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Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients: Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts

Reporter: Aviva Lev-Ari, PhD, RN

 

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients: Design of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts

Bruce M. Psaty, MD, PhD, Christopher J. O’Donnell, MD, MPH, Vilmundur Gudnason, MD, PhD, Kathryn L. Lunetta, PhD, Aaron R. Folsom, MD, Jerome I. Rotter, MD,André G. Uitterlinden, PhD, Tamara B. Harris, MD, Jacqueline C.M. Witteman, PhD,Eric Boerwinkle, PhD and on Behalf of the CHARGE Consortium

Author Affiliations

From the Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Wash; Center for Health Studies, Group Health (B.M.P.), Seattle, Wash; the National Heart, Lung and Blood Institute and the Framingham Heart Study (C.J.O.D.), Framingham, Mass; Icelandic Heart Association and the Department of Cardiovascular Genetics (Y.G.), University of Iceland, Reykjavik, Iceland; Department of Biostatistics (K.L.), Boston University School of Public Health, Mass; Division of Epidemiology and Community Health (A.R.F.), University of Minnesota, Minneapolis; Medical Genetics Institute (J.I.R.), Cedars-Sinai Medical Center, Los Angeles, Calif; Departments of Internal Medicine (A.G.U.) and Epidemiology (A.G.U., J.C.M.W.), Erasmus Medical Center, Rotterdam, The Netherlands; Laboratory of Epidemiology, Demography, and Biometry (T.B.H.), Intramural Research Program, National Institute on Aging, Bethesda, Md; and Human Genetics Center and Division of Epidemiology (E.B.), University of Texas, Houston.

Guest editor for this article was Elizabeth R. Hauser, PhD.

Abstract

Background— The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration.

Methods— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility—Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.

Conclusions— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.

Example of Coronary Heart Disease

The cohort-study methods papers provide detail about many of the phenotypes listed in Table 2. For coronary heart disease, investigators knowledgeable about the phenotype in each study decided to focus on fatal and nonfatal myocardial infarction (MI) as the primary outcome because the MI criteria differed in only trivial ways among the studies. There were some minor differences in the definition of the composite outcome of MI, fatal coronary heart disease, and sudden death, which became the secondary outcome. Only subjects at risk for an incident event were included in the analysis. MI survivors whose DNA was drawn after the event were not eligible. The primary analysis was restricted to Europeans or European Americans. Patients entered the analysis at the time of the DNA blood draw, and were followed until an event, death, loss to follow up, or the last visit. The main recommendations of the Analysis Committee were adopted, and a threshold of 5×10−8 was selected for genome-wide statistical significance. Analyses in progress include about 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients. Each cohort conducted its own analysis, and results were uploaded to a secure share site for the fixed-effects meta-analysis. Even with this number of events (Supplemental Figure 2), power is good for only for relatively high minor allele frequencies (>0.25) and large relative risks (>1.3).

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Discussion

In thousands of published papers, the 5 CHARGE cohort studies and many of the collaborating studies have already characterized the risk factors for and the incidence and prognosis of a variety of aging-related and cardiovascular conditions. The analysis of the incident MI, for instance, is free from the survival bias typically associated with cross-sectional or case-control studies. The methodologic advantages of the prospective population-based cohort design, the similarity of phenotypes across 5 studies, the availability of genome-wide genotyping data in each cohort, and the need for large sample sizes to provide reliable estimates of genotype-phenotype associations have served as the primary incentives for the formation of the CHARGE consortium, which includes GWAS data on about 38 000 individuals. The consortium effort relies on collaborative methods that are similar to those used by the individual contributing cohorts.

Phenotype experts who know the studies and the data well are responsible for phenotype-standardization across cohorts. The coordinated prospectively planned meta-analyses of CHARGE provide results that are virtually identical to a cohort-adjusted pooled analysis of individual level data. This approach–the within-study analysis followed by a between-study meta-analysis–avoids the human subjects issues associated with individual-level data sharing.

Editors, reviewers, and readers expect replication as the standard in science.6 The finding of a genetic association in one population with evidence for replication in multiple independent populations provides moderate assurance against false-positive reports and helps to establish the validity of the original finding. In a single experiment, the discovery-replication structure is traditionally embodied in a 2-stage design. The CHARGE consortium includes up to 5 independent replicate samples as well as additional collaborating studies for some phenotype working groups, so that it would have been possible to set up analysis plans within CHARGE to mimic the traditional 2-stage design for replication. For instance, the 2 largest cohorts could have served as the discovery set and the others as the replication set. However, attaining the extremely small probability values expected in GWAS requires large sample sizes. For any phenotype, a prospective meta-analysis of all participating cohorts, with a properly selected level of genome-wide statistical significance to minimize the chance of false-positives, is the most powerful approach to finding new genuine associations for genetic loci.25 When findings narrowly miss the prespecified significance threshold, genotyping individuals in other independent populations provides additional evidence about the association. For findings that substantially exceed pre-established significance thresholds, the results of a CHARGE meta-analysis effectively provide evidence of a multistudy replication.

The effort to assemble and manage the CHARGE consortium has provided some interesting and unanticipated challenges. Participating cohorts often had relationships with outside study groups that predated the formation of CHARGE. Timelines for genotyping and imputation have shifted. Purchases of new computer systems for the volume of work were sometimes necessary. Each cohort came to the consortium with their own traditions for methods of analysis, organization, and authorship policies that, while appropriate for their own work, were not always optimal for collaboration with multiple external groups. Within each cohort, the investigators had often formed working groups that divided up the large number of available phenotypes in ways that made sense locally but did not necessarily match the configuration that had been adopted by other cohorts. The Research Steering Committee has attempted to create a set of CHARGE working groups that accommodate the needs and the conventions of the various cohorts. Transparency, disclosure, and professional collaborative behavior by all participating investigators have been essential to the process.

Resource limitations are another challenge. Grant applications that funded the original single-study genome-wide genotyping effort typically imagined a much simpler design. The CHS whole-genome study had as its primary aim, for instance, the analysis of data on 3 endpoints, coronary disease, stroke and heart failure. With a score of active phenotype working groups, the CHARGE collaboration broadened the scope of the short-term work well beyond initial expectations for all the participating cohorts.

One of the premier challenges has been communications among scores of investigators at a dozen sites. CHS and ARIC are themselves multi-site studies. To be successful, the CHARGE collaboration has required effective communications: (1) within each cohort; (2) between cohorts; (3) within the CHARGE working groups; and (4) among the major CHARGE committees. In addition to the traditional methods of conference calls and email, the CHARGE “wiki,” set up by Dr J. Bis (Seattle, Wash), has provided a crucial and highly functional user-driven website for calendars, minutes, guidelines, working group analysis plans, manuscript proposals, and other documents. In the end, there is no substitute for face-to-face meetings, especially at the beginning of the collaboration, and this complex meta-organization has benefited from several CHARGE-wide meetings.

The major emerging opportunity is the collaboration with other studies and consortia. Many working groups have already incorporated nonmember studies into their efforts. Several working groups have coordinated submissions of initial manuscripts with the parallel submission of manuscripts from other studies or consortia. Several working groups have embarked on plans for joint meta-analyses between CHARGE and other consortia. CHARGE has tried to acknowledge and reward the efforts of champions, who assume leadership responsibility for moving these large complex projects forward and who are often hard-working young investigators, the key to the future success of population science.

