Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2617_Библиотеки_им_академика_М_И_Перельмана
.pdf
290
https://t.me/medicina_free
P. Carraro
ues. If the patient is breathing a mixture of oxygen-enriched
air, then the instrument allows you to enter the FiO2 and consequently express the correct calculated parameters for this
factor; the interpretation of the result will be correct only if
this information is reported. A similar reasoning concerns
the body temperature, in particular if extreme values are
reached; this happens, for example, in hypothermic cardioplegia, where all the calculated parameters must be corrected
for temperatures that can reach 32–25°C in moderate hypothermia and 24–18°C in deep hypothermia. This information should also be reported in the report when the deviation
from the physiological values is important.
An interpretative suggestion can be introduced into the
report through computer algorithms, which, however, must
be shared with the clinicians who use the examination, in
order to make them aware of the limitations offered by these
systems. These algorithms should not be applied for extreme
values of the variables considered.
Blood Gas inVarious Situations
Emergency Room
so must be measured with a blood gas analyzer, which
exhibits sufcient analytical performance.
Pneumological Evaluation
Blood gas analysis is frequently an integral part of spirometry evaluation in the monitoring of pulmonopathic patients.
For these types of subjects, an instrument equipped only with
the classic parameters is normally sufcient. Given the great
spread of chronic obstructive pulmonary disease, the measurement of pCO2 under resting conditions is fundamental;
decision-making levels indicative of disease severity are values >45mmHg and >60mmHg, often accompanied by pO2
<60 mmHg. The current trend of care of these subjects
involves pneumological visits at home, thus avoiding moving the patient; this solution necessarily requires the availability of a portable tool. Some pneumological structures are
also equipped with semi-intensive units that therefore require
instrumentation similar to other hospital intensive care units.
Dialysis Treatments
This examination is the cornerstone of the initial evaluation
of the critical patient or with a risk of organ deciency; in
particular, this is true where a subject is unable to report his
health conditions, a traumatized, a chest pain, a severe dyspnea, a state of coma, an intoxicated. It is advisable that an
extended panel of analytes is available in the emergency
room, including electrolytes, metabolites, and oximetry.
Operating Room
In these situations, the clinical use mainly concerns ventilation (pCO2) and oxygenation (sO2). Due to the presence of
anesthetic gases, it is also preferable that oxygen saturation
be calculated with an oximeter.
Intensive Care andCoronary Units
In the context of intensive care, a further important parameter is lactic acid that allows the evaluation of peripheral
perfusion in the state of shock and has a prognostic value
in sepsis. The availability of blood sugar testdeserves a
special mention: in fact, tight blood glucose control protocols are frequently activated with repeated examinations
and insulin infusion; under these conditions, the analytical performance of common portable glucometers is
insufcient and the patient is exposed to the risk of severe
hypoglycemia. For this reason the glucose concentration
In subjects with severe renal insufciency, in particular
before and after dialysis treatments, the determination of
blood gas analysis may be required, with particular regard to
pH, bicarbonate, and potassium levels. This information is
obviously related to the instability of the dialyzed subject
with regard to electrolytes and pH.It should also be borne in
mind that dialysis or hemoltration can also be used as an
acute treatment of hyperkalemia. For these specic purposes,
the bloodcollection can be carried out at the level of the vascular shunt(a blood sample that is not completely arterialized) access that is more convenient in these cases. In the
case of circulatory or respiratory imbalances induced by
dialysis, arterial sampling will be needed, normally from the
radial artery. Analyzers that also determine urea and creatinine can provide an overall picture of the patient that,
together with hemoglobin, avoid the use of the laboratory for
the completion of the biochemical prole.
Interpretation ofResults
Classical Interpretation
This is based on the pathophysiological principles already
described and can also be automated, albeit with the limitations already described (Table 21.3). The simple clinical
conditions most often linked to these disorders are listed in
Table21.4. In this regard, dedicated software are also available. In this approach, the rst step is the cross-evaluation of
21 Blood Gas Analysis
https://t.me/medicina_free
291
Table 21.3 Interpretation of the acid–base balance in some simple
clinical conditions
Disorder pH Main disturbance Compensation
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
↓ ↓ HCO
↑ ↑ HCO
↓ ↑ pCO
↑ ↓ pCO
−
3
−
3
2
2
↓ pCO
↑ pCO
↑HCO
↓HCO
2
2
−
3
−
3
Table 21.4 Main causes of simple acid–base balance disorders
Respiratory
acidosis
Airway obstruction, asthma, chronic obstructive
pulmonary disease (COPD)
Central nervous system depression
Poor ventilation for neuromuscular or traumatic
causes
Hyperthermia
Respiratory
alkalosis
Anxiety
Central stimulation of breathing
Hypoxemia
Pneumonia, pulmonary edema, pneumothorax
Metabolic
alkalosis
Metabolic
acidosis
Acid loss, vomiting, gastric aspiration
Hypochloremic hypovolemia
Loss of H
+
, diuretics
Renal failure
Diabetic ketoacidosis
Alcoholic intoxication
Lactic acidosis
pH, pCO2, and bicarbonates; the combination of these simple
data provides an identication of the main disorder. An
example of this mode of interpretation was suggested by
G.S.Arbus with a specic nomogram (Fig.21.4). It is estimated, however, that more than half of the cases that come
for observation present a mixed or complex disorder.
