuretic peptide (proband) is a biomarker closely related to CS development. The aim of this study is to investigate the potential for preventing progression of hemodynamic instability by early inotropic support with low-dose dobutamine infusion administrated after revascularization in AMI patients with intermediate to high risk of in-hospital CS development. Methods This investigator-initiated, double-blinded, placebo-controlled, randomized, single-center, clinical trial will include 100 AMI patients (≥ 18 years) without CS at hospital admission and at intermediate-high risk of in-hospital CS development (ORBI risk score ≥ 10). Patients will be randomized in a 1:1 ratio to a 24 h intravenous (IV) infusion of dobutamine (5 μg/kg/min) or placebo (NaCl) administrated after acute percutaneous coronary intervention (PCI) (

Abstract Background Inflammation in ST-segment elevation myocardial infarction (STEMI) is an important contributor to both acute myocardial ischemia and reperfusion injury after primary percutaneous coronary intervention (PCI). Methylprednisolone is a glucocorticoid with potent anti-inflammatory properties with an acute effect and is used as an effective and safe treatment of a wide range of acute diseases. The trial aims to investigate the cardioprotective effects of pulse-dose methylprednisolone administered in the pre-hospital setting in patients with STEMI transferred for primary PCI. Methods This trial is a randomized, blinded, placebo-controlled prospective clinical phase II trial. Inclusion will continue until 378 patients with STEMI have been evaluated for the primary endpoint. Patients will be randomized 1:1 to a bolus of 250 mg methylprednisolone intravenous or matching placebo over a period of 5 min in the pre-hospital setting. All patients with STEMI transferred for primary PCI at Rigshospitalet, Copenhagen University Hospital, Denmark, will be screened for eligibility. The main eligibility criteria are age ≥ 18 years, acute onset of chest pain with

Background: Intracoronary physiology, particularly fractional flow reserve (FFR), has been used as a guide for revascularization for patients with coronary artery disease (CAD). The optimal treatment in the physiological grey-zone area has been unclear and remains subject to ongoing debate. Methods: We conducted a systematic review of randomized controlled trials and observational studies comparing the prognostic effect of percutaneous coronary revascularization (PCI) and optimal medical therapy (OMT) in patients with CAD. Studies were identified by medical literature databases. The outcomes of interest were major adverse cardiac events (MACE) and its components, death, myocardial infarction (MI), and repeat revascularization. Results: A total of 16 studies with 27,451 patients were included. The pooled analysis demonstrated that PCI was associated with a prognostic advantage over OMT in patients with FFR value ≤0.80 (RR: 0.64, 95 % CI: 0.45–0.90, p 0.80 were shown to benefit more from OMT (RR 1.38, 95 % CI 1.24–1.53, p 0.80, OMT was associated with favorable outcomes over PCI in reducing the risk of MACE. However, among patients with FFR values ≤0.80, revascularization was superior in terms of reducing MACE. The available evidence supports the guideline-recommended use of an FFR cut-off of ≤0.80.

[This corrects the article DOI: 10.1371/journal.pone.0208645.].

Background The long‐term course of coronary atherosclerosis has not been studied in large nationwide cohorts. Understanding the natural history of coronary atherosclerosis could help identify patients at risk for future coronary events. Methods and Results All coronary artery segments with

Abstract As part of normal ageing, conductance arteries lose their cushion function, left ventricle (LV) filling and also left atrial emptying are impaired. The relation between conductance artery stiffness and LV diastolic function is normally explained by arterial hypertension and LV hypertrophy as needed intermediaries. We examined whether age-related aortic stiffening may influence LV diastolic function in normal healthy subjects. Aortic distensibility and pulse wave velocity (PWV) were related to LV emptying and filling parameters and left atrial emptying parameters as determined by magnetic resonance imaging in 36 healthy young ( 35 years) with normal arterial blood pressure and myocardial mass. In the overall cohort, total aorta PWV correlated to a decrease in LV peak-emptying volume (r = 0.43), LV peak-filling (r = 0.47), passive atrial emptying volume (r = 0.66), and an increase in active atrial emptying volume (r = 0.47) (all p 35-year-old were considered (r = 0.53; p

