bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin 17A-correlated myocarditis in patients with psoriasis: cardiac recovery following secukinumab administration
Authors: Frustaci A , Galea N , Dominici L , Verardo R , Alfarano M , Scialla R , Richetta A G 
Published: November 2023

Abstract

Background
Psoriasis (PS) is a common immune-mediated disease of the skin with possible extension to joints, aorta and eye. Myocardial inflammation has been rarely suggested.

Purpose
Report of PS-related myocarditis.

Methods
One hundred consecutive patients with PS were screened for cardiac involvement. Among them, five male patients (aged 56 ± 9.5 years) with moderate-severe form showed a dilated cardiomyopathy (LVEF &lt;35%) with normal coronary arteries and valves. They underwent a left ventricular endomyocardial biopsy for evaluation of myocardial substrate. Endomyocardial samples were processed for histology and immunohistochemistry, including myocardial expression of Toll-Like Receptor 4 (TLR4) and interleukin-17A (IL-17A), which plays a major role in psoriasis pathogenesis; real-time PCR for cardiotropic viruses and Western blot analysis for myocardial expression of IL-17A. Patients’ sera were tested for anti-heart autoantibodies.

Results
An active lymphocytic myocarditis was revealed in all 5 patients, characterized by absence of viral genomes at PCR, positive anti-heart autoantibodies, overexpression of TLR-4 and enhancement of IL-17-A at western blot analysis showing a 2,48-fold increase in psoriatic myocarditis compared with no psoriatic myocarditis and a 6-fold increase compared to myocardial controls. Treatment included combination of prednisone (1 mg/Kg daily for 4 weeks, tapered to 0.33 mg/Kg) + azathioprine (2 mg/Kg, daily) in 3 pts or secukinumab (SK, 100 mg/monthly) in 2 pts for 6 months. LVEDD and LVEF improved in the first 3 pts (-14% and + 118%, respectively) while completely recovered (LVEF&gt; 50%) in the last 2 pts on SK.

Conclusion
IL-17A-related myocarditis can occur in up-to 5% of patients with psoriasis. It manifests as a progressive dilated cardiomyopathy. It may completely recover following SK administration.
Figure Legend
Endomyocardial biopsy findings from pt 5 with PS-related myocarditis including histology (panel A). Immune-histochemistry for IL 17-A (panel B) and anti-heart abs (panels C, D). It shows an active lymphocytic myocarditis with overexpression of IL 17-A and positive anti-heart abs (panel C), cross-reacting with skeletal muscle (panel D).
Diabetes and chronic kidney disease synergistically contribute to left ventricular diastolic dysfunction and coronary microvascular disease in swine
Authors: Hamers J , Sittig T , Bierschenk S , D'alessio C , Zhang H , Clauss S , Schuettler D , Tomsits P , Vlcek J , Pauly V , Hesse N , Sen P , Merkus D 
Published: November 2023

Abstract

Background
Chronic kidney disease (CKD) and diabetes (DM) are common causes of cardiovascular disease (CVD), and contribute to the development of left ventricular diastolic dysfunction (LVDD) and coronary microvascular dysfunction (CMD).

Purpose
To investigate if CKD and DM contribute synergistically to the development of CMD and LVDD by increasing myocardial interstitial fibrosis in a swine model.

Methods
CKD was induced by renal microembolization at 10-12 weeks of age in 8 wild type (WT) and 6 DM (INSC94Y) swine, while 6 WT and 5 DM swine served as control. LVDD was assessed using pressure volume loops and coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in the left anterior descending coronary artery. Afterwards, myocardium and kidney tissues were histologically examined for interstitial fibrosis.

Results
DM was confirmed by increased blood glucose values in the DM and DMCKD (figure 1-A). Renal embolization resulted in renal fibrosis in the WTCKD and DMCKD (figure 1-B), which was accompanied by a trend towards proteinuria, i.e., elevated protein/creatinine ratios (figure 1-C). LVDD was evidenced by an increase in the slope of the end-diastolic pressure volume relationship (EDPVR) in WTCKD, DM and DMCKD as compared to WT, with the largest increase in DMCKD (figure 1-D). WTCKD and DMCKD animals showed higher interstitial fibrosis levels in the LV (figure 1-E). CFR tended to be decreased in WTCKD, DM and DMCKD swine compared to WT (figure 1-F).

