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Novel Pathogenesis and Treatments for Cardiovascular Disease
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excessive accumulation of body fat, with the amount of this excess fat being directly
responsible for most obesity-associated health risks [27]. Although body mass index
(BMI) is the established clinical measurement to estimate CVD risk associated
with excess body weight, increasing evidence suggests that abdominal obesity, as
assessed by the waist-hip ratio (WHR), could represent a better marker of CVD risk
than BMI [28].
The incidence of obesity is increasing at a rapid and concerning rate in most
regions worldwide, with direct consequences on the risk of developing several chronic
diseases such as systemic hypertension [29] and type 2 diabetes [30]. More seriously,
obesity usually occurs with a cluster of metabolic disturbances such as impaired glucose metabolism, atherogenic dyslipidemia, and hypertension, and obese individuals
have an increased risk of CVD [26]. Interestingly, perceived societal stigma due to
weight discrimination was shown to contribute to HCC [31], complicating the association of elevated cortisol with obesity. Still, HCC was associated with higher BMI in
obese individuals (BMI>30kg/m2) compared to average weight (BMI: 18.5–24.9) and
nonobese overweight (BMI: 25.0–29.9) people [19]. A meta-analysis confirmed the
positive associations between HCC and stress-related anthropometric measures
(BMI and WHR) and reported a 9.8% increase in HCC per 2.5 points BMI [18].
. Dyslipidemia
Dyslipidemia is a common metabolic disorder and an established risk factor for
cardiovascular disease [32]. The condition is characterized by high-risk lipid levels
with an increased level of serum total cholesterol (TC), triglycerides (TG), lowdensity lipoprotein cholesterol (LDL-C), or a decreased concentration of serum
high-density lipoprotein cholesterol (HDL-C) [33]. Dyslipidemia is closely linked
with obesity, a disease characterized by an adverse effect on lipoproteins a known
cardiometabolic risk factor [34].
The relationship between hair cortisol with lipids varied considerably across studies. The MASHAD study, a prospective cohort population study, found that increased
serum total cholesterol levels were positively associated with absolute CVD risk
among men and women [33]. However, after adjusting for confounding factors, high
serum TC only significantly increased the risk of myocardial infarction in men. Kuehl
etal. reported a positive association between triglycerides and HCC [35]. Another
study found a positive association between low-density lipoprotein cholesterol (LDLC) and HCC [3]. Since dyslipidemia is one of the main cardiovascular risk factors,
further research is needed to examine chronic cortisol exposure and its effect on lipid
metabolism.
. Diabetes
Cardiovascular diseases are the most common cause of morbidity and mortality
among patients with diabetes mellitus [36]. More than 90% of people with diabetes
mellitus suffer from type 2 diabetes (T2D), a disease characterized by hyperglycemia,
insulin resistance, and impaired glucose tolerance [37]. T2D and CVD have several
shared characteristics; both conditions increase with age, are associated with an
adverse lipid profile, obesity, and a sedentary lifestyle, and lifestyle modifications of
common risk factors can reduce the risk of both [38]. Generally, patients with T2D
also display other comorbidities such as obesity, hypertension, and dyslipidemia,
increasing the risk for CVD [36].

The Association of Hair Cortisol and Cardiometabolic Risk Factors in Cardiovascular…
DOI: http://dx.doi.org/10.5772/.108356
Recently the CAPTURE study, a study assessing the prevalence of established
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CVD and its management in adults with T2D across 13 countries and five continents,
reported that CVD was prevalent in 34.8% of patients with T2D [39]. Elevated
cortisol levels are consistently associated with glycated hemoglobin, the diagnostic
measure of T2D [18, 40] or diabetes [41–43]. Manenschijn etal. reported that HCC is
associated with CVD and diabetes [13]. Since CVD and T2D share so many characteristics, further study of HCC measurements could be interesting in trying to discriminate between the two diseases or show that they are inextricably linked.
. Conclusion
The prevention and sensible management of cardiometabolic risk factors such
as hypertension, obesity, dyslipidemia, and diabetes can markedly alter cardiovascular morbidity and mortality. Interestingly, cardiovascular risk is often associated
with more than one cardiometabolic risk factor related to elevated cortisol levels.
Themetabolic syndrome describes this group of interrelated disorders such as insulin
resistance, abdominal obesity, glucose intolerance, dyslipidemia, and hypertension
[18]. HCC levels provide a measure of long-term exposure to chronic stress and
have the potential as a suitable biomarker of CMR and contribute to the prevention,
early diagnosis, treatment, and management of CVD. Hair cortisol measurements
potentially reduce the variability associated with self-reported measures and provide
a more robust view than the acute cortisol determinations in urine, saliva, and blood
samples. While the evidence for the relationship between cardiometabolic risk and
cortisol is clear and compelling, inconsistencies in the data must be addressed and
understood.
A recent meta-analysis showed that adherence to several healthy lifestyle
behaviors simultaneously reduced cardiovascular disease risk by 66% compared
with adopting none or only one behavior [44]. However, no evidence exists that
interventions that reduce cardiometabolic risk factors decrease hair cortisol levels in
preventing or treating CVD [7]. More extensive studies are needed to ascertain the
use of hair cortisol as an effective measure of stress reduction interventions. Also,
further research is required to delineate whether HCC is a biomarker of CVD or CVD
risk to utilize HCC in clinical settings effectively. Further insight into the mechanisms
underlying increased cortisol exposure is necessary for the more effective implementation of cortisol-lowering therapies and potential new treatment targets.
Acknowledgements
I express my sincere gratitude to Francina (Riah) Van Wyk and Momar Milliones
for their continued support.
Conflict of interest
The author declares no conflict of interest.