IntroductionA higher 30-day mortality has been observed in patients with first-presentation ST elevation myocardial infarction (STEMI) who have no standard modifiable cardiovascular risk factors (SMuRFs), i. e., diabetes, hypertension, hyperlipidemia, and current smoker. In this study, we evaluate the clinical outcomes and CMR imaging characteristics of patients with and without SMuRFs who presented with first-presentation STEMI.MethodsPatients from the Third DANish Study of Acute Treatment of Patients With ST-Segment Elevation Myocardial Infarction (DANAMI-3) with first-presentation STEMI were classified into those with no SMuRFs vs. those with at least one SMuRF.ResultsWe identified 2,046 patients; 283 (14%) SMuRFless and 1,763 (86%) had >0 SMuRF. SMuRFless patients were older (66 vs. 61 years, p < 0.001) with more males (84 vs. 74%, p < 0.001), more likely to have left anterior descending artery (LAD) as the culprit artery (50 vs. 42%, p = 0.009), and poor pre-PCI (percutaneous coronary intervention) TIMI (thrombolysis in myocardial infarction) flow ≤1 (78 vs. 64%; p < 0.001). There was no difference in all-cause mortality, non-fatal reinfarction, or hospitalization for heart failure at 30 days or at long-term follow-up. CMR imaging was performed on 726 patients. SMuRFless patients had larger acute infarct size (17 vs. 13%, p = 0.04) and a smaller myocardial salvage index (42 vs. 50%, p = 0.02). These differences were attenuated when the higher LAD predominance and/or TIMI 0-1 flow were included in the model.ConclusionDespite no difference in 30-day mortality, SMuRFless patients had a larger infarct size and a smaller myocardial salvage index following first-presentation STEMI. This association was mediated by a larger proportion of LAD culprits and poor TIMI flow pre-PCI.Clinical trial registrationclinicaltrials.gov, unique identifier: NCT01435408 (DANAMI 3-iPOST and DANAMI 3-DEFER) and NCT01960933 (DANAMI 3-PRIMULTI).

Background Left ventricular hypertrophy (LVH) has often been supposed to be associated with abnormal myocardial blood flow and resistance. The aim of this study was to evaluate and quantify the physiological and pathological changes in myocardial blood flow and microcirculatory resistance in patients with and without LVH attributable to severe aortic stenosis. Methods and Results Absolute coronary blood flow and microvascular resistance were measured using a novel technique with continuous thermodilution and infusion of saline. In addition, myocardial mass was assessed with cardiac magnetic resonance imaging. Fifty‐three patients with aortic valve stenosis were enrolled in the study. In 32 patients with LVH, hyperemic blood flow per gram of tissue was significantly decreased compared with 21 patients without LVH (1.26±0.48 versus 1.66±0.65 mL·min−1·g−1; P=0.018), whereas minimal resistance indexed for left ventricular mass was significantly increased in patients with LVH (63 [47–82] versus 43 [35–63] Wood Units·kg; P=0.014). Conclusions Patients with LVH attributable to severe aortic stenosis had lower hyperemic blood flow per gram of myocardium and higher minimal myocardial resistance compared with patients without LVH.

Abstract Background Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD. Methods From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale. Results Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p

