tbuckley/cabot-search huggingface dataset:
Swimming training induced sex-specific differences in cardiac hypertrophy and blood levels of the renin-angiotensin system
Authors: M O I Otmani Idrissi, F A Frobert, A C De Chambrier, M S Stumpe, M F Fluck, M N Nikodemski, M N G Giraud
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): FNS Background Exercise promotes physiological cardiac hypertrophy that is adaptive and reversible and influenced by age, genetics, sex, exercise intensity and type. The renin-angiotensin system (RAS) plays a crucial role in cardiovascular remodelling at both systemic and tissue levels. However, a significant gap exists in our understanding of sex differences in response to physical activity. Our objective is to characterise swimming-induced cardiac remodelling in female and male rats and RAS at both the cardiac tissue and systemic levels. Methods Male and female Lewis rats swam in a container filled with tap water at 32° C for 1 hour per day for 4 weeks or up to 8 weeks, respectively. Sedentary animals served as control. Echocardiography and immunostaining of RAS components, including angiotensin-converting enzyme 2 (ACE2) on cardiac sections' staining were performed. Cardiomyocyte (CM) size was measured. Cardiac RAS receptors were quantified with RT-PCR. Blood levels of Angiotensinogen, Angiotensins (Ang) were measured with Mass Spectrometry. Renin activity was calculated by the ratio Ang1/Angiotensinogen. Results After 4 weeks, an increase in ventricle diameter was shown in exercised male rats compared to the control. The cardiac hypertrophy was confirmed by increased heart/body weight (H/BW= 3x10-3±1.3x10-4vs2.5x10-3±3.10-5mg/g p&amp;lt;0.0001) and CM size (288±23 vs 198±1μm2 p=0.0028) associated with increased intra-CM immunostained ACE2 (AC2 area fraction: 38.5%±2.8%vs20%±5 p=0.0001). In females, ventricle diameter was unchanged, but wall thickness increased. Exercise was pursued for up to 8 weeks. At 6 and 8 weeks, echocardiography measurements remained similar as at 4 weeks. Hypertrophy was then confirmed by increased H/BW (3.2x10-3±1.7x10-4vs control:2.7x103 ±1.8x104mg/g p&amp;lt;0.0001) and CM size (335±47vs233±25μm2 p= 0.0019). An increased intra-CM-ACE2 was characterised by immunostaining (55.8%±6vs32.5%±6.6% p&amp;lt;0.0001) and confirmed by the increased ACE2 gene expression in cardiac tissue. At 4 weeks, the blood levels of RAS components were similar in trained and control males as well as renin activity. On contrary, exercised female rats showed increased blood levels of Angiotensinogen (4.2x10-4±7x10-5 vs 3x10-4±7x10-5au p=0.0288), Ang1 (2±1.9vs0.0±0.9au p=0.0151), Ang2 (1.2±1.5vs0.0±0.9au p=0.0204), and Ang1-7 (3.4±2.9vs 0.0±0.9au p=0.0058). The blood levels of these RAS compounds returned to the control levels after 6 and 8 weeks. In addition, a sex-distinct blood proteome was identified. Conclusion Our results showed a sex-distinct RAS regulation post-exercise and suggested a sex difference in the timing of adaptive responses at the system and cardiac tissue levels.
