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Posts Tagged ‘Macrovascular Disease’


Reporter: Aviva Lev-Ari, PhD, RN

International Consortium Finds 15 Novel Risk Loci for Coronary Artery Disease

“lipid metabolism and inflammation as key biological pathways involved in the genetic pathogenesis of CAD”

Themistocles Assimes from Stanford University Medical Center said in a statement that these findings begin to clear up its role. “Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause,” he said.

On this Open Access Online Scientific Journal, lipid metabolism and inflammation were researched and exposed in the following entries.

However, it is ONLY,  these 15 Novel Risk Loci for Coronary Artery Disease published on 12/3/2012 that provides the genomics loci and the genetic explanation for the following empirical results obtained in the recent research on Cardiovascular diseases, as present in the second half of this post, below.

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

What is the role of plasma viscosity in hemostasis and vascular disease risk?

https://pharmaceuticalintelligence.com/2012/11/28/what-is-the-role-of-plasma-viscosity-in-hemostasis-and-vascular-disease-risk/

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

https://pharmaceuticalintelligence.com/2012/11/28/pik3ca-mutation-in-colorectal-cancer-may-serve-as-a-predictive-molecular-biomarker-for-adjuvant-aspirin-therapy/

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

https://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

https://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

The Essential Role of Nitric Oxide and Therapeutic NO Donor Targets in Renal Pharmacotherapy

https://pharmaceuticalintelligence.com/2012/11/26/the-essential-role-of-nitric-oxide-and-therapeutic-no-donor-targets-in-renal-pharmacotherapy/

Nitric Oxide Function in Coagulation

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/Nitric Oxide Function in Coagulation

15 Novel Risk Loci for Coronary Artery Disease

December 03, 2012

NEW YORK (GenomeWeb News) – A large-scale association analysis of coronary artery disease has detected 15 new loci associated with risk of the disease, bringing the total number of known risk alleles to 46. As the international CARDIoGRAMplusC4D Consortium reported in Nature Genetics yesterday, the study also found that lipid metabolism and inflammation pathways may play a part in coronary artery disease pathogenesis.

“The number of genetic variations that contribute to heart disease continues to grow with the publication of each new study,” Peter Weissberg from the British Heart Foundation, a co-sponsor of the study, said in a statement. “This latest research further confirms that blood lipids and inflammation are at the heart of the development of atherosclerosis, the process that leads to heart attacks and strokes.”

For its study, the consortium, which was comprised of more than 180 researchers, performed a meta-analysis of data from the 22,233 cases and 64,762 controls of the CARDIoGRAM genome-wide association study and of the 41,513 cases and 65,919 controls from 34 additional studies of people of European and South Asian descent. Using the custom Metabochip array from Illumina, the team tested SNPs for disease association in those populations. The SNPs that reached significance in that stage of the study were then replicated using data from a further four studies.

From this, the team identified 15 new loci with genome-wide significance for risk of coronary artery disease, in addition to known risk loci.

The consortium also reported an additional 104 SNPs that appeared to be associated with coronary artery disease but did not meet the cut-off for genome-wide significance.

Then looking to other known risk factors for coronary artery disease, like blood pressure and diabetes, the researchers assessed whether any of those risk factors were associated with the risk loci. Of the 45 known risk loci, 12 were associated with blood lipid content and five with blood pressure. And while people with type 2 diabetes have a higher risk of developing coronary artery disease, none of the known risk loci were linked to diabetic traits.

An analysis of the pathways that SNPs linked to coronary artery disease fall in revealed that many of them are involved in lipid metabolism and inflammation pathways — 10 risk loci were found to be involved in lipid metabolism. “Our network analysis identified lipid metabolism and inflammation as key biological pathways involved in the genetic pathogenesis of CAD,” the researchers wrote in the paper. “Indeed, there was significant crosstalk between the lipid metabolism and inflammation pathways identified.”