Table21.5 summarizes the most frequent conditions of the
combined disorders.
Stewart’s Quantitative Approach
This is based on the ratio of strong ions to weak ions, the socalled strong ion difference (SID). The rst category includes
the Na, K, Ca, and Mg cations and the Cl anions and organic
acids. It is therefore called SID, i.e., the difference between
the rst and the second. At the physiological pH for the principle of electrical neutrality, we will have SID + H+ = 0 or
SID = -H+.
Weak acids are mostly represented by plasma proteins
(A+). Starting from the concentrations of SID and A+, it will
be possible to obtain an interpretation of acid–base disorders
but only of metabolic or non-respiratory ones. This approach
solves some limitations typical of classical interpretation but
Fig. 21.4 The Arbus invivo
nomogram for an initial
interpretation of acid–base
simple disturbances
Bicarbonate
mEq/L
50
45
40
35
30
25
20
15
10
7.7
7.6
Acute and
chronic metabolic
alkalosis
7.5
pH=7.4
Chronic respiratory
acidosis
7.3
7.2
7.1
Acute respiratory acidosis
Acute Respiratory
Alkalosis
Normal range
7.0
6.9
Acute and
chronic metabolic
acidosis
6.8
5
10 20 30 40 50
mm Hg
pCO
2
60 70 80 90 100
292
https://t.me/medicina_free
P. Carraro
Table 21.5
Possible interpretation of some mixed imbalances
Common
Disorder Characteristics
Respiratory
acidosis with
metabolic acidosis
↓pH
↓ HCO
↑ PaCO
3
2
conditions
Cardiac arrest
Intoxication
Multiple organ
failure
Respiratory
alkalosis with
metabolic
alkalosis
↑pH
↑HCO
↓ PaCO
−
3
2
Hepatic
insufciency and
diuretics
Vomiting in
pregnancy
Hyperventilation
in COPD
Respiratory
acidosis with
metabolic
alkalosis
Respiratory
alkalosis with
metabolic acidosis
pH normal↑ pCO
pH normal
↓ pCO
2
↓HCO
3
,↑HCO
2
−
COPD and
3
diuretics
Severe
hypokalemia
Sepsis
Renal failure and
hypoxia
Severe hepatic
impairment
Metabolic acidosis
with metabolic
alkalosis
pH normal
−
HCO
normal
3
Vomiting in renal
failure and
diuretics
has some critical calculations and requires the simultaneous
concentration of several analytes, some of which can only be
estimated. It is also understandable how this approach represents a renement of the concept of the anion gap as an estimate of the amount of organic acids. In this sense, some
interpretative formulas have been proposed that allow evaluating the contribution of proteins that represent a weak component but, at the same time, have a buffering effect, thus
reducing the diagnostic inaccuracy of the anion gap (Palmer
and Clegg 2023).
The Clinical Approach
Another highly pragmatic approach is based on clinical conditions. Leaving aside pathophysiology reasoning, we can in
fact compare the clinical picture under consideration with
that of the particular conditions listed in Table21.6.
