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Abstract Myocardial infarction with nonobstructive coronary arteries (MINOCA) has several possible underlying causes, including coronary microvascular dysfunction (CMD). Early cardiovascular magnetic resonance imaging (CMR) is recommended, however cannot provide a diagnosis in 25% of cases. Quantitative stress CMR perfusion mapping can identify CMD, however it is unknown if CMD is present during long-term follow-up of MINOCA patients. Therefore, this study aimed to evaluate presence of CMD during long-term follow-up in MINOCA patients with an initial normal CMR scan. MINOCA patients from the second Stockholm myocardial infarction with normal coronaries study (SMINC-2), with a normal CMR scan at median 3 days after hospitalization were investigated with comprehensive CMR including stress perfusion mapping a median of 5 years after the index event, together with age- and sex-matched volunteers without symptomatic ischemic heart disease. Cardiovascular risk factors, medication and symptoms of myocardial ischemia measured by the Seattle Angina Questionnaire 7 (SAQ-7), were registered. In total, 15 patients with MINOCA and an initial normal CMR scan (59 ± 7 years old, 60% female), and 15 age- and sex-matched volunteers, underwent CMR. Patients with MINOCA and an initial normal CMR scan had lower global stress perfusion compared to volunteers (2.83 ± 1.8 vs 3.53 ± 0.7 ml/min/g, p = 0.02). There were no differences in other CMR parameters, hemodynamic parameters, or cardiovascular risk factors, except for more frequent use of statins in the MINOCA patient group compared to volunteers. In conclusion, global stress perfusion is lower in MINOCA patients during follow-up, compared to age- and sex-matched volunteers, suggesting that CMD may be a possible pathophysiological mechanism in MINOCA. Clinical Trial Registration: Clinicaltrials.gov identifier NCT02318498. Registered 2014-12-17.

Abstract Aims Coronary microvascular dysfunction (CMD) has been proposed as an important pathophysiological mechanism in Takotsubo syndrome (TTS). Our aims were (i) to evaluate and compare levels of CMD in patients with TTS and patients with ischaemia and no obstructive coronary arteries (INOCA) and (ii) to investigate associations between CMD and clinical parameters, left ventricular function, and coronary atherosclerosis in TTS. Methods and results We conducted a prospective study of 27 female TTS patients and an equally sized, age‐ and gender‐matched, cohort of INOCA patients. Coronary microvascular function was quantified invasively using the index of microcirculatory resistance (IMR), coronary flow reserve (CFR), and resistive reserve ratio (RRR). CMD was defined as IMR ≥ 25 and/or CFR ≤ 2. In the TTS patients, left ventricular function was assessed with echocardiography and cardiovascular magnetic resonance (CMR) imaging, and coronary atherosclerosis was visualized with intravascular ultrasound with near‐infrared spectroscopy (IVUS‐NIRS). The incidence of CMD was higher in the TTS patients than in the INOCA cohort (78% vs. 44%, P = 0.01), with higher IMR (30 vs. 14, P = 0.002), lower CFR (1.8 vs. 2.8, P = 0.009), and lower RRR (2.1 vs. 3.5, P = 0.003). In apical compared with midventricular TTS, IMR was numerically higher (50 vs. 28, P = 0.20), whereas CFR and RRR were lower (1.5 vs. 2.5, P = 0.003 and 1.6 vs. 2.7, P = 0.01, respectively). Global longitudinal strain and global circumferential strain, assessed with CMR imaging, were more impaired in apical than in midventricular TTS (−11 vs. −14, P

Abstract Despite abundant knowledge about the relationship between inflammation and coronary atherosclerosis, it is still unknown whether systemic inflammation measured as high-sensitivity C-reactive protein (hsCRP) is associated with coronary atherosclerosis in a general population. This study aimed to examine the association between hsCRP and coronary computed tomography angiography (CCTA)-detected coronary atherosclerosis in a population-based cohort. Out of 30,154 randomly invited men and women aged 50 to 64 years in the Swedish Cardiopulmonary Bioimage Study (SCAPIS), 25,408 had a technically acceptable CCTA and analysed hsCRP. Coronary atherosclerosis was defined as presence of plaque of any degree in any of 18 coronary segments. HsCRP values were categorised in four groups. Compared with hsCRP below the detection limit, elevated hsCRP (≥ 2.3 mg/L) was weakly associated with any coronary atherosclerosis (OR 1.15, 95% CI 1.07–1.24), coronary diameter stenosis ≥ 50% (OR 1.27, 95% CI 1.09–1.47), ≥ 4 segments involved (OR 1.13, 95% CI 1.01–1.26 ) and severe atherosclerosis (OR 1.33, 95% CI 1.05–1.69) after adjustment for age, sex and traditional risk factors. The associations were attenuated after further adjustment for body mass index (BMI), although elevated hsCRP still associated with noncalcified plaques (OR 1.16, 95% CI 1.02–1.32), proposed to be more vulnerable. In conclusion, the additional value of hsCRP to traditional risk factors in detection of coronary atherosclerosis is low. The association to high-risk noncalcified plaques, although unlikely through a causal pathway, could explain the relationship between hsCRP and clinical coronary events in numerous studies.