The role of inflammation in coronary artery disease has been up for debate — a debate centering on whether it is a cause or a consequence of the disease — and study author Themistocles Assimes from Stanford University Medical Center said in a statement that these findings begin to clear up its role. “Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause,” he said.

Related Stories

SOURCE:

http://www.genomeweb.com//node/1159041?hq_e=el&hq_m=1424172&hq_l=3&hq_v=09187c3305

 

GWAS, Meta-Analyses Uncover New Coronary Artery Disease Risk Loci

March 07, 2011

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Three new studies — including the largest meta-analysis yet of coronary artery disease — have identified dozens of coronary artery disease risk loci in European, South Asian, and Han Chinese populations. All three papers appeared online yesterday in Nature Genetics.

For the first meta-analysis, members of a large international consortium known as the Coronary Artery Disease Genome-wide Replication and Meta-Analysis study, or CARDIoGRAM, sifted through data on more than 135,000 individuals from the UK, US, Europe, Iceland, and Canada. In so doing, they tracked down nearly two-dozen new and previously reported coronary artery disease risk loci.

Because only a few of these loci have been linked to other heart disease-related risk factors such as high blood pressure, those involved say the work points to yet unexplored heart disease pathways.

“[W]e have discovered several new genes not previously known to be involved in the development of coronary heart disease, which is the main cause of heart attacks,” co-corresponding author Nilesh Samani, a cardiology researcher affiliated with the University of Leicester and Glenfield Hospital, said in a statement. “Understanding how these genes work, which is the next step, will vastly improve our knowledge of how the disease develops, and could ultimately help to develop new treatments.”

Samani and his co-workers identified the loci by bringing together data on 22,233 individuals with coronary artery disease and 64,762 unaffected controls. The participants, all of European descent, had been sampled through 14 previous genome-wide association studies and genotyped at an average of about 2.5 million SNPs each. The team then assessed the top candidate SNPs found in this initial analysis in another 56,582 individuals (roughly half of whom had coronary artery disease).

The search not only confirmed associations between coronary artery disease and 10 known loci, but also uncovered associations with 13 other loci. All but three of these were distinct from loci previously implicated in other heart disease risk factors such as hypertension or cholesterol levels, researchers noted.

Consequently, those involved in the study say that exploring the biological functions of the newly detected genes could offer biological clues about how heart disease develops — along with strategies for preventing and treating it.

The genetic complexity of coronary artery disease being revealed by such studies has diagnostic implications as well, according to some.

“Each new gene identified brings us a small step closer to understanding the biological mechanisms of cardiovascular disease development and potential new treatments,” British Heart Foundation Medical Director Peter Weissberg, who was not directly involved in the new studies, said in a statement. “However, as the number of genes grows, it takes us further away from the likelihood that a simple genetic test will identify those most of risk of suffering a heart attack or a stroke.”

Meanwhile, researchers involved with Coronary Artery Disease Genetics Consortium did their own meta-analysis using data collected from four GWAS to find five coronary artery-associated loci in European and South Asian populations.

The group initially looked at 15,420 individuals with coronary artery disease — including 6,996 individuals from South Asia and 8,424 from Europe — and 15,062 unaffected controls. Participants were genotyped at nearly 575,000 SNPs using Illumina BeadChips. Most South Asian individuals tested came from India and Pakistan, researchers noted, while European samples came from the UK, Italy, Sweden, and Germany.

For the validation phase of the study, the team focused in on 59 SNPs at 50 loci from the discovery group that seemed most likely to yield authentic new disease associations. These variants were assessed in 10 replication groups comprised of 21,408 individuals with coronary artery disease and 19,185 individuals without coronary artery disease.

All told, researchers found five loci that seem to influence coronary artery disease risk in the European and South Asian populations: one locus each on chromosomes 7, 11, and 15, along with a pair of loci on chromosome 10.

