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Summary of Genomics and Medicine: Role in Cardiovascular Diseases


Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author: Larry H. Bernstein, MD, FCAP

The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.
  1. Genomics and Medicine
  2. Epigenetics – Modifyable Factors Causing CVD
  3. Determinants of CVD – Genetics, Heredity and Genomics Discoveries
  4. Individualized Medicine Guided by Genetics and Genomics Discoveries
The first part established the
  • rapidly evolving science of genomics
  • aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
that have a significant association with the development of
  • cardiovascular diseases,
  • hypercoagulable state,
  • atherosclerosis,
  • microvascular disease,
  • endothelial disruption, and
  • type-2DM, to name a few.
These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,
  • essentially because the involvement of the circulation is systemic in nature.

Part 1

establishes an important connection between RNA and disease expression.  This development has led to
  • the necessity of a patient-centric approach to patient-care.
When I entered medical school, it was eight years after Watson and Crick proposed the double helix.  It was also
  • the height of a series of discoveries elucidating key metabolic pathways.
In the period since then there have been treatments for some of the important well established metabolic diseases of
  • carbohydrate,
  • protein, and
  • lipid metabolism,
such as –  glycogen storage disease, and some are immense challenges, such as
  • Tay Sachs, or
  • Transthyretin-Associated amyloidosis.
But we have crossed a line delineating classical Mendelian genetics to
  • multifactorial non-linear traits of great complexity and
involving combinatorial program analyses to resolve.
The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery.  This resulted in the identification of
genomic alterations in
  • cardiovascular disease,
  • cancer,
  • microbial,
  • plant,
  • prion, and
  • metabolic diseases.
This has also led to
  • the identification of genomic targets
  • that are either involved in transcription or
  • are involved with cellular control mechanisms for targeted pharmaceutical development.
In addition, there is great pressure on the science of laboratory analytics to
  • codevelop with new drugs,
  • biomarkers that are indicators of toxicity or
  • of drug effectiveness.
I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because
  • this portion of the genome is not identified in transcription of proteins.
However, it has become a lightning rod to ongoing genomic investigation because of
  • an essential role in the regulation of nuclear and cytoplasmic activities.
Changes in the three dimensional structure of these genes due to
  • changes in Van der Waal forces and internucleotide distances lead to
  • conformational changes that could have an effect on cell activity.

Part 2

is an exploration of epigenetics in cardiovascular diseases.  Epigenetics is
  • the post-genomic modification of genetic expression
  • by the substitution of nucleotides or by the attachment of carbohydrate residues, or
  • by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.
This could operate in a manner similar to the conformational changes just described.  These changes
  • may be modifiable, and they
  • may be highly influenced by environmental factors, such as
    1. smoking and environmental toxins,
    2. diet,
    3. physical activity, and
    4. neutraceuticals.
While neutraceuticals is a black box industry that evolved from
  • the extraction of ancient herbal remedies of agricultural derivation
    (which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).

The best examples are the importance of

  • n-3 fatty acids, and
  • fiber
  • dietary sulfur (in the source of methionine), folic acid, vitamin B12
  • arginine combined with citrulline to drive eNOS
  • and of iodine, which can’t be understated.
In addition, meat consumption involves the intake of fat that contains

  • the proinflammatory n-6 fatty acid.

The importance of the ratio of n-3/n-6 fatty acids in diet is not seriously discussed when

  • we look at the association of fat intake and disease etiology.
Part 2 then leads into signaling pathways and proteomics. The signaling pathways are
  • critical to understanding the inflammatory process, just as
  • dietary factors tie in with a balance that is maintained by dietary intake,
    • possibly gut bacteria utilization of delivered substrate, and
    • proinflammatory factors in disaease.
These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.
This portion extended into the diagnosis of cardiovascular disease, and
  • elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.
It explored protein, proteomic, and genomic markers
  1. for identifying and classifying types of disease pathobiology, and
  2. for following treatment measures.

Part 3

connected with genetics and genomic discoveries in cardiovascular diseases.

