Biomarkers of Necrosis and Myocardial Remodeling: August 2015

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Biomarkers of Necrosis and Myocardial Remodeling
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DOI: 10.1007/978-94-007-7740-8_42-1
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General Methods in Biomarker Research and their Applications
DOI 10.1007/978-94-007-7740-8_42-1
# Springer Science+Business Media Dordrecht 2014
Biomarkers of Necrosis and Myocardial Remodeling

Juan Antonio Vílcheza,b, Esteban Orenes-Piñeroa, Diana Hernández-Romeroa, Mariano Valdésa and Francisco Marína*
a
Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, University of Murcia, Murcia, Spain
b
Department of Clinical Analysis, Hospital Universitario Virgen de la Arrixaca, University of Murcia, Murcia, Spain
Abstract
Multiple biomarkers have helped us to understand the pathophysiology of cardiovascular medicine, being
ischemic heart disease and heart failure the most active fields in which biomarkers have shown to be
useful. Furthermore, in several cardiovascular diseases, as heart failure, hypertrophic or dilated cardio-
myopathies have demonstrated the presence of remodeling in both ventricles, with mainly changes in the
extracellular matrix. The initial post-MI phase of left ventricular remodeling is resulted from a fibrotic
repair of the necrotic area with scar formation, elongation, and thinning of the infarcted zone.
This book chapter summarizes a review about biomarkers of necrosis and myocardial remodeling and
all the knowledge that their study has improved the complex role of this cardiac pathology. The continued
research of new molecules that helped us to understand necrosis and remodeling focuses our attention in
different groups of biomarkers as troponins, growth factors, matrix metalloproteinases, and collagen
peptides. This chapter is also focused on how the renin-angiotensin system influences the cardiac
remodeling and the role of microRNAs in extracellular changes.
Introduction
The adult heart is a dynamic organ with the capability to overcome injury and hemodynamic overload by
using a repertoire of physiological responses that include myocyte hypertrophy, reexpressing of fetal
cardiac genes, and remodeling of the extracellular matrix (ECM) (Hill and Olson 2008). Initially, cardiac
remodeling is an adaptive response; however, it slowly progresses to become maladaptive, leading to a
decompensation in function.
In several cardiovascular diseases, as heart failure (HF), hypertrophic cardiomyopathy (HCM), or
dilated cardiomyopathy, a ventricular remodeling has been demonstrated, with mainly changes in the
extracellular matrix. Moreover, an atrial remodeling could appear directly related to atrial fibrillation
(AF) development (Bogdanov 2012). Thus, ECM is not a passive structure, but is a dynamic entity with
great importance in the remodeling process that occurs in various cardiovascular diseases (Spinale 2007).
ECM is a three-dimensional structural network of interstitial collagens where other matrix components
are attached and clearly influences cardiac remodeling. A well-structured ECM is necessary to maintain
strength, functional integrity of the cardiac tissue, and cellular communication within the heart. The ECM
of the healthy heart is subjected to a balanced turnover, so new ECM components are synthesized by
Funding: This work was partially supported by Sociedad Española de Cardiología, RD06/0014/039, (RECAVA) from ISCIII,
Beca Cajamurcia-FFIS 2010, and PI081531-FEDER from ISCIII.
Competing interests: None declared in relation to this manuscript for all authors. JAV and DHR have received funding for
research from Abbott. MV has received funding for research and consultancy from Abbott and Boston Scientific. FM has
received funding for research, consultancy, and lecturing from Abbott, Boston Scientific, Bayer, AstraZeneca, Daiichi-Sankyo,
BMS/Pfizer, and Boehringer Ingelheim.
*Email: fcomarino@hotmail.com
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DOI 10.1007/978-94-007-7740-8_42-1
cardiac fibroblasts, and in contrast, ECM components are continuously degraded by the action of a large
family of matrix metalloproteinases (MMPs). The accumulation of ECM proteins can be attributed to an
imbalance between MMPs and their tissue inhibitors (TIMPs), which have an opposing effect by reducing
proteolytic activity (Spinale 2007).
Changes in the ECM may play an important role in the genesis of diastolic or systolic dysfunction. The
collagen deposition increases the stiffness of the left ventricular chamber and compromises ventricular
filling during the diastole. The deposition of collagen is increased in cardiovascular diseases like HCM,
appearing as a predominant increase in collagen types I and III synthesis instead of degradation. Also
there are associated different changes in the MMP activity, the main enzymes responsible for the
degradation of matrix components, and their inhibitors TIMPs (Lombardi et al. 2003). The issue is not
yet clarified whether the alteration in the ECM appears only due to the activation of fibroblasts in response
to mechanical or humoral factors, without loss of cardiomyocytes or conversely, is associated with death
cell, stimulating the growth of the ECM (Fig. 1).
So, ventricular remodeling reflects an alteration in ventricular architecture, with an increased volume
and altered chamber configuration associated. Moreover, histological changes in ventricular remodeling
present a combination of pathologic myocyte hypertrophy, myocyte apoptosis, myofibroblast prolifera-
tion, and interstitial fibrosis. Although originally described after myocardial infarction (MI), ventricular
remodeling develops in response to a variety of forms of myocardial injury and increased wall stress (Opie
et al. 2006).
