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Voices from the Cleveland Clinic On Circulating apoA1: A Biomarker for a Proatherogenic Process in the Artery Wall

Posted in Atherogenic Processes & Pathology, Best evidence, Cardiovascular Research, Evidence-based decision-making, Frontiers in Cardiology and Cardiovascular Disorders, Origins of Cardiovascular Disease, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Research, Translational Science on January 29, 2014| Leave a Comment »

Voices from the Cleveland Clinic On Circulating apoA1: A Biomarker for a Proatherogenic Process in the Artery Wall

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 3/4/2019

People with Diabetes May Be Missing Out on HDL Cardiovascular Protections

Glycation lowers ApoA1 stability, destroys HDL in T2DM

A Cleveland Clinic study for the first time revealed a mechanism that rapidly destroys high-density lipoprotein (HDL) in people with Type 2 diabetes, negating cardiovascular protections of the so-called good cholesterol.

Sangeeta Kashyap, MD, in Cleveland Clinic’s Endocrinology & Metabolism Institute, and co-author Jonathan D. Smith, PhD, the Geoffrey Gund Endowed Chair for Cardiovascular Research in the Department of Cellular & Molecular Medicine in the Lerner Research Institute, and senior author Takhar Kasumov, PhD, adjunct in Gastroenterology and Hepatology at Cleveland Clinic and fulltime faculty at NEOMED, published a clinical research article in The Journal of Clinical Endocrinology & Metabolism.

The study, “Glycation Reduces the Stability of APOAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes,” looks at the role of hyperglycemia-induced glycation on ApoA1 kinetics and stability in patients with diet-controlled type 2 diabetes mellitus (T2DM).

Derailing ApoA1

The study found that in people with diabetes, glycation of the ApoA1 molecule causes it to degrade three times faster than in a person without diabetes.

“When ApoA1 is destroyed faster, it is not able to perform its main function for reverse cholesterol uptake, which means taking the bad cholesterol and disposing of it,” says study co-author Sangeeta Kashyap, MD. “The bottom line is that it does not just matter how much good cholesterol you have, but how the cholesterol works to protect you. In people with diabetes, good cholesterol does not work normally to protect them from atherosclerotic heart disease.”

From a clinical perspective, Dr. Kashyap says, the data highlights that normal, or even elevated, HDL levels in T2DM does not equate to adequate functionality. Glycation of ApoA1, she says, is a marker for hyperglycemia-induced HDL dysfunction that blunts the anti-atherogenic and anti-oxidant functions of HDL.

These findings were reached using 2H20-metabolic labeling – a novel heavy water-based non-radioactive technique that looks at the kinetics of HDL by measuring the production and destruction of ApoA1. They study also found ApoA1 instability is related to early glycation of lysine on ApoA1 and associated with glycated hemoglobin (HbA1c) levels – a measure of long-term hyperglycemia.

When Good Cholesterol Goes Bad

“The important clinical piece for practitioners is that even if you see normal or high HDL levels, don’t think it’s working in their favor,” Dr. Kashyap says. “If they have high blood sugar, that’s a marker that HDL is not working to protect them from the atherogenic process.

Dr. Kashyap says lowering glucose levels could be a way to restore HDL functionality in people with diabetes. While previous articles theorized that high triglycerides were related to good cholesterol, this study found that HDL functionality is related to ambient glucose levels.

Reversing the Damage

Next steps involve looking at various glucose lowering interventions, including the effects of the diabetic drug Metformin and insulin, to lower glucose levels.

“We’re interested in looking at specific interventions to lower glucose levels to see if these defects are reversible. We believe they are,” Dr. Kashyap says. “This is an early glycation process. If we are able to lower blood sugar levels, we can reverse levels of lysine glycation of ApoAI and restore functionality of HDL.”

SOURCE

https://consultqd.clevelandclinic.org/people-with-diabetes-may-be-missing-out-on-hdl-cardiovascular-protections/?utm_campaign=qd%20tweets&utm_medium=social&utm_source=twitter&utm_content=171204%20diabetes%20cardiovascular&cvosrc=social%20network.twitter.qd%20tweets&cvo_creative=171204%20diabetes%20cardiovascular

 

NATURE MEDICINE | ARTICLE

An abundant dysfunctional apolipoprotein A1 in human atheroma

Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med2014; published online December 26, 2014. DOI:10.1038/nm.3459. Abstract

Affiliations

Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.

  • Ying Huang,
  • Joseph A DiDonato,
  • Bruce S Levison,
  • Dave Schmitt,
  • Lin Li,
  • Jennifer Buffa,
  • Timothy Kim,
  • Gary S Gerstenecker,
  • Xiaodong Gu,
  • Chandra S Kadiyala,
  • Zeneng Wang,
  • Miranda K Culley,
  • Jennie E Hazen,
  • Anthony J DiDonato,
  • Xiaoming Fu,
  • Stela Z Berisha,
  • Daoquan Peng,
  • Truc T Nguyen,
  • Leslie Cho,
  • Paul L Fox,
  • Valentin Gogonea,
  • W H Wilson Tang,
  • Jonathan D Smith &
  • Stanley L Hazen

  1. Department of Mathematics, Cleveland State University, Cleveland, Ohio, USA.

    • Yuping Wu

  2. Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA.

    • Gary S Gerstenecker &
    • Valentin Gogonea

  3. Cleveland Heart Lab, Cleveland, Ohio, USA.

    • Shaohong Liang

  4. Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Chia-Chi Chuang &
    • John S Parks

  5. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.

    • Leslie Cho,
    • Edward F Plow,
    • W H Wilson Tang,
    • Jonathan D Smith &
    • Stanley L Hazen

  6. Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA.

    • Edward F Plow

  7. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • John S Parks

  8. Department of Cardiovascular Medicine, New York University School of Medicine, New York, New York, USA.

    • Edward A Fisher

Contributions

Y.H. participated in all laboratory, animal and human studies, assisted in statistical analyses, helped design the experiments and drafted the manuscript. B.S.L., G.S.G., V.G., C.S.K., Z.W. and X.F. assisted with various laboratory and mass spectrometry studies. D.S., J.B., M.K.C., S.Z.B. and C.-C.C. helped perform various animal experiments. J.A.D., D.S., T.K., X.G., M.K.C., J.E.H., A.J.D. and D.P. helped make various bacterial expression clones and produce and purify recombinant proteins used. J.A.D. and S.L. helped with mAb generation and screening. T.K. and T.T.N. helped with ELISA assays. L.L. and Y.W. provided statistical analyses of clinical data. J.A.D., L.C., E.F.P., P.L.F., V.G., W.H.W.T., J.S.P., E.A.F., J.D.S. and S.L.H. provided experimental analysis and expertise. All authors took part in critical review of the manuscript. The project was scientifically conceived and directed by S.L.H.

Corresponding author

Correspondence to:

Published online 26 January 2014

Nature Medicine (2014) doi:10.1038/nm.3459

Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl− system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.

SOURCE

http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.3459.html

Oxidized, Dysfunctional HDL Evident in Atheroma

January 27, 2014

Topic Alert

DRUG & REFERENCE INFORMATION

CLEVELAND, OH — In the latest twist on the complicated nature of HDL cholesterol, researchers have published a study this week showing that when oxidized at a specific site on apolipoprotein A1 (apoA1), HDL cholesterol becomes dysfunctional and proinflammatory [1] . Importantly, the group also found that this dysfunctional apoA1 accounts for 20% of apoA1 in arteries diseased with atherosclerosis.
In the study, published online January 26, 2014 in Nature Medicine, Dr Ying Huang (Cleveland Clinic, OH) and colleagues report that apoA1, the primary protein that makes up approximately 75% of HDL particles, is oxidized by myeloperoxidase (MPO) at Trp72, and such oxidation impairs the cardioprotective functions of HDL.”In the artery wall, within a plaque, the HDL literally gets blown apart,” senior investigator Dr Stanley Hazen (Cleveland Clinic, OH) told heart wire . “It gets so heavily oxidized that it’s not even a particle anymore. And over 97% of the modified form of apoA1 is no longer sitting on HDL. Even though we’re calling it dysfunctional HDL, it’s truly dysfunctional. It’s been beaten up and broken up to the point where it’s no longer an HDL particle.”
First Identified Role of MPO, Now This 
In 2004, Hazen, who is also the vice chair of translational research at the Lerner Research Institute, published a study showing that apoA1 is a selective target for MPO-catalyzed oxidation, and when this occurs, the HDL is inactivated or becomes dysfunctional. In essence, MPO oxidation prevented reverse cholesterol transport and the ability of HDL to unload cholesterol from cholesterol-loaded macrophage foam cells.
“Since then, we have started mapping where it gets modified and how it gets modified,” said Hazen. “The truth is we found over 50 site-specific modifications. We started doing all kinds of mutagenesis studies to find out which residue is important. This led us to focus on the current site, a tryptophan that is critical for the cholesterol-carrying function of apoA1. It took a long time to identify. Even though this is such an abundant product in atherosclerotic plaque, it’s evident in very low levels in circulation. We believe it’s actually getting made in the artery wall and leeching back out into the bloodstream, and it’s this tiny amount that we’re detecting.”
In the present study, Hazen and colleagues report that apoA1 is metabolized by MPO at Trp72. In vivo and in vitro studies showed that when MPO oxidizes apoA1 at Trp72, it disables the protein’s ability to interact with the ATP-binding cassette transporter A1 (ABCA1), the major pathway for loading cholesterol onto the apoA1 particle and forming an HDL particle. The oxidized Trp72-apoA1 complex is found in very low abundance in circulation but accounted for approximately 20% of the apoA1 in atherosclerotic plaque.
When the oxidized Trp72-apoA1 complex was assessed, the researchers found that it exerted a proinflammatory effect on endothelial cells as evidenced by increases in adhesion proteins and proinflammatory markers. In contrast, healthy HDL (as well as apoA1) has anti-inflammatory effects.
In an analysis of 627 individuals presenting to the cardiology clinic, the researchers found that increased plasma levels of oxidized Trp72-apoA1 were associated with increased cardiovascular risk on top of existing risk factors and blood tests. Hazen suggested the whole process might be the result of a “feed-forward” loop, such that apoA1 might get stuck in the artery wall with atherosclerosis, become modified by MPO, and in turn generate the proinflammatory form, a “dysfunctional HDL.”  The feed-forward loop then exacerbates the whole atherosclerotic disease process.

