bluuebunny/crossref_metadata_2025_split huggingface dataset:
The combination of a neprilysin inhibitor (sacubitril) and angiotensin-II receptor blocker (valsartan) improves ejection fraction and longitudinal strain in mice treated with doxorubicin through NLRP3
Authors: Quagliariello V , Bonelli A , Paccone A , Buccolo S , Iovine M , Rea D , Cerrone F , Botti G , Maurea N 
Published: October 2021

Abstract

Background
Doxorubicin-mediated- adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction.

Purpose
Here, we aim to assess whether LCZ 696, administered during doxorubicin, reduces in vitro anticancer drugs-related cardiotoxicity compared to Valsartan (V), used as a control drug.

Methods
Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (at 200 nM) alone or in combination with LCZ-696 (100 mM) for 72 h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin (DOXO, n=6), LCZ-696 (LCZ, n=6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n=6). DOXO was injected intraperitoneally. Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd8, NF-kB and chemokines and cytokines were quantified after treatments through ELISA method.

Results
LCZ 696 co-incubated with doxorubicin exerts cardioprotective effects, enhancing cell viability of 48–54.6% compared to only doxorubicin-treated cells (p&lt;0,001 for all); LCZ 696 reduced significantly the cardiotoxicity through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms. In preclinical study, LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart tissues was also seen in DOXO-LCZ group compared to DOXO mice (p&lt;0.001)

Conclusion
We demonstrated, for the first time, that the LCZ696 exerts direct effects in cardiomyocytes and preclinical models during doxorubicin exposure, turning on a new light on its possible use in cancer patients to reduce cardiovascular side effects.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministero della Salute, Ricerca Corrente project
Irreversible cardiac remodeling promotes cancer progression via secreted factors in ATF3 transgenic mouse model
Authors: Awwad L , Aronheim A 
Published: October 2021

Abstract

Cardiac hypertrophy and cancer are the leading cause of deaths worldwide. While heart failure and cancer have been considered separate diseases, it is becoming evident that they are highly connected and affect each other's outcome. Recent studies using mouse models mimicking myocardial infraction and aortic stenosis were shown to promote cancer progression. These two mouse models involve major irreversible surgeries. Here, we employed a transgenic mouse model for heart hypertrophy and examined the crosstalk between the hypertrophied heart and cancer progression. Heart hypertrophy was induced by adult ATF3 expression in cardiomyocytes followed by either PyMT, breast cancer cells or Lewis lung carcinoma (LLC) cells implantation. PyMT and LLC tumors grow larger in size and display increased cell proliferation in ATF3-transgenic mice as compared with control mice. In addition, pulmonary experimental metastasis assay revealed augmented number and size of metastasis lesions in the lungs. Subsequently, we identified five putative cardiac secreted factors that are highly expressed in the hearts derived from ATF3-transgenic that may be involved in tumor progression. These include Fibronectin, CP, serpin3, CTgF and PSTN. Next, we addressed whether the cause or the effect are necessary to promote tumor growth. Towards this end, ATF3 expression was turned-off after cardiac hypertrophy development followed by cancer cell implantation. The tumor promotion phenotype as well as enhancement of metastatic seeding in these mice was fully preserved, suggesting the generation of an irreversible viscous cycle that lead to cancer progression. Significantly, the expression of Fibronectin and CTgF was dampened in the presence of doxycycline, thus exclude their putative role in mediating the tumor promotion and metastatic seeding phenotypes.
Collectively, heart hypertrophy and cancer diseases communicate via secreted factors that result in cancer promotion and disease deterioration.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Israel Science Foundation
Breast cancer radiotherapy and risk of pacemaker implantation: an epidemiologic analysis using the French nationwide claims database
Authors: Errahmani M Y , Thariat J , Ferrieres J , Bernier M O , Boveda S , Jacob S 
Published: October 2021

Abstract

Background
Radiotherapy (RT) is a major treatment for breast cancer (BC), but it is also associated with an increased long-term (&gt;5–10 years) risk of cardiac complications. Specific data on cardiac arrhythmias and conduction disorders are warranted.

Purpose
To evaluate whether pacemaker (PM) implantation risk is higher in BC patients treated with RT compared to the general population or population of BC patients treated without RT.