Conclusions
Renal embolization resulted in proteinuria and renal fibrosis, particularly in DM animals. DM and CKD also caused myocardial interstitial fibrosis, which impaired left ventricular diastolic function. The effects tended to be larger in DMCKD as compared to DM or WTCKD. Moreover, CFR tended to be decreased, suggestive of CMD, with the largest effect in DMCKD. In conclusion, DM and CKD contributed synergistically to LVDD and CMD.
Epicardial tissue derived leptin promotes myocardial injury in metabolic syndrome rats through PKC/NADPH oxidase/ROS pathway
Authors: Chen H , Tian G 
Published: November 2023

Abstract

Background
The epicardial adipose tissue (EAT) of metabolic syndrome (MetS) is abnormally accumulated with dysfunctional secretion of adipokines, closely relating to cardiac dysfunction. The adipokines leptin has been proven to induce cardiac fibroblasts collagen metabolism disorder in hypertensive left ventricular hypertrophy rats.

Purpose
The study was designed to identify the effects of EAT-derived leptin on the myocardium of MetS rats and explore the potential molecular mechanisms.

Methods and results
MetS rat model was established in eight-week-old male Wistar rats by 12 week high-fat diet. MetS rats exhibited increased leptin secretion from EAT, cardiac hypertrophy and diastolic dysfunction with preserved systolic function. The myocardium of MetS rats had abnormal structure and mitochondrial morphology, increased oxidative stress injury and inflammatory factors level, especially the subepicardial myocardium, which was correlated with the EAT-derived leptin level, but not the serum leptin (Figure 1). The EAT was separated from each group rats to prepare EAT-Conditioned Medium (EAT-CM). The H9C2 rat cardiomyoblasts were treated with EAT-CM or leptin, plus various signaling pathway inhibitors. EAT derived leptin from MetS rats promoted mitochondrial oxidative stress and dysfunction, induced mitochondrial pathway apoptosis and inhibited cell viability in H9C2 cardiomyoblasts via PKC/NADPH oxidase/ROS pathway. EAT derived leptin from MetS rats stimulated inflammation in H9C2 cardiomyocytes by promoting AP-1 nuclear translocation via PKC/NADPH oxidase/ROS pathway. Leptin promoted the interaction between p-p47phox and gp91phox in H9C2 cardiomyocytes via PKC, activating NADPH oxidase, increasing ROS generation, and inhibiting cell viability.

Conclusions
EAT derived leptin induces the MetS related myocardial injury though the following two cooperative ways via PKC/NADPH oxidase/ROS pathway: 1. Inducing mitochondrial pathway apoptosis by promoting mitochondrial oxidative stress and dysfunction; 2. Stimulating inflammation by promoting AP-1 nuclear translocation (Figure 2). The results reveal the potential molecular mechanisms of EAT in MetS related myocardial injury, providing novel insights for the further study of MetS related cardiovascular diseases.Figure 1Figure 2
Long-term clinical-pathologic results of enzyme replacement therapy in pre-hypertrophic Fabry disease cardiomyopathy
Authors: Frustaci A , Verardo R , Galea N , Alfarano M , Magnocavallo M , Scialla R , Sansone L , Belli M , Cristina M , Frustaci E , Russo M A , Chimenti C 
Published: November 2023

Abstract

Background
Limited ability of ERT in removing Gb-3 from cardiomyocytes is recognized for advanced FDCM. Pre-hypertrophic FDCM is believed to be cured or stabilized by ERT. However, no pathologic confirmation is available.

Purpose
Long-term clinical-pathologic impact of ERT on pre-hypertrophic FDCM.

Methods
Fifteen Fabry patients with LVMWT ≤ 10.5 mm at CMR required EMB because of angina and/or ventricular arrhythmias. EMB showed coronary small vessel disease in angina cohort and vacuoles in smooth muscle cells and cardiomyocytes around 20% of cell surface containing myelin bodies at electron microscopy. Patients received α-agalsidase in 8 and β-agalsidase in 7 cases. Both groups referred symptoms improvement except 2 patients treated with α- and β-agalsidase respectively. After ERT administration ranging from 4 and 20 years all patients had control CMR and LVEMB because of persistence of symptoms or patients enquiry on disease resolution.

