To Örebro University

Inflammatory signaling is a major contributor to cardiac dysfunction in diseases such as sepsis, myocarditis, and heart failure, yet existing in vitro models lack the multicellular complexity and physiological relevance needed to accurately recapitulate human cardiac pathology. In this study, we used human cardiac spheroids, three dimensional microtissues composed of cardiomyocytes, fibroblasts, and endothelial cells to study lipopolysaccharide induced inflammation. High resolution confocal microscopy confirmed a radial distribution of cell types within the spheroids. Following 24 h LPS stimulation, the spheroids exhibited no significant increase in lactate dehydrogenase release, indicating preserved membrane integrity and absence of overt cytotoxicity. Nevertheless, a robust inflammatory response was observed at both transcriptional and protein levels, including significant upregulation and secretion of TLR2, IL6, TNF, CXCL8, and CCL2. Mitochondrial stress testing revealed significantly reduced basal respiration, ATP production, and maximal respiratory capacity. Functional analyses showed impaired contractility characterized by reduced beat rate, delayed time to peak contraction, and prolonged relaxation time. Together, these findings demonstrate that human cardiac spheroids mount a physiologically relevant, multicellular inflammatory response that compromises both mitochondrial metabolism and mechanical performance. The model offers a powerful platform for investigating innate immune activation and for screening therapeutic interventions targeting inflammation induced cardiac dysfunction.

Background: Influenza causes seasonal epidemics worldwide. Bacterial coinfection is a serious complication that, due to diagnostic uncertainty, often results in empirical antibiotic overuse. We aimed to identify clinical and biochemical factors associated with antibiotic initiation and bacterial coinfection in adults with confirmed influenza at the emergency department.

Methods: Adult patients presenting to the emergency department with laboratory-confirmed influenza were included across three influenza seasons (2017-2020). Clinical and biochemical data were collected through medical chart review.

Results: A total of 174 influenza-positive patients were included. Independent predictors of antibiotic initiation were clinical scores NEWS2 >= 7 (aOR 8.99, 95% CI 2.38-33.96) and CRB-65 >= 2 (aOR 13.22, 95% CI 2.70-64.73), as well as biomarkers CRP (aOR 1.57, 95% CI 1.21-2.02), and white blood cell count (aOR 1.25, 95% CI 1.07-1.46). Only CRP was independently associated with bacterial coinfection (aOR 1.47, 95% CI 1.16-1.86). A CRP threshold >= 20 mg/L demonstrated 100% sensitivity for detecting bacterial coinfection.

Conclusion: NEWS2, CRB-65, CRP, and white blood cell count were independently associated with antibiotic initiation in adults with influenza, while only CRP predicted bacterial coinfection. Our findings could improve antibiotic stewardship strategies by underscoring the limited predictive value of clinical scores and the optimal use of biomarkers.

Background: Knowledge on the influence of mental disorders and unfavourable sociodemographic factors in patients experiencing myocardial infarction with non-obstructive coronary arteries (MINOCA) remains limited. We investigated the prevalence of mental disorders, psychotropic drug dispensation, and sociodemographic factors in patients with MINOCA and MI with coronary artery disease (MI-CAD) and assessed their association with prognosis.

Methods and results: In this nationwide register-based cohort study of 8367 MINOCA and 109,059 MI-CAD patients, mental disorders (4.3% vs 2.6%, p < 0.001) and psychotropic drug dispensation (26.1% vs 17.4%, p < 0.001) were more frequent in MINOCA, particularly female patients. MINOCA patients were also more often divorced (21.1% vs 19.7%, p < 0.001), widowed (6.8% vs 4.9%, p < 0.001), or on sick leave (4.4% vs 3.2%, p < 0.001). Over a median 5.5-year follow-up, a major adverse cardiovascular event (MACE) occurred in 25.5% of MINOCA and 27.8% of MI-CAD patients (p < 0.001). Adjusted analyses showed that mental disorders and dispensed psychotropic drugs independently predicted MACE in both MINOCA (HR 1.27; 95% CI 1.15-1.40) and MI-CAD (HR 1.35; 95% CI 1.31-1.39).