Abstract Background In the aftermath of a myocardial infarction with non-obstructive coronary arteries (MINOCA) or Takotsubo syndrome (TS), patients commonly express high levels of stress and anxiety. Current treatment alternatives rarely address these issues. Methods The study is a randomised controlled trial, where 90 patients with a discharge diagnosis of MINOCA or TS who also report symptoms of stress or anxiety will be randomised 2–6 weeks after their cardiac event. The treatment consists of 10 weeks of Internet-based cognitive behaviour therapy (CBT) and starts immediately after randomisation for the treatment group. The control group receives usual care. Main outcomes are symptoms of anxiety measured with the Hospital Anxiety and Depression scale, anxiety subscale, and perceived stress measured with the Perceived Stress Scale, 14-item version, 10 weeks after randomisation. Secondary measures include cardiac specific anxiety, symptoms of post-traumatic stress, quality of life, cortisol measured in hair and physiological stress responses (heart rate variability, blood pressure and saliva cortisol) during a stress procedure. Ten weeks after randomisation, the control group will also receive treatment. Long-term follow-up in the self-report measures mentioned above will be conducted 20 and 50 weeks after randomisation where the total group’s development over time is followed, and the groups receiving intervention early versus late compared. Discussion At present, there are no randomised studies evaluating psychological treatment for patients with MINOCA or TS. There is an urgent need for treatment alternatives aiming at relieving stress and anxiety considering the high mental stress and anxiety levels observed in MINOCA and TS, leading to decreased quality of life. CBT aiming at reducing mental stress has been shown to be effective regarding prognosis in patients with coronary artery disease. The current protocol describes a randomised open-label controlled trial evaluating an Internet-based CBT program for reduction of stress and anxiety in patients with increased mental stress and/or anxiety with a discharge diagnosis of either MINOCA or TS. Trial registration ClinicalTrials.gov NCT04178434 . Registered on 26 November 2019

Objectives Early identification of inpatients at risk of developing delirium and implementing preventive measures could avoid up to 40% of delirium cases. Machine learning (ML)-based prediction models may enable risk stratification and targeted intervention, but establishing their current evolutionary status requires a scoping review of recent literature.Methods We searched ten databases up to June 2022 for studies of ML-based delirium prediction models. Eligible criteria comprised: use of at least one ML prediction method in an adult hospital inpatient population; published in English; reporting at least one performance measure (area under receiver-operator curve (AUROC), sensitivity, specificity, positive or negative predictive value). Included models were categorised by their stage of maturation and assessed for performance, utility and user acceptance in clinical practice.Results Among 921 screened studies, 39 met eligibility criteria. In-silico performance was consistently high (median AUROC: 0.85); however, only six articles (15.4%) reported external validation, revealing degraded performance (median AUROC: 0.75). Three studies (7.7%) of models deployed within clinical workflows reported high accuracy (median AUROC: 0.92) and high user acceptance.Discussion ML models have potential to identify inpatients at risk of developing delirium before symptom onset. However, few models were externally validated and even fewer underwent prospective evaluation in clinical settings.Conclusion This review confirms a rapidly growing body of research into using ML for predicting delirium risk in hospital settings. Our findings offer insights for both developers and clinicians into strengths and limitations of current ML delirium prediction applications aiming to support but not usurp clinician decision-making.