The CHARGE Consortium represents an innovative model of collaborative research conducted by research teams that know well the strengths, the limitations, and the data from 5 prospective population-based cohort studies. By leveraging the dense genotyping, deep phenotyping and the diverse expertise, prospective meta-analyses are underway to identify and replicate the major common genetic determinants of risk factors, measures of subclinical disease, and clinical events for cardiovascular disease and aging.

SOURCE:

Circulation: Cardiovascular Genetics.2009; 2: 73-80

doi: 10.1161/ CIRCGENETICS.108.829747

 

Read Full Post »


Comorbidity of Diabetes and Aging in Cardiovascular Diseases

Reporter: Aviva Lev-Ari, PhD, RN

Heart and Aging Research in Genomic Epidemiology1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients

Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) ConsortiumDesign of Prospective Meta-Analyses of Genome-Wide Association Studies From 5 Cohorts

Bruce M. Psaty, MD, PhD, Christopher J. O’Donnell, MD, MPH, Vilmundur Gudnason, MD, PhD, Kathryn L. Lunetta, PhD, Aaron R. Folsom, MD, Jerome I. Rotter, MD, André G. Uitterlinden, PhD, Tamara B. Harris, MD, Jacqueline C.M. Witteman, PhD, Eric Boerwinkle, PhD and on Behalf of the CHARGE Consortium

Author Affiliations

From the Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Wash; Center for Health Studies, Group Health (B.M.P.), Seattle, Wash; the National Heart, Lung and Blood Institute and the Framingham Heart Study (C.J.O.D.), Framingham, Mass; Icelandic Heart Association and the Department of Cardiovascular Genetics (Y.G.), University of Iceland, Reykjavik, Iceland; Department of Biostatistics (K.L.), Boston University School of Public Health, Mass; Division of Epidemiology and Community Health (A.R.F.), University of Minnesota, Minneapolis; Medical Genetics Institute (J.I.R.), Cedars-Sinai Medical Center, Los Angeles, Calif; Departments of Internal Medicine (A.G.U.) and Epidemiology (A.G.U., J.C.M.W.), Erasmus Medical Center, Rotterdam, The Netherlands; Laboratory of Epidemiology, Demography, and Biometry (T.B.H.), Intramural Research Program, National Institute on Aging, Bethesda, Md; and Human Genetics Center and Division of Epidemiology (E.B.), University of Texas, Houston.

Guest editor for this article was Elizabeth R. Hauser, PhD.

Abstract

Background— The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration.

Methods— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility—Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.

Conclusions— The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.

Example of Coronary Heart Disease

The cohort-study methods papers provide detail about many of the phenotypes listed in Table 2. For coronary heart disease, investigators knowledgeable about the phenotype in each study decided to focus on fatal and nonfatal myocardial infarction (MI) as the primary outcome because the MI criteria differed in only trivial ways among the studies. There were some minor differences in the definition of the composite outcome of MI, fatal coronary heart disease, and sudden death, which became the secondary outcome. Only subjects at risk for an incident event were included in the analysis. MI survivors whose DNA was drawn after the event were not eligible. The primary analysis was restricted to Europeans or European Americans. Patients entered the analysis at the time of the DNA blood draw, and were followed until an event, death, loss to follow up, or the last visit. The main recommendations of the Analysis Committee were adopted, and a threshold of 5×108 was selected for genome-wide statistical significance. Analyses in progress include about 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients. Each cohort conducted its own analysis, and results were uploaded to a secure share site for the fixed-effects meta-analysis. Even with this number of events (Supplemental Figure 2), power is good for only for relatively high minor allele frequencies (>0.25) and large relative risks (>1.3).

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Discussion

In thousands of published papers, the 5 CHARGE cohort studies and many of the collaborating studies have already characterized the risk factors for and the incidence and prognosis of a variety of aging-related and cardiovascular conditions. The analysis of the incident MI, for instance, is free from the survival bias typically associated with cross-sectional or case-control studies. The methodologic advantages of the prospective population-based cohort design, the similarity of phenotypes across 5 studies, the availability of genome-wide genotyping data in each cohort, and the need for large sample sizes to provide reliable estimates of genotype-phenotype associations have served as the primary incentives for the formation of the CHARGE consortium, which includes GWAS data on about 38 000 individuals. The consortium effort relies on collaborative methods that are similar to those used by the individual contributing cohorts.

Phenotype experts who know the studies and the data well are responsible for phenotype-standardization across cohorts. The coordinated prospectively planned meta-analyses of CHARGE provide results that are virtually identical to a cohort-adjusted pooled analysis of individual level data. This approach–the within-study analysis followed by a between-study meta-analysis–avoids the human subjects issues associated with individual-level data sharing.

Editors, reviewers, and readers expect replication as the standard in science.6 The finding of a genetic association in one population with evidence for replication in multiple independent populations provides moderate assurance against false-positive reports and helps to establish the validity of the original finding. In a single experiment, the discovery-replication structure is traditionally embodied in a 2-stage design. The CHARGE consortium includes up to 5 independent replicate samples as well as additional collaborating studies for some phenotype working groups, so that it would have been possible to set up analysis plans within CHARGE to mimic the traditional 2-stage design for replication. For instance, the 2 largest cohorts could have served as the discovery set and the others as the replication set. However, attaining the extremely small probability values expected in GWAS requires large sample sizes. For any phenotype, a prospective meta-analysis of all participating cohorts, with a properly selected level of genome-wide statistical significance to minimize the chance of false-positives, is the most powerful approach to finding new genuine associations for genetic loci.25 When findings narrowly miss the prespecified significance threshold, genotyping individuals in other independent populations provides additional evidence about the association. For findings that substantially exceed pre-established significance thresholds, the results of a CHARGE meta-analysis effectively provide evidence of a multistudy replication.

The effort to assemble and manage the CHARGE consortium has provided some interesting and unanticipated challenges. Participating cohorts often had relationships with outside study groups that predated the formation of CHARGE. Timelines for genotyping and imputation have shifted. Purchases of new computer systems for the volume of work were sometimes necessary. Each cohort came to the consortium with their own traditions for methods of analysis, organization, and authorship policies that, while appropriate for their own work, were not always optimal for collaboration with multiple external groups. Within each cohort, the investigators had often formed working groups that divided up the large number of available phenotypes in ways that made sense locally but did not necessarily match the configuration that had been adopted by other cohorts. The Research Steering Committee has attempted to create a set of CHARGE working groups that accommodate the needs and the conventions of the various cohorts. Transparency, disclosure, and professional collaborative behavior by all participating investigators have been essential to the process.

Resource limitations are another challenge. Grant applications that funded the original single-study genome-wide genotyping effort typically imagined a much simpler design. The CHS whole-genome study had as its primary aim, for instance, the analysis of data on 3 endpoints, coronary disease, stroke and heart failure. With a score of active phenotype working groups, the CHARGE collaboration broadened the scope of the short-term work well beyond initial expectations for all the participating cohorts.

One of the premier challenges has been communications among scores of investigators at a dozen sites. CHS and ARIC are themselves multi-site studies. To be successful, the CHARGE collaboration has required effective communications: (1) within each cohort; (2) between cohorts; (3) within the CHARGE working groups; and (4) among the major CHARGE committees. In addition to the traditional methods of conference calls and email, the CHARGE “wiki,” set up by Dr J. Bis (Seattle, Wash), has provided a crucial and highly functional user-driven website for calendars, minutes, guidelines, working group analysis plans, manuscript proposals, and other documents. In the end, there is no substitute for face-to-face meetings, especially at the beginning of the collaboration, and this complex meta-organization has benefited from several CHARGE-wide meetings.

