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1.
Oral ketone esters acutely improve myocardial contractility in post-hospitalized COVID-19 patients: A randomized placebo-controlled double-blind crossover study.
Wodschow, HZ, Davidovski, FS, Christensen, J, Lassen, MCH, Skaarup, KG, Nygaard, H, Møller, N, Rungby, J, Biering-Sørensen, T, Rossing, P, et al
Frontiers in nutrition. 2023;:1131192
Abstract
BACKGROUND COVID-19 is associated with subclinical myocardial injury. Exogenous ketone esters acutely improve left myocardial function in healthy participants and patients with heart failure, but the effects have not been investigated in participants previously hospitalized for COVID-19. METHODS This is a randomized placebo-controlled double-blind crossover study comparing a single oral ketone ester dose of 395 mg/kg with placebo. Fasting participants were randomized to either placebo in the morning and oral ketone ester in the afternoon or vice versa. Echocardiography was performed immediately after intake of the corresponding treatment. Primary outcome was left ventricular ejection fraction (LVEF). Secondary outcomes were absolute global longitudinal strain (GLS), cardiac output and blood oxygen saturation. Linear mixed effects models were used to assess differences. RESULTS We included 12 participants previously hospitalized for COVID-19 with a mean (±SD) age of 60 ± 10 years. The mean time from hospitalization was 18 ± 5 months. Oral ketone esters did not increase LVEF between placebo and oral ketone ester [mean difference: -0.7% (95% CI -4.0 to 2.6%), p = 0.66], but increased GLS [1.9% (95% CI: 0.1 to 3.6%), p = 0.04] and cardiac output [1.2 L/min (95% CI: -0.1 to 2.4 L/min), p = 0.07], although non-significant. The differences in GLS remained significant after adjustment for change in heart rate (p = 0.01). There was no difference in blood oxygen saturation. Oral ketone esters increased blood ketones over time (peak level 3.1 ± 4.9 mmol/L, p < 0.01). Ketone esters increased blood insulin, c-peptide, and creatinine, and decreased glucose and FFA (all p ≤ 0.01) but did not affect glucagon, pro-BNP, or troponin I levels (all p > 0.05). CONCLUSION In patients previously hospitalized with COVID-19, a single oral dose of ketone ester had no effect on LVEF, cardiac output or blood oxygen saturation, but increased GLS acutely. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov/, identifier NCT04377035.
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2.
Postsystolic shortening on echocardiography as a gateway to cardiac computed tomography in patients with suspected stable angina pectoris.
Brainin, P, Olsen, FJ, Lassen, MCH, Bech, J, Claggett, B, Fritz-Hansen, T, Folke, F, Gislason, GH, Biering-Sørensen, T
The international journal of cardiovascular imaging. 2020;(2):309-316
Abstract
Postsystolic shortening (PSS) by speckle-tracking echocardiography (STE) is a marker of myocardial ischemia and may improve diagnostic strategy. We sought to evaluate if PSS is associated with the coronary artery calcium score (CACS) and stenosis by computed tomography angiography (CTA) in patients with suspected stable angina pectoris (SAP). We retrospectively studied 437 SAP patients (age 58 ± 11 years, 41% male) who underwent STE, evaluation of CACS and assessment of significant stenosis (≥ 50%) by CTA. The postsystolic index (PSI) was defined as follows: 100x([peak negative strain cardiac cycle - peak negative strain systole])/peak negative strain cardiac cycle. A wall had PSS if any segment within the wall had a PSI ≥ 20%. We defined categories for walls with PSS: 0, 1, 2 and ≥ 3, and CACS 0, 1-100, 101-400 and > 400. Each additional wall with PSS was associated with a 43% relative increase in CACS (95%CI +9% to +87%, P = 0.010), while each 1% absolute increase in the PSI was associated with a 9% relative increase in CACS (95%CI +1% to +18%, P = 0.031). Walls with PSS (OR 1.81 per 1 wall increase, 95%CI 1.27-2.59, P = 0.001) and the PSI (OR 1.12 per 1% increase, 95%CI 1.04-1.21, P = 0.004) were associated with the occurrence of CACS > 400. Additionally, walls with PSS (OR 1.53 per 1 wall increase, 95%CI 1.21-1.93, P < 0.001) was a predictor of significant stenosis by CTA. PSS is associated with CACS and significant stenosis by CTA in patients with SAP and may aid in the selection of patients referred for cardiac computed tomography.
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3.
Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.
Sivapalan, P, Ulrik, CS, Bojesen, RD, Lapperre, TS, Eklöf, JV, Håkansson, KEJ, Browatzki, A, Tidemansen, C, Wilcke, JT, Janner, J, et al
Trials. 2020;(1):513
Abstract
OBJECTIVES The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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4.
