bluuebunny/crossref_metadata_2025_split huggingface dataset:
Underprescribing of cardioprotective novel antidiabetic drugs in marginalized patients with type II diabetes mellitus
Authors: Khidhir A , Aladesua T 
Published: November 2023

Abstract

Background
Cardiovascular disease is the most common cause of increased mortality in patients with type 2 diabetes mellitus (T2DM). Novel antidiabetic agents such as sodium-glucose co-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists were shown to reduce this risk. SGLT-2 inhibitors are considered a secondary treatment option in patients with heart failure with reduced ejection fraction (HFrEF) in patients with or without T2DM. In patients with T2DM, these medications not only reduce hyperglycemia but also reduce the progression of chronic kidney disease (CKD). GLP-1 agonists are indicated for treatment of not only T2DM, but also obesity, and were shown to improve left ventricular ejection fraction, myocardial contractility, and endothelial function. The literature suggests that there may be disparities in prescribing patterns in marginalized populations.

Objective
The purpose of this study was to conduct a retrospective chart review to assess the adherence to the new guidelines regarding the use of SGLT2 inhibitors and GLP-1 agonists in marginalized patients with T2DM.

Methods
The study was conducted at a resident-run clinic that serves a large number of under-resourced individuals. Inclusion criteria included patients between the ages of 18 and 75 with T2DM seen in the clinic within 18 months prior to the start of the study with an A1c greater than 9.0. Exclusion criteria included patients with type 1 diabetes mellitus and patients with T2DM under care of endocrinology. We performed retrospective chart review to determine providers’ prescription practices. We created electronic patient database for this study.

Results
The data showed that 26.87% (n= 381) of the clinic’s population had an A1c greater than 9.0, of those 343 patients met the inclusion criteria. About 7.87% (27/343) of patients were identified with HFrEF. Of those, only 40.74% (11/27) were found to be on an SGLT2 inhibitor. Patients with CKD constituted 17.49% (60/343) of patients, and only 16.67% (10/60) of those were on an SGLT2 inhibitor. We identified 27.70% (95/343) of patients with a BMI between 30-35, and 30.32% (104/343) with a BMI greater than 35, but only 56.84% and 64.42% of those, respectively, were on a GLP-1 agonist. The patients that were not on the cardioprotective agents were 50.19% (135/269), 11.15% (9/269), and 12.64% (34/269) African American, Hispanic, and Asian American, respectively.

Conclusions
This study demonstrates that SGLT2 inhibitors and GLP-1 agonists are underprescribed in marginalized patients diagnosed with T2DM, even in those with the additional indication of heart failure and CKD. Most of those patients are of racial minorities. There are a number of barriers that could be contributing to the poor adherence to the guidelines in this population. Our next step is to analyze those barriers and develop a quality improvement project that would improve guideline-directed therapy for this under-resourced population.
Initial clinical experience with new technology: ePatch extended Holter monitoring
Authors: Blanch P , Ortega A , Escura S , Gomez-Choco M , Freixa-Pamias R 
Published: November 2023

Abstract

Introduction
Holter monitor electrocardiography is used to detect potential cardiac arrhythmias such as atrial fibrillation (AF). However, conventional ECG monitoring, data analysis and reporting methods can be labor-intensive and inefficient, leading to high upfront costs and long turnaround times. At the same time, traditional Holter devices can be cumbersome to wear, while inconvenient processes may reduce patient compliance and satisfaction – which impacts diagnostic yield. This new device (ePatch®) is a simple patch application, enrollment and activation with no battery charging needed and no cable attachments (Figure 1). Up to 14 days of continuous ECG recording. Wearable in shower, during exercise and while sleeping. Single-channel, up to 14 days. Two-channel, up to 5 days

Purpose
Our goal is to evaluate the quality and diagnostic efficacy of ePatch® in different clinical settings.

Methods
Prospective study of patients with ePatch® placed in our center requested for study of undocumented palpitations, syncope or cryptogenic stroke. Clinical variables, diagnostic accuracy, and time to diagnostic event are analyzed.

