| 26. |
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| 27. |
- Manti, Maria, et al.
(author)
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Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspring.
- 2020
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 116:3, s. 619-632
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Journal article (peer-reviewed)abstract
- Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is suggested to increase the risk for cardiovascular disease. How PCOS may lead to adverse cardiac outcomes is unclear and here we hypothesized that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity in mice induce adverse metabolic and cardiac programming in female offspring that resemble the reproductive features of the syndrome.The maternal obese PCOS phenotype was induced in mice by chronic high-fat-high-sucrose consumption together with prenatal DHT exposure. The prenatally androgenized (PNA) female offspring displayed cardiac hypertrophy during adulthood, an outcome that was not accompanied by aberrant metabolic profile. The expression of key genes involved in cardiac hypertrophy was up-regulated in the PNA offspring, with limited or no impact of maternal obesity. Furthermore, the activity of NADPH oxidase, a major source of reactive oxygen species in the cardiovascular system, was down-regulated in the PNA offspring heart. We next explored for early transcriptional changes in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an up-regulation of transcription factors involved in cardiac hypertrophic remodelling and of the calcium-handling gene, Slc8a2. Finally, to determine the specific role of androgens in cardiovascular function, female mice were continuously exposed to DHT from pre-puberty to adulthood, with or without the antiandrogen flutamide. Continuous exposure to DHT led to adverse left ventricular remodelling, and increased vasocontractile responses, while treatment with flutamide partly alleviated these effects.Taken together, our results indicate that intrauterine androgen exposure programmes long-lasting heart remodelling in female mouse offspring that is linked to left ventricular hypertrophy and highlight the potential risk of developing cardiac dysfunction in daughters of mothers with PCOS.
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Mulholland, Megan, et al.
(author)
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Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation
- 2024
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 120:6, s. 581-595
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Journal article (peer-reviewed)abstract
- Aims: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis.Methods and results: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade.Conclusion: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.
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| 32. |
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| 33. |
- Olin, JW, et al.
(author)
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A plasma proteogenomic signature for fibromuscular dysplasia
- 2020
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 116:1, s. 63-77
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Journal article (peer-reviewed)abstract
- AimsFibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.Methods and resultsFemales with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.ConclusionFMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.
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| 34. |
- Paloschi, Valentina, et al.
(author)
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Organ-on-a-chip technology : a novel approach to investigate cardiovascular diseases
- 2021
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 117:14, s. 2742-2754
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Journal article (peer-reviewed)abstract
- The development of organs-on-chip (OoC) has revolutionized in vitro cell-culture experiments by allowing a better mimicry of human physiology and pathophysiology that has consequently led researchers to gain more meaningful insights into disease mechanisms. Several models of hearts-on-chips and vessels-on-chips have been demonstrated to recapitulate fundamental aspects of the human cardiovascular system in the recent past. These 2D and 3D systems include synchronized beating cardiomyocytes in hearts-on-chips and vessels-on-chips with layer-based structures and the inclusion of physiological and pathological shear stress conditions. The opportunities to discover novel targets and to perform drug testing with chip-based platforms have substantially enhanced, thanks to the utilization of patient-derived cells and precise control of their microenvironment. These organ models will provide an important asset for future approaches to personalized cardiovascular medicine and improved patient care. However, certain technical and biological challenges remain, making the global utilization of OoCs to tackle unanswered questions in cardiovascular science still rather challenging. This review article aims to introduce and summarize published work on hearts- and vessels-on chips but also to provide an outlook and perspective on how these advanced in vitro systems can be used to tailor disease models with patient-specific characteristics.
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| 35. |
- Pawelzik, SC, et al.
(author)
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von Willebrand factor's vascular crossroad
- 2022
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 118:2, s. 353-354
-
Journal article (other academic/artistic)
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| 36. |
- Pol, Tymon, et al.
(author)
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Using multimarker screening to identify biomarkers associated with cardiovascular death in patients with atrial fibrillation.