Results
In 13 asymptomatic FDCM patients, LVMWT and LV-mass, cardiomyocyte diameter, vacuole surface/cell surface ratio and vessels remained unchanged even after 20 years observation and storage material was still present at electron microscopy. In 2 symptomatic patients, FDCM progressed with larger and more engulfed by Gb-3 myocytes being associated to myocardial virus-negative lymphocytic inflammation.

Conclusions
ERT stabilizes storage deposits and myocyte dimensions in 87% of patients with pre-hypertrophic FDCM. Gb-3 is never completely removed even after long-term treatment. Immune-mediated myocardial inflammation can overlap limiting ERT activity.
Figure legend
Long-term ERT effects on FDCM.
ERT improves symptoms, stabilizes storage deposits and left ventricular mass index in 87% of patients with pre-hypertrophic FDCM. In 13% of patients there is a progression of the disease in spite of ERT, with a superimposed immune-mediated myocardial inflammation at EMB.
Prognostic significance and pathophysiological insights of functional phenotypes clustering
Authors: Bandera F , Mollo A , Boveri S , Alfonzetti E , Milani V , Ambrogi F , Guazzi M 
Published: November 2023

Abstract

Background
Functional capacity (FC) is a marker of cardiorespiratory fitness reflecting the integrity of cardiac, respiratory and peripheral metabolic systems. Cardiopulmonary exercise test (CPET) is the method of reference to quantify the functional capacity through a multiparametric approach. Functional phenotypes can be identified according with the patterns of CPET variables. We sought to explore the prognostic role of CPET-derived functional phenotypes, identified by an automatic clustering process, and to understand the underlying cardiac pathophysiology as assessed by exercise-echocardiography (Exe-Echo).

Methodology
1379 unselected subjects who underwent to CPET combined with Exe-Echo were included in the study. Cluster analysis based on CPET variables (% of predicted peakVO2, anaerobic threshold, VE/VCO2, peak respiratory ratio, chronotropic index, O2 pulse, peak PetCO2, VO2/WR slope and heart rate recovery) identified 4 clusters (C1= 207, C2= 546, C3= 475, C4= 151 subjects), differing primarily for a progressive worsening of FC (% of PeakVO2: 87±18, 75±13, 60±14, 48±13%; VE/VCO2 25.3±2.7, 26.5±3.0, 30.8±4.3, 39.4±7.8; in C1, C2, C3, C4 respectively, all p&lt;.001). Rest and exercise parameters of Exe-Echo were used to define cardiac characteristics and presented in a standardized radar clustering (fig 1). Patients were tracked for the combined end-point of death + heart failure hospitalization.

Results
C1 presented normal cardiac morphology and function with expected increase of stroke volume (SV) and cardiac output (CO) during exercise, without significant valvular disease; C2 and C3 showed a mild-to-medarately abnormal rest and exercise echo parameters, characterized by LV progressive dilatation, mild systolic dysfunction, mitral regurgitation (MR) and increased systolic pulmonary pressure (SPAP); C4 corresponded to severe cardiac remodelling with LV and left atrial enlargement, severe MR, rest pulmonary hypertension and severely impaired contractile reserve (reduced exercise SV and CO). The 4 clusters were strongly associated with prognosis, as shown by KM of survival free from combined event (p&lt;.0001; fig 2).

Conclusions
automatic clustering of CPET parameters identified 4 clusters strongly associated with hard end-points (mortality and HF hospitalization). Exe-Echo provided cluster-related pathophysiological insights explaining the mechanisms responsible for prognosis decline. This combined CPET-ExeEcho approach may help in identifying high risk patients and in defining new therapeutic targets.Radar chart of echo variablesKM of combined end-point (death+HF)
Histidine triad nucleotide-binding protein 2 deficiency induce myocardial glucose utilization disorder in mice
Authors: Fan M K , Yao L H , Huang Y , Sheng H Z 
Published: November 2023

Abstract

Introduction
Histidine triad nucleotide-binding protein 2 (HINT2) has been shown to be benefit to energy metabolism after myocardial infarction. However, the exact mechanism of HINT2 in myocardial metabolism remains unclear.

Purpose
To explore the effect of HINT2 deficiency on cardiac function and metabolic profile.

