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Objective: Oxygen-dependent changes in vascular diameters may be detrimental when the endothelium is dysfunctional. Design: Endothelial responsiveness was evaluated by brachial ultrasound and flow-mediated/nitroglycerin-mediated dilation (FMD/NMD). FMD/NMD was investigated in males with increased risk of cardiovascular disease (mean age 44+/-2 years, n=10) and matched controls without risk factors (44+/-2 years, n=10). FMD/NMD was assessed during normoxia (21% O2, 79% N2), while inhaling hypoxic gas (12.5% O2, FMDHyp/NMD), and 100% O2 supplementation (FMDO2/NMD). In a second study we addressed the effect of lipid lowering. Twenty persons with cardiovascular risk (mean age 50+/-2 years) were treated with atorvastatin (80 mg/day) and FMD/NMD was measured during normoxia, hypoxia and oxygen supplementation before, after 1 day and 3 months. Results: Oxygen supplementation evoked vasoconstriction, while FMDHyp/NMD was reduced compared to FMD/NMD. Atorvastatin significantly lowered total cholesterol, LDL cholesterol, and ADMA after 1 day of treatment, while triglycerides, ApoB and hsCRP were lowered after 3 months. Atorvastatin did not change FMD/NMD irrespective of oxygen tension. Conclusion: Irrespective of risk factors or atorvastatin, hypoxia reduced endothelial vasodilation while oxygen supplementation evoked vasoconstriction. [ABSTRACT FROM AUTHOR]

Objective: To study 1) variations in esophageal motility and pH values and 2) electrocardiographic ST-segment changes in patients with angina-like chest pain but normal coronary angiograms.Design: Cross-sectional study.Setting: Tertiary cardiologic referral center.Patients: 63 consecutive patients referred to the study center over a 3-year period and 22 healthy controls. Patients were grouped according to the results of exercise electrocardiography: normal response to exercise (n = 28) and ischemic response to exercise (n = 35).Measurements: 1) 24-hour three-channel esophageal manometry and two-channel pH monitoring, 2) provocation testing with intravenous edrophonium chloride and esophageal acid perfusion, and 3) Holter electrocardiography conducted during the first two tests. In conventional time-weighted analyses, values during periods of pain and the 2 minutes before pain developed were compared with baseline values.Results: Regardless of the outcome of exercise testing, no differences were seen in 24-hour esophageal variables between patients and controls. Forty-six patients had a total of 248 spontaneous episodes of chest pain. Only minor differences were seen between baseline and the prepain and pain periods. Edrophonium chloride provocation and acid perfusion caused chest pain in 9 patients (14%) and 10 patients (16%), respectively. Esophageal monitoring variables did not differ between patients with a positive response to one or both provocation tests (n = 16 [25%]) and controls and did not change between baseline and the prepain or pain perioids. Forty-eight ST-segment depressions were recorded on Holter monitoring in 16 patients (25%), but these depressions were associated with one prepain period and four pain periods. No ST-segment changes were seen during esophageal provocation testing.Conclusion: The rationale for routine esophageal investigations in this patient group is questionable. [ABSTRACT FROM AUTHOR]

