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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5571_Библиотеки_им_академика_М_И_Перельмана
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The identification of methods aimed at reprogramming of the human somatic cells
to so-called induced pluripotent stem (iPS) offers the possibility to generate tailormade human cardiomyocytes that will most probably allow the development of
ethnical or disease -specific drug actions on cardiomyocytes [68, 69].
These in vitro assays based on pluripotent stem cells generated cardiomyocytes in
combination with high-throughput assay systems bride the gap to the complex models
of primary tissues such as perfused ventricular wedge preparations or Langendorffperfused hearts [9, 70].
6.3 NONARRHYTHMIC CARDIAC TOXICITY
In addition to cardiac side effects based on interactions of compounds with ion
channels causing arrhythmia, nonarrhythmic toxic effects may occur, referred to as
cardiac cytotoxicity. The importance of this form of cardiac toxicity is illustrated with
the following example.
Some of the most potent cardiotoxic compounds in terms of nonarrhythmic
toxicity belong to anthracyclins. Anthracyclins are among the most effective antineoplastic agents with broad-spectrum antitumor activity. The first two anthracyclins,
doxorubicin and daunorubicin, were discovered over 50 years ago and clinical trials
initiated in the 1960s (Figure 6.11). Although there was initial success in the treatment
of patients with acute leukemia and lymphoma, it was realized that these anthracyclins induced irreversible cardiac damage in patients on chronic therapy.
In a retrospective analysis of three trials [71], the cumulative perc entages of patients
developing congestive heart failure after admission of doxorubicin was 5%, 26%, and
48% at a dose of 400, 550, and 700 mg/m
2
, respectively. The exact mechanisms of
cardiac damage currently remains unclear [72], but mitochondrial damage and the
formation of reactive oxygen species have been proposed [73].
N
O
N
H
S
O
O
H
N
S
O
O
Figure 6.10 hERG blocker dofetilide.
OH
OMeOO OH O
H
OH
OH O
O
OH
NH
2
Doxorubicin
OMeOO OH O
H
OH
OH O
O
OH
NH
2
Daunorubicin
Figure 6.11 Nonarrhythmic cardiotoxic anthracyclins doxorubicin and daunorubicin.
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In an attempt to overcome cardiac damage without reducing efficacy, a pegylated
form of doxorubicin was developed, which reported a reduction in toxicity [72, 74].
However, chemical modifications of compounds are only successful if predictive test
systems are available for screening both efficacy as well as unwanted side effects.
In addition to anthracyclins, anticancer drugs of other classes also exhibit cardiacspecific side effects [75]. The emergence of small molecules acting as inhibitors to
kinases will require more demanding relevant toxicological modeling of cardiac side
effects to minimizes adverse effects within this organ [76].
6.3.1 Definition of Drug-Induced Cardiac Toxicity
According to Wallace et al. [77], three different types of drug-induced cardiac toxicity
can be identified:
(1) structural damage,
(2) functional deficits that may or may not be associated with histopathological
changes, and
(3) altered cell or tissue homeostasis in the absence of obvious structural or
functional deficits.
Functional deficits of the heart may be assessed in vivo using standard techniques
(e.g., by MRI). Conversely, structural damage, histopathological changes, and altered
cell or tissue homeostasis have to be assessed post mortem, using ex vivo or in vitro
test systems, or in vivo by appropriate biomarkers for cardiac damage. Models and
techniques to analyze nonarrhythmic cardiac side effects that allow in-depth analysis
of different mechanisms of cardiac toxicity are outlined in Sections 6.3.2 and 6.3.3.
6.3.2 Assays for Detection of Nonarrhythmic Cardiac Toxicity
Methods and techniques for measuring functional deficits are described in Section 6.2.
To detect nonarrhythmic cardiac toxicity, various models are available, ranging from
standard in vivo techniques such as ventriculography to sophisticated in vitro systems
that analyze the molecular basis for a given effect.
For this discussion, the term “in vivo” is used for examinations on living animals,
either conscious or anesthetized; “ex vivo ” for experiments on isolated organs and
tissue preparations; and “in vitro” for investigations using either primary cells isolated
from tissue or other suitable cellular models.
6.3.2.1 In Vivo Techniques In vivo systems can be used to monitor the mechanic
action of the heart, that is, its function as a pump. The key parameter to measure is the
ejection fraction, that is, the volume of blood pumped out of the ventricles with every
heartbeat. In addition to electrophysiological disturbances, several other events such
as loss of functional active cardiomyocytes, myocardial infarction, inflammation, and
cardiomyocyte hypertrophy/cardiomyopathy can cause altered cardiac function.