The major emerging opportunity is the collaboration with other studies and consortia. Many working groups have already incorporated nonmember studies into their efforts. Several working groups have coordinated submissions of initial manuscripts with the parallel submission of manuscripts from other studies or consortia. Several working groups have embarked on plans for joint meta-analyses between CHARGE and other consortia. CHARGE has tried to acknowledge and reward the efforts of champions, who assume leadership responsibility for moving these large complex projects forward and who are often hard-working young investigators, the key to the future success of population science.

The CHARGE Consortium represents an innovative model of collaborative research conducted by research teams that know well the strengths, the limitations, and the data from 5 prospective population-based cohort studies. By leveraging the dense genotyping, deep phenotyping and the diverse expertise, prospective meta-analyses are underway to identify and replicate the major common genetic determinants of risk factors, measures of subclinical disease, and clinical events for cardiovascular disease and aging.

SOURCE:

Circulation: Cardiovascular Genetics.2009; 2: 73-80

doi: 10.1161/ CIRCGENETICS.108.82974

 

Read Full Post »


Stem Cell Therapy for Coronary Artery Disease (CAD)

Author and Curator: Larry H. Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

 

There is great interest and future promise for stem cell therapy in ischemic heart disease.  This is another report for the active work in cardiology with stem cell therapy by MA Gaballa and associates at University of Arizona.

Stem Cell Therapy for Coronary Heart Disease

Julia N. E. Sunkomat and Mohamed A. Gaballa

The University ofArizona Sarver Heart Center, Section of Cardiology, Tucson, Ar
Cardiovascular Drug Reviews 2003: 21(4): 327–342

Keywords: Angiogenesis — Cardiac therapy — Coronary heart disease — Heart failure — Myoblasts — Myocardial ischemia — Myocardial regenera­tion — Stem cells

ABSTRACT

Coronary artery disease (CAD) remains the leading cause of death in the Western world. The high impact of its main sequelae, acute myocardial infarction and congestive heart failure (CHF), on the quality of life of patients and the cost of health care drives the search for new therapies. The recent finding that

stem cells contribute to neovascularization and possibly improve cardiac function after myocardial infarction makes stem cell therapy the most highly active research area in cardiology. Although the concept of stem cell therapy may revolutionize heart failure treatment, several obstacles need to be ad­dressed. To name a few:

  1.  Which patient population should be considered for stem cell therapy?
  2.  What type of stem cell should be used?
  3.  What is the best route for cell de­livery?
  4.  What is the optimum number of cells that should be used to achieve functional effects?
  5.  Is stem cell therapy safer and more effective than conventional therapies?

The published studies vary significantly in design, making it difficult to draw conclusions on the efficacy of this treatment. For example, different models of

  1. ischemia,
  2. species of donors and recipients,
  3. techniques of cell delivery,
  4. cell types,
  5. cell numbers and
  6. timing of the experiments

have been used. However, these studies highlight the landmark concept that stem cell therapy may play a major role in treating cardiovascular diseases in the near future. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease.

  • Non-ischemic cardiomyopathy,
  • peripheral vascular disease, and
  • aging may be treated by stem cells.

Stem cells could be used as vehicle for gene therapy and eliminate the use of viral vectors. Finally, stem cell therapy may be combined with phar­macological, surgical, and interventional therapy to improve outcome. Here we attempt a systematic overview of the science of stem cells and their effects when transplanted into ischemic myocardium.

INTRODUCTION

Background

Congestive heart failure (CHF) is the leading discharge diagnosis in patients over the age of 65 with estimates of $24 billion spent on health care in the US (1,11). The number one cause of CHF is coronary artery diseases (CAD). Coronary care units, reperfusion therapy (lytic and percutaneous coronary intervention) and medical therapy with anti-pla­telet agents, statins, ACE-inhibitors and â-adrenoceptor antagonists all significantly reduce morbidity and mortality of CAD and CHF (9), but it is very difficult to regenerate new viable myocardium and new blood vessels.

Identification of circulating endothelial progenitor cells in peripheral blood that incor­porated into foci of neovascularization in hindlimb ischemia (4) and the successful engraftment of embryonic stem cells into myocardium of adult dystrophic mice (31) intro­duced a new therapeutic strategy to the field of cardiovascular diseases: tissue regeneration. This approach is supported by the discovery of primitive cells of extracardiac origin in cardiac tissues after sex-mismatched transplants suggesting that an endogenous repair mechanism may exist in the heart (35,45,54). The number of recruited cells varied significantly from 0 (19) to 18% (54), but the natural course of ischemic cardiomyopathy implies that cell recruitment for tissue repair in most cases is insufficient to prevent heart failure. Therefore, investigational efforts are geared towards

  • augmenting the number of multipotent stem cells and endothelial and myocardial progenitor cells at the site of ischemia to induce clinically significant angiogenesis and potentially myogenesis.

Stem and Progenitor Cells

Stem cells are defined by their ability to give rise to identical stem cells and progenitor cells that continue to differentiate into a specific tissue cell phenotype (23,33). The po­tential of mammalian stem cells varies with stage of development and age (Table 1).

In mammals, the fertilized oocyte and blastomere cells of embryos of the two to eight cell stage can generate a complete organism when implanted into the uterus; they are called totipotent stem cells. After the blastocyst stage, embryonic stem cells retain the ability to differentiate into all cell types, but

  • cannot generate a complete organism and thus are denoted pluripotent stem cells.

Other examples of pluripotent stem cells are embryo­nic germ cells that are derived from the gonadal ridge of aborted embryos and embryonic carcinoma cells that are found in gonadal tumors (teratocarcinomas) (23,33). Both these cell types can also differentiate into cells of all three germ layers, but are not as well inves­tigated as embryonic stem cells.

It is well established that embryonic stem cells can differentiate into cardiomyocytes (7,10,13,14,31,37,76), endothelial cells (55), and smooth muscle cells (5,22,78) in vitro, but it is unclear whether

  • pure populations of embryonic stem cell-derived cardiomyocytes can integrate and function appropriately in the heart after transplantation.
  • one study reported arrhythmogenic potential of embryonic stem cell-derived cardiomyocytes in vitro (80).

Adult somatic stem cells are cells that have already committed to one of the three germ layers: endoderm, ectoderm, or mesoderm (76). While embryonic stem cells are defined by their origin (the inner cell mass of the blastocyst), the origin of adult stem cells in mature tissues is still unknown. The primary role of adult stem cells in a living organism is thought to be maintaining and repairing the tissue in which they reside. They are the source of more identical stem cells and cells with a progressively more distinct phenotype of specialized tissue cells (progenitor and precursor cells) (Fig. 1). Until recently adult stem cells were thought to be lineage-specific, meaning that they can only differentiate into the cell-type of their original tissue. This concept has now been challenged with the discovery of multipotent stem and progenitor cells (26, 50, 51).

The presence of multipotent stem and progenitor cells in adult mammals has vast im­plications on the availability of stem cells to research and clinical medicine. Recent publi­cations, however, have questioned whether the adaptation of a phenotype in those dogma-challenging studies is really a result of trans-differentiation or rather a result of cell and nuclear fusion (60,68,75,79). Spontaneous fusion between mammalian cells was first re­ported in 1961 (8), but how frequently fusion occurs and whether it occurs in vivo is not clear.

The bone marrow is a known source of stem cells. Hematopoietic stem cells are fre­quently used in the field of hematology. Surface receptors are used to differentiate hematopoietic stem and progenitor cells from mature cells. For example, virtually all

  • hematopoietic stem and progenitor cells express the CD34+ glycoprotein antigen on their cell membrane (73),

though a small proportion of primitive cells have been shown to be CD34 negative (58).