The working diagnosis Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA) is being increasingly recognized with the common use of high-sensitivity troponins and coronary angiography, accounting for 5% to 10% of all acute myocardial infarction presentations. Cardiac magnetic resonance (CMR) imaging is pivotal in patients presenting with suspected MINOCA, mainly to delineate those with a nonischemic cause, for example, myocarditis and Takotsubo syndrome, from those with true ischemic myocardial infarction, that is, MINOCA. The optimal timing for CMR imaging in patients with suspected MINOCA has been uncertain and, until recently, not been examined prospectively. Previous retrospective studies have indicated that the diagnostic yield decreases with time from the acute event. The SMINC studies (Stockholm Myocardial Infarction with Normal Coronaries) show that CMR should be performed early in all patients with the working diagnosis of MINOCA, with the possible exception of patients who are clearly identified as having Takotsubo syndrome as determined by echocardiography. In addition to CMR imaging, other investigations of importance in selected patients may be pulmonary artery computed tomography to exclude pulmonary embolism, optical coherence tomography to identify plaque disruption, and acetylcholine provocation to identify coronary artery spasm. Imaging of patients with the working diagnosis MINOCA, which is centered on CMR together with supplemental investigations, results in a clear diagnosis in approximately threequarters of the patients. This is a good example of personalized medicine, because a correct diagnosis will not only increase the satisfaction of the individual patient but also result in optimizing treatment without harming the patient. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different populations and may have separate pathophysiological mechanisms, with greater inflammatory activity in MINOCA compared to MI-CAD. Helicobacter pylori (Hp) can cause systemic inflammation and has been associated with cardiovascular disease (CVD). We aimed to investigate whether Hp infection is associated with concentrations of protein biomarkers of inflammation and CVD. In a case-control study, patients with MINOCA (n = 99) in Sweden were included, complemented by matched subjects with MI-CAD (n = 99) and controls (n = 100). Protein biomarkers were measured with a proximity extension assay in plasma samples collected 3 months after MI. The seroprevalence of Hp and cytotoxin-associated gene A (CagA) was determined using ELISA. The associations between protein levels and Hp status were studied with linear regression. The prevalence of Hp was 20.2%, 19.2%, and 16.0% for MINOCA, MI-CAD, and controls, respectively (p = 0.73). Seven proteins were associated with Hp in an adjusted model: tissue plasminogen activator (tPA), interleukin-6 (IL-6), myeloperoxidase (MPO), TNF-related activation-induced cytokine (TRANCE), pappalysin-1 (PAPPA), soluble urokinase plasminogen activator receptor (suPAR), and P-selectin glycoprotein ligand 1 (PSGL-1). Hp infection was present in one in five patients with MI, irrespective of the presence of obstructive CAD. Inflammatory proteins were elevated in Hp-positive subjects, thus not ruling out that Hp may promote an inflammatory response and potentially contribute to the development of CVD.

Background and aim: In the aftermath of a myocardial infarction with non-obstructive coronary arteries (MINOCA) or Takotsubo syndrome (TS), patients commonly express high levels of stress and anxiety. Current treatment alternatives rarely address these issues. The planned E-health Treatment of Stress and Anxiety in Stockholm Myocardial Infarction With Non-obstructive Coronaries Study (e-SMINC) aims to evaluate the effects of an internet-based intervention, building on cognitive behavioral therapy (CBT) by comparison with treatment as usual using an RCT approach. This was a small-scale single arm study designed to test the feasibility of the RCT, addressing uncertainties regarding recruitment, data collection, and intervention delivery. Methods: Participant recruitment and screening took place before discharge from the coronary care unit at a large Swedish hospital. Eligible patients were invited to a nine-step psychologist guided, internet-based CBT intervention. The sample size was set in advance to 10 participants completing the intervention. The recruitment and flow of participants were documented and evaluated in relation to seven pre-defined progression criteria. Self-reports of anxiety (HADS-A), stress (PSS-14), cardiac anxiety (CAQ), posttraumatic stress (IES-6) and quality of life (Rand-36), collected at screening, pre-intervention and post-intervention, were analysed descriptively and by effect sizes (Cohen's d). Individual interviews targeting participant experiences were conducted. Results: Six out of seven progression criteria yielded no concerns. Out of 49 patients with a working diagnosis of MINOCA or TS, 31 were eligible for screening, 26 consented to participate, and 14 were eligible with regard to symptoms of stress and/or anxiety. Eleven completed the pre-assessment and were given access the intervention, and 9 completed the intervention. Only the number of patients screened prior to eligibility assessment was slightly lower than expected, indicating possible concerns. Self-reports of anxiety, stress, cardiac anxiety, posttraumatic stress, and quality of life all indicated symptom reduction from pre- to post-intervention, generally showing large effect sizes (d = 0.6–2.6). The general consensus among participants was that the programme was helpful and relevant, and that the personal contact with the psychologist was highly valued. Setting aside time to complete assignments was found critical. Conclusion: Conducting a full scale RCT was found feasible. Inclusion of more study sites and minor amendments to the protocol and intervention were decided to improve feasibility further. Trial registration: Clinicaltrials.gov NCT04178434

Background: Morphine delays ticagrelor effect in ST-segment elevation myocardial infarction (STEMI) patients, likely due to impaired gastrointestinal motility. The aim was to evaluate if the morphine dose impacts ticagrelor effect in STEMI patients presenting for percutaneous coronary intervention. Methods: The patient cohort was divided into quartiles based on morphine dose (mg/kg). Platelet inhibition was measured with vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) and high on-treatment platelet reactivity (HPR) was defined as ≥50% PRI. Blood samples for analyses of VASP PRI and plasma concentrations of morphine, ticagrelor, and AR-C124910XX were taken at baseline (arrival in the catherization lab) and one and 2 h later. The primary endpoint was PRI difference between the highest morphine dose quartile compared with the lowest morphine dose quartile 2 h after study inclusion. Results: A total of 80 STEMI patients treated with morphine and ticagrelor were included in the study. The time from ticagrelor administration to randomization did not differ significantly between the different morphine dose quartiles, with an overall median of 44 min (interquartile range, IQR: 35–57 min). The primary outcome variable PRI at 2 h after study inclusion was significantly higher in patients in quartile 4 compared with quartile 1 (61.7% [42.4–91.2] vs. 26.6% [9.17–73.6], p = 0.024). Ticagrelor concentrations were significantly lower in both quartile 3 and 4 compared with quartile 1 at all the three timepoints. Conclusion: STEMI patients with higher weight-based morphine doses had significantly lower uptake and antiplatelet effect after a 180 mg loading dose ticagrelor.