The team didn’t see significant differences in the frequency or effect sizes of these newly identified variants between the European and South Asian populations, though they emphasized that their approach may have missed some potential risk variants, particularly in those of South Asian descent.

“[C]urrent genome-wide arrays may not capture all important variants in South Asians,” they explained, “Nevertheless, all of the known and new variants were significantly associated with [coronary artery disease] risk in both the European and South Asian populations in the current study, indicating the importance of genes associated with [coronary artery disease] beyond the European ancestry groups in which they were first defined.”

Finally, using a three-stage discovery, validation, and replication GWAS approach, Chinese researchers identified a single coronary artery disease risk variant in the Han Chinese population.

In this first phase of that study, researchers tested samples from 230 cases and 230 controls from populations in Beijing and in China’s Hubei province that were genotyped at Genentech and CapitalBio using Affymetrix Human SNP5.0 arrays.

From the nearly three-dozen SNPs identified in the first stage of the study, they narrowed in on nine suspect variants. After finding linkage disequilibrium between two of the variants, they did validation testing on eight of these in 572 individuals with coronary artery disease and 436 unaffected controls, all from Hubei province.

That analysis implicated a single chromosome 6 SNP called rs6903956 in coronary artery disease — a finding the team ultimately replicated in another group of 2,668 coronary artery disease cases and 3,917 controls from three independent populations in Hubei, Shandong province, and northern China.

The team’s subsequent experiments suggest that the newly detected polymorphism, which falls within a putative gene called C6orf105 on chromosome 6, curbs the expression of this gene. The functional consequences of this shift in expression, if any, are yet to be determined.

Because C6orf105 shares some identity and homology with an androgen hormone inducible gene known as AIG1, those involved in the study argue that it may be worthwhile to investigate possible ties between C6orf105 expression, androgen signaling, and coronary artery disease.

“Androgen has previously been reported to be associated the pathogenesis of atherosclerosis,” they wrote. “Future studies are needed to explore whether C6orf105 expression can be induced by androgen and to further determine the potential mechanism of [coronary artery disease] associated with decreased C6orf105 expression.”

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Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Author and Investigator Initiated Study: Aviva Lev-Ari, PhD, RN

 

Macrovascular Disease – Therapeutic Potential of cEPCs: Promise for CV Risk Reduction

  • Introduction
  • Biomarker Discovery – a comprehensive Post on this topic is forthcoming
  • What are our Contributions in the Domain of Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk
  • Postulates of Multiple Indications for the Method Presented: Positioning of a Therapeutic Concept for Endogenous Augmentation of cEPCs — Potential Therapeutic Indications for ElectEagle
  • A Three Component Method for Endogenous Augmentation of cEPCs — Macrovascular Diseases – Therapeutic Potential of cEPCs
  • The Promise of the Proposed Pharmacotherapy as a Method of CVD Risk Reduction
  • Emergence of Clinical Trial Results on Genous R stent — Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth – (HEALING II)
  • Conclusions
  • References

Key words: coronary artery disease, circulating Endothelial Progenitor Cells (cEPCs), Endothelial Progenitor Cells (EPC), genetic engineering, CVD, CAD, CHF, myocardial infarction, neovascularization, vascular repair, “multimarker biomarker”, macrovascular disease, Endogenous Augmentation of cEPCs, Primary Endpoint, Secondary Endpoint.

Abbreviations used: ED, endothelial dysfunction; CAD, coronary artery disease; CVD, cardiovascular disease; cEPCs, circulating Endothelial Progenitor Cells; EPC, Endothelial Progenitor Cells; CHF, congestive heart failure; MI, myocardial infarction; MNC, mononuclear cells; VEGF, vascular endothelial growth factor; BMMNCs, bone marrow-derived mononuclear cells; G-CSF, granulocyte colony-stimulating factor; SDF, stromal derived factor; PB-MNCs, peripheral blood-mononuclear cells; EF, ejection fraction; PO2, partial pressure of oxygen; BMS, bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; GP, glycoprotein; LAD, left anterior descending; LCx, left circumflex; MI, myocardial infarction; RCA, right coronary artery; S/P , status-post stent implantation; MACE, Major Adverse Cardiac Events; TLR, target lesion revascularization; TVR, target vessel revascularization; TVF, target lesion vessel failure; eNOS, endothelial Nitric Oxide Synthase 

