bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonalcoholic fatty liver disease worsens cardiac repair after myocardial infarction
Authors: Hamidou F , De Azevedo Laplace T , Duval V , Biquard L , Alayrac P , Achab Ali A , Lemitre M , Vilar J , Camus S , Rautou P E , Silvestre J S 
Published: October 2024

Abstract

Background
There is a strong epidemiological link between nonalcoholic fatty liver disease (NAFLD) and ischemic heart disease such as myocardial infarction (MI). Yet, a causal relationship between liver injury and post-MI cardiac repair remains to be established.

Purpose
NAFLD impairs post-MI myocardial repair processes. In particular, we hypothesized that the pathological liver could transmit deleterious signals shaping the inflammatory reaction in the infarcted milieu.

Methods
To characterize post-MI cardiac function and remodeling in three mouse models of liver damage mimicking different stages of NAFLD without cardiovascular (CV) risk factors : i) choline-deficient, L-amino-acid-defined, high fat diet (CDA-HFD) causing severe non-alcoholic steatohepatitis; ii) NEMOLPC-KO mice deficient for NF-κB in liver parenchymal cells, exhibiting liver inflammation and fibrosis, but mild steatosis; and ATGLLPC-KO animals deficient for Adipose Triglyceride Lipase in liver parenchymal cells displaying strong steatosis.

Results
In our three experimental models, liver damages were characterized by inflammation, steatosis and fibrosis but were not associated with metabolic syndrome. More interestingly, left ventricular ejection fraction were reduced by 1.2-fold, 1.3-fold and 1.3-fold in CDA-HFD, NEMOLPC-KO and ATGLLPC-KO male and female mice, respectively when compared to their respective controls, at 35 days post-MI (n=12-25 per group). NAFLD-induced cardiac dysfunction was not associated with worsen cardiac remodeling as infarct size, fibrosis and vascular density were not significantly affected. On the same note, flow cytometry experiments, at 7- and 14-days post-MI, showed no changes in the number or type of inflammatory cells, particularly that of cardiac resident macrophages, in CDAHFD, ATGLLPC-KO and NEMOLPC-KO mice. We next hypothesized that reduced left ventricular function could be induced by altered cardiomyocyte contractility. To corroborate this hypothesis, we isolated cardiomyocytes from hearts of infarcted mice with or without NAFLD and assessed cell contractility using IonOptix technology. Our preliminary results, in the CDAHFD model, showed that there was a reduction in contraction amplitude, defining by the ratio of the difference in sarcomere length during contraction/relaxation to the sarcomere length at the time of relaxation. The speed of contraction and relaxation were also decreased in CDAHFD mice compared with control animals.

Conclusions
NAFLD favors cardiac dysfunction post-MI. We now aim to identify molecular and cellular entities participating to such pathogenic dialogue between the dysfunctional liver and the infarcted heart.
Risk of recurrent ischaemic events in ACS patients with baseline LDL-C below guideline-recommended thresholds: insights from the prospective SPUM-ACS study
Authors: Denegri A , Kraler S , Wenzl F , Raeber L , Gencer B , Muller O , Nanchen D , Klingenberg R , Luescher T F 
Published: October 2024

Abstract

Introduction
The 2023 European Society of Cardiology (ESC) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with acute coronary syndromes (ACS), adding ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) to achieve recommended target goals (LDL-C&lt;55 mg/dL).

Purpose
This population-based, real-world study aimed to examine cardiovascular (CV) events in ACS patients with baseline LDL-C levels below current guideline thresholds.

Methods
ACS patients admitted to four Swiss University Hospitals and enrolled in the multicenter SPUM registry (NCT 01000701) between 2009 and 2017 were followed prospectively until 1 year. The composite primary endpoint was major adverse cardiac and cerebrovascular events (MACCE); i.e., non-fatal stroke, myocardial infarction (MI), and death) at 1 year. Multivariable-adjusted Cox proportional hazard regression models were fit to estimate ischaemic risk among those with LDL-C&lt;55 mg/dL.

