Promise of autologous CD34+ stem/progenitor cell therapy for treatment of cardiovascular disease

2020 ◽  
Vol 116 (8) ◽  
pp. 1424-1433 ◽  
Author(s):  
Megha Prasad ◽  
Michel T Corban ◽  
Timothy D Henry ◽  
Allan B Dietz ◽  
Lilach O Lerman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Therapy ◽  
Therapeutic Potential ◽  
Microvascular Disease ◽  
Microvascular Dysfunction ◽  
Therapeutic Angiogenesis ◽  
Phase Iii ◽  
Potential Safety ◽  
Cd34 Cells ◽  
Phase Iii Trials

Abstract CD34+ cells are haematopoietic stem cells used therapeutically in patients undergoing radiation or chemotherapy due to their regenerative potential and ability to restore the haematopoietic system. In animal models, CD34+ cells have been associated with therapeutic angiogenesis in response to ischaemia. Several trials have shown the potential safety and efficacy of CD34+ cell delivery in various cardiovascular diseases. Moreover, Phase III trials have now begun to explore the potential role of CD34+ cells in treatment of both myocardial and peripheral ischaemia. CD34+ cells have been shown to be safe and well-tolerated in the acute myocardial infarction (AMI), heart failure, and angina models. Several studies have suggested potential benefit of CD34+ cell therapy in patients with coronary microvascular disease as well. In this review, we will discuss the therapeutic potential of CD34+ cells, and describe the pertinent trials that have used autologous CD34+ cells in no-options refractory angina, AMI, and heart failure. Lastly, we will review the potential utility of autologous CD34+ cells in coronary endothelial and microvascular dysfunction.

The disconnect between phase II and phase III trials of drugs for heart failure

2013 ◽  
Vol 10 (2) ◽  
pp. 85-97 ◽  
Author(s):  
Muthiah Vaduganathan ◽  
Stephen J. Greene ◽  
Andrew P. Ambrosy ◽  
Mihai Gheorghiade ◽  
Javed Butler
Keyword(s):  
Heart Failure ◽  
Phase Ii ◽  
Phase Iii ◽  
Phase Iii Trials

scholarly journals Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction

2021 ◽  
Author(s):  
Aish Sinha ◽  
Haseeb Rahman ◽  
Andrew Webb ◽  
Ajay M Shah ◽  
Divaka Perera
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Obstructive Coronary Artery Disease ◽  
Microvascular Disease ◽  
Microvascular Dysfunction ◽  
Common Finding ◽  
Coronary Microvascular Dysfunction ◽  
Preserved Ejection Fraction ◽  
Flow Reserve ◽  
Artery Disease

Abstract Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD–HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD–HFpEF, as well as the clinical and research implications of the CMD–HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients.

Characterization Of Bone Marrow Derived CD34+ Cells With Different Mobility Potentials By Micro RNA Fingerprinting

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4844-4844
Author(s):  
Blake Warbington ◽  
Daniel Weinstein ◽  
David Mallinson ◽  
Daria Olijnyk ◽  
Sarah Paterson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Therapy ◽  
Mirna Expression ◽  
Phase Iii ◽  
Employment Equity ◽  
Cd34 Cells ◽  
Release Assay ◽  
Equity Ownership