Introduction

Cardinal to the study of reendothelialization and neovascularization is the mechanism of action (MOA) of EPCs. It requires exact biological phenotype of the true EPC and its MOA on the endothelium. Is the EPC autocrine or paracrine in its functional role? It is critical to understand this biological unknown for planning therapeutic approaches. Patients with unstable angina and no evidence of cardiac necrosis exhibited increased cEPCs. Systemic inflammation and recognized growth factors may play a role in peripheral mobilization of EPCs in patients with unstable anginal syndromes. Proportion of cEPCs in coronary ischemia, acute or chronic and its potential for restoring left ventricular dysfunction is still experimental. EC injury facilitates an accelerated development of atherosclerotic plaque which triggers cardiovascular risk factors where the magnitude of the endothelial dysfunction predicts the level of risk for a macrovascular event (George, 2004).

Diminished level of cEPCs is associated with risk factors for CVD implicating impaired endothelial repair as a contributor to a dynamic state of endothelial dysfunction. cEPCs is further reduced if multiple risk factors for CVD are present. Endothelial dysfunction is associated with cEPCs counts. It is only if cEPCs counts are low then endothelial dysfunction (ED) emerges. In the case of ED, the cells were more senescent compared with an age group without CVD and the risk factors involved with it. Impaired repair capacity due to reduced availability of cEPCs enhances the exposure to risk factors when injury occurs due to endothelial denudation, ischemic tissue, neointima build up and remodeling.

Mobilization and EPC-mediated neovascularization is critically regulated. Statins and physical exercise are stimulatory while risk factors for CAD are inhibitory in the modulation function of the level of cEPCs. Recruitment of cEPCs requires a coordinated sequence of adhesive and signaling events including adhesion and migration by integrins, chemoattraction of SDF-1/CXCR4 and differentiation of EC.

Bone-marrow derived cells in the circulating blood have an endothelial phenotype and peripheral blood can be cultured to generate ECs. cEPCs provide both diagnostic and prognostic information on CVD. EPCs are analyzed by their phenotypic markers, as discerned by fluorescence-activated cell sorting (FACS) analysis as well as by their functional capability to produce colonies in culture conditions.

Kiernan (2006) identifies the two classes of therapeutic applications of cEPCs: (a) induction of angiogenesis and (b) large vessel repair. Transplantation of autologous EPCs over-expressing eNOS in injured vessels enhances the vasculoprotective properties of the reconstituted endothelium, leading to inhibition of neointimal hyperplasia. This cell-based gene therapy strategy may be useful in treatment of vascular disease. Stents coated in CD34 antibody which binds to the CD34 antigen of cEPCs have the capability to promote re-endothelialisation in minutes to hours. This mechanism seeks to restore the normal biology of the vessel wall rather than perpetuate the wall disruption as drug eluting stents are found recently to be implicated to cause both restenosis and thrombosis (Tung et al., 2006). Thus, cEPCs are of cardinal importance in healing cardiovascular injury. Identification of augmentation methods which are endogenous in nature, are systemic rather than local, as cell-based therapy is, and therefore, it will deliver systemic protective measures against atherosclerosis delaying angioplasty and potentially avoiding cell implantation or vascular engrafting.