Conclusion: Mental disorders and psychotropic drug dispensation were more common in MINOCA than MI-CAD, particularly in female patients. Unfavourable sociodemographic factors were common in both groups, with a modest excess in MINOCA. The association between mental health variables and adverse outcomes in both conditions suggests shared mechanisms beyond traditional cardiovascular risk factors.

BACKGROUND: Patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) or Takotsubo syndrome (TS) often suffer from poor mental health and low quality-of-life post event, with no current evidence-based treatments available. This study aimed to evaluate the effects of an internet-delivered cognitive behavioral therapy program on stress and anxiety symptoms in patients diagnosed with myocardial infarction with nonobstructive coronary arteries or TS.

METHODS: A parallel, multicenter, randomized controlled trial with a wait-list control group was conducted. Patients with elevated symptoms of stress or anxiety were included (the 14-item perceived stress scale ≥25 or hospital anxiety and depression scale, anxiety subscale ≥8). The primary outcome was normalized stress and anxiety levels 10 to 12 weeks after randomization. Secondary outcomes included normalized stress and anxiety separately and symptoms as continuous measures.

RESULTS: A total of 88 patients were randomized (treatment: 45, control: 43). The treatment group showed a greater, though not statistically significant proportion of normalized patients (odds ratio, 2.37 [95% CI, 0.88-6.38], P=0.09). Secondary analyses indicated treatment effects on anxiety normalization and on symptoms as continuous measures (effect sizes: d=0.44-0.67). There was also an interaction between treatment and diagnosis (TS versus non-TS), favoring a treatment effect in TS patients (P=0.016).

CONCLUSIONS: The patient-tailored internet-delivered cognitive behavioral therapy program reduced stress and anxiety symptoms in patients with myocardial infarction with nonobstructive coronary arteries or TS and normalized anxiety symptoms in a greater proportion of treated patients than controls. Exploratory analyses indicated that patients with TS may experience greater benefit from the internet-delivered cognitive behavioral therapy intervention, but this warrants further research.

Background: Secondary preventive medications following myocardial infarction (MI) reduce the risk of new cardiovascular events. Discontinuation and suboptimal adherence are common and affect prognosis. However, there is limited knowledge regarding adherence in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA). We therefore aim to evaluate the adherence to guideline recommended medications in patients with MINOCA and myocardial infarction with obstructive coronary arteries (MI-CAD).

Methods: This was a Swedish nationwide observational study of MI patients recorded in the SWEDEHEART registry between 2006 & horbar;2017. A total of 9,138 MINOCA and 107,240 MI-CAD patients were followed for a mean 5.9 years. Initiation of therapy, implementation determined using medication possession ratio, and persistence rates during different time periods were calculated.

Results: Patients with MINOCA were less frequently prescribed secondary preventive medications than MI-CAD. The percentage of patients taking medication as prescribed were lower in MINOCA than in MI-CAD at all time points; during months 6-12 after discharge: aspirin 94.8% vs 97.2% (p < 0.001), statins 90.3% vs 94.7% (p < 0.001), and ACEI/ARBs 97.7% vs 98.5% (p = 0.002) and at 12 months: aspirin 84.4% vs 93.7% (p < 0.001), statins 83.8% vs 94.8% (p < 0.001), ACEI/ARBs 85.0% vs 92.2% (p < 0.001) and beta blockers 80.4% vs 89.6% (p < 0.001).

Conclusion: The rates of initiation, implementation, and persistence of secondary preventive medications were high in both MINOCA and MI-CAD patients during the first 5 years after MI. The lower rates in patients with MINOCA may be partially due to uncertainties regarding the diagnosis of MINOCA, differences in patient characteristics, and psychosocial factors. Suboptimal medical adherence in patients with MINOCA may adversely affect prognosis as previously demonstrated in MI-CAD patients.

BACKGROUND: Symptom burden and disease effects following myocardial infarction with nonobstructive coronary arteries (MINOCA) are not well studied. We aimed to evaluate the prevalence of angina pectoris, sick leave, and quality-of-life levels 1 year after the index event, using patients with myocardial infarction due to obstructive coronary artery disease (MI-CAD) as controls.

