bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of prophylactic and therapeutic low molecular weight heparins on mortality in 15,704 COVID-19 patients. A systematic review and a meta-analysis
Authors: Pani A , Giossi R , Menichelli D , Tratta E , Romandini A , Roncato R , Nani A , Schenardi P , Diani E , Fittipaldo V A , Farcomeni A , Scaglione F , Pastori D 
Published: October 2021

Abstract

Background
Antithrombotic treatment, including low molecular weight heparin (LMWH), has been proposed as a potential therapy for Coronavirus disease 2019 (COVID-19), to counteract diffuse intravascular clotting activation. However, it is unclear whether prophylactic or therapeutic doses are similarly effective in reducing mortality.

Methods
We performed a systematic review and meta-analysis of clinical studies to evaluate the efficacy of heparin (either, LMWH or fondaparinux) compared to no anticoagulation in reducing overall mortality. A subgroup analysis comparing prophylactic or therapeutic regimen was performed. Secondary endpoints were major bleeding and length of hospital stay (LOS).

Results
12 studies were included, 2 prospective and 10 retrospective with 15,704 patients. Of these, 11,251 (71.6%) were on heparins. Ten studies reported data on all-cause mortality (figure), showing that both prophylactic and full dose reduced mortality (pooled Hazard Ratio [HR] 0.55, 95% confidence interval [CI] 0.48–0.63 and HR 0.49, 95% CI 0.41–0.59, respectively). The prophylactic dose was associated with a lower risk of major bleeding (Odds Ratio [OR] 0.60, 95% CI 0.41–0.87), while a non-significant trend towards an increased risk of bleeding for the therapeutic dose was noted (OR 1.55, 95% CI 0.98–2.43). Finally, LOS was evaluated in 3 studies; the mean difference for prophylactic heparin treatment was −2.38 (−3.14, −1.61) days.

Discussion
Heparin is effective in reducing mortality in COVID-19 patients, with therapeutic and prophylactic regimens showing a similar reduction in the mortality rate. Prophylactic dose may be considered as the first choice in all patients with COVID-19 requiring hospital admission.

Funding Acknowledgement
Type of funding sources: None.
Strategies to bridge therapeutic gap in low-density-lipoprotein cholesterol lowering among 90,590 Chinese population with atherosclerotic cardiovascular diseases on stable statin monotherapy
Authors: Sun H , Lai A , Yan B 
Published: October 2021

Abstract

Background
Current guideline recommends addition of PCSK9-inhibitor to achieve low-density-lipoprotein cholesterol (LDL-C) lowering by ≥50% to target LDL-C &lt;1.4mmol/L for patients with established atherosclerotic cardiovascular disease (ASCVD) already on maximum tolerated dose of statin and ezetimibe.

Purpose
We aimed to evaluate the residual distance to target LDL-C (LDL-C lowered by ≥50% and &lt;1.4mmol/L) in ASCVD patients on statin monotherapy and the proportion projected to reach target LDL-C by up-titration to high potency statin, addition of ezetimibe and PCSK9-inhibitor.

Methods
We retrospectively analyzed 90,590 patients with ASCVD on stable dose of statin monotherapy prior to lipid profile assessment from 43 public hospitals in Hong Kong between Aug 2016 and Jul 2020. Patients were divided into (i) high potency statin (HP-S; rosuvastatin ≥20mg, atorvastatin ≥40mg or simvastatin ≥80mg) and (ii) non-high potency statin (NHP-S; other statin doses) statin users. We calculated the mean percentage LDL-C reduction required to reach the target of LDL-C lowered by ≥50% and &lt;1.4mmol/L. We assumed up-titration from NHP-S to HP-S would further reduce LDL-C by approximately 5–10%; addition of ezetimibe 15–20% and PCSK-9 inhibitor 50–60%.