The function of the CD34+ receptor is not yet fully understood. It has been suggested that it may act as a regulator of hematopoietic cell adhesion in the bone marrow microenvironment. It also appears to be involved in the maintenance of the hematopoietic stem/progenitor cell phenotype and function (16,21). The frequency of immature CD34+ cells in peripheral circulation diminishes with age.

  • It is the highest (up to 11%) in utero (69) and decreases to 1% of nucleated cells in term cord blood (63).
  • This equals the per­centage of CD34+ cells in adult bone marrow.
  • The number of circulating stem cells in adult peripheral blood is even lower at 0.1% of nucleated cells.

Since hematopoietic stem cells have been identified as endothelial progenitor cells (29,30,32) their low density in adult bone marrow and blood could explain the inadequacy of endogenous recruitment of cells to injured organs such as an ischemic heart. The bone marrow is also home to another stem cell population the so-called mesenchymal stem cells. These may constitute a subset of the bone marrow stromal cells (2,43). Bone marrow stromal cells are a mixed cell popu­lation that generates

  1. bone,
  2. cartilage,
  3. fat,
  4. connective tissue, and
  5. reticular network that sup­ports cell formation (23).

Mesenchymal stem cells have been described as multipotent (51,52) and as a source of myocardial progenitor cells (41,59). They are, however, much less defined than the hematopoietic stem cells and a characteristic antigen constellation has not yet been identified (44).

Another example of an adult tissue containing stem cells is the skeletal muscle. The cells responsible for renewal and growth of the skeletal muscle are called satellite cells or myoblasts and are located between the sarcolemma and the basal lamina of the muscle fiber (5). Since skeletal muscle and cardiac muscle share similar characteristics such as they both are striated muscle cells, satellite cells are considered good candidates for the repair of damaged myocardium and have been extensively studied (20,25,38–40,48,56, 64–67). Myoblasts are particularly attractive, because they can be autotransplanted, so that issues of donor availability, ethics, tumorigenesis and immunological compatibility can be avoided. They also have been shown to have a high growth potential in vitro and a strong resistance to ischemia in vivo (20). On the down side

  • they may have more arrhythmogenic potential when transplanted into myocardium than bone marrow or peripheral blood de­rived stem cells and progenitor cells (40).

Isolation of Cells Prior to Transplantation

Hematopoietic stem and progenitor cells are commonly identified by the expression of a profile of surface receptors (cell antigens). For example, human hematopoietic stem cells are defined as CD34+/CD59+/Thy-1+/CD38low//c-kit/low/lin, while mouse hema-topoietic stem cells are defined as CD34low//Sca-1+/Thy-1+/low/CD38+/c-kit+/lin (23). Additional cell surface receptors have been identified as markers for subgroups of hema-topoietic stem cells with the ability to differentiate into non-hematopoetic tissues, such as endothelial cells (57,78). These can be specifically targeted by isolation methods that use the receptors for cell selection (positive selection with antibody coated magnetic beads or fluorescence-activated cell sorting, FACS). Other stem cell populations are identified by their behavior in cell culture (mesenchymal stem cells) or dye exclusion (SP cells). Finally, embryonic stem cells are isolated from the inner cell mass of the blastocyst and skeletal myoblasts are mechanically and enzymatically dissociated from an easily acces­sible skeletal muscle and expanded in cell culture.

FIG. 1. Maturation process of adult stem cells: with acquisition of a certain phenotype the cell gradually loses its self-renewal capability.  (unable to transfer)

METHODICAL APPROACHES 

j.1527-3466.2003.tb00125.x  fig stem cell

FIG. 2. Intramyocardial injection:

the cells are injected directly into the myocardium through the epicardium. Usually a thoracotomy or sternotomy is required. Transendocardial injection: access can be gained from the ar­terial vasculature. Cells are injected through the endocardium into the myocardium, ideally after identifying the ischemic myocardium by perfusion studies and/or electromechanical mapping. Intracoronary injection: the coronary artery is accessed from the arterial vasculature. Stem cells are injected into the lumen of the coronary artery. Proximal washout is prevented by inflation of a balloon. Cells are then distributed through the capillary system. They eventually cross the endothelium and migrate towards ischemic areas.

The intracoronary delivery of stem cells (Fig. 2) and distribution through the coronary system has also been explored (6,62,74). This approach was pioneered by Robinson et al. (56), who demonstrated successful engraftment within the coronary distribution after intracoronary delivery of genetically labeled skeletal myoblasts. The risk of intracoronary injection is comparable to that of a coronary angiogram and percutaneous transluminal coronary angioplasty (PTCA) (62), which are safe and clinically well established.

RESULTS IN ANIMAL STUDIES AND HUMAN TRIALS

Dif­ferentiation into cardiomyocytes was observed after transplantation of embryonic stem cells, mesenchymal stem cells, lin/c-kit+ and SP cells. The induction of angiogenesis was observed after transplantation of embryonic stem cells, mesenchymal stem cells, bone marrow-derived mononuclear cells, circulating endothelial progenitor cells, SP cells and lin/c-kit+ cells.

The use of embryonic stem cells in ischemia was examined in two studies (42,43). These studies demonstrated that mice embryonic stem cells transplanted into rat myo­cardium exhibited cardiomyocyte phenotype at 6 weeks after transplantation. In addition, generation of myocardium and angiogenesis were observed at 32 weeks after allogenic transplantation in rats. In these two studies no arrhythmias or cardiac tumors were reported.

Several studies have shown retardation of LV remodeling and improvement of cardiac function after administration of bone marrow-derived mononuclear cells. For example, decreases in infarct size, and increase in ejection fraction (EF), and left ventricular (LV) time rate change of pressure (dP/dtmax) were observed after direct injection of bone marrow-derived mononuclear cells 60 min after ischemia in swine (28). In humans, intra-coronary delivery and transendocardial injection of mononuclear cells leads to a decrease in LV dimensions and improvement of cardiac function and perfusion (49,62). A decrease in end systolic volume (ESV) and an increase in EF as well as regional wall motion were observed following intracoronary administration of CD34+/CD45+ human circulating en­dothelial cells (6). Injection of circulating human CD34+/CD117+ cells into infarcted rat myocardium induced neoangiogenesis and improved cardiac function (32). This study suggests that the improvement in LV remodeling after infarction appears to be in part me­diated by a decrease in apoptosis within the noninfarcted myocardium. Two other studies reported increased fractional shortening, improved regional wall motion and decreased left ventricular dimensions after transplantation of human CD34+ cells (29,30). Improved global left ventricular function and infarct perfusion was demonstrated after intramyo-cardial injection of autologous endothelial progenitor cells in humans (61).

DISCUSSION AND OUTLOOK

The idea of replacing damaged myocardium by healthy cardiac tissue is exciting and has received much attention in the medical field and the media. Therefore, it is important for the scientist to know what is established and what is based on premature conclusions. Currently, there are data from animal studies and human trials (Table 2). However, some of these data are not very concrete. For example,

  • many animal studies do not report the level of achieved neoangiogenesis and/or regeneration of myocardium.
  • In studies where the numbers of neovessels and new cardiomyocytes are specified, these numbers are often very low.

While these experiments confirm the concept that bone marrow and peripheral blood-derived stem and progenitor cells can differentiate into cardiomyocytes and endo­thelial cells when transplanted into ischemic myocardium, they also raise the question how effective this treatment is.