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The Association of Hair Cortisol and Cardiometabolic Risk Factors in Cardiovascular…
DOI: http://dx.doi.org/10.5772/.108356
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Chapter 20
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Use of Cardiac Troponin for the
Diagnosis of Cardiac Pathology
in Postmortem Samples Taken at
Autopsy
David C.Gaze
Abstract
T
he diagnosis of acute cardiac pathology is a clinical challenge in both the living
and in the postmortem setting. Cardiac troponin (cTn) T and cardiac troponin I
released from the contractile apparatus of cardiomyocytes into the circulation can be
detected by sensitive and specific immunoassays and are the gold standard biochemical test for diagnosis of acute coronary syndromes (ACS). Recently with the advent of
more sensitive detection methods, elevation in non-ACS has become apparent causing
clinical confusion. In most cases, these elevations are related to subclinical cardiac
damage and often confer poor prognosis in cTn-positive patients. Biomarkers of
cardiomyocyte damage may be of value in routine hospital and medico-legal autopsy.
A significant body of evidence has emerged since the late 1990s, assessing the clinical
utility of cardiac troponin in biological fluids or in immunohistochemical staining
of cardiac tissue to aid in the diagnosis of acute cardiac pathology when standard
microscopic evidence is inconclusive. This chapter reviews the extensive literature on
the subject and details the disparity between pericardial fluid and serum for the use
of cTn in the postmortem setting.
Keywords: cardiovascular disease, risk, diagnostics, therapeutic intervention,
treatment, prediction
. Introduction
Cardiac troponins (cTn) T (cTnT) and I (cTnI) are the gold standard biochemical
markers used to identify acute cardiac pathologies in patients who present with typical and atypical chest pain to the emergency department. These muscle-associated
proteins confer superior diagnostic and prognostic ability compared to conventional
nonspecific muscle derived enzyme markers such as creatine kinase (CK), its MB
isoform (CK-MB), or myoglobin. Cardiac troponin determination is central to the
diagnosis of non-ST segment elevation acute myocardial infarction (NSTEMI),
contributing to international guidelines for diagnosis and management of NSTEMI
patients [1].

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Recent advancement in laboratory technology driven both by clinical demand and
the commercial in vitro diagnostic market has seen the emergence of highly analyti-
cally sensitive immunoassays for the termination of cTnT and cTnI in biological
samples, mainly serum and plasma. The role out and increasing popularity of the
sensitive methods have introduced new clinical challenges, notably defining acceptable reference intervals in the apparently healthy population, sex-specific cut-off
values and novel clinical roles in non-acute cardiac diseases where often secondary
underlying cardiac disease is present [2].
One area of interest has been the potential value of cTnT and cTnI in the postmortem setting and may provide insight into the cause of death. Troponin analysis in
postmortem blood and pericardial fluid during autopsy investigations can potentially
help medical examiners and forensic pathologists attribute what happened before,
during, and after a death. This chapter will explore the use of cardiac troponin in the
postmortem setting, from its application in routine hospital as well as medico-legal
autopsy and forensics, assessing the usefulness in offering a clearer picture of an
individual’s final moments.
. Clinical utility of cardiac troponin in myocardial damage
Cardiac-specific isoforms of the contractile protein complex troponin, namely
cTnT and cTnI, are released into the bloodstream following damage to cardiomyocytes. The mechanism by which these structural proteins are released into the
circulation has been debated significantly over many years. Initially, it was thought
that cTn could only be released following overt cellular necrosis; however, recently it
has been suggested that release can occur in ischemia without necrosis [3]. A review
of the subject by Ragusa and colleagues suggest release mechanisms, including
apoptosis, necroptosis, physiological cardiomyocyte renewal, and cellular wounding
can contribute to cTn release as well as necrosis [4]. An immunohistochemical study
using a canine model of coronary occlusion ranging from 30minutes to 6hours demonstrated variable loss of both cTnT and cTnI in paraffin-embedded left ventricular
myocardial sections [5]. Loss was variable but more so for cTnT than for cTnI, and
loss was greater at the periphery of the infarct area rather than the centralised region
(Figure ).
Figure 1.
Canine left ventricular myocardial tissue following 6h of coronary artery occlusion. Immunohistochemical
staining of (A) cTnI demonstrating decreased but non-uniform staining in the central necrotic area (asterisk);
(B) cTnT demonstrating loss at edge of infarct zone (arrows) and (C) canine left ventricular myocardial tissue
following 45min of coronary artery occlusion demonstrating loss of cTnI in the zone of necrosis (asterisk) (source:
Adapted from [5]).

