Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

The adult human heart can only adapt to heart diseases by starting a myocardial remodeling process to compensate for the loss of functional cardiomyocytes, which ultimately develop into heart failure. In recent decades, the evolution of new strategies to regenerate the injured myocardium based on cellular reprogramming represents a revolutionary new paradigm for cardiac repair by targeting some key signaling molecules governing cardiac cell fate plasticity. While the indirect reprogramming routes require an in vitro engineered 3D tissue to be transplanted in vivo, the direct cardiac reprogramming would allow the administration of reprogramming factors directly in situ, thus holding great potential as in vivo treatment for clinical applications. In this framework, cellular reprogramming in partnership with nanotechnologies and bioengineering will offer new perspectives in the field of cardiovascular research for disease modeling, drug screening, and tissue engineering applications. In this review, we will summarize the recent progress in developing innovative therapeutic strategies based on manipulating cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.

A Canadian perception of the nursing practice, research, and theoretical implications associated with Autologous Cell Transplantation

Heart failure is a progressive disorder. An estimated 400,000 Canadians are diagnosed annually with heart failure, and a quarter experience severe heart failure that is unresponsive to medical therapy. Autologous cell transplantation (ACT) has been proposed as a new approach for cardiac repair, and holds enormous potential for the regeneration of injured myocardium cells. Currently, ACT is under investigation in Canada. The use of ACT as a treatment alternative for heart failure patients has been established over the past 5 years across Europe and the United States. This paper will present a Canadian perception of the nursing practice, research, and theoretical implications associated with this new and innovative therapy.

Postsystolic thickening is a potential new clinical sign of injured myocardium in marfan syndrome

The mechanisms leading to cardiac remodeling in Marfan syndrome (MFS) are a matter of debate since it could be either due to structural dysfunction of the myocardial extracellular matrix or to increased afterload caused by the dilated aorta. We aim to characterize the presence of abnormal myocardial function in MFS and to investigate its potential association with increased afterload. Aorta, left ventricle (LV) and the postsystolic thickening (PST) were analyzed in echocardiography in Fbn1C1039G/+ mice and in patients with MFS in comparison with wild type (WT) mice and healthy humans. PST was more frequent in MFS than in WT mice (p < 0.05). MFS mice with PST showed larger aorta than those without PST. Patients with MFS showed larger aorta, poorer LV function and a higher prevalence of PST (56%) than did the healthy controls (23%); p = 0.003. Blood pressure was similar. The higher prevalence of PST in an experimental murine model and in MFS patients, regardless of systemic arterial pressure, suggests an increased afterload on the LV myocardium. This finding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therapy.

A Canadian perception of the nursing practice, research, and theoretical implications associated with Autologous Cell Transplantation

Heart failure is a progressive disorder. An estimated 400,000 Canadians are diagnosed annually with heart failure, and a quarter experience severe heart failure that is unresponsive to medical therapy. Autologous cell transplantation (ACT) has been proposed as a new approach for cardiac repair, and holds enormous potential for the regeneration of injured myocardium cells. Currently, ACT is under investigation in Canada. The use of ACT as a treatment alternative for heart failure patients has been established over the past 5 years across Europe and the United States. This paper will present a Canadian perception of the nursing practice, research, and theoretical implications associated with this new and innovative therapy.

A Canadian perception of the nursing practice, research, and theoretical implications associated with Autologous Cell Transplantation

Heart failure is a progressive disorder. An estimated 400,000 Canadians are diagnosed annually with heart failure, and a quarter experience severe heart failure that is unresponsive to medical therapy. Autologous cell transplantation (ACT) has been proposed as a new approach for cardiac repair, and holds enormous potential for the regeneration of injured myocardium cells. Currently, ACT is under investigation in Canada. The use of ACT as a treatment alternative for heart failure patients has been established over the past 5 years across Europe and the United States. This paper will present a Canadian perception of the nursing practice, research, and theoretical implications associated with this new and innovative therapy.

Cell type–specific microRNA therapies for myocardial infarction

Current interventions fail to recover injured myocardium after infarction and prompt the need for development of cardioprotective strategies. Of increasing interest is the therapeutic use of microRNAs to control gene expression through specific targeting of mRNAs. In this Review, we discuss current microRNA-based therapeutic strategies, describing the outcomes and limitations of key microRNAs with a focus on target cell types and molecular pathways. Last, we offer a perspective on the outlook of microRNA therapies for myocardial infarction, highlighting the outstanding challenges and emerging strategies.