Background Takotsubo syndrome (TS) is a potentially life‐threatening acute cardiac syndrome with a clinical presentation similar to myocardial infarction and for which the natural history, management, and outcome remain incompletely understood. Our aim was to assess the relative short‐term mortality risk of TS, ST‐segment–elevation myocardial infarction (STEMI), and non‐STEMI (NSTEMI) and to identify predictors of in‐hospital complications and poor prognosis in patients with TS. Methods and Results This is an observational cohort study based on the data from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry). We included all patients (n=117 720) who underwent coronary angiography in Sweden attributed to TS (N=2898 [2.5%]), STEMI (N=48 493 [41.2%]), or NSTEMI (N=66 329 [56.3%]) between January 2009 and February 2018. We compared patients with TS to those with NSTEMI or STEMI. The primary end point was all‐cause mortality at 30 days. Secondary outcomes were acute heart failure (Killip Class ≥2) and cardiogenic shock (Killip Class 4) at the time of angiography. Patients with TS were more often women compared with patients with STEMI or NSTEMI. TS was associated with unadjusted and adjusted 30‐day mortality risks lower than STEMI (adjusted hazard ratio [adjHR], 0.60; 95% CI, 0.48–0.76; P

Background: Takotsubo syndrome (TS) is a recently recognized serious heart condition that mainly affects women. Despite that 80–90% of the patients are women, few studies have focused on sex-specific characteristics such as female sex hormones and reproductive history. The aim of the study was to compare reproductive history in patients with TS with controls.Methods: This register-based cohort study compared reproductive history and off-spring birth characteristics between 158 TS patients without coronary artery stenoses and 236 age- and sex-matched controls (C) with coronary artery stenoses because of acute coronary syndrome (ACS-C), respectively, 285 without coronary artery stenoses with chest pain (CP-C).Results: There were no differences in pregnancy complications between TS and CP-C. Gestational length did not differ, but infants born to TS patients had lower birth weight for gestational age than CP-C with an odds ratio of 1.7 (95% confidence interval 1.2–2.5) for infants born small.Conclusion: The results showing an association between birth weight for gestational age and TS later in life are hypothesis-generating. The association is not likely causal and before delivery of small for gestational age infants can be considered as a risk marker for TS later in life the results need to be confirmed in independent studies

Abstract Background The risk of ventricular arrhythmias in patients on QT prolonging drugs is indicated to be increased early after cardioversion (CV) of atrial fibrillation (AF) to sinus rhythm (SR). Sotalol, used to prevent AF relapse, prolongs cardiac repolarization and corrected QT interval (QTc). A pronounced QTc prolongation is an established marker of pro‐arrhythmias. Our objective was to use novel technique to quantify and evaluate the diurnal variation of the QTc interval after elective CV to SR in patients on sotalol or metoprolol. Methods Fifty patients underwent twelve‐lead Holter recording for 24 hr after elective CV for persistent AF. All patients had the highest tolerable stable dose of sotalol (n = 27) or metoprolol (n = 23). Measurements of QT and RR intervals were performed on all valid beats. Results A clear diurnal variation of both HR and QTc was seen in both groups, more pronounced in patients on sotalol, where a high percentage of heartbeats with QTc >500 ms was observed, especially at night. Six patients (22%) on sotalol but none on metoprolol had >20% of all heart beats within the 24‐hour recording with QTc >500 ms. Conclusion Twenty‐four‐hour Holter recordings with QT‐measurement immediately after CV demonstrated that one in five patients on sotalol had >20% of all heart beats with prolonged QTc >500 ms, especially during night‐time. The QTc diurnal variation was retained in patients on β‐blockade or a potent class III anti‐arrhythmic drug with β‐blocking properties.