Part 4

is the tie between life style habits and disease etiology, going forward with
  • the pursuit of cardiovascular disease prevention.
The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.
It further discussed gene therapy and congenital heart disease.  But the most interesting presentations are
  • in the pharmacogenomics for cardiovascular diseases, with
    1. volyage-gated calcium-channels, and
    2. ApoE in the statin response.

This volume is a splendid example representative of the entire collection on cardiovascular diseases.

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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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Diagnostic Value of Cardiac Biomarkers


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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Triggering of Plaque Disruption and Arterial Thrombosis

Curator and Reporter: Larry H Bernstein, MD, FCAP

 

This discussion is a very interesting experimental model for the elucidation of plaque rupture in acute coronary syndromes.  The knowledge exists that there is a series of steps in develoiping atheromatous plaque.  We also know that platelets and endothelium are the location of this pathological development.  We don’t know exactly the role or mechanism of the contribution of hyperlipidemia, and what triggers plaque rupture.  This work reported is an experimental rabbit model that sheds light on the triggering of plaque rupture.

Triggering of Plaque Disruption and Arterial Thrombosis in an Atherosclerotic Rabbit Model

George S. Abela, MD, MSc; Paulo D. Picon, MD, MSc; Stephan E. Friedl, MEE; Otavio C. Gebara, MD; Akira Miyamoto, MD; Micheline Federman, PhD; Geoffrey H. Tofler, MB; James E. Muller, MD
From the Institute for Prevention of Cardiovascular Disease, Cardiovascular Division (G.S.A., S.E.F., G.H.T., J.E.M.), and the Department of Pathology (C.S.A., M.F.), Deaconess Hospital, Harvard Medical School, Boston, Mass; the Department of Pharmacology, Federal University and University of Passo Fundo (P.D.P.), Rio Grande de Sul, Brazil; the Heart Institute, University of São Paulo (O.C.G.), São Paulo, Brazil; and the First Department of Internal Medicine, National Defense Medical College (A.K.), Saitama, Japan.

Abstract

Background

It is now recognized that plaque disruption and thrombosis, a process often triggered by activities of the patient, is generally the cause of the onset of acute coronary syndromes. Understanding of disease onset could be greatly enhanced by the availability of a suitable animal model of plaque disruption and thrombosis. The aim of this study was to replicate and further characterize an atherosclerotic rabbit model of triggering of arterial thrombosis that was introduced by Constantinides and Chakravarti more than 30 years ago but not subsequently used.

  • Aortic plaques were induced by a high-cholesterol diet, by mechanical balloon injury of the artery, or by a combination of the two.
  • Triggering was attempted by injection of Russell’s viper venom (RVV), which is a proteolytic procoagulant, and histamine.

 Methods and Results

A total of 53 New Zealand White rabbits were exposed to one of four preparatory regimens:

  1. rabbits in group I (n=9) were fed a regular diet for 8 months;
  2. rabbits in group II (n=13) were fed a diet of 1% cholesterol for 2 months alternated with 2 months of a regular diet for a total of 8 months;
  3. rabbits in group III (n=5) underwent balloon-induced arterial wall injury, then were given a regular diet for 8 months; and
  4. rabbits in group IV (n=14) underwent balloon-induced arterial wall injury, then were given a diet of 1% cholesterol for 2 months followed by a regular diet for 2 months for a total of 4 months. After completion of the preparatory regimen, triggering of plaque disruption and thrombosis was attempted by injection of RVV (0.15 mg/kg IP) and histamine (0.02 mg/kg IV).
  • In group I, normal control rabbits without atherosclerosis, only one small thrombus was noted in 1 of 9 rabbits.
  • In group II, cholesterol-fed rabbits, thrombosis occurred in 3 of 13 rabbits.
  • Thrombus occurred in all rabbits in group III (5 of 5) and in 10 of 14 rabbits in group IV.
Although the frequency of thrombosis was not significantly different between groups I and II, possibly due to a small sample size, it was significantly different among all four groups (P<.001). Also, the frequency and amount of thrombus formation were significantly different among all four groups (P<.001; P<.0001) but not between groups I and II. Rabbits with atherosclerosis (those in groups II and IV) demonstrated plaque disruption and overlying platelet-rich thrombus formation similar to that observed in patients with acute coronary syndromes. The surface area covered by thrombus was
  1. 2 mm^2 in group I, 1
  2. 5.3±19.2 mm^2 in group II,
  3. 223±119 mm^2 in group III, and
  4. 263±222 mm^2 in group IV.
Rabbits in groups III and IV had the greatest amount of thrombus, and this amount was significantly greater than in rabbits in groups I and II (P<.001 and P<.03, respectively).

