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BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival of HTx patients. Mitochondrial dysfunction has been reported in both arteriosclerotic coronary disease and heart failure. However, myocardial mitochondrial function has not been examined in HTx patients with CAV.METHODS: 43 HTx patients (21 patients with CAV and 22 patients without CAV) ≥12 months after HTx were enrolled. Endomyocardial biopsies were analyzed using high-resolution respirometry for glucose-coupled mitochondrial respiration. Number and area of mitochondria profiles as well as cristae morphology were assessed by transmission electron microscopy. Echocardiography and coronary angiography were used to measure global longitudinal strain (GLS) and grade CAV.RESULTS: Complex I+II-linked respiration was reduced in patients with CAV compared with patients without CAV (82.7 ± 31.9 pmol O2/(s•mg) vs 116 ± 35.9 pmol O2/(s•mg), p = 0.003). Mitochondrial respiratory function measured as oxidative phosphorylation coupling efficiency was positively associated with left ventricular GLS (r = 0.49, p = 0.002) and negatively associated with elevated biomarkers (Troponin T: r=-0.33, p = 0.04 and NT-proBNP: r = -0.41, p = 0.009). Mitochondrial profile number and area did not differ. However, patients with CAV had a larger proportion of mitochondria with abnormal cristae morphology (p < 0.001).CONCLUSIONS: Myocardial mitochondrial respiration is impaired in patients with CAV and is associated with an abnormal cristae morphology. The mitochondrial dysfunction appears to be associated with reduced myocardial contractile function and elevated biomarkers. These results highlight that mitochondrial targeted treatment in patients with CAV should be assessed in future clinical studies.

BACKGROUND: The incidence of sudden cardiac death (SCD) following heart transplantation (HTx) accounts for approximately 10% of post-HTx deaths. Ischemia, brady- and tachy-arrhythmias caused by rejection and cardiac allograft vasculopathy (CAV) seem related to SCD. Hence, we aimed to investigate the relation between CAV, arrhythmias and silent ischemia in long-term HTx patients. Methods: 49 HTx patients were included. Patients were CAV-classified in accordance with guidelines from the International Society of Heart and Lung Transplantation. Patients were divided into predefined CAV groups (CAV 0, CAV 1, CAV 2 + 3). Incidences of arrhythmia and silent ischemia were detected by 48-h electrocardiogram monitoring and analyzed blinded to CAV-status. Results: Median time since transplantation was 9 years [IQR 4-14]. We observed a higher incidence of non-sustained ventricular tachycardia (NSVT) in CAV 2 + 3 patients than CAV 0 and 1 patients (p = 0.01). Likewise, isolated premature ventricular complexes (PVC) (p =0 .01) and PQ-interval prolongation (p = .01) were more frequent in CAV 2 + 3 patients than CAV 0 and 1 patients. Silent ischemia was only observed among CAV 3 patients (p = 0.04). We saw no significant difference in the incidence of supraventricular tachycardia among CAV groups (p = 0.21). Likewise, no difference in the right bundle branch block was observed (p = 0.68). Conclusion: NSVT was associated with CAV status in long-term HTx patients. Patients with moderate to severe CAV showed higher incidences of PVCs and PQ-interval prolongation than patients with mild or no CAV. Silent ischemia was only seen in patients with severe CAV.