PurposeAcute symptomatic pituitary apoplexy is a rare and potentially life-threatening condition. However, pituitary apoplexy can also present with milder symptoms and stable hemodynamics. Due to the rarity of this inhomogeneous condition, clinical studies are important to increase the knowledge.MethodsWe retrospectively reviewed all consecutive cases of pituitary apoplexy being admitted between January 1st, 2005 and December 31st, 2019 at the Karolinska University Hospital, Stockholm, Sweden, for symptoms, results of magnetic resonance (MRI), biochemistry, management and mortality.ResultsThirty-three patients were identified with pituitary apoplexy, 18 were men (55%) and mean age was 46.5 (17.2) years. The incidence of symptomatic pituitary apoplexy was 1.6 patients/year (0.76 patients/1,000,000 inhabitants/year). The majority presented with headache (n=27, 82%) and hormonal deficiencies (n=18, 55%), which were most frequent in men. ACTH deficiency was present in nine patients (27% but 50% of those with hormonal deficiencies). All had the characteristic findings on MRI. Only three patients (9%) required acute pituitary surgery, while eight were operated after more than one week. Seven (21%) were on antithrombotic therapy. None of the patients died in the acute course. During follow-up (7.6 ± 4.3 years) none of the hormonal deficiencies regressed and 3 patients died from non-related causes.ConclusionOur study confirmed the rarity and the symptoms of this condition. Surprisingly, only 3 patients needed acute neurosurgical intervention, perhaps due to milder cases and a general intensified treatment of precipitating factors. An early awareness and in severe cases decision on pituitary surgery is of utmost importance to avoid severe complications.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 triggers an immune response with local inflammation in the lung, which may extend to a systemic hyperinflammatory reaction. Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications. In addition to the release of cytokines, referred to as cytokine release syndrome or “cytokine storm,” increased pro-inflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an “eicosanoid storm,” which contributes to the uncontrolled systemic inflammation. Specialized pro-resolving mediators, which are derived from omega-3 PUFA, limit inflammatory reactions by an active process called resolution of inflammation. Here, the rationale for omega-3 PUFA supplementation in COVID-19 patients is presented along with a brief overview of the study protocol for the trial “Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids - A single-blind, randomized, placebo-controlled feasibility study” (COVID-Omega-F). EudraCT: 2020-002293-28; clinicaltrials.gov: NCT04647604.

BackgroundThe involvement of patient research partners (PRPs) in research aims to safeguard the needs of patient groups and produce new interventions that are developed based on patient input. Myocardial infarction with nonobstructive coronary arteries (MINOCA), unlike acute myocardial infarction (MI) with obstructive coronary arteries, is presented with no significant obstructive coronary artery disease. Patients with this diagnosis are a subset of those diagnosed with traditional MI and often need more psychological support, something that is presently not established in the current treatment scheme in Swedish health care or elsewhere, to our knowledge. An internet-delivered intervention might offer patients with MINOCA the opportunity to access a psychological treatment that is tailored to their specific needs after MINOCA and could therefore supplement the existing medical care in an easily accessible format. ObjectiveThis paper aims to describe the development of a therapist-guided, internet-delivered psychological intervention designed specifically for patients with MINOCA. MethodsThe study used a participatory design that involved 7 PRPs diagnosed with MINOCA who collaborated with a team consisting of researchers, cardiologists, and psychologists. Intervention content was developed iteratively and presented to the PRPs across several prototypes, each continually adjusted and redesigned according to the feedback received. The intervention and experience of it were discussed by PRPs in a final meeting and then presented to a panel of 2 clinical psychologists and a cardiologist for further input. ResultsThe outcome of the collaboration between PRPs and the research group produced a web-based psychological 9-step program focusing on stress, worry, and valued action. The input from PRPs contributed substantially to the therapy content, homework tasks, interactive activities, multimedia, and design presentation. ConclusionsWorking with PRPs to develop an intervention for people with MINOCA produced a web-based intervention that can be further evaluated with the goal of offering a new psychological treatment option to a patient group currently without one. Direct contribution from PRPs enabled us to obtain relevant, insightful, and valuable feedback that was put towards the overall design and content of the intervention.

Abstract Background Takotsubo cardiomyopathy (TCM), also known as “broken heart syndrome”, is a type of heart failure characterized by transient ventricular dysfunction in the absence of obstructive coronary lesions. Although associated with increased levels of catecholamines, pathophysiological mechanisms are unknown. Relapses and family heritability indicate a genetic predisposition. Several small studies have investigated associations between three different loci; the β1-adrenic receptor (ADRB1), G-protein-coupled receptor kinase 5 (GRK5), Bcl-associated athanogene 3 (BAG3) and TCM but no consensus has been reached. Methods Participants were recruited using the Swedish Coronary Angiography and Angioplasty Register (SCAAR). TCM patients without coronary artery disease (CAD)(n = 258) were identified and age- and sex-matched subjects with (n = 164) and without (n = 243) CAD were selected as controls. DNA was isolated from saliva and genotyped for candidate single nucleotide polymorphisms in the ADRB1, GRK5 and BAG3 genes. Allele frequencies and Odds Ratios (OR) with 95% Confidence Intervals (CI) for the investigated polymorphisms were compared, respectively calculated for TCM patients and controls. Results There were no differences in allele frequencies between TCM patients and controls. OR (CI) for TCM patients having at least one minor allele using controls as reference were 1.07 (0.75–1.55) for ADRB1, 0.45 (0.11–1.85) for GRK5 and 1.27 (0.74–2.19) for BAG3. Conclusion By genotyping a large takotsubo cohort, we demonstrate a lack of association between candidate SNPs in the ADRB1, GRK5 and BAG3 genes, earlier suggested to contribute to TCM. Our result indicates a need to expand the search for new genetic candidates contributing to TCM.