Sensory thresholds and brain evoked potentials were determined in 12 healthy volunteers using electrical stimulation of the oesophagus 28 and 38 cm from the nares. The peaks of the evoked potentials were designated N for negative deflections and P for positive. Continuous electrical stimulation (40 Hz) at the 38 cm position resembled heartburn (five of 12 subjects) while non-specific ('electrical') sensations were provoked at 28 cm (10 of 12). Thresholds of sensation and of pain were lower at the initial than the second determination, but did not differ with respect to stimulation site. The pain summation threshold to repeated stimuli (2 Hz, 5 stimuli) was determined for the first time in a viscus. This threshold was lower than the pain threshold to single stimuli at 38 cm (p < 0.02). Evoked potential latencies did not change significantly over a six month period while the N1/P2 amplitude was higher at the first measurement (p < 0.05). P1 and N1 latencies were significantly shorter 38 cm (medians 100 and 141 ms) than 28 cm from the nares (102 and 148 ms) (p = 0.04 and p = 0.008). Electrical stimulation of the oesophagus may serve as a human experimental model for visceral pain. Longer evoked potential latencies from the proximal compared with distal stimulations provide new information about the sensory pathways of the oesophagus. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate the role of nociception in patients with angina despite normal coronary angiograms and to investigate whether any abnormality is confined to visceral or somatosensory perception.Methods: Perception, pain threshold, and brain evoked potentials to nociceptive electrical stimuli of the oesophageal mucosa and the sternal skin were investigated in 10 patients who had angina but normal coronary angiograms, no other signs of cardiac disease, and normal upper endoscopy. Controls were 10 healthy volunteers. The peaks of the evoked potential signal were designated N for negative deflections and P for positive. Numbers were given to the peaks in order of appearance after the stimulus. The peak to peak amplitudes (P1/N1, N1/P2) were measured in microV.Results: (1) Angina pectoris was provoked in seven patients following continuous oesophageal stimulation. (2) Distant projection of pain occurred after continuous electrical stimulation of the oesophagus in four patients and in no controls. (3) Patients had higher oesophageal pain thresholds (median 16.3 mA v 7.3 mA, P = 0.02) to repeated stimuli than controls, whereas the values did not differ with respect to the skin. There were no intergroup differences in thresholds to single stimuli. (4) Patients had substantially reduced brain evoked potential amplitudes after both single oesophageal (P1/N1, median values: 7.2 microV, controls: 29.0 microV; N1/P2: 16.5 microV, controls: 66.0 microV; P < 0.001 for both) and skin (N1/P2: 13.5 microV; controls: 76.0 microV; P < 0.001) stimuli despite the similar pain thresholds.Conclusion: Central nervous system responses to visceral and somatosensory nociceptive input are altered in patients who have angina despite normal coronary angiograms. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate transmural pressure and longitudinal stretch modulation of K[sup+]- and Ca[sup2+]-induced constriction of porcine conductance coronary arteries. In a pressure myograph set-up, left anterior descendent coronary arteries from 70 to 90 kg pigs were investigated at pressures from 20 to 120 mmHg. Longitudinal extension ratio (λ = L/L[sup−1[sub0], where L[sub0] is the in situ length and L the examination length) varied between 0.9 and 1.1. Two protocols were carried out: (1) Outer diameter response to maximal depolarization by K[sup+] 125 mM at 20–120 mmHg and λ at 0.90–1.10. (2) Concentration-response curves with K[sup+] (4.7–125 mM) and Ca[sup2+] (0.05–4.0 mM) at four combinations of P and λ(P = 100 mmHg, λ = 0.9; P = 100 mmHg, λ = 1.1; P = 40 mmHg, λ = 0.9; p = 40 mmHg, λ = 1.1). Results: Endothelial function was preserved. A slight (<5% diameter reduction) basal tone and no myogenic response was found. Protocol 1: the constriction to K[sup+] 125 mM was maximal in a wide pressure range from 40 to 120 mmHg. Despite the fact that K[sup+]-induced diameter changes were statistically insignificant between 40 and 120 mmHg, there was a linear trend towards smaller diameter changes in this pressure range (r = -0.54, P < 0.01). Stretch influenced constriction at 20 mmHg because λ = 0.90 and 0.95 resulted in smaller diameter-reductions than λ = 1.00–1.10 (P < 0.05 for all). Contrastingly, at 120 mmHg the constriction at λ = 1.10 was smaller than the responses at λ = 0.90–1.05 (P < 0.05 for all). Protocol 2: EC[sub50] and EC[sub10] values for K[sup+]- and Ca[sup2+] were generally higher (more sensitive) at 40 compared with 100 mmHg. Stretch was of no significant importance for EC[sub50] and EC[sub10] at 40 and 100 mmHg. It is concluded that porcine coronary artery constriction to non-metabolized agonists is... [ABSTRACT FROM AUTHOR]