The rise of peer-to-peer platforms has represented one of the major economic and societal developments observed in the last decade. We investigated whether people engage in racial discrimination in the sharing economy, and how such discrimination might be explained and mitigated. Using a set of carefully controlled experiments (N = 1,599), including a pre-registered study on a nationally representative sample, we find causal evidence for racial discrimination. When an identical apartment is presented with a racial out-group (vs. in-group) host, people report more negative attitudes toward the apartment, lower intentions to rent it, and are 25% less likely to choose the apartment over a standard hotel room in an incentivized choice. Reduced self-congruence with apartments owned by out-group hosts mediates these effects. Left-leaning liberals rated the out-group host as more trustworthy than the in-group host in non-committing judgments and hypothetical choice, but showed the same in-group preference as right-leaning conservatives when making a real choice. Thus, people may overstate their moral and political aspirations when doing so is cost-free. However, even in incentivized choice, racial discrimination disappeared when the apartment was presented with an explicit trust cue, as a visible top-rating by other consumers (5/5 stars). (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BACKGROUND: Long-term survival after heart transplantation (HTx) is compromised by cardiac allograft vasculopathy (CAV) characterized by coronary macro- and microvascular disease. The pathogenesis of CAV is unclear and may involve coronary thrombosis. We investigated whether HTx patients with CAV had higher platelet aggregation and turnover than HTx patients without CAV and healthy controls. Furthermore, we investigated the anti-platelet effect of low-dose aspirin in HTx patients.METHODS: We included 57 patients who had undergone HTx (median 8.3 years from HTx) and 57 healthy controls. Platelet aggregation was measured on-aspirin and off-aspirin using impedance aggregometry with adenosine diphosphate (ADP) and arachidonic acid (AA). We evaluated platelet turnover by flow cytometry, CAV burden by coronary angiography and echocardiography, and microvascular function by echocardiographic coronary flow velocity reserve (CFVR).RESULTS: Off-aspirin, HTx patients with CAV (n = 21) had higher ADP-induced platelet aggregation than healthy controls (p < 0.01) and HTx patients without CAV (n = 36) (p < 0.05). Aspirin treatment reduced AA-induced platelet aggregation in both HTx groups, but HTx patients with CAV had higher platelet aggregation on-aspirin than HTx patients without CAV (p < 0.05). Platelet turnover did not differ between HTx patients with CAV and HTx patients without CAV (p > 0.34). HTx patients with lower CFVR values had higher platelet aggregation than HTx patients with higher CFVR values (p < 0.05).CONCLUSIONS: Off-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV and healthy controls. On-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx patients with CAV.

Background Following heart transplantation (HTx), long-term survival is reduced mainly due to development of a specific form of coronary artery disease, coronary allograft vasculopathy (CAV). Using optical coherence tomography to visualize the coronary artery wall, we have recently shown that layered fibrotic plaques resembling organized clots are the dominant plaque component in CAV. Thus, thrombosis is suggested as a possible mechanism contributing to development and progression of CAV. Aspirin is widely used after HTx despite limited evidence and lack of specific guidelines. The antiplatelet effect of aspirin has not been thoroughly examined in HTx-patients. Purpose To investigate baseline platelet aggregation and the antiplatelet effect of aspirin in HTx-patients with and without CAV. Methods We included 68 HTx-patients (median 8.6 years from HTx). In 66 patients taking 75 mg aspirin for a minimum of 7 days, platelet aggregation was measured in whole blood using impedance aggregometry with the following agonists: Adenosine diphosphate (ADP) stimulating ADP-receptors and arachidonic acid (AA) for monitoring of aspirin treatment. Aspirin compliance was confirmed by measuring serum-thromboxane B2. Platelet aggregation prior to aspirin therapy was measured in 59 patients as it was not considered clinically safe to interrupt ongoing aspirin treatment for one week prior to blood sampling in 9 patients mainly due to previous coronary stenting. CAV burden was determined by coronary angiography and echocardiography based on international classification. Patients were divided into two groups; no CAV (n=37) and CAV (n=29). Results In HTx-patients not treated with aspirin, we found significantly increased ADP-induced platelet aggregation in patients with CAV vs. patients without CAV (904 (95% CI 813–995) vs. 786 (95% CI 728–843) AU*min, P=0.02). Baseline AA-induced aggregation was also higher in patients with CAV vs. patients without CAV, though non-significant (994 (95% CI 907–1081) vs. 905 (95% CI 839–972) AU*min, P=0.10). Even though aspirin reduced AA-induced platelet aggregation in both groups, patients with CAV had significantly increased AA-induced platelet aggregation compared with patients without CAV on aspirin treatment (380 (95% CI 295–465) vs. 286 (95% CI 239–334) AU*min, P=0.04) (Fig. 1). Conclusions HTx-patients with CAV have increased platelet aggregation before and after aspirin treatment compared with HTx-patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx-patients with CAV. Acknowledgement/Funding Aarhus University (PhD-salary)

We studied interactions between polar bear peroxisome proliferator-activated receptor gamma (pbPPARG) and selected compounds using a luciferase reporter assay and predictions through molecular docking. Furthermore, we studied adipogenesis by liver and adipose tissue extracts from a polar bear and three synthetic mixtures of contaminants in murine 3T3-L1 preadipocytes and polar bear adipose tissue-derived stem cells (pbASCs). PCB153 and p,p'-DDE antagonized pbPPARG, although their predicted receptor-ligand affinity was weak. PBDEs, tetrabromobisphenol A, and PCB170 had a weak agonistic effect on pbPPARG, while hexabromocyclododecane, bisphenol A, oxychlordane, and endosulfan were weak antagonists. pbPPARG-mediated luciferase activity was suppressed by synthetic contaminant mixtures reflecting levels measured in polar bear adipose tissue, as were transcript levels of PPARG and the PPARG target gene fatty acid binding protein 4 (FABP4) in pbASCs. Contaminant extracts from polar bear tissues enhanced triglyceride accumulation in murine 3T3-L1 cells and pbASCs, whereas triglyceride accumulation was not affected by the synthetic mixtures. Chemical characterization of extracts using nontarget methods revealed presence of exogenous compounds that have previously been reported to induce adipogenesis. These compounds included phthalates, tonalide, and nonylphenol. In conclusion, major legacy contaminants in polar bear adipose tissue exert antagonistic effects on PPARG, but adipogenesis by a mixture containing emerging compounds may be enhanced through PPARG or other pathways.