METHODS AND RESULTS: Patients with first-time myocardial infarction, assessed by coronary angiography and registered in the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry 2005 to 2022 were eligible and included if attending the 1-year follow-up. Patients with previous coronary intervention, heart failure, arrhythmia at admission, and not fully revascularized MI-CAD were excluded. Outcomes were prospectively collected during standard care. A total of 46 428 patients (mean age, 62years; 71% men; MINOCA, n=5281/MI-CAD, n=41 157) were assessed after 1 year. Angina prevalence was 11.6% in MINOCA and 8.8% in fully revascularized MI-CAD (crude risk ratio, 1.32 [95% CI, 1.21-1.47]; odds ratio, 1.18 [95% CI, 1.07-1.30], adjusted for potential confounders). Patients with MINOCA had a higher degree of sick leave than patients with MI-CAD both at index care and at 1 year (8.0% versus 5.6% and 13.4% versus 10.9%, respectively; both P<0.001). Quality-of-life measures were lower in MINOCA. These associations were unaffected when adjusting for angina status but were attenuated when adjusting for potential confounders.

CONCLUSIONS: Patients with MINOCA have significant distress, with higher levels of angina pectoris and sick leave and worse quality of life at 1 year compared with fully revascularized MI-CAD counterparts.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) and other disorders with similar features are common genetic disorders that remain underdiagnosed and undertreated, due in part to the cost of screening. The aim of this study was to design and implement a whole gene targeted NGS panel for the molecular diagnosis of FH and statin intolerance with an emphasis on high quality variant calling, including copy number analysis.

METHODS: A whole gene panel for hybridisation-based short read NGS was designed for the dominant FH-genes low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proproteinconvertas subtilisin/kexin type 9 (PCSK9), apolipoprotein E (APOE) and the recessive FH-genes low density lipoprotein receptor adaptor protein 1 (LDLRAP1), ATP binding cassette subfamily member 5/8 (ABCG5/8) and lipase A, lysosomal acid type (LIPA), as well as solute carrier organic anion transporter family member 1B1 (SLCO1B1), not an FH gene but linked to statin intolerance. Polygenetic risk score markers were also included. The panel was used for screening of a Swedish FH-study population (n = 133).

RESULTS: The panel sequencing resulted in high coverage and confident variant calling of included genes. Known causal variants were found in common dominant FH-genes in 43 % of the cohort. Copy number variants were found in LDLR in 10 individuals and a whole gene deletion of SLCO1B1 in one individual. In addition, coding variants in recessive genes and rare non-coding intronic and untranslated region variants were found in a large proportion of the study individuals highlighting the need for extended gene panels.

CONCLUSIONS: This new tool can be used for a comprehensive high-quality molecular genetic analysis according to guidelines for the diagnosis and treatment of FH.

BACKGROUND AND AIMS: The familial risk among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is unknown. Previous studies of family history in myocardial infarction (MI), have not made a distinction between MINOCA and MI due to coronary artery disease (MI-CAD), based on angiographic findings. We therefore sought to investigate familial risk of MI without and with obstructive coronary arteries.

METHODS: Register-based cohort study with a total of 15,462 MINOCA cases, 204,424 MI-CAD cases, 38,220 control subjects without MI and with non-obstructive coronary arteries. First-degree relatives were identified 1995-2020. Cox proportional hazard regression models were used to compare familial risk in MINOCA and MI-CAD with control subjects.

RESULTS: During a mean follow-up of 8.1 ± 4.2 years, MINOCA occurred in 1.0% of first-degree relatives with MINOCA whereas MI-CAD occurred in 9.7% of first-degree relatives of MINOCA. The age- and sex-adjusted hazard ratio (HR) for a MINOCA-relative experiencing MINOCA and MI-CAD, compared to control subjects, was 0.99 (95% confidence interval [CI] 0.80-1.23) and 1.10 (95% CI 1.03-1.18), respectively. During a mean follow-up of 8.5 ±4.8 years, MI-CAD occurred in 12.2% of first- degree relatives with MI-CAD with age- and sex-adjusted HR 1.43 (95% CI 1.37-1.49).