Results
Of 90,590 patients (63.2% male, mean age 66.8±11.3), 80.5% had coronary artery, 1.6% had peripheral artery and 21% had cerebrovascular disease; 18.7% were on HP-S and 81.3% on NHP-S. LDL-C lowered by ≥50% and &lt;1.4mmol/L were not achieved in 96.8% (n=71,333/73,655) patients on NHP-S and 93.9% (n=15,896/16,935) patients on HP-S. In these patients, mean LDL-C was 1.8±0.6 and 1.9±0.6mmol/L and mean percentage LDL-C reduction required to reach target LDL-C goal was 40.5±15.4% and 39.3±17.8%, respectively. The proportion of patients who required 5–10%, 10–30%, 30–60% and &gt;60% further reduction to reach target LDL-C were 2.5%, 22.1%, 65.4% and 9%, respectively. Proportion of NHP-S patients projected to reach LDL-C goal by up-titrating to HP-S is 2.2% (n=1,569/71,333). Addition of ezetimibe is projected to achieve LDL-C target in 20.5% (n=17,519/85,660) patients on HP-S who are not at goal. Overall, 78.1% (n=68,141/87,229) of patients on HP-S and ezetimibe were expected to need PCSK-9 inhibitor and is projected to achieve LDL-C target in 98% of cases (n=66,806/68,141).

Conclusion
Our “real-world” study showed the use of HP-S in ASCVD patients was low and &gt;90% did not reach LDL-C target. High potency statin plus ezetimibe was projected to bridge about one fifth of these patients to target LDL-C. PCSK-9 inhibitor is likely required in significant number of patients despite HP-S plus ezetimibe.

Funding Acknowledgement
Type of funding sources: None.
Risk of death with sodium-glucose co-transporter-2 inhibitors across the hallmark cardiovascular and renal outcome trials: an updated meta-analysis
Authors: Patoulias D , Boulmpou A , Tranidou A , Nikolaidis A , Mouselimis D , Papadopoulos C E , Vassilikos V , Doumas M 
Published: October 2021

Abstract

Background
Patients with type 2 diabetes mellitus (T2DM) experience a 15% increase in the risk for death compared to the general population, with age less than 55 years, insufficient glycemic control and albuminuria representing the major risk factors for all-cause and cardiovascular mortality. Despite progression in diagnosis and treatment, mortality remains elevated among affected individuals. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are considered as the optimal treatment option for patients with T2DM and concomitant cardiovascular or renal disease, while these regimens demonstrated a clear benefit in all-cause and cardiovascular mortality compared to placebo.

Purpose
As we recently welcomed the publication of large-scale randomized controlled trials (RCTs) with SGLT-2 inhibitors addressing surrogate, hard endpoints, we sought to perform an updated meta-analysis, investigating the effect of SGLT-2 inhibitors on all-cause, cardiovascular and renal death among the high- or very-high risk patients enrolled in those trials.

Methods
We pooled data from the relevant, recent hallmark RCTs; 10 trials were included in our analysis encompassing a total of 71,533 enrolled participants, assigned either to SGLT-2 inhibitor treatment or placebo. We set cardiovascular death as the primary efficacy outcome, while we assessed all-cause death and renal death as secondary efficacy outcomes.

Results
Treatment with SGLT-2 inhibitors resulted in a significant decrease in the risk of cardiovascular death, equal to 14% (RR = 0.86, 95% CI; 0.80 to 0.93, I2=22%). Only canagliflozin produced a significant result, while dapagliflozin led to a marginally non-significant reduction in cardiovascular mortality (Figure 1). Notably, SGLT-2 inhibitors led to a significant decrease in the risk for all-cause death, equal to 14% (RR=0.86, 95% CI; 0.81 to 0.92, I2=34%) the result was significant only for canagliflozin and dapagliflozin, while none of the rest SGLT-2 inhibitors resulted in a significant decrease in the risk for all-cause death (Figure 1). SGLT-2 inhibitors also produced a non-significant decrease in the risk for renal death (RR=0.36, 95% CI; 0.12 to 1.14, I2=0%). Neither canagliflozin nor dapagliflozin had a significant impact on risk reduction for renal death, while no cases of renal death were reported in VERTIS CV trial. No subgroup differences were identified for any of the three comparisons (Figure 2).