Peroxisome proliferator-activated receptor alfa (PPARA/NR1C1) is a ligand activated nuclear receptor that is a key regulator of lipid metabolism in tissues with high fatty acid catabolism such as the liver. Here, we cloned PPARA from polar bear liver tissue and studied in vitro transactivation of polar bear and human PPARA by environmental contaminants using a luciferase reporter assay. Six hinge and ligand-binding domain amino acids have been substituted in polar bear PPARA compared to human PPARA. Perfluorocarboxylic acids (PFCA) and perfluorosulfonic acids induced the transcriptional activity of both human and polar bear PPARA. The most abundant PFCA in polar bear tissue, perfluorononanoate, increased polar bear PPARA-mediated luciferase activity to a level comparable to that of the potent PPARA agonist WY-14643 (~8-fold, 25 μM). Several brominated flame retardants were weak agonists of human and polar bear PPARA. While single exposures to polychlorinated biphenyls did not, or only slightly, increase the transcriptional activity of PPARA, a technical mixture of PCBs (Aroclor 1254) strongly induced the transcriptional activity of human (~8-fold) and polar bear PPARA (~22-fold). Polar bear PPARA was both quantitatively and qualitatively more susceptible than human PPARA to transactivation by less lipophilic compounds.

The rise of peer-to-peer platforms has represented one of the major economic and societal developments observed in the last decade. We investigated whether people engage in racial discrimination in the sharing economy, and how such discrimination might be explained and mitigated. Using a set of carefully controlled experiments (N = 1,599), including a pre-registered study on a nationally representative sample, we find causal evidence for racial discrimination. When an identical Airbnb apartment is presented with a racial out-group (vs. in-group) host, people report more negative attitudes towards the apartment, lower intentions to rent it, and are 25% less likely to choose the apartment over a standard hotel room in an incentivized choice. Reduced self-congruence with apartments owned by out-group hosts mediates these effects. Left-leaning liberals rated the out-group host as more trustworthy than the in-group host in non-committing judgments and hypothetical choice, but showed the same in-group preference as right-leaning conservatives when making a real choice. Thus, people may overstate their moral and political aspirations when doing so is cost-free. However, even in incentivized choice, racial discrimination disappeared when the apartment was presented with an explicit trust cue, as a visible top-rating by other consumers (5/5 stars).

Purpose Cardiac allograft vasculopathy (CAV) remains the Achilles’ heel of long-term survival of heart transplanted (HTx) patients. CAV affects approximately 50 % of HTx patients 10 years after transplant. We evaluated whether cardiac allograft vasculopathy is associated with mitochondrial dysfunction. Methods A total of 36 HTx patients (18 patients with CAV and 18 patients without CAV) ≥ 12 months after HTx were enrolled. Endomyocardial biopsies were analyzed using high-resolution respirometry for glucose-coupled mitochondrial respiration. Echocardiography and coronary angiography were used to grade CAV according to ISHLT nomenclature. Results Maximally coupled respiration of mitochondrial complex I and II was significantly reduced in patients with CAV compared with patients without CAV (97.2 pmol O2/(s*mg) [65.5; 133.6] vs. 59.1 pmol O2/(s*mg) [53.9; 83.0], p = 0.009) (Fig. 1). Patients with positive donor specific antibodies (MFI > 3000) had a lower maximally coupled respiration compared with patients without (56.5 pmol O2/(s*mg) [53.3; 69.0] vs. 90.6 pmol O2/(s*mg) [59.8; 113.9], p = 0.009). Mitochondrial respiratory function measured as oxidative phosphorylation coupling efficiency was positively associated with both left ventricular function (global longitudinal strain, r2=0.239, p = 0.0045) and right ventricular function (tricuspid annular plane systolic excursion, r2=0.133, p=0.03). Conclusion Mitochondrial respiration is impaired in patients with CAV compared with patients without CAV. Decreased mitochondrial respiratory function is associated with impaired myocardial contractile function.