The initial post-myocardial infarction (MI) phase of left ventricular (LV) remodeling results from
fibrotic repair of the necrotic area with scar formation, elongation, and thinning of the infarcted zone
(Fig. 2) (Cohen et al. 2000). Beyond this early stage, the remodeling process is driven predominantly by
hypertrophic myocyte elongation in the non-infarcted zone, resulting in increased wall mass, chamber
enlargement, and a change of shift, from an elliptical to a more spherical chamber configuration. These
changes, together with a decline in performance of the pathologically hypertrophied myocyte and
interstitial fibrosis within the non-infarcted zone, result in a progressive decline in ventricular perfor-
mance. Pathologic LV remodeling is closely linked to the activation of several neuroendocrine, paracrine,
and autocrine factors, which are upregulated after myocardial injury and in the setting of increased LV
wall stress and hemodynamic derangement (Konstam et al. 2011).
Fig. 1 (a) Image of a heart tissue stained with Masson, where fibrosis is visible in blue color. (b) Cardiac tissue image with
picrosirius red staining. The fibrosis remains evident in red
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DOI 10.1007/978-94-007-7740-8_42-1
POST-MI REMODELING
Acute Infarct Zone Spherical Ventricular
Infarction Thinning & Elongation Dilation
Increased
Interstitial
Collagen
Fibrous Scar
Myocyte Hypertrophy
Fig. 2 Post-myocardial infarction left ventricular remodeling. In the early phase, a thinning and elongation of the fibrous scar
within the infarcted zone appear. Subsequent left ventricular dilation by a diffuse myocyte hypertrophy appears associated with
a major apoptosis and a major deposition of interstitial collagen. Figure illustration by Craig Skaggs (Adapted from Konstam
et al. 2011)
Biomarkers in Cardiovascular Disease

Biomarkers are molecules that are objectively (and easily) measured by laboratory techniques, which can
give us useful information about normal biological processes, abnormal pathophysiology, and prognosis,
as well as in assisting differential diagnosis. In cardiovascular medicine, the most active fields in which
biomarkers have shown to be useful have been ischemic heart disease and heart failure. For example, in
ischemic heart disease, multiple biomarkers have helped us to understand the pathophysiology of the
atheromatous plaque. Such biomarkers have also been used to predict the risk for coronary artery disease
and its sequel, as it is known for B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP)
are useful in the diagnostic and prognostic pathway in patients with HF (Wu et al. 2003). The measure-
ment of biomarkers related to necrosis and cardiac remodeling could also provide interesting information
about abnormal pathophysiology and prognosis.
Pathophysiology of Cardiac Remodeling: Structural Remodeling

Cardiac fibroblasts are the most numerous cell types in the heart and are essential to the regulation of
cardiac ECM metabolism. The metabolism of ECM, more precisely collagen biosynthesis, is tightly
regulated by fibrogenic growth factors, particularly by transforming growth factor (TGF)-b and posttran-
scriptionally by the rate-limiting enzyme prolyl-4-hydroxylase (Jugdutt 2003).
On the other hand, there are accumulating data suggesting that inflammation and abnormal oxidative
stress are pivotal pathophysiological features involved in the development of cardiac remodeling.
Oxidative stress can be defined as an excess in the production of reactive oxygen species (ROS) relative
to antioxidant defense leading to cellular dysfunction and damage. ROS activate transcription factors and
mediate apoptosis (Tsutsui et al. 2011). They also stimulate cardiac fibroblast proliferation and activate
the MMPs, leading to ECM remodeling. Moreover, ROS also activate a broad variety of hypertrophy
signaling kinases promoting myocyte hypertrophy, another characteristic feature of cardiac structural
remodeling (Tsutsui et al. 2011).
Hypertrophic growth manifests enlargement of cardiomyocyte size and enhancement of protein
synthesis through reprogramming of cardiac gene expression and the activation of “fetal” cardiac
genes. Several molecular pathways are responsible for the coordinated control of the hypertrophic
program, and these include the renin-angiotensin system (RAS), natriuretic peptides, the adrenergic
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system, adhesion and cytoskeletal proteins, interleukin-6 (IL-6) cytokine family, MEK-ERK1/2 signal-
ing, histone acetylation, and calcium-mediated modulation (Barry et al. 2008).
The RAS is a key regulator of the cardiovascular system because many of its effects involve cardiac
fibroblasts. It has been observed that levels of angiotensin II (Ang II), the main effector molecule of the
RAS, are elevated in the failing heart, and there is a clear evidence indicating that this peptide contributes
to changes in cardiac structure and function leading to progressive worsening in heart failure (Iwata
et al. 2011), thus being a potential biomarker in cardiac remodeling.
Recent studies have reported that microRNAs (miRNAs) are aberrantly expressed in the cardiovascular
system under some pathological conditions. Indeed, in vitro and in vivo models have revealed that
miRNAs are essential for cardiac development and remodeling (da Costa Martins et al. 2008). Clinically,
there is increasing evidence of the potential diagnostic role of miRNAs as potential diagnostic biomarkers,
and they may represent a novel therapeutic target in several cardiovascular disorders.