Abstract Background AMR-001, an autologous CD34+ cell product derived from mini-marrow harvest, is currently undergoing Phase II trials to treat acute myocardial infarction (AMI). AMR-001 is administered to the patient by infusion via the infarct related artery within five to ten days following coronary artery stenting post AMI. At the time of infusion, it is believed that the infarct-region SDF-1 (stromal derived factor) levels are peaked and scar formation has not yet occurred. It was found that, in addition to the quantity of CD34+ cells infused, improvement in cardiac perfusion and infarct size correlated with the mobility potential of CD34+ cells mediated by a SDF-1 gradient (Quyyumi et al, Am Heart J 2011, 161:98–105). We have developed a cell based in vitro mobility assay as a potential potency release assay for AMR-001. However, this assay is not suitable for a Phase III or commercial scale release assay due to the length of the assay, high skill level required to perform, and variability. To develop a more robust assay, we have initiated a study to identify potential microRNAs (miRNAs) that may be used as biomarkers for CD34+ cell SDF-1 driven migration. Our preliminary results suggest CD34+ cells with different mobility potentials may be characterized by miRNA fingerprinting. Methods Cryopreserved purified CD34+ cells derived from bone marrow of healthy donors were purchased from a commercial vendor. Thawed CD34+ cells were washed and the cells were assayed in an in vitro transwell system (Jo et al, J Clin Invest 2000, 105:101-111). The trans-membrane migration of CD34+ cells into the lower chamber in the presence of SDF-1, as well as the non-mobilized CD34+ cells in the upper chamber, were collected after 4 hours incubation at 37°C. Total RNA of the cells was isolated and the miRNA expression profile was analyzed using SurePrint G3 Human v16 microRNA 8x60K microarray slide (Agilent, Santa Clara, CA). A normalization algorithm was used to generate miRNA expression profiles (SistemQC™, Sistemic, Ltd) for the characterization of untreated cells, the mobilized population that migrate towards SDF-1, and non-mobilized population; from two independent donors. Results Two hundred and four (204) miRNAs were reliably detected across the cell samples. The mobilized cells had different miRNA profiles compared with non-mobilized/untreated cells. Hierarchical cluster analysis showed that mobilized cells grouped separately from the non-mobilized/untreated cells. Conclusion Analysis of the miRNA profiles of the CD34+ cells across two independent donors, identified a number of key miRNAs (kmiRs™) that represent possible markers for a mobility phenotype. Additional samples will be analyzed to confirm these preliminary findings. This approach will enable the identification of markers associated with mobility potential of CD34+ cells and the potential development of a molecular biomarker assay for potency. Disclosures: Warbington: Progenitor Cell Therapy, LLC: Employment. Weinstein:Progenitor Cell Therapy, LLC: Employment. Mallinson:Sistemic, Ltd.: Employment, Equity Ownership. Olijnyk:Sistemic, Ltd.: Employment. Paterson:Sistemic, Ltd.: Employment. Ridha:Sistemic, Ltd.: Employment. O'Brien:Sistemic, Ltd.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Lin:Progenitor Cell Therapy, LLC: Employment. LeBlon:Progenitor Cell Therapy, LLC: Employment. Fong:NeoStem, Inc.: Employment. Chan:Progenitor Cell Therapy, LLC: Employment.

Cardiovascular events (CVEs) associated with tyrosine kinase inhibitor (TKI) therapy in patients with metastatic renal cell carcinoma (mRCC) at a regional cancer center

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16040-e16040
Author(s):  
J. McGhie ◽  
M. J. Mackenzie ◽  
E. Winquist ◽  
S. Ernst ◽  
L. Sax ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Kinase Inhibitor ◽  
Cardiac Risk ◽  
Phase Iii ◽  
Cancer Center ◽  
True Rate ◽  
Cardiac Risk Factors ◽  
Coronary Syndrome ◽  
Phase Iii Trials

e16040 Background: Recent studies suggest the incidence of CVEs associated with TKIs has been underestimated. Phase III trials have reported low incidences of heart failure, cardiac ischemia and hypertension. A recent observational study reported that one third of patients taking sunitinib or sorafenib experienced a cardiovascular event often without symptoms. We assessed the incidence of CVEs in mRCC patients who received TKIs at our centre. Methods: Eligible mRCC patients were identified from a mRCC database between January 2006 and November 2008. Data was retrospectively extracted including age, sex, diagnosis, histology, past cardiac history, cardiac risk factors, number and type of TKI regimens, and CVEs. A CVE was defined as unexplained death, acute coronary syndrome (ACS), heart failure, or arrhythmia requiring intervention. We also identified any new or exacerbated cases of hypertension after the start of TKI therapy, as a CVE. Results: Eighty-five eligible patients were identified. Average age was 61 years (range, 23–78), 72% were male and 80% were clear cell in origin. A total of 31 CVEs occurred in 28 patients (33%). These events occurred at a median of 5 weeks of TKI therapy (range, 1 - 64 weeks). There were 8 cases of ACS, 2 of heart failure, 2 of arrhythmia, and 3 unknown causes of death. Only 2 of these particular CVEs were associated with new or increased hypertension. There were 16 cases of hypertension alone. Those who had CVEs had a higher mean number of cardiac risk factors. They were also more likely to have an echocardiogram during treatment, and less likely to receive sorafenib following sunitinib. Conclusions: Our study suggests a lower rate of CVEs than recent studies, but the true rate may be underestimated, as routine cardiac studies were not performed in all patients. Rational surveillance strategies for patients receiving TKI therapies should be developed. Prospective trials should address predictive and prognostic factors for CVEs. [Table: see text] [Table: see text]