An assay for oxidized Trp72-apoA1 is expected to be available from Cleveland Heart Lab by the end of the year. What’s exciting about this assay, said Hazen, is that it detects not just a marker, but also a molecule involved in the disease process. If oxidized apoA1 can be measured and ultimately lowered, there is hope that doing so might reduce the risk of cardiovascular disease.The cardiovascular focus on raising HDL-cholesterol levels to prevent clinical events has been hit with disappointments in recent years, with numerous high-profile studies showing that while it’s possible to raise HDL-cholesterol levels with various agents, doing so does not translate into clinical benefit. One of the hypotheses behind such failures, including

has been that despite raising HDL-cholesterol levels, the HDL particle is dysfunctional.

Hazen, along with three coauthors, reports being a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics or therapeutics. He is a paid consultant to AstraZeneca, Cleveland Heart Lab, Esperion, Lilly, Liposcience, Merck, Pfizer, Procter & Gamble, and Takeda. He reports research funding from the Cleveland Heart Lab, Liposcience, Procter & Gamble, and Takeda. Finally, Hazen reports the right to receive royalty payments for inventions/discoveries related to cardiovascular diagnostics or therapeutics from the Cleveland Heart Lab, Esperion, Frantz Biomarkers, and Liposcience . Other disclosures for the coauthors are listed in the online version of the paper.

REFERENCE
Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med2014; published online December 26, 2014. DOI:10.1038/nm.3459. Abstract
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Other articles on Apo1 and HDL published on this Open Access Online Scientific Journal include the following:

LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/18/ldl-hdl-tg-apoa1-and-apob-genetic-loci-associated-with-plasma-concentration-of-these-biomarkers-a-genome-wide-analysis-with-replication/

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

Voice from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/21/voices-from-the-cleveland-clinic-on-the-new-lipid-guidelines-and-on-the-accaha-risk-calculator

Endothelial Dysfunction (release into the circulation of damaged endothelial cells) as A Risk Marker for Ischemia and MI

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/01/12/endothelial-dysfunction-as-risk-marker/

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/11/15/artherogenesis-predictor-of-cvd-the-smaller-and-denser-ldl-particles/

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

Lp(a) Gene Variant Association

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/03/06/10447/

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

http://pharmaceuticalintelligence.com/2013/05/17/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/

Assessing Cardiovascular Disease with Biomarkers

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://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?

Larry H Bernstein, MD and Aviva Lev-Ari, PhD, RN

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

Read Full Post »

More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes

Posted in Cardiovascular Research, Diabetes Mellitus, Diagnostic Immunology, Evidence-based decision-making, Frontiers in Cardiology and Cardiovascular Disorders, Immunodiagnostics, Proteomics, Quality Assurance, Systemic Inflammatory Response Related Disorders, Total error, Translational Research, Translational Science, tagged , , , , , , , , on January 20, 2014| Leave a Comment »

More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes

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

 

UPDATED on 9/1/2019

Risk-Based Thresholds for hs-Troponin I Safely Speed MI Rule-Out

HISTORIC suggests benefit to patients, clinicians

PARIS — Using different cutoffs for high-sensitivity cardiac troponin I (hs-cTnI) testing based on risk accurately ruled out MI and sent patients home from the emergency department sooner without missing adverse cardiac events, the HISTORIC trial found.

In the stepped-wedge trial of over 30,000 consecutive patients, introduction of the risk-based approach reduced length of stay at the emergency department by over 3 hours compared with standard care (6.8 vs 10.1 hours, P<0.001), reported Nicholas Mills, MD, PhD, of the University of Edinburgh in Scotland.

And 74% of patients under the new pathway were discharged without requiring hospital admission versus 53% under standard protocols (adjusted risk ratio 1.57, 95% CI 1.34-1.83, P<0.001).

For the primary safety endpoint, 2.5% of patients in the standard group died from cardiac causes or had an MI at 12 months post-discharge versus 1.8% of those in the early rule-out group (adjusted OR 1.02, 95% CI 0.74-1.40).

“Adoption of this approach will have major benefit for both patients and healthcare providers,” said Mills during a late-breaking press briefing at the 2019 European Society of Cardiology (ESC) congress.

For example, many patients will need only a single troponin test under the algorithm to lead to a decision on admission, he noted, which could have “absolutely enormous” cost savings.

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81926?xid=nl_mpt_ACC_Reporter_2019-09-01&eun=g5099207d2r

 

UPDATED on 8/7/2018

Siemens’ high-sensitivity Troponin I (TnIH) assays got FDA clearance for use in diagnosing acute myocardial infarction. (Cardiovascular Business) The first high-sensitivity Troponin T test was cleared last year, as MedPage Today reported.

SOURCE

https://www.medpagetoday.com/cardiology/prevention/74423?xid=nl_mpt_cardiobreak2018-08-06&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Ca

 

This is the final up to date review of the status of hs troponin T (or I) with or without the combined use of the Brain Type Natriuretic Peptide or its Amino Terminal peptide precursor.  In addition, a new identification of the role of the Atrial Natriuretic Peptide has been reported with respect to arrythmogenic activity.  On the one hand, the diagnostic value of the NT-proBNP has been seen as disappointing, in part because of the question of what information is gained by the test in overt known congestive heart failure, and in part because of uncertainty about following the test during a short hospital stay.  At least, this is the view of this reviewer.  However, in the last several years there has been an emphasis on the value this test adds to prediction of adverse outcomes.   In addition, there has been a hidden nvariable that has much to do with the original reference values that were established for age ranges, without any consideration of pathophysiology that might affect the values within those ranges, leading one to consider values in an aging population as normal, that might well be high.  Why is this?  Aging patients are more likely to have hypertension, and also the onset of type-2 diabetes mellitus, with cardiovascular disease consequences.  Type-2 diabetes mellitus (T2DM), for instance, is associated with insulin resistance and also fat gain with generation of adipokines, but the is also a hyalinization of insulin forming beta-cells of the pancreas, and there is hyalinization of glomeruli (glomerulosclerosis) and afferent arteriolonephrosclerosis with expected decline in glomerular filtrattion rate and hypertension as well.   Of course, this is also associated with hepatosteatosis.   Nevertheless, a reference range is established that takes none of this pathophysiology into account.   While a more reasonable approach has been pointed out, there has been no followup in the literature.

On the other hand, there has been much confusion over the restandardization of a high sensitivity troponin I or T test (hs-Tn(I or T).  The reference range declines precipitously, and there is a good identification of patients who are for the most part disease free, but there is no delineation of patients who are at high risk of acute coronary syndrome with plaque rupture, vs a  host of other cardiovascular conditions.  These have no relationship to plaque rupture, but may be serious and require further evaluation.  The question then becomes whether to admit for a hospital stay, to refer to clinic after an evaluation in the ICU without admission, or to do an extensive evaluation in the emergency department overnight before release for followup.  There is still another dimension of this that has to do with prediction of outcomes using hs-Tn(s) with or without the natriuretic peptides.  Another matter that is not for discussion in this article is the underutilization of hs-CRP.  Originally used for a marker of sepsis in the 1970s, it has come to be tied in with identification of an ongoing inflammatory condition.  Therefore, the existence of a known inflammatory condition in the family of autoimmune diseases, with one exception, might make it unnecessary.

The discussion is broken into three parts:

Part 1.   New findings on the troponins.
Part 2.  The use of combined hs-Tn with a natriuretic peptide (NT-proBNP)
Part 3.  Atrial natriuretic peptide

Part 1.    New findings on the troponins.

Troponin: more lessons to learn

C Liebetrau,HM Nef,andCW.Hamm*
KerckhoffHeartandThoraxCenter;DepartmentofCardiology,BadNauheim,
Germany; (GermanCentreforCardiovascularResearch),partnersite
RheinMain,BadNauheim, Germany; and UniversityofGiessen,Medizinische
KlinikI,KardiologieundAngiologie,Giessen,Germany
European Hear tJournal
http://dx.doi.org/10.1093/eurheartj/eht357This editorial refers to ‘Risk stratification in patients with acute chest pain
using three high-sensitivity cardiac troponin assays’,
by P. Haafetal. http://dx.doi.org/10.1093/eurheartj/eht218Cardiac troponin entered our diagnostic armamentarium 20 years ago and –
unlike any other biomarker –

  • is going through constant expansion in its application.

Troponin started out as a marker of risk in unstable angina’, then was used

  • as gold standard for risk stratification and therapy guiding in acute coronary syndrome
  •  served further to redefine myocardial infarction, and
  • has also become a risk factor in apparently healthy subjects.

The recently introduced high-sensitivity cardiac troponin (hs-cTn) assays

  • have not only expanded the potential of troponins, but
  • have also resulted in a certain amount of confusion
    • among unprepared users.

After many years troponins were accepted as the gold standard in

  • patients with chest pain by
  • classifying them into troponin-positive and
    • troponin-negative patients.

The new generation of hs-cTn assays has

  • improved the accuracy at the lower limit of detection and
  • provided incremental diagnostic information especially
    • in the early phase of myocardial infarction.

Moreover, low levels of measurable troponins

  • unrelated to ACS have been associated with
    • an adverse long-term outcome.

Several studies demonstrated that

  • these low levels of cardiac troponin measureable 
    • only by hs-Tn assays
  • are able to predict mortality in patients with ACS
  • as well as patients with assumed
    • stable coronary artery disease.

Furthermore, hs-cTn has the potential

  • to play a role in the care of patients
    • undergoing non-cardiac surgery.

The additional determination of hs-cTn

  • improves risk stratification despite
  • established risk scores providing both diagnosis and
  • for prognosis prediction in chest pain patients.

The daily clinical challenge in using the highly sensitive assays is to 

  • interpret the troponin concentrations, especially
  • in patients with concomitant diseases
    • independently from myocardial ischaemia
  • influencing cardiac troponin concentrations
    (e.g. chronic kidney disease, or stroke). 

The troponin test lost its ‘pregnancy test’ quality with the different users.
Different opinions exist on

  • the change of hs-cTn levels compared to simple ‘positive–negative’ interpretation
  • and thereby makes diagnosis finding more complex than before.

This uncertainty probably has the paradigm that

  • serial measurements of troponins are necessary, and also
    • boosted the number of diagnoses of ACS and
    • invasive diagnostic procedures in some locations.

