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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3701_Библиотеки_им_академика_М_И_Перельмана

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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>30kg/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 etal. 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 etal. 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. Themetabolic 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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[18] Stalder T etal. Cortisol in hair and
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[35] Kuehl LK etal. Hair cortisol
and cortisol awakening response are associated with criteria of the metabolic syndrome in opposite directions. Psychoneuroendocrinology. 2015;:365-370
[36] Matheus ASdM etal. Impact of
diabetes on cardiovascular disease: An update. International Journal of Hypertension. 2013;:1-15
[37] Olokoba AB, Obateru OA,
Olokoba LB. Type 2 diabetes mellitus: Areview of current trends. Oman Medical Journal. 2012;(4):269
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Stern MP. Diabetes and cardiovascular disease: The “common soil” hypothesis. Diabetes. 1995;(4):369-374
[39]
Mosenzon O etal. CAPTURE: A multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries. Cardiovascular Diabetology. 2021;(1):1-13
[40]
Lehrer HM etal. Hair cortisol concentration and glycated hemoglobin in African American adults. Psychoneuroendocrinology. 2016;:212-218
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Feller S etal. Predictors of hair cortisol concentrations in older adults. Psychoneuroendocrinology. 2014;:132-140
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Staufenbiel SM etal. Determinants of hair cortisol and hair cortisone concentrations in adults. Psychoneuroendocrinology. 2015;:182-194
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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 30minutes to 6hours 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 6h 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 45min 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
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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,