The pharmacokinetics after a 180-mg loading dose (LD) of ticagrelor has not been thoroughly investigated in NSTEMI patients. We aimed to compare the ticagrelor uptake and on-treatment platelet reactivity between non-ST-segment elevation myocardial infarction (NSTEMI) patients and a control group of patients with stable coronary artery disease (SCAD) undergoing elective percutaneous coronary intervention. We performed an observational, prospective, single-center study including 40 NSTEMI patients and 20 SCAD controls. Key exclusion criteria included ongoing opioid treatment. Both groups received a 180-mg ticagrelor LD, and blood samples were taken pre-dose and 1, 2, 3, 4, 5, and 6 hours post-LD. Plasma concentrations of ticagrelor and its active metabolite AR-C124910XX were determined by validated methods. Platelet aggregation was tested using ADP-induced multiple electrode aggregometry. The primary endpoint was the time to maximal ticagrelor concentration (Tmax). Clinical trial registration identifier number: NCT02292277. None of the pharmacokinetic variables differed significantly between the groups, including the Tmax of ticagrelor (2.0h [1.0–3.0] versus 2.0h [2.0–3.0], p = 0.393) and the active metabolite AR-C124910XX (3.0 [2.0–4.0] versus 3.0 [2.5–4.0], p = 0.289). High on-treatment platelet reactivity (HPR) was defined as > 46 aggregation units and was at one hour seen in 15% of the NSTEMI patients versus 10% of the controls (p = 1.0). At two hours post the 180-mg ticagrelor LD, 3% of the NSTEMI patients had HPR compared with none of the controls (p = 1.0). In conclusion, the uptake of ticagrelor was not significantly slower in NSTEMI patients not receiving opioids compared with the SCAD controls, leading to adequate onset of platelet inhibition in both groups.

Use of d,l-sotalol for rhythm control in patients with atrial fibrillation (AF) has raised safety concerns. Previous randomized studies are few and not designed for mortality outcome. The purpose of this study was to compare the incidences of mortality and ventricular arrhythmias in AF patients treated with d,l-sotalol for rhythm control vs matched control patients treated with cardioselective beta-blockers. This population-based cohort study included AF patients from the Swedish National Patient Registry (2006–2017) who underwent rhythm control after a second cardioversion. Incidence rates (IRs) and adjusted hazard ratios (aHRs) for mortality and a composite endpoint of cardiac arrest/death and ventricular arrhythmias were calculated for the overall cohort and a 1:1 propensity score matched cohort of d,l-sotalol vs beta-blocker treatment. Among patient treated with d,l-sotalol (n = 4987) and beta-blocker (n = 27,078) (mean follow-up 458 days), all-cause mortality was lower in patients treated with d,l-sotalol: IR 1.21; 95% confidence interval 0.95–1.52 vs 2.42 (2.26–2.60) deaths per 100 patient-years; aHR 0.66 (0.52–0.83). The difference in mortality persisted in the propensity score matched comparison (n = 4953 in each group): aHR 0.63 (0.48–0.86). No differences were observed in the composite outcome: IR in propensity cohorts 2.13 (1.78–2.52) vs 2.07 (1.73–2.53) events per 100 years; aHR 1.01 (0.78–1.29). There was no excess mortality with d,l-sotalol compared with cardioselective beta-blockers in patients undergoing rhythm control treatment for AF after a second cardioversion. Our results indicate that the risk associated with d,l-sotalol treatment for AF can be mitigated by careful patient selection and strict adherence to follow-up protocols. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) is common with a prevalence of 6% of all patients fulfilling the diagnosis of myocardial infarction. MINOCA should be considered a working diagnosis. Cardiac Magnetic Resonance (CMR) imaging has recently been suggested to be of great value to determine the cause behind MINOCA. The objectives of this paper are to describe the rationale behind the second Stockholm Myocardial Infarction with Normal Coronaries (SMINC-2) study and to discuss the protocol for investigation of MINOCA patients in the light of the recently published position paper from the European Society of Cardiology. Methods The SMINC-2 study is an open non-randomised study using historical controls for comparison. The primary aim is to prove that MINOCA patients investigated with the latest CMR imaging technique can achieve a diagnosis in 70% of all cases entirely by imaging. By including 150 patients we will have >80% chance to prove that the diagnostic accuracy can be improved by 20 absolute % with a p-value of less than 0.05 when compared with CMR imaging in the SMINC-1 study. Furthermore, in addition to invasive coronary angiography, coronary arteries are evaluated by computed tomography angiography to investigate coronary causes and questionnaires are used to describe Quality-of-Life (QoL). By January 1st 2017, 75 patients have been included. Discussion Whether CMR imaging can provide a diagnosis to an adequate proportion of MINOCA patients is unknown. Well-defined inclusion and exclusion criteria will be used to compare a MINOCA cohort from the population with an appropriate control group. Positive results are likely to influence future guidelines of the management of MINOCA. Furthermore, the study will give mechanistic insights into MINOCA in particular in patients with “true” myocardial infarction and describe QoL in this vulnerable group of patients. Trial registration Clinical Trials NCT02318498 .