Integrated Management inthePOCT
Table 21.6
Blood gas and electrolyte picture commonly associated
with some pathological conditions
Pulmonary
embolism
Moderate respiratory alkalosis
Hypoxia related to severty
More than 90mmHg in ambient air excluding
embolism
Acute pulmonary
edema
Hypoxia
CO
initially normal until the condition worsens
2
Asthma
Constant hypoxemia is proportionate to the
severity of CO
normal at 40mmHg, then there is ventilator
impediment and if 45 or more, then mechanical
ventilation have to be considered
COPD
Only moderate hypoxia in “pink puffers”
Increase in CO
severty index
If normal pH, then consider a compensatory
situation
Neurological,
muscular, and
traumatic
pathologies
Acute respiratory acidosis even before
hypoxemia
If CO
tends to increase, then mechanical
2
ventilation is needed
Sepsis
Initially, acute respiratory alkalosis
Then, metabolic acidosis is associated with a
mixed disorder: a normal pH with decreased HCO
Critical condition if pH decreases, in particular
in case of lactic acidosis
Diabetes
Metabolic acidosis, with variable phases during
insulin treatment
if decompensatedHCO
anion gap increased
Diuretic therapy
Metabolic alkalosis
Nasogastric tube
Metabolic alkalosis
Severe diarrhea
Metabolic acidosis with decreased HCO
Na and K are often deiminushed while Cl
tending to increase
that is normally decreased. If
2
in “blue bloaters,” with the CO2
2
−
decreased, K elevated,
3
−
3
−
3
Blood gas analysis was one of the rst decentralized laboratory diagnostics to be integrated into a laboratory management and control. This has been possible for many yearsdue
to the analyzers equipped with their own computer system
for instrumental management, which lends itself well to connectivity. The management of the POCT is dealt with by specic national and international guidelines, but, here, we must
remember some specic aspects mainly related to the mode
of communication. In fact, the integration of this analysis
into systems for data management is a priority for several
reasons: the number and complexity of the results for each
sample; the need to perform, in particular in intensive care;
numerous analyses with the related problems of their historicization; and the need to monitor critical patients through
computer systems that integrate different measurements and
diagnostics.
21 Blood Gas Analysis
https://t.me/medicina_free
293
Focusing more on the intensive context, it is clear that
the architecture of the connections includes the following
units: an analyzer, a concentrator for the bidirectional networking of the instruments and a remote control, a department management system (or an electronic medical record),
and a laboratory computer system. In all, this must be
added to the criticality of the safe identication of the
patient, since these are operational contexts in which the
analyses are normally assigned to nurses who also have to
perform many other tasks and often face emergency situations with little time available. In practice, the identication can take place in two ways: the rst requires a computer
acceptance with the generation of a sampling label, similar
to the other analyses for the laboratory, with which the
syringe to be loaded on the instrument is identied; the second mode can allow simplied management, without preacceptance, and makes use of the reading of a personal
identication code (for example, the bracelet) with the use
of a portable reader connected to a bench instrument, and
the automatic generation of the acceptance (and then a
report) with the patient’s personal details. It is understandable how, in any case,the secure identity of the patient in
both ways can be wellassuredby requiring a second step:
or with aconrmation with the name of the patientor with
a manual validationof data.
Recommended Readings
http://www.nejm.org/doi/full/10.1056/NEJMvcm0803851
https://www.westgard.com/biodatabase1.htm
Palmer BF, Clegg DJ (2023) Respiratory Acidosis and Respiratory
Alkalosis: Core Curriculum 2023. Am J Kidney Dis. 82(3);347–
359. https://doi.org/10.1053/j.ajkd.2023.02.004
Cardiac Biomarkers
https://t.me/medicina_free
AldoClerico andMartinaZaninotto
22
Introduction
Cardiovascular diseases represent the rst cause of morbidity, mortality, and hospital admission in industrialized countries and the most important item of expenditure of the
National Health Service. For these reasons, the assessment
of cardiovascular risk factors and the early diagnosis of heart
disease are now universally considered primary objectives of
the health organization. Cardiovascular biomarkers are
essential for diagnosis, prognosis, and therapy monitoring.
Thus, it is not surprising the growing interest in the research
of new biomarkers and the development of suitable methods
for their determination.
However, 30years ago, the laboratory made available to
the cardiologist only very few biomarkers that could support
the diagnosis of myocardial necrosis, such as creatine phosphokinase (CK), lactate dehydrogenase (LDH), and some
aminotransferases (transaminases) (Fig. 22.1). These biomarkers are insensitive and nonspecic for cardiac injury, as
they are present not only in the myocardium but also in
numerous other tissues. It was not until the 1980s that some
more sensitive and specic methods for assessingmyocardial injury were developed, such as immunometric methods
for measuring CK-MB isoenzyme and myoglobin. The real
revolution in cardiological diagnostics began only after the
development of methods for measuring cardio-specic biomarkers, such as cardiac troponin I (cTnI) and T (cTnT) isoforms and cardiac natriuretic peptides.
At the same time, an increasing number of biomarkers
have been proposed for assessing the risk of cardiovascular
mortality together with the well-known and traditional markers of cardiovascular risk (Table 22.1). However, in recent
years, biochemistry and pathophysiology studies led to the
identication of molecules closely related to the pathophysiological processes underpinning cardiac remodeling and
myocardial brosis. Some of these, especially galectin-3 and
the soluble interleukin 33 receptor protein (IL-33), called
sST2, have been intensively studied, and numerous clinical
studies have shown their prognostic relevance. Indeed, some
recent international guidelines have suggested their use in
patients with heart failure.