Biomarkers Related to Necrosis

Acute MI commonly starts with a coronary artery blockage caused by an episode of thrombosis. If the
resulting ischemia exceeds a critical threshold and is left untreated for a determined time, it will cause
irreversible myocardial cell damage (infarction) or death (Jabre et al. 2011).
A biomarker for detecting myocardial injury commonly needs to be expressed in relatively high levels
within cardiac tissue, with high clinical sensitivity and specificity, and moreover has to be detectable in
blood early after the onset of chest pain.
Historically, total creatine kinase (CK), aspartate aminotransferase (AST), and total lactate dehydro-
genase (LDH) levels have been evaluated as biomarkers of cardiac necrosis. The problem appears with
their wide tissue distribution, evidencing that these biomarkers had poor specificity detecting cardiac
injury. This fact has arranged a wide researching on new biomarkers of myocardial damage, as cardiac
troponins, in particular, that have become the elected biomarkers for patients with acute coronary
syndromes (ACS).
– Creatine Kinase MB Isoenzyme (CK-MB). The determination of CK and CK-MB levels has long
been used for the diagnosis of acute MI. CK, an enzyme present in many tissues, including the
myocardium and skeletal muscle, has three isoenzymes: MM, MB, and BB. CK-MB is present in a
relatively high concentration in the myocardium (around 20 % of total myocardial CK), whereas the
CK-MM levels are higher in skeletal muscle (98 % of total muscle CK) and only about 2 % of CK-MB
(Lewandrowski et al. 2002). The specificity and sensitivity of CK-MB for detecting myocardial
necrosis is low, due to its presence in other tissues such as skeletal muscle. Following myocardial
injury, the initial CK-MB rise occurs 4–9 h after the onset of chest pain, peaks at 24 h, and returns to
baseline at 48–72 h. An advantage of CK-MB over other markers is that it could appear elevated for
longer periods, and that is why it is easier to detect reinfarction using serial CK-MB measurements.
A CK-MB to CK ratio of 0.025 is a good indicator of MI (Apple et al. 2001). Moreover, in patients with
acute MI, the detection of reinfarction may be challenging. Because troponin levels remain elevated for
up to 14 days, it may not be possible to identify reinfarction in patients with a recent acute MI. In
contrast, CK-MB exhibits a much shorter rise-and-fall pattern than troponin and, therefore, is the
preferred marker for the diagnosis of reinfarction. Furthermore, the CK-MB isoenzymes can be
separated by high-voltage electrophoresis into two isoforms: CK-MB 1 and CK-MB 2. CK-MB 2 is
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the tissue form that is released from damaged myocardium. The CK-MB 2 isoform begins to increase
2 h after acute MI and peaks appear at 4–6 h. The method for measuring CK-MB isoenzymes relies in
the use of a semiautomated electrophoresis system, a technique that is not automated and supposes that
only a few laboratories offer this determination.
– Myoglobin. It is an oxygen-binding protein found in a high concentration in cardiac and skeletal
muscle. The major advantage of myoglobin as a cardiac marker lies on its release earlier from damaged
cells than other cardiac markers, permitting an earlier detection of acute MI. Similar to CK-MB
presents a low specificity as a cardiac marker, but it is the earliest marker released from infarcted
myocardium. Myoglobin levels rise faster than any other cardiac marker, becoming a very sensitive
marker in early detection of acute MI, which significantly increases within 1–3 h after the event, peaks
at 9–12 h, and then rapidly clears in 24 h (Jaffe et al. 2006; Lewandrowski et al. 2002) (Fig. 3).
– Troponins T and I. Troponin is a regulatory complex formed by three protein subunits located on the
thin filament of the myocardial contractile apparatus. The three subunits are designated as troponin
C (the calcium-binding component), troponin T (the tropomyosin-binding component), and troponin
I (the inhibitory component). Thus, troponins I and T (TnI and TnT) have similar release kinetics from
damaged myocardium. Both troponins increase in serum within 4–9 h after acute MI, with a peak at
12–24 h, and remain elevated for up to 14 days (Fig. 3) (Jaffe et al. 2006).