Results
We enrolled the first 57 patients, of whom 27 (50%) were women, with a mean age of 67.8 years (range 27 to 89). The most common indication was undocumented palpitations (35.1%) and cryptogenic stroke (35.1%), followed by syncope (29.6%). All the patients had correct compliance, tolerance and the ECG monitored was of good quality. A conclusive diagnosis: (symptomatic sustained tachyarrhythmia, atrial-ventricular block with bradyarrhythmia, significant pauses or AF) was obtained in 5 patients (8.7% of the total). The average event time since ePatch registration started was 2.4 days (range 1 to 5 days).

Conclusions
The ePatch® is a new extended Holter device offering a simple, complete and efficient ECG monitoring system. This new technology is safe and has numerous advantages: spend less time on logistics and device handling, prepare your patients efficiently, eliminate the need for additional consumables and constant battery replacement. The ECG monitor of our study is of 5 days, but it can be used for up to 14 days. It is designed to address the challenges of traditional Holter monitoring.
Early cardiologist follow-up determines treatment rates and survival among aortic stenosis patients
Authors: Rapp O , Shimoni O , Klempner R , Segev A , Pounds C , Massalha E 
Published: November 2023

Abstract

Background
Aortic valve replacement (AVR) has been constant as it is considered an effective disease-modifying procedure for patients with severe aortic stenosis (sAS). However, the implanter is only one part of it. Patients with sAS generally require ongoing care and support from a multidisciplinary team that includes general cardiologists (GC) and other primary care providers, who guide and manage the patient through the therapeutic process.

Purpose
The current study aims to assess the impact of a cardiologist or other primary care provider managing the therapeutic process in the early period first phase following the sAS diagnosis.

Methods
A large-scale database of Maccabi Health Services, the second largest health maintenance organization (HMO) in Israel, counting Israel with nearly 2.8 million members, was retrospectively analyzed from 2005 to 2021 for all patients over 60 years, with detailed echocardiography compatible with a diagnosis of sAS. The database was extracted using the MDClone healthcare data platform, generating the synthetic cohort database reliably representing the original population. sAS patients managed by GC versus non-GC care providers were assessed for differences in AVR rates, and all-cause mortality was assessed in sAS patients managed by GC versus non-GC care providers.

Results
A total of 1570 sAS patients were included in the final analysis. Of them, GCs managed GC managed 65% in the early phase (3 months) following the sAS diagnosis. sAS with heart failure (21% vs. 17%) and atrial fibrillation (26% vs. 19%) were less likely managed by GC. No statistically significant differences were observed in other baseline characteristics, including age, gender, and comorbidities.
A propensity score matching analysis revealed a significant difference in 12-month and 24-month AVR rates following diagnosis between the GC versus non-GG groups (19% vs. 3%, and 28% vs. 9%, respectively. P&lt;0.01 for both). sAS patients managed by a GC show a significant survival benefit, 31% vs. 36% within five years after diagnosis P &lt; 0.05.

Conclusions
Patients with sAS managed by a GC within three months after diagnosis had significantly higher chances for AVR and, consequently, better prognosis. These findings emphasize the importance of GC management in sAS.
Outcomes in the South African SHARE-TAVI registry: comparison of mortality and risk between treated and untreated cohort, and recent 1-year outcomes in the maturing local TAVR programme
Authors: Schaafsma E , Weich H , Scherman J , Tsabedze N , Ntsekhe M 
Published: November 2023

Abstract

The South African SHARE TAVI Registry collects local TAVI data to inform health policy, promote access to healthcare, and benchmark the local TAVI programme against recognised best practice. Strong Funder resistance still hampers treatment of aortic stenosis patients after &gt;10 years of TAVI in SA.

Method
A web-based voluntary all-comers prospective registry captured 2083 patients' clinical history, demographics, TAVI outcomes, complications (VARC 2 definitions) and follow up at 30d, annually post TAVI (8 years). 462 patients assessed for TAVI but not implanted(49 exited prior to funding application, 413 during or after process) were also captured and followed up to 1-year, 413 of these exited during/after the funding application process, 49 exited prior to process (patient declined/unsuitable anatomy).