Background: Remodeling due to myocardial infarction (MI) significantly increases patient arrhythmic risk. Simulations using patient-specific models have shown promise in predicting personalized risk for arrhythmia. However, these are computationally- and time- intensive, hindering translation to clinical practice. Classical machine learning (ML) algorithms (such as K-nearest neighbors, Gaussian support vector machines, and decision trees) as well as neural network techniques, shown to increase prediction accuracy, can be used to predict occurrence of arrhythmia as predicted by simulations based solely on infarct and ventricular geometry. We present an initial combined image-based patient-specific in silico and machine learning methodology to assess risk for dangerous arrhythmia in post-infarct patients. Furthermore, we aim to demonstrate that simulation-supported data augmentation improves prediction models, combining patient data, computational simulation, and advanced statistical modeling, improving overall accuracy for arrhythmia risk assessment.Methods: MRI-based computational models were constructed from 30 patients 5 days post-MI (the “baseline” population). In order to assess the utility biophysical model-supported data augmentation for improving arrhythmia prediction, we augmented the virtual baseline patient population. Each patient ventricular and ischemic geometry in the baseline population was used to create a subfamily of geometric models, resulting in an expanded set of patient models (the “augmented” population). Arrhythmia induction was attempted via programmed stimulation at 17 sites for each virtual patient corresponding to AHA LV segments and simulation outcome, “arrhythmia,” or “no-arrhythmia,” were used as ground truth for subsequent statistical prediction (machine learning, ML) models. For each patient geometric model, we measured and used choice data features: the myocardial volume and ischemic volume, as well as the segment-specific myocardial volume and ischemia percentage, as input to ML algorithms. For classical ML techniques (ML), we trained k-nearest neighbors, support vector machine, logistic regression, xgboost, and decision tree models to predict the simulation outcome from these geometric features alone. To explore neural network ML techniques, we trained both a three - and a four-hidden layer multilayer perceptron feed forward neural networks (NN), again predicting simulation outcomes from these geometric features alone. ML and NN models were trained on 70% of randomly selected segments and the remaining 30% was used for validation for both baseline and augmented populations.Results: Stimulation in the baseline population (30 patient models) resulted in reentry in 21.8% of sites tested; in the augmented population (129 total patient models) reentry occurred in 13.0% of sites tested. ML and NN models ranged in mean accuracy from 0.83 to 0.86 for the baseline population, improving to 0.88 to 0.89 in all cases.Conclusion: Machine learning techniques, combined with patient-specific, image-based computational simulations, can provide key clinical insights with high accuracy rapidly and efficiently. In the case of sparse or missing patient data, simulation-supported data augmentation can be employed to further improve predictive results for patient benefit. This work paves the way for using data-driven simulations for prediction of dangerous arrhythmia in MI patients.

Background The optimal timing of invasive examination and treatment of high‐risk patients with non–ST‐segment–elevation acute coronary syndrome has not been established. We investigated the efficacy of early invasive coronary angiography compared with standard‐care invasive coronary angiography on the risk of all‐cause mortality according to the GRACE (Global Registry of Acute Coronary Events) risk score in a predefined subgroup analysis of the VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) trial. Methods and Results Patients with clinical suspicion of non–ST‐segment–elevation acute coronary syndrome with ECG changes indicating new ischemia and/or elevated troponin, in whom invasive coronary angiography was clinically indicated and deemed logistically feasible within 12 hours, were eligible for inclusion. Patients were randomized 1:1 to an early (≤12 hours) or standard (48–72 hours) invasive strategy. The primary outcome of the present study was all‐cause mortality. Of 2147 patients randomized in the VERDICT trial, 2092 patients had an available GRACE risk score. Of these, 1021 (48.8%) patients had a GRACE score >140. During a median follow‐up of 4.1 years, 192 (18.8%) and 54 (5.0%) patients died in the high and low GRACE score groups, respectively. The risk of death with the early invasive strategy was increased in patients with a GRACE score ≤140 (hazard ratio [HR], 2.04 [95% CI, 1.16–3.59]), whereas there was a trend toward a decreased risk of death with the early invasive strategy in patients with a GRACE score >140 (HR, 0.83 [95% CI, 0.63–1.10]) (Pinteraction=0.006). Conclusions In patients with non–ST‐segment–elevation acute coronary syndrome, we found a significant interaction between timing of invasive coronary angiography and GRACE score on the risk of death. Randomized clinical trials are warranted to establish the efficacy and safety among high‐risk and low‐risk patients with non–ST‐segment–elevation acute coronary syndrome. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02061891.

Transcutaneous aortic valve implantation (TAVI) has led to a paradigm shift in the treatment of severe aortic stenosis (AS) in the elderly and is expanding to still younger and lower-risk patients with severe AS as an alternative to surgical aortic valve replacement (SAVR). While the role of coronary artery bypass grafting with SAVR is well-documented, the analog of percutaneous coronary intervention with TAVI is less so. The aim of this review is to provide an overview of the important challenges in treating severe AS and co-existing coronary artery disease in patients planned for TAVI.