Troponins have more advantages over other cardiac biomarkers, which has led to their adoption as the
new gold standard for myonecrosis. It is important to note that TnT and TnI are not detected normally
(or minimally detected) in the blood of healthy people. Consequently, significant elevations of TnT or TnI
are thought to reflect myocardial necrosis. Patients with detectable serum troponin but no detected
CK-MB may exhibit microscopic zones of myocardial necrosis (microinfarction). Thus, cardiac TnI
and TnT levels have been considered the most specific biomarkers for the diagnosis of acute
MI. Moreover, due to the improved analytical performance of the new high-sensitivity TnT or TnI
(hs-TnT or hs-TnI) assays, TnT concentrations within reference intervals can now be measured in most
healthy individuals, and imprecision at the 99th percentile reference value concentrations is below 10 %
CV (Jabre et al. 2011). With a decrease in the diagnostic cutoff by implementation of more sensitive and
precise assays, sensitivity is further increased, but specificity is decreased owing to detection of more
Fig. 3 Timing of release of cardiac markers after acute myocardial infarction. Shown are the activity curves for the different
biomarkers. It is important to note that cardiac troponin in some patients shows a second peak. CV coefficient of variation
(Adapted from Jaffe et al. 2006)
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acute, subacute, and chronic cardiac diseases not related to ACS, such as heart failure and cardiomyop-
athies (Pegg et al. 2011). To ensure clinical specificity for MI diagnosis, adherence to the criteria of the
universal MI definition is paramount because there is an emerging need for serial testing to distinguish an
acute from a chronic elevation of hs-TnT (Volz et al. 2012).
Moreover, among patients undergoing most cardiac surgery procedures, a measurable degree of
myocardial injury is expected. In most cases, this injury is an epiphenomenon of the procedure, but in
certain cases, significant myocardial necrosis could result. In these cases, TnT has demonstrated to be
superior to CK-MB, monitoring patients’ follow-up to cardiac surgery and predicting complications and
postoperative mortality (Januzzi et al. 2002).
Another point of view lies in trying to link biomarkers to apoptosis pathway in cardiac necrosis.
Myocardial ischemia leads to initial damage that is characterized by an intense inflammatory response.
Caspase-1 is a key modulator of the inflammatory response to tissue injury and participates both in the
amplification of the inflammatory response and also in the promotion of cell death. Caspase-1 activity is
increased in the myocardium minutes after the onset of ischemia, remains elevated for several days, and
leads to cardiomyocyte death (Merkle et al. 2007). A recent study (Mezzaroma et al. 2011) confirms the
presence of cryopyrin inflammasomes in leukocytes, endothelial cells, and fibroblasts in the granulation
tissue early during the infarct period and describes formation of active cryopyrin inflammasomes in
cardiomyocytes bordering the infarct zone later during the infarct process. Using an isolated culture of
adult cardiac myocytes, it is observed that the induction of the inflammasome led to a significant increase
in caspase-1 activity accompanied by a dose-dependent increase in cell death. These findings suggest a
significant role for the inflammasome in the cardiomyocyte and identify disruption of this as a unique
strategy to prevent further loss of functional myocardium following AMI and to prevent adverse cardiac
remodeling (Mezzaroma et al. 2011).
Biomarkers Related to Cardiac Remodeling
Myocyte Stress
Brain natriuretic peptide (BNP) is a neurohormone secreted from the myocytes in response to increased
wall tension, such as volume or pressure overload. The levels also increase in states of hemodynamic
stress (left ventricular hypertrophy, ventricular dilatation, HF, ACS, and AF (Daniels and Maisel 2007)).
B-type natriuretic peptide is synthesized as an inactive prohormone (NT-proBNP) that will be cleaved in
the active hormone, BNP, which has an important role in cardiovascular remodeling and volume
homeostasis (Daniels and Maisel 2007). High plasma BNP levels have been found in patients with
heart failure of different etiologies including dilated, restrictive, and obstructive and nonobstructive HCM
(Pieroni et al. 2007). Initial studies also described elevated levels of natriuretic peptides in patients with
AF compared with matched controls in sinus rhythm (Shelton et al. 2006). Thus, the study of natriuretic
peptides is well established as biomarkers of parietal stress and has also been associated with ventricular
remodeling. However, the whole mechanism involving natriuretic peptides is explained in another chapter
of this book.
Myocardial Necrosis Biomarkers: Cardiac Troponins

Beyond ACS, serum cardiac TnT could report a behavior in patients with idiopathic dilated cardiomy-
opathy with particularly poor prognosis, showing increased serum levels of TnT in the absence of
significant coronary stenoses (Sato et al. 2001). In outpatients with stable chronic HF of a nonischemic
nature, the detection of TnT, even at low levels, means an increased risk of adverse cardiac events, which
seems to be independent of other clinical, analytical, and ECG variables (Pascual-Figal et al. 2008). These
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elevated levels of TnT could imply ongoing myocardial damage or leakage of myofibrillar components
and reflect the loss of viable cardiac myocyte characteristic of progressive HF (Sato et al. 2003b). All these
studies, based on classical TnT determination methods, revealed strong discrepancies among the number
of positive TnT patients, probably due to the heterogeneous detection limit of the used technique and the
selected cutoff point. In addition, the hemodynamic state (acute or stable patients) of the TnT determi-
nation also adds difficulty to the evaluation of this biomarker in other cardiac diseases different from
ACS. Slight elevations in troponin level were then observed in a proportion of patients with stable
coronary artery disease and HF and also in elderly apparently healthy individuals, and they are associated
with worse outcomes and increased mortality independently of conventional major coronary risk factors
(Omland et al. 2009).