Methods
HINT2-/- mice was generated for experiment in vivo by CRISPR/Cas9 technique. Neonatal mouse ventricle myocytes were used for in vitro experiment. Transthoracic echocardiography and histological analyses were performed to assess ventricle structure and function. Transmission electron microscopy was used to observe ultrastructure in ventricle tissues. Conjoint analysis of proteomics and metabolomics was to screen the metabolism profile and signal pathway. Seahorse XFe 96 analysis was performed to detect oxygen consumption rates and glycolysis rate. Immunoprecipitation mass spectrometry was used to explore the HINT2-interacting protein. Co-immunoprecipitation and proximity ligation assay were used to detect the interaction between proteins.

Results
Comparing to HINT2+/+, HINT2 deficient mice had higher level of left ventricular posterior wall thickness, and lower left ventricular ejection fraction. The heart weight/tibia length, cross-sectional area and cardiac fibrosis area were increased in HINT2 deficient mice. In HINT2 deficient, using transmission electron microscopy, thicker cardiac muscle fibers was observed, with disorganized and disorganized mitochondria. Conjoint analysis of proteomics and metabolomics exhibited the network of differential protein and metabolite, which proved HINT2 deficiency activated the pathway of diabetic cardiomyopathy. Immunoprecipitation showed that the level of glycosylated modification in heart tissues was higher in HINT2 deficient mice. Seahorse analysis showed that the basal and max oxygen consumption rate in HINT2 deficient mice was significantly lower, and so was the mitochondria related Proton efflux. With immunoprecipitation mass spectrometry detection, we found that PDK4 may have interaction with HINT2. Both co-immunoprecipitation and proximity ligation assay proved that HINT2 and PDK4 has interaction and subcellular localization.

Conclusions
HINT2 plays an important role in cardiac function and glucose metabolism, which is a critical molecule in process of diabetic cardiomy.
Disturbance of iron metabolism related genes in advanced heart failure
Authors: Tarazon E , Perez Carrillo L , Madejon M , Gimenez Escamilla I , Delgado Arija M , Gonzalez I , Portoles M , Rosello-Lleti E 
Published: November 2023

Abstract

Background/Introduction
Heart failure (HF) is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization, and premature mortality. Iron is a nutrient required in all organ systems for various metabolic processes, such as mitochondrial function, oxygen transport, myocardial and skeletal muscle metabolism, among others. Maintaining iron homeostasis is essential for proper cardiac function since both iron deficiency and iron overload are associated with HF through complex mechanisms, such as ferroptosis.

Purpose
The aim of this study was to analyse the status of iron metabolism in hearts from patients with dilated (DCM) and ischemic cardiomyopathy (ICM) and its implication with the pathophysiology of the disease.

Methods
Cardiac tissue samples were used to evaluated transcriptome differences in genes involved iron metabolism by mRNA-sequencing (mRNA-seq; ICM, n=13; DCM, n=13; CNT, n=10). Furthermore, the miRNA implicated in the mRNA posttrasciptional regulation was studied through non-coding RNA-seq (ICM, n=22; DCM, n=20; CNT, n=8).

Results
We observed a decrease in iron import with SNX4 underexpression in ICM (FC=-1.28) and DCM (FC=-1.27) patients, p&lt;0.05. While the export is reduced only in patients with MCD: HAMP is underexpresed (FC=-2.41, p&lt;0.01) and its miRNA, miR-184, overexpressed (FC=2.77, p&lt;0.01). We also found alterations in molecules of iron homeostasis and transporters of both aetiologies: IREB2 (ICM, FC=-1.27, p&lt;0.05; DCM, FC=-1.48, p&lt;0.001), STEAP3 (ICM, FC=-1.63, p&lt;0.05; DCM, FC=-2.24, p&lt;0.001), NOX4 (DCM, FC=1.70, p&lt;0.05), SLC39A14 (ICM, FC=-1.97, p&lt;0.05) and SLC39A8(ICM, FC=-1.60, p&lt;0.05; DCM, FC=-1.78, p&lt;0.01). Myoglobin was increased (FC=1.18, p&lt;0.05) and its miRNA, miR-133a-3p, decreased (FC=-1.39, p&lt;0.05) in DCM patients. While other molecules implicated in iron metabolism such as NFE2L2 (ICM, FC=-1.52; DCM, FC=-1.30; p&lt;0.05) and AGPAT5 (ICM, FC=-1.84, p&lt;0.05) are decreased. It is worth noting the correlation with ventricular dysfunction shown by SLC39A8 (end systolic diameter, r=-0.674; end diastolic diameter, r=-0.648; p&lt;0.05) in ICM patients and NFE2L2 (ejection fraction, r=0.609, p&lt;0.05) in DCM patients.