- 2021
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In: Cardiovascular Research. - : Oxford University Press. - 0008-6363 .- 1755-3245. ; 118:9, s. 2112-2123
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Journal article (peer-reviewed)abstract
- AIMS: Atrial fibrillation (AF) is associated with higher mortality. Biomarkers may improve the understanding of key pathophysiologic processes in AF that lead to death. Using a new multiplex analytic technique, we explored the association between 268 biomarkers and cardiovascular (CV) death in anticoagulated patients with AF.METHODS AND RESULTS: A case-cohort design with 1.8 -1.9 years follow-up. The identification cohort included 517 cases and 4057 randomly selected patients from ARISTOTLE. The validation cohort included 277 cases and 1042 randomly selected controls from RE-LY. Plasma collected at randomization was analyzed with conventional immunoassays and the OLINK proximity extension assay-panels; CVDII, CVDIII, and Inflammation. Association between biomarkers and CV-death was evaluated using Random Survival Forest, Boruta and adjusted Cox-regression analyses.The biomarkers most strongly and consistently associated with CV-death were (hazard ratio for inter-quartile comparison [95% CI]): N-terminal pro-B-type natriuretic peptide (NT-proBNP; 1.63 [1.37-1.93]), cardiac troponin T (cTnT-hs; 1.60[1.35-1.88]), interleukin-6 (IL-6; 1.29[1.13-1.47]), growth differentiation factor-15 (GDF-15; 1.30[1.10-1.53]) fibroblast growth factor 23 (FGF-23; 1.21[1.10-1.33]), urokinase receptor (uPAR; 1.38[1.16-1.64]), trefoil factor 3 (TFF3; 1.27[1.10-1.46]), tumor necrosis factor receptor 1 (TNFR1; 1.21[1.01-1.45]), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2; 1.18[1.04-1.34]) and cathepsin L1 (CTSL1; 1.22[1.07-1.39]).CONCLUSION: In this comprehensive screening of 268 biomarkers in anticoagulated patients with AF the underlying mechanisms most strongly associated with CV-death were cardiorenal dysfunction (NT-proBNP, cTnT-hs, CTSL1, TFF3), oxidative stress (GDF-15), inflammation (IL-6, GDF-15), calcium balance, vascular and renal dysfunction (FGF-23), fibrinolysis (suPAR) and apoptosis (TNFR1, TRAILR2). These findings provide novel insights into pathophysiologic aspects associated with CV-death in AF.TRANSLATIONAL PERSPECTIVE: In patients with AF there is an unmet need for better understanding of the pathophysiological processes involved with CV-death. Using a targeted proteomic approach, 10 biomarkers were identified as having a strong association with CV-death. The identified biomarkers reflect several biological pathways involved with CV-death in AF. The present study provides valuable insights into important processes involved with CV-death in patients with AF and may facilitate the identification of important risk factors for death, thus allowing for earlier intervention and possibly even for targeted therapy to reduce AF-related mortality.CLINICALTRIALS.GOV IDENTIFIER: NCT00412984 and NCT00262600.
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| 37. |
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| 38. |
- Samuelsson, Anne-Maj, et al.
(author)
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VEGF-B hypertrophy predisposes to transition from diastolic to systolic heart failure in hypertensive rats.
- 2023
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 119:7, s. 1553-1567
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Journal article (peer-reviewed)abstract
- Cardiac energy metabolism is centrally involved in heart failure (HF), although the direction of the metabolic alterations is complex and likely dependent on the particular stage of HF progression. Vascular endothelial growth factor B (VEGF-B) has been shown to modulate metabolic processes and to induce physiological cardiac hypertrophy; thus, it could be cardioprotective in the failing myocardium. This study investigates the role of VEGF-B in cardiac proteomic and metabolic adaptation in HF during aldosterone and high-salt hypertensive challenges.Male rats overexpressing the cardiac-specific VEGF-B transgene (VEGF-B TG) were treated for 3 or 6 weeks with deoxycorticosterone-acetate combined with a high-salt (HS) diet (DOCA + HS) to induce hypertension and cardiac damage. Extensive longitudinal echocardiographic studies of HF progression were conducted, starting at baseline. Sham-treated rats served as controls. To evaluate the metabolic alterations associated with HF, cardiac proteomics by mass spectrometry was performed. Hypertrophic non-treated VEGF-B TG hearts demonstrated high oxygen and adenosine triphosphate (ATP) demand with early onset of diastolic dysfunction. Administration of DOCA + HS to VEGF-B TG rats for 6 weeks amplified the progression from cardiac hypertrophy to HF, with a drastic drop in heart ATP concentration. Dobutamine stress echocardiographic analyses uncovered a significantly impaired systolic reserve. Mechanistically, the hallmark of the failing TG heart was an abnormal energy metabolism with decreased mitochondrial ATP, preceding the attenuated cardiac performance and leading to systolic HF.This study shows that the VEGF-B TG accelerates metabolic maladaptation which precedes structural cardiomyopathy in experimental hypertension and ultimately leads to systolic HF.
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| 39. |
- Savarese, G, et al.
(author)
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Cardiovascular effects of non-insulin glucose-lowering agents: a comprehensive review of trial evidence and potential cardioprotective mechanisms
- 2022
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 118:10, s. 2231-2252
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Journal article (peer-reviewed)abstract
- Type 2 diabetes mellitus (T2DM) is highly prevalent and associated with a two-fold increased mortality, mostly explained by cardiovascular diseases. Trial evidence on older glucose-lowering agents such as metformin and sulfonylureas is limited in terms of cardiovascular efficacy. Since 2008, after rosiglitazone was observed to increase the risk of myocardial infarction and heart failure (HF), cardiovascular outcome trials (CVOTs) have been required by regulators for licensing new glucose-lowering agents. In the following CVOTs, dipeptidyl peptidase 4 inhibitors (DPP4i) have been shown to be safe but not to improve mortality/morbidity, except for saxagliptin which increased the risk of HF. Several glucagon-like peptide-1 receptor agonists (GLP1-Ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to reduce the risk of cardiovascular mortality and morbidity. SGLT2i have shown a class effect for the reduction in risk of HF events in patients with T2DM, leading to trials testing their efficacy/safety in HF regardless of T2DM. In the DAPA-HF and the EMPEROR-Reduced trials dapagliflozin and empagliflozin, respectively, improved cardiovascular mortality/morbidity in patients with HF with reduced ejection fraction (HFrEF), with and without T2DM. Therefore, these drugs are now key part of HFrEF pharmacotherapy. In the SOLOIST-WHF, sotagliflozin reduced cardiovascular mortality/morbidity in patients with T2DM and a recent acute episode of HF regardless of ejection fraction (EF). In the EMPEROR-Preserved, empagliflozin reduced CV mortality/morbidity in patients with heart failure with mildly reduced (HFmrEF) and preserved (HFpEF) EF regardless of comorbid T2DM. The DELIVER is currently testing dapagliflozin in patients with HFmrEF and HFrEF. A strong renal protective role of SGLT2i has also emerged in trials enrolling patients with and without T2DM.