Do ultrathin strut bare-metal stents with passive coating improve efficacy in large coronary arteries? Insights from the randomized, multicenter BASKET-PROVE trials.
Hansen, KW, Jeger, R, Sørensen, R, Kaiser, C, Pfisterer, M, Biering-Sørensen, T, Bjerking, LH, Galatius, S
BMC cardiovascular disorders. 2019;(1):226
Abstract
BACKGROUND The new generation thinner-strut silicon carbide (SiC) coated cobalt chromium (CoCr) bare-metal stents (BMS) are designed to accelerate rapid endothelialisation and reduce thrombogenicity when implanted in coronary arteries. However, smaller studies suggest higher rates of symptomatic restenosis in patients receiving the newer generation BMS. We investigated the efficacy of a newer generation ultrathin strut silicon-carbide coated cobalt-chromium (CoCr) BMS (SCC-BMS) as compared to an older thin-strut uncoated CoCr BMS (UC-BMS) in patients presenting with coronary artery disease requiring stenting of large vessels (≥3.0 mm). METHODS All patients randomized to SCC- (n = 761) or UC-BMS (n = 765) in the two BASKET-PROVE trials were included. Design, patients, interventions and follow-up were similar between trials except differing regimens of dual antiplatelet therapy. The primary endpoint was clinically driven target-vessel revascularization within 24 months. Safety endpoints of cardiac death, non-fatal myocardial infarction (MI), and definite/probable stent thrombosis (ST) were also assessed. We used inverse probability weighted proportional hazards Cox regressions adjusting for known confounders. RESULTS Demographics, clinical presentation, and risk factors were comparable between the groups, but patients receiving SCC-BMS underwent less complex procedures. The risk for clinically driven TVR was increased om the SCC-BMS group compared to the UC-BMS group (cumulative incidence, 10.6% vs. 8.4%; adjusted relative hazard [HR], 1.49 [95% CI, 1.05-2.10]). No differences in safety endpoints were detected, cardiac death (1.6% vs. 2.8%; HR, 0.62 [CI, 0.30-1.27]), non-fatal MI (3.2% vs. 2.5%; HR, 1.56 [CI, 0.83-2.91]), and definite/probable ST (0.8% vs. 1.1%; HR, 1.17 [CI, 0.39-3.50]). Differences in strut thickness between the two stents did not explain the association between stent type and clinically driven TVR. CONCLUSIONS In patients requiring stenting of large coronary arteries, use of the newer generation SCC-BMS was associated with a higher risk of clinically driven repeat revascularization compared to the UC-BMS with no signs of an offsetting safety benefit.
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5.
Ideal Cardiovascular Health and the Prevalence and Severity of Aortic Stenosis in Elderly Patients.
Sengeløv, M, Cheng, S, Biering-Sørensen, T, Matsushita, K, Konety, S, Solomon, SD, Folsom, AR, Shah, AM
Journal of the American Heart Association. 2018;(3)
Abstract
BACKGROUND The relationship between ideal cardiovascular health reflected in the cardiovascular health score (CVHS) and valvular heart disease is not known. The purpose of this study was to determine the association of CVHS attainment through midlife to late life with aortic stenosis prevalence and severity in late life. METHODS AND RESULTS The following 6 ideal cardiovascular health metrics were assessed in ARIC (Atherosclerosis Risk in Communities) Study participants at 5 examination visits between 1987 and 2013 (visits 1-4 in 1987-1998 and visit 5 in 2011-2013): smoking, body mass index, total cholesterol, blood pressure, physical activity, and blood glucose. Percentage attained CVHS was calculated in 6034 participants as the sum of CVHS at each visit/the maximum possible score. Aortic stenosis was assessed by echocardiography at visit 5 on the basis of the peak aortic valve velocity. Aortic stenosis was categorized sclerosis, mild stenosis, and moderate-to-severe stenosis. Mean age was 76±5 years, 42% were men, and 22% were black. Mean percentage attained CVHS was 63±14%, and the prevalence of aortic stenosis stages were 15.9% for sclerosis, 4.3% for mild stenosis, and 0.7% for moderate-to-severe stenosis. Worse percentage attained CVHS was associated with higher prevalence of aortic sclerosis (P<0.001 for trend), mild stenosis (P<0.001), and moderate-to-severe stenosis (P=0.002), adjusting for age, sex, and race. CONCLUSIONS Greater attainment of ideal cardiovascular health in midlife to late life is associated with a lower prevalence of aortic sclerosis and stenosis in late life in a large cohort of older adults.