Cardiac Recovery During Long-Term Left Ventricular Assist Device Support

Wever-Pinzon, Omar; Drakos, Stavros G.; McKellar, Stephen H.; Horne, Benjamin D.; Caine, W.T.; Kfoury, Abdallah G.; Li, Dean Y.; Fang, James C.; Stehlik, Josef; Selzman, Craig H.

doi:10.1016/j.jacc.2016.07.743

Cited by 165 publications

(174 citation statements)

References 43 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…It is noteworthy that IGF1 and IGFBP4 expression has been reported to be upregulated during cardiac benign reverse remodelling processes [57], consistently with the overall antiremodelling CPC profile on CG-N supported by all the above-mentioned secreted factors. A clinically relevant correlation has been recently reported in humans between medical parameters associated, among others, with antifibrotic properties of resident CPCs and the reversal of maladaptive cardiac remodelling processes [17, 58, 59]. This further strengthens the model of bidirectional positive reinforcement between antiremodelling features of resident CPCs and beneficial ECM properties in pathological cardiac conditions.…”

Section: Discussionsupporting

confidence: 64%

Normal versus Pathological Cardiac Fibroblast-Derived Extracellular Matrix Differentially Modulates Cardiosphere-Derived Cell Paracrine Properties and Commitment

Pagano

Angelini

Castaldo

et al. 2017

Stem Cells International

View full text Add to dashboard Cite

Human resident cardiac progenitor cells (CPCs) isolated as cardiosphere-derived cells (CDCs) are under clinical evaluation as a therapeutic product for cardiac regenerative medicine. Unfortunately, limited engraftment and differentiation potential of transplanted cells significantly hamper therapeutic success. Moreover, maladaptive remodelling of the extracellular matrix (ECM) during heart failure progression provides impaired biological and mechanical signals to cardiac cells, including CPCs. In this study, we aimed at investigating the differential effect on the phenotype of human CDCs of cardiac fibroblast-derived ECM substrates from healthy or diseased hearts, named, respectively, normal or pathological cardiogel (CG-N/P). After 7 days of culture, results show increased levels of cardiogenic gene expression (NKX2.5, CX43) on both decellularized cardiogels compared to control, while the proportion and staining patterns of GATA4, OCT4, NKX2.5, ACTA1, VIM, and CD90-positive CPCs were not affected, as assessed by immunofluorescence microscopy and flow cytometry analyses. Nonetheless, CDCs cultured on CG-N secreted significantly higher levels of osteopontin, FGF6, FGF7, NT-3, IGFBP4, and TIMP-2 compared to those cultured on CG-P, suggesting overall a reduced trophic and antiremodelling paracrine profile of CDCs when in contact with ECM from pathological cardiac fibroblasts. These results provide novel insights into the bidirectional interplay between cardiac ECM and CPCs, potentially affecting CPC biology and regenerative potential.

show abstract

Section: Discussionsupporting

confidence: 64%

Normal versus Pathological Cardiac Fibroblast-Derived Extracellular Matrix Differentially Modulates Cardiosphere-Derived Cell Paracrine Properties and Commitment

Pagano

Angelini

Castaldo

et al. 2017

Stem Cells International

View full text Add to dashboard Cite

show abstract

“…We explored the relationship of RyR-sarcolemma distance with clinical measures which have been related to cardiac recovery in previous work, 25, 30 (Online Table 2). These measures included LV mass and volume as well as measures of diastolic function.…”