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| 40. |
- Savarese, G, et al.
(author)
-
Global burden of heart failure: a comprehensive and updated review of epidemiology
- 2022
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 118:17, s. 3272-3287
-
Journal article (peer-reviewed)abstract
- Heart Failure (HF) is a multi-faceted and life-threatening syndrome characterized by significant morbidity and mortality, poor functional capacity and quality of life, and high costs. HF affects more than 64 million people worldwide. Therefore, attempts to decrease its social and economic burden have become a major global public health priority. While the incidence of HF has stabilized and seems to be declining in industrialized countries, the prevalence is increasing due to the ageing of the population, improved treatment of and survival with ischaemic heart disease, and the availability of effective evidence-based therapies prolonging life in patients with HF. There are geographical variations in HF epidemiology. There is substantial lack of data from developing countries, where HF exhibits different features compared with that observed in the Western world. In this review, we provide a contemporary overview on the global burden of HF, providing updated estimates on prevalence, incidence, outcomes, and costs worldwide.
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| 41. |
- Schutte, Aletta E., et al.
(author)
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Addressing global disparities in blood pressure control : perspectives of the International Society of Hypertension
- 2023
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 119:2, s. 381-409
-
Research review (peer-reviewed)abstract
- Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework.
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| 42. |
- Sciarretta, S, et al.
(author)
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Caloric restriction mimetics for the treatment of cardiovascular diseases
- 2021
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 117:6, s. 1434-1449
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Journal article (peer-reviewed)abstract
- Caloric restriction mimetics (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis, or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy. Previous evidence demonstrated the ability of CRMs to ameliorate cardiac function and reduce cardiac hypertrophy and maladaptive remodelling in animal models of ageing, mechanical overload, chronic myocardial ischaemia, and in genetic and metabolic cardiomyopathies. In addition, CRMs were found to reduce acute ischaemia–reperfusion injury. In many cases, these beneficial effects of CRMs appeared to be mediated by autophagy activation. In the present review, we discuss the relevant literature about the role of different CRMs in animal models of cardiac diseases, emphasizing the molecular mechanisms underlying the beneficial effects of these compounds and their potential future clinical application.
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| 43. |
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| 44. |
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| 45. |
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| 46. |
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| 47. |
- van der Velden, J, et al.
(author)
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Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart
- 2022
-
In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 118:15, s. 3016-3051
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Journal article (peer-reviewed)abstract
- Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational ‘valley of death’, which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.
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| 48. |
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| 49. |
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| 50. |
- Wanhainen, Anders, et al.
(author)
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The effect of ticagrelor on growth of small abdominal aortic aneurysms-a randomized controlled trial
- 2020
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 116:2, s. 450-456
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Journal article (peer-reviewed)abstract
- Aims: To evaluate if ticagrelor, an effective platelet inhibitor without known non-responders, could inhibit growth of small abdominal aortic aneurysms (AAAs). Methods and results: In this multi-centre randomized controlled trial, double-blinded for ticagrelor and placebo, acetylic salicylic acid naive patients with AAA and with a maximum aortic diameter 35-49mm were included. The primary outcome was mean reduction in log-transformed AAA volume growth rate (%) measured with magnetic resonance imaging (MRI) at 12months compared with baseline. Secondary outcomes include AAA-diameter growth rate and intraluminal thrombus (ILT) volume enlargement rate. A total of 144 patients from eight Swedish centres were randomized (72 in each group). MRI AAA volume increase was 9.1% for the ticagrelor group and 7.5% for the placebo group (P=0.205) based on intention-to-treat analysis, and 8.5% vs. 7.4% in a per-protocol analysis (P=0.372). MRI diameter change was 2.5mm vs. 1.8mm (P=0.113), US diameter change 2.3mm vs. 2.2mm (P=0.778), and ILT volume change 12.9% vs. 10.4% (P=0.590). Conclusion: In this RCT, platelet inhibition with ticagrelor did not reduce growth of small AAAs. Whether the ILT has an important pathophysiological role for AAA growth cannot be determined based on this study due to the observed lack of thrombus modulating effect of ticagrelor.
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