This is more than understandable, with acute chest pain using

  • three high-sensitivity cardiac troponins with their respective baseline value
    • before the diagnosis of acute myocardial infarction (AMI) can be made.

What is a relevant change in concentrations compatible with acute myocardial necrosis and

  • what is only biological variation for the specific biomarker and assay?

Changes in serial measurements between 20% and 200% have been debated, and
the discussion is ongoing. Furthermore, it has been proposed that

  • absolute changes in cardiac troponin concentrations 
    • have a higher diagnostic accuracy for AMI
  • compared with relative changes, and

it might be helpful in distinguishing AMI from other causes of cardiac troponin elevation.

Do we obtain any helpful directives from experts and guidelines for our daily practice?
Foreseeing this dilemma, the 2011 European Society of Cardiology (ESC) Guidelines

  • on non ST-elevation ACS acted.
  • Minor elevations of  troponins were accepted as hs-cTn values in the ‘grey zone’.

This was and still is the rule, but

  • the ESC provided a general algorithm on how to manage patients with limited data.

The ‘Study Group on Biomarkers in Cardiology’ suggested

  • a rise of 50% from the baseline value at low concentrations.

However, this group of experts could also not find a substitute for the missing data

  • needed to validate the proposed recommendation.

The story is just too complex:

  • different troponin assays with
  • different epitope targets,
  • different patient populations,
  • different sampling protocols,
  • different follow-up lengths, and much more.

Therefore, any study that helps us to see better through the fog is welcome here.

Haaf et al. have now presented the results of their study of

  • different hs-cTn assays
    (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; and  hs-cTnI, Siemens)

    • with respect to the -outcome of patients with acute chest pain.

The authors examine 1117 consecutive patients presenting with acute chest pain.
[340 patients with ACS (30.5%)] from the Advantageous Predictors of Acute Coronary Syndrome
Evaluation (APACE) study. Blood was collected

  • directly on admission and
  • serially thereafter at 2, 3, and 6h.

Eighty-two patients (7.3%) died during the 2-year follow-up. The main finding of the study is that

  1. hs-cTnT predicts mortality more accurately than the hs-cTnI assays, 
  2. -that a single measurement is sufficient
  3. challenges causes of cardiac troponin elevation.

These results of APACE remain in contrast to recent findings from a GUSTO IV cohortof 1335 patients with ACS (Table1).

Table1 Studies investigating high sensitivity troponins for long-term prognosis

Variable                                                       APACE (n 5 1117)              GUSTO IV (n 5 1335)              PEACE (n 5 3567)

………………………………………………………………………………………………………………………………………………………….

Patient cohort                                                   Unstable                            Unstable                               Stable

Blood sampling                                     On admission,1,2,3,6h                    48h after
study randomization           Before randomization

No. of patients with detection limit             883 (79.1%)                                 UKN                                      UKN

No. of patients with hs-cTnT.
99thpercentile                                        401 (35.9%)                              1015 (76%)                          395 (10.9%)

No. of patients with hs-cTnI (Abbott).
detection limit                                           UKN                                             UKN                              3567 (98.5%)

No.of patients with hs-cTnI (Abbott).
99th percentile                                          UKN                                         988(74%)                           105 (2.9%)

No. of patients with NSTEMI                     170 (15.2%)                              100 (100%)                             0 (0%)

Follow-up                                               24 months                                  12 months                            5.2 years

Non-fatal AMI                                           UKN                                              UKN                               209 (5.9%)

Mortality or primary endpoint                    82 (7.3%)                                 119(8.9%)                           203 (5.7%)

………………………………………………………………………………………………………………………………………………………….

Key findings                                    cTnT better than cTnI                      cTnI ¼cTnT                   cTnI better than cTnT

Single cTn sample sufficient

AMI, acute mycordial infaction; cTn, cardiac tropononin; NSTEMI ,non-ST-elevation myocardial infarction; UKN, unknown

NSTEMI defined in the GUSTO IV trial:
  1. one or more episodes of angina lasting ≥ 5min,
  2. within 24h of admission and
  3. either a positive cardiac TnT or I test
    (above the upper limit of a normal for the local assay; during the years 1999 and 2000)
  4. or ≥ 0.5 mm of transient or persistent ST-segment depression.

the prognostic capacity of four different sensitive cardiac troponin assays were compared

  1. hs-cTnT; Roche Diagnostics,
  2. cTnI and hs-cTnI;
  3. Abbott Diagnostics, and
  4. Acc-cTnI; Beckman-Coulter.

In total, 119 patients (8.9%) died during the 1-year follow-up. Looking at their

  • receiver operating characteristic curve (ROC) analyses,
  • there were only negligible diffferences
    • in the area under the curves between the assays.

Contrasting results have also been reported in patients(n 1/4 3.623)

  • with stable coronary artery disease and preserved systolic left ventricular function

from the PEACE trial (Table1).

During a median follow-up period of 5.2 years,

  • there were 203 (5.6%) cardiovascular deaths or
  • first hospitalization for heart failure.

Concentrations of hs-cTnI (Abbott Diagnostics) at or above

  • the limit of detection of the assay were measured in 3567 patients (98.5%), but
  • concentrations of hs-cTnI at or above the gender-specific 99th percentile
    • were found in only 105 patients (2.9%).

This study revealed that

  • there was a strong and graded association
  • between increasing quartiles of hs-cTnI concentrations and
  • the risk for cardiovascular death or heart failure.

Hs-cTnI provided incremental prognostication information

  • over conventional risk markers and
  • other established cardiovascular biomarkers,
  • including hs-cTnT.

In contrast to the APACE results, only hs-cTnI, but

  • no ths-cTnT, was significantly
  • associated with the risk for AMI.

Is there a real difference between cardiac troponin T and cardiac troponin I

  • in predicting long term prognosis?

The question arises of whether there is a true clinically relevant

  • difference between cTnT and cTnI.

Given the biochemical and analytical differences,the two

  • troponins display rather similar serum profiles during AMI.

While minor biological differences between cTnT and cTnI are

  • apparently not relevant for diagnosis
  • and clinical management in the acute setting of ACS.

This is a provocative theory, but appears premature in our opinion.
Above all, the results of the current study appear

  • too inconsistent to allow such conclusions.

In the present study, hs-cTnT (Roche Diagnostics) outperformed

  • hs-cTnI (Siemens and Beckman-Coulter) in terms of
  • very long term prediction of cardiovascular death and
    • heart failure in stable patients.

We don’t know how hs-cTnI from Abbott Diagnostics

  • performs in the APACE consort.

The number of patients and endpoints provided

  • by the APACE registry are rather low.
  • The results could, therefore, be a chance finding.

It is far too early to favour one high sensitivity assay over the other. The findings need confirmation.

Implications for clinical practice

There is no doubt that high-sensitivity assays

  • are the analytical method of choice
    • in terms of risk stratification in patients with ACS.

What is new?
A single measurement of hs-cTn seems to be adequate

  • for long-term risk stratification in patients without AMI.

However, the question of which troponin might be preferable

  • for long-term risk stratification remains unanswered.

Part 2. ability of high-sensitivity cTnT and NT pro-BNP to predict cardiovascular events and death in patients with T2DM

Hillis GS; Welsh P; Chalmers J; Perkovic V; Chow CK; Li Q; Jun M; Neal B; Zoungas S; Poulter N; Mancia G; Williams B; Sattar N; Woodward M
Diabetes Care.  2014; 37(1):295-303 (ISSN: 1935-5548)

OBJECTIVE

Current methods of risk stratification in patients with

  • type 2 diabetes are suboptimal.

The current study assesses the ability of

  • N-terminal pro-B-type natriuretic peptide (NT-proBNP) and
  • high-sensitivity cardiac troponin T (hs-cTnT)

to improve the prediction of cardiovascular events and death in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A nested case-cohort study was performed in 3,862 patients who participated in the Action in Diabetes and Vascular Disease:

Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

RESULTS

Seven hundred nine (18%) patients experienced a

  • major cardiovascular event

(composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and

  • 706 (18%) died during a median of 5 years of follow-up.

In Cox regression models, adjusting for all established risk predictors,

  • the hazard ratio for cardiovascular events for NT-proBNP was 1.95 per 1 SD increase (95% CI 1.72, 2.20) and
  • the hazard ratio for hs-cTnT was 1.50 per 1 SD increase (95% CI 1.36, 1.65). The hazard ratios for death were
    • 1.97 (95% CI 1.73, 2.24) and
    • 1.52 (95% CI 1.37, 1.67), respectively.

The addition of either marker improved 5-year risk classification for cardiovascular events
(net reclassification index in continuous model,

  • 39% for NT-proBNP and 46% for hs-cTnT).

Likewise, both markers greatly improved the accuracy with which the 5-year risk of death was predicted.
The combination of both markers provided optimal risk discrimination.

CONCLUSIONS

NT-proBNP and hs-cTnT appear to greatly improve the accuracy with which the

  • risk of cardiovascular events or death can be estimated in patients with type 2 diabetes.

PreMedline Identifier: 24089534


Part 3. M-Atrial Natriuretic Peptide

M-Atrial Natriuretic Peptide and Nitroglycerin in a Canine Model of Experimental Acute Hypertensive Heart Failure:
Differential Actions of 2 cGMP Activating Therapeutics.

Paul M McKie, Alessandro Cataliotti, Tomoko Ichiki, S Jeson Sangaralingham, Horng H Chen, John C Burnett
Journal of the American Heart Association 01/2014; 3(1):e000206. http://dx.doi.org/10.1161/JAHA.113.000206
Source: PubMed

ABSTRACT

Systemic hypertension is a common characteristic in

  • acute heart failure (HF).

This increasingly recognized phenotype

  • is commonly associated with renal dysfunction and
  • there is an unmet need for renal enhancing therapies.

In a canine model of HF and acute vasoconstrictive hypertension

  • we characterized and compared the cardiorenal actions of M-atrial natriuretic peptide (M-ANP),
    a novel particulate guanylyl cyclase (pGC) activator, and
  • nitroglycerin, a soluble guanylyl cyclase (sGC) activator.

HF was induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II
infusion. We characterized the cardiorenal and humoral actions

  • prior to,
  • during, and
  • following intravenous infusions of
  1. M-ANP (n=7),
  2. nitroglycerin (n=7),
  3. and vehicle (n=7) infusion.