The results of the clinical trials that have been conducted are encouraging, but they need to be interpreted with caution. The common endpoints of these studies include left ventricular dimensions, perfusion, wall motion and hemodynamic function. While all studies report improvement after mononuclear cell, myoblast or endothelial progenitor cell transplantation, it is difficult to separate the effects of stem cell transplantation from the effects of the state-of-the art medical care that the patients typically received.

CONCLUSION

While the majority of studies demonstrate neoangiogenesis and some studies also show regeneration of myocardium after stem/progenitor cell transplantation, it remains unclear whether the currently achieved level of tissue regeneration is sufficient to affect clinical outcome. Long-term follow-up of patients that received stem/progenitor cells in clinical trials will provide important information on the potential risks of neoplasm and arrhythmias and, therefore, safety of this treatment. Ultimately, postmortem histological confirmation of scar tissue repair by transplanted cells and randomized placebo control trials with long-term follow-up are required to prove efficacy of this treatment.

REFERENCES (10)

1. American Heart Association Disease and Stroke Statistics-2003 Update, Dallas TX, American Heart Associ­ation; 2002 http://http://www.americanheart.org/downloadable/heart/10461207852142003HDSStatsBook.pdf

2. Arai A, Sheikh F, Agyeman K, et al. Lack of benefit from cytokine mobilized stem cell therapy for acute myocardial infarction in nonhuman primates. J Am Coll Cardiol 2003;41(Suppl 6A):371.

3. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999;85:221–228.

4. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–967.

5. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki M. Myogenic specification of side population cells in skeletal muscle. J Cell Biol 2002;159(1):123–134.

6. Assmus B, Schaechinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration en­hancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002;106:r53–r61.

7. Bader A, Al-Dubai H, Weitzer G. Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circ Res 2000;86(7):787–794.

8. Barski G, Sorieul S, Cornefert F. “Hybrid” type cells in combined cultures of two different mammalian cell strains. J Natl Cancer Inst 1961;26:1269–1291.

9. Boersma E, Mercado N, Poldermans D, Gardien M, Vos J, Simoons M. Acute myocardial infarction. Lancet 2003;361:847–58.

  1. 10.          Boheler K, Czyz J, Tweedie D, Yang H, Anisimov S, Wobus A. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res 2002;91:189–201.

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The Implications of a Newly Discovered  CYP2J2 Gene Polymorphism  Associated with Coronary Vascular Disease in the Uygur Chinese Population

Author, Curator: Larry H Bernstein, MD, FCAP

This is an interesting genomic study of the relationship of genetic polymorphism in the Chinese Uygur population that highlights the difficulty in CVD genomics, and casts a promising light on difficulties over
1.  possibly no more than 8 genetic signatures to account for all of human CVD conditions
2.  genetic signatures may no be equally distributed over studied populations
3.  genetic signatures may be more pronounced in different populations
4.  there is little predictable validity in such studies over large assimilated populations (such as African-Americans
5.  the best genomic evidence for meaningful associations does appear to tie in with endothelial metabolism
6.  the greatest difficulty in all studies is the small dose of information provided by an such linkage
7.  there has been too little information provided in studies of the effect of dietary factors on the affected population, which would entail nutrigenomics.
8.  there is an association between certain distinct CVD’s and later development of coronary heart disease (CHD).
This study concepts, methods and difficulties were recently reviewed in the following articles:
Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging
Aviva Lev-Ari, PhD, RN
Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013
Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP
Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems
Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP
Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus
Justin D. Pearlman, MD, PhD, and Aviva Lev-Ari, PhD, RN
Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?
Aviva Lev-Ari, PhD, RN
Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs
Aviva Lev-Ari, PhD, RN
Endothelial Function and Cardiovascular Disease
Larry H Bernstein, MD, FCAP
Reversal of Cardiac Mitochondrial Dysfunction
Larry H Bernstein, MD, FCAP
A Second Look at the Transthyretin Nutrition Inflammatory Conundrum
Larry H Bernstein, MD, FCAP

A Novel Polymorphism of the CYP2J2 Gene is Associated with Coronary Artery Disease in Uygur Population in China

Qing Zhu, Zhenyan Fu, Yitong Ma, Hong Yang, Ding Huang, Xiang Xie, Fen Liu, Yingying Zheng, Erdenbat Cha
PII: S0009-9120(13)00174-4    Available online 15 May 2013
Reference: CLB 8375
To appear in: Clinical Biochemistry
Received date: 17 February 2013
Revised date: 13 April 2013
Accepted date: 3 May 2013
Background: Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs).
  • The EETs are potent endogenous vasodilators and
  • inhibitors of vascular inflammation.
The aim of the present study was to assess the association between the human CYP2J2 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China.
We use two independent case-control studies:
  1. a Han population (206 CAD patients and 262 control subjects) and
  2. a Uygur population (336 CAD patients and 448 control subjects).
All CAD patients  and controls were genotyped for the same three single nucleotide polymorphisms (SNPs)
  1. rs890293
  2. rs11572223
  3. rs2280275
of CYP2J2 gene by a Real-time PCR instrument.
Results: In the Uygur population, for total, the distribution of SNP3 (rs2280275) genotypes showed a significant difference between CAD and control participants (P=0.048).
For total and men, the distribution of SNP3 (rs2280275) alleles and the dominant model (CC vs CT + TT)
  • showed a significant difference between CAD and control participants (for allele: P=0.014 and P=0.035, respectively; for dominant model: P=0.014 and P=0.034, respectively).
The significant difference in dominant model was retained after adjustment for covariates (OR: 0.279, 95% confidence interval [CI]: 0.176-0.440, P=0.001; OR: 0.240, 95% CI: 0.128-0.457, P=0.001, respectively).
Conclusions: The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China.
Highlights:
1. We used two independent case-control studies: one was in a Han population and the other was in a Uygur population.
2. The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China.
3. Polymorphism of the CYP2J2 gene can affect the synthesis of epoxyeicosatrienoic acids (EETs).
Reviewer Observations:
This article describes the association between CYP2J2 polymorphism(SNP1, SNP2 and SNP3) and coronary artery disease (CAD) in two populations of China (Han and Uygur).
Results show that
  1. the frequency of T allele of rs2280275 (SNP3 of the CYP2J2) is higher in CAD patients than in control subjects and
  2. that CC genotype of rs 2280275 is significantly lower in CAD patients than in control subjects.
  3. “T allele of rs2280275 was significantly higher in CAD patients than in control participants. CC genotype of rs2280275 was significantly lower in CAD patients than in control participants.”;
  4. It appears that CC is the homozygous and dominant state of this SNP3 sequence in a pairing-combination.
  5. The effect of decreased CHD is seen only in the CC double combination, in men and not women. The difference between men and women with CAD is in LDL.
For Uygur population,
(1) after adjusting major confounding factors such as Glu、LDL、EH、DM and smoking, the effect of decreased CAD is seen only in the CC double combination, in men and not women.
(2) for men, the LDL level is higher in CAD than in control, for women, there isn’t a difference of LDL level between CAD and control.
(3) for men, the distribution of T and C allele is different between CAD and control (p=0.035), and not in women (p=0.118).
The T allele of SNP3 is increased in CAD. So the C allele is important, and a CT pair is neutral. Neither SNP1 or SNP2, or presumably both have lower incidence.

I might conjecture that having(heterozygous rs2280275), a C & a T, and eating a lot of fish and/or flax seed would show a difference

  • because of the intimal enzymatic conversion of arachidonic acid to EETs.