High-throughput proteomic analysis unveils metabolic and mitochondrial signaling rewiring by chronic ivabradine treatment in duchenne muscular dystrophy
Authors: C Dostal, P L Szabo, J Marksteiner, B K Podesser, K Hilber, A Kiss
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Austrian Science Fund (FWF) Objective Ivabradine (IVA) is indicated in symptomatic treatment of chronic stable angina, heart failure, and also in those who are unable to tolerate or have contraindications to the use of beta-blockers. It has been showed IVA may have cardiovascular benefits in Duchenne muscular dystrophy (DMD) patients. This study was aimed to investigate the sustained impact of chronic ivabradine (IVA) administration on cardiac function and potential underlying mechanism using high throutput proteomic analysis. Methods DMDmdx male and Sprague–Dawley wt (Sprague–Dawley) male rats were randomly allocated to vehicle (n = 6) or IVA (n=6; 10 mg/kg/day via drinking water for four months). Transthoracic echocardiography and unbiased proteomic analysis were performed to assess cardiac function and left ventricular (LV) tissue, respectively. Protein-protein interactions were graphically represented, and cluster analysis with subsequent enrichment analyses was conducted. Results Chronic IVA treatment significantly enhanced the LV ejection fraction (p&amp;lt;0.05 compared to vehicle-treated DMDmdx rats). Proteomic data identified possible transcription factors (SPI1, IRF1, PPARA), consistent with previous studies. The reduction in copper metabolic changes associated with DMD can be attributed to the upregulation of Atox1 following IVA treatment. Mitochondrial dysfunction was effectively mitigated by IVA, as indicated by the different abundance of mitochondrial proteins. In addition, intercellular adhesion molecule 1 showed a reduction in the number of animals treated with ivabradine, indicating a further positive effect of the treatment. Conclusion In summary, this study demonstrated the beneficial effects of IVA in DMDmdx rat hearts. Cluster analysis of proteomic data revealed notable changes in cardiac metabolism, inflammation, and mitochondrial function. Ivabradine has emerged as a potential therapeutic approach to address these shifts, while proteomic pathway analysis may uncover new drugable targets to alleviate cardiomyopathy progression in DMD.Interaction of IvabradinProtein-protein interaction network
Stage specific effects of insulin and Wnt on cell fate decisions in human induced pluripotent stem cell-derived cardiomyocytes
Authors: Q Yuan, R Dinani, D W D Kuster, R A Boon, J Van Der Velden, J W Buikema
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background Reactivation of the so-called fetal gene programs and pathways have been reported in failing hearts, however, it remains unclear whether this phenomenon is beneficial or detrimental to the remaining functional myocardium. During cardiac development, the orchestration of these embryonic growth pathways, facilitate temporal and stage-specific cell fate decisions such as required for specification and growth of the various myocardial compartments. Previously, we demonstrated that molecular activation of the Wnt pathway resulted in massive expansion of immature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Yet, it is unknown what exact cues guide the cell fate decisions of immature hiPSC-CMs to either proliferate or terminally differentiate into more mature cardiomyocytes. Purpose This work uncovers the embryonic growth pathways that control the cues for proliferation versus terminal differentiation in functional immature hiPSC-CMs. Methods We utilised spontaneously beating hiPSC-CMs at day 11 of differentiation and performed a combinatory screen for various dosages of CHIR99021/Wnt and Insulin/Akt pathway. Proliferation was determined by quantification of cell number and the proportion of Ki67 positive hiPSC-CMs. Terminal differentiation was evaluated by presence of more mature sarcomere markers and cell cycle exit. Results Our combinatory screen for Insulin/Akt and CHIR99021/Wnt demonstrates synergistic effects on proliferation of immature hiPSC-CMs, whereas the absence of these pathway activators leads to rapid cell cycle exit and terminal differentiation of hiPSC-CMs. Detailed characterization reveals that CHIR99021/Wnt also importantly regulates sarcomere homeostasis and architecture in hiPSC-CMs. Moreover, we identify a novel temporal interplay between CHIR99021/Wnt via TCF and Insulin/Akt via FOXO as regulators of cell-fate decision in immature hiPSC-CMs. Conclusions Molecular targeting of the embryonic growth pathways in acute and chronic forms of heart failure requires a detailed understanding of the specific effects on cardiomyocyte function and sarcomere architecture. This work provides a starting point to develop future strategies to target acute and chronic forms of heart failure via modulation of embryonic growth pathways.Graphical Summary
Timing of capillary enlargement after adenoviral VEGF gene transfer does not support post-ischemic skeletal muscle recovery in hyperlipidemic mice