Mean arterial pressure (MAP) was reduced by

  1. M-ANP (139±4 to 118±3 mm Hg, P<0.05) and
  2. nitroglycerin (137±3 to 116±4 mm Hg, P<0.05);

similar findings were recorded for

  1. pulmonary wedge pressure (PCWP) with M-ANP (12±2 to 6±2 mm Hg, P<0.05)
  2. and nitroglycerin (12±1 to 6±1 mm Hg, P<0.05).

M-ANP enhanced renal function with significant increases (P<0.05) in

  • glomerular filtration rate (38±4 to 53±5 mL/min),
  • renal blood flow (132±18 to 236±23 mL/min), and
  • natriuresis (11±4 to 689±37 mEq/min) and
  • also inhibited aldosterone activation (32±3 to 23±2 ng/dL, P<0.05), whereas

nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation.

Our results advance

the differential cardiorenal actions of

  • pGC (M-ANP) and sGC (nitroglycerin) mediated cGMP activation.

These distinct renal and aldosterone modulating actions make

M-ANP an attractive therapeutic for HF with concomitant hypertension, where

  • renal protection is a key therapeutic goal.

Read Full Post »

Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)

Posted in Atherogenic Processes & Pathology, Best evidence, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cardiovascular Research, Curation, Curation methodology, Diabetes Mellitus, Discovery process, Evidence-based decision-making, Evolutionary cognition, Experimental validation, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Indigent Nutrition, Innovation in Immunology Diagnostics, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medicare and Medicaid, Metabolomics, Nephrology, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Systemic Inflammatory Response Related Disorders, Theoretic convergence, Translational Effectiveness, Translational Research, Translational Science, Uninsured and Underinsured, tagged , , , , , , , , , , , , , on January 15, 2014| Leave a Comment »

Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)

Curator:  Larry H. Bernstein, MD, FCAP

Article ID #106: Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD). Published 1/15/2014

WordCloud Image Produced by Adam Tubman

This is a multipart article that develops the pathological effects of type-2 diabetes in the progression of a systemic inflammatory disease with a development of neuropathy, and fully developing into cardiovascular disease.  It also identifies a systemic relationship to the development of chronic obstructive pulmonary disease (COPD).

The more we learn about diabetes, we learn about its generalized systemic effects.

This article has the following SIX Parts:

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Part 5.   How to use C-reactive protein in acute coronary care

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

INTRODUCTION

Type 2 diabetes mellitus is a common chronic disease which develops insidiously over time, and is associated with obesity, nutritional imbalance (high fructose beverages, high starch and processed foods, carbohydrate excess intake, and an imbalance of proinflammatory to anti-inflammatory polyunsaturated  fatty acids), which makes it an acquired and manageable disease.  The long term effects of T2DM is played out on cardiovascular disease and stroke-risk, obstructive sleep apnea, progressive renal insufficiency, development of neuropathy, congestive heart failure and chronic obstructive pulmonary disease, all of which are occuring related to an systemic inflammatory condition that proceeds for some time prior to the identification of overt diabetes.
A detailed story of a significant part of these associations continues in the SIX Part series.

Part 1. Role of Autonomic Cardiovascular Neuropathy in Pathogenesis of ischemic heart disease in patients with diabetes mellitus

This article is an abstract only of a related publication of the pathogenesis of autonomic neuropathy in diabetics leading to ischemic heart disease.

Subjects: Medicine (General), Medicine, Medicine (General),
Health Sciences Authors: Popović-Pejičić Snježana, Todorović-Đilas Ljiljana, Pantelinac Pavle
Publisher: Društvo lekara Vojvodine Srpskog lekarskog društva
Publication: Medicinski Pregled 2006; 59(3-4): Pp 118-123 (2006) ISSN(s): 0025-8105  Added to DOAJ: 2010-11-11
http://dx.doi.org/10.2298/MPNS0604118P  http://www.doiserbia.nb.rs/img/doi/0025-8105/2006/0025-81050604118P.pdf

Keywords: diabetes mellitus, autonomic nervous system diseases, heart diseases, myocardial ischemia, comorbidity

Introduction.

Diabetes is strongly associated with macrovascular complications, among which

  • ischemic heart disease is the major cause of mortality.

Autonomic neuropathy increases the risk of complications, which calls for an early diagnosis. The aim of this study was to determine

  • both presence and extent of cardiac autonomic neuropathy,

in regard to the type of diabetes mellitus, as well as

  • its correlation with coronary disease and
  • major cardiovascular risk factors.

Material and methods. We have examined 90 subjects, classified into three groups, with 30 patients each: those with type 1 diabetes, type 2 diabetes and control group of healthy subjects. All patients underwent

  • cardiovascular tests (Valsalva maneuver, deep breathing test, response to standing, blood pressure response to standing sustained, handgrip test),
  • electrocardiogram,
  • treadmill exercise test and
  • filled out a questionnaire referring to major cardiovascular risk factors: smoking, obesity, hypertension, and dyslipidemia.

Results. Our results showed that cardiovascular autonomic neuropathy was

  • more frequent in type 2 diabetes,
  • manifesting as autonomic neuropathy.

In patients with autonomic neuropathy, regardless of the type of diabetes,

  • the treadmill test was positive, i.e. strongly correlating with coronary disease.

In regard to coronary disease risk factors,

  • the most frequent correlation was found for obesity and hypertension.

Discussion

Cardiovascular autonomic neuropathy is considered to be the principal cause of arteriosclerosis and coronary disease. Our results showed that the occurrence of cardiovascular autonomic neuropathy increases the risk of coronary disease due to dysfunction of autonomic nervous system.

Conclusions

Cardiovascular autonomic neuropathy is a common complication of diabetes that significantly correlates with coronary disease. Early diagnosis of cardiovascular autonomic neuropathy points to increased cardiovascular risk, providing a basis for preventive and therapeutic measures.

Part 2. A Longitudinal Cohort Study of the Cardiovascular Experience of Individuals at High Risk for Diabetes

This second part is a description of a longitudinal cohort study of individuals at high-risk for diabetes.  Unlike the SSA study, the study is not focused on protein-energy malnutrition.

Protocol for ADDITION-PRO: a longitudinal cohort study of the cardiovascular experience of individuals at high risk for diabetes recruited from Danish primary care

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Johansen NB, Hansen Anne-Louise S, Jensen TM, Philipsen A, Rasmussen SS, Jørgensen ME, Simmons RK, Lauritzen T, Sandbæk A, Witte DR
Publisher: BioMed Central    Date of publication: 2012 Dec Published in: BMC Public Health 2012; 12(1): 1078    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12 http://dx.doi.org/10.1186/1471-2458-12-1078       http://www.biomedcentral.com/1471-2458/12/1078

Keywords: Diabetes, Cardiovascular disease, Primary care, Complications, Microvascular, Impaired fasting glucose, Impaired glucose intolerance, Aortic stiffness, Physical activity, Body composition

Background

Screening programmes for type 2 diabetes inevitably find more individuals at high risk for diabetes than people with undiagnosed prevalent disease. While well established guidelines for the treatment of diabetes exist, less is known about treatment or prevention strategies for individuals found at high risk following screening. In order to make better use of the opportunities for primary prevention of diabetes and its complications among this high risk group, it is important to

  • quantify diabetes progression rates and to examine
  • the development of early markers of cardiovascular disease and
  • microvascular diabetic complications.

We also require a better understanding of the

  • mechanisms that underlie and drive early changes in cardiometabolic physiology.

The ADDITION-PRO study was designed to address these issues among individuals at different levels of diabetes risk recruited from Danish primary care.

Methods/Design

ADDITION-PRO is a population-based, longitudinal cohort study of individuals at high risk for diabetes. 16,136 eligible individuals were identified at high risk following participation in a stepwise screening programme in Danish general practice between 2001 and 2006.

  • All individuals with impaired glucose regulation at screening,
  • those who developed diabetes following screening, and
  • a random sub-sample of those at lower levels of diabetes risk

were invited to attend a follow-up health assessment in 2009–2011 (n = 4,188), of whom 2,082 (50%) attended. The health assessment included

  • detailed measurement of anthropometry,
  • body composition,
  • biochemistry,
  • physical activity and
  • cardiovascular risk factors including aortic stiffness and central blood pressure.

All ADDITION-PRO participants are being followed for incident cardiovascular disease and death.

Discussion

The ADDITION-PRO study is designed to increase

  • understanding of cardiovascular risk and
  • its underlying mechanisms among individuals at high risk of diabetes.

Key features of this study include

  • (i) a carefully characterised cohort at different levels of diabetes risk;
  • (ii) detailed measurement of cardiovascular and metabolic risk factors;
  • (iii) objective measurement of physical activity behaviour; and
  • (iv) long-term follow-up of hard clinical outcomes including mortality and cardiovascular disease.

Results will inform policy recommendations concerning cardiovascular risk reduction and treatment among individuals at high risk for diabetes. The detailed phenotyping of this cohort will also allow a number of research questions concerning early changes in cardiometabolic physiology to be addressed.

Part 3.  Clinical significance of cardiovascular dysmetabolic syndrome

This study also addresses the issue of diabetes insulin resistance leading to cardiovascular dysmetabolic syndrome.

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Deedwania Prakash C Publisher: BioMed Central            Date of publication: 2002 Jan
Published in: Trials 2002; 3: 1(2)   ISSN(s): 1468-6708  Added to DOAJ: 2004-06-03
http://dx.doi.org/10.1186/1468-6708-3-2   http://cvm.controlled-trials.com/content/3/1/2

Keywords: cardiovascular dysmetabolic syndrome, coronary heart disease, diabetes mellitus, hyperinsulinemia, insulin resistance

Although diabetes mellitus is predominantly a metabolic disorder,

  • recent data suggest that it is as much a vascular disorder.
  • Cardiovascular complications are the leading cause
    • of death and disability in patients with diabetes mellitus.

A number of recent reports have emphasized that

  • many patients already have atherosclerosis in progression
  • at the time they are diagnosed with clinical evidence of diabetes mellitus.

The increased risk of atherosclerosis and cardiovascular complications in diabetic patients is related to

  • the frequently associated dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and endothelial dysfunction.

The evolving knowledge regarding the variety of

  • metabolic,
  • hormonal, and
  • hemodynamic abnormalities in patients with diabetes mellitus

has led to efforts designed for early identification of individuals at risk of subsequent disease. It has been suggested that

  • insulin resistance, the key abnormality in type II diabetes,
  • often precedes clinical features of diabetes by 5–6 years.