Methods
Our study was based on the Echantillon Généraliste de Bénéficiaires (EGB), the 1/97 random sample of the French nationwide health insurance claims database. The population of patients treated for BC consisted of adult women with a first BC identified by the ICD-10 diagnosis codes between 2008 and 2016, and followed through 2018. PM implantations and RT were identified with medical procedures codes in the french Common Classification of Medical Procedures (CCAM). For each year from 2008 to 2018, the reference population included all adult women of the EGB database. History of PM or BC was an exclusion criteria. Annual incidence rates of PM implantations were evaluated between 2008 and 2018 in the reference populations. The number of PM cases observed in BC patients at least one year after BC diagnosis was compared with the expected number of PM cases calculated by using reference incidence rates with age standardization. We then computed the standardized incidence ratio (SIR) as the ratio of the observed number of PM to the expected number of PM, with 95% confidence intervals (CIs). Thereafter, a survival analysis was performed in BC patients using a Cox regression model (Hazard Ratio – HR) in order to evaluate the risk of PM associated with treatment including RT (RT) compared with treatment not including RT (no RT).

Results
A total of 3,853 patients were included in the population of patients treated for BC between 2008 and 2016 with a mean age of 60 years old and a mean follow-up of 5.6 years. In this population, 35 cases of PM were observed, compared with 19.9 expected cases of PM, corresponding to a significant SIR=1.76 (95% CI: 1.22 - 2.39). This excess risk was carried by the RT group of 2973 patients (77% of BC population): 28 observed PM vs 12.9 expected, SIR=2.18 (95% CI: 1.45–3.06). In Cox regression analysis, after adjustment on age, RT was associated with an increased risk of PM compared with no RT, but this result did not reach statistical significance (HR=1.73; p-value=0.21).

Conclusion
Based on our study, BC patients receiving RT appeared to be at higher risk of PM implantation than general female population and BC patients without RT, illustrating a potential association between cardiac exposure during BC RT and conduction disorders.

Funding Acknowledgement
Type of funding sources: None.
A smartwatch as a rhythm monitor in prehospital emergency care
Authors: Cobos Gil M A 
Published: October 2021

Abstract

Background
A ubiquitous, portable rhythm monitor would be potentially useful in out of hospital emergencies. Smartwatches with ECG capability (SW-ECG) can obtain a single lead ECG similar to lead I.

Purpose
We propose a new method to use the SW-ECG to monitor cardiac rhythm when attending cardiac emergencies in the prehospital setting

Methods
The SW-ECG is used as shown in the figure. The explorer grabs the left hand of the patient and the back of the watch and touches the face of the patient with the watch crown. A record of the difference of potential between the head and the left arm is obtained. The EC lead so formed (head – left arm (HL)) is quite similar to lead I, and can be used to explore the cardiac rhythm in a patient.
In 15 volunteers we recorded the I and HL leads using an SW-ECG. The records were compared for diagnostic accuracy.

Results
In all cases, the records were qualitatively similar (see figure). There was an excellent correlation between the heart rate measured by the two procedures (R2=0,92). All the abnormalities present in lead I (1 case AF, 1 case RBBB, 1 case LBBB, 1 case frequent premature ventricular contractions) were also evident in the HL lead. The mean time required to obtain a diagnostic record was 3.9 seconds.

Conclusion
We propose a quick, simple method to use the SW-ECG to assess heart rhythm in out of hospital emergencies. SW-ECG

Funding Acknowledgement
Type of funding sources: None.
Evidence in crisis: a closer look into the quality of published systematic reviews in the cardiology literature
Authors: Abushouk A , Yunusa I , Elmehrath A O , Elmatboly A M , Saad A , Fayek S H , Abdelfattah O , Ghanem E , Isogai T , Shekhar S , Reed G W , Puri R , Kalra A , Kapadia S R 
Published: October 2021

Abstract

Background
Systematic reviews are usually considered as the highest level of evidence and are increasingly used in shaping cardiology policies and guidelines. However, as the rate of publishing systematic reviews increases annually, there are rising concerns regarding their quality and reporting standards.

Purpose
The current analysis provides an insight into the quality of published systematic reviews in cardiology and provides recommendations for researchers, clinicians, and stakeholders in this regard.

Methods
Using a comprehensive Medline/PubMed search, we retrieved all systematic reviews, published between 2009 and 2019 in five general cardiology journals with the highest impact factor as per the Clarivate Analytics 2019 Journal Impact Factor List (Circulation, European Heart Journal, Journal of the American College of Cardiology, Circulation Research, and JAMA Cardiology). We assessed the methodological characteristics, eligibility criteria, reporting standards, as well as review quality scores according to the AMSTAR tool.