Background In ST‐segment–elevation myocardial infarction, angiography‐based complete revascularization is superior to culprit‐lesion‐only percutaneous coronary intervention. Quantitative flow ratio (QFR) is a novel, noninvasive, vasodilator‐free method used to assess the hemodynamic significance of coronary stenoses. We aimed to investigate the incremental value of QFR over angiography in nonculprit lesions in patients with ST‐segment–elevation myocardial infarction undergoing angiography‐guided complete revascularization. Methods and Results This was a retrospective post hoc QFR analysis of untreated nontarget vessels (any degree of diameter stenosis [DS]) from the randomized multicenter COMFORTABLE AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST‐Elevation Myocardial Infarction) trial by assessors blinded for clinical outcomes. The primary end point was cardiac death, spontaneous nontarget vessel myocardial infarction, and clinically indicated nontarget vessel revascularization (ie, ≥70% DS by 2‐dimensional quantitative coronary angiography or ≥50% DS and ischemia) at 5 years. Of 1161 patients with ST‐segment–elevation myocardial infarction, 946 vessels in 617 patients were analyzable by QFR. At 5 years, the rate of the primary end point was significantly higher in patients with QFR ≤0.80 (n=35 patients, n=36 vessels) versus QFR >0.80 (n=582 patients, n=910 vessels) (62.9% versus 12.5%, respectively; hazard ratio [HR], 7.33 [95% CI, 4.54–11.83], P30% DS by 3‐dimensional quantitative coronary angiography. Conclusions Our study suggests incremental value of QFR over angiography‐guided percutaneous coronary intervention for nonculprit lesions among patients with ST‐segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Background: Coronary collateral circulation and conditioning from remote ischemic coronary territories may protect culprit myocardium in the elderly, and younger STEMI patients could suffer from larger infarcts. We evaluated the impact of age on myocardial salvage and long-term prognosis in a contemporary STEMI cohort. Methods: Of 1603 included STEMI patients 807 underwent cardiac magnetic resonance. To assess the impact of age on infarct size and left ventricular ejection fraction (LVEF) as well as the composite endpoint of death and re-hospitalization for heart failure we stratified the patients by an age cut-off of 60 years. Results: Younger STEMI patients had smaller final infarcts (10% vs. 12%, P = 0.012) and higher final LVEF (60% vs. 58%, P = 0.042). After adjusting for multiple potential confounders age did not remain significantly associated with infarct size and LVEF. During 4-year follow-up, the composite endpoint occurred less often in the young (3.2% vs. 17.2%; P

AimsInsulin resistance associates with development of metabolic syndrome and risk of cardiovascular disease. The link between insulin resistance and cardiovascular disease is complex and multifactorial. Confirming the genetic link between insulin resistance, type 2 diabetes, and coronary artery disease, as well as the extent of coronary artery disease, is important and may provide better risk stratification for patients at risk. We investigated whether a genetic risk score of 53 single nucleotide polymorphisms known to be associated with insulin resistance phenotypes was associated with diabetes and burden of coronary artery disease.Methods and resultsWe genotyped patients with a coronary angiography performed in the capital region of Denmark from 2010-2014 and constructed a genetic risk score of the 53 single nucleotide polymorphisms. Logistic regression using quartiles of the genetic risk score was performed to determine associations with diabetes and coronary artery disease. Associations with the extent of coronary artery disease, defined as one-, two- or three-vessel coronary artery disease, was determined by multinomial logistic regression. We identified 4,963 patients, of which 17% had diabetes and 55% had significant coronary artery disease. Of the latter, 27%, 14% and 14% had one, two or three-vessel coronary artery disease, respectively. No significant increased risk of diabetes was identified comparing the highest genetic risk score quartile with the lowest. An increased risk of coronary artery disease was found for patients with the highest genetic risk score quartile in both unadjusted and adjusted analyses, OR 1.21 (95% CI: 1.03, 1.42, p = 0.02) and 1.25 (95% CI 1.06, 1.48, pConclusionsAmong patients referred for coronary angiography, only a strong genetic predisposition to insulin resistance was associated with risk of coronary artery disease and with a greater disease burden.