Conclusions

A suitable animal model is available for the study of plaque disruption and arterial thrombosis.

  • Hypercholesterolemia and mechanical arterial wall injury seemed to produce plaques vulnerable to triggering of disruption and thrombosis, whereas
  • normal arteries were relatively resistant to triggering.
This model provides a method to evaluate agents that might decrease the occurrence of vulnerable plaques or the amount of thrombus formed after triggering. Most important, the model can be used to identify the features of vulnerable plaques and the pharmacological stressors that trigger plaque disruption and thrombus formation.

Key Words: thrombosis, atherosclerosis, balloon, histamine, RVV

Introduction

Plaque disruption and subsequent arterial thrombosis are now recognized as critical to the onset of acute coronary ischemic syndromes. It is hypothesized that occurrence of thrombotic coronary occlusion has three components.
  1. First, a plaque that is vulnerable to disruption must be present.
  2. Second, acute physiological events are required to induce plaque disruption and thrombosis.
  3. Third, a relatively hypercoagulable state and heightened vasomotor tone increase the likelihood that arterial thrombosis will produce complete lumen occlusion.
 Recent epidemiological studies of human patients with myocardial infarction have demonstrated that in many cases a triggering activity, such as physical exertion, precipitates the acute onset of the disorder. Although a better understanding of plaque vulnerability and triggering would be of great value, knowledge of this process is limited because human studies are difficult and a suitable animal model has not been used.
In human patients, the opportunity to study factors responsible for acute onset of myocardial infarction is limited because coronary angiography performed before the event cannot prospectively identify plaques vulnerable to disruption.(9) After the event, angiography cannot distinguish the features of the plaque responsible for the disruption from those resulting from the disruption.(10) Although findings at autopsy provide detailed information about plaque disruption, these observations may be biased toward more advanced disease, since plaque disruptions producing total vascular occlusion and death may be more severe than those occurring in asymptomatic individuals or in patients with unstable angina or nonfatal myocardial infarction.
These difficulties, inherent in the study of plaque disruption and thrombosis in human patients, create a great need for an animal model of the process. More than 30 years ago, Constantinides and Chakravarti(13) developed such a model in atherosclerotic rabbits. Atherosclerotic plaques were produced in New Zealand White rabbits by intermittent cholesterol feeding. Triggering of plaque disruption and thrombosis was then accomplished by intraperitoneal injection of Russell’s viper venom (RVV, a procoagulant and endothelial toxin) followed by the intravenous injection of histamine, a vasopressor in rabbits. The aortas of the rabbits were then found to have disrupted atherosclerotic plaques with overlying platelet-rich thrombi.
Despite the similarity of these lesions to those observed in human patients, the model has received little attention or use during the past 3 decades. A recent review of the animal models of thrombosis currently in use noted that “thus far, it has not been possible to duplicate in a model the most common clinical cause of thrombosis—an ulcerated atherosclerotic plaque.”(14)
The advantage of the Constantinides model over other animal models used to study thrombosis is that it uses a biological intervention to trigger localized atherosclerotic plaque disruption and formation of platelet-rich arterial thrombi. The model facilitates the study of the process because the investigator determines when disruption and thrombosis will occur.
Disadvantages of the Constantinides model are
  • (1) the low yield of triggering (only about one third of the rabbits developed thrombosis) and
  • (2) the long (8-month) preparatory period. In addition, there is a need to replicate the findings of Constantinides and Chakravarti(13) from 30 years ago because of the biological variability of rabbit strains and RVV.
It cannot be assumed that the rabbits and RVV currently available will produce the results obtained in the 1960s.
In this study, we attempted to reproduce the original model of Constantinides.13 In addition, we wanted to determine whether mechanical injury to the aorta early in the preparatory phase could enhance the development of vulnerable plaques, thereby increasing the yield of disrupted plaques and shortening the preparatory period.