Conclusions
Our results show an alteration in the iron metabolism specific of aetiology in HF, both in the genes involved in different functions of the pathway and in its post-translational regulation. These results offer new possible therapeutic targets and valuable information to elucidate the complex mechanisms that relate iron homeostasis to HF.
Association of microvascular dysfunction with cardiovascular outcomes in heart failure with preserved ejection fraction
Authors: Tao M , Radakrishnan A , Liu Y , Dhaliwal S , Despotidis G , Rahman T 
Published: November 2023

Abstract

Background
Heart failure with preserved ejection fraction (HFpEF) is a disease that portends an increased risk of morbidity and mortality. Studies have reported an association between HFpEF and microvascular dysfunction, however this association and its prognostic significance remain unclear. The purpose of this meta-analysis is to evaluated the association of microvascular dysfunction with cardiovascular outcomes in patients with HFpEF.

Methods
A literature search was conducted for studies evaluating the association between microvascular dysfunction measured with global myocardial flow reserve (GMFR) and coronary flow reserve (CFR) and major adverse cardiovascular events (MACE) in patients with HFpEF. The search included the following databases: Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar. The search was not restricted to time or publication status. The minimum follow up duration was one year.

Results
A total of 5 studies with 448 patients (252 with HFpEF, 196 healthy controls) met inclusion criteria for evaluation of the association of GMPR with HFpEF. Patients with HFpEF had a significantly lower GMPR compared to healthy controls (SMD -0.83, 95% CI -1.03,-0.63; p&lt;0.01). Heterogeneity was moderate: Chi2=9.5, df=4, I2 = 58%. Only 2 studies were identified that reported on the evaluation of CFR in patients with HFpEF so meta-analysis could not be reliably performed.
A total of 4 studies with 591 HFpEF patients (284 with reduced CFR and 307 with normal CFR) met inclusion for evaluating the association with MACE. Mean follow-up was 36 months. Patients with impaired CFR &lt;2.0 had significantly higher risk of MACE compared to patients with normal CFR (OR 8.89, 95% CI 3.77-20.92; P&lt;0.01). Heterogeneity was low: Chi2=4.77, df=3, I2=37%.

Conclusion
Patients with HFpEF have significant microvascular disease compared to patients without HFpEF, which is associated with an increased risk of MACE. Additional high-quality studies are required to further elucidate this association and determine the utility of targeted medical therapy.
Exercise gas exchange and echo-derived analysis in HFpEF based on patterns of oxygen peripheral utilization
Authors: Pina M , Rusconi I , Mondelli G , Giustiniani A , Guazzi M 
Published: November 2023

Abstract

Background
Exercise limitation is a key signature of heart failure with preserved ejection fraction (HFpEF) syndrome evolution with studies highlighting a significant cardiac reserve limitation and others identifying a predominant limit in the peripheral VO2 kinetics and utilization.

Aims
To clarify the cardiopulmonary and hemodynamic response in HFpEF according to the high or low peripheral O2 utilization patterns during maximal exercise.

Materials and Method
38 patients with a HFpEF diagnosis based on the ESC HFpEFF criteria underwent cardiopulmonary exercise test (CPET) combined with stress echocardiography. Patients were divided in two groups according to the median peak c(A-V) O2 difference (Group 1: &lt; 11 mL/dL and Group 2: &gt; 11 mL/dL). Cardiac output (CO) was calculated by echocardiography according to the formula LVOT velocity integral x LVOT area. Data were obtained after a familiarization CPET session.

Results
Group 1 and 2 presented similar rest demographic, left and right hemodynamic data (table). The relationship between CO and c (A-V) O2 in terms of VO2 isopleths at peak exercise were not related to any difference in CO (figure)

Conclusions
In HFpEF, an impairment in O2 utilization during exercise appears independent of the cardiac reserve response (similar peak CO increase) but rather peripheral mechanisms implicated in O2 diffusion/release seem to play a dominant role, emerging as selective therapeutic targets for improving functional capacity and symptoms.