Objective To prospectively validate the CT-Valve score, a new risk score designed to identify patients with valvular heart disease at a low risk of coronary artery disease (CAD) who could benefit from multislice CT (MSCT) first instead of coronary angiography (CAG).Methods This was a prospective cohort study of patients referred for valve surgery in the Capital Region of Denmark and Odense University Hospital from the 1 February 2015 to the 1 February 2017. MSCT was implemented for patients with a CT-Valve score ≤7 at the referring physician’s discretion. Patients with a history of CAD or chronic kidney disease were excluded. The primary outcome was the proportion of patients needing reevaluation with CAG after MSCT and risk of CAD among the patients determined to be low to intermediate risk.Results In total, 1149 patients were included. The median score was 9 (IQR 3) and 339 (30%) had a score ≤7. MSCT was used for 117 patients. Of these 29 (25%) were reevaluated and 9 (7.7%) had CAD. Of the 222 patients with a score ≤7 that did not receive an MSCT, 14 (6%) had significant CAD. The estimated total cost of evaluation among patients with a score ≤7 before implementation was €132 093 compared with €79 073 after, a 40% reduction. Similarly, estimated total radiation before and after was 608 mSv and 362 mSv, a 41% reduction. Follow-up at a median of 32 months (18–48) showed no ischaemic events for patients receiving only MSCT.Conclusion The CT-Valve score is a valid method for determining risk of CAD among patients with valvular heart disease. Using a score ≤7 as a cut-off for the use of MSCT is safe and cost-effective.

Background: Patients with cyanotic congenital heart disease (CCHD) may have a low burden of atherosclerosis. Endothelial dysfunction is an early stage of atherosclerosis and endothelial function is previously studied in smaller CCHD groups with different techniques and variable results. We aimed to examine endothelial function and carotid atherosclerosis in a larger group of CCHD patients. Methods: This multicentre study assessed endothelial function in adults with CCHD and controls by measuring the dilatory response of the brachial artery to post-ischemic hyperaemia (endothelium-dependent flow-mediated-vasodilatation (FMD)), and to nitroglycerin (endothelium-independent nitroglycerin-induced dilatation (NID)). Flow was measured at baseline and after ischaemia (reactive hyperaemia). Carotid-intima-media-thickness (CIMT), prevalence of carotid plaque and plaque thickness (cPT-max) were evaluated ultrasonographically. Lipoproteins, inflammatory and vascular markers, including sphingosine-1-phosphate (S1P) were measured. Results: Forty-five patients with CCHD (median age 50 years) and 45 matched controls (median age 52 years) were included. The patients presented with lower reactive hyperaemia (409 ± 114% vs. 611 ± 248%, p

Background Efficacy data on drug‐eluting stents (DES) versus bare‐metal stents (BMS) in saphenous vein grafts are controversial. We aimed to compare DES with BMS among patients undergoing saphenous vein grafts intervention regarding long‐term outcome. Methods and Results In this multinational trial, patients were randomized to paclitaxel‐eluting or BMS. The primary end point was major adverse cardiac events (cardiac death, nonfatal myocardial infarction, and target‐vessel revascularization at 1 year. Secondary end points included major adverse cardiac events and its individual components at 5‐year follow‐up. One hundred seventy‐three patients were included in the trial (89 DES versus 84 BMS). One‐year major adverse cardiac event rates were lower in DES compared with BMS (2.2% versus 16.0%, hazard ratio, 0.14; 95% CI, 0.03–0.64, P=0.01), which was mainly driven by a reduction of subsequent myocardial infarctions and need for target‐vessel revascularization. Five‐year major adverse cardiac event rates remained lower in the DES compared with the BMS arm (35.5% versus 56.1%, hazard ratio, 0.40; 95% CI, 0.23–0.68, P

BackgroundIt 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.MethodsThe 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.ResultsA 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.ConclusionIn 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 numberNCT01496638.

ObjectiveMorbidity and mortality due to heart failure (HF) as a complication of myocardial infarction (MI) is high, and remains among the leading causes of death and hospitalisation. This study investigated the association between family history of MI with or without HF, and the risk of developing HF after first MI.MethodsThrough nationwide registries, we identified all individuals aged 18–50 years hospitalised with first MI from 1997 to 2016 in Denmark. We identified 13 810 patients with MI, and the cohort was followed until HF diagnosis, second MI, 3 years after index MI, emigration, death or the end of 2016, whichever occurred first. HRs were estimated by Cox hazard regression models adjusted for sex, age, calendar year and comorbidities (reference: patients with no family history of MI).ResultsAfter adjustment, we observed an increased risk of MI-induced HF for those having a sibling with MI with HF (HR 2.05, 95% CI 1.02 to 4.12). Those having a sibling with MI without HF also had a significant, but lower increased risk of HF (HR 1.39, 95% CI 1.05 to 1.84). Parental history of MI with or without HF was not associated with HF.ConclusionIn this nationwide cohort, sibling history of MI with or without HF was associated with increased risk of HF after first MI, while a parental family history was not, suggesting that shared environmental factors may predominate in the determination of risk for developing HF.