Section: Resultsmentioning

confidence: 99%

Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading

et al. 2017

Self Cite

View full text Add to dashboard Cite

Background Cardiac recovery in response to mechanical unloading by left ventricular assist devices (LVADs) has been demonstrated in subgroups of chronic heart failure (HF) patients. Hallmarks of HF are depletion and disorganization of the transverse tubular system (t-system) in cardiomyocytes. Here, we investigated remodeling of the t-system in human end-stage HF and its role in cardiac recovery. Methods Left ventricular biopsies were obtained from 5 donors (CTRL) and 26 chronic HF patients undergoing implantation of LVADs. Three-dimensional confocal microscopy and computational image analysis were applied to assess t-system structure, density, and distance of ryanodine receptor (RyR) clusters to the sarcolemma, including the t-system. Recovery of cardiac function in response to mechanical unloading was assessed by echocardiography during turn-down of the LVAD. Results The majority of HF myocytes showed remarkable t-system remodeling, particularly sheet-like invaginations of the sarcolemma. Circularity of t-system components was decreased in HF vs CTRL (0.37±0.01 vs 0.46±0.02, p<0.01), and the volume/length ratio was increased in HF (0.36±0.01μm2 vs 0.25±0.02μm2, p<0.0001). T-system density was reduced in HF, leading to increased RyR-sarcolemma distances (0.96±0.05μm vs 0.64±0.1μm, p<0.01). Low RyR-sarcolemma distances at time of LVAD implantation predicted high post-LVAD left-ventricular ejection fractions (EF, p<0.01) and EF increase during unloading (p<0.01). EF in patients with pre-LVAD RyR-sarcolemma distances larger than 1μm did not improve following mechanical unloading. Additionally, calcium transients were recorded in field-stimulated isolated human cardiomyocytes and analyzed with respect to local t-system density. Calcium release in HF myocytes was restricted to regions proximal to the sarcolemma. Local calcium upstroke was delayed (23.9±4.9ms vs 10.3±1.7ms, p<0.05) and more asynchronous (18.1ms±1.5ms vs 8.9±2.2ms, p<0.01) in HF cells with low t-system density versus cells with high t-system density. Conclusions The t-system in end-stage human HF presents a characteristic novel phenotype consisting of sheet-like invaginations of the sarcolemma. Our results suggest that the remodeled t-system impairs excitation-contraction coupling and functional recovery during chronic LVAD unloading. An intact t-system at time of LVAD implantation may constitute a precondition and predictor for functional cardiac recovery following mechanical unloading.

show abstract

“…These new avenues of investigations could lead to new treatments that target phylogenetically conserved pathways involved in cardiac reparative mechanisms rather than perpetuating current approaches of targeting pathways that attenuate adverse remodeling (3). They also have the potential to change the paradigm in the treatment of chronic HF from one of attenuation of adverse cardiac remodeling to induction of self-repair mechanisms in specific patient populations, and to revise the existing dogma that severe HF requiring MCS support always indicates end-stage, nonreversible, myocardial disease (34–36). With these possibilities in mind, the Working Group made the following recommendations (and specific examples for each) to the NHLBI regarding areas of need and opportunity in the science and engineering of cardiac recovery associated with MCS (37):

Explore mechanistic approaches at the genetic, molecular, cellular, microstructural, or physiological level to improve the understanding of myocardial recovery and develop novel interventions.

…”

mentioning

confidence: 99%

Advancing the Science of Myocardial Recovery with Mechanical Circulatory Support: A Working Group of the National, Heart, Lung, and Blood Institute

Drakos¹,

Pagani

Lundberg

et al. 2017

ASAIO Journal

Self Cite

View full text Add to dashboard Cite

The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts from June 2 to 3, 2016, in Bethesda, Maryland, to develop NHLBI recommendations aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MCS devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling. Research in this field could be innovative in many ways, and the Working Group specifically discussed opportunities associated with genome-phenome systems biology approaches; genetic epidemiology; bioinformatics and precision medicine at the population level; advanced imaging modalities, including molecular and metabolic imaging; and the development of minimally invasive surgical and percutaneous bioengineering approaches. These new avenues of investigations could lead to new treatments that target phylogenetically conserved pathways involved in cardiac reparative mechanisms. A central point that emerged from the NHLBI Working Group meeting was that the lessons learned from the MCS investigational setting can be extrapolated to the broader HF population. With the precedents set by the significant effect of studies of other well-controlled and tractable subsets on larger populations, such as the genetic work in both cancer and cardiovascular disease, the work to improve our understanding of cardiac recovery and resilience in MCS patients could be transformational for the greater HF population.

show abstract

Cardiac Recovery During Long-Term Left Ventricular Assist Device Support

Cited by 165 publications

References 43 publications

Normal versus Pathological Cardiac Fibroblast-Derived Extracellular Matrix Differentially Modulates Cardiosphere-Derived Cell Paracrine Properties and Commitment

Normal versus Pathological Cardiac Fibroblast-Derived Extracellular Matrix Differentially Modulates Cardiosphere-Derived Cell Paracrine Properties and Commitment

Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading

Advancing the Science of Myocardial Recovery with Mechanical Circulatory Support: A Working Group of the National, Heart, Lung, and Blood Institute

Contact Info

Product

Resources

About