Conclusions
Antidiabetic treatment with SGLT-2 inhibitors provides a clear benefit in terms of cardiovascular and all-cause mortality for the very high-risk patients enrolled in the cardiovascular and renal outcome trials. Canagliflozin seems to be associated with the greatest impact on risk reduction for all-cause and cardiovascular death, followed by dapagliflozin.

Funding Acknowledgement
Type of funding sources: None. Figure 1Figure 2
SIRT1 improves endothelial function by suppressing oxidative stress in diabetic mice
Authors: Yang K , Velagapudi S , Camici G , Xu A , Luescher T F 
Published: October 2021

Abstract

Background
The activation of longevity gene and the intracellular expression of the protein SIRT1 in vivo shows beneficial effects in different organs including cardiovascular function [1]. However, it is not known whether extracellular SIRT1 plays a role and has favorable effects on endothelial and vascular function.

Purpose
The current study aimed to investigate the effects of in-vivo treatment of diabetic mice with recombinant mouse SIRT1 (rcSIRT1) on endothelial and vascular dysfunctions.

Methods
Db/db mice of 12 weeks of age and their lean controls were treated with vehicle or rcSIRT1 protein intraperitoneally for 4 weeks with a dose of 5μg/mouse /day. At the end of the treatment period, pulse wave velocity of carotid arteries was examined with echocardiology and the activities of mouse were recorded through metabolic cage housing system. Aorta, carotid arteries, and mesenteric arteries were isolated at sacrifice to assess endothelial and vascular function in myograph systems.

Results
The db/db mice treated with rcSIRT1 were more active in the dark cycle. Their vascular functions were improved as aortas exhibited reduced contractions to phenylephrine and increased relaxations to acetylcholine. Carotid arteries also performed better function as the pulse wave velocity was reduced and endothelium-dependent contracting factors were significantly decreased after treatment. Mesenteric resistance arteries had preserved endothelial dependent hyperpolarization compared to the controls. Incubation with different inhibitors showed that rcSIRT1 exerted beneficial effects on vascular function by supressing oxidative stress which were mediated by NADPH oxidase and COX-1 pathways.

Conclusions
Exogenous treatment of diabetic mice with recombinant SIRT1 significantly improves endothelial and vascular function. Circulating Sirt1 may be a novel therapeutic preventing diabetic vascular disease.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation
Gastrointestinal bleeding risk following concomitant treatment with oral glucocorticoids in patients with atrial fibrillation on direct-acting oral anticoagulants
Authors: Holt A , Blanche P , Zareini B , Rasmussen P V , Strange J E , Rajan D , Jensen M H , El-Sheikh M , Schjerning A M , Schou M , Gislason G H , Torp-Pedersen C , McGettigan P , Lamberts M K 
Published: October 2021

Abstract

Background
Oral glucocorticoids and direct-acting oral anticoagulants (DOAC) have both been associated with a risk of gastrointestinal (GI) bleeding. However, drug safety, especially regarding the risk of bleeding, in relation to concomitant treatment with oral glucocorticoids and DOACs is insufficiently explored.

Purpose
We aimed to investigate the short-term risk of GI bleeding in patients with atrial fibrillation (AF) following concomitant treatment with DOACs and oral glucocorticoids.

Methods
Register-based, retrospective and nationwide Danish study including patients with AF and on DOAC treatment during 2012–2018. Patients were defined as exposed to oral glucocorticoids from the date of a redeemed prescription and 60 days forward. We associated concomitant treatment with GI bleeding and reported hazard ratios (HR) via a nested case-control design and standardized 60-day absolute risk adjusted for comorbidities using a cohort design. In both analyses, exposed were compared to non-exposed controls matched on age, sex, calendar year, follow-up time and DOAC agent.

Results
We included 98,376 patients (age [interquartile range]: 75 [68– 82], 44% females) with AF on DOAC treatment. The use of oral glucocorticoids among included patients was widespread with 16% redeeming at least one prescription within three years, 4% redeeming at least five (Figure 1A). Lung disease was the most frequent indication (Figure 1B). Concomitant treatment with DOACs and oral glucocorticoids was associated with an increased incidence of GI bleeding (total n=4,946) compared with only DOAC treatment, including a dose-response trend (&lt;20mg daily dose, HR [95% confidence interval (CI)]: 1.64 [1.38–1.95]; ≥20mg daily dose, HR [95% CI]: 2.29 [1.90–2.77]). Likewise, the standardized 60-day absolute risk of GI bleeding from first oral glucocorticoid exposure was increased compared with non-exposed (Figure 2).