Biomarker Discovery – a comprehensive Post on this topic is forthcoming

A comprehensive review of “Traditional” vs. “Novel” risk markers for cardiovascular disease was recently undertaken by Folsom et al., (2006) and the Editorial to this article by Lloyd-Jones and Tian (2006). Among the “Traditional” Risk Markers, they list: Age, Race, Sex, Total/HDL levels, Smoking Status, Diabetes, Systolic BP and Use of antihypertensive  drugs. The list of “Novel” Risk Markers is impressively longer and includes: CRP, Lp-PLA2, E-Selectin, Fibrinogen, PAI-1, Vitamin B6, D-dimer, ICAM-1, Homocysteine, IL-6, HSV-1 Antibody, CMV Antibody and Folate.

Only two risk factors make the top five list following the data adjustment to Age and /or All the Traditional Risk Factors, respectively, I would conclude that only the following two are of paramount importance for clinical application and drug therapy design.

Risk Factor RANKING

Risk Factor RANKING if

Data Adjusted to

AGE

Risk Factor RANKING if

Data Adjusted to

All “Traditional” Risk Factors

1 Chlamydia Intracellular adhesion molecule
2 Lp-PLA2 lipoprotein-associatedphospholipase A2 Cytomegalovirus
3 Tisshe Plasminogen Activator D-Dimer
4 Tissue inhibitor of Metalloproteinase1 IL-6
5 Intracellular adhesion molecule Tissue inhibitor of Metalloproteinase1

In light of these results, chiefly edified by Folsom et al., (2006)  conclusion that: “Based on the totality of evidence, however, CRP level does not emerge as a clinically useful addition to basic risk factor assessment for identifying patients at risk of a first CHD event.” (Folsom, 2006, 1372).

What are our Contributions in the Domain of

Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

(a) This is the first paper to look at cEPCs from two academic schools of thought.  One, represented by the review article of Dzau et al., Hypertension, 2005 with 122 references which treats cEPCs from two perspectives: Vascular Biology and Molecular Cardiology. The other, is the review article by Lapidot & Petit, Experimental Hematology, 2002 with 86 references which treats cEPCs as stem cells and covers the research in Immunology and in Hematology, cEPCs is circulating in our blood, it is a stem cell! The overlap between the references N=122 in Dzau and N=86 in Lapidot & Petit is zero. These two schools do not cite the findings of the other school. That happens when both schools (Vascular Biology/Molecular Cardiology) and (Immunology/Hematology), BOTH schools are researching the same biologic phenomenon, i.e., one circulating EPC. We are the first to put together in one paper the two schools in the context of cEPCs. The pathophysiology of cECs, cEPCs and Trans-Endothelium Cell Migration in one location.

(b) Table of content of Part I yielded a theoretical treatment of cEPCs not in existence anywhere.  We defined for the first time that the Clinical Frontier for cEPCs is of quadruple nature: (Vascular Biology/Molecular Cardiology) PLUS (Immunology/Hematology). We made the statement that the Clinical Frontier has 20 Future Fast Acting Therapy modality currently under research. We cited the limitation of exogenous methods for augmentation of cEPCs as a scientifically derived justification for our selection of an endogenous augmentation method.

Upon selection of the endogenous method, we specified three components:

–   inhibition of ET-1

–   induction of eNOS

–   stimulation of PPAR-gamma

The proposed combination drug therapy yielded a new multimarker biomarker for reduction of CVD risk for macrovascular events, called the ElectEagle Version I. We specified the potential indications for the ElectEagle Version I method in terms of cardiovascular disease and co-morbidity with other endothelial dysfunction derived disease.

Method name:            ElectEagle

E.L.E.C.T.

E – Efficient

L – Ligands of cEPCs

E – Elective and Individualized Diagnosis and Therapy

C – Cardiovascular diseases & secondary sequalea

T – Treatment adjustable by three agents

E.A.G.L.E.