New developed techniques, such as hs-TnT determination, could help in the diagnosis and probably in
the prognosis in these other pathologies. A clear example of a different role of hs-TnT levels could be seen
in patients with HCM, patients who seem to present a moderate increase in troponin levels and an intense
cardiac remodeling (Moreno et al. 2010; Sato et al. 2003a). However, troponin circulating levels show an
association with a significantly lower shortening fraction and thicker interventricular septum. In HCM,
ischemia may occur due to massive heart weight, myocyte disarray, or small vessel disease (Sato
et al. 2003a). In fact, the study by Moreno et al. (2010) showed that hs-TnT serum levels were elevated
in up to 42 % of our cohort of patients with HCM and in only 4.4 % of healthy paired control subjects. This
elevation may reflect a continuous myocyte loss due to a moderate range of necrosis, and it is associated
with parameters of HCM severity as the functional class, systolic dysfunction, and fibrosis assessed by
cardiac magnetic resonance imaging. Pop et al. (2006) also showed that raised levels of troponin may be
present in patients with HCM without overt coronary heart disease. Sato et al. (2003a) demonstrated that
HCM patients with increased serum TnT concentrations had a decrease in LV fractional shortening and
ventricular septal thickness on echocardiogram during follow-up, and they suggested TnT as an indicator
of subclinical myocyte injury and/or progression to dilated HCM. They found 50 % of TnT-positive
patients in a small sample of 30 HCM patients, supporting the results by Moreno et al. (Sato et al. 2003a).
Another study including 60 patients with dilated cardiomyopathy showed up to 28.3 % of TnT-positive
patients in samples taken in an acute or subacute moment (Sato et al. 2001).
On the other hand, Omland et al. (2009) describe a low but detectable increase in hs-TnT circulating
levels in stable coronary artery disease patients. Those authors presented hs-TnT elevation in patients with
stable coronary artery disease and its association with the incidence of cardiovascular death and HF. In
earlier studies based on chronic stable patients, only <10 % of patients showed elevated TnT when
determined with classic methods (Pascual-Figal et al. 2008).
Hence, the pathologic changes observed in cardiac myocytes and fibroblasts are important components
of cardiac remodeling. Besides myocyte injury and apoptosis, fibroblasts and collagen turnover also play
important roles in myocardial remodeling. Coronary microvascular dysfunction, severe hypertrophy, and
myocyte disarray are associated with an unfavorable outcome in patients with HCM or HF (Sato
et al. 2001). The association between TnT concentration and fibrosis presence has been previously
observed in idiopathic dilated cardiomyopathy and secondary cardiomyopathy groups, where a subgroup
of patients with raised concentrations of serum collagen and TnT showed poor short-term prognosis. In
line with these findings, something similar occurs in HCM patients (Moreno et al. 2010).
Profibrotic Biomarkers: Growth Factors

The Transforming Growth Factor (TGF)
TGF comprises a superfamily of more than 30 members with a wide range of functions during develop-
ment, cell cycle control and growth, extracellular matrix regulation, and immune response (Topper 2000).
This large family of related proteins can be subdivided into two main groups, the TGF-b/activin and bone
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morphogenetic protein and the GDF branches, based on their sequence similarity. These cytokines are
involved in a wide variety of tissue differentiation and proliferation processes.
In the heart, TGFb-1 induces expression of ECM constituents by cardiac fibroblasts (i.e., fibrillar
collagen, fibronectin, and proteoglycans); it has a positive feedback effect on its own expression in cardiac
myocytes and fibroblasts, and it provokes contractile protein gene expression in cardiomyocytes. The
noncanonical pathway is more associated with pathological remodeling, recognizing that TGFb-1
contributes to cardiac hypertrophic and fibrotic remodeling (Lim and Zhu 2006). TGFb-1 can be induced
by cardiac injury and hypertrophic stimuli, such as angiotensin II and pressure overload (Lim and Zhu
2006). TGFb-1 is the most abundant and well studied of the three TGF-b isoforms. It is demonstrated how
TGF-b increased during HF and contributed to the hypertrophy of myocytes and fibrosis. Both
cardiomyocytes and cardiac fibroblasts produce TGFb-1 which can modulate the function of cardiac
cells through autocrine or paracrine pathways. In fact, recently it has been observed how connective tissue
growth factor is upregulated via the TGF-b1/Smad pathway in the atrial myocardium of AF patients,
suggesting that the TGF-b1/Smad pathway may play an important role in the structural remodeling during
atrial fibrosis (Li et al. 2013), and that is why it is a via that continues to be investigated.
Growth Differentiation Factor-15 (GDF-15)

GDF-15 is a member of the TGF-b superfamily. Clinical studies have shown that cardiovascular diseases
such as ischemia, inflammation, or injury notoriously upregulate GDF-15 expression in the heart. These
pathologic situations could indicate that this factor acts as a stress sign for the cardiomyocytes. Several
clinical and experimental reports have provided evidence of a link between GDF-15 and vascular
disorders (Eggers et al. 2008; Kempf et al. 2009); additionally, increased levels of GDF-15 were
associated with poor prognosis in acute coronary syndrome (Eggers et al. 2010) and more recently in
HF (Anand et al. 2010). Although it has not been formally demonstrated, these observations suggest that
elevated GDF-15 levels identify high-risk patients across a broad spectrum of cardiovascular diseases and
that it might display a regulatory role in the process of hypertrophy (Heger et al. 2010).