Novel tools for new therapies in the era of contemporary percutaneous coronary revascularisation

: Percutaneous coronary intervention (PCI) is an expanding treatment option for patients with coronary artery disease (CAD). It is considered the default strategy for unstable presentation of CAD. PCI techniques have evolved over the last 4 decades with significant improvements in stent design, increase in functional assessment of coronary lesions, and the use of intra-vascular imaging. Nonetheless, the morbidity and mortality related to CAD remain significant. Advances in technology have allowed better understanding of the nature andprogression of CAD. New tools are now available that reflect the pathophysiological changes at the level of the myocardium and coronary atherosclerotic plaque. Certain changes within the plaque would render it more prone to rupture leading to acute vascular events. These changes are potentially detected using novel tools invasively, such near infra-red spectroscopy, or non-invasively using T2 mapping cardiovascular magnetic resonance imaging (CMR)and18F-Sodium Fluoride positron emission tomography/computed tomography. Similarly, changes at the level of the injured myocardium are feasibly assessed invasively using index microcirculatory resistance or non-invasively using T1 mapping CMR. Importantly, these changes could be detected immediately with the opportunity to tailor treatment to those considered at high risk. Concurrently, novel therapeutic options have demonstrated promising results in reducingfuture cardiovascular risks in patients with CAD. This Review article will discuss the role of these novel tools and their applicability in employing mechanical and pharmacological treatment to mitigate cardiovascular risk in patients with CAD.

Paeonol Protects Against Myocardial Ischemia/Reperfusion-Induced Injury by Mediating Apoptosis and Autophagy Crosstalk

Many studies have shown that crosstalk exists between apoptosis and autophagy, despite differences in mechanisms between these processes. Paeonol, a major phenolic compound isolated from Moutan Cortex Radicis, the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), is widely used in traditional Chinese medicine as an antipyretic, analgesic and anti-inflammatory agent. In this study, we investigated the detailed molecular mechanisms of the crosstalk between apoptosis and autophagy underlying the cardioprotective effects of paeonol in rats subjected to myocardial ischemia/reperfusion (I/R) injury. Myocardial I/R injury was induced by occlusion of the left anterior descending coronary artery (LAD) for 1 h followed by 3 h of reperfusion. Paeonol was intravenously administered 15 min before LAD ligation. We found that paeonol significantly improved cardiac function after myocardial I/R injury and significantly decreased myocardial I/R-induced arrhythmia and mortality. Paeonol also significantly decreased myocardial infarction and plasma LDH activity and Troponin-I levels in carotid blood after I/R. Compared with vehicle treatment, paeonol significantly upregulated Bcl-2 protein expression and significantly downregulated the cleaved forms of caspase-8, caspase-9, caspase-3 and PARP protein expression in the I/R injured myocardium. Myocardial I/R-induced autophagy, including the increase of Beclin-1, p62, LC3-I, and LC3-II protein expression in the myocardium was significantly reversed by paeonol treatment. Paeonol also significantly increased the Bcl-2/Bax and Bcl-2/Beclin-1 ratios in the myocardium after I/R injury. The cardioprotective role of paeonol during I/R injury may be due to its mediation of crosstalk between apoptotic and autophagic signaling pathways, which inhibits apoptosis and autophagic cell death.

A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction

Background: Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear. Methods: In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays. Results: We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, Helios high Nrp-1 high phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4 + T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4 + T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone. Conclusions: We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.

Cardioprotection by remote ischemic conditioning is transferable by plasma and mediated by exosomes

Background Remote ischemic conditioning (RIC) by brief periods of limb ischemia and reperfusion protects against ischemia-reperfusion injury. However, the mechanism is unknown. Purpose We studied the role of exosomes for mediating the cardioprotective signal and whether they accumulate in injured myocardium. Methods Blood samples from 12 healthy male volunteers were obtained prior to and one hour after RIC. Plasma obtained before and after RIC (n=4) (P-Pre and P-Post) was used to evaluate the transferability of RIC. Pre- and Post-RIC plasma (n=8) was separated into an exosome rich fraction (Exo-Pre and Exo-Post) and an exosome depleted fraction (Prot-Pre and Prot-Post) by size exclusion chromatography. All studies were carried out in duplicate samples from each volunteer. Infarct size was compared in Sprague-Dawley rat hearts perfused with plasma, exosomes and exosome depleted fractions in a Langendorff model. We investigated changes in the miRNA content of the exosomes after RIC by a human miRNA panel. Additionally, fluorescently labeled exosomes isolated from C2C12 cells were used to assess accumulation in injured myocardium in an in vivo rat model. Rats were divided into an infarct group (n=6) (left anterior descending artery ligation) and a sham group (n=6) (without ligation). Labelled exosomes were injected in the femoral vein prior to reperfusion. Exosome-accumulation in infarcted or sham myocardium was evaluated. Results P-Post reduced infarct size by 15% points compared with P-Pre (55±4% vs 70±6%, p=0.03) (Fig. 1a). Exo-Post reduced infarct size by 16% points compared with Exo-Pre (53±15% vs 68±12%, p=0.03) (Fig. 1b). Prot-Post did not affect infarct size compared to Prot-Pre (64±3% and 68±10%, p&gt;0.99). We found miRNA-16, miRNA-144 and miRNA-451 to be upregulated in exosomes after RIC and the mTOR-pathway as a potential target for these miRNAs. In the in vivo model, labelled exosomes accumulated more intensively in the infarct area than in remote areas and sham hearts (Fig. 1c). Conclusion Cardioprotection by RIC is mediated by exosomes with a changed miRNA profile and exosomes accumulate in injured myocardium. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novo synergy