Arachidonic acid is a derivative of linoleic acid,an n-6 PUFA, while linolenic acid is an omega-3 PUFA. Substantial documentation of the effect of EETs is given. The anti-inflammatory advantage of an n-3 PUFA is also known.
It appears that the intimal conversion results in an omega-3 product.  In addition, the EET activates eNOS, so that there is endothelial NO produced.

The studies of both Spiecker and Ping Yin Liu showed the polymorphism of CYP2J2 (rs890293, SNP1) has relation with CAD. However, in this study, the authors found there was no association between the polymorphism of CYP2J2 (rs890293, SNP1) and CAD in Han population and Uygur population. We found (rs 2280275, SNP3) has association with CAD.
  • “The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China”
All participants had a differential diagnosis for chest pain encountered in the Cardiac Catheterization Laboratory of First Affiliated Hospital of Xinjiang Medical University. We recruited randomly CAD group and control group, subjects with valvular disease were excluded, control subjects were not healthy individuals, some of them have hypertension, some of them have DM, some of them have hyperlipidemia, which means control group expose to the same risk factors of CAD while the results of coronary angiogram is normal. All control subjects underwent a coronary angiogram and have no coronary artery stenosis.
The analysis was a logistic regression analysis, we used the major variables of CAD to analysis and found the CC genotype was the dependent useful factor after adjusting for major confounding factors such as Glu、LDL、EH、DM and smoking.
Schematic of EET interactions with cardiovascularion channels.
A: In the cardiac myocyte, EETs activate sarcolemmal or mitochondrial KATP channels.
B: In the vasculature, EETs activate endothelial small-(SKCa) or intermediate (IKCa)–conductance calcium-activated channels to cause hyperpolarization, which can be transmitted to the vascular smooth muscle via myoendothelial gap junctions. EETs also activate TRPV4 channels to activate Ca2+influx. In the vascular smooth muscle, EETs activate large conductance, calcium-activated (BK-Ca) channels through a G protein-Coupled event.
C: In platelets, EETs activate BK-Ca channels.calcium-activated (BK-Ca) channels through a G-protein-coupled event. C, In platelets, EETs activate BK-Ca channels.

Association of the ADRA2A polymorphisms with the risk of type 2 diabetes: A meta-analysis

Xi Chen, Lei Liu, Wentao He, Yu Lu, Delin Ma, Tingting Du, Qian Liu, Cai Chen, Xuefeng Yu
Clinical Biochemistry 2013;  46 (9): 722–726   http://dx.doi.org/10.1016/j.clinbiochem.2013.02.004
Results from the published studies on the association of ADRA2A (adrenoceptor alpha 2A) variants with type 2 diabetes (T2D) are conflicting and call for further assessment. The aim of this meta-analysis was to quantitatively summarize the effects of the two recently reported ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 on T2D risk.
Results
Twelve studies with 40,828 subjects from seven eligible papers were included in the meta-analysis. Overall, the present meta-analysis failed to support a positive association between ADRA2A SNPs (rs553668 and rs10885122) and susceptibility to T2D (OR = 1.05, p = 0.17, 95% CI: 0.98, 1.12; and OR = 1.06, p = 0.11, 95% CI: 0.99, 1.13; respectively).
However, in the subgroup analysis by ethnicity, the significant association between rs553668 and the risk of T2D was obtained in Europeans under the recessive genetic model (OR = 1.36, p = 0.02, 95% CI: 1.05, 1.76).
Conclusion
The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P < 0.05) but not in Asians. The results from our case-control study and meta-analyses might be explained by genetic heterogeneity in the susceptibility of CHD and ethnic differences between Asians and Caucasians.

Association between PCSK9 and LDLR gene polymorphisms with coronary heart disease: Case-control study and meta-analysis

Lina Zhang, Fang Yuan, Panpan Liu, Lijuan Fei, Yi Huang, Limin Xu, et al.
Clinical Biochemistry 2013; 46 (9): 727–732
► Association of rs11206510 and rs1122608 with CHD in 813 Chinese participants.
► The first association test of rs1122608 with the risk of CHD in Han Chinese.
► Meta-analyses were performed for rs11206510 and rs1122608.
► The two SNPs were associated with CHD in Caucasians but not in Asians.
Objective
To explore the association of rs11206510 (PCSK9 gene) and rs1122608 (LDLR gene) polymorphisms with coronary heart disease (CHD) in Han Chinese.
Methods
A total of 813 participants (290 CHD cases, 193 non-CHD controls and 330 healthy controls) were recruited in the case-control study. DNA genotyping was performed on the SEQUENOM® Mass–ARRAY iPLEX® platform. χ2-test was used to compare the genotype distribution and allele frequencies. Two meta-analyses were performed to establish the association between the two polymorphisms with CHD.
Results
No significant associations between the two SNPs and the risk of CHD were observed in the present study. The meta-analysis of rs11206510 of PCSK9 gene comprises 11 case-control studies with a total of 69,054 participants. Significant heterogeneity was observed in Caucasian population in subgroup analysis of the association studies of rs11206510 with CHD (P = 0.003, I2 = 67.2%). The meta-analysis of LDLR gene rs1122608 polymorphism comprises 7 case-control studies with a total of 20,456 participants and the heterogeneity of seven studies was minimal (P = 0.148, I2 = 36.7%).
Conclusion
The results of the meta-analyses indicated that both SNPs were associated with CHD in Caucasians (P < 0.05) but not in Asians.

The effect of hyperhomocysteinemia on aortic distensibility in healthy individuals

I Eleftheriadou, P Grigoropoulou, I Moyssakis, A Kokkinos. et al.
Nutrition 18 Feb 2013; 29 (6): 876-880, PII: S0899-9007(13)00015-4
Elevated plasma homocysteine (HCY) levels have been associated with increased risk for cardiovascular disease. Aortic distensibility and aortic pulse wave velocity (PWV) are indices of aortic elasticity. The aim of the present study was to determine the effect of acute methionine-induced HHCY on aortic distensibility and PWV in healthy individuals and the effect of acute HHCY on myocardial performance of the left ventricle (Tei index).
Thirty healthy volunteers were included in this crossover study. Aortic distensibility and Tei index were determined non-invasively by ultrasonography at baseline and 3 h after methionine or water consumption, while PWV was measured by applanation tonometry at baseline and every 1 h for the same time interval.
Oral methionine induced an increase in total plasma HCY concentrations (P < 0.001), whereas HCY concentrations did not change after water consumption. Aortic distensibility decreased 3 h after methionine load (P < 0.001) and Tei index increased (P < 0.001), suggesting worsening compared with baseline values. Water consumption had no effect on aortic distensibility or Tei index values. PWV values did not change after either methionine or water consumption.
Acute methionine-induced HHCY reduces aortic distensibility and worsens myocardial performance in healthy individuals. Further research is warranted to examine in the long term the direct effects of HHCY on cardiovascular function and the indirect effects on structural remodeling.
Micrograph of an artery that supplies the hear...

Micrograph of an artery that supplies the heart with significant atherosclerosis and marked luminal narrowing. Tissue has been stained using Masson’s trichrome. (Photo credit: Wikipedia)

Estimated propability of death or non-fatal my...

Estimated propability of death or non-fatal myocardial-infarction over one year corresponding ti selectet values of the individual scores. Ordinate: individual score, abscissa: Propability of death or non-fatal myocardial infarction in 1 year (in %) (Photo credit: Wikipedia)

 

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Reporter: Aviva Lev-Ari, PhD, RN

Walking Versus Running for Hypertension, Cholesterol, and Diabetes Mellitus Risk Reduction

  1. Paul T. Williams,
  2. Paul D. Thompson

 

From the Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA (P.T.W.); and Division of Cardiology, Hartford Hospital, Hartford, CT (P.D.T.).
 