Careful attention to the criteria described for the cardiovascular dysmetabolic syndrome

  • should help identify those at risk at an early stage.

The application of nonpharmacologic as well as newer emerging pharmacologic therapies can have beneficial effects

  • in individuals with cardiovascular dysmetabolic syndrome and/or diabetes mellitus
  • by improving insulin sensitivity and related abnormalities.

Early identification and implementation of appropriate therapeutic strategies would be necessary

  • to contain the emerging new epidemic of cardiovascular disease related to diabetes.

Part 4.   Waist circumference a good indicator of future risk for type 2 diabetes and cardiovascular disease

Subjects: Public aspects of medicine, Medicine, Public Health, Health Sciences
Authors: Siren Reijo, Eriksson Johan G, Vanhanen Hannu
Publisher: BioMed Central      Date of publication: 2012 Aug
Published in: BMC Public Health 2012; 12: 1(631)    ISSN(s): 1471-2458   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1471-2458-12-631    http://www.biomedcentral.com/1471-2458/12/631

Keywords: Waist circumference, Type 2 diabetes, Cardiovascular disease, Middle-aged men

Background

Abdominal obesity is a more important risk factor than overall obesity in

  • predicting the development of type 2 diabetes and cardiovascular disease.

From a preventive and public health point of view it is crucial that

  • risk factors are identified at an early stage,
  • in order to change and modify behaviour and lifestyle in high risk individuals.

Methods

Data from a community based study was used to assess

  • the risk for type 2 diabetes,
  • cardiovascular disease and
  • prevalence of metabolic syndrome in middle-aged men.

In order to identify those with increased risk for type 2 diabetes and/or cardiovascular disease

  • sensitivity and specificity analysis were performed, including
  • calculation of positive and negative predictive values, and
  • corresponding 95% CI for eleven different cut-off points,
    • with 1 cm intervals (92 to 102 cm), for waist circumference.

Results

A waist circumference ≥94 cm in middle-aged men,

  • identified those with increased risk for type 2 diabetes
  • and/or for cardiovascular disease

with a sensitivity of 84.4% (95% CI 76.4% to 90.0%), and a specificity of 78.2% (95% CI 68.4% to 85.5%). The positive predictive value was 82.9% (95% CI 74.8% to 88.8%), and negative predictive value 80.0% (95% CI 70.3% to 87.1%), respectively .

Conclusions

Measurement of waist circumference in middle-aged men

  • is a reliable test to identify individuals at increased risk for type 2 diabetes and cardiovascular disease.

This measurement should be used more frequently in daily practice in primary care

  • in order to identify individuals at risk and when planning health counselling and interventions.

Part 5.  How to use C-reactive protein in acute coronary care

Luigi M. Biasucci, Wolfgang Koenig, Johannes Mair, Christian Mueller, Mario Plebani, Bertil Lindahl, Nader Rifai,Per Venge,Christian Hamm, and the Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association of the European Society of Cardiology
Department of Cardiology B, Aarhus University Hospital, Tage Hansens Gade2, Aarhus DK-8000,Denmark; Germany, U.K., U.S., Italy
European Heart Journal Advance Access published Nov 7, 2013.  Current Opinion.  http://dx.doi.org/10.1093/eurheartj/eht435

Introduction

 C-reactive protein (CRP) is an acute phase protein and an established marker for detection, risk stratification, and monitoring of infections, and inflammatory and necrotic processes.. Because C-reactive protein is sensitive but not specific, its values must be nterpreted  in the clinical context. Inpatients with acute myocardial infarction (AMI), CRP increases within 4–6h of symptoms, peaks 2–4 days later,and returns to baseline after 7–10 days.

CRP has gained interest recently as a marker for risk stratification in acute coronary syndrome (ACS) when measured by high-sensitivity CRP assays. These assays have greater analytical sensitivity and reliably measure CRP concentrations within the reference range with low imprecision (5–10%). Because of evidence that atherosclerosis is an inflammatory disease, high-sensitivity CRP can be used as a biomarker of risk
in primary prevention and in patients with known cardiovascular disease. The aim of this review is to evaluate the use of CRP in patients with acute coronary disease.

The in-vitro stability of high-sensitivity C-reactive protein is excellent. Specific blood sampling conditions aren’t necessary.  However, retesting may be necessary with some assays if there is marked lipaemia.  Baseline and subsequent measures are in good for agreement for risk stratification despite biological variability of 30–60%.

The upper reference limit is method-dependent but usually 8mg/L for standard assays. The distribution of high-sensitivity CRP concentrations is skewed in both genders with a 50th percentile of_1.5mg/L (excluding women on hormone replacement therapy). Race differences have been reported. Most studies have reported no relationship with age,  but to circadian and seasonal variation. CRP concentrations are increased by smoking, obesity, and hormone replacement therapy and reduced by exercise, moderate alcohol drinking, and statin use. Correction for these factors is essential in reference range studies. CRP assays are not standardized. We recommend  the use of third-generation high-sensitivity CRP assays that combine features of standard and high-sensitivity CRP assays.  Required assay precision should be < 10% in the range of 3 and 10 mg/L.

Biochemical and analytical issues

Critical clinical concepts

(1) CRP concentrations are reported in mg/L
(2) CRP test results are method-dependent

  •  classification of patients into risk categories is usually comparable
(3) Third generation CRP assay are recommended
(4) No specific patient preparation before blood sampling is necessary
(5) The in-vitro stability of CRP is high

This is only a portion of the published concensus document. What is relevant to this discussion is that the hs-CRP is an extremely valuable marker for inflammatory disease.  It is not ordered often enough because of the broad range of values that we have become accustomed to for years, and it is elevated in rheumatologic conditions, but even then, it is widely used in pediatrics because children may present with rapidly emergent sepsis with very minimal sympoms.
The hs-CRP has opened a window to subliminal inflammatory disease that is diabetes, with accompanied arteriolar endothelial inflammation.

Part 6.  Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

Subjects: Diseases of the circulatory (Cardiovascular) system,
Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Authors: Mirrakhimov Aibek E
Publisher: BioMed Central      Date of publication: Oct 2012   ISSN(s): 1475-2840
Published in: Cardiovascular Diabetology 2012; 11(1):132   Added to DOAJ: 2013-03-12
http://dx.doi.org/10.1186/1475-2840-11-132      http://www.cardiab.com/content/11/1/132

Keywords: COPD, Dysglycemia, Insulin resistance, Obesity, Metabolic syndrome, Diabetes mellitus endothelial dysfunction, Vasculopathy

Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus

  • are common and underdiagnosed medical conditions.

It was predicted that chronic obstructive pulmonary disease

  • will be the third leading cause of death worldwide by 2020.

The healthcare burden of this disease is even greater

  • if we consider the significant impact of chronic obstructive pulmonary disease on
    • the cardiovascular morbidity and mortality.

Chronic obstructive pulmonary disease

  • may be considered as a novel risk factor for new onset type 2 diabetes mellitus via

multiple pathophysiological alterations such as:

  1. inflammation and oxidative stress,
  2. insulin resistance,
  3. weight gain and
  4. alterations in metabolism of adipokines.

On the other hand, diabetes may act as an independent factor,

  • negatively affecting pulmonary structure and function.

Diabetes is associated with an increased risk of

  1. pulmonary infections,
  2. disease exacerbations and
  3. worsened COPD outcomes.

On the top of that, coexistent OSA

  • may increase the risk for type 2 DM in some individuals.

The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and

  • chronic obstructive pulmonary disease may be viewed as a risk factor for
  • the new onset type 2 diabetes mellitus.

Conversely, both types of diabetes mellitus should be viewed as

  • strong contributing factors for the development of obstructive lung disease.

Such approach can potentially improve the outcomes and medical control for both conditions,

  • and, thus, decrease the healthcare burden of these major medical problems.

CONCLUSIONS

This discussion  presents a spectrum of cardiovascular risk associated with type 2 diabetes mellitus, with high risk for CVD, stroke, endothelial dysfunction, and an association with obesity, measured by waist circumference, and an underlying proinflammatory state that can be measured by CRP.

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Cardiovascular Risk Reduction in Diabetes in Sub-Saharan Africa

Posted in Curation, Diabetes Mellitus, Evidence-based decision-making, Explanatory, Health Economics and Outcomes Research, Historical relevance, HTN, Metabolomics, Nutrition, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Translational Effectiveness, Translational Science, tagged , , , , , on January 13, 2014| Leave a Comment »

Cardiovascular Risk Reduction in Diabetes in Sub-Saharan Africa

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

 

In the immediate preceding article we discussed the problem of small subsistence farming and dependence on crop, and milk as a main source of food. We discussed the dilemma of unavailability of adequate nutrition, that posed a dilemma.  Insects invade and destroy the vegetation.  That can be avoided by either of two choices, crop-treatment with pesticide or by GMO crops resistant to types of destruction, both having unaffordable costs that impose an austere challenge and abject poverty with marginal after sales gains, in no way comparable to farming in Iowa, Wisconsin, Minnesota, or California, U.S.  So the situation could be improved by the introduction of/or development of a practical genome-based synthetic tehnology that might be free of Western dominance, if there were the home-based universities and scientific research.
I also touched on the consequences of the malnutrition in that region because of a diet that imposes either marasmic or kwashiorkor-like feature, the distinction being made based on the body compartment related to loss of fat mass or the loss of lean body mass, the latter being more serious.

Cardiovascular Risk Reduction in Diabetes in Sub-Saharan Africa

The abstract of this discussion is directly taken from an article published in Clinical Medicine Insights: Cardiology; 2008: 2: 25-31,  Libertas Academica, ISSN(s):1178-1165.  Added to DOAJ: 2008-05-01
http://la-press.com/article.php?article_id=529

Cardiovascular Risk Reduction in Diabetes in Sub-Saharan Africa: What should the Priorities be in the Absence of Global Risk Evaluation Tools?

Subjects: Diseases of the circulatory (Cardiovascular) system, Specialties of internal medicine, Internal medicine, Medicine, Cardiovascular, Medicine (General), Health Sciences
Andre Pascal Kengne, Alfred Kongnyu Njamnshi, Jean Claude Mbanya

Keywords: diabetes mellitus, cardiovascular disease, risk factors, prevention, Sub-Saharan Africa

Background

The growing burden of type 2 diabetes in Sub-Saharan Africa (SSA) and related cardiovascular complications call for vigorous actions into prevention. Comprehensive cardiovascular risk evaluation is important for the success of such actions.