E – Endogenous

A – Augmentation

G – Gamma-PPAReceptor

L – Ligand occupied ETA and ETA-ETB – binding Nitric Oxide

E – EPCs fast generator

ElectEaglestands for an Efficient Ligands of cEPCs Elective and Individualized Diagnosis and Therapy for Cardiovascular diseases & secondary vascular sequalea, using Treatment adjustable by three agents. It is a method for Endogenous Augmentation of circulating EPCs by using Gamma-PPAR agonists, inhibitors of Ligand occupied ETA and ETA-ETB and agonist for binding Nitric Oxide and induce eNOS.

A Three Component Method for Endogenous Augmentation of cEPCs — Macrovascular Diseases – Therapeutic Potential of cEPCs

Observations on Intellectual Property Development For an Unrecognized Future Fast Acting Therapy for Patients at High Risk for Macrovascular events

ElectEagle represents a discovery of a novel “multimarker biomarker” for cardiovascular disease that innovates on four counts.

First, it proposes new therapeutic indications for acceptable drugs.

Second, it defines a specific combination of therapeutic agents, thus, it put forth a proprietary drug combination.

Third, it targets receptor systems that have not been addressed in the context of cEPCs augmentation methods. Chiefly, modulation of the following three-targeted receptor systems: (a) inhibition of ET-1, ETA and ETA-ETB receptors by antagonists (b) induction of eNOS, by agonists and NO stimulation and (c) upregulation of PPAReceptor-gamma by agonists (TZD). While (b) and (c) are implicated as having favorable effects of cEPCs count, each exerting its effect by a different pathway, it is suggested in this project that (a) might be identify to be the more powerful of the three markers. Our method, ElectEagleis the FIRST to postulate the following: (1) time concentration dependence on eNOS reuptake (2) dose concentration dependence on NO production (3) time and dose concentration dependence for ET-1, ETA and ETA-ETB inhibition, and (4) dose concentration dependence on PPAReceptor-gamma. Points First, Second and Third are covered in Part II where a special focus is placed on ET-1, ETA and ETA-ETB receptors.

Fourth, ElectEagle proposes a platform with triple modes of delivery and use of the test, as described in Part III. The triple modes are as follows: (A) an automated platform from a centralized lab with integration to Lab’s information management system. (B) a point-of-care testing device with appropriate display of test results (small benchtop analyzers in PCP office). (C) a device used for home monitoring of analytes (the hand-held device facilitates rapid read of scores and their translation to drug concentration of each of the three therapeutic agents, with computation of the three drug concentrations done by the device. Thus, it offers quicker optimization of treatment.  ElectEagle is the FIRST to propose a CVD patient kit, hand-held device, which calculates on demand an adjustable therapeutic regimen as a function of cEPCs count biomarker. In this regard, a similarity to the pump, in management of blood sugar in DM patients, exists. Since there is a high co-morbidity between DM and CVD, our methods, ElectEagle may eventually become a targeted therapy for the DM Type 2 population.

Postulates of Multiple Indications for the Method Presented: Positioning of a Therapeutic Concept for Endogenous Augmentation of cEPCs — Potential Therapeutic Indications for ElectEagle

ElectEagle can become the drug therapy of choice for the following indications:

  •      CAD patients
  •      Endothelial Dysfunction in DM patients with or without Erectile Dysfunction
  •      Atherosclerosis patients: Arteries and or veins
  •      pre-stenting treatment phase
  •      post-stenting treatment phase
  •      if stent is a Bare Metal stent (BMS)
  •      if stent is Drug Eluting stent (DES)
  •      if stent is EPC antibody coated (the ElectEagle method increase cEPCs generation in vitro) so availability of cEPCs is increased
  •      post CABG patients (the ElectEagle enhances healing by endogenous augmentation of cEPCs)
  •      target sub segments of CVD patients on blood thinner drugs (the ElectEagle does not require treatment with antiplatelet agents, it is suitable for all patients on Coumadin. This population have a counter indication for antiplatelet agents which is a follow up treatment after stent implantation for 30 days, with stent-eluting long term regimen of antiplatelet agents, 6 months and in some cases indefinitely (Tung, 2006).
  •      ElectEagle is based on systemic therapeutics (versus the localized stent solution requiring multiple and even overlapping stents)
  •      ElectEagle will be having potential in three contexts