Patients receiving psychiatric medication, like the antipsychotic drug haloperidol, are at an increased risk of sudden cardiac death (SCD). Haloperidol blocks the cardiac rapidly-activating delayed rectifier potassium current, thereby increasing electrical dispersion of repolarization which can potentially lead to arrhythmias. Whether these patients are also at a higher risk to develop SCD during an acute myocardial infarction (AMI) is unknown. AMI locally shortens action potential duration, which might further increase repolarization dispersion and increase the risk of arrhythmia in the presence of haloperidol compared to without. Our aim was to test whether treatment with haloperidol implies an increased risk of SCD when eventually experiencing AMI. Twenty-eight female Danish Landrace pigs were randomized into three groups: low dose haloperidol (0.1 mg/kg), high dose (1.0 mg/kg) or vehicle-control group. One hour after haloperidol/vehicle infusion, AMI was induced by balloon-occlusion of the mid-left anterior descending coronary artery and maintained for 120 min, followed by 60 min of reperfusion. VF occurred during occlusion in 7/11 pigs in the control group, 3/11 in the low dose (p = 0.198) and 2/6 in the high dose group (p = 0.335). High dose haloperidol significantly prolonged QT, and reduced heart rate, vascular resistance and blood pressure before and during AMI. Premature ventricular contractions in phase 1b during AMI were reduced with high dose haloperidol. AMI-induced arrhythmia was not aggravated in pigs with haloperidol treatment. Our results do not suggest that AMI is contributing to the excess mortality in patients treated with antipsychotic drugs seen in epidemiological studies. Keywords: Antipsychotic drugs, Haloperidol, Sudden cardiac death, Acute myocardial infarction, Ventricular fibrillation, Porcine model

Background Potassium disturbances per se increase the risk of ventricular fibrillation (VF). Whether potassium disturbances in the acute phase of ST‐segment–elevation myocardial infarction (STEMI) are associated with VF before primary percutaneous coronary intervention (PPCI) is uncertain. Methods and Results All consecutive STEMI patients were identified in the Eastern Danish Heart Registry from 1999 to 2016. Comorbidities and medication use were assessed from Danish nationwide registries. Potassium levels were collected immediately before PPCI start. Multivariate logistic models were performed to determine the association between potassium and VF. The main analysis included 8624 STEMI patients of whom 822 (9.5%) had VF before PPCI. Compared with 6693 (77.6%) patients with normokalemia (3.5–5.0 mmol/L), 1797 (20.8%) patients with hypokalemia (5.0 mmol/L) were older with more comorbidities. After adjustment, patients with hypokalemia and hyperkalemia had a higher risk of VF before PPCI (odds ratio 1.90, 95% CI 1.57–2.30, P

[This corrects the article DOI: 10.1371/journal.pone.0226625.].

AIMS:To investigate seasonality and association of increased enterovirus and influenza activity in the community with ventricular fibrillation (VF) risk during first ST-elevation myocardial infarction (STEMI). METHODS:This study comprised all consecutive patients with first STEMI (n = 4,659; aged 18-80 years) admitted to the invasive catheterization laboratory between 2010-2016, at Copenhagen University Hospital, Rigshospitalet, covering eastern Denmark (2.6 million inhabitants, 45% of the Danish population). Hospital admission, prescription, and vital status data were assessed using Danish nationwide registries. We utilized monthly/weekly surveillance data for enterovirus and influenza from the Danish National Microbiology Database (2010-2016) that receives copies of laboratory tests from all Danish departments of clinical microbiology. RESULTS:Of the 4,659 consecutively enrolled STEMI patients, 581 (12%) had VF before primary percutaneous coronary intervention. In a subset (n = 807), we found that VF patients experienced more generalized fatigue and flu-like symptoms within 7 days before STEMI compared with the patients without VF (OR 3.39, 95% CI 1.76-6.54). During the study period, 2,704 individuals were diagnosed with enterovirus and 19,742 with influenza. No significant association between enterovirus and VF (OR 1.00, 95% CI 0.99-1.02), influenza and VF (OR 1.00, 95% CI 1.00-1.00), or week number and VF (p-value 0.94 for enterovirus and 0.89 for influenza) was found. CONCLUSION:We found no clear seasonality of VF during first STEMI. Even though VF patients had experienced more generalized fatigue and flu-like symptoms within 7 days before STEMI compared with patients without VF, no relationship was found between enterovirus or influenza exposure and occurrence of VF.