Methods

We have reviewed 3 currently existing sets of recommendations for cardiovascular prevention in diabetes in SSA. Distribution of major risk factors and patterns of reported cardiovascular outcomes are used to suggest orientations for cardiovascular prevention in diabetes in this region. Papers and reports published over the period 1990 to 2007 were used.

Results

Existing guidelines share some similarities, but also have areas of inconsistencies. They are generally adaptations of existing guidelines, focused more on individual risk factors, and are not usually backed-up by local evidence.

  • They all have a projection on blood pressure lowering.

This focus is supported by the high prevalence of hypertension among people with diabetes in SSA.

  • Blood pressure and tobacco smoking are the modifiable risk factors accessible to evaluation and interventions on a wide scale in SSA.

Appropriate blood pressure control will have a major impact on stroke (the commonest cardiovascular disease) through

  • a reduction of the cerebrovascular risk, and
  • to a lesser extent on coronary heart disease and
  • total deaths in diabetes in this region.

Conclusions

In the absence of global risk evaluation tools,

  • the use of blood pressure lowering as a primary focus of cardiovascular prevention strategies is relevant for SSA.

However, there is a need to set-up diabetes and stroke registers

  • to monitor outcomes and generate tools for accurate risk prediction and management in diabetes in this region.

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Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Posted in Atherogenic Processes & Pathology, Best evidence, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, Congenital Heart Disease, Cytoskeleton, Diabetes Mellitus, Diagnostic Immunology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Evidence-based decision-making, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, HTN, Human Immune System in Health and in Disease, Immunodiagnostics, Innovation in Immunology Diagnostics, International Global Work in Pharmaceutical, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Theoretic convergence, Translational Effectiveness, Translational Research, Translational Science, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on January 5, 2014| Leave a Comment »

Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals.  The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA).  The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA).  The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease.  There is also a long history of the measurement of  circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.

There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of

1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity.  Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.

There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke.  Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation.  A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium.   Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.

It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life.  Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association.  In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age.  The establishment of an epigenetic change is diluted in a diverse population.  There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.

This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series.  Below is a diagram of this volume in the series.

PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data
VIDEO:  Implementing Biomarker Programs ­ P Ridker PART 2 – Epigenetics – Modifiable
Factors Causing CVD
Diseases Etiology
   Environmental Contributors
Implicated as Causing CVD
   Diet: Solids and Fluid Intake
and Nutraceuticals
   Physical Activity and
Prevention of CVD
   Psychological Stress and
Mental Health: Risk for CVD
   Correlation between
Cancer and CVD
PART 3  Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Introduction
    Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
     Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG
     Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013
     Commentary on Biomarkers for Genetics and Genomics of CVD
PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries
    Preventive Medicine: Cardiovascular Diseases
    Walking and Running: Similar Risk Reductions for Hypertension, Hypercholesterolemia,
DM, and possibly CAD
http://pharmaceuticalintelligence.com/2013/04/04/walking-and-running-similar-risk-reductions-for-hypertension-hypercholesterolemia-dm-and-possibly-cad/
    Prevention of Type 2 Diabetes: Is Bariatric Surgery the Solution?
http://pharmaceuticalintelligence.com/2012/08/23/prevention-of-type-2-diabetes-is-bariatric-surgery-the-solution/
Gene-Therapy for CVD
Congenital Heart Disease/Defects
   Medical Etiologies: EBM – LEADING DIAGNOSES, Risks Pharmacogenomics for Cardio-
vascular Diseases
   Signaling Pathways     Response to Rosuvastatin in
Patients With Acute Myocardial Infarction:
Hepatic Metabolism and Transporter Gene
Variants Effect
http://pharmaceuticalintelligence.com/2014/
01/02/response-to-rosuvastatin-in-patients-
with-acute-myocardial-infarction-hepatic-
metabolism-and-transporter-gene-variants-effect/
   Proteomics and Metabolomics      Voltage-Gated Calcium Channel and Pharmaco-
genetic Association with Adverse Cardiovascular
Outcomes: Hypertension Treatment with Verapamil
SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)
http://pharmaceuticalintelligence.com/2014/01/02/
voltage-gated-calcium-channel-and-pharmacogenetic-
association-with-adverse-cardiovascular-outcomes-
hypertension-treatment-with-verapamil-sr-ccb-vs-
atenolol-bb-or-trandolapril-ace/
      SNPs in apoE are found to influence statin response
significantly. Less frequent variants in
PCSK9 and smaller effect sizes in SNPs in HMGCR
http://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

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Diagnostic Value of Cardiac Biomarkers

Posted in Atherogenic Processes & Pathology, Best evidence, Ca2+ triggered activation, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, Curation, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Evidence-based decision-making, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genomic Testing: Methodology for Diagnosis, Immunodiagnostics, Inferential analysis, Medical and Population Genetics, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Nephrology, Nutritional Supplements: Atherogenesis, lipid metabolism, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Proteomics, Quality Assurance, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Science, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on January 4, 2014| Leave a Comment »

Diagnostic Value of Cardiac Biomarkers

Author and Curator: Larry H Bernstein, MD, FCAP 

These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years.  The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation.  The world health organization (WHO) standard definition then was the presence of two of three:

1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm

2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.

3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.

The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel.  Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.

So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century.  However, the role of biomarkers broadened.  Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury.  This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP).  The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.

Thus, we have identified the use of traditional cardiac biomarkers for:

1. Diagnosis
2. Therapeutic monitoring

The story is only the beginning.  Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic.  This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium.  The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease.  Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.

While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature.  There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require

1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement  on multitest automated analyzers with high capability in proteomic measurement  (MS, time of flight, MS-MS)

nejmra1216063_f1 Atherosclerotic Plaques Associated with Various Presentations               nejmra1216063_f2 Inflammatory Pathways Predisposing Coronary Arteries to Rupture and Thrombosis.        atherosclerosis progression

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Genomics and Medicine: The Physician’s View

Posted in Best evidence, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cerebrovascular and Neurodegenerative Diseases, Coagulation Therapy and Internal Bleeding, Evidence-based decision-making, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, HealthCare IT, Hematopoiesis, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Liver & Digestive Diseases Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Myelodysplasia, Myelofibrosis, Neurodegenerative Diseases, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Pre-Clinical Animal Model Development, Prescription Drugs Costs, Regenerative Biology and Medicine, Stem Cells for Regenerative Medicine, Translational Effectiveness, Translational Science, tagged , , , , , , , , , , , , on January 3, 2014| Leave a Comment »

Genomics and Medicine: The Physician’s View

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

 

Genomics has had a rapid growth of research into variability of human genetics in both healthy populations in the study of population migration, and in the study of genetic sequence alterations that may increase the risk of expressed human disease.  This is the case for cardiology, cancer, inflammtory conditions, and gastrointestinal diseases. For the most part, genomics research in the last decade has shed light on potential therapeutic targets, but the identification of drug toxicities in late phase trials has been associated with a 70 percent failure rate in bringing new drugs to the market.   Despite good technologies for investigative studies, initial work is carried out on animals and then the transferrability of the work from a “model” to man has to be assured.  That is the first issue of concern.

Secondly, there is a well considered reluctance on the part of experienced and well prepared physicians to be “early” adopters to newly introduced drugs, with the apprehension that unidentified clinical problems can be expected to be unmasked.  It is, however, easier to consider when a new drug belongs to an established class of medications, and it has removed known adverse effects.  In this case, the adverse effects are known side effects, but not necessarily serious drug reactions that would preclude use.

A third consideration is the cost of drug development, and the cost of development is passed on to the healthcare organization in the purchasing cost. We can rest assured that the Pharmacy and Therapeutics Review Committee will not cease meeting on a regular schedule anytime soon.  Further, how do the drug failures become embedded in the cost of the pharmaceutical budget passed on to the recipient.  Historically, insurance is an actuarial discipline.  But in the lifetime of an individual, they are bound to see a physician for acute or chronic medical attention.  Only the timing cannot be predicted.  As a result, dealing with the valid introduction of new medications is a big concern for both the public and the private insurer.

How does this compute for the physician provider.  The practice of medicine is not quickly adaptive, as the physician’s primary concern is to do no harm.   Genomics testing is not widely available, and it is for the most part not definitive for diagnostic purposes as things stand today.  It may provide assessment of risk, or of survival expectation.  The physician uses a step by step assessment, using the patient and family history, a focused physical exam, laboratory and radiology, proceeding to other more specialized exams.  Much of the laboratory testing is based on the appearance in the circulation of changes in blood chemistry of the nature of electrolytes, circulating cells in the blood and of the blood forming organ, proteins, urea and uric acid.  They are not exquisitely sensitive, but they might be sufficient for their abnormal concentrations appearing at the time the patient presents with a complaint. What tests are ordered is determioned by a need for relevant information to make a medical decision.

The relevant questions are:

1. acuity of symptoms and signs.
2. actions to be taken.
3. tests that are needed to clarify the examination findings.

once a provisional diagnosis is obtained, referrals, additional testing, and medication orders are provided based on the assessment.

Where does genetic testing fit into this? At this point, it will only be used

  1. to confirm a restricted list of diagnoses that have a high association with the condition, and
  2. only with the participation of a medical geneticist, when
  3. profiling the patient and other members of the family is required.

