ALT Study outline for investigating the efficacy of intravenous administration TY1 in a mouse two-hit model of HFpEF. Wildtype c57BL/6 mice were placed on a high-fat diet and the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester (L-NAME) for five weeks whereafter they were randomized to receive intravenous (retro-orbital) infusions of vehicle (saline; negative control) or TY1 (0.15 mg/kg) at frequencies of every other week, weekly, or biweekly (total of 10 weeks). TY1 administration reduced diastolic dysfunction as indicated by echocardiographic E/e´(n = 4–10 animals per group).

ALT Venn diagram illustrating relative proportion and overlap of DMPs within HFpEF and HFrEF relative to CON, and X–Y plot of overlapping DMPs revealing a strong positive correlation irrespective of disease etiology.

ALT Different treatments can recruit interorgan protective afferent (blue), and efferent PNS (red) signalling pathways. Sympathetic signalling pathways are shown in green.

ALT Mechanisms of immune-checkpoint inhibition resulting in changes in T-cell metabolism and gene transcription, as well as anti-tumor response and potentially cardiovascular immune-related adverse events.

ALT Schematic overview of immune checkpoint-inhibitor-related myocarditis. Modified from: Seidel JA, Otsuka A, Kabashima K (2018) Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front Oncol 8:86. https:// doi. org/ 10. 3389/ fonc.2018. 00086

ALT Effect of ventricular fibrillation on infarct size in patients with STEMI The area under the curve (AUC) of 48-h troponin I was significantly lower in the VF group than in the CTRL group (right panel). Data are expressed as median (first-to-third quartiles). The circles represent individual data.

ALT CD4+T cells were isolated from WT and 4E-BP3 KO EAM mice and stimulated with MyHC-α peptide for 48 h. Cytokine levels in the culture supernatants were analyzed by ELISA, n = 6 per group. Results are presented as the mean ± SEM. *P < 0.05. EAM experimental autoimmune myocarditis; SEM standard error of mean; WT wild type; KO,knockout.

ALT The current study aimed to assess the effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice. Anti-PD-1 treatment caused systolic dysfunction in the lean, normocholesterolemic mice, nevertheless, systolic dysfunction was not observed in the obese, hypercholesterolemic mice. This effect was independent of the sexes.

ALT Single-cell landscapes of ECs across 24 organs in human. Heatmap showing the scaled expression levels of top 10 tissues-specific marker genes (left). Expression patterns of 49 marker genes conserved in two or more tissues are shown on the right (z-score, Poisson mixed model; corresponding P value calculated from two-sided Wilcoxon rank-sum test, FDR < 0.01). PFC, prefrontal cortex; ACC, anterior cingulate cortex; EC, entorhinal cortex; OC, occipital cortex; OTC, occipitotemporal cortex; HIP, hippocampus; RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle; AX, apex; SP, septum; MG, mammary gland; SAT, subcutaneus adipose tissue; VAT, visceral adipose tissue; PIT, pituitary; SC, spinal cord.

ALT Response to ischemia–reperfusion injury. Differences in cardiac infarct size (n = 11 for control and n = 10 for adenine, **P < 0.01, Student’s t test). (Data are expressed as mean ± SD)

ALT Pooled and site-specific analysis of infarct size from the 5 sites providing triphenyl-tetrazolium-chloride images. A) Pooled analysis of IS quantified by TTC revealed a significant reduction in IS with IPC (closed squares) when compared to I/R (open squares). B) Sitespecific analysis of IS revealed significant reduction in IS with IPC in 4 sites and no reduction in IS with IPC at one site. Data are presented as minimum and maximum (whiskers), interquartile range, mean (square), median (line), and outlier (x) in a box plot and as intra-individual single data points. AAR area-at-risk, IPC ischemic preconditioning, I/R ischemia/reperfusion, IS infarct size, TTC triphenyl-tetrazolium-chloride.