In this sense, there has been an increasing attention toward GDF-15 as a marker of multiple stress
pathways in myocardium. HCM or HF is associated with a decreased functional status; hence, it was
pertinent to compare GDF-15 levels and other severity factors in the three well-defined New York Heart
Association (NYHA) groups. As indicated by other reports, long-standing hypertension may be the most
common secondary cause of hypertrophy. Montoro-Garcia S et al. showed elevated GDF-15 levels
associated with severe disease features in HCM patients, such as increased age, severe NYHA functional
class (NYHA II), comorbidities and poor outcome predictors (hypertension, dyspnea, or AF), limited
exercise capacity, and a mild reduction in creatinine clearance (CLcr) (Montoro-Garcia et al. 2012). In line
with these results, Eggers et al. also reported that concentrations of GDF-15 were higher in different
comorbidities such as hypertension or diabetes (Eggers et al. 2008). In addition, GDF-15 levels were
related to hypertension and nonsustained ventricular tachycardia (NSVT), both comorbidities irremedi-
ably aggravate remodeling and hypertrophy, and GDF-15 levels could reflect pathophysiological changes
that occur in left ventricular remodeling. NSVT has been proven to be a strong determinant of progressive
HF and death in young patients with HCM; however, in patients over 40 years old, NSVT is more related
to a progressive myocyte loss and fibrosis (Eggers et al. 2008).
Galectin-3
This biomarker is a soluble b-galactoside-binding lectin directly related to be a mediator of profibrotic
pathways and as a potential biomarker of adverse cardiac remodeling (Sharma et al. 2004). It is known
that galectin-3 is expressed by activated macrophages and induces cardiac fibroblasts to proliferate and
deposit collagen type I in the myocardium. Studies on animal models of HF have shown how the
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expression of galectin-3 is upregulated and occurs before the development of overt clinical HF (Liu
et al. 2009). This protein is linked to areas of fibrosis, suggesting an active role in modulation of the
extracellular matrix (Sharma et al. 2004). The results of a pilot study suggested that the concentration of
galectin-3 after ACS was associated with the risk of developing subsequent HF, highlighting an interest in
the active role that galectin-3 plays promoting cardiac fibrosis and adverse remodeling (Grandin
et al. 2012). Therefore, galectin-3 appears to link pathways of inflammation and fibrosis and may
contribute to the development of HF by mediating progressive alteration of the myocardial extracellular
matrix. Myocardial injury generates inflammatory signals that recruit activated macrophages to the
myocardium. Mediators such as osteopontin stimulate these macrophages to secrete galectin-3, which
appears to act through upregulation of TGF-b/Smad3 signaling pathway, causing cardiac fibroblasts to
proliferate and produce collagen type I, ultimately leading to an accumulation of myocardial collagen and
impaired diastolic and systolic function (Liu et al. 2009; Sharma et al. 2004). Moreover, in patients with
chronic HF, galectin-3 concentrations have been correlated with markers of extracellular matrix turnover,
such as type III amino-terminal propeptide of procollagen (PIIINP) and MMP-2, implying a relationship
between macrophage activation and collagen turnover (Lin et al. 2009). But the role of galectin-3 will be
discussed extensively in another chapter of this book.
Collagen Peptides as Fibrotic Biomarkers

The collagen network is a metabolically active structure referred to a balance between synthesis and
degradation of collagen, a fact that determines the collagen “turnover.” This turnover is estimated to be
performed between 80 and 120 days (Lopez et al. 2010). Procollagen types I and III are synthesized and
secreted by fibroblasts and myofibroblasts as a triple-helix procollagen precursor and contain terminal
propeptides that are cleaved in block by specific procollagen proteinases. The released molecules reach
the bloodstream, and it permitted their detection by laboratory techniques. The propeptides are cleaved by
every molecule of collagen – that is why their circulation levels could reflect the amount of collagen
formed – and these propeptides could be used as indexes of collagen synthesis (Lopez et al. 2010). The
propeptides of collagen synthesis cleaved are the carboxyterminal propeptide of procollagen type I (PICP)
and the amino-terminal propeptide of procollagen type I (PINP) (Fig. 4). Multiple researches for
Procollagen type I
PINP Collagen type I PICP
Amino-terminal telopeptide CITP
GHL Other matrikines and degradation products
PINP GHL CITP PICP
Blood vessel
Fig. 4 Peptides released during the extracellular synthesis and degradation of collagen type I that reach the bloodstream from
the tissue interstitium (Adapted from Lopez et al. 2010)
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biomarkers of collagen metabolism have provided several molecules classified into two categories:
biomarkers related to the synthesis of molecules that form new collagen fibers and biomarkers related
to degradation of the molecules that comprise mature collagen fibers (Lopez et al. 2010).