Authors: G Wirth, G Juusola, H Laakso, P Korpisalo, S Yla-Herttuala
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Finish Academy (Clinical Researcher 324070 and Research Project 339560). Finnish Foundation for Cardiovascular Research Background Transient capillary enlargement has been shown to be essential for successful post-ischemic tissue recovery as it may facilitate the return of arterial driving pressure by supporting collateral maturation. It also leads to an intussusceptive increase in capillary density that supports efficient oxygen delivery and muscle regeneration. Hyperlipidemia has been shown to blunt post-ischemic capillary reactivity and hinder skeletal muscle recovery from ischemia. Therefore, it can be hypothesized that correction of capillary reactivity might improve post-ischemic muscle recovery under hyperlipidemia. Purpose The aim of this study was to test the ability of angiogenic VEGF gene therapy in improving post-ischemic muscle recovery under hyperlipidemia. Methods AdVEGF gene transfer was performed into the calf muscles of aged, hyperlipidemic LDLR-/-ApoB100/100 mice after acute ischemia induction. The effects of AdVEGF on capillary phenotype, tissue edema, restoration of blood flow parameters, microvascular hemoglobin oxygenation and tissue damage/regeneration were evaluated for up to 29 days post-procedure as compared to AdLacZ control using immuno- and histological analyses, magnetic resonance, contrast-enhanced ultrasound and photoacoustic imaging, respectively. Results AdVEGF gene therapy was able to promote capillary enlargement that led to recovery of arterial driving pressure in ischemic LDLR-/-ApoB100/100 muscles. However, capillary enlargement induced by AdVEGF appeared late, lasted up to 29 days and did not promote intussusception. Consequently, the negative effect of long-lasting enlargement, i.e., massive tissue edema, delayed blood flow recovery and aggravated ischemic tissue damage. Conclusion Proper time of induction and duration of capillary enlargement are crucial to yield a functional vascular response supporting post-ischemic tissue recovery.
Modeling doxorubicin-induced cardiotoxicity with human myocardial tissue slices: insights on genetic susceptibility and cardioprotection
Authors: J S A Van Der Geest, I R Kelters, N P Van Der Kaaij, A Dendorfer, P A F M Doevendans, T P De Boer, L W Van Laake, J P G Sluijter, V Sampaio Pinto
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PSIDER and HARVEY (ZonMW) Introduction Cardiotoxicity poses a significant challenge in drug development, often leading to the withdrawal of approved drugs. To address this issue, there is a critical need for improved models to predict cardiac adverse effects. In line with the imperative for animal-free preclinical testing, this study aimed to develop a novel model using human myocardial tissue slices to get a deeper understanding and potential prevention of doxorubicin-Induced cardiotoxicity. Methods Human myocardial tissue slices of 300 μm thick were derived from end-stage heart failure patients explanted hearts, including those harbouring likely or pathogenic cardiovascular mutations (class 4 and 5) (N=3) and non-genetic cardiovascular etiology (N=3). Myocardial tissue slices were cultured under physiological mechanical and electrical conditions. Slices were exposed to doxorubicin (1 µM) over a 10-day culture period, and their responses were compared to DMSO-vehicle controls, by recording contractile force and Ca2+ transients. Additionally, a subset of slices was treated with a cardioprotective agent, dexrazoxane (100 µM), 1 day prior to and during doxorubicin exposure to assess potential cardioprotection. Results Doxorubicin-exposed slices with a pathogenic mutation exhibited reduced mechanical force, increased threshold potential, and impaired ability to follow pacing at higher frequencies. Additionally, aberrations in calcium handling, manifested as arrhythmia-like disconnection of muscle fibers, were notably observed in these slices. Instead, slices from patients without pathogenic mutations showed minimal cardiotoxicity when exposed to doxorubicin. Encouragingly, pretreatment with dexrazoxane demonstrated a protective effect against doxorubicin-induced cardiotoxicity in the genetically susceptible group. Our functional findings corroborated our structural data, highlighting the breakdown of sarcomere structure and cell-cell connections and increased DNA damage, particularly in patients harbouring a genetic cardiovascular mutation. Conclusion In summary, human myocardial tissue slices faithfully recapitulate doxorubicin-induced cardiotoxicity. Importantly, our data suggests the utility of employing genetic testing for known cardiovascular mutations as a valuable step before initiating doxorubicin treatment. Additionally, we demonstrate for the first time the in vitro cardioprotective potential of dexrazoxane in a human tissue model. These findings pave the way for using ex vivo myocardial tissue slices to evaluate cardiotoxicity and their value as a powerful tool for evaluating the efficacy and delivery approaches.