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Generally, the left ventricular ejection fraction (LVEF) is used as the marker for
correct pumping of the heart. Ejection fraction is defined in Equation 6.1.
E
f
¼
V
stroke
V
enddia
¼
V
enddia
V
endsys
V
enddia
ð6:1Þ
with V
stroke
¼ stroke volume (volume of blood ejected with each heartbeat); V
enddia
¼
end diastolic volume (volume of blood within a ventricle immediately before a
contraction); and V
endsys
¼ endsystolic volume (volume of blood left within the
ventricle at the end of contraction).
Measurement of the LVEF can be performed by various methods, most of which
are standard clinical diagnostic procedures adapted to the requirements of in vivo
testing:
Echocardiography is one of the most common diagnostic techniques for detection
of cardiac disease. It is possible to monitor the morphology of the heart, detect
dysfunction in blood flow as well as hypertrophy-induced cardiomyopathy, and to
determine the volume of the ventricles using ultrasound 2D or 3D image analysis and
Doppler measurements. The method is noninvasive and usually does not interfere
with normal physiological behavior of the heart [78].
Ventriculography is the method in which a dye is injected into the ventricle to stain
and visualize the blood volume that is pumped during cardiac action. This can be used
either in conjunction with cardiac catheterization, or with magnetic resonance
imaging (MRI) (see below).
Cardiac magnetic resonance imaging (MRI) is another noninvasive clinical
diagnostic tool that can be used to monitor heart function [79] and viability [78]
as well as screening for morphological changes such as infarction sites, scars, and fat
deposits. The method can be combined with application of contrast dyes for increased
visibility of morphological abnormalities and blood flow or imaging agents such as
gadolinium for targeted visualization of structures and proteins [80].
Magnetic resonance spectroscopy (MRS) can be used to monitor biochemical
processes within a given tissue or organ as opposed to MRI to image morphological
structures and function. Radioisotopes of standard ions are injected to provide
information about cardiac physiology on the molecular level [81]. In contrast to
MRI, this method is mainly used for research purposes, and not as a standard
diagnostic tool.
The methods described above are adapted from clinical use in patients to
preclinical and basic research using animals. Since the physiology (e.g., beating
frequency) of laboratory animals can greatly vary from those of humans, modifications have to be applied to allow for reliable and predictive models [82]. Standard
animal models for in vivo studies include mouse, guinea pig, rabbit, dog, and swine,
with the latter usually used sequentially during safety evaluation.
In vivo test systems have drawbacks even though they are a critical component of
drug development. The test systems are very costly in terms of time and resources and
not suitable for screening of medium or large compound libraries. Many in vivo tests
lack details concerning the mechanism on the cellular and/or molecular basis. Due to
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the different species used in vivo, interspecies extrapolation of the results is required to
conduct risk assessment. Current in vivo tests conducted according to protocols that
could be revised typically remain unmodified since regulatory acceptance has been
obtained.
6.3.2.2 Biomarkers of Cardiac Damage: Cardiac Troponin T as the Gold
Standard The detection of a tissue-specific marker in the peripheral blood or any
other accessible compartment of the body is another possibility for screening of druginduced, tissue-specific toxicities. The term “biomarker” was standardized by an NIH
working group in 2001 as “a characteristic that is objectively measured and evaluated
as an indicator of normal biological processes, pathogenic processes, or pharmacological response to a therapeutic intervention” [83]. Quantification of biomarkers is
primarily conducted by an in vivo experiment, and may be an ideal supplemental to the
methods described above.
As stated by Wallace et al. [77], an “ideal” biomarker for a given toxicity should be
.
specific (e.g., not expressed by nontarget tissues, high tissue/serum ratio),
.
sensitive (e.g., low baseline level, immediate release after injury, indication of
early and reversible toxicity),
.
predictive (e.g., release proportional to extent of injury),
.
robust,
.
noninvasive/accessible, and
.
bridge preclinical and clinical findings.
Highly specific and sensitive biomarkers may be difficult to identify if the type of
damage is a common cellular event that affects cardiomyocytes as well as other cell
types. For example, if cardiomyocytesundergo apoptosis, the same signaling cascades
are engaged in other cell types resulting in caspase activation, DNA laddering, and
blebbing of the cells. General markers for cell death that can be determined in the
circulationof an individual will usually not disclose the type of damage. Moreover, it is
more difficult to define an accessible, noninvasive, and robust biomarker as the
intricacy and subtleness of a drug-induced change in the physiology increases. Due
to these limitations, the key biomarkers for cardiac damage that can be measured in
biological samples include cardiac troponin T and cardiac troponin I for myocardial
necrosis, ischemia modified albumin (IMA) for ischemia of cardiomyocytes, and typeB natriuretic peptides for acute and chronic cardiac failure (for review, see Ref. 84).