On the other hand, collagen type III is derived from a larger protein, the procollagen type III, with two
terminal extensions on both sides. Some of the molecules of amino-terminal propeptide (PIIINP:
N-terminal propeptide of procollagen type III) are released; meanwhile, the synthesis and deposition of
collagen type III are active, and other molecules are retained as part of the collagen fibers (Lombardi
et al. 2003).
MMPs initiate digestion of collagen by hydrolysis of the peptide bond after a glycine residue. The
procollagen carboxyterminal telopeptide type I (ICTP) is released by the resultant action of MMP-1
(Fig. 4). There exists a relationship between the numbers of molecules of collagen type I degraded and the
ICTP molecules released. Thus, the amount of ICTP found in circulation could be proportional to
degraded fibrillar collagen (Lopez et al. 2010). The final fragmented matrix peptides or matrikines
released by the action of these enzymes have biological activities in the regulation of collagen metabolism
and angiogenesis. For instance, the tripeptide glycyl-histidyl-lysine (GHL) derived from collagen type
I stimulates new collagen synthesis by fibroblasts.
Therefore, the evaluation of collagen peptides as potential biomarkers representing a turnover
presented in HF or HCM may report the pathogenesis of myocardial remodeling. So, a continuous
extracellular matrix turnover appears, leading to an increase of interstitial fibrosis due to the higher levels
of collagen type I/III deposited. The cardiomyocyte death by apoptosis may be more common than is
supposed to be, stimulating repair processes that contribute to the expansion of the interstitium.
Cardiomyocyte apoptosis also leads to thinning of the ventricular wall, act described in HCM (Thaman
et al. 2004), and to an impaired systolic function. In recent clinical trials conducted in patients with HCM,
it was observed that the fibrosis is associated with diastolic dysfunction and disruption with systolic
dysfunction. However, the relations between the changes of myocardial collagen and impaired cardiac
function are not yet clear and may not be seen isolated from possible alterations of other components of
the extracellular matrix and also influence the ventricular chamber stiffness during diastolic or systolic
myocardial contractility.
Schwartzkopff et al. showed how PICP levels are not increased in patients with dilated cardiomyop-
athy, in opposite to the levels of ICTP, together with the values of MMP-1 and their inhibitors
(Schwartzkopff et al. 2002). These findings suggest that the degradation of collagen type I could play
important roles in extracellular tissue remodeling that occurs in diseases such as dilated cardiomyopathy
or HCM, contributing to left ventricular dilation. Similarly, collagen type III deposition in this remodeling
would be important as indicated by several studies in which it is increased (Lombardi et al. 2003).
In the early phase of cardiac remodeling, collagen type III is mainly accumulated, while collagen type I
becomes predominant in severely damaged heart, as evidenced in the advanced state (Kim et al. 2000).
Therefore, in the first stage of remodeling, collagen type I is increasingly degraded, then it is replaced by
collagen type III, whereas with advancing disease would appear in the balance of collagen, increasing
collagen type I deposition.
Lin et al. explored the interstitial remodeling, by measuring the serum levels of PIIINP in HF patients.
In this study, PIIINP is proposed as a serum biomarker of cardiac autonomic control and risk of sudden
cardiac death (SCD) (Lin et al. 2010). Interestingly, a recent report by Ho et al. also studied different
biomarkers of fibrosis and interstitial remodeling and revealed that PICP seems to indicate increased
myocardial collagen synthesis in sarcomere mutation carriers without overt disease (Ho et al. 2010). They
proposed that this profibrotic state precedes the development of LV hypertrophy or fibrosis visible on
magnetic resonance imaging (MRI) (Ho et al. 2010). Fibrosis may provide electrical heterogeneity and a
substrate for arrhythmogenicity, which may cause SCD, a feared first symptom that can appear at the onset
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of both pathologies (HF and HCM) (Ho et al. 2010; Lin et al. 2010). Thus, it could be an important
evaluation of collagen turnover in HCM, through different serum levels of formation and degradation
collagen peptides and their relation with different clinical values of the severity of the disease.
Lombardi et al. (2003) also showed that collagen turnover was enhanced in HCM, presenting increased
concentrations of PIIINP and ICTP compared to healthy controls. They also defended that collagen
I synthesis prevails over degradation and correlated a passive dysfunction in HCM patients. Data
presented by Ho et al. showed elevated levels of PICP in HCM patients without overt disease, reflecting
an increased myocardial collagen synthesis on the early disease (Ho et al. 2010). Vílchez et al. did not find
that relation in a study population with developed HCM (72.6 % of them presented fibrosis) (Vilchez
et al. 2011); however, we were able to find a higher ratio of PICP/ICTP in patients compared to controls in
the Ho et al. and previous studies (Ho et al. 2010; Shim et al. 2009).
Several studies published by Diez et al. have delved into the study of PICP related to cardiac
remodeling (Diez et al. 1996; Diez and Laviades 1997). In a recent study (Ho et al. 2010), they evaluated
the concentrations of different collagen peptides in patients with HCM, corroborated with a ventricular
hypertrophy observed by late gadolinium enhancement (LGE) and another group of patients with early
development of HCM without ventricular hypertrophy associated or positive LGE. So, in the patient
cohort, higher levels of PICP were found, suggesting that increased collagen synthesis contributes to the
appearance of the first pathophysiological changes that characterize the HCM, while in the group with
HCM and ventricular hypertrophy, the ratio PICP/ICTP was also increased among patients and controls.