Conclusion
Caution should be exercised when prescribing even short-term oral glucocorticoid treatment for DOAC treated patients, most notably in high doses and for patients with elevated bleeding risk.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Ib Mogens Kristiansens Almene FondandHelsefonden
Ranolazine exerted cardioprotection against doxorubicin-induced cardiotoxicity through inhibiting excessive autophagy in rats
Authors: Arinno A , Maneechote C , Khuanjing T , Chunchai T , Prathumsap N , Ongnok B , Arunsak B , Jaiwongkam T , Kerdphoo S , Shinlapawittayatorn K , Chattipakorn S C , Chattipakorn N 
Published: October 2021

Abstract

Background
Doxorubicin (Dox) is a highly effective chemotherapeutic agent for several malignancies. However, its cardiotoxicity and progressive heart failure are the most serious adverse effects that compromised its clinical use. Recently, ranolazine, the late sodium (Na+) current inhibitor for patients with chronic angina, has been suggested as a potential agent to treat early cardiotoxicity induced by antitumor drugs. In that single report, pretreatment with ranolazine improved cardiac function and decreased mortality rates in the Dox-treated rats, by decreasing oxidative stress and apoptosis. Nevertheless, its protective mechanisms on autophagy in the Dox-treated rats have never been elucidated.

Purpose
We hypothesized that ranolazine exerts cardioprotection in the Dox-treated rats by improving left ventricular (LV) function and reducing cardiac injury though suppressing excessive autophagy.

Methods
Male Wistar rats (n=24) received either normal saline solution (NSS, n=8) or Dox (3 mg/kg/day, i.p.) for 6 doses. Then, the Dox-treated rats were assigned to orally administered with either saline (n=8) or ranolazine (305 mg/kg/day, n=8) for 30 consecutive days. Following the treatment, the LV function, cardiac injury, and autophagy were determined.

Results
Dox caused LV dysfunction as indicated by the decreased %LV ejection fraction (LVEF) and the increased serum cardiac troponin-I (cTn-I) levels (Fig. 1A). In addition, Dox induced excessive autophagy by increasing Beclin-1, p62, and light chain 3-II/I (LC3II/I) protein expressions (Fig. 1B). Treatment with ranolazine attenuated autophagic-related proteins (Beclin-1, p62, and LC3II/I), and improved LV function (Fig. 1A-B).

Conclusion
Ranolazine exerted cardioprotection in the Dox-treated rats through suppressing autophagic-regulatory proteins, suggesting its potential cardioprotective roles as a concomitant therapy for cancer patients receiving Dox.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): the NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand and the National Research Council of Thailand
Validity and utility of the questionnaire-based FRAIL scale in elderly patients with heart failure: findings from the FRAGILE-HF
Authors: Nozaki K , Kamiya K , Hamazaki N , Saitou H , Saitou K , Ogasawara Y , Maekawa E , Konishi M , Kitai T , Iwata K , Jujo K , Kagiyama N , Matsue Y 
Published: October 2021

Abstract

Introduction
The coexistence of heart failure (HF) and frailty leads to a worse prognosis. Frailty is generally diagnosed using the Fried criteria. To assess whether patients are frail according to the Fried scale, face-to-face physical examinations are required. However, with the COVID-19 pandemic, to avoid the spread of the virus in hospitals, it is important to screen hospitalized patients for frailty without contact. Therefore, non-contact measurement methods, such as questionnaires, should be used to screen for frailty in clinical practice. The FRAIL scale is a questionnaire used to screen for frailty. There are no studies regarding the consistency of the FRAIL scale with the Fried criteria, the impact on mortality, and physical dysfunction in elderly patients with HF.

Purpose
We investigated whether the FRAIL scale questionnaire is consistent with the Fried criteria, predicts all-cause mortality, and reflects physical dysfunction in patients with HF.