Results
Out of 4’787 ACS patients, 226 patients (4.7%) had baseline LDL-C&lt;55 mg/dL. These patients were older (69.7±11.3 vs 63.4±12.4, p&lt;0.001), more frequently male (20.8%vs 15.9%, p&lt;0.001), had more often traditional CV risk factors (all p&lt;0.001) and were more likely to have a complex history of CV disease, such as previous MI (37.2% vs 10.9%, p&lt;0.001), prior percutaneous (47.8% vs 13.2%, p&lt;0.001) or surgical (15.0% vs 3.5%, p&lt;0.001) coronary revascularization. Inflammatory biomarkers were also higher (hs-CRP, 30.1±63.6 vs 10.7±25.8 mg/L), with most patients being on high-dose statin therapy (82.4% vs 38.7%, p&lt;0.001). At 1 year, patients with LDL-C&lt;55 mg/dL had a higher rate of MACCE (16.4% vs 7.0%, p&lt;0.001), with individual components of the primary endpoint occurring more frequently among these patients (all p&lt;0.001), except for a numerical increase in CE (2.7% vs 1.7%, p=n.s.), as shown in the figure (Panel A). The enhanced MACCE risk persisted after adjustment for potential differences in baseline characteristics, with a 51% (adj. HR 1.51, CI95% 1.05-2.17, p=0.026) increase in MACCE (Panel B). Diabetes, low eGFR and high hs-CRP levels remained independent predictors of MACCE in patients with low baseline LDL-C (all p&lt;0.001).

Conclusions
Our real-world data confirm that even ACS-patients reaching currently recommended LDL-C thresholds have a substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to further reduce CV risk.Event-risk according to baseline LDL-C
Causal association between visceral fat and coronary artery disease: a large-scale mendelian randomization analysis
Authors: Porcheddu T , Petretto G , Isgender M , Bilotta F , Merella P , Talanas G , Casu G , Navarese E P 
Published: October 2024

Abstract

Background
While increased body mass index (BMI) is an established risk factor, the residual risk associated with visceral fat, remains a concern. We aimed to perform a Mendelian randomization to explore the causal relationship between visceral fat and the risk of coronary artery disease (CAD), aiming to address gaps left by observational studies that may be influenced by confounding factors and reverse causation.

Methods
Leveraging large-scale genome-wide association study (GWAS) databases, we identified single-nucleotide polymorphisms (SNPs) associated with visceral fat. These genetic instruments were analyzed to infer causal relationships with CAD outcomes, drawing data from the CARDIoGRAMplusC4D consortium for CAD, and additional databases for related cardiovascular conditions. We performed a Two-sample Mendelian Randomization (MR) to test the genetic association between the visceral obesity and Coronary Artery Disease (CAD).

Results
The analysis encompassed data from a combined cohort exceeding 500,000 participants, revealing a significant causal relationship between increased levels of visceral fat and the risk of CAD. The observed odds ratio (OR) for CAD per standard deviation (SD) increase in visceral fat was [OR, 1.48 ] ([95% CI, 1.33-1.64]; P&lt;0.001), indicating a robust association which remains independent from BMI on mediation analysis. Notably, the study's methodology ensured minimal risk of pleiotropy, reinforcing the validity of the findings.

Conclusions
This Mendelian randomization study provides compelling evidence of a genetic causal link between visceral fat and coronary artery disease. The findings suggest that beyond BMI, visceral fat represents a significant, independent risk factor for CAD, underscoring the importance of considering comprehensive lipid management in cardiovascular risk reduction strategies. Further research is warranted to explore potential mechanisms and therapeutic targets associated with visceral fat in the context of cardiovascular disease.
Impact of stress hyperglycemia ratio on periprocedural myocardial infarction in patients with NSTEMI
Authors: Asta C , Cavallo D , Suma N , Marinelli V , Casuso Alvarez M , Canton L , Fedele D , Bodega F , Pastore G , Ryabenko K , Bergamaschi L , Rinaldi A , Angeli F , Paolisso P , Pizzi C 
Published: October 2024

Abstract

Background
Stress hyperglycemia ratio (SHR), a new marker that reflects the true metabolic hyperglycemic state of patients regardless of the presence of diabetes mellitus, is strongly associated with adverse clinical outcomes in patients with acute myocardial infarction (AMI). However, studies on the impact of SHR on peri-procedural (type 4a) myocardial infarction (MI) are limited.

Purpose
The aim was to elucidate the relationship between SHR and type 4a MI in patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI) undergoing percutaneous coronary intervention (PCI).

Methods
We evaluated consecutive patients with NSTEMI, both diabetic and non-diabetic, who underwent PCI and exhibited stable (≤20% variation) or falling pre-procedure baseline cardiac troponin values and with sampled glycated hemoglobin available during hospitalization. Using receiver operating characteristic (ROC) curves, we categorized patients into two groups (higher SHR and lower SHR) based on the value associated with the highest Youden index. Subsequently, we assessed the incidence of type 4a MI in these two groups. Finally, we conducted Cox regression analyses to determine the independent prognostic impact of SHR on the risk of developing type 4a MI.