ALT Early molecular and functional changes Post CKD in the heart.

ALT Macrophages enhance the effects of flecainide on cardiomyocytes. For electrophysiological analysis, patch-clamp of CMs in coculture conditions with macrophages were compared with a single suspension of CMs. (a) Co-culture experiments show a more positive RMP and a decrease in APA with an increase in Vmax and APD50. Application of flecainide does not significantly change the absolute values in CM alone. However, we can see the expected change as a trend towards a lower Vmax after the application of flecainide. In contrast, under co-culture conditions with macrophages significant changes can be observed upon flecainide treatment. Numbers of individual experiments are indicated in the figure.

ALT The field of cardio-oncology presents both chances and challenges. Currently, many of the existing recommendations are based on expert consensus, which highlights the need for further research to better understand the interactions between cancer, cancer treatments and cardiovascular health. The simultaneous management of cancer and cardiovascular disease requires seamless multidisciplinary team coordination. It is therefore essential to implement comprehensive cardio-oncology programmes based on personalised risk scores to optimise resource investment. Ensuring equitable access to cardiooncology care remains a challenge. Integrating cardiovascular care into oncology is an effective strategy for improving overall patient outcomes.

ALT Example of segmentation areas, showing two slices (the third slice in basal orientation and the fourth slice in apical orientation) from a representative experiment. AAR area at risk, TTC triphenyl tetrazolium chloride.

ALT Possible mechanisms of cancer-related cardiac wasting.

ALT Integrated atlas of cardiac fibroblasts from different disease models. UMAP embeddings, showing the integrated fibroblast atlas colored by cell clusters, i.e. the integrated fibroblast states (IFS). Labels indicate possible fibroblast differentiations based on functional characterization.

ALT Mechanisms and proposed therapies for anthracycline cardiotoxicity. This figure summarizes the complex interactions between the mechanisms of cardiotoxicity and the potential therapeutic interventions that could ameliorate these effects. Left Panel: Various mechanisms contributing to anthracycline cardiotoxicity are depicted. Right Panel: Proposed cardioprotective therapies than can target the mechanisms of anthracycline cardiotoxicity (AC).

ALT Immunotherapy drugs mechanisms; A) CTLA-4 mAbs; B) PD-1/PD-L1 mAbs

ALT Exercise protects heart in breast cancer via STAT3. Exercise protects against breast cancer-induced cardiac injury via activating cardiac STAT3-miRNA crosstalk, proved by Adeno-associated virus erotype 9 (AAV) control (AAVc) or with AAV driving STAT3 tyrosine 705 mutation (AAVmu) injection.

ALT β3-adrenergic receptor overexpression in cardiomyocytes reduces infarct size and improves cardiac function after ischemia-reperfusion. Histological evaluation of IS in cβ3Tg mice with mirabegron injection (n = 9) and without mirabegron (n = 8) versus littermate Wt controls (n = 9 and n = 8).

ALT Histological criteria of Ruffini-like corpuscles (RLCs) in the human pericardium. Histological criteria of these receptors are the presence of meandered vessels and scattered nerve fibers, the occurrence of pale epitheloid cells, a minor density of collagenous fibers compared to the surrounding area, and demarcation from the environment by straightened elastic fibers. Since not all criteria of an RLC are always in one histological plane, we show a variety of receptors to demonstrate all previously mentioned criteria. All fusiform structures within the pericardium that fulfill at least three of the histological criteria were counted as RLC.

ALT Four weeks of AngII infusion deteriorate the left-ventricular function of Mfsd2b+/+ but not Mfsd2b−/− mice. Mfsd2b−/− leads to cardiac S1P and Sphingosine accumulation. Cardiac output before and after 4-weeks of AngII treatment in the same mice.

ALT MRI-analysis of global LV function in the Phase 1 pilot study. Global LV function analysis using MRI. After rhPlGF-2 infusion, the mean EF of all treatment groups tended to improve from 4 to 8 weeks compared to CON (P = 0.056) .