Results
Patient populations are similar to other registries and studies using similar generation devices (Schaafsma et al 2022).
Outcomes at 30d, 1, 2, and 5 years are comparable to other early TAVI programmes (GARY, Corevalve, PARTNER 1).
Average days to Mortality of 813/2545 full patient cohort calculated from date of TAVI Assessment & TAVI procedure date if applicable was highest in implanted patients (693d & 612d) , and lowest in those exiting the programme with no changes to treatment (216d). Most common exit reason was declined funding (71 pts) or death in the funding application process (105pts). Mortality in 68 pts waiting for a response averaged at 93d with STS of 10.996%, and 37 pts with approved funding demised prior to the TAVI date at average 78d in funding process with STS of 9.7%.
NON-TAVI patients (n=49) referred for medical or surgical treatment had a longer life expectancy (475 & 366d) than patients who immediately declined implants after the assessment (182d with STS score 7.943). 1year mortality in the 2021 cohort is 14.1%, and in 2022 cohort procedural success is 99.3%, mortality at 30d is 2.53%.

Conclusion
SA's TAVI programme provides clear benefit to Aortic stenosis patients in terms of life expectancy and the maturing programme's high procedural success and extended life expectancy as shown in local data may be used to support access to treatment in the face of funding resistance.Table 1
Sarcomere disassembly and transfection efficiency in proliferating human iPSC-derived cardiomyocytes
Authors: Yuan Q , Maas R , Brouwer E , Sluijter J , Van Der Velden J , Buikema J A N W 
Published: November 2023

Abstract

Introduction
Proper contraction of cardiomyocytes (CMs) is dictated by the architecture of the sarcomeres and appears together with polyploidy inversely correlated with limited self-renewal and regeneration of the adult heart. This limited regenerative potential correlates with the decrease in mononuclear diploid cells in adult versus neonatal myocardium. Previous animal studies have shown that the sarcomeres are dissembled during proliferation of neonatal CMs. However, little is known about sarcomere assemblage during human CMs nuclear and/or cell division, which would be relevant information for strategies to boost endogenous heart repair.

Purpose
In this study we used the human induced pluripotent stem cell (hiPSC) model to investigate sarcomere assemblage during mitosis, followed by cytokinesis, multinucleation and/or self-duplication in massively expanding hiPSC-CMs. Furthermore, we examined whether CMs undergoing nuclear and/or cellular duplication would be more susceptible for genomic editing than non-proliferative hiPSC-CMs.

Methods
hiPSC-CMs were massively expanded using our previously described CHIR99021 small molecular treatment and cell-cell contact removal. We then performed immunofluorescence staining with cardiac Troponin T (cTnT) and Ki67 to follow sarcomere organization during cell cycle activity. Next, we performed Time-Lapse imaging in a hiPSC-CM culture system to follow the sequence of cellular and nuclear divisions in hiPSC-CMs. RNA sequencing lookup was performed for proliferation, sarcomere and molecular pathway-related genes. Efficiency of non-viral vector-based fluorescence (mCherry) expression and transfection efficiency was done by flow cytometry analysis and Time-Lapse imaging.

Results
We observed that both mononuclear and binuclear hiPSC-CMs give rise to mononuclear daughter cells or binuclear progeny. Within this source of highly proliferative hiPSC-CMs, treated with CHIR99021 small molecule, we found that Wnt and Hippo signaling were more present when compared to metabolic matured and non-proliferative hiPSC-CMs and adult human heart tissue. Moreover, we found that CHIR99021 treatment increased the efficiency of non-viral vector incorporation in high-proliferative hiPSC-CMs, in which fluorescent transgene expression became present after completion of chromosomal segregation (M-phase).