Finally, in more recent years, the diffusion and broader
availability of genetic analysis have alsoallowed their application to cardiovascular diseases. It is therefore hoped that
new laboratory tests will soon be made available to clinicians, helpful both to ascertain the diagnosis of a cardiological disease and evaluate other possible risk factors to
optimize pharmacological treatment (target therapy).
Based on the above considerations, laboratory tests,
which can be used in clinical practice as an aid in the diagnosis, prognosis, and monitoring of patients with heart disease,
can be classied into four groups: biomarkers of cardiac
injury, biomarkers of cardiac function, biomarkers of myocardial remodeling and brosis and genetic biomarkers associated with cardiovascular disease. In truth, since some of the
biomarkers may fall into more than one of the four groups,
their differentiation into distinct sections serves more of a
didactic than a conceptual function.
A. Clerico
Sant’Anna School of Advanced Studies Pisa, Pisa, Italy
M. Zaninotto (
Department of Laboratory Medicine, University-Hospital of
Padova, Padova, Italy
e-mail: martina.zaninotto@aopd.veneto.it
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Ciaccio (ed.), Clinical and Laboratory Medicine Textbook, https://doi.org/10.1007/978-3-031-24958-7_22
*)
295
296
Years
https://t.me/medicina_free
A. Clerico and M. Zaninotto
Fig. 22.1 History of the
development of methods for
determining cardiac
biomarkers. Milestones in the
development of methods for
myocardial damage
biomarkers (AST, LDH, CK,
CK-MB, myoglobin, cTnI,
and cTnT), function (ANP,
BNP, and NT-proBNP), and
remodeling (sST2 and
Galectin-3). EIA
immunoenzymatic method,
IRMA immunoradiometric
method, hs high sensitivity
method, Iso isoform, Mono
method using monoclonal
antibodies, RIA
radioimmunoassay method.
(Copyright EDISES 2021.
Reproduced with permission)
Table 22.1
Cardiovascular risk factors
Age
Sex
Positive family history for cardiovascular disease
Systemic arterial hypertension
Smoking habit
Dyslipidemia
Physical inactivity
Obesity
Diabetes
Prolonged states of psychophysical and/or psychological stress
Difcult economic conditions
Circulating biomarkers of cardiovascular risk
Natriuretic peptides (ANP, BNP, CNP)
Cardiac troponins (cTnI, cTnT)
Homocysteine
Fibrinogen
Lipoprotein (a)
Urinary albumin
γ-glutamyl transferase (GGT)
Renin–angiotensin–aldosterone system
Uric acid
Markers of coagulation and brinolytic function (tissue plasminogen
activator, [TPA], its inhibitor PAI-1, D-dimer, and factor V Leiden)
Inammation markers (C-reactive protein, adhesion molecules and
proinammatory cytokines, interleukin-6, tumor necrosis factor
[TNF], sST2, galectin-3, and GDF-15)
Extracellular matrix renewal markers (MMP, TIMP, PICP, PIIINP,
and ICTP)
Infectious agents (cytomegalovirus, herpes simplex virus, Chlamydia
pneumoniae, and Helicobacter pylori)
MicroRNA
Risk factors and biomarkers of cardiovascular diseases
IsoCK
IsoLDH
Electrophoresis
AST
CK
LDH
1970 1980 1990 2000 2010 2020
Myoglobin
CK-MB
Biomarkers ofMyocardial Injury
The rst biomarkers of tissue injury used for the diagnosis
and monitoring of acute myocardial infarction (AMI) were
the enzymes of the amino-transferase group (in particular
ECLIA
hs-cTnT and
MonoECLIA
NT-proBNP
ADVIA
cTnI
sSt2
Gal-3
Architect
hs-cTnI
Other
hs-cTnI
assay
RIA
CK-MB
EIA
cTnT
RIA
ANP
IRMA
ANP
BNP
ECLIA
NT-proBNP
cTnT
EIA
cTnI
aspartate aminotransferase [AST]), which were then gradually replaced by the CK enzyme due to its better diagnostic
sensitivity and specicity. Subsequently, the development of
standardized and relatively fast chromatographic and electrophoretic procedures led to the development of methods
for measuring CK and LDH isoenzymesto be implemented
in clinical practice (Fig. 22.1). Finally, many immunoassays
to measure proteins with structural and cytoplasmic localization, such as the CKMB isoenzyme (commonly referred to
as “CK-MB mass” determination), myoglobin, myosin, and
cTnI, and cTnT, have been developed in the last 25 years
(Fig.22.1).
According to some of the most recent national and international guidelines, the determination of CK-MB and myoglobin and, even more, AST and LDH enzymes, should be
denitively abandoned and replaced, in patients with suspected ACS, by onlycardiac troponins.