Results
Among 352 retrieved reviews, 275 (75.3%) performed direct head-to-head analysis and 164 (46.6%) included only clinical trials. The median numbers of searched databases and included studies were 3 (IQR: 2, 3) and 13 (IQR: 7, 30). The primary outcomes were often hard clinical endpoints as mortality (39.2%) and stroke (11.9%). 64 (18.2%) registered their protocol, 208 (58.4%) used validated tools for risk of bias assessment, 177 (52.3%) assessed for publication bias, and 221 (62.8%) adhered to the PRISMA checklist. Thirty-five reviews detected significant publication bias, which was significantly associated with heterogeneity of the primary outcome. The AMSTAR quality scores were low or critically low in 71% of evaluated reviews. Further, 87 (24.7%) did not report on whether they received funding or not, 33 (9.4%) reported receiving no funding, and 232 adequately reported on their funding sources [70 (19.9%) from governmental/academic sources, 120 (34.1%) from pharmaceutical companies, and 42 (11.9%) from both sources]. analysis showed that reviews with advanced statistical analysis, those that included RCTs, adhered to the PRISMA checklist, or had higher AMSTAR quality scores had significantly higher citation metrics (p&lt;0.05).

Conclusion
Due to the widespread low quality and poor reporting in cardiovascular systematic reviews, clinicians should be educated on the value of methodological quality in interpreting systematic review findings. In addition, academic societies and guideline writing groups should implement rigorous critical appraisal and peer review policies to improve the synthesis and utilization of systematic reviews in evidence-based cardiovascular medicine.

Funding Acknowledgement
Type of funding sources: None.
STING inhibition in myocardial remodelling following myocardial infarction
Authors: Rech L , Abdellatif M , Poettler M , Stangl V , Ulcar E , Ablasser A , Rainer P P 
Published: October 2021

Abstract

Background
Myocardial infarction (MI) is one of the prevalent causes of death in the world, with some patients developing heart failure from myocardial remodelling after infarction. Inflammatory processes trigger remodelling post-MI. One inflammatory factor is Type 1 Interferon which can be released by cytosolic dsDNA, sensed via the STING-receptor. The aim of this study was to reduce this inflammatory response by inhibiting the STING-receptor and thus reduce post-infarctional remodelling.

Methods
Surgery was performed to trigger infarction for 30 minutes by ligating of the proximal LAD in 22 wildtype male mice (C57BL6/J), another 10 mice have undergone sham operation. Echocardiographic assessment of the endocardial systolic fractional area change (FAC) was carried out before, one day after and three weeks after surgery. The mice with ligation were separated into two groups with eleven individuals each, as well as the sham operated mice in five each group. One group was treated with the STING-Inhibitor while the other received a control substance. Treatment was applied intraperitoneally once per day for three weeks.

Results
– Procedural success was good as evidenced by immediate FAC decline in MI animals.
– One day post-op no significant difference in FAC and infarct size can be seen between the two groups of MI mice
– Three weeks post-op a highly significant difference in FAC can be observed in the group treated with STING-Inhibitor compared to the control group in the MI mice
– The sham operated mice never showed any difference between the groups at any time.
– Fibrosis and Cross sectinal area significantly reduced in treated MI group compared to control
– Ifi44 and Cxcl10 expression levels in the infarct area showed significant reduction in the inhibitor MI group compared to the control MI group after three weeks

Conclusion
STING-Inhibitor potentially improves outcome after a myocardial infarction.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Area Network on Cardiovasczlar Diseases (ERA-CVD) PhD-Program Molecular Medicine - Medical Unviersity of Graz
Attenuated cardiac post-ischemic injury and endothelial dysfunction by stimulation of soluble guanylyl cyclase in red blood cells from patients with type 2 diabetes
Authors: Jiao T , Zhou Z , Mahdi A , Tengbom J , Tratsiakovich Y , Yang J , Pernow J 
Published: October 2021

Abstract

Background
Reduced bioavailability of nitric oxide (NO) contributes to ischemic heart disease in type 2 diabetes (T2D). Red blood cells (RBCs) are known to produce NO bioactivity and to contain a functional soluble guanylyl cyclase (sGC) that is activated by NO. Recent studies revealed that RBCs from patients with T2D exacerbates ischemia-reperfusion (I/R) injury and induces endothelial dysfunction via a mechanism that is dependent on reduced export of NO bioactivity from RBCs. It remains unknown whether stimulation of sGC in RBCs from patients with T2D protects against myocardial I/R injury and endothelial dysfunction.

Purpose
To test the hypothesis that stimulation of sGC in RBCs from T2D patients protects against myocardial I/R injury and improves endothelial function.

Methods
RBCs collected from T2D patients and healthy subjects were incubated with vehicle or the sGC stimulator CYR715 before being administered to isolated Langendorff-perfused rat hearts subjected to 25 min global ischemia and 60 min reperfusion. Left ventricular developed pressure (LVDP) and infarct size were determined. In addition, isolated rat aortic rings were incubated with RBCs subsequent determination of endothelium-dependent relaxation (EDR).