ALT Inhibition of SGLT2 and SGLT1 in 11 and 22 mmol/L glucose at reperfusion. Mizagliflozin, abrogates the excess injury associated with elevated glucose. Representative mid-ventricular myocardial slices shown. *p < 0.05 versus respective control

ALT Overview of cellular effects of ICI administration in preclinical models on cardiovascular integrity and functioning. ICI immune checkpoint inhibitor.

ALT Immune checkpoint inhibition in cancer therapy and its cardiovascular adverse effects. (Left) Inhibition of immune checkpoints via monoclonal antibodies is an effective pharmacological strategy for anti-cancer treatment. (Right) Immune checkpoint inhibition is associated with immune-related adverse events, including cardiovascular side effects. These include myocarditis, cardiac dysfunction or heart failure, progression of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD), vasculitis, pericardial disease, and venous thromboembolism (VTE). LAG-3: lymphocyte-activation gene-3, PD-1: programmed cell death protein-1, PD-L1: programmed death ligand-1, CTLA-4: cytotoxic T-lymphocyte-associated protein 4.

ALT Propionate and short-chain acylcarnitines in control and germfree (GF) mice. Simplified circulating system, with syringe markers indicating locations for blood sample withdrawal and propionate levels in plasma obtained from the hepatic vein (HV), portal vein (PV), and renal vein (RV) in both control and GF mice.

ALT Bone marrow was harvested from the femur of female donor transgenic rats expressing green fluorescent protein (GFP). Recipient irradiated wild-type male rats received GFP+ bone marrow cells, injected into the femur. After 5–6 weeks, an occluder was implanted on LAD and the rats were subjected to repetitive ischemia (RI) for 17 days to stimulate blood vessel growth in the heart. Measurements of heart function and myocardial blood flow were made at day 0 and at the end of the RI protocol to evaluate the extent of coronary collateral growth. To do single-cell RNA sequencing, after killing, the heart was enzymatically treated to disassociate cells. GFP+ cells from the bone and heart of Control and surgeried rats were used for single-cell study.

ALT Molecular mechanisms of anthracycline-induced cardiomyocyte death. Anthracyclines, in particular doxorubicin, treatment initiates multiple pathways including upregulation of death receptors, calcium overload, disruption in iron homeostasis with lipid peroxidation, generation of ROS with final DNA damage and cell death. AMPK 5ʹ adenosine monophosphate-activated protein kinase, DNA deoxyribonucleic acid, Fe2+ iron, GLC glucose, MyD88 Myeloid differentiation primary response 88, IL-1β R Interleukin-1 beta receptor, NF-kB Nuclear factor kappa-light-chain-enhancer of activated B cells, ROS reactive oxygen species, TLR toll-like receptor.

ALT Polar map imaging of the cMRI infarct transmurality (upper panel) and [18F]FDG PET tracer uptake (bottom panel). Note the high [18F]FDG PET uptake in the infarcted area at 3 days and lower tracer uptake with higher transmurality and larger infarction at 30 days after reperfused myocardial infarction in the Mismatch group.

ALT Cardiac mechano-energetic coupling. In the healthy heart, oxidative phosphorylation produces 95% of the adenosine triphosphate (ATP) required to fuel excitation–contraction coupling.