Biochemical Characteristics andBiological
Function ofTroponins
The sarcomere troponin complex is a structure that regulates
muscle contraction and consists of three protein subunits:
troponin C (TnC), troponin I (TnI), and troponin T (TnT).
The cTnI and cTnT have a molecular weight of approximately 23,500 Da and 37,000 Da, respectively, and have
slightly different peptide chains in the NH2-terminal part
(the rst 40 amino acids) than the musculoskeletal ones. TnC
(18,000Da) has three main domains: two terminal globular
and one central α-helical. The C-terminal domain contains
two high-afnity calciumsites. The other two sites (in the
N-terminal region) have low afnity and bind Ca++ ions only
after they have occupied the high-afnity sites. The low-
Basal (T0)
Afte
3 hours (T1)
* Ischemic setting:
equiv
22 Cardiac Biomarkers
https://t.me/medicina_free
297
afnity sites are the activators of the contraction process. The
Ca++ ion at high concentrations occupies all the TnC sitesleading to conformational changes in the troponin complex
that, through TnT, are transmitted to tropomyosin, which
slides along the actin lament groove byremoving the inhibitory effect of TnI on actin. Free actin can then interact with
myosin by stimulating its ATPase function.
Clinical Relevance ofTroponins Measurement
In recent years, the development of detection methods for
cTnI and cTnT with progressively increasing analytical sensitivity, which can detect myocardial necrosis of microscopic
size, has led to a revolution in the denition of acute myocardial infarction. According to the latest denition of myocardial infarction, the measurement of cardiac troponin plays a
central and essential role in its diagnosis.
This new denition of AMI is having a signicant clinical
(but also social and economic) impact, as, since its introduction, diagnosed cases of infarction have increased by
20–40%, compared with when the World Health Organization
(WHO) denition of AMI, published in 1973, was used. The
WHO denition considered three distinct criteria for the
diagnosis of myocardial infarction:
• The presence of typical ischemic symptoms
• The presence of typical electrocardiographic signs
• The typical upward/downward trend in the values of the
so-called cardiac enzymes (AST, CK, and LDH).
However, only two of these three criteria were necessary
for the diagnosis. According to this denition, in a patient
with typical symptoms (anginal pain) and electrocardiographic (ECG) alterations (such as ST-segment elevation),
the IMAdiagnosis is established. In patients with ST-segment
elevation myocardial infarction (STEMI), the cTnI or cTnT
assay can only conrm the diagnosis and be used for monitoring and prognosis. The cardiac troponins measurement
becomes essential for diagnosing patients with typical ischemic symptoms without ECG alterations; in these patients, if
they have an altered troponins kinetics, a diagnosis of non ST elevated myocardial infarction (NSTEMI) is made.
The most evident and relevant clinical advantage of the
new methods for measuring cTnI and cTnT with higher analytical sensitivity is the reduction of the time required to
diagnose AMI.Indeed, from diagnostic algorithms based on
serial sampling on admission and after 12–24hours by the
rst generation methods (1990–2002), there has been a gradual shift to more rapid diagnostic algorithms (6–12hours in
the years 2003–2007), which, by methods at high analytical
sensitivity, require a second sampling 3hours after admission (Fig. 22.2). Finally, in the European Society of
ACUTE CHEST PAIN
Tn <99th
percentile
r
alent) and/or ECG changes and/or imaging changes
Fig. 22.2 Algorithm for diagnosing acute myocardial infarction (AMI)
in accordance with national guidelines. 3-hour algorithm for the diagnosis of IMA NSTEMI, using a highly sensitive measurement method.
Ischemic setting: patient with medium-high risk of the acute coronary
syndrome, without a pathognomonic ECG for STEMI.The diagnosis of
NSTEMI is ascertained when at least in a sample collected within
3hours of admission, a troponin (Tn) value higher than the 99
tile of the reference population is found and the change from the baseline value (admission to the Emergency Department) is greater than
50%. (Copyright EDISES 2021. Reproduced with permission)
Tn >99th percentile
with >50% change
ISCHEMIC SETTING*
symptoms (chest pain or ischemic
Tn ≥99th
percentile
Tn >99th percentile
with >50% change
AMI
th
percen-
Cardiology (ESC) guidelines published in 2015, and subsequently updated in 2018, an assessment of biomarker kinetics involving a second sampling (T1) after 1 hour is
suggested.