Brown bears (Ursus arctos) prepare for winter by overeating and increasing adipose stores, before hibernating for up to six months without eating, drinking, and with minimal movement. In spring, the bears exit the den without any damage to organs or physiology. Recent clinical research has shown that specific lipids and lipid profiles are of special interest for diseases such as diabetes type 1 and 2. Furthermore, rodent experiments show that lipids such as sulfatide protects rodents against diabetes. As free-ranging bears experience fat accumulation and month-long physical inactivity without developing diabetes, they could possibly be affected by similar protective measures. In this study, we investigated whether lipid profiles of brown bears are related to protection against hibernation-induced damage. We sampled plasma from 10 free-ranging Scandinavian brown bears during winter hibernation and repeated sampling during active state in the summer period. With quantitative shotgun lipidomics and liquid chromatography-mass spectrometry, we profiled 314 lipid species from 26 lipid classes. A principal component analysis revealed that active and hibernation samples could be distinguished from each other based on their lipid profiles. Six lipid classes were significantly altered when comparing plasma from active state and hibernation: Hexosylceramide, phosphatidylglycerol, and lysophosphatidylglycerol were higher during hibernation, while phosphatidylcholine ether, phosphatidylethanolamine ether, and phosphatidylinositol were lower. Additionally, sulfatide species with shorter chain lengths were lower, while longer chain length sulfatides were higher during hibernation. Lipids that are altered in bears are described by others as relevant for and associated with diabetes, which strengthens their position as potential effectors during hibernation. From this analysis, a range of lipids are suggested as potential protectors of bear physiology, and of potential importance in diabetes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tekin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Registry-based randomized controlled trials (RRCTs) are increasingly used, promising to address challenges associated with traditional randomized controlled trials. We identified strengths and limitations reported in planned and completed RRCTs to inform future RRCTs., Study Design and Setting: We conducted an environmental scan of literature discussing conceptual or methodological strengths and limitations of using registries for trial design and conduct (n = 12), followed by an analysis of RRCT protocols (n = 13) and reports (n = 77) identified from a scoping review. Using framework analysis, we developed and refined a conceptual framework of RRCT-specific strengths and limitations. We mapped and interpreted strengths and limitations discussed by authors of RRCT articles using framework codes and quantified the frequencies at which these were mentioned., Results: Our conceptual framework identified six main RRCT strengths and four main RRCT limitations. Considering implications for RRCT conduct and design, we formulated ten recommendations for registry designers, administrators, and trialists planning future RRCTs., Conclusion: Consideration and application of empirically underpinned recommendations for future registry design and trial conduct may help trialists utilize registries and RRCTs to their full potential., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Women have a worse prognosis after ST-segment elevation myocardial infarction (STEMI) than men. The prognostic role of thrombus burden (TB) in influencing the sex-related differences in clinical outcomes after STEMI has not been clearly investigated., Objectives: The aim of this study was to assess the sex-related differences in TB and its clinical implications in patients with STEMI., Methods: Individual patient data from the 3 major randomized clinical trials of manual thrombus aspiration were analyzed, encompassing a total of 19,047 patients with STEMI, of whom 13,885 (76.1%) were men and 4,371 (23.9%) were women. The primary outcome of interest was 1-year cardiovascular (CV) death. The secondary outcomes of interest were recurrent myocardial infarction, heart failure, all-cause mortality, stroke, stent thrombosis (ST), and target vessel revascularization at 1 year., Results: Patients with high TB (HTB) had worse 1-year outcomes compared with those presenting with low TB (adjusted HR for CV death: 1.52; 95% CI: 1.10-2.12; P = 0.01). In unadjusted analyses, female sex was associated with an increased risk for 1-year CV death regardless of TB. After adjustment, the risk for 1-year CV death was higher only in women with HTB (HR: 1.23; 95% CI: 1.18-1.28; P < 0.001), who also had an increased risk for all-cause death and ST than men., Conclusions: In patients with STEMI, angiographic evidence of HTB negatively affected prognosis. Among patients with HTB, women had an excess risk for ST, CV, and all-cause mortality than men. Further investigations are warranted to better understand the pathophysiological mechanisms leading to excess mortality in women with STEMI and HTB., Competing Interests: Funding Support and Author Disclosures Dr Manzi has received a research grant from the European Society of Cardiology during the conduct of this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

A vegetarian diet has been associated with a lower risk of coronary artery disease (CAD). Plasma triacylglycerols, ceramides, and phosphatidylcholines may improve prediction of recurrent coronary events. We sought to investigate effects of a lacto-ovo-vegetarian diet (VD) on plasma lipidome in CAD patients and simultaneously assess associations of plasma lipids with the extent of coronary atherosclerotic burden. We analyzed 214 plasma lipids within glycerolipid, sphingolipid, and sterol lipid classes using lipidomics from a randomized controlled, crossover trial comprising 31 CAD patients on standard medical therapy. Subjects completed a four-week intervention with VD and isocaloric meat diet (MD), separated by a four-week washout period. The VD increased levels of 11 triacylglycerols and lowered 7 triacylglycerols, 21 glycerophospholipids, cholesteryl ester (18:0), and ceramide (d18:1/16:0) compared with MD. VD increased triacylglycerols with long-chain polyunsaturated fatty acyls while decreased triacylglycerols with saturated fatty acyls, phosphatidylcholines, and sphingomyelins than MD. The Sullivan extent score (SES) exhibited on coronary angiograms were inversely associated with triacylglycerols with long-chain unsaturated fatty acyls. Phosphatidylcholines that were lower with VD were positively associated with SES and the total number of stenotic lesions. The VD favorably changed levels of several lipotoxic lipids that have previously been associated with increased risk of coronary events in CAD patients.