(a) Coronary disease

(b) Periphery vascular disease

(c) Cerebrovascular

Comparative analysis of endogenous and exogenous cEPCs augmentation methods:

A. Endogenous augmentation method properties:

  •         temporal – while drug therapy in use – drug action is interruptible
  •         time concentration on eNOS reuptake
  •         dose concentration on NO production
  •         time and dose concentration manner for ETB inhibition
  •         dose concentration on PPAR-gamma

B.  Cell-based and other exogenous methods

  • permanent colonization till apoptosis if no repeated attempts of re-transfer,
  • re-implantation as the protocol usually has several stages

The Promise of the Proposed Pharmacotherapy as a Method of CVD Risk Reduction

It is expected that ElectEagle will be resulting in potential delay of stenting implantation. Patients that are target for stenting may benefit form ElectEagle that will facilitate and accelerate healing after the stent is in place. EPC antibody coated stents will work if and only if the patient has more that just low cEPCs, most patient undergoing stenting tend to have low level of cEPC. The ElectEagle method can be coupled with that type of new stents, called Genous, now in clinical trials (HEALING II, III). These stents enhance the body ability in mobilization of cEPCs, only. However, if the initial population of cEPCs is low, an endogenous fast acting cell augmentation method is needed for pretreatment before the PCI procedure with Genous is scheduled.

Emergence of Clinical Trial Results on Genous R stent — Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth – (HEALING II)

Latest publications on HEALING II – Clinical Trial of EPC coated stent

Genous R stent
n=63
Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth – II

S Silber et al; 12 Month Outcomes of the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) Worldwide Registry; EuroIntervention 2011;6:819-825

P Damman et al; Coronary Stenting With the Genous Bio-engineered R stent in Elderly Patients – 12-month Outcomes From the e-HEALING Registry; Circulation Journal 2011;75(11):2590-2597

P Damman et al; Twelve-month Outcomes After Coronary Stenting With the Genous Bio-Engineered R Stent in Diabetic Patients from the e-HEALING Registry; Journal of Interventional Cardiology 2011;24(4):285-94 

J Aoki et al; Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry.J.Am.Coll.Cardiol. 2005 May 17;45(10):1574-9

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Comment #6 by Aviva Lev-Ari, PhD, RN

to Allan, M. Brandt’s article in NEJM, January 5, 2012

A Reader’s Guide to 200 Years of the New England Journal of Medicine

Circulating Endothelial Progenitor Cells Milestones in the research on Circulating Endothelial Progenitor Cells as diagnostic markers of cardiovascular risk have been reported in NEJM 2003 348:593– 600; (2005); Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes, NEJM, 353: 999-1007; Circulating Endothelial Progenitor Cells Correspondence http://www.nejm.org december 15, 2005; (2005) Correspondence to the Editor on Circulating Endothelial Progenitor Cells. NEJM, 353:24, 2613-2616; Werner, N & Nickenig, G. (2005b). Authors Reply to Correspondence to the Editor on Circulating Endothelial Progenitor Cells. NEJM, 353:24, 2613-2616. Based on that state of the art of research, I defined in 2006 an independent research study and carried out research on “Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk” An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPCs) as a Therapeutic Target for Pharmacological Therapy Design for Cardiovascular Risk Reduction: A New Multimarker Biomarker Discovery. I’ll attribute my increasing interest in Molecular Cardiology to above NEJM articles.

http://www.nejm.org/doi/full/10.1056/NEJMp1112812#t=comments

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Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Curator: Aviva Lev-Ari, PhD, RN

An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPCs) as a Therapeutic Target for Pharmacological Therapy Design for Cardiovascular Risk Reduction: A New Multimarker Biomarker Discovery

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