Background Morphine administration is a strong predictor of delayed onset of action of orally administered ticagrelor in patients with ST‐segment–elevation myocardial infarction, likely because of impaired gastrointestinal motility. The aim of this study was to evaluate whether the peripheral opioid antagonist methylnaltrexone could improve pharmacodynamics and pharmacokinetics of orally administered ticagrelor in patients with ST‐segment–elevation myocardial infarction receiving morphine. Methods and Results The MOVEMENT (Methylnaltrexone to Improve Platelet Inhibition of Ticagrelor in Morphine‐Treated Patients With ST‐Segment Elevation Myocardial Infarction) trial was a multicenter, prospective, randomized, controlled trial in patients with ST‐segment–elevation myocardial infarction treated with morphine and ticagrelor. Upon arrival to the catheterization laboratory, patients were randomized to a blinded intravenous injection of either methylnaltrexone (8 or 12 mg according to weight) or 0.9% sodium chloride. The proportion of patients with high on‐treatment platelet reactivity and plasma concentrations of ticagrelor and AR‐C124910XX were assessed at baseline (arrival in the catheterization laboratory) and 1 and 2 hours later. A total of 82 patients received either methylnaltrexone (n=43) or placebo (n=39). Median (interquartile range) time from ticagrelor administration to randomization was 41 (31–50) versus 45.5 (37–60) minutes (P=0.16). Intravenous methylnaltrexone administration did not significantly affect prevalence of high on‐treatment platelet reactivity at 2 hours after inclusion, the primary end point, when compared with placebo (54% versus 51%, P=0.84). Plasma concentrations of ticagrelor and its active metabolite, the prespecified secondary end points, did not differ significantly between the groups over time. There was no significant difference in patient self‐estimated pain between the groups. Conclusions Methylnaltrexone did not significantly improve platelet reactivity or plasma concentrations of orally administered ticagrelor in patients with ST‐segment–elevation myocardial infarction receiving morphine. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02942550.

Background: Collagen type IV is the major constituent of basement membranes underlying endothelial cells and is important for endothelial cell attachment and function. Autoantibodies against native collagen type IV have been found in various autoimmune diseases. Oxidation of LDL in the vascular wall results in the formation of reactive aldehydes, which could modify surrounding matrix proteins. Like oxidized LDL, these modified matrix proteins are likely to induce immune responses. We examined whether autoantibodies against native or aldehyde-modified collagen type IV are associated with myocardial infarction. Methods: IgM and IgG against native and aldehyde-modified collagen type IV were measured by ELISA in serum from 387 survivors of a first myocardial infarction and 387 age- and sex-matched controls. Results: Post-infarction patients had significantly increased levels of IgM against native collagen type IV, and IgG against native collagen type IV was present at detectable level in 17% of patients as opposed to 7% of controls (p

OBJECTIVES: Patients presenting with acute myocardial infarction and angiographically normal coronary arteries (MINCA) represent a diagnostic and a therapeutic challenge. Cardiac computed tomography (CT) allows detection of coronary artery disease (CAD) even in the absence of significant stenosis. We aimed to investigate whether patients suffering from MINCA had a greater coronary plaque burden, as determined by cardiac CT, than a matched group of healthy volunteers. METHODS: Consecutive patients, aged 45 to 70, with MINCA were enrolled in the Stockholm metropolitan area. Patients with myocarditis were excluded using cardiovascular magnetic resonance imaging. Remaining patients underwent cardiac CT, as did a reference group of healthy volunteers matched by age and gender, with no known cardiovascular disease. Plaque burden was evaluated semi-quantitatively on a per patient and a per segment level. RESULTS: Despite a higher prevalence of smoking and hypertension, patients with MINCA did not have more CAD than healthy volunteers. Among 57 MINCA patients and 58 volunteers no signs of CAD were found in 24 (42%) and 25 (43%) respectively. On a per segment level, MINCA patients had less segments with stenosis ≥ 20% (2% vs. 5%, p