Results
We identified a threshold value of SHR=1.14 using ROC curves (AUC=0.684). The final study population comprised 837 patients with NSTEMI who underwent PCI, with 362 patients exhibiting SHR &gt;1.14 at hospital admission. At baseline, patients with SHR &gt;1.14 were older and had more comorbidities, including hypertension, diabetes, chronic kidney disease, and atrial fibrillation. Regarding coronary angiography and PCI characteristics, patients with higher SHR exhibited more frequent multivessel disease and consequently underwent more complex PCI procedures. Patients with SHR &gt;1.14 developed type 4a MI more frequently than those with lower SHR (27.6% vs. 9.7%, p&lt;0.001). Cox regression analysis demonstrated that, after adjusting for major comorbidities and complex PCI, the presence of SHR &gt;1.14 at admission independently predicted a higher risk of type 4a MI after PCI in NSTEMI patients (OR=3.36; 95% CI 2.23 - 5.13; p&lt;0.001). The adverse prognostic impact of higher SHR was further confirmed concerning in-hospital and long-term outcomes.

Conclusions
In patients presenting with NSTEMI undergoing PCI, elevated SHR (&gt;1.14) at hospital admission is strongly associated with an increased risk of type 4a MI post-PCI, independent of major comorbidities and procedural complexity. These findings underscore the importance of SHR as a valuable prognostic tool in risk-stratifying patients with NSTEMI undergoing PCI, suggesting its potential utility for optimizing patient management strategies and improving clinical outcomes.
Impact of Lp(a) on lipid control in patients with acute coronary syndrome
Authors: Cesani N , Marchese A , Bocciolone M , Ammaturo T , Reimers B , Condorelli G , Panico C 
Published: October 2024

Abstract

Background
The lipoprotein(a) (Lp[a]) is a genetically determined low-density lipoprotein (LDL)-like particle. Lp(a) levels above 50mg/dl have been correlated to an increased risk of atherosclerosis and major adverse cardiovascular events. Thus, treatments designed to reduce Lp(a) levels are currently under investigation.
However, it is unknown how high Lp(a) concentrations affect the control of lipid profile.

Purpose
The purpose of this project is to investigate how Lp(a) impacts lipid profile control in individuals with acute coronary syndromes (ACS).

Methods
We designed a single-center prospective registry including consecutive patients admitted for ACS. Lp(a) levels were obtained from all enrolled patients during hospitalization; lipid profile (total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, triglycerides) was obtained at admission and at the 6-month follow-up (6MFU). Patients were stratified according Lp(a) concentration (low-Lp(a): Lp(a) &lt; 50 mg/dL; high-Lp(a): Lp(a) ≥ 50 mg/dL). LDL-cholesterol (LDLcorr) levels corrected for concentration of Lp(a) were calculated as LDLcorr= LDLmeasured – 30%Lp(a). At discharge cholesterol lowering drugs were introduced or titrated as standard of care.
The primary endpoint was the percentage of patients reaching target LDL and LDLcorr (&lt;55 mg/dL) at 6MFU.
The secondary endpoints were the correlations between Lp(a) levels and lipid profile, both at baseline and at 6MFU, as well as the correlation between Lp(a) levels and the total number of traditional cardiovascular risk factors in the study population.

Results
From February 2020 through September 2023, a total of 409 patients were included: 305 (74.6%) with Lp(a) &lt; 50 mg/dL; 104 (25.4%) with Lp(a) ≥ 50 mg/dL (Table 1). High-Lp(a) patients showed a lower prevalence of diabetes (14.2% vs 27.87%, P = 0.0055), an overall lower number of traditional cardiovascular risk factors (&gt;2 in 25.9% vs 38.1%, P=0.0244).
High-Lp(a) patients showed higher level of LDL-cholesterol compared to the low-Lp(a) population both at baseline (124±52 mg/dL vs 110.4±44 mg/dL, P= 0.0263) and at 6MFU (70.5±21 vs 63.8±29, P= 0.0208) with fewer patients achieving the target LDL cholesterol levels (21.57% vs 40.13%, P=0.0184).
Estimating the true LDL concentration (LDLcorr) the percentage of patients reaching target LDL cholesterol levels at FU significantly increased in the high-Lp(a) group (from 21.57% to 76.5%), with a minimal increase noticeable in the low-Lp(a) population (from 40.13% to 48.41%, p 0,1870).