Methods

Fifty-three New Zealand White rabbits weighing between 2 and 3 kg were started on the experimental protocol; 41 survived until the time of attempted triggering. In these 41 rabbits, four dietary and interventional regimens were used in preparation for attempted triggering (Fig 1⇓). The control group, group I, consisted of normal rabbits (n=9) that were fed a regular diet for 8 months. Group II rabbits (n=13) were fed a high-cholesterol diet (1% cholesterol, ICN) for 2 months alternated with 2 months of a regular diet for a total of 8 months.15 Rabbits in group III (n=5) underwent balloon-induced arterial injury and were maintained on a regular diet for 8 months. Rabbits in group IV (n=14) underwent balloon-induced arterial injury, were maintained on a 1% cholesterol diet for 2 months, then were given a regular diet for 2 months for a total of 4 months.
Balloon-induced arterial wall injury of the aorta was performed with a 4F Fogarty catheter introduced through a femoral artery cutdown. The catheter was advanced in a retrograde fashion to the aortic valve and then withdrawn 3 cm. The balloon was inflated with 1.5 cm3 of air, and the catheter was retracted down to the iliofemoral artery. This was repeated three times in each rabbit as cm3 described previously.16 Rabbits were anesthetized with ketamine (50 mg/kg IM) and xylazine (20 mg/kg IM).

Of the 12 rabbits that died during the preparatory period, 5 were in group II, 2 in group III, and 5 in group IV. Seven of the 12 rabbits that died prematurely underwent an autopsy, and none had evidence of plaque disruption or arterial thrombosis. The causes of death included respiratory infection and liver failure from lipid infiltration.

The triggering agents RVV (Sigma Chemical Co) and histamine (Eli Lilly) were administered according to the method of Constantinides and Chakravarti.(13) RVV (0.15 mg/kg) was given by intraperitoneal injection 48 and 24 hours before the rabbits were killed. Thirty minutes after each RVV injection, histamine (0.02 mg/kg) was administered intravenously through an ear vein. Rabbits were killed by an overdose of intravenous pentobarbital and potassium chloride. The aorta and iliofemoral arteries were dissected and excised, and the intimal surface was exposed by an anterior longitudinal incision of the vessel.

The total surface area of the aorta, from the aortic arch to the distal common iliac branches, was measured. The surface area covered with atherosclerotic plaque and the surface area covered with antemortem thrombus were then determined. Images of the arterial surface were collected with a color charge-coupled device camera (TM 54, Pulnix) and digitized by an IBM PC/AT computer with a color image processing subsystem. The digitized images were calibrated by use of a graticule, and surface areas were measured by use of a customized quantitative image analysis package.

Tissue samples (1 cm in length) were taken from the thoracic aorta, 3 and 6 cm distal to the aortic valve; from the abdominal aorta, 7 and 4 cm proximal to the iliac bifurcation; and from the iliofemoral arteries. and prepared for and examined by light microscopy and they were examined by quantitative colorimetric assay.  Electron microscopy was also carried out with a Hitachi 600 microscope.

Biochemical analysis was done for tissue cholesterol. Free cholesterol and cholesteryl esters in the aorta were determined by high-performance liquid chromatography (HPLC) on the basis of the method of Kim and Chung. Each sample of aorta was ground to a fine powder with anhydrous sodium sulfate and extracted twice with 5 mL chloroform: methanol (2:1). The extract was dried under nitrogen and redissolved in 5 mL isopropanol.   Serum cholesterol, plasma fibrinogen, and platelet counts were done.

Overall comparison among the four groups was conducted with Fisher’s exact test and the Kruskal-Wallis test for discrete and continuous data, respectively. Comparisons between any two groups of rabbits were made by an exact Wilcoxon midrank test.23 P<.05 was considered statistically significant, and measured data were reported as mean±SD.