OBJECTIVES: Due to the frequent use of coronary angiography the awareness of Takotsubo stress cardiomyopathy (TSC) has increased although the exact pathophysiology of TSC is still largely unknown. Our objective was to investigate the effects of mental stress on myocardial function, heart rate variability (HRV) and salivary cortisol (SC) in TSC patients. DESIGN: This study is a case-control study and a sub-study of the Stockholm Myocardial Infarction with Normal Coronaries (SMINC) study. SETTING: Mental stress test was performed more than 6 months after the acute event in TSC patients and age- and sex-matched controls. Standard echocardiography and tissue Doppler imaging (TDI) -derived time-phases of cardiac cycle were recorded to calculate myocardial performance index (MPI) to assess ventricular function before and during mental stress. Holter-ECG recording was made to estimate HRV before, during and after mental stress. SC was measured at baseline, before and 20 minutes after mental stress. SUBJECTS: Twenty-two TSC patients and 22 sex-and age-matched controls were recruited from the SMINC-study and investigated with a mental stress test. All TSC patients had a previous normal cardiovascular magnetic resonance investigation. RESULTS: There were no significant differences at rest or during mental stress for left and right ventricular MPI or other standard diastolic variables between TSC patients and controls. HRV did not differ between TSC patients and controls. There was a trend towards less increase in SC after mental stress in TSC patients compared to controls. CONCLUSION: Mental stress did not induce a significant difference in myocardial function or HRV response between TSC and controls. Moreover, no significant difference could be seen in SC response at baseline, during or after mental stress. This study indicates that myocardial vulnerability to mental stress does not persist in TSC patients.

Apolipoprotein (apo) B is the structural protein moiety of plasma low density lipoprotein (LDL), an important risk factor for coronary heart disease (CHD). There is evidence that the rate of synthesis of apoB-containing lipoproteins may play an important role in the regulation of plasma LDL levels. However, it is generally thought that transcriptional regulation of the apoB gene is not a significant determinant of the synthesis of apoB-containing lipoproteins, and by inference, of the regulation of the plasma LDL concentration. Here we report the discovery of a common polymorphism in the promoter region of the apoB gene, a C to T substitution at position −516. The −516T allele is associated with an increase in the basal transcription of the apoB gene (+41%, P < 0.05) in vitro in transfected HepG2 cells. Healthy middle-aged men who are homozygous for the −516T allele have 12% higher plasma LDL cholesterol levels than healthy homozygotes for the −516C allele (P < 0.05). The frequency of the −516T allele is significantly higher in young postinfarction patients (0.38) than in population-based controls (0.30) when the comparison is restricted to subjects without severe hypercholesterolemia who are homozygous for the apoE3 allele (P < 0.05). It is concluded that variation in the rate of transcription of the apoB gene can affect plasma LDL levels and influences the risk of CHD in middle-aged men.—van 't Hooft, F. M., S. Jormsjö, B. Lundahl, P. Tornvall, P. Eriksson, and A. Hamsten. A functional polymorphism in the apolipoprotein B promoter that influences the level of plasma low density lipoprotein. J. Lipid Res. 1999. 40: 1686–1694.

Exaggerated and prolonged postprandial triglyceridemia is a characteristic of patients with precocious coronary heart disease. Although large very low density lipoprotein (VLDL) particles accumulate during alimentary lipemia, the biological properties of the postprandial VLDL remain unknown. In the present study, an intravenous infusion of a chylomicron-like emulsion was given to healthy normolipidemic men to examine the effects of transient triglyceridemia in vivo on compositional and cell biological characteristics of VLDL. The postinfusion large(Svedberg flotation rate (Sf) (60–400) VLDL was found to have increased capacity to inhibit low density lipoprotein (LDL) binding to the LDL-receptor and a greater ability to suppress the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity of cultured fibroblasts compared to VLDL isolated from fasting plasma. These alterations in cellular interactions were accompanied by increases in the number of apolipoprotein (apo) E, C-I, and C-III molecules per large VLDL particle and loss of apoC-II, compositional changes similar to those observed after an oral fat load. The increase in number of apoE molecules per large VLDL particle correlated positively and significantly with the increase in the capacity of large VLDL to inhibit LDL binding to the LDL receptor (r = 0.76, P = 0.01, n = 10). In contrast, the composition of the small (Sf 20–60) VLDL particles did not change significantly, nor was the LDL receptor-mediated processing of these particles altered consistently. These observations indicate that large VLDL particles that accumulate during alimentary lipemia undergo compositional changes that render them more prone to cellular binding and uptake.—Björkegren, J., F. Karpe, S. Vitols, P. Tornvall, and A. Hamsten. Transient triglyceridemia in healthy normolipidemic men increases cellular processing of large very low density lipoproteins by fibroblasts in vitro.