Conclusions
In ACS population, patients with high Lp(a) concentrations have fewer traditional CV risk factors and a lower prevalence of diabetes. High-Lp(a) patients, furthermore, seem more challenging to meet LDL target at 6 month follow up, but not when the LDL values are adjusted for Lp(a).
Clinical and experimental evidence for differences between cardiac troponin I and T in acute and chronic cardiovascular conditions
Authors: Zimmermann T , Koechlin L , Walter J E , Lopez-Ayala P , Rentsch K , Strebel I , Diebold M , Twerenbold R , Lindahl B , Meex S , Mills N L , Marsano A , Hammarsten O , Mueller C 
Published: October 2024

Abstract

Background
Clinical and scientific practice operate under the assumption that systemic levels of cardiac troponin I (cTnI) and troponin T (cTnT) are indicative of the same underlying pathophysiological mechanisms and can be utilized interchangeably.

Purpose
To assess cTnI and cTnT levels and their ratio for differences in various cardiovascular conditions.

Methods
Individuals from three prospective clinical studies with a centrally adjudicated diagnosis were categorized into three groups: no known cardiac disease, chronic cardiac disease, and acute cardiac disease. Circulating cTnI and cTnT concentrations were measured using high-sensitivity assays (hs-cTnI-Architect, hs-cTnT-Elecsys) and the cTnI/cTnT ratio was calculated. Findings were validated using a second hs-cTnI assay (hs-cTnI-Clarity) and externally validated in independent cohorts. The cTnI/cTnT ratio was also assessed in five different non-lethal and lethal experimental models of cardiomyocyte injury.

Results
Of the 9704 included individuals, 9% had no known cardiac disease, 69% chronic cardiac disease, and 22% acute cardiac disease. No known cardiac disease and chronic cardiac disease were associated with a disproportional increase in cTnT compared to cTnI (cTnI/cTnT ratio, median 0.50, IQR 0.38-0.69 and 0.53, IQR 0.37-0.80). In contrast, cTnI concentrations were increased compared to cTnT in patients with acute cardiac disease, resulting in a cTnI/cTnT ratio of 1.62 (IQR 0.77-4.31).
Findings were consistent using an alternative cTnI assay and in external validation cohorts (n=2776) where the cTnI/cTnT ratio was lower in those without cardiac disease (0.33 (IQR 0.25-0.50), 0.64 (IQR 0.40-1.05)) and with chronic cardiac disease (0.50 (IQR 0.32-0.75), 0.60 (IQR 0.38-1.00)), compared to those with acute cardiac disease (2.22 (IQR 1.08-5.27), 2.28 (IQR 1.01-5.67)).
Non-lethal cardiomyocyte injury models showed a predominant release of cTnT with cTnI/cTnT ratios &lt;0.5, and lethal injury models a predominant release of cTnI with cTnI/cTnT ratios &gt;1.

Conclusion
Differences in cTnI and cTnT levels were observed in individuals with chronic and acute cardiac conditions, leading to distinct cTnI/cTnT ratios in both clinical and experimental settings. As a result, the interchangeability of cTnI and cTnT in present-day clinical and scientific settings needs to be reevaluated.Central illustration
Plasma levels of human growth differentiation factor 15 (GDF-15) and their effect of alirocumab on major adverse cardiovascular events and all-cause death after acute coronary syndrome
Authors: Jukema J , Van Neer N J , Szarek M , Cobbaert C , Bittner V A , Schwertfeger M , Bhatt D L , Fazio S , Garon G , Goodman S G , Harrington R A , Steg P G , Stevanovic I , White H D , Schwartz G G 
Published: October 2024

Abstract

Background
Human growth differentiation factor 15 (GDF-15) is a stress response cytokine of the transforming growth factor-β superfamily with roles in health and disease, cell survival and inflammation, and whose elevated plasma levels impair muscle metabolism and cause cachexia. GDF-15 also may play multiple roles in the pathophysiology of cardiovascular disease.

Methods
The ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab to placebo added to high-intensity or maximum-tolerated statin in patients post-acute coronary syndrome (ACS). We assessed in &gt;11,000 patients for whom biobank samples were available, the relation between GDF-15 levels (Roche Diagnostics) at baseline and at 4 months with risk of major adverse cardiovascular events (MACE; primary endpoint, comprising coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischaemic stroke, unstable angina requiring hospitalization) and all-cause death, with adjustment for age and sex.

