Recovery of hibernating myocardium using stem cell patch with coronary bypass surgery

Heart failure (HF) describes a heterogenous complex spectrum of pathological conditions that results in structural and functional remodeling leading to subsequent impairment of cardiac function, including either systolic dysfunction, diastolic dysfunction, or both. Several factors chronically lead to HF, including cardiac volume and pressure overload that may result from hypertension, valvular lesions, acute, or chronic ischemic injuries. Major forms of HF include hypertrophic, dilated, and restrictive cardiomyopathy. The severity of cardiomyopathy can be impacted by other comorbidities such as diabetes or obesity and external stress factors. Age is another major contributor, and the number of patients with HF is rising worldwide in part due to an increase in the aged population. HF can occur with reduced ejection fraction (HF with reduced ejection fraction), that is, the overall cardiac function is compromised, and typically the left ventricular ejection fraction is lower than 40%. In some cases of HF, the ejection fraction is preserved (HF with preserved ejection fraction). Animal models play a critical role in facilitating the understanding of molecular mechanisms of how hearts fail. This review aims to summarize and describe the strengths, limitations, and outcomes of both small and large animal models of HF with reduced ejection fraction that are currently used in basic and translational research. The driving defect is a failure of the heart to adequately supply the tissues with blood due to impaired filling or pumping. An accurate model of HF with reduced ejection fraction would encompass the symptoms (fatigue, dyspnea, exercise intolerance, and edema) along with the pathology (collagen fibrosis, ventricular hypertrophy) and ultimately exhibit a decrease in cardiac output. Although countless experimental studies have been published, no model completely recapitulates the full human disease. Therefore, it is critical to evaluate the strength and weakness of each animal model to allow better selection of what animal models to use to address the scientific question proposed.

show abstract

“…These open-chest protocols constitute higher risks of postoperative complications, such as infections or, more dangerously, bleeding. 68,69…”

Section: Animal Models Of Hfrefmentioning

confidence: 99%

Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction

Pilz

Chang

Kiss

et al. 2022

Circulation Research

View full text Add to dashboard Cite

show abstract

“…When using an adjunctive MSC patch, however, we saw an improvement in systolic function without a significant increase in regional blood flow. This suggests that the underlying regenerative mechanism may be independent of coronary blood flow [ 16 ]. In this study, adjunctive MSC therapy during CABG restored the parameters of diastolic filling and increased the expression of PGC1α, which supports the findings of other investigators [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, adjunctive MSC therapy during CABG restored the parameters of diastolic filling and increased the expression of PGC1α, which supports the findings of other investigators [ 36 ]. We were able to show that the therapeutic effect of our MSC patch is not due to structural support from the patch itself [ 16 ] but likely to the consequence of alterations in cellular metabolism, as well as oxidative and inflammatory signaling [ 16 ]. These finding support the notion that stem cell-based therapies might be able to reverse the persisting hibernation-induced changes following CABG, thereby improving the myocardial functional recovery beyond surgical revascularization.…”

Section: Discussionmentioning

confidence: 99%

“…HIB presents a unique target for stem cell therapy as it is fully viable but has dysfunctional myocardium with the potential to be rescued. Mesenchymal stem cells (MSCs) are an ideal candidate for treatment, as previous studies have shown they have the potential to increase PGC1α, which is a key mediator of mitochondrial biogenesis [ 16 ]. PGC1α might therefore be a promising target of MSCs for overcoming the current limitations in the treatment of chronically ischemic myocardium.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium

Aggarwal

Potel

Shao

et al. 2023

IJMS

View full text Add to dashboard Cite

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress–inflammatory signaling and myofibroblast presence in the myocardial tissue.

show abstract

“…What is becoming clearer is that the multitude of hurdles to the development of functional and clinically impactful myocardial patches are gradually being overcome. Advances are being made in adequate cell isolation; expansion and growth of patches large enough for large animal testing and eventual human use; and adequate maturation of cardiomyocytes into structures that mirror those in native myocardium both structurally and functionally, including excitability and contractility, action potential conduction, calcium handling, and proper cardiomyocyte size and function [154,[157][158][159]. As with many of the findings in the field of cell therapy, much of the improvement observed in several of these studies is felt to be due to cell secretomes, and not a direct action of the cells themselves [156].…”

Section: Mixed Products and Bioengineered Constructsmentioning

confidence: 99%

Stem Cells in Cardiovascular Diseases: 30,000-Foot View

Povsic

Gersh

2021

Cells

View full text Add to dashboard Cite

Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future.

show abstract

Recovery of hibernating myocardium using stem cell patch with coronary bypass surgery

Cited by 14 publications

References 48 publications

Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction

Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium

Stem Cells in Cardiovascular Diseases: 30,000-Foot View

Contact Info

Product

Resources

About