10d0de1 Vitruvian Man by Leonardo da Vinci

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The Cost to Value Conundrum in Cardiovascular Healthcare Provision

Posted in Accountable Care Organizations, Affordable Care Act, Anemia, Atherogenic Processes & Pathology, Best evidence, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Ca2+ triggered activation, Ca2+ triggered activation, Calcium Signaling, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Curation, Curation methodology, Cytoskeleton, Diabetes Mellitus, Electrophysiology, Evidence-based decision-making, Experimental validation, Federal Budget Appropriations, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, Healthcare Reform, Historical relevance, HTN, HTN in Youth, Indigent Nutrition, Interviews with Scientific Leaders, Ionic Transporters Na+, K, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Medicare and Medicaid, Na-K transport, Na-K-ATPase, Nephrology, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Prescription Drugs Costs, Regenerative Biology and Medicine, Resident-cell-based, Skilled Nursing Facilities, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systematic Error (Bias), Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Capital Expenses, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Science, Uninsured and Underinsured, Valves & Tools, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on January 1, 2014| Leave a Comment »

The Cost to Value Conundrum in Cardiovascular Healthcare Provision

Author: Larry H. Bernstein, MD, FCAP

Article ID #98: The Cost to Value Conundrum in Cardiovascular Healthcare Provision. Published on 1/1/2014

WordCloud Image Produced by Adam Tubman

I write this introduction to Volume 2 of the e-series on Cardiovascular Diseases, which curates the basic structure and physiology of the heart, the vasculature, and related structures, e.g., the kidney, with respect to:

1. Pathogenesis
2. Diagnosis
3. Treatment

Curation is an introductory portion to Volume Two, which is necessary to introduce the methodological design used to create the following articles. More needs not to be discussed about the methodology, which will become clear, if only that the content curated is changing based on success or failure of both diagnostic and treatment technology availability, as well as the systems needed to support the ongoing advances.  Curation requires:

  • meaningful selection,
  • enrichment, and
  • sharing combining sources and
  • creation of new synnthesis

Curators have to create a new perspective or idea on top of the existing media which supports the content in the original. The curator has to select from the myriad upon myriad options available, to re-share and critically view the work. A search can be overwhelming in size of the output, but the curator has to successfully pluck the best material straight out of that noise.

Part 1 is a highly important treatment that is not technological, but about the system now outdated to support our healthcare system, the most technolog-ically advanced in the world, with major problems in the availability of care related to economic disparities.  It is not about technology, per se, but about how we allocate healthcare resources, about individuals’ roles in a not full list of lifestyle maintenance options for self-care, and about the important advances emerging out of the Affordable Care Act (ACA), impacting enormously on Medicaid, which depends on state-level acceptance, on community hospital, ambulatory, and home-care or hospice restructuring, which includes the reduction of management overhead by the formation of regional healthcare alliances, the incorporation of physicians into hospital-based practices (with the hospital collecting and distributing the Part B reimbursement to the physician, with “performance-based” targets for privileges and payment – essential to the success of an Accountable Care Organization (AC)).  One problem that ACA has definitively address is the elimination of the exclusion of patients based on preconditions.  One problem that has been left unresolved is the continuing existence of private policies that meet financial capabilities of the contract to provide, but which provide little value to the “purchaser” of care.  This is a holdout that persists in for-profit managed care as an option.  A physician response to the new system of care, largely fostered by a refusal to accept Medicaid, is the formation of direct physician-patient contracted care without an intermediary.

In this respect, the problem is not simple, but is resolvable.  A proposal for improved economic stability has been prepared by Edward Ingram. A concern for American families and businesses is substantially addressed in a macroeconomic design concept, so that financial services like housing, government, and business finance, savings and pensions, boosting confidence at every level giving everyone a better chance of success in planning their personal savings and lifetime and business finances.

http://macro-economic-design.blogspot.com/p/book.html

Part 2 is a collection of scientific articles on the current advances in cardiac care by the best trained physicians the world has known, with mastery of the most advanced vascular instrumentation for medical or surgical interventions, the latest diagnostic ultrasound and imaging tools that are becoming outdated before the useful lifetime of the capital investment has been completed.  If we tie together Part 1 and Part 2, there is ample room for considering  clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.  Why should this be?  Because for generations of IT support systems, they are historically focused on billing and have made insignificant inroads into the front-end needs of the clinical staff.

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Risk of Bias in Translational Science

Posted in Accountable Care Organizations, Affordable Care Act, Best evidence, Bias measurement tools, Biomedical Measurement Science, Computational Biology/Systems and Bioinformatics, Evidence-based decision-making, FDA Regulatory Affairs, Health Economics and Outcomes Research, Health Law & Patient Safety, HealthCare IT, Inferential analysis, Intra-rater error, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Quality Assurance, Random Error, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systematic Error (Bias), Technology Transfer: Biotech and Pharmaceutical, Total error, Translational Effectiveness, Translational Research, Translational Science, tagged , , , , , , , , on November 3, 2013| Leave a Comment »

Risk of Bias in Translational Science

Author: Larry H. Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

 

Assessment of risk of bias in translational science

Andre Barkhordarian1, Peter Pellionisz2, Mona Dousti1, Vivian Lam1,Lauren Gleason1, Mahsa Dousti1, Josemar Moura3 and Francesco Chiappelli14*  

1Oral Biology & Medicine, School of Dentistry, UCLA, Evidence-Based Decisions Practice-Based Research Network, Los Angeles, USA

2Pre-medical program, UCLA, Los Angeles, CA

3School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

4Evidence-Based Decisions Practice-Based Research Network, UCLA School of Dentistry, Los Angeles, CA

Journal of Translational Medicine 2013, 11:184   http://dx.doi.org/10.1186/1479-5876-11-184
http://www.translational-medicine.com/content/11/1/184

This is an Open Access article distributed under the terms of the Creative Commons Attribution License 
http://creativecommons.org/licenses/by/2.0

Abstract

Risk of bias in translational medicine may take one of three forms:

  1. a systematic error of methodology as it pertains to measurement or sampling (e.g., selection bias),
  2. a systematic defect of design that leads to estimates of experimental and control groups, and of effect sizes that substantially deviate from true values (e.g., information bias), and
  3. a systematic distortion of the analytical process, which results in a misrepresentation of the data with consequential errors of inference (e.g., inferential bias).

Risk of bias can seriously adulterate the internal and the external validity of a clinical study, and, unless it is identified and systematically evaluated, can seriously hamper the process of comparative effectiveness and efficacy research and analysis for practice. The Cochrane Group and the Agency for Healthcare Research and Quality have independently developed instruments for assessing the meta-construct of risk of bias. The present article begins to discuss this dialectic.

Background

As recently discussed in this journal [1], translational medicine is a rapidly evolving field. In its most recent conceptualization, it consists of two primary domains:

  • translational research proper and
  • translational effectiveness.

This distinction arises from a cogent articulation of the fundamental construct of translational medicine in particular, and of translational health care in general.

The Institute of Medicine’s Clinical Research Roundtable conceptualized the field as being composed by two fundamental “blocks”:

  • one translational “block” (T1) was defined as “…the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans…”, and
  • the second translational “block” (T2) was described as “…the translation of results from clinical studies into everyday clinical practice and health decision making…” [2].

These are clearly two distinct facets of one meta-construct, as outlined in Figure 1. As signaled by others, “…Referring to T1 and T2 by the same name—translational research—has become a source of some confusion. The 2 spheres are alike in name only. Their goals, settings, study designs, and investigators differ…” [3].

1479-5876-11-184-1 Fig 1. TM construct

Figure 1. Schematic representation of the meta-construct of translational health carein general, and translational medicine in particular, which consists of two fundamental constructs: the T1 “block” (as per Institute of Medicine’s Clinical Research Roundtable nomenclature), which represents the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention as well as their first testing in humans, and the T2 “block”, which pertains to translation of results from clinical studies into everyday clinical practice and health decision making [[3]]. The two “blocks” are inextricably intertwined because they jointly strive toward patient-centered research outcomes (PCOR) through the process of comparative effectiveness and efficacy research/review and analysis for clinical practice (CEERAP). The domain of each construct is distinct, since the “block” T1 is set in the context of a laboratory infrastructure within a nurturing academic institution, whereas the setting of “block” T2 is typically community-based (e.g., patient-centered medical/dental home/neighborhoods [4]; “communities of practice” [5]).

For the last five years at least, the Federal responsibilities for “block” T1 and T2 have been clearly delineated. The National Institutes of Health (NIH) predominantly concerns itself with translational research proper – the bench-to-bedside enterprise (T1); the Agency for Healthcare Research Quality (AHRQ) focuses on the result-translation enterprise (T2). Specifically: “…the ultimate goal [of AHRQ] is research translation—that is, making sure that findings from AHRQ research are widely disseminated and ready to be used in everyday health care decision-making…” [6]. The terminology of translational effectiveness has emerged as a means of distinguishing the T2 block from T1.

Therefore, the bench-to-bedside enterprise pertains to translational research, and the result-translation enterprise describes translational effectiveness. The meta-construct of translational health care (viz., translational medicine) thus consists of these two fundamental constructs:

  • translational research and
  • translational effectiveness,

which have distinct purposes, protocols and products, while both converging on the same goal of new and improved means of

  • individualized patient-centered diagnostic and prognostic care.

It is important to note that the U.S. Patient Protection and Affordable Care Act (PPACA, 23 March 2010) has created an environment that facilitates the pursuit of translational health care because it emphasizes patient-centered outcomes research (PCOR). That is to say, it fosters the transaction between translational research (i.e., “block” T1)(TR) and translational effectiveness (i.e., “block” T2)(TE), and favors the establishment of communities of practice-research interaction. The latter, now recognized as practice-based research networks, incorporate three or more clinical practices in the community into

  • a community of practices network coordinated by an academic center of research.

Practice-based research networks may be a third “block” (T3)(PBTN) in translational health care and they could be conceptualized as a stepping-stone, a go-between bench-to-bedside translational research and result-translation translational effectiveness [7]. Alternatively, practice-based research networks represent the practical entities where the transaction between

  • translational research and translational effectiveness can most optimally be undertaken.

It is within the context of the practice-based research network that the process of bench-to-bedside can best seamlessly proceed, and it is within the framework of the practice-based research network that

  • the best evidence of results can be most efficiently translated into practice and
  • be utilized in evidence-based clinical decision-making, viz. translational effectiveness.

Translational effectiveness

As noted, translational effectiveness represents the translation of the best available evidence in the clinical practice to ensure its utilization in clinical decisions. Translational effectiveness fosters evidence-based revisions of clinical practice guidelines. It also encourages

  • effectiveness-focused,
  • patient-centered and
  • evidence-based clinical decision-making.

Translational effectiveness rests not only on the expertise of the clinical staff and the empowerment of patients, caregivers and stakeholders, but also, and

  • most importantly on the best available evidence [8].

The pursuit of the best available evidence is the foundation of

  • translational effectiveness and more generally of
  • translational medicine in evidence-based health care.

The best available evidence is obtained through a systematic process driven by

  • a research question/hypothesis that is articulated about clearly stated criteria that pertain to the
  • patient (P), the interventions (I) under consideration (C), for the sought clinical outcome (O), within a given timeline (T) and clinical setting (S).