Results
Median GDF-15 (quartile [Q]1, Q3) at baseline was 1022 (755, 1465) pg/mL and was reduced by a placebo-adjusted median of 22 pg/mL with alirocumab (p=0.0009) at month 4. This lowering of GDF-15 by alirocumab may represent the first such report via pharmacotherapy. In the placebo group, baseline GDF-15 was significantly associated with risks of MACE (Figure Panel A) and death (Panel B). Relative risk reduction with alirocumab did not vary according to baseline GDF-15 levels for MACE (Panel C) and death (Panel D). Four-year MACE absolute risk reduction [ARR (95% CI)] with alirocumab at Q1 and Q3 of baseline GDF-15 was 2.0% (0.1%, 3.9%) and 2.6% (0.2%, 5.0%), respectively. Reduction of GDF-15 with alirocumab at month 4 was not associated with subsequent MACE (p=0.46) but was associated with death (p=0.0009), with greater reductions translating to lower risk.

Conclusion
In patients with recent ACS, GDF-15 is a strong predictor of both MACE and death. Reduction of GDF-15 with alirocumab at month 4 was not associated with subsequent MACE but was associated with death (p=0.0009), with greater ARR reductions translating to lower risk.
Figure. Splines for baseline GDF-15 vs risk of MACE (Panel A; spline p&lt;0.0001) or all-cause death (Panel B; spline p&lt;00001) through 4 years in the placebo group; treatment hazard ratio for MACE (Panel C; spline p=0.52) and all-cause death (Panel D; spline p=0.78). All splines reflect adjustment for age and sexFigure
Growth differentiation factor-15 and 5-years cardiovascular risk in chest pain patients presenting to the emergency department: a multicenter cohort study
Authors: Crisanti L , Lopez-Ayala P , Boeddinghaus J , Koechlin L , Nestelberger T , Bima P , Glaeser J , Spagnuolo C , Miro O , Martin Sanchez F J , Christ M , Mueller C 
Published: October 2024

Abstract

Background
Growth differentiation factor 15 (GDF-15) has been explored as a prognostic biomarker in multiple disease entities, including ischemic heart disease and heart failure (HF), but its role as a prognostic marker in chest pain patients presenting to the emergency department (ED) is unknown.

Purpose
To investigate the association between GDF-15 and 5-year all-cause mortality, cardiovascular mortality, and major adverse cardiac events (MACE), and to evaluate its prognostic incremental value.

Methods
Patients presenting to the ED with acute chest pain were prospectively enrolled in an international multicenter diagnostic study. GDF-15 concentrations were measured in a blinded fashion upon ED presentation. Follow-ups were performed at 3 months, 1-, 2- and 5-years. MACE was defined as the composite of cardiovascular mortality, acute myocardial infarction, stroke, and HF rehospitalization. Associations between GDF-15 and each prognostic outcome were modeled using multivariable Cox proportional hazard regression fitting restricted cubic splines to continuous variables. The magnitude of the effect of each GDF-15 unit change on multivariable-adjusted models was assessed graphically using dose-response plots. To compute an HR for the dose-response plots we chose a GDF-15 value of 1200 pg/mL as a reference value as this has been chosen in previous literature1. For the restricted cubic splines three knots were used. The added prognostic value of GDF-15 was evaluated by the increase in the C-statistic between a base and an extended model and the fraction of new information (FNI) provided by GDF-15.

Results
A total of 4779 chest pain patients had baseline GDF-15 values available. The median age was 61 [48-74] and 33% were female. Higher GDF-15 levels were more strongly associated with heart failure, kidney dysfunction, older age, hypertension, diabetes and coronary artery disease. GDF-15 was independently associated with 5-years all-cause mortality, cardiovascular mortality and MACE (Figure). When adding GDF-15 to a rich-for-prior-information base model which included age, sex, cardiovascular risk factors, creatinine, cardiac troponin and NT-proBNP, GDF-15 provided relevant incremental prognostic discrimination for 5-years all-cause death and cardiovascular death. (Table).

Conclusions
In chest pain patients presenting to the emergency department, GDF-15 concentration on admission was associated with 5-years all-cause mortality, cardiovascular mortality, and MACE. In addition, it provided relevant incremental prognostic information when added on top of troponin and NT-proBNP, the two current prognostic gold standard biomarkers.FigureTable