Quality Specications ofTroponin
Measurement Methods
All the most recent national and international guidelines
published since 2000 recommend an increase in cTnI and
cTnT concentrations above the 99th percentile of the distribution of values measured in a reference population of
healthy individualsas a decision level for the diagnosis of
AMI . The same guidelines recommend, at this concentration, an analytical imprecision ≤10% (expressed as coefcient of variation [CV]). However, only since 2007methods
with these quality specications havebeen introduced commercially in Italy. Therefore, in accordance with national and
international guidelines, only immunometric methods measuring the 99th percentile of the distribution of cTnI and cTnT
concentrations in the reference population with a CV%
≤10% should be dened as new generation high sensitivity
methods for troponin measurement. These high analytical
298
https://t.me/medicina_free
A. Clerico and M. Zaninotto
sensitivity methods should also be able to measure cTnI and
cTnT in the majority (>75% of subjects) of healthy adults.
Newer generation methods, which have intermediate imprecision (CV between 10 and 20%) at the 99th percentile level,
should be dened as clinically usable, i.e., they can be used
in clinical practice but should not be dened as having higher
sensitivity. Finally, methods (such as most POCT systems)
that have an inaccuracy >20% should not be used to diagnose
AMI but only for the initial screening of patients with suspected acute coronary syndrome, especially when higher
sensitivity methods are not available.
Another advantage of introducing methods with higher
analytical sensitivity is the possibility of measuring thebiomarker in healthy subjects, including pediatric age. The most
recent studies have shown that circulating cTnI and cTnTlevels in healthy subjects depend on age and sex. From a clinical
point of view, it is essential to emphasize that the 99th percentile varies greatly when calculated in a population of
apparently healthy subjects over 65compared to the value
measured in blood donors between 20 and 55years.
The immunometric methods for measuring cTnI currently
available have very different reference values and provide
different results since they use different antibodies and calibration materials. The method for the measurement of cTnT,
which is governed by an international patent and uses control
materials and reagents from one manufacturer, allows for
more harmonized results, even though the reagents are
applied to different platforms. Because cardiac troponins'decision values (99th percentile of the reference population) are both method- and population-dependent, national
guidelines recommend that clinicians and laboratory medicine experts jointly agree on the most appropriate decision
levels according to the clinical context in which the test is
applied.
Clinical Interpretation ofResults Obtained by
High-Sensitivity Analytical Methods
An improvement in analytical sensitivity also leads to an
improvement in clinical sensitivity, equating to an increase
in the number of patients diagnosed with NSTEMI. This
group of patients has less extensive myocardial ischemic
lesions, which are not detectable by ECG, compared to
patients with STEMI.
However, since an improvement in the clinical sensitivity
of a laboratory test can be obtained only at the expense of
specicity, the use of methods for measuring troponins with
higher sensitivity results in an increase in the number of
patients who, although not clinically having an AMI, have
values of cTnI or cTnT above the decision level and, therefore, signicantly detectable myocardial injury. Indeed, in
recent years, there has been a progressive increase, over
30%, of patients diagnosed with NSTEMI and a parallel
decrease in the number of patients diagnosed with unstable
angina. The list of clinical conditions that can cause increased
circulating levels of cTnI and cTnT are many and tend to
increase with the age of patients. The most frequent causes
of increased levels of cTnI and cTnT in conditions other than
AMI are shown in Table22.2.
It is important to emphasize that some of these clinical
conditions may have a worse prognosis than AMI (e.g., dissecting aortic aneurysm, pulmonary embolism, and stroke),
so an elevation of cardiac troponins must always becarefully
evaluated. From a clinical point of view, two important
aspects must be considered when an increase in cTnI and
cTnT levels is observed. The rst is that an increase in troponins always indicates cardiac tissue injury. However, a positive test cannot suggest the mechanism responsible for the
cardiac injury, which may not even be ischemic. Withoutclinical evidence of myocardial ischemia, a biomarker value
above the decision level should stimulate the clinician to
thoroughly search for other causes of myocardial injury
(Table22.2). However, it is important to stress that, considering the close relationship between damaged tissue and
released protein, higher circulating concentrations indicate
larger areas of injury and, therefore, a higher cardiovascular
risk. The second point that must be carefully considered is
that there is no minimum threshold below which an increase
in cTnI and cTnT is considered irrelevant from a prognostic
Table 22.2 Clinical conditions other than acute myocardial infarction
in which circulating troponin levels above the 99th percentile of the reference population may be observed
Acute or chronic heart failure
Acute or chronic inammatory myocarditis with myocardial
inltration (amyloidosis and sarcoidosis)
Tachycardia or bradycardia
Systemic arterial hypertension, especially if associated with
ventricular hypertrophy
Heart surgery or ablation
Heart transplant rejection
Takotsubo myocardiopathy, stress heart
Pulmonary embolism or severe pulmonary hypertension
Respiratory distress syndrome
Dissecting aneurysm of the aorta
Stroke, subarachnoid hemorrhage
Shock
Sepsis
Renal dysfunction/failure
Hypothyroidism
Intense physical exercise (marathon, cycle race, and endurance tests)
Cardiac trauma
Cardiotoxic drugs
Critically ill patients admitted to intensive care
Chronic inammatory musculoskeletal or congenital neuro-muscular
diseases (cTnT only)
Severe anemia
AMI acute myocardial infarction
(plasma pool)
22 Cardiac Biomarkers
https://t.me/medicina_free
299
point of view, as demonstrated by numerous studies.