PICOTS is tested on the appropriate bibliometric sample, with tools of measurements designed to establish the level (e.g., CONSORT) and the quality of the evidence. Statistical and meta-analytical inferences, often enhanced by analyses of clinical relevance [9], converge into the formulation of the consensus of the best available evidence. Its dissemination to all stakeholders is key to increase their health literacy in order to ensure their full participation

  • in the utilization of the best available evidence in clinical decisions, viz., translational effectiveness.

To be clear, translational effectiveness – and, in the perspective discussed above, translational health care – is anchored on obtaining the best available evidence,

  • which emerges from highest quality research.
  • which is obtained when errors are minimized.

In an early conceptualization [10], errors in research were presented as

  • those situations that threaten the internal and the external validity of a research study –

that is, conditions that impede either the study’s reproducibility, or its generalization. In point of fact, threats to internal and external validity [10] represent specific aspects of systematic errors (i.e., bias) in the

  • research design,
  • methodology and
  • data analysis.

Thence emerged a branch of science that seeks to

  • understand,
  • control and
  • reduce risk of bias in research.

Risk of bias and the best available evidence

It follows that the best available evidence comes from research with the fewest threats to internal and to external validity – that is to say, the fewest systematic errors: the lowest risk of bias. Quality of research, as defined in the field of research synthesis [11], has become synonymous with

  • low bias and contained risk of bias [12–15].

Several years ago, the Cochrane group embarked on a new strategy for assessing the quality of research studies by examining potential sources of bias. Certain original areas of potential bias in research were identified, which pertain to

(a) the sampling and the sample allocation process, to measurement, and to other related sources of errors (reliability of testing),

(b) design issues, including blinding, selection and drop-out, and design-specific caveats, and

(c) analysis-related biases.

A Risk of Bias tool was created (Cochrane Risk of Bias), which covered six specific domains:

1. selection bias,

2. performance bias,

3. detection bias,

4. attrition bias,

5. reporting bias, and

6. other research protocol-related biases.

Assessments were made within each domain by one or more items specific for certain aspects of the domain. Each items was scored in two distinct steps:

1. the support for judgment was intended to provide a succinct free-text description of the domain being queried;

2. each item was scored high, low, or unclear risk of material bias (defined here as “…bias of sufficient magnitude to have a notable effect on the results or conclusions…” [16]).

It was advocated that assessments across items in the tool should be critically summarized for each outcome within each report. These critical summaries were to inform the investigator so that the primary meta-analysis could be performed either

  • only on studies at low risk of bias, or for
  • the studies stratified according to risk of bias [16].

This is a form of acceptable sampling analysis designed to yield increased homogeneity of meta-analytical outcomes [17]. Alternatively, the homogeneity of the meta-analysis can be further enhanced by means of the more direct quality-effects meta-analysis inferential model [18].

Clearly, one among the major drawbacks of the Cochrane Risk of Bias tool is

  • the subjective nature of its assessment protocol.

In an effort to correct for this inherent weakness of the instrument, the Cochrane group produced

  • detailed criteria for making judgments about the risk of bias from each individual item[16], and
  • that judgments be made independently by at least two people, with any discrepancies resolved by discussion [16].

This approach to increase the reliability of measurement in research synthesis protocols

  • is akin to that described by us [19,20] and by AHRQ [21].

In an effort to aid clinicians and patients in making effective health care related decisions, AHRQ developed an alternative Risk of Bias instrument for enabling systematical evaluation of evidence reporting [22]. The AHRQ Risk of Bias instrument was created to monitor four primary domains:

1. risk of bias: design, methodology, analysis scoring – low, medium, high

2. consistency: extent of similarity in effect sizes across studies within a bibliome scoring – consistent, inconsistent, unknown

3. directness: unidirectional link between the interventions of interest and the sought outcome, as opposed to multiple links in a casual chain scoring – direct, indirect

4. precision: extent of certainty for estimate of effect with respect to the outcome scoring – precise, imprecise In addition, four secondary domains were identified:

a. Dose response association: pattern of a larger effect with greater exposure (Present/Not Present/Not Applicable or Not Tested)

a. Confounders: consideration of confounding variables (Present/Absent)

a. Strength of association: likelihood that the observed effect is large enough that it cannot have occurred solely as a result of bias from potential confounding factors (Strong/Weak)

a. Publication bias

The AHRQ Risk of Bias instrument is also designed to yield an overall grade of the estimated risk of bias in quality reporting:

•Strength of Evidence Grades (scored as high – moderate – low – insufficient)

This global assessment, in addition to incorporating the assessments above, also rates:

–major benefit

–major harm

–jointly benefits and harms

–outcomes most relevant to patients, clinicians, and stakeholders

The AHRQ Risk of Bias instrument suffers from the same two major limitations as the Cochrane tool:

1. lack of formal psychometric validation as most other tools in the field [21], and

2. providing a subjective and not quantifiable assessment.

To begin the process of engaging in a systematic dialectic of the two instruments in terms of their respective construct and content validity, it is necessary

  • to validate each for reliability and validity either by means of the classic psychometric theory or generalizability (G) theory, which allows
  • the simultaneous estimation of multiple sources of measurement error variance (i.e., facets)
  • while generalizing the main findings across the different study facets.

G theory is particularly useful in clinical care analysis of this type, because it permits the assessment of the reliability of clinical assessment protocols.

  • the reliability and minimal detectable changes across varied combinations of these facets are then simply calculated [23], but
  • it is recommended that G theory determination follow classic theory psychometric assessment.

Therefore, we have commenced a process of revision the AHRQ Risk of Bias instrument by rendering questions in primary domains quantifiable (scaled 1–4),

  • which established the intra-rater reliability (r = 0.94, p < 0.05), and
  • the criterion validity (r = 0.96, p < 0.05) for this instrument (Figure 2).

????????????????????????????????????????

 

Figure 2. Proportion of shared variance in criterion validity (A) and inter-rater reliability (B) in the AHRQ Risk of Bias instrument revised as described.
Two raters were trained and standardized [20] with the revised AHRQ Risk of Bias and with the R-Wong instrument, which has been previously validated[24]. Each rater independently produced ratings on a sample of research reports with both instruments on two separate occasions, 1–2 months apart. Pearson correlation coefficient was used to compute the respective associations. The figure shows Venn diagrams to illustrate the intersection between each two sets data used in the correlations. The overlap between the sets in each panel represents the proportion of shared variance for that correlation. The percent of unexplained variance is given in the insert of each panel.

A similar revision of the Cochrane Risk of Bias tool may also yield promising validation data. G theory validation of both tools will follow. Together, these results will enable a critical and systematic dialectical comparison of the Cochrane and the AHRQ Risk of Bias measures.

Discussion

The critical evaluation of the best available evidence is critical to patient-centered care, because biased research findings are fundamentally invalid and potentially harmful to the patient. Depending upon the tool of measurement, the validity of an instrument in a study is obtained by means of criterion validity through correlation coefficients. Criterion validity refers to the extent to which one measures or predicts the value of another measure or quality based on a previously well-established criterion. There are other domains of validity such as: construct validity and content validity that are rather more descriptive than quantitative. Reliability however is used to describe the consistency of a measure, the extent to which a measurement is repeatable. It is commonly assessed quantitatively by correlation coefficients. Inter-rater reliability is rendered as a Pearson correlation coefficient between two independent readers, and establishes equivalence of ratings produced by independent observers or readers. Intra-rater reliability is determined by repeated measurement performed by the same subject (rater/reader) at two different points in time to assess the correlation or strength of association of the two sets of scores.

To establish the reliability of research quality assessment tools it is necessary, as we previously noted [20]:

•a) to train multiple readers in sharing a common view for the cognitive interpretation of each item. Readers must possess declarative knowledge a factual form of information known to be static in nature a certain depth of knowledge and understanding of the facts about which they are reviewing the literature. They must also have procedural knowledge known as imperative knowledge that can be directly applied to a task in this case a clear understanding of the fundamental concepts of research methodology, design, analysis and inference.

•b) to train the readers to read and evaluate the quality of a set of papers independently and blindly. They must also be trained to self-monitor and self-assess their skills for the purpose of insuring quality control.

•c) to refine the process until the inter-rater correlation coefficient and Cohen coefficient of agreement are about 0.9 (over 81% shared variance). This will establishes that the degree of attained agreement among well-trained readers is beyond chance.

•d) to obtain independent and blind reading assessments from readers on reports under study.

•e) to compute means and standard deviation of scores for each question across the reports, repeat process if the coefficient of variations are greater than 5% (i.e., less than 5% error among the readers across each questions).

The quantification provided by instruments validated in such a manner to assess the quality and the relative lack of bias in the research evidence allows for the analysis of the scores by means of the acceptable sampling protocol. Acceptance sampling is a statistical procedure that uses statistical sampling to determine whether a given lot, in this case evidence gathered from an identified set of published reports, should be accepted or rejected [12,25]. Acceptable sampling of the best available evidence can be obtained by:

•convention: accept the top 10 percentile of papers based on the score of the quality of the evidence (e.g., low Risk of Bias);

•confidence interval (CI95): accept the papers whose scores fall at of beyond the upper confidence limit at 95%, obtained with mean and variance of the scores of the entire bibliome;

•statistical analysis: accept the papers that sustain sequential repeated Friedman analysis.

To be clear, the Friedman test is a non-parametric equivalent of the analysis of variance for factorial designs. The process requires the 4-E process outlined below:

•establishing a significant Friedman outcome, which indicates significant differences in scores among the individual reports being tested for quality;

•examining marginal means and standard deviations to identify inconsistencies, and to identify the uniformly strong reports across all the domains tested by the quality instrument

•excluding those reports that show quality weakness or bias

•executing the Friedman analysis again, and repeating the 4-E process as many times as necessary, in a statistical process akin to hierarchical regression, to eliminate the evidence reports that exhibit egregious weakness, based on the analysis of the marginal values, and to retain only the group of report that harbor homogeneously strong evidence.

Taken together, and considering the domain and the structure of both tools, expectations are that these analyses will confirm that these instruments are two related entities, each measuring distinct aspects of bias. We anticipate that future research will establish that both tools assess complementary sub-constructs of one and the same archetype meta-construct of research quality.

References

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