CONCLUSIONS: No increased familial risk of MINOCA was observed for MINOCA-patients whereas there was an increased familial risk for MI-CAD when compared to control subjects. These results may indicate that genetic factors and shared environmental factors within a family leading to CAD are important also for MINOCA, thus MI-CAD and MINOCA could share underlying mechanisms.

BACKGROUND: Poor adherence to secondary preventive medication after myocardial infarction (MI) negatively affects long-term prognosis, but knowledge is lacking regarding the impact of poor adherence on prognosis for patients with myocardial infarction with non-obstructive coronary arteries (MINOCA). We therefore investigated the effect of persistence to secondary preventive medication on prognosis in patients with MINOCA compared with patients with myocardial infarction with obstructive coronary arteries (MI-CAD).

METHODS: In this nationwide observational study of 116,143 patients with MI recorded in the SWEDEHEART registry between 2006─2017, MINOCA were identified in 9,124 patients and MI-CAD in 107,019 patients. Persistence to treatment with aspirin, statins, beta blockers and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) was investigated for 5 years post discharge and patients were followed for a composite endpoint of major adverse cardiovascular events (MACE), including all-cause death, MI, ischemic stroke and heart failure.

RESULTS: Persistent use of secondary preventive medications was associated with a decrease in the risk of MACE during follow-up in both MINOCA and MI-CAD patients; aspirin HR 0.70 (CI 0.60-0.82) vs. HR 0.60 (CI 0.57-0.64), statins HR 0.80 (CI 0.68-0.95) vs. HR 0.66 (CI 0.63-0.69), beta blockers HR 0.77 (CI 0.65-0.92) vs. HR 0.76 (CI 0.73-0.80) and ACEIs/ARBs HR 0.62 (CI 0.50-0.77) vs. 0.67 (CI 0.63-0.71).

CONCLUSION: Persistence to secondary preventive medications after MI is associated with a reduction in the risk for MACE in both patients with MINOCA and MI-CAD. Continuous efforts to improve adherence to evidence-based medications in general to all patients with MI should be a priority.

BACKGROUND: Myocardial infarction with non-obstructive coronary arteries (MINOCA) and takotsubo syndrome (TS) are both characterised by lack of significant coronary artery stenoses and a higher prevalence of mental health disorders preceding the event. Currently, little is known about their pathological aetiologies and subsequent treatment plans, giving cause for concern among those affected. The objective of this review is to provide a comprehensive overview of mental health status and quality of life (QoL) in MINOCA- and TS-patients after the acute event, compared to both cardiac and non-cardiac populations, and over time.

METHODS: A systematic search was conducted via Cochrane Library, CINAHL, PyschINFO, PubMed, ASSIA, Web of Science, Scopus and Embase from inception to May 2024. The review was registered in PROSPERO and methods, and results were reported in accordance with the PRISMA guidelines. Quality assessment and risk of bias were evaluated using the Newcastle-Ottawa Scale for cross-sectional and cohort studies.

RESULTS: Sample sizes ranged from 13 to 5,322 participants. The risk of bias was high in 18/28, medium in 7/28, and low in 3/28 studies. Across the symptoms assessed, MINOCA- and TS-patients reported worse mental health status or QoL than non-cardiac groups in 10/13 studies, and cardiac groups in 10/20 studies. Investigating change over time, 1/5 studies found deteriorating mental health status, 3/5 reported improved mental health status or QoL and 1/5 reported no change in MINOCA- and TS-patients.

CONCLUSIONS: Patients with MINOCA or TS seem to have worse mental health status and QoL after the acute event than non-cardiac individuals, but it is yet difficult to conclude whether mental distress and QoL are equal or worse compared to CHD-patients. There is no convincing evidence that mental health status or QoL of MINOCA- and TS- patients naturally improve over time after the acute event. Among the studies evaluated, risk of bias was high. More high-quality studies are needed, investigating mental health status and QoL among MINOCA- and TS-patients.