Guidelines indicate cardiac troponins and natriuretic peptides as biomarkers of the rst choice for stratifyingcardiovascular risk in general population and patients with
cardiovascular diseases.
Among the various clinical conditions that may present
with increased circulating levels of cTnI and cTnT, it is
essential to mention the intake of potentially cardiotoxic
agents, particularly anticancer drugs. The development of
symptomatic heart failure after anticancer therapy is quite
frequent, with an incidence ranging from 30% to 40% ten
years after treatment. It is important to emphasize that the
troponin assay can highlight the onset of cardiac remodeling at a stage when the pathological process is still reversible, and symptoms and signs of cardiac dysfunction
(including instrumental ECG and echocardiographic signs)
are absent. At this early stage of cardiotoxic damage, an
appropriate clinical intervention can prevent progression
to symptomatic decompensation, as recent international
guidelinesrecommend.
Biomarkers ofCardiac Function
Myocardiocyte
pre-proBNP
proBNP
(cardiac pool)
BNP
proBNP
NT-proBNP
Fig. 22.3 The myocardiocyte’s production, secretion, and peripheral
degradation of natriuretic-type B peptides (proBNP, BNP, and
NT-proBNP). The active hormone BNP derives from a 108 amino acid
precursor, called proBNP. ProBNP can be transformed by specic
enzymes (chorin and furin) in the cytoplasm of myocardiocytes (cardiac pool) and in the circulation (plasma pool) into two peptides, one
longer NT-proBNP, inactive peptide, and one shorter BNP, the active
hormone. These peptides, in turn, can be degraded by proteolytic
enzymes into even shorter polypeptides. (Copyright EDISES 2021.
Reproduced with permission)
Degradation
products
Degradation
products
Plasma
Biochemical Characteristics andBiological
Function ofCardiac Natriuretic Peptides
It has been known since the rst half of the twentieth century
that atrial myocardiocytes contain secretory granules.
However, it was demonstrated only in the years 1980/1990
that the heart also possesses an endocrine function because it
synthesizes and secretes a family of peptide hormones, called
cardiac natriuretic peptides, with a potent diuretic, natriuretic, and vasodilating action, as well as complex interactions with both the neurohormonal and immunological
systems.
Natriuretic peptides constitute a complex family of interrelated peptides that include ANP, BNP, CNP, urodilatin, and
DNP. However, only ANP and BNP peptides are produced
and secreted in appreciable amounts by the heart and, thus,
deserve the denition of cardiac natriuretic peptides. Cardiac
natriuretic peptides are produced as prepro-hormones
(prepro- ANP and prepro-BNP), containing a signal peptide
at the NH2-terminal level (Fig. 22.3). The respective prohormones (proANP and proBNP) are formed after the signal
peptide’s enzymatic removal and stored in the secretory
granules of myocells. The pro-hormones are then cleaved
into two fragments upon release from the myocardiocyte: a
longer one, comprising the NH2-terminal portion (termed
NT-proANP and NT-proBNP), and a shorter COOH-terminal
one, which constitutes the active hormone (ANP and BNP).
The active hormones, ANP and BNP, have a faster plasma
clearance than their respective propeptides, NT-proANP and
NT-proBNP, and, consequently, lower circulating levels.
Recent studies have also shown that proBNP is also present
in the circulation (Fig.22.3) and represents the predominant
circulating peptide in patients with heart failure.
The contractile and neuroendocrine functions of cardiomyocytes are closely linked and inuence each other through
numerous complex feedback mechanisms, contributing
together to determine cardiac function proper. Consequently,
tests that assess contractile function (such as ECG and echocardiography) and those that measure neurohormonal levels
provide different but complementary information about cardiac function.These aspects should be evaluated separately
using appropriate methods tobetter understanding the role of
the heart in some complex clinical conditions, especially in
heart failure.
Clinical Relevance ofCardiac Natriuretic
Peptide Measurement
BNP and related peptides (such as NT-proBNP) are now
considered in all national and international guidelines as
rst-line biomarkers for the diagnosis of heart failure, acute
and chronic, as well as for mortality/morbidity risk stratication, not only in patients with heart failure but also in those
with the acute coronary syndrome and all other cardiovascular diseases. In particular, the BNP/ NT-proBNP assay is recommended in the differential diagnosis of acute and chronic
heart failure, especially to exclude disease because of its
300
AIA TRIAGE ADVIA CMIA POCT
BNP (ng/L)
https://t.me/medicina_free
A. Clerico and M. Zaninotto
high negative predictive value and favorable cost/benet
ratio. Many clinical studies, including meta-analyses, have
also shown that BNP/NT-proBNP can reliably guide to personalized treatment of acute and chronic heart failure.