Results
Administration of RBCs from T2D patients impaired post-ischemic recovery of LVDP and induced endothelial dysfunction in comparison with RBCs from healthy subjects (P&lt;0.001). Pre-incubation of RBCs from patients with T2D with CYR715 prior to administration to the isolated heart enhanced the recovery of LVDP (Fig.1A), reduced infarct size (Fig.1B), and attenuated endothelial dysfunction (Fig.1C). CYR715 did not induce cardioprotection in the absence of RBCs. The sGC inhibitor ODQ did not significantly affect cardiac recovery per se but totally abolished the protective effect of CYR715 (Fig.1A).

Conclusions
Stimulation of sGC in RBCs from patients with T2D protects against cardiac I/R injury and prevents development of endothelial dysfunction. Stimulation of the NO-sGC pathway in RBCs appears to be an attractive therapeutic strategy to prevent cardiovascular injury in T2D.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Swedish Heart and Lung Foundation, the Swedish Research Council
Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up
Authors: El-Chami Mikhael F , Bockstedt Lindsay , Longacre Colleen , Higuera Lucas , Stromberg Kurt , Crossley George , Kowal Robert C , Piccini Jonathan P 
Published: October 2021

AbstractAims Clinical trials have demonstrated the safety and efficacy of the Micra leadless VVI pacemaker; however, longer-term outcomes in a large, real-world population with a contemporaneous comparison to transvenous VVI pacemakers have not been examined. We compared reinterventions, chronic complications, and all-cause mortality at 2 years between leadless VVI and transvenous VVI implanted patients.Methods and results The Micra Coverage with Evidence Development study is a continuously enrolling, observational, cohort study of leadless VVI pacemakers in the US Medicare fee-for-service population. Patients implanted with a leadless VVI pacemaker between March 9, 2017, and December 31, 2018, were identified using Medicare claims data linked to manufacturer device registration data (n = 6219). All transvenous VVI patients from facilities with leadless VVI implants during the study period were obtained directly from Medicare claims (n = 10 212). Cox models were used to compare 2-year outcomes between groups. Compared to transvenous VVI, patients with leadless VVI had more end-stage renal disease (12.0% vs. 2.3%) and a higher Charlson comorbidity index (5.1 vs. 4.6). Leadless VVI patients had significantly fewer reinterventions [adjusted hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.45–0.85, P = 0.003] and chronic complications (adjusted HR 0.69, 95% CI 0.60–0.81, P &lt; 0.0001) compared with transvenous VVI patients. Adjusted all-cause mortality at 2 years was not different between the two groups (adjusted HR 0.97, 95% CI 0.91–1.04, P = 0.37).Conclusion In a real-world study of US Medicare patients, the Micra leadless VVI pacemaker was associated with a 38% lower adjusted rate of reinterventions and a 31% lower adjusted rate of chronic complications compared with transvenous VVI pacing. There was no difference in adjusted all-cause mortality at 2 years.
Living systematic reviews in a context of rapidly emerging diseases: challenges and lessons learned
Authors: Iannizzi C , Dorando E , Burns J , Weibel S , Dooley C , Wakeford H , Estcourt LJ , Skoetz N , Piechotta V 
Published: October 2021

Abstract

Background
In a context of a rapid emerging disease, like the COVID-19 pandemic, we are confronted with clinical uncertainty, evolving epidemiological setting and lacking evidence. Within the context of such a high-priority topic, living systematic reviews (LSRs) are an important systematic review type characterized through regular updating and permanent surveillance of continuously evolving evidence. However, with the new pandemic-related challenges, the standard LSR methodology had to be adapted.

Objectives
The objective is to discuss certain challenges that occurred when conducting LSRs in a rapidly emerging disease context. In particular, we give insights in the lessons we have learned from the conduct of two COVID-19 LSRs and highlight emerging methodological aspects.

Results
With the evolving knowledge around the virus and its caused disease, we learned that the initial plan for inclusion of study designs, publication types, interventions and comparators, outcomes and the search strategy had to be adapted. The author teams for example had to revise outcome measures or included observational data in addition to evidence from randomized controlled trials, as they provided substantial information on the safety of investigated interventions. For deciding when to update a LSR, additional aspects, such as policy relevance or waiting for important evidence dependent on the individual research question were considered. To avoid biases in the review process, we learned that transparent reporting of any methodological adaptations is highly relevant; between protocol and review, as well as between each review update.

Conclusions
Our experience showed that LSRs are highly suitable in a pandemic context, in particular when facing unexpected methodological and clinical challenges. The research question, study designs and the methodology, should be revisited and critically discussed before each update, to be flexible enough for addressing the pandemic context.

Key messages
Living systematic reviews are highly relevant in a pandemic context, but the methodology and decision when to update the review have to be adapted to respond purposeful to the emerging topic. To avoid biases in the review process, we learned that transparent reporting of any methodological adaptations is highly relevant; between protocol and review, as well as between each review update.