Results

Extent of Thrombosis After Triggering

In the 41 rabbits that underwent attempted triggering, the frequency of plaque disruption and focal thrombosis varied markedly depending on the type of preparatory regimen. In group I, only 1 of 9 control rabbits developed a thrombus. This was a small white thrombus with a surface area of 2 mm^2. Three of the 13 rabbits in group II on a 1% cholesterol diet developed white thrombi, all of which were small but were larger than that observed in group I (mean surface area, 15.3±19.2 mm^2). In group III, each of the 5 rabbits that had balloon-induced arterial wall injury developed large white thrombi (mean surface area, 223.0±119 mm^2). Ten of 14 group IV rabbits, with combined arterial wall injury and a high-cholesterol diet, developed white thrombi, all of which were large (mean surface area, 263.0±222 mm^2).

Both the frequency of occurrence and the amount of thrombus formation were significantly different among all four groups (P<.001 and P<.0001, respectively). However, the frequency and the amount of thrombus formation tested individually between groups I and II were not statistically different. The average surface area covered by thrombi in rabbits from groups III and IV was significantly greater than that observed in group II (P=.03 and P=.02) or group I (P=.001 and P=.001) rabbits. The average surface area covered by thrombi did not significantly differ between rabbits in group III versus those in group IV.

No white thrombi were noted in the ascending aorta or the aortic arch. In the non–balloon-treated rabbits in groups I and II, only 1 of 5 thrombi was in the abdominal aorta. In the balloon-injured rabbits in groups III and IV, the thrombi were almost evenly distributed between the thoracic and abdominal aorta (48 versus 66). There were more thrombi in the balloon-injured rabbits than in the non–balloon-injured rabbits (P<.002).

Extent of Plaque Covering the Arterial Surface

 The plaque surface area was significantly different among the four groups (P<.0001). Plaque was present in all the rabbits that were maintained on a high-cholesterol diet or that had balloon-induced arterial injury. The plaque distribution for each group is shown in Fig 4⇓. (not shown) Individual comparisons showed a larger amount of plaque in rabbits from groups III and IV than in those from group II (P=.04 and P=.001, respectively). There was no significant difference in the amount of the plaque in group III versus group IV rabbits. The Table demonstrates the relations of the various groups regarding frequency of disruption with the amount of thrombus formation and plaque surface area.
 The intima in group I rabbits appeared normal by gross inspection. In group II rabbits, white-yellow plaque was widely distributed over the arterial surface, with focal punctate ulceration occasionally noted under a dissecting microscope. In group III rabbits, the intima was smooth and widely covered with white plaque. Group IV rabbits had extensive sheets of elevated white-yellow plaque. By gross visualization, ulceration of the surface was present without superimposed thrombus in two rabbits in group IV.

Histological Features of Plaque Disruption and Thrombosis

 Over 4500 tissue sections were prepared and evaluated. Light microscopy of arterial samples from group I showed normal vascular histology. Group II samples had a predominance of foam cell infiltration of the intima surrounded with connective tissue. Group III samples had fibromuscular plaque composed mostly of muscular cell elements and minimal fibroconnective tissue. This was confirmed by Masson’s trichrome stains showing mostly red muscle cells and minimal blue fibrous tissue. Group IV samples had extensive plaque with an infiltration predominantly composed of foam cells.

Light microscopic examination of adjacent serial sections from thrombosis sites revealed platelet-rich thrombi with interrupted but long adhesion sites to the arterial wall over most of their length. Early organization and inflammatory cell infiltration were present within the thrombi. In sections from groups II and IV, some areas of plaque directly adjacent to the thrombi had marked thinning of the connective tissue cap and areas of dehiscent foam cells,. These observations were rare and were noted in <0.5% of the examined lesions. In most cases, the arterial thrombus was not located at a site of obvious plaque rupture. Foam cell infiltration was also noted adjacent to sites of thrombosis.

Figure 6.