Interpreting BNP/NT-proBNP results requires knowledge of the pathophysiologic role of natriuretic hormones.
Circulating levels of natriuretic peptides increase progressively during adult life, especially after 50 years and are
higher in females than in males, especially during the fertile period. Moreover, some physiopathological conditions,
such as physical activity, physical constitution (BMI), and
pregnancy, as well as many pathological conditions, such
as cardiovascular, endocrine, renal, hepatic, and neoplastic
diseases, inuence the circulating levels of these hormones.
Finally, some drugs, often used in patients with cardiovascular diseases (digitalis, β-blockers, ACE-inhibitors, and diuretics), as well as neuro-hormonal factors (catecholamines,
endothelin, vasopressin/adiuretin system, renin–angiotensin–aldosterone system, thyroid hormones, corticosteroid
hormones, estro-progestinic, prostaglandinic, and cytokines), can interact with the natriuretic peptide system.
Pathophysiological andClinical Interpretations
ofChanges incirculatingBNP/NTproBNP
Circulating BNP/NT-proBNP concentrations should not be
considered an indicator of a specic cardiac disease (such as
heart failure) nor, even less, a surrogate for echocardiographic examination. On the contrary, it is important to
understand how the results of their determination must
always be evaluated, keeping in mind the state of activation
of the neurohormonal system and the general clinical state of
the patient, especially in consideration of concomitant morbid conditions and the pharmacological therapy. BNP, a hormone produced and secreted by the heart, must be considered,
above all, an index of the state of activation of the neuroimmune- hormonal system; this, among other, explains why
circulating levels of BNP/NT-proBNP are inuenced by
therapy in heart failure. The most widely used and effective
drugs (β-blockers, ACE inhibitors, specic angiotensin II
receptor blockers, and diuretics) act by inhibiting the neuroimmune- hormonal system (including the adrenergic system,
the renin–angiotensin–aldosterone system, the argininevasopressin system, the endothelin system, and the cytokine
system). The response to drug treatment is clinically signicant as it is the factor that most affects mortality.
Another essential aspect to consider when evaluating and,
more importantly, comparing BNP and NT-proBNP values
to each other is that the results are strictly method dependent.
Indeed, there are differences between the circulating levels
of the various peptides (BNP vs. NT-proBNP) and the different methods specic for a single peptide (Fig.22.4). In par-
220
200
180
160
140
120
100
80
60
40
20
0
Fig. 22.4 Systematic differences between commercially available
BNP assay methods. Results of external quality control
CardioOrmocheck in the cycles from 2005 to 2008: 112 participating
laboratories, 28 control samples, and 2354 determinations. The 10
th
25
, 50th (median), 75th, and 90th percentiles are shown in the box plots.
The results obtained by all the methods show signicant differences
between them. In particular, the AIA and ADVIA methods measure
BNP values that are approximately half of the TRIAGE Access and
POCT methods. (Copyright EDISES 2021. Reproduced with
permission)
th
,
ticular, the methods for determining BNP currently on the
market are sandwich-type solid-phase dual-antibody immunoassay systems, which use different calibrators and antibodies. Generally, one of the two antibodies is specic for
the part of the peptide chain with the ring shape, which binds
to specic biological receptors, while the other is specic for
the NH2 or COOH-terminal part. Since BNP is degraded in
vivo and in vitro by various enzyme systems attacking the
peptide chain at different positions, there are several degradation products and many potential interferent peptide molecules in plasma. Currently available commercial
methodsuse different antibodies specic for different epitopes of the BNP peptide chain, as well as different calibration materials, resulting in different values and strictly
method-dependent reference ranges and decision limits
(Fig.22.4).
As previously noted, from a strictly diagnostic point of
view, determiningBNP/NT-proBNP peptides should be used
to exclude heart failure (HF). Many studies indicate that the
most appropriate decision level for this differential diagnosis
may correspond to the 97.5th (or 99th) percentile of the distribution of BNP/NT-proBNP values in the healthy population,
preferably divided into groups concerning age and sex.
Although this value is different for each measurement
method, the distribution of peptide values in each method is
relatively constant for the various populations studied.
Thus,it seems reasonable to use in clinical practice the corresponding value indicated by scientic studies or by the
manufacturing companies if calculated on a numerically signicant population.
Соседние файлы в папке Библиотека им академика М.И. Перельмана