Altered firing activity of intracardiac neurons isolated from mice carrying the Scn5a-1798insD mutation
Authors: S Casini, T M De Waal, C Schumacher, M W Veldkamp, C A Remme
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements None. Background Dysfunction of the cardiac sodium channel Nav1.5 (encoded by SCN5A) is associated with arrhythmias and sudden cardiac death, the mechanisms of which have been extensively studied in cardiomyocytes. However, patients carrying an SCN5A mutation often display clinical symptoms which are not readily explained solely by alterations in cardiomyocyte electrophysiology. For instance, carriers of the SCN5A-1795insD mutation, which is associated with features of Brugada syndrome and Long QT syndrome type 3 (LQT3), display severe bradycardia leading to excessive QT-prolongation and sudden death especially occurring at rest or during the night, suggesting autonomic triggers. Interestingly, SCN5A is not only present in cardiomyocytes, but also in intracardiac neurons (ICN). ICN modulate cardiac electrophysiological properties and their dysregulation may contribute to arrhythmogenesis. Purpose To explore whether ICN from mice carrying the Scn5a-1798insD mutation (the murine equivalent of SCN5A-1795insD) display electrophysiological alterations that may (in part) contribute to the arrhythmogenic phenotype. Methods and Results ICN were isolated by enzymatic dissociation from fat pads located in the pulmonary veins and sinoatrial node regions of the hearts of wild-type (WT) and Scn5a-1798insD mice. Immunodetection of the cholinergic marker ChAT confirmed the prominent cholinergic phenotype of ICN. In agreement with previous reports in other species, we also detected the presence of Nav1.5 in murine ICN. Nav1.5 expression was mainly observed in ChAT positive cells. To evoke repetitive action potential (AP) firing in single ICN, 500 ms-sustained depolarizing current pulses were applied of increasing amplitude (from 0 pA to 150 pA). Two types of neurons were identified on the basis of firing pattern characteristics: accommodating (neurons that discharged multiple APs decrementing in frequency during the pulse) and tonic (neurons that discharged multiple APs at a high frequency). APs firing frequency did not differ between WT and Scn5a-1798insD accommodating ICN, while it was significantly increased in Scn5a-1798insD tonic ICN as compared to WT (at 100 pA, AP count/500ms in WT CMs: 29.5±1.7, n=24; at 100 pA, AP count/500ms in Scn5a-1798insD: 36.2±2.0, n=18, p=0.02). Conclusions The impact of SCN5A mutations on ICN function are unexplored, but may play an essential role in arrhythmogenesis. The increased AP firing frequency observed in Scn5a-1798insD ICN may lead to increased release of neurotransmitters, such as acetylcholine, that in turn may contribute to the bradycardia observed in patients. Overall, further elucidation of the electrophysiological consequences of inherited Nav1.5 dysfunction in ICN might provide novel therapeutic targets to prevent lethal arrhythmias.