Cardiac troponin is a complex of three proteins (troponin C, troponin I, and
troponin T) that are attached to tropomyosin, which prevents binding of myosin to the
actin filaments in a relaxed muscle cell. Once the muscle cell becomes excited,
calcium ions release from the sarcoplasmatic reticulum leads to conformational
changes in the troponin–tropomyosin complex, which enables cross-binding of the
actin filament with the myosin proteins [85].
Troponin T is the calcium-binding subunit of the troponin complex. Similar to the
other two troponins, it is highly specific, stably released in the circulation upon
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cardiac muscle damage, and a background level is not detected by common assay
systems [77, 86]. The determination of cardiac troponin was therefore established as
the “gold standard” for the detection of necrosis of cardiomyocytes [87]. In a patient,
cardiac troponins can be released due to different mechanisms of cardiac damage.
Myocardial infarction is the most common cause of injury. Nonischemic damage of
cardiac tissue such as inflammation, cardiac trauma, and drug-induced necrosis will
also result in elevated troponin levels.
In addition to diagnosing heart infarction clinically, several studies have shown
that determination of cardiac troponin is also a useful tool for preclinical studies [88,
89]. Due to its high specificity and sensitivity, the release of troponin T highly
correlates with histopathological extent of injury, the degree of impairment of cardiac
function, and prognosis. This data allows for a direct translation of preclinical
development to clinical outcome. Various assays are commercially available for
detection of troponin T release in laboratory animals [89] and can be easily
implemented in any preclinical strategy for detecting cardiotoxicity. Therefore, the
combination of in vivo experiments with measurement of troponin levels in the
circulation will allow for constant monitoring of nonarrhythmic cardiac side effects.
However, for highly predictive results, the biological model (species) and the assay
system must be chosen carefully [89].
6.3.2.3 Ex Vivo Test Systems Ex vivo test systems either consist of the whole
isolated organ (e.g., the Langendorff-perfused heart) or a part of the organ, such as
papillary muscle strips [90, 91]. All of these models require highly skilled operators to
avoid inter-experimental variations. Moreover, these tests are not capable of medium
or high-throughput screening, can be used only for acute experiments, and experimental results may be affected by the procedure that is used to prepare and isolate the
material. These test systems are mainly used for screening of ion channel-related
cardiac toxicity (Section 6.2). However, monitoring the biochemical and molecular
processes of drug-induced cardiac toxicity is also suitable. Explanted rat hearts have
been applied to investigate aspects of injuries induced by ischemic reperfusion, for
example, apoptosis [92], and anthracycline-induced cardiac toxicity [93]. In contrast
to primary cardiomyocytes isolated from the heart, isolated organs or tissue strips
retain their natural 3D structure as well as the cell-to-cell contacts, which are
necessary for proper physiological behavior [94].
6.3.2.4 In Vitro Test Systems Determination of cardiac-specific toxicity on the
cellular, biochemical, or molecular level demands the use of either primary cardiomyocytes isolated from cardiac tissue or cell lines, which mostly resembles
cardiomyocyte physiology [95, 96]. In contrast to test systems for detection of ion
channel-related cardiac toxicity, the use of artificial cell lines only transfected with
cardiac ion channels for determination of cardiac cytotoxicity is not an option.
Primary cardiomyocytes isolated from different species at different stages of
development (neonatal, adult) represent established models in toxicological and
physiological test systems. Freshly isolated primary cardiomyocytes possessing
in vivo physiological properties are costly, time-consuming to produce, and difficult
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to standardize [97, 98]. Moreover, cells are easily damaged during the isolation
procedure since strong cell-to-cell connections within the cardiac tissue are
formed [94]. Primary cardiomyocyte preparations are usually contaminated with
other cells types (e.g., fibroblasts, endothelial cells), which may overgrow the culture
of cardiomyocytes within a short time [98]. These contaminations also increase the
variability of data and reduce the reliability of test results that are derived from a
population of cells as opposed to a single cell. For example, a preparation of primary
cardiomyocytes with 70% purity is used in a standard cytotoxicity assay in which 30%
of the cells are killed by a given drug at a certain concentration. It is not obvious if the
30% dead cells consist of cardiomyocytes, contaminating cells, or a mixture of both.