Conclusion
This study demonstrates that there is a complex landscape in proliferation, multinucleation and self-duplication of human CMs. Moreover, enhanced incorporation of alien non-viral vectors is related to Wnt activation and cell cycle activity of hiPSC-CMs. Altogether, our findings provide insights in duplication of human CMs and tools for molecular gene studies.
Single-cell transcriptomics analysis reveals Cilp+Cd200+ fibroblasts promote mesenchymal endothelial transition (MEndoT) in cardiac injury
Authors: Lin Y , Cai W , Dong W , Wen D , Zeng C , Guan H , Shentu W 
Published: November 2023

Abstract

Background
Cardiac fibroblasts are considered to be highly heterogeneous mesenchymal cells after a cardiac injury. Understanding the heterogeneity of cardiac fibroblasts is of fundamental importance for fibroblast-targeted strategies to treat patients with heart disease. Advances in the single-cell RNA-sequencing (scRNA-Seq) technology have provided a possibility to elaborate the heterogeneity of cells in more depth. However, currently, most studies on scRNA-Seq of cardiac fibroblasts are performed using non-myocyte cells isolated at a certain point in time, which include a very complex, interdependent community of interstitial cells. scRNA-Seq based on lineage-tracing of cardiac fibroblasts is essential for a deeper understanding of cellular heterogeneity of specific cell type populations, which can reveal how a pre-existing cardiac fibroblast population responds to cardiac injury. Our previous studies demonstrated that a subset of cardiac fibroblasts can adopt the endothelial cell phenotype by undergoing mesenchymal–endothelial transition (MEndoT) and contributes to cardiac repair by revascularizing the damaged myocardium.

Purpose
To decipher which subgroup of the preexisting cardiac fibroblasts involved in MEndoT respond to cardiac injury.

Methods and Results
For lineage-tracing-based studies, Col1a2 Cre ERT: R26R td-Tomato transgenic mice were generated for reliable cardiac fibroblast tracking. 10X scRNA-Seq was performed to analyze the diversity of prelabeled cardiac fibroblasts after sham or transverse aortic constriction injury. Using the Seurat R package, the td-Tomato labeled cells were further clustered into 11 distinct populations. In addition, the cell trajectory assay shows both Cilp and Cd200 positive (Cilp+/Cd200+) cluster located in the early state and showing the phenotype of mesenchymal stem cells, indicating that this clusters have high diversity with regard to differentiation and directly contribute to angiogenesis. Besides, we isolated Cilp+/Cd200+ cardiac fibroblasts from wild-type mice by flow sorting and performed matrigel tube formation and acetylated low-density lipoprotein (Ac-LDL) uptake to measure the potential of MEndoT. Interestingly, compared with Cilp-/Cd200- cardiac fibroblasts, both matrigel tube formation and Ac-LDL uptake of the Cilp+/Cd200+ group were significantly increased (∼1.3 fold higher in matrigel tube formation, P&lt;0.05;∼3.3 fold higher in Ac-LDL uptake, P&lt;0.05).

Conclusion
Our findings indicated that Cilp+/Cd200+ is the main group of cardiac fibroblasts involved in MEndoT and plays a major role in the organization of the extracellular matrix and cell differentiation. This study provided new therapeutic strategies for cardiac hypertrophy by accurately regulating the cardiac fibroblasts.
HIF-1 regulates common bidirectional gene expression changes during hypoxia and iron deficiency in human induced pluripotent stem cell derived cardiomyocytes
Authors: Papadopoulou C , Reinhold J , Price J L , Hoole S , Smith J G , Miska E 
Published: November 2023

Abstract

Background
Heart failure regardless of cause is characterised by extensive transcriptional reprogramming and a switch to foetal developmental programmes via unknown mechanisms (1-3). An additional factor that adversely impacts heart failure patients is iron deficiency (ID)(4). ID is also associated with worse prognosis in acute coronary syndromes (5). However, the mechanisms by which ID interferes with clinical outcomes in heart disease remain incompletely understood.

Purpose
The purpose of this study was to investigate gene expression changes in human cardiomyocytes during hypoxia and ID, two important stressors in the context of ischaemia and heart failure.

Methods
In this study, we use human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) derived through a protocol that promotes left ventricle cardiomyocyte differentiation (6). Cells were harvested at different stages of differentiation (day 6 and day 32) and mature (day 32) hiPSC-CMs were treated with 30 μM deferoxamine to induce ID either under normoxic or hypoxic conditions with 1% O2. hiPSC contraction was assessed using musclemotion software and metabolism through use of a Seahorse extracellular flux analyser. RNA was isolated using standard isolation kits and RNA-seq (n=5) was performed. Data was analysed for gene expression by alignment with the human hg19 reference genome using the software STAR. A log2 fold change of 1 and P value of &lt;0.0001 were considered significant.