Use of Cardiac Troponin for the Diagnosis of Cardiac Pathology in Postmortem Samples Taken…
DOI: http://dx.doi.org/10.5772/.111799
Using monoclonal antibodies specific to the cardiac isoforms, immunoassay tech
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nologies can quantify the amount of cTnT or cTnI in a biological matrix [6]. Initially,
early immunoassays utilised high clinical cut-off values (high specificity and low
sensitivity) allowed the separation of patients with overt acute myocardial infarction
(AMI) from apparently healthy persons who were deemed negative for cTn based on
the equivalent cTnT or cTnI concentration to the then-used gold standard tests (CK
or CK-MB). Subsequently, the large body of evidence demonstrating elevation of CK
and CK-MB in the absence of an elevated cTn questioned the cardio-specificity of
the enzyme markers, along with approximately 30% of patients ruled out with AMI
-
Figure 2.
Categories of cardiac troponin release in acute and chronic diseases. All conditions have documented evidence of
elevated cTn. AF, atrial fibrillation; CAD, coronary artery disease; CHF, chronic heart failure; CKD, chronic
kidney disease; ESRD end-stage renal disease; LV left ventricle; MVO2, myocardial oxygen consumption; PAH,
pulmonary artery hypertension; RAAS, renin-angiotensin-aldosterone system; RV, right ventricle (source: [2],
with authors permission).

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demonstrating positive cTn which is associated with poor prognosis, resulted in the
adoption of cTn as the gold standard test for diagnosis of AMI [6].
Integral to the adoption of cTn was the appropriate definition of cut-off to confer
an abnormal concentration. This was subsequently defined as the 99th percentile
value of an apparently healthy population. When adopted into routine clinical
practice, this lowered the sensitivity of the assays allowing early diagnosis in the
evolving infarction but at the cost of specificity. Initially, this caused clinical confusion with a larger number of patients presenting with low concentrations of cTn
just above the AMI cut-off value, but further research of such patients found the
presence of comorbid conditions (Figure ) often with underlying cardiovascular
pathophysiology [2].
. Biochemical testing in assisting cause of death at postmortem
Biochemical testing in postmortem investigations (termed thanatochemistry,
necrochemistry or the chemistry of death) was initially established in the early 1950s,
and a great number of biochemical analytes have proved an adjunctive tool to assist
the cause of death at postmortem [7]. Adoption of biochemical testing especially in
the medico-legal forensic autopsy has often been limited. The determination of death
may have significant impact on those directly or indirectly involved in the death of an
individual and can carry a custodial sentence. Thus, the scientific evidence presented
in court is intensely scrutinised both by the prosecution and defence counsels. Whilst
no biochemical test is infallible, many are associated with the likelihood of a disease
process rather than a definitive diagnosis of the disease. Often the barrier to use is
the interpretation of results of biochemical assays from cadaveric sampling, hindered
by the lack of reference normality in death; thus, results are compared to reference
intervals generated in the living [7, 8] with few studies demonstrating corresponding
histopathological findings to the biochemical results. Interpretation is further complicated by factors such as postmortem interference in the assay technology, appropriate
sampling matrices, postmortem autolysis, microbial metabolism, fluid redistribution,
and postmortem interval (PMI). Molecular biophysical properties such as molecular
weight, structure, intracellular location, electrical charge, ionic strength, protein
affinity, and cell membrane permeability may differ between life and death and can
influence interpretation in both situations [7].
There are a number of fluid components which are suitable for cadaveric biochemical testing, namely vitreous humour from the posterior segment of the eye,
cerebral spinal fluid (CSF), synovial fluid, pericardial fluid (PCF), venous femoral
blood, venous jugular blood, peripheral blood sampling, urine, gastric contents and
right ventricle heart whole blood [7–9]. Analytes and potential uses in postmortem
samples are listed in Table .
. Conventional cardiac biomarkers at postmortem
The importance of cardiac biomarkers assisting in postmortem diagnosis was
highlighted in cases where a suspected myocardial lesion cannot be diagnosed by
routine histological analysis. They were utilised initially for the determination of
sudden cardiac death. Initially, CK and lactate dehydrogenase isoenzyme analysis of
pericardial fluid was utilised [10, 11], followed by K:Na ratio [12]; CK isoenzymes,
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