ALT Schematic representation of noble gas and endogenous gasotransmitter interaction with cellular organelles. Gases can interact with various cellular organelles, including mitochondria, endoplasmic reticulum, and nucleus, influencing cellular signaling and function. Mitochondria play a major role. Green cloud: NO; yellow cloud: H2S; blue cloud: SO2; red cloud: CO; orange cloud: He; gray cloud: Xe; light-blue cloud: Ar. Created with BioRender.com. I, II, III, IV, and V (ATP synthase) indicate respiratory chain complexes; Ar, argon; ADP, adenosine diphosphate; ATP, adenosine triphosphate; β-AR, β adrenergic receptor; BKCa, large conductance Ca2+-activated K+ channels; Ca2+, calcium; CBS, cystine beta-synthesis enzyme; CO, carbon monoxide; CSE, cystathionine gamma-lyase; Cyt c, cytochrome c; ETC, electron transport chain; H2S, hydrogen sulfide; He, helium; HO-1, heme oxygenase-1; K+, potassium; mitoKATP, mitochondrial ATP-sensitive potassium channel; mPTP, mitochondrial permeability pore

ALT Schematic of malonate inhibition of IRI in MI. Ischemia-accumulated succinate is rapidly oxidized on reperfusion by SDH upon reperfusion. This drives the ROS burst at reperfusion via RET at complex I, which subsequently primes cardiomyocytes for cell death and leads to post-MI HF. Malonate inhibits SDH, slowing down succinate oxidation and ROS production on reperfusion, reducing cell death. Malonate entry into cardiomyocytes can be enhanced by ischemia or low pH, driving the entry of monocarboxylate malonate via MCT1. Whether malonate can prevent post-MI HF by preventing RET-ROS on reperfusion is currently unknown. (MCT1 monocarboxylate transporter 1, DIC dicarboxylate carrier, SDH succinate dehydrogenase, CxI complex I, RET reverse electron transport, ROS reactive oxygen species, TCA tricarboxylic acid cycle, EF ejection fraction)

ALT Mechanisms and contributors to myocardial injury in cardiac surgery. Cardiac surgery involving cardioplegic arrest and reperfusion leads to a variety of insults to the myocardium including generation of reactive oxygen species, microvascular dysfunction, abnormal calcium signaling, altered metabolism, and increased inflammation.

ALT NFAT5-deficiency significantly increases collagen deposition and intercalated disc structural damage in the heart and decreases CVB3-induced stress granule formation in target cells. Picrosirius red staining of vertical and cross sections of mouse hearts showing collagen (red) and cardiac fibres (yellow). Scale bars: 250 μm. B) Quantification of collagen by ImageJ scanning. Stained areas were selected from five representative views of each group. Data were analyzed by Student’s t test with Welch’s correction. Data are means ± SEM, n = 5.

ALT Neutrophil-specific Gnai2-deficiency protects from mIRI. a) Mouse model to achieve neutrophil-specific Gnai2-deficiency (Gnai2nko). b) Infarct size determined after 1 h of myocardial ischemia followed by 2 h reperfusion in Gnai2nko (blue; Gnai2nko; genotype: Gnai2fl/fl; LysM-Cre+/tg) mice compared to ctrl (black; ctrl; genotype: Gnai2fl/fl; LysM-Cre+/+). Percentage of necrotic tissue within the AAR is significantly reduced in Gnai2nko mice (n = 6–7 mice).

ALT NO contributes to exercise-induced coronary vasorelaxation in healthy swine, which is lost in swine with diabetes, hypercholesterolemia and chronic kidney disease (DM + HFD + CKD). In diseased swine increased NOX2 and ceramide production together with (mitochondrial) ROS augment mitochondrial derived H2O2. Despite increased catalase activity, H2O2 mitigates coronary vasoconstriction induced by loss of NO. ROS scavengers MPG + TEMPOL did not change the vascular tone in Normal animals but increased vascular tone in DM + HFD + CKD animals.

ALT Effects of UUO on the cardiac functional parameters at different time durations in mice. (f) left-ventricular mass [mg], (g) cardiac output [ml/min]

ALT Summary of the metabolic changes detected by our genomewide transcriptomic and proteomic analyses. Major changes were observed in genes/proteins involved in oxidative phosphorylation (oxphos), fatty acid oxidation, pyruvate uptake, ketone body metabolism and Branched-Chain Amino Acid (BCAA) metabolism at the stage of cardiac decompensation. No fundamental differences were observed between the RV and the LV. However, the expressional but also functional changes appeared to be more pronounced in diseased LV tissue and cardiomyocytes. Depicted are also some of the differentially expressed genes / proteins (Cox4i1, Cox8a, NDUFB5, NDUFV2, MPC-1, MPC-2, BCAT2, BCKDHB, ACADS, ACADSB, ACADM, ACADVL) that were experimentally confirmed by our analyses.