[This corrects the article DOI: 10.1371/journal.pone.0226936.].

Abstract Background Cohort studies have revealed an increased risk for ventricular fibrillation (VF) and sudden cardiac death (SCD) in patients with atrial fibrillation (AF). In this study, we hypothesized that single nucleotide polymorphisms (SNP) previously associated with AF may be associated with the risk of VF caused by first ST-segment elevation myocardial infarction (STEMI). Methods We investigated association of 24 AF-associated SNPs with VF in the prospectively assembled case–control study among first STEMI-patients of Danish ancestry. Results We included 257 cases (STEMI with VF) and 537 controls (STEMI without VF). The median age at index infarction was 60 years for the cases and 61 years for the controls (p = 0.100). Compared to the control group, the case group was more likely to be male (86% vs. 75%, p = 0.001), have a history of AF (7% vs. 2%, p = 0.006) or hypercholesterolemia (39% vs. 31%, p = 0.023), and a family history of sudden death (40% vs. 25%, p

An amendment to this paper has been published and can be accessed via the original article.

BACKGROUND:The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. METHODS:1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. RESULTS:Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p

ObjectivesThe aim of the study was to investigate the incidence, risk factors and long-term prognosis of acute kidney injury (AKI) in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (primary PCI).MethodA large-scale, retrospective cohort study based on procedure-related variables, biochemical and mortality data collected between 2009 and 2014 at Rigshospitalet, Copenhagen, Denmark. AKI was defined as an increase in serum creatinine of 25% during the first 72 hours after the index procedure.ResultsA total of 4239 patients were treated with primary PCI of whom 4002 had available creatinine measurements allowing for assessment of AKI and inclusion in this study. The mean creatinine value upon presentation for all patients was 84 μmol/l (standard deviation (SD) ±40) and 97 μmol/l (SD ±53) at peak. AKI occurred in a total of 765 (19.1%) patients. Independent risk factors for the occurrence of AKI were age, time from symptom onset to procedure, peak value of troponin-T, female sex and the contrast volume to eGFR ratio. In a multivariable adjusted analysis AKI was independently associated with a higher mortality rate at 5 years follow-up (hazard ratio 1.39 [95%-confidence interval 1.03-1.88]).ConclusionIn STEMI patients treated with primary PCI one in five experiences acute kidney injury, which was associated with a substantial increase in both short- and long-term mortality.

BackgroundMidregional proadrenomedullin (MR‐proADM) has demonstrated prognostic potential after myocardial infarction (MI). Yet, the prognostic value of MR‐proADM at admission has not been examined in patients with ST‐segment–elevation MI (STEMI). Methods and ResultsThe aim of this substudy, DANAMI‐3 (The Danish Study of Optimal Acute Treatment of Patients with ST‐segment–elevation myocardial infarction), was to examine the associations of admission concentrations of MR‐proADM with short‐ and long‐term mortality and hospital admission for heart failure in patients with ST‐segment–elevation myocardial infarction. Outcomes were assessed using Cox proportional hazard models and area under the curve using receiver operating characteristics. In total, 1122 patients were included. The median concentration of MR‐proADM was 0.64 nmol/L (25th–75th percentiles, 0.53–0.79). Within 30 days 23 patients (2.0%) died and during a 3‐year follow‐up 80 (7.1%) died and 38 (3.4%) were admitted for heart failure. A doubling of MR‐proADM was, in adjusted models, associated with an increased risk of 30‐day mortality (hazard ratio, 2.67; 95% confidence interval, 1.01–7.11; P=0.049), long‐term mortality (hazard ratio, 3.23; 95% confidence interval, 1.97–5.29; P