A, Light micrograph shows that degenerated foam cells are present in a large cavity below a cap separating the cavity from the intimal surface of thoracic aorta from a rabbit in group IV (Movat’s pentachrome, magnification ×40). B, Light micrograph of large thrombus attached to the luminal surface of the thoracic aorta in the same rabbit shown in A. The cavitation is seen below the thrombus, and the intimal surface is markedly thinned (Masson’s trichrome, magnification ×16). C, Light micrograph of thrombus overlying a region of plaque with a large accumulation of foam cells from a rabbit in group IV. The free edges of the thrombus correspond to the underlying contour of the plaque, which suggests that the thrombus became detached during fixation (Masson’s trichrome, magnification ×25). D, Light micrograph of thrombus from the abdominal aorta in a rabbit from group IV, 48 hours after triggering. The thrombus is firmly attached and becoming organized. The yellow stain represents red blood cells, and the fibrin and platelets appear pink (Carstair’s stain, magnification ×25).
The degree of blue staining indicative of fibrous tissue in Masson’s trichrome–prepared slides was greatest in group II samples, as represented by values closer to the pure blue region (0.0) on CIE coordinates. Group II samples (0.33±0.046, mean±SD) were more blue than group III (0.43±0.06, P<.001) or group IV samples (0.38±0.05, P<.001). The degree of blue staining was not statistically different between samples from groups III and IV.
Scanning electron microscopy demonstrated fissures of various lengths below areas from which overlying thrombi were removed. Endothelial cells could be seen lining the intimal surface of the aorta in the rabbits that had undergone balloon-induced arterial wall injury 8 months earlier. Surface blebs and focal endothelial breakdown with ulcer formation, without grossly visible thrombosis, were occasionally seen in samples from groups II and IV. The base of these ulcers was layered with platelets, fibrin, and red blood cells. Transmission electron microscopy of areas with thrombosis confirms that the thrombi were platelet rich.

Biochemical Findings

 Baseline serum cholesterol for all rabbits was 50±25 mg/dL and did not differ among the four groups. In rabbits in groups II and IV, which received cholesterol feeding, serum cholesterol rose to an average peak level of 2500± 1200 mg/dL.
In the two groups that received cholesterol feeding, the total cholesterol content in tissue samples pooled from the thoracic and abdominal aorta was significantly higher in group IV (16±7.2 mg/g) than in group II (2.8±1.6 mg/g) (P<.0001). Rabbits that were maintained on a regular diet (groups I and III) had equally low levels of tissue cholesterol (0.05±0.04 versus 0.06±0.02 mg/g, P=NS).

Hematological Changes Accompanying Triggering

The average fibrinogen level before triggering in the 27 rabbits in which fibrinogen was measured was 210±119 mg/dL; it rose to 403±168 mg/dL 48 hours after triggering (P<.001). Plasma fibrinolytic activity did not change after triggering (85.5±37.8 versus 94.8±33.5 arbitrary units). Platelet counts (measured in only 19 rabbits in groups II and IV) decreased from 350±84×103 to 215±116×103 per cubic millimeter after triggering (P<.001). White blood cell count did not decrease after triggering (12.8±13.0 versus 12.8±7.1×103 cells per cubic millimeter). However, the hematocrit dropped from 35.7±3.8% to 32.0±5.8% (P<.0002).

Discussion

The results demonstrate that vulnerable plaques can be produced and that plaque disruption and platelet-rich arterial thrombus formation may be triggered pharmacologically in an animal model of arterial plaque. This finding documents that the New Zealand White rabbit strains and the RVV currently available can be used to obtain the same results observed by Constantinides and Chakravarti(13) more than 30 years ago.
The frequency of successful triggering was dependent on the type of preparatory regimen used. In control rabbits maintained on a regular diet, only 1 of 9 developed a small thrombus after injection of the triggering agents. Although rabbits fed a high-cholesterol diet had more thrombosis after triggering, the values were not statistically different between rabbits in groups I and II. In other studies of triggering of cholesterol-fed rabbits, a total of 7 of 30 rabbits have developed thrombi, but this also does not achieve statistical significance (unpublished data, 1994). The number of rabbits studied may have been too low to demonstrate a moderate difference of thrombus occurrence. However, earlier work by Constantinides and Chakravarti(13 24) demonstrated a frequency of thrombi in 1 of 22 rabbits not fed cholesterol versus 22 of 77 rabbits fed cholesterol, which does achieve statistical significance (P<.02). This indicates that a larger sample may demonstrate a difference between groups I and II and that cholesterol feeding increases the likelihood of the disruption and thrombosis process in the rabbit model. Thus, our results in conjunction with those of Constantinides and Chakravarti suggest that thrombosis triggered by RVV and histamine may be facilitated in the presence of atherosclerosis. However, these observations do not preclude the possibility of thrombosis in a normal artery, which can be induced by injury from various triggers.
Rabbits subjected to arterial balloon injury developed extensive thrombosis only after triggering, as did rabbits subjected to both arterial injury and a high-cholesterol diet. Thus, a high-cholesterol diet especially in the presence of mechanical injury is capable of producing a plaque vulnerable to disruption and thrombosis by triggering with RVV and histamine.