AIM: To clarify if use of adverse cardiovascular risk profile (ARP) grafts is associated with impaired long-term outcomes after heart transplantation (HTx).METHODS: Survival was obtained from Scandia Transplant and a local database.ARP DONOR INCLUSION CRITERIA: ≥55 years, diabetes mellitus, arterial hypertension, hypoxemia-induced death, impaired left ventricular (LV) ejection fraction. ARP donors were compared to donors not meeting the eligibility criteria. Sub-analyses were made for donor age.RESULTS: In total, 302 HTxs were performed in 296 patients from 31 December 1992 to 11 August 2016. Median survival was 16.5 years (95% CI, 14.3-22.9), there was no difference between profiles (HR 0.63 (95% CI, 0.33-1.19), P = 0.15). LV systolic function was significantly better in ARP donors (P < 0.05). Freedom from cardiac allograft vasculopathy (CAV) was comparable between profiles, HR 0.9 (95% CI 0.5-1.5). Donor age predisposes to CAV (high to low age: HR 2.8 (95% CI 1.7-4.5), P < 0.0001). Median survival was comparable in patients receiving allograft ≥55 and CONCLUSION: Long-term survival and graft function were excellent in patients receiving ARP grafts. Older grafts were associated with CAV but did not influence survival. Thus, the strategy of expanding availability using ARP grafts seems safe.

Background Optical coherence tomography (OCT) enables in-vivo cardiac allograft vasculopathy (CAV) microstructure characterization. Early coronary artery microstructure changes after heart transplantation (HTx) may provide valuable mechanistic information regarding CAV development. Our in this study was to describe and characterize changes in the coronary artery microstructure during the first year after HTx using serial OCT scans. Methods Twenty-six patients were enrolled at routine baseline coronary angiography 3 months after HTx. Coronary OCT scans were performed on all 3 major vessels at baseline and were repeated 12 months after HTx. We contoured the vessel layers for absolute and relative measurements. Lipid plaques, calcified plaques, layered fibrotic plaques (LFPs) and bright spots were analyzed by delineating circumferential borders and measuring angulation of total circumference. Results A total of 8,789 frames from 71 vessels were analyzed after 3 and 12 months (vessel length 79 ± 24 mm vs 82 ± 23 mm, respectively, p = 0.39). Mean intima area increased by 20% from 3 months to 12 months (1.6 [1.2 to 2.7] mm2 vs 1.9 [1.3 to 3.2] mm2, p Conclusions Early CAV formation during the first year after HTx is characterized by a pronounced intima layer thickening strongly associated with LFP progression. In contrast, the extent of lipid plaque and calcifications remained stable. LFP formation may be a key mechanism in CAV.

Purpose Sudden cardiac death (SCD) is a frequent and unexplained complication in relation to heart transplantation (HTx). The mechanism is expectedly multifactorial and Cardiac Allograft Vasculopathy (CAV) is possibly related to SCD. We aimed to investigate the relation between CAV and arrhythmias and silent ischemia in long-term HTx patients. Methods CAV was classified in accordance with the International Society of Heart and Lung Transplantation guideline by coronary angiography and echocardiography . Patients were divided into three CAV groups (CAV 0, 1 and 2+3). Incidence of arrhythmias and silent ischemia were detected by 48-hour electrocardiogram monitoring , and analyzed blinded to CAV status. Results We included 49 HTx patients transplanted a median of 9 years ago [4-14]. We saw a higher incidence of nonsustained ventricular tachycardia (NSVT) in CAV 2+3 patients than in CAV 0 and 1 patients (p=0.01). Also, isolated premature ventricular contractions (PVC) were more frequently observed in this group than in CAV 0 and 1 patients (p=0.01). No difference in incidence of isolated premature atrial contractions (p=0.67) and supraventricular tachycardia (p=0.13) was observed between the CAV groups. Silent ischemia was only observed in CAV 2+3 patients (p=0.04), all patients with silent ischemia (n=3) died within 12 months. The PQ-interval was increased in CAV patients compared with patients without CAV (p=0.01) but no episodes of advanced AV-block were detected. Conclusion Patients with substantial CAV showed a higher incidence of PVCs and NSVT. However, the burden of ventricular rhythm-disturbances was modest and not clearly indicating an increased risk of SCD. In contrast, presence of silent ischemia in patients with severe CAV was associated with high mortality.