Acquired control over proliferation and differentiation of ventricular cardiomyocytes to break down the mechanisms of cardiac repair
Authors: A Ramkisoensing, J Zhang, D A Pijnappels, A A F De Vries
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements None. Loss of myocardial tissue remains a leading cause of morbidity and mortality by causing heart rhythm disturbances and heart failure. The (pre-)clinical effects of inducing cardiac regeneration by cardiac cell therapy have been disappointing. In order to find new curative options for these disabling cardiac diseases a shift of focus towards steering the heart to regenerate itself is needed. The aim of this study was to generate a robust ventricular cardiomyocyte model in which proliferation and differentiation could be tightly controlled to investigate cardiac regeneration. To accomplish this we have generated a line of immortalized neonatal rat ventricular cardiomyocytes (nrVMs) through expression of the cell cycle regulators cyclin-dependent kinase 4 and cyclin D1 (CDK4-D1). The CDK4-D1 expressing nrVMs were positive for the proliferation marker Ki67 in contrast to control nrVMs. Cardiomyogenic differentiation could still be induced after multiple passages (&amp;gt; passage 10) as evidenced by immunocytochemistry and optical voltage mapping. These contractile and excitable cells were indeed positive for the cardiac-specific sarcomeric proteins alpha actinin and troponin T in a sarcomeric pattern similar to native nrVMs. Passaging of the control nrVM cultures, however, ultimately led to a senescent cell population lacking sarcomeric markers after passage 3. Electrophysiological analysis of immortalized monolayers, after inducing cardiomyogenic differentiation, showed not only uniform propagation of electrical signal throughout the cultures, but also re-entrant activity although at low frequency. In conclusion, these data show that were able to immortalize ventricular cardiomyocytes by preserving their contractile and excitable phenotype upon significant expansion. Further optimisation of this model will lead to a research model of ventricular cardiomyocytes which will give us the opportunity to unravel the process of cardiomyogenesis and uncover mechanisms which could allow us to enhance the ability of the heart to regenerate itself.
Imbalance of thalamic metabolites in an experimental model of hypertension: role of bergamot polyphenols
Authors: A Cardamone, C Carresi, A R Coppoletta, A Mollace, V Musolino, M Gliozzi, V Mollace
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements None. Hypertension is emerging as a pathogenic factor in vascular-based cognitive impairment, altering the structure and function of cerebral vasculature, and representing the main risk factor for cerebral small vessel diseases and neuronal loss. Some studies correlated a reduction in regional cerebral blood flow in the thalamus of elderly hypertensive brains with the decrease in certain cerebral metabolites, because of hypoperfusion. Patients with severe hypertension show a reduced oxygen consumption in regions with reduced cerebral blood flow suggesting that, the vascular dysfunction and the reduced cerebral blood flow could be related to reduced metabolic demands due to brain dysfunction and damage. Chronic cerebral hypoperfusion is associated with increased inflammatory state and oxidative stress. Herein, we hypothesized to prevent or reduce the onset of oxidative stress using natural occurring antioxidant compounds could be of particular importance for the management of hypertension-induced cerebral complications. Hypertension was induced on Wistar male rats by left renal artery ligation (RAL). After complete recovery from surgery, the animals were treated with 20 mg/kg deoxycorticosterone acetate twice a week for 4 weeks, and 1% sodium chloride (NaCl) water. A subgroup of hypertensive rats received Bergamot Polyphenolic Fraction (BPF) by gavage. A control group was treated with sub-cutaneous injection of saline. At baseline (T0), after 2 weeks (T1) and at the end of the experimental period (T2), the thalamic neurochemical profile were evaluated using proton magnetic resonance spectroscopy (1H-MRS), performed with a Bruker Pharmascan 70/16 7T. VAPOR water-suppression module was used and optimized to reduce residual water, then thalamic spectra were acquired using a short echo time single voxel point-resolved spectroscopy technique (voxel size 3x3x3 mm). The absolute quantification of metabolite concentrations has been performed using TARQUIN (v.4.3.10). A reduction tending to significance of the tNAA/tCr ratio, emerged in the thalamus of RAL DOCA-Salt rats compared to control rats at T2. A significant reduction of the tNAA/tCr ratio was observed in the group of RAL DOCA-Salt rats at the T2 compared to the same animals at the T1. In addition, a significantly decrease of the tCho/tCr ratio was highlighted in the RAL DOCA-Salt animals compared to the CTRL rats starting from the T1. The administration of BPF ameliorates the tNAA/tCr ratios in the thalamus of RAL DOCA-Salt rats. Such evidence of the influence of hypertension on tNAA/tCr and tCho/tCr ratios could better explain the relationship between brain structure and modulation of some metabolites, providing new insights into hypertension-induced brain complications and the contribution that the use of natural compounds could give to their management.