Abstract 16130: Plasma Proteomic Analysis of Association Between Atrial Fibrillation, Coronary Microvascular Disease and Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Cevher Ozcan ◽  
GUNJAN DIXIT ◽  
John Blair
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Proteomic Analysis ◽  
Microvascular Disease ◽  
Microvascular Dysfunction ◽  
Coronary Microvascular Dysfunction ◽  
Matrix Remodeling ◽  
Label Free ◽  
Inflammatory Processes ◽  
Novel Biomarkers

Introduction: Atrial fibrillation (AF) commonly occurs in patients with heart failure with preserved ejection fraction (HFpEF). Recent studies showed a high prevalence of coronary microvascular dysfunction (CMD) in patients with HFpEF and a likely association with AF. Yet, the biomarkers and mechanisms of their association have not been characterized. Hypothesis: Plasma proteomic analysis can identify novel biomarkers of the association between AF, CMD and HFpEF, and mechanistic pathways of their association. Methods: We studied the plasma samples from the patients with AF, CMD and/or HFpEF. Liquid chromatography-mass spectrometry based untargeted and label-free quantification proteomic analysis was performed. Circulating plasma proteins were screened to determine candidate biomarkers and the mutual mechanistic pathways in these disease processes. Results: We identified 130 dysregulated proteins across the groups with the independent patient replicates. Discovery-based untargeted plasma proteomic analysis identified 35 proteins in association with AF, CMD and HFpEF candidate biomarkers of their association (Fig). SAA1, LRG1 and APOC3 were significantly elevated in the coexistence of AF, CMD and HFpEF. LCP1, PON1 and C1S were markedly downregulated in their associations. Combined downregulation of PON1 and C1S was a marker of the HFpEF and CMD. Low PON1 was associated with HFpEF. Low C1S was a marker of CMD. Reduced levels of LCP1, KLKB1 and C4A were associated with AF in patients with CMD and HFpEF. These dysregulated proteins are associated with inflammatory processes, coagulation pathways, oxidative stress, metabolism, complement system and extracellular matrix remodeling. Conclusions: Plasma proteomic profile provides biomarkers and mechanistic insight into the association of AF, CMD and HFpEF. Circulation dysregulated proteins can be clinically useful for risk stratification.

scholarly journals New Directions in Therapeutic Angiogenesis and Arteriogenesis in Peripheral Arterial Disease

2021 ◽  
Vol 128 (12) ◽  
pp. 1944-1957 ◽  
Author(s):  
Brian H. Annex ◽  
John P. Cooke
Keyword(s):  
Peripheral Arterial Disease ◽  
Cell Therapy ◽  
Randomized Clinical Trials ◽  
Microvascular Disease ◽  
Arterial Disease ◽  
The United States ◽  
Therapeutic Angiogenesis ◽  
Cardiovascular Death ◽  
Lipid Lowering ◽  
Peripheral Arterial

The prevalence of peripheral arterial disease (PAD) in the United States exceeds 10 million people, and PAD is a significant cause of morbidity and mortality across the globe. PAD is typically caused by atherosclerotic obstructions in the large arteries to the leg(s). The most common clinical consequences of PAD include pain on walking (claudication), impaired functional capacity, pain at rest, and loss of tissue integrity in the distal limbs that may lead to lower extremity amputation. Patients with PAD also have higher than expected rates of myocardial infarction, stroke, and cardiovascular death. Despite advances in surgical and endovascular procedures, revascularization procedures may be suboptimal in relieving symptoms, and some patients with PAD cannot be treated because of comorbid conditions. In some cases, relieving obstructive disease in the large conduit arteries does not assure complete limb salvage because of severe microvascular disease. Despite several decades of investigational efforts, medical therapies to improve perfusion to the distal limb are of limited benefit. Whereas recent studies of anticoagulant (eg, rivaroxaban) and intensive lipid lowering (such as PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors) have reduced major cardiovascular and limb events in PAD populations, chronic ischemia of the limb remains largely resistant to medical therapy. Experimental approaches to improve limb outcomes have included the administration of angiogenic cytokines (either as recombinant protein or as gene therapy) as well as cell therapy. Although early angiogenesis and cell therapy studies were promising, these studies lacked sufficient control groups and larger randomized clinical trials have yet to achieve significant benefit. This review will focus on what has been learned to advance medical revascularization for PAD and how that information might lead to novel approaches for therapeutic angiogenesis and arteriogenesis for PAD.

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