Results
We show that both hypoxic and ID hiPSC-CMs demonstrate impaired contractility and reduced oxygen consumption, features of cardiomyocytes from failing hearts. Importantly, hiPSC-CMs exposed to hypoxia, ID or the combination of the two exhibit bidirectional gene expression changes with significant overlap (Figure 1). Focusing on the commonly affected gene set, it becomes evident that hypoxia & ID work via similar mechanisms involving activation of the HIF-1 pathway, that in turn orchestrates the metabolic switch to glycolysis and glutamine oxidation similar to foetal cells. Overall, hypoxia promotes a shift towards immature gene programmes, with 45% of dysregulated genes in hypoxia mimicking expression patterns of less mature cells. Interestingly changes in long non-coding RNA (lncRNA) profiles in hypoxia and ID mimic gene expression changes in these conditions (figure 2). Although restoring oxygen levels in hypoxic hiPSC-CMs rescues the hypoxic transcriptional signature, hiPSC-CMs previously exposed to hypoxia can use glycolytic pathways more efficiently upon further exposures to hypoxia.

Conclusion
These results shed light into the mechanisms ID impacts heart disease patients and are suggestive that HIF-1 is a key player in orchestrating the gene switch in ID and hypoxia.
Impact of microtubule detyrosination on subcellular distribution of Nav1.5 in mdx cardiomyocytes
Authors: Casini S , Nasilli G , De Waal T , Marchal G A , Rothenberg E , Delmar M , Remme C A 
Published: November 2023

Abstract

Background
Subcellular trafficking and distribution of the cardiac sodium channel Nav1.5 in cardiomyocytes is dependent on the microtubule network as well as Nav1.5 interacting proteins. Duchenne muscular dystrophy (DMD) is associated with loss of dystrophin, a Nav1.5-interacting protein localized at the lateral membrane of cardiomyocytes, leading to sodium current (INa) reduction in this microdomain. Cardiomyocytes of DMD (mdx) mice also display increased microtubule detyrosination, but its impact on INa and Nav1.5 distribution is unclear.

Purpose
To investigate the effect of reducing microtubule detyrosination by the compound parthenolide (PTL) on INa and subcellular Nav1.5 distribution in mdx cardiomyocytes (CMs).

Methods and Results
Isolated ventricular CMs from wild type (WT) and mdx (DMD) mice were incubated with either 10 µM PTL or DMSO for 3-5 hours. INa properties were assessed using the patch-clamp technique, confocal microscopy was used to investigate microtubule detyrosination, and stochastic optical reconstruction microscopy (STORM) was employed to assess Nav1.5 cluster density and size, as well as Nav1.5 cluster distribution (crest vs groove) at the cardiomyocyte lateral membrane. Compared to WT. mdx CMs displayed increased levels of detyrosinated tubulin and decreased whole-cell INa. Incubation with PTL decreased the fraction of detyrosinated tubulin and significantly increased whole-cell INa magnitude in mdx CMs, but had no effect in WT CMs. No effect of PTL on INa gating properties were observed, indicating that it increased INa by enhancing Nav1.5 membrane trafficking. Indeed, STORM analysis showed that PTL increased Nav1.5 cluster density at both the lateral membrane and intercalated disc region in mdx CMs while it had no effect on WT CMs. Furthermore, Nav1.5-α-actinin cluster distance analysis showed that PTL increased Nav1.5 clusters specifically at the crest of the lateral membrane in mdx CMs.

Conclusions
In mdx CMs, reduction of MT detyrosination rescues INa density and increases Nav1.5 cluster density both at the intercalated disc and lateral membrane. Hence, in addition to loss of the Nav1.5-interacting protein dystrophin, MT remodelling contributes to INa reduction in DMD. The PTL-induced increase in Nav1.5 at the crest of the lateral membrane of mdx CMs is likely due to a dystrophin-independent mechanism since dystrophin is normally absent from this microdomain. Overall, our findings identify MT detyrosination as a potential therapeutic target for modulating INa and subcellular Nav1.5 distribution during pathophysiological conditions.