Methods
The present study was secondary analysis of FRAGILE-HF, a cohort study that enrolled participants from 2016 to 2018 and followed up for 1-year of discharge. A prospective multicenter cohort study in which 15 hospitals in Japan (8 university hospitals and 7 non-university teaching hospitals) participated. We prospectively enrolled 1332 consecutive hospitalized patients with HF ≥65 years old and analyzed 1028 patients after excluding 304 patients with missing data on the FRAIL scale. The FRAIL scale, the Fried model, and physical function were measured before discharge. The endpoint was all-cause mortality.

Results
According to the FRAIL scale, 459 (44.6%) and 491 (47.8%) were classified as frail and pre-frail, respectively. The Kappa coefficient between the FRAIL scale and the Fried criteria were 0.39 (95% confidence interval [CI]: 0.34–0.44; P value: &lt;0.001). The area under the receiver-operating characteristic curves for frailty diagnosed by the Fried criteria of the FRAIL scale was 0.74 (95% CI: 0.71–0.76; P value: &lt;0.001). A total of 118 deaths occurred during 1 year of follow-up. After adjusting for the MAGGIC score and log-BNP, The FRAIL scale predicted all-cause mortality (hazard ratio: 1.17; 95% CI: 1.01–1.36; P value = 0.035). The FRAIL scale was also associated with various physical dysfunction that correlated with poor prognosis.

Conclusions
The FRAIL scale had moderate consistency with the Fried criteria, predicted all-cause mortality, and reflected clinically important physical dysfunction.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): the Japan Society for the Promotion of Science Grant-in-Aid (JSPS KAKENHI, Grant Number 19K19884)
Determination of left ventricular diastolic dysfunction using machine learning methods
Authors: Kuznetsova N , Sagirova Z H , Dhif I , Gognieva D , Gogiberidze N , Chomakhidze P , Kopylov P 
Published: October 2021

Abstract

Introduction
Nowadays, more than 50% of new cases of heart failure (HF) are due to heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction of left ventricular underlies the development of HFpEF. Determination of diastolic function can be determinated using echocardiographic examination but not as a method of screening.

Purpose
Create a Machine Learning model to determinate severe (2nd or 3rd degrees) left ventricular diastolic dysfunction (LV DD) using single channel ECG.

Methods
The study prospectively included 375 patients aged between 18 and 88 years. Each of them underwent an assessment of left ventricular diastolic function using echocardiography based on ASE/EACVI guidelines and standard 2016. ECG was registered in I standard lead for 3 minutes. Then a spectral analysis of the ECG was performed using a wavelet transform based on the Fourier transform. Prediction of LV DD was implemented based on different machine learning methods.

Results
Based on the time intervals between the waves, the energy of the ECG signal in the target zones of the complexes, the amplitude at different points of the ECG complexes and the asymmetry indicators, different mathematical models were created to determine the severe (2nd or 3rd degree) LV DD. Lasso regression predicted the presence of severe LV DD with sensitivity 90% and specificity 80,6% (AUC- 0.856). The most significant for this method were the following variables: TA, SDNN, RonsF, ASEPMAX, B1, TpTe, ADP, SEPMAX, Sbeta, SEPF, RR, SRP-B0, Pan.1, QT/TQ, PpeakN, SA, SRP-B1. Random Forest also showed high sensitivity 80% and specificity 89, 3% (AUC- 0.860). For Random Forest model the most dignificant were: TpTe, VAT, QTc, QT/TQ, J80A, TA, Tenergy, Tpenergy, Beta, QRS11energy, Pan, Pan.1, RA, Pfi, QRSst, QRSfi, PpeakP, PpeakN, Rpeak, Speak, RonsF, B0-B1, SEP, SEP-B1, SEP-B0, SRP, SRP-B1, SRP-B0, ASEP. LV DD 1 degree did not have markers in our study.

Conclusion
Several machine learning methods have shown high sensitivity and specificity in identifying severe LV DD. Potentially ECG can be used as a screening method for determination of the LV DD.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital biodesign and personalized healthcare” No. 075-15-2020-926