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Posts Tagged ‘biomarker assays’

Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases


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
https://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?
https://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
https://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)
https://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
https://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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Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Curator: Larry Bernstein, MD, FCAP

 

UPDATED on 12/12/2017

Evidence Mounts for Myocardial Injury After Noncardiac Surgery

Patrice Wendling

December 11, 2017

Based on an absolute rise of high-sensitivity cardiac troponin T (hs-cTnT) of >14 ng/L from presurgery to postsurgery levels, perioperative myocardial injury (PMI) occurred in one out of seven surgeries (16%) in the prospective BASEL-PMI study.

Despite being at increased CV risk, 82% of patients did not show any ischemic symptoms and only 6% had chest pain. Overall, only 29% of patients fulfilled any of the additional criteria required for spontaneous acute MI such as loss of viable myocardium on imaging or ECG findings suggestive of myocardial ischemia.

Senior author and long-time proponent of hs-cTnT, Dr Christian Mueller (University Hospital of Basel), said in an email, “The current evidence may justify different conclusions on which patients undergoing noncardiac operations should receive hs-cTnT screening. Likely Dr Puelacher’s is the more precise one.

“On the other hand, the criteria to receive screening in our study are such that not all physicians (and patients) would consider these patients ‘high-risk patients’ (eg, all patients above the age of 65 years [until 85 years]).”

Patients with PMI had more CV comorbidities at baseline and a higher rate of nonelective surgery than those without.

Patients with PMI had six times the 30-day mortality of those without PMI (9.8% vs 1.6%), with the excess mortality persisting up to 1 year (22.5% vs 9.3%; both P<0.001).

Of special note, 30-day and 1-year mortality was comparable in PMI patients not fulfilling any additional criteria required for spontaneous AMI vs those fulfilling at least one additional criteria (10.4% vs 8.7%, P=0.684; and 22.1% vs 29.1%, P=0.47).

Although the use of hs-cTnT testing was approved in the US in 2017, he’s aware of only three hospitals that do routine troponin testing in noncardiac surgery patients—two in Switzerland and one in Brazil.

“We have a very close cooperation with anesthesiology and also with the surgical department, and that’s a prerequisite for actually doing this; maybe we need to look outside of our own realm to actually find this cooperation,” he added.

For those wanting to screen, the researchers caution that preoperative troponin measurements are needed to reliably distinguish PMI from chronic hs-cTnT elevations. In BASEL-PMI, 51% of patients already had preoperative hs-cTnT levels at or above 14 ng/L, while 13.8% patients in VISION had their peak value before surgery.

SOURCE

https://www.medscape.com/viewarticle/889852?nlid=119520_3866&src=WNL_mdplsfeat_171212_mscpedit_card&uac=93761AJ&spon=2&impID=1506822&faf=1

Frederick K. Korley, MD, Allan S. Jaffe, MD
Journal of the American College of Cardiology
J Am Coll Cardiol. 2013;61(17):1753-1758.

It is only a matter of time before the use of high-sensitivity cardiac troponin assays (hs-cTn) becomes common throughout the United States. In preparation for this inevitability, this article raises a number of important issues regarding these assays that deserve consideration. These include:

the need for the adoption of a universal nomenclature;

the importance of defining uniform criteria for reference populations;

the challenge of discriminating between acute and nonacute causes of hs-cTn elevations, and between type 1 and type 2 acute myocardial infarction (AMI);

factors influencing the analytical precision of hs-cTn;

ascertaining the optimal duration of the rule-out period for AMI;

the need for further evaluation to determine the causes of a positive hs-cTn in non-AMI patients; and

the use of hs-cTn to risk-stratify patients with disease conditions other than AMI.

This review elaborates on these critical issues as a means of educating clinicians and researchers about them.

Highlights:

Need for a Universally Accepted Nomenclature

Defining Uniform Criteria for Reference Populations

Discriminating Between Acute and Nonacute Causes of hs-cTn Elevations

Distinguishing Between Type 1 and Type 2 AMI

Analytical Imprecision in Cardiac Troponin Assays

Ruling Out AMI

Investigating the Causes of Positive Troponin Values in Non-AMI Patients

Risk Stratifying Patients With Nonacute Coronary Syndrome Conditions

Conclusions

typical changes in CK-MB and cardiac troponin ...

typical changes in CK-MB and cardiac troponin in Acute Myocardial Infarction (Photo credit: Wikipedia)

Troponin activation. Troponin C (red) binds Ca...

Troponin activation. Troponin C (red) binds Ca2+, which stabilizes the activated state, where troponin I (yellow) is no longer bound to actin. Troponin T (blue) anchors the complex on tropomyosin. (Photo credit: Wikipedia)

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