Production of Vulnerable Plaque by Cholesterol Feeding

The technique of pulsed cholesterol feeding used in this study has been shown to be an effective method of producing experimental atherosclerosis, as have continuous cholesterol feeding regimens. Recently, it has been demonstrated that cholesterol feeding induces an upregulation of vascular cell adhesion molecule-1 in rabbit endothelium. This may predispose a site to monocyte adhesion and migration into the subendothelial space. Continued macrophage accumulation may make the site particularly vulnerable to disruption and thrombosis.
Autopsy studies in humans have led to the hypothesis that a lesion with a lipid pool beneath a thin cap is particularly vulnerable to disruption and thrombosis.4 5 This morphology has been shown to generate stress concentrations that would predispose a plaque to disrupt.  Although sites with lipid pools and thin caps were noted in the present study, their occurrence was too limited to permit studies to determine whether these were sites particularly prone to thrombosis. Cholesterol feeding for 2 years may be required to produce a sufficient number of such lesions to determine their vulnerability to disruption.

Production of Vulnerable Plaque by Balloon-Induced Injury

An important finding of this study is that vulnerability to disruption and thrombosis was present 8 months after deendothelialization with balloon-induced arterial wall injury in rabbits on a regular diet (group III). This occurred in the presence of a regenerated endothelium overlying a diffuse fibromuscular plaque. Previous reports have demonstrated that endothelium that regenerates after balloon deendothelialization is physiologically dysfunctional for a prolonged period. From our study, it appears that endothelial function is compromised in its role as a thrombosis-resistant surface over a long period as well. An important factor that may contribute to the altered function is the presence of underlying plaque.

Triggering Agents RVV and Histamine

Among its numerous constituents, RVV contains proteases that activate factors V and X. Such activation leads to thrombosis, which is most likely to occur at sites of cell injury. In addition to this procoagulant effect, RVV is a direct endothelial toxin.31 However, in the absence of arterial abnormalities produced by cholesterol feeding or other means, RVV alone or in combination with a vasoconstrictor agent rarely produces thrombosis.4 The increase in fibrinogen levels and the stability of hematological factors during triggering indicate that RVV does not act by producing a disseminated coagulopathy. The localization of thrombus at focal arterial sites is further evidence that this model does not merely produce a nonspecific thrombotic effect.
Histamine is an arterial vasoconstrictor in rabbits. This effect is mediated by an H1 receptor that regulates release of norepinephrine at the presynaptic norepinephrine sites. Histamine may contribute to plaque disruption by raising the arterial pressure and stress on the plaque and/or by the development of vasospasm. Other, similar agents, thromboxane A2 and serotonin, also have been shown to result in severe vasoconstriction of epicardial coronary arteries that is mediated by platelet deposition at stenosed sites.

Comparison With Other Models

This is a unique model that combines features of several other animal models that have been used to study atherosclerosis and thrombosis. With regard to thrombosis, the model provides the opportunity to extend observations previously made in other animal models of thrombosis to the special conditions surrounding triggering of acute cardiovascular syndromes. While the model of Folts et al has been invaluable in assessing enhanced platelet deposition in dog and pig coronary arteries, it requires both endothelial injury and the production of a 60% to 70% lumen stenosis. Moreover, it does not use an atherosclerotic artery with a vulnerable plaque.
Badimon et al used a flow chamber to evaluate platelet deposition on activated arterial surfaces. They demonstrated that deep arterial injury results in more thrombus formation than superficial injury. However, their model does not recreate the in vivo environment or provide an opportunity for evaluation of various thrombogenic sites, as does the model presented in this study.