This limitation can be overcome by more sophisticated read-out systems such as
image analysis and high-content screening (HCS) that will break down a given effect
to the single cell level.
Cardiomyocytes isolated from either juvenile or adult hearts will not proliferate in
culture and tend to dedifferentiate and lose their phenotype within a short time [99].
This limits their use to short-term experiments.
Cardiac cell lines that have been developed to overcome the limitations of primary
isolated cardiomyocytes are mainly constructed from immortalized or tumorigenic
cardiomyocytes [95, 96]. Although such cell lines have been widely used in recent
years, the relevance and predictive ability of drug-induced nonarrhythmic cardiac
toxicity is currently not proven.
A promising cellular model that combines the advantages of cell lines (e.g., purity,
high standardization, ease of use) with those of primary cells (fully functional, normal
physiological behavior) are pluripotent stem cell-derived cardiomyocytes, either
from mouse or human origin. Gen eration of the mouse ES cell line D3 and their
differentiation into cardiac myocytes was published in 1985 by Doetschman
et al. [100]. Almost 20 years later the generation of human ES cells and differentiation
into cardiomyocytes were described [101, 102], followed by the recent development
of human-induced pluripotent stem cells [68, 69]. The usefulness, relevance, and
predictivity of stem cell-derived cardiomyocytes as well as other cell types for
determination of drug-induced toxicity have been well recognized during the past
years (for review, [103–105]). Besides their unique primary-like functional behavior,
mouse ES cell-derived cardiomyocytes can be produced at 100% purity in large and
uniform lot sizes and stockpiled in liquid nitrogen. Their availability allows for full
library screening approaches and are suitable for all types of experimental setups and
read-outs, that is, standard cytotoxicity assays, apoptosis, and calcium signaling [104,
106–110]. Embryonic stem cell-derived cells and tissues are therefore a perfect tool
for cell-based in vitr o assays and overcome the limitations of the current models such
as unspecific cell lines and primary tissue.
6.3.3 Biochemical and Molecular Basis of Drug-Induced Cardiac
Toxicity—Impairment of Mitochondrial Function
Recently, it has been acknowledged that toxic effects on mitochondria can be a major
cause for the side effects of a drug and subsequently its withdrawal from the market. In
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a recent review, Dykens and Will reported that 50% of drugs with FDA Black Box
Warningsfor cardiovascular toxicity have documented mitochondrial liabilities [111].
Among those drugs are anticancer agents such as anthracyclines and the modern
tyrosine kinase inhibitor Sorafenib [112], NSAIDs such as Celecoxib [113], and the
antidiabetic drugs Rosiglitazone and Metformin (Figure 6.12) [114].
Mitochondrial dysfunction can be caused either by interaction of a drug with the
self-replication of this cell organelle (e.g., by nucleotide reverse transcriptase
inhibitors, [115]) or by interference of the drug with the process of oxidative
phosphorylation, for example, via inhibition of the electron transport chain or
uncoupling of electron transport from ATP synthesis [116–118]. Since cardiomyocytes highly demand oxygen, disturbances in oxidative phosphorylation will immediately cause damage to this cell type, whereas inhibition of mitochondrial DNA
synthesis will gradually decrease mitochondrial function.
Historically, it was almost impossible to detect mitochondrial liabilities of drug
candidates within the drug development process using common in vivo and ex vivo
test systems. Most often, mitochondrial toxicity was only retrospectively analyzed
after clinical reports of unwanted side effects. Although ex vivo systems using isolated
perfused hearts are suitable to detect mitochondrial toxicity [93, 119], this setup is not
capable of medium or high throughput and is therefore not compat ible with early
stages of drug development and toxicity testing.
NHN
H
Cl
F
3
C
O
N
N
H
O
O
N
N
CF
3
S
H
2
N
O
O
NNHNH
2
NH NH
Metformin
Celecoxib
Sorafenib
N
N
O
S
H
N
O
O
H
Rosiglitazone
Figure 6.12 Compounds with FDA Black Box Warnings for cardiovascular toxicity with
mitochondrial liabilities. Sorafenib, Celecoxib, Rosiglitazone, and Metformin.
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Most recently, in vitro test systems for mitochondrial function and dysfunction
have been developed that can be used either with transformed cell lines, isolated
mitochondria from animal tissues, or with primary or ES-cell-derived cardiomoyocytes [116, 120, 121]. The current strategy of toxicity testing within drug development
will now need to adapt and incorporate these assays that allow high-throughput
screening for mitochondrial liabilities.
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