BACKGROUND:Recent GWAS studies have identified more than 300 SNPs associated with variation in blood pressure. We investigated whether a genetic risk score constructed from these variants is associated with burden of coronary heart disease. METHODS:From 2010-2014, 4,809 individuals admitted to coronary angiography in Capital Region of Copenhagen were genotyped. We calculated hypertension GRS comprised of GWAS identified SNPs associated with blood pressure. We performed logistic regression analyses to estimate the risk of hypertension and prevalent CHD. We also assessed the severity of CHD associated with the GRS. The analyses were performed using GRS quartiles. We used the Inter99 cohort to validate our results and to investigate for possible pleiotropy for the GRS with other CHD risk factors. RESULTS:In COGEN, adjusted odds ratios comparing the 2nd, 3rd and 4th cumulative GRS quartiles with the reference were 1.12(95% CI 0.95-1.33), 1.35(95% CI 1.14-1.59) and 1.29(95% CI 1.09-1.53) respectively, for prevalent CHD. The adjusted multinomial logistic regression showed that 3rd and 4th GRS quartiles were associated with increased odds of developing two(OR 1.33, 95% CI 1.04-1.71 and OR 1.36, 95% CI 1.06-1.75, respectively) and three coronary vessel disease(OR 1.77, 95% CI 1.36-2.30 and OR 1.65, 95% CI 1.26-2.15, respectively). Similar results for incident CHD were observed in the Inter99 cohort. The hypertension GRS did not associate with type 2 diabetes, smoking, BMI or hyperlipidemia. CONCLUSION:Hypertension GRS quartiles were associated with an increased risk of hypertension, prevalent CHD, and burden of coronary vessel disease in a dose-response pattern. We showed no evidence for pleiotropy with other risk factors for CHD.

Several common genetic variants have been associated with either ventricular fibrillation (VF) or sudden cardiac death (SCD). However, replication efforts have been limited. Therefore, we aimed to analyze whether such variants may contribute to VF caused by first ST-elevation myocardial infarction (STEMI).We analyzed 27 single nucleotide polymorphisms (SNP) previously associated with SCD/VF in other cohorts, and examined whether these SNPs were associated with VF caused by first STEMI in the GEnetic causes of Ventricular Arrhythmias in patients with first ST-elevation Myocardial Infarction (GEVAMI) study on ethnical Danes. The GEVAMI study is a prospective case-control study involving 257 cases (STEMI with VF) and 537 controls (STEMI without VF).Of the 27 candidate SNPs, one SNP (rs11720524) located in intron 1 of SCN5A which was previously associated with SCD was significantly associated with VF caused by first STEMI. The major C-allele of rs11720524 was present in 64% of the cases and the C/C genotype was significantly associated with VF with an odds ratio (OR) of 1.87 (95% CI: 1.12-3.12; P = 0.017). After controlling for clinical differences between cases and controls such as age, sex, family history of sudden death, alcohol consumption, previous atrial fibrillation, statin use, angina, culprit artery, and thrombolysis in myocardial infarction (TIMI) flow, the C/C genotype of rs11720524 was still significantly associated with VF with an OR of 1.9 (95% CI: 1.05-3.43; P = 0.032). Marginal associations with VF were also found for rs9388451 in HEY2 gene. The CC genotype showed an insignificant risk for VF with OR = 1.50 (95% CI: 0.96-2.40; P = 0.070).One common intronic variant in SCN5A suggested an association with VF caused by first STEMI. Further studies into the functional abnormalities associated with the noncoding variant in SCN5A may lead to important insights into predisposition to VF during STEMI.

BackgroundApproximately one third of patients with ST‐segment elevation myocardial infarction (STEMI) have left ventricular hypertrophy (LVH), which is associated with impaired outcome. However, the causal association between LVH and outcome in STEMI is unknown. We evaluated the association between LVH and: myocardial infarct size, area at risk, myocardial salvage, microvascular obstruction, left ventricular (LV) function (all determined by cardiac magnetic resonance [CMR]), and all‐cause mortality and readmission for heart failure in STEMI patients treated with primary percutaneous coronary intervention. Methods and ResultsIn this substudy of the DANAMI‐3 trial, 764 patients underwent CMR. LVH was defined by CMR and considered present if LV mass exceeded 77 (men) and 67 g/m2 (women). One hundred seventy‐eight patients (24%) had LVH. LVH was associated with a larger final infarct size (15% [interquartile range {IQR}, 10–21] vs 9% [IQR, 3–17]; P