Correspondence to Paul T. Williams, PhD, Life Sciences Division, Lawrence Berkeley National Laboratory, Donner 464, 1 Cycloton Rd, Berkeley, CA 94720. E-mailptwilliams@lbl.gov
Abstract

Objective—To test whether equivalent energy expenditure by moderate-intensity (eg, walking) and vigorous-intensity exercise (eg, running) provides equivalent health benefits.

Approach and Results—We used the National Runners’ (n=33 060) and Walkers’ (n=15 945) Health Study cohorts to examine the effect of differences in exercise mode and thereby exercise intensity on coronary heart disease (CHD) risk factors. Baseline expenditure (metabolic equivant hours per day [METh/d]) was compared with self-reported, physician-diagnosed incident hypertension, hypercholesterolemia, diabetes mellitus, and CHD during 6.2 years follow-up. Running significantly decreased the risks for incident hypertension by 4.2% (P<10−7), hypercholesterolemia by 4.3% (P<10−14), diabetes mellitus by 12.1% (P<10−5), and CHD by 4.5% per METh/d (P=0.05). The corresponding reductions for walking were 7.2% (P<10−7), 7.0% (P<10−8), 12.3% (P<10−4), and 9.3% (P=0.01). Relative to <1.8 METh/d, the risk reductions for 1.8 to 3.6, 3.6 to 5.4, 5.4 to 7.2, and ≥7.2 METh/d were as follows: (1) 10.0%, 17.7%, 25.1%, and 34.9% from running and 14.0%, 23.8%, 21.8%, and 38.3% from walking for hypercholesterolemia; (2) 19.7%, 19.4%, 26.8%, and 39.8% from running and 14.7%, 19.1%, 23.6%, and 13.3% from walking for hypertension; and (3) 43.5%, 44.1%, 47.7%, and 68.2% from running, and 34.1%, 44.2% and 23.6% from walking for diabetes mellitus (walking >5.4 METh/d excluded for too few cases). The risk reductions were not significantly different for running than walking for diabetes mellitus (P=0.94), hypercholesterolemia (P=0.06), or CHD (P=0.26), and only marginally greater for walking than running for hypercholesterolemia (P=0.04).

Conclusions—Equivalent energy expenditures by moderate (walking) and vigorous (running) exercise produced similar risk reductions for hypertension, hypercholesterolemia, diabetes mellitus, and possibly CHD.

http://atvb.ahajournals.org/content/early/2013/04/04/ATVBAHA.112.300878.abstract.html?papetoc

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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.”

 SOURCE:

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

Reporter: Aviva Lev-Ari, PhD, RN

 

Updated on 10/3/2018

Treatment concentration of high-sensitivity C-reactive protein

Published:November 13, 2017DOI:https://doi.org/10.1016/S0140-6736(17)32865-9

Interleukin 1β has multiple potential mechanisms that contribute to the pathogenesis of atherothrombotic cardiovascular disease.

Induction of interleukin 6 leads to the release of acute phase reactants including hsCRP. Thus, hsCRP serves as a surrogate marker of the overall inflammatory milieu,

often in situations where patients have multiple co-morbidities,

with a cumulative dose-response indicating a higher risk.

References

  • Ridker PM
  • Everett BM
  • Thuren T
  • et al.
Antiinflammatory therapy with canakinumab for atherosclerotic disease.

N Engl J Med. 2017; 3771119-1131

  • Libby P
Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond.

J Am Coll Cardiol. 2017; 702278-2289

  • Pokharel Y
  • Sharma PP
  • Qintar M
  • et al.
High-sensitivity C-reactive protein levels and health status outcomes after myocardial infarction.

Atherosclerosis. 2017; 26616-23

  • Wang A
  • Liu J
  • Li C
  • et al.
Cumulative exposure to high-sensitivity C-reactive protein predicts the risk of cardiovascular disease.

J Am Heart Assoc. 2017; 6e005610

    • Ridker PM
    • MacFadyen JG
    • Everett BM
    • et al.

on behalf of the CANTOS Trial Group

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.

Lancet. 2017; (published online Nov 13.)

SOURCE

 

 

 

 

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic StrokeAtherosclerosis.

 

Watch VIDEO

webinar

Lp-PLA2 Overview Webinar

Source: http://www.plactest.com/healthcare/webinar

Watch VIDEO

 american-heart-association-2007-lppla2-highlights

American Heart Association 2007 Lp-PLA2 Presentation

Source: http://www.plactest.com/healthcare/american-heart-association-2007-lppla2-highlights

diaDexus’s PLAC, the test measuting Lp-PLA2 as a novel and valuable cardiovascular risk inflammatory marker a vascular-specific inflammatory marker implicated in the formation of rupture-prone plaque, and is the only blood test cleared by the FDA to assess risk for coronary heart disease and ischemic stroke associated with atherosclerosis. (2003 and in 2005 received additional clearance as an aid in the assessment of risk for ischemic stroke associated with atherosclerosis.)

 

In 2007 the PLAC Test was granted a Category I CPT Code (83698) by the American Medical Association and is reimbursed by the Centers for Medicare and Medicaid Services (CMS) with a National Limitation Amount (NLA) of $47.77 in the 2011 CMS Clinical Laboratory Fee Schedule.

In July 2010, diaDexus completed a reverse merger with VaxGen. diaDexus currently trades on the OTC Bulletin Board (DDXS.OB).

 

PLAC Test is an alternative to C- Reactive Protein Test

 

The PLAC® Test is a simple blood test to detect Lp-PLA2 in the bloodstream. It is used to help predict risk for coronary heart disease and ischemic stroke associated with atherosclerosis.

 

  • The PLAC Test measures Lp-PLA2
    (lipoprotein-associated phospholipase A2), a vascular-specific inflammatory enzyme implicated in the formation of rupture-prone plaque. It is plaque rupture and thrombosis, not stenosis, that causes the majority of cardiac events.
  • A substantial body of evidence, including over 100 studies and abstracts in peer-reviewed journals and conferences, support Lp-PLA2 as a cardiovascular risk marker that provides new information, over and above traditional risk factors.
  • Consistent with ATP III and European guidelines, the PLAC Test should be used as an adjunct to traditional risk factor assessment to identify which moderate or high risk patients, as initially assessed by traditional risk factors, may actually be at higher risk.
  • An elevated PLAC Test may indicate a need for more aggressive patient management.
    • 50% of cardiovascular events strike in patients with unremarkable lipid levels, highlighting the prevalence of hidden cardiovascular risk.
    • LDL-C and total cholesterol have proven not to be reliable predictors of stroke; the PLAC Test addresses this unmet clinical need.
  • Lipid lowering therapies, including statins, are proven to reduce cardiovascular events regardless of baseline LDL-C levels.

 

Basic Science of Lp-PLA2

The PLAC® Test measures Lp-PLA2 (lipoprotein-associated phospholipase A2) a vascular-specific inflammatory enzyme implicated in the formation of rupture-prone plaque. It is plaque rupture and thrombosis that cause the majority of cardiac events, not stenosis.