Background A vegetarian diet (VD) may reduce future cardiovascular risk in patients with ischemic heart disease. Methods and Results A randomized crossover study was conducted in subjects with ischemic heart disease, assigned to 4-week intervention periods of isocaloric VD and meat diet (MD) with individually designed diet plans, separated by a 4-week washout period. The primary outcome was difference in oxidized low-density lipoprotein cholesterol (LDL-C) between diets. Secondary outcomes were differences in cardiometabolic risk factors, quality of life, gut microbiota, fecal short-chain and branched-chain fatty acids, and plasma metabolome. Of 150 eligible patients, 31 (21%) agreed to participate, and 27 (87%) participants completed the study. Mean oxidized LDL-C (-2.73 U/L), total cholesterol (-5.03 mg/dL), LDL-C (-3.87 mg/dL), and body weight (-0.67 kg) were significantly lower with the VD than with the MD. Differences between VD and MD were observed in the relative abundance of several microbe genera within the families Ruminococcaceae, Lachnospiraceae, and Akkermansiaceae. Plasma metabolites, including l-carnitine, acylcarnitine metabolites, and phospholipids, differed in subjects consuming VD and MD. The effect on oxidized LDL-C in response to the VD was associated with a baseline gut microbiota composition dominated by several genera of Ruminococcaceae. Conclusions The VD in conjunction with optimal medical therapy reduced levels of oxidized LDL-C, improved cardiometabolic risk factors, and altered the relative abundance of gut microbes and plasma metabolites in patients with ischemic heart disease. Our results suggest that composition of the gut microbiota at baseline may be related to the reduction of oxidized LDL-C observed with the VD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02942628.

Mesenchymal stem cells (MSCs) for cardiovascular cell therapy are procured from different sources including bone marrow and adipose tissue. Differently located MSCs differ in growth potential, differentiation ability and gene expression when cultured in vitro, and studies show different healing abilities for different MSC subgroups. In this study, bone marrow derived MSCs (BMSCs) and adipose tissue derived MSCs (ADSCs) from six human donors with coronary artery disease were compared for growth potential and expression of target genes (Angpt1, LIF, HGF, TGF-β1 and VEGF-A) in response to exposure to 1% and 5% O 2 , for up to 48 h. We found greater growth of ADSCs compared to BMSCs. ADSCs expressed higher levels of Angpt1, LIF and TGF-β1 and equal levels of VEGF-A and HGF as BMSCs. In BMSCs, exposure to low oxygen resulted in upregulation of TGF-β1, whereas other target genes were unaffected. Upregulation was only present at 1% O 2 . In ADSCs, LIF was upregulated in both oxygen concentrations, whereas Angpt1 was upregulated only at 1% O 2 . Different response to reduced oxygen culture conditions is of relevance when expanding cells in vitro prior to administration. These findings indicate ADSCs as better suited for cardiovascular cell therapy compared to BMSCs.

Objectives: We evaluated the diagnostic performance of quantitative flow ratio (QFR) assessment of nonculprit lesions (NCLs) based on acute setting angiograms obtained in patients with ST-segment elevation myocardial infarction (STEMI) with QFR, fractional flow reserve (FFR), and instantaneous wave-free ratio (iFR) in the staged setting as reference., Background: QFR is an angiography-based approach for the functional evaluation of coronary artery lesions., Methods: This was a post-hoc analysis of the iSTEMI study. NCLs were assessed with iFR in the acute setting and with iFR and FFR at staged (median 13 days) follow-up. Acute and staged QFR values were computed in a core laboratory based on the coronary angiography recordings. Diagnostic cut-off values were ≤0.80 for QFR and FFR, and ≤0.89 for iFR., Results: Staged iFR and FFR data were available for 146 NCLs in 112 patients in the iSTEMI study. Among these, QFR analysis was feasible in 103 (71%) lesions assessed in the acute setting with a mean QFR value of 0.82 (IQR: 0.73-0.91). Staged QFR, FFR, and iFR were 0.80 (IQR: 0.70-0.90), 0.81 (IQR: 0.71-0.88), and 0.91 (IQR: 0.87-0.96), respectively. Classification agreement of acute and staged QFR was 93% (95%Cl: 87-99). The classification agreement of acute QFR was 84% (95%CI: 76-90) using staged FFR as reference and 74% (95%CI: 65-83) using staged iFR as reference., Conclusions: Acute QFR showed a very good diagnostic performance with staged QFR as reference, a good diagnostic performance with staged FFR as reference, and a moderate diagnostic performance with staged iFR as reference., (© 2019 Wiley Periodicals, Inc.)