ALT Epigenetic modifications and cardiomyocyte death. Anticancer drugs can provoke alterations in epigenetic modifications, triggering cardiomyocytes death and consequently giving rise to cardiotoxicity. Including histone modification, DNA methylation, RNA methylation, and non-coding RNA. Apoptosis is the main mode of cardiomyocytes death. It has also been found that epigenetic alterations can lead to autophagy and necroptosis of cardiomyocytes.

ALT Infarct size in hearts from Cx43fl/fl mice (wild type) and from 4OHT-treated Cx43.Cre−ER(T)/fl (Cx43-deficient) animals submitted to 35 min of global ischemia followed by reperfusion. Data are shown as box plot depicting median (horizontal line), mean (+), and individual values (color symbols).

ALT An overview of suggested intra- and intercellular mechanosensitive pathways involved in vascular homeostasis (black arrows) and pathologic condition in ATAA (red arrows). In impaired vascular homeostasis, intracellular pathways leading to nuclear translocation of Hippo pathway effector YAP inducing proliferation. Downregulation of Notch1 and DLL1/4 proteins can have significant effects on cellular function and may impact various physiologic processes. When Notch1 and DLL1/4 proteins are downregulated, it can lead to reduced activation of Notch Intracellular Domain (NICD). In this scenario, the transcriptional repressor Hes1 fails to activate, which is pivotal for VSMC proliferation. Therefore, dysregulation of the Notch signaling pathway could potentially contribute to pathologic processes involved in the development and progression of ATAA.

ALT Schematic diagram of physiological and pathological processes during cardiomyocyte cell cycle progression.

ALT Scatterplot of the retrospectively calculated statistical power for a significance level of α = 0.05 of infarct size data sets which were published between 2013 and 2023 in preclinical papers in Basic Research in Cardiology, Cardiovascular Research and Circulation Research. Only infarct size measured by TTC-staining, MRI, or SPECT techniques and the most reasonable primary infarct size data sets were considered. Closed symbols indicate data with reported statistical significance, open symbols without statistical significance. Square symbols indicate data from studies with a prospective power calculation.

ALT M peak to peak time. Non-parametric t-test was performed to calculate significances (n = 34–39 hCOs/group). N Representative contractility plots of AAV6-circZFPM2 and AAV6-Ctrl. treated HCM-hCOs.

ALT Graphical representation of exercise training-mediated attenuation of lactylation and inhibition of myocardial ischemia–reperfusion injury by impeding YTHDF2. Exercise decreases myocardium lactylation while I/R remodeling significantly increases it. In cardiomyocytes, lactylation promotes YTHDF2 expression. YTHDF2 contributes to cardiomyocytes’ cell size change and OGD/R-stimulated apoptosis in an RNA m6A-independent manner via regulating G3BP1. YTHDF2 is required for exercise-induced physiological cardiac hypertrophy and attenuates I/R remodeling. Modulating lactylation/YTHDF2/G3BP1 axis might represent a promising therapeutic strategy for cardiovascular diseases.

ALT Markers associated with CD40(L)–TRAF signaling observed in CHD patients with no comorbidity or hypertension or hypertension + diabetes.

ALT NR protected against cardiac IR injury in low glycolysis condition. Hearts were perfused with glucose and free fatty acid (Glu + FFA). After 25 min baseline, hearts were subjected to 35 min ischemia followed by 90 min reperfusion, along with administration of vehicle or NR (50 mg/L); quantified infarct size related to AAR below.