 

 

 

 

Lp-PLA2 is a calcium-independent serine lipase that is associated with both low-density lipoprotein (LDL) and, to a lesser extent, high-density lipoprotein (HDL) in human plasma and serum and is distinct from other phospholipases such as cPLA2 and sPLA2. Lp-PLA2 is produced by macrophages and other inflammatory cells and is expressed in greater concentrations in advanced atherosclerotic lesions than early-stage lesions.

 

Lp-PLA2 has demonstrated modest intra- and inter-individual variation, commensurate with other cardiovascular lipid markers and substantially less than C-reactive protein (CRP). In addition, Lp-PLA2 is not elevated in systemic inflammatory conditions, and may be a more specific marker of vascular inflammation. The relatively small biological variation of Lp-PLA2 and its specificity are of value in the detection and monitoring of cardiovascular risk.

SOURCE:

http://www.plactest.com/healthcare/basic-science.html

 

 

Clinical Utility of the PLAC Test

 

The PLAC® Test Measures Lp-PLA2, a Unique Marker  
The PLAC Test for Lp-PLA2 is the only blood test cleared by the FDA to aid in assessing risk for both coronary heart disease and ischemic stroke associated with atherosclerosis. The PLAC Test measures lipoprotein-associated phospholipase A2 (Lp-PLA2), a vascular-specific biomarker implicated in the formation of rupture-prone plaque. The majority of all heart attacks and strokes are caused by plaque rupture and thrombosis (clots) – not stenosis (narrowing of arteries).

Lp-PLA2 is a unique marker for vascular-specific inflammation and is produced by macrophages in inflamed plaque. Lp-PLA2 provides additive risk information when combined with other markers such as hs-CRP to help you personalize your treatment options, beyond the limitations of the traditional cardiovascular (CV) risk factors.

The PLAC Test Helps Identify Hidden Risk
Lp-PLA2 is an independent risk marker for stroke. At every level of blood pressure, an Lp-PLA2 value above the median almost doubles the risk for stroke.  Current stroke guidelines include consideration of Lp-PLA2 measurement in asymptomatic patients to identify those who may be at increased risk of stroke.

The PLAC Test Helps Improve Patient Management 
Periodic measurement of the amount of Lp-PLA2 in the blood for patients with 2 or more CVD risk factors can aid clinical decisions for at-risk patients, allowing you to assess or reassess the effect of lipid lowering therapies on vascular inflammation, intensify therapeutic lifestyle changes, and reinforces doctors’ recommendations for patient management.

 

 

 

 

Essential Information to Guide Treatment

In accordance with ATP III Guidelines, patients with 2 or more CV risk factors may be candidates for advanced lipid testing.

Measure the amount of Lp-PLA2 in your patient’s blood stream with the PLAC Test to determine whether they may be at increased risk for heart attack or stroke.

If the PLAC Test results are 200 ng/mL or greater, cardiovascular disease may be present. Review your patient’s advanced lipid panel results to determine where more aggressive patient management may be needed.

 

* additional reduction of Lp-PLA2 seen when added to statin therapy.

Based on:

Shalwitz R, et al. ATVB Annual Mtg. 2007.

Kuvin J, et al. Am J Cardiol. 2006.

Albert M, et al. Atherosclerosis 2005.

Schaefer EJ, et al. Am J Cardiol. 2005.

Saougos VG, et al. ATVB 2007.

Muhlestein JB, et al. JACC 2006.

      Early detection and more aggressive treatment can help prevent cardiovascular events.


 

SOURCE:

http://www.plactest.com/Default.aspx?PageID=4620488&A=PrinterView

 

 

REFERENCES

 

Pathophysiology and Genetics Studies

 

A Twin Study of Heritability of Plasma Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Mass and ActivityLenzini L, Antezza K, Caroccia B, Wolfert RL, Szczech R, Cesari M, Narkiewicz K, Williams CJ, Rossi GP. A Twin Study of Heritability of Plasma Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Mass and Activity. Atherosclerosis. 2009; 205(1): 181-5.

Enhanced Expression of Lp-PLA2 and Lysophosphatidylcholine in Symptomatic Carotid Atherosclerotic PlaqueMannheim D, Herrmann J, Versari D, Gössl M, Meyer FB, McConnell JP, Lerman LO, Lerman A. Enhanced Expression of Lp-PLA2 and Lysophosphatidylcholine in Symptomatic Carotid Atherosclerotic Plaque. Stroke. 2008; 39: 1448-55.

Expression of Lipoprotein-Associated Phospholipase A2 in Carotid Artery Plaques Predicts Long-term Cardiac OutcHerrmann J, Mannheim D, Wohlert C, Versari D, Meyer FB, McConnell JP, Gössl M, Lerman LO, Lerman A. Expression of Lipoprotein-Associated Phospholipase A2 in Carotid Artery Plaques Predicts Long-term Cardiac Outcome. Eur. Heart J. 2009 Dec; 30(23): 2930-8.

Lipoprotein-Associated Phospholipase A2 is an Independent Marker for Coronary Endothelial Dysfunction in HumansYang EH, McConnell JP, Lennon RJ, Barsness GW, Pumper G, Hartman SJ, Rihal CS, Lerman LO, Lerman A. Lipoprotein-Associated Phospholipase A2 is an Independent Marker for Coronary Endothelial Dysfunction in Humans. Arterioscler Thromb Vasc Biol. 2006; 26(1): 106-11.

Lipoprotein-Associated Phospholipase A2 Protein Expression in the Natural Progression of Human Coronary AtherosclerosisKolodgie FD, Burke AP, Skorija KS, Ladich E, Kutys R, Makuria AT, Virmani R. Lipoprotein-Associated Phospholipase A2 Protein Expression in the Natural Progression of Human Coronary Atherosclerosis. Arterioscler Thromb Vasc Biol. 2006; 26: 2523-9.

 

Therapeutic Modulation Studies

 

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial.Robins SJ, Collins D, JJ, Bloomfield HE, Asztalos BF. Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2008; 28(6): 1172-8.

Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) TrialWhite HD, Simes J, Barnes, E et al. Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) Trial. Circulation, abstract 14857, AHA 2011

Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, Elisaf M, Tselepis AD. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2. Arterioscler Thromb Vasc Biol. 2007; 27: 2236-43.

Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control SubjectsSchaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ. Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control Subjects. Am J Cardiol. 2005; 95: 1025-32.

Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery DiseaseKuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, Karas RH. Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery Disease. Am J Cardiol. 2006; 98: 743-5.

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial.Robins SJ, Collins D, JJ, Bloomfield HE, Asztalos BF. Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2008; 28(6): 1172-8.

Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) TrialWhite HD, Simes J, Barnes, E et al. Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) Trial. Circulation, abstract 14857, AHA 2011

Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, Elisaf M, Tselepis AD. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2. Arterioscler Thromb Vasc Biol. 2007; 27: 2236-43.

Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control SubjectsSchaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ. Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control Subjects. Am J Cardiol. 2005; 95: 1025-32.

Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery DiseaseKuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, Karas RH. Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery Disease. Am J Cardiol. 2006; 98: 743-5.

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial.Robins SJ, Collins D, JJ, Bloomfield HE, Asztalos BF. Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2008; 28(6): 1172-8.

Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) TrialWhite HD, Simes J, Barnes, E et al. Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) Trial. Circulation, abstract 14857, AHA 2011

Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, Elisaf M, Tselepis AD. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2. Arterioscler Thromb Vasc Biol. 2007; 27: 2236-43.

Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control SubjectsSchaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ. Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control Subjects. Am J Cardiol. 2005; 95: 1025-32.

Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery DiseaseKuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, Karas RH. Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery Disease. Am J Cardiol. 2006; 98: 743-5.

 

 

 

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