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.
Abstract
While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged ...in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF.
Graphical Abstract
Graphical Abstract
Assembling the acute heart failure (AHF) in a translational view. Different causes of AHF can be reproduced in pre-clinical models to unveil novel pathophysiological and molecular mechanisms. Identifying novel molecular targets amongst organelles and cellular compartments can be tested again in the pre-clinical models. Effective strategies can be exploited in human scenarios. Image was partially created with BioRender.com.
Graphical Abstract
Graphical Abstract
A proposed conceptual framework for understanding atrial disease. Subclinical atrial disease develops under the effect of stressors such as aging, ...cardio-metabolic risk factors and diseases, and genetic predisposition that activate pathogenic mechanisms, such as inflammation, endothelial and microvascular dysfunction, fibrosis, hypercoagulability and atrial stretch that in turn affect the atrial myocardium. Subclinical atrial disease is characterized by structural, electrical and functional changes, also termed atrial remodelling, that progress to overt clinical disease, manifesting as atrial fibrillation, heart failure and further to thromboembolism. The potential detection of subclinical atrial disease with imaging, biomarkers and other modalities offers a window opportunity for interventions that would prevent deterioration to clinical disease and could potentially allow reversal of subclinical disease. CMR, cardiac magnetic resonance; CT, computed tomography; ECG, electrocardiogram; RF, risk factors.
Background:
Initiation of veno-arterial (VA) Extracorporeal Membrane Oxygenator (ECMO) is associated with severe complications. It is unknown whether these adverse consequences occur more often after ...initiations during out of hours service compared to working hours.
Methods:
All patients receiving VA-ECMO for cardiogenic shock between 2009 and 2020 were categorized into a working hours group (between 8 am and 5 pm on weekdays) and an out of hours service group (between 5 pm and 8 am, or between Friday 5 pm and Monday 8 am). Primary outcome was all-cause mortality at 30 days. Secondary outcomes included vascular complications (including limb ischemia and/or bleeding), bloodstream infections and length of ICU stay. Propensity scores were used to adjust for potential confounding effects.
Results:
Among 250 patients (median (IQR) age 56 (42–64) years) receiving VA-ECMO (median duration 3.5 (1.0–9.0) days), 160 (64%) runs were initiated between 5 pm and 8 am whereas the remainder (36%) started during working hours. Characteristic did not differ between the working hours- and out of hours-group. By day 30, 37 (41.1%), and 68 (42.5%) patients in either group had died, respectively (p = 0.831). VA-ECMO support duration and length of stay on the ICU did not differ significantly in both crude and adjusted analyses. More complications occurred during out of hours service (p = 0.039).
Conclusions:
Out of hours- versus working hours-initiation of VA-ECMO for cardiogenic shock was not associated with higher mortality, longer VA-ECMO support duration, or longer length of stay on the intensive care. Vascular complications were more common in the out of hours group.
Almost 7 years after their first derivation from human embryos, a pressing urgency to deliver the promises of therapies based on human embryonic stem cells (hESC) has arisen. Protocols have been ...developed to support long-term growth of undifferentiated cells and partially direct differentiation to specific cell lineages. The stage has almost been set for the next step: transplantation in animal models of human disease. Here, we review the state-of-the-art with respect to the transplantation of embryonic stem cell-derived heart cells in animals. One problem affecting progress in this area and functional analysis in vivo in general, is the availability of genetically marked hESC. There are only a few cell lines that express reporter genes ubiquitously, and none is associated with particular lineages; a major hurdle has been the resistance of hESC to established infection and chemical transfection methodologies to introduce ectopic genes. The methods that have been successful are reviewed. We also describe the processes for generating a new, genetically-modified hESC line that constitutively expresses GFP as well as some of its characteristics, including its ability to form cardiomyocytes with electrophysiological properties of ventricular-like cells.
Cardiomyocytes derived from stem cells Van Laake, Linda W.; Van Hoof, Dennis; Mummery, Christine L.
Annals of medicine (Helsinki),
01/2005, Letnik:
37, Številka:
7
Journal Article
Recenzirano
Odprti dostop
One way to restore failing heart function following myocardial infarction would be to replace lost or damaged cardiac cells by local or systemic injection. The sources of replacement cells presently ...discussed include embryonic stem cells, hematopoietic and non-hematopoietic stem cells from bone marrow or cord blood and small stem cell populations thought to reside in the heart itself or in skeletal muscle. Here we review this area of stem cell research with focus particularly on recent laboratory advances towards producing cardiomyocytes from embryonic stem cells. We conclude that embryonic stem cells and cardiac progenitors in the heart itself are the only proven sources of cardiomyocytes and that reported clinical effects of bone marrow stem currently undergoing validation are likely mediated by other mechanisms.
Accumulating evidence suggests that patients with abdominal aortic aneurysm (AAA) suffer from a systemic dilating condition affecting all arteries. Matrix metalloproteinases (MMPs) and their natural ...inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), appear to be involved in aneurysm formation, as evidenced by increased aortic tissue MMP activity and plasma MMP levels in patients with AAA. Hypothesizing that an imbalance in plasma MMP/TIMP level might be associated with a systemic dilation diathesis, we studied mechanical vessel wall properties of non-affected arteries of patients with either AAA or aorto-iliac obstructive lesions in association with plasma MMP-9 and TIMP-1 levels.
Twenty-two patients with AAA and 12 with aorto-iliac occlusive disease (AOD) were included. Diastolic diameter (d) and distension (Δd) were measured at the level of the common carotid artery (CCA) and suprarenal aorta (SA) using ultrasonography. Distensibility (DC) and compliance (CC) were calculated from d, Δd and brachial pulse pressure. Plasma MMP-9 and TIMP-1 were determined with specific immunoassays.
The average (±SD) age was 72.3±5.6 and 65.0±8.2 years for the AAA and AOD patients, respectively, (P=0.005). CCA diameter was 9.1±1.3mm in AAA patients and AOD 7.8±1.4mm in AOD patients, P=0.009. This difference persisted after correction for age. Plasma MMP-9 and TIMP-1 did not differ significantly between AAA and AOD patients. In the total 34 patients, the MMP-9/TIMP-1 ratio was correlated inversely with distensibility (r=−0.74, P=0.002) and to compliance (r=−0.58, P=0.024) of the suprarenal aorta.
The CCA diameter was larger in AAA patients compared to AOD patients. MMP-9/TIMP-1 ratio was associated with decreased distensibility and compliance of the suprarenal aorta. These data support the idea that AAA patients exhibit a systemic dilation diathesis, which might be attributable to MMP/TIMP imbalances.
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