Relation of the Model to Human Coronary Thrombosis

Certain features of the lesions seen in this model are similar to those of human lesions seen at autopsy of patients with fatal myocardial infarction, ie, a lesion with a fissured collagen cap overlying a lipid mass of amorphous and crystalline lipid. However, most of the lesions in the model did not have these features and were more consistent with a recent pathological study of fatal coronary thrombosis, which revealed that in approximately half the cases, the plaque was relatively intact but an inflammatory infiltrate was present.36 Perhaps the incidence of plaque rupture causing thrombus may be even lower in patients with nonfatal coronary thrombosis, as suggested from angioscopic studies of coronary arteries that have shown plaque ulceration of various severities.
Although the model we used produced lesions with many similarities to the nonruptured lesions described in patients, extension of this preparation for a 2-year period has been documented to produce lesions with deep fissures similar to those observed in many patients with fatal coronary thrombosis. Also, use of balloon injury in this model to enhance plaque development resulted in plaques that were morphologically similar to advanced plaques induced by the alternating high-cholesterol diet.
Analyses of human plaques have demonstrated that disrupted plaques have significantly less collagen, glycosaminoglycans, and smooth muscle cells and more extracellular lipid and macrophages than do nondisrupted plaques. This is consistent with findings in our study that rabbits in group II had more connective tissue and a lower rate of disruption and thrombosis than those in groups III and IV.
Perhaps the major limitation of this study is that it used a complex pharmacological mixture as the trigger, which makes speculation on the mechanism of action difficult. Further studies will be necessary to determine which components of RVV and histamine are responsible for the focal thrombosis.

Potential Utility of the Model to Study Plaque Disruption and Thrombosis

The observation that large, platelet-rich thrombi can be obtained by triggering in animals with underlying plaques produced by cholesterol feeding or by balloon injury broadens the types of plaque that can be studied for vulnerability. Various types of preparatory regimens could be studied for their ability to promote or retard the development of vulnerable plaque.
The model also can be used to test pharmacological agents that may reduce the development of vulnerable atherosclerotic plaques, such as lipid-lowering agents, antioxidants, calcium channel blocking agents, and angiotensin-converting enzyme inhibitors. Antiplatelet and other antithrombotic drug therapies can be tested for the ability to reduce the amount of thrombus complicating plaque disruption. Finally, the model can be used to characterize the biochemical and cellular bases for plaque vulnerability by comparing the features of sites that do and do not develop thrombi soon after triggering.

 References

3 Friedman M, van den Bovenkamp GJ. The pathogenesis of a coronary thrombus. Am J Pathol. 1966;80:19-44.
4 Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res. 1966;6:1-17.
5 Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction causing sudden ischaemic death, and crescendo angina. Br Heart J. 1985;53:363-373. FREE Full Text
8 Tofler GH, Stone PH, Maclure M, Edelman E, Davis VG, Robertson T, Antman EM, Muller JE, and the MILIS Study Group. Analysis of possible triggers of acute myocardial infarction (the MILIS Study). Am J Cardiol. 1990;66:22-27. CrossRefMedline
9  Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78:1157-1166. Abstract/FREE Full Text
10 Ambrose JA, Winters SL, Arora RR, Eng A, Riccio A, Gorlin R, Fuster V. Angiographic evolution of coronary artery morphology in unstable angina. J Am Coll Cardiol. 1986;7:472-478. Abstract
11 Davies MJ, Bland MJ, Hartgartner WR, Angelini A, Thomas AC. Factors influencing the presence or absence of acute coronary thrombi in sudden ischemic death. Eur Heart J. 1989;10:203-208. Abstract/FREE Full Text
12  JH, Fuster V, Badimon L, Taubman M, Badimon J, Cheseboro JH. Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol. 1990;15:1667-1687. Abstract
13 Constantinides P, Chakravarti RN. Rabbit arterial thrombosis production by systemic procedures. Arch Pathol. 1961;72:197-208. Medline
14  Runge RS, Haber E. Animal models for the study of thrombolysis in vivo. Circulation. 1991;83(suppl IV): IV-1-IV-2. Abstract.
15 Constantinides P, Booth J, Carlson G. Production of advanced cholesterol atherosclerosis in the rabbit. Arch Pathol. 1960;70:80-92.

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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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