Therefore, these data support same results of other studies (Shim et al. 2009; Vilchez et al. 2011),
suggesting that the synthesis of collagen exceeds degradation in established disease.
Matrix Metalloproteinases and Their Inhibitors Related to Cardiac Remodeling

MMPs constitute a family of zinc-dependent proteinases, which participate in the degradation of ECM
components, and are regulated by their inhibitors, TIMPs (Visse and Nagase 2003). Decreased concen-
trations of MMP-1 and raised levels of its inhibitor, TIMP-1, have been noted in hypertensive patients,
which appear to be associated with depressed extracellular degradation of collagen type I, especially in
patients with LV hypertrophy. Moreover, TIMP-1 has been related to diastolic dysfunction in hyperten-
sive patients. Importantly, these alterations have also been reported in remodeling after acute MI and in
advanced congestive HF (Jordan et al. 2007; Spinale 2007; Visse and Nagase 2003).
Studies have shown an increase in the MMP-1/TIMP-1 ratio (both in tissue and serum samples) in
hypertensive systolic heart failure compared with hypertensive diastolic heart failure (Lopez et al. 2006).
In a study by Jordan et al., patients with moderate congestive HF (most with NYHA class II) showed high
levels of TIMP-1 and TIMP-1/MMP-1 ratio and low levels of MMP-1 compared with controls. These data
suggested diminished collagen degradation, which could be interpreted as more myocardial fibrosis
(Jordan et al. 2007). Furthermore, Roldán et al. showed an interesting association between clinical,
biologic markers (NT-proBNP and MMP system) and radiologic images (LGE regions). They showed
how MMP system, which has been responsible for left ventricular remodeling and fibrosis in other
cardiovascular diseases, plays an important role in HCM with MMP-9 being an independent factor
associated with the presence of fibrosis (Roldan et al. 2008).
Role of the Renin-Angiotensin System (RAS) in Cardiac Remodeling

In addition to maintain cardiovascular homeostasis through its influence on electrolytes and water
regulation and vascular tone, RAS contributes to the remodeling process through indirect effects such
as interactions with other neurohormonal systems and by direct effects on cardiac cells. Ang II, which is
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an octapeptide, is generated by angiotensin-converting enzyme (ACE) from Ang I (a decapeptide), which

is formed by renin from angiotensinogen. Ang production in the heart depends on kidney-derived renin
and/or prorenin. Both are taken up from the circulation, either through diffusion into the cardiac
interstitium or by binding to cardiac cells, and prorenin is activated to renin in cardiac cells. Ang II
binds primarily to Ang II type 1 receptor (AGT1R) to promote cell growth and hypertrophy activating
cardiac fibroblast functions and increasing the amount of ECM in the heart (Gurantz et al. 2005). Ang II
also stimulates to aldosterone synthase (CYP11B2) for the synthesis and release of aldosterone, which
promotes fluid retention and cardiac fibrosis (Pagliaro and Penna 2005). Thus, several components of the
RAS are involved in cardiac remodeling and will be discussed in the next sections of this chapter.
Angiotensin II
ACE is a membrane-bound enzyme which is located in vascular endothelial cells and is widely distributed
in the body that converts Ang I to active Ang II and inactivates a vasodilator and natriuretic peptide
bradykinin. Ang II, the end product of the RAS, is a potent vasopressor peptide, which also has cell
growth-promoting or cell growth-modulating features. Ang II exerts its function mainly after binding to
its type 1 receptor (AGT1R). It is important to remark that both Ang II levels and AGT1R density are
increased in the myocardium of remodeling hearts (Gurantz et al. 2005). Moreover, results from studies
performed in animal models and from clinical trials in human patients provide unequivocal evidence that
blocking RAS activation favorably influences cardiac remodeling and improves outcomes including
increased survival (Granger et al. 2003).
On the other hand, a homolog of ACE termed angiotensin-converting enzyme 2 (ACE2) catalyzes the
cleavage of the carboxyl-terminal amino acid from Ang II resulting in the formation of Ang-(1–7), a
heptapeptide with vasodilator and cardioprotective properties that has been reported to counteract effects
of Ang II preventing adverse cardiac remodeling. To assess the potential role of Ang-(1–7) on cardiac
remodeling, several analyses have been carried out (Iwata et al. 2011). These studies suggest that
Ang-(1–7) may play an important regulatory role during cardiac remodeling by inhibiting cardiac
fibroblast ECM synthesis and releasing of hypertrophic growth factors. However, the pathways through
which Ang-(1–7) initiates favorable anti-remodeling effects have not been completely elucidated.
Aldosterone
Aldosterone is a potent mineralocorticoid that promotes sodium retention and elevation of arterial
pressure. Independent of its effect on blood pressure, aldosterone may also play a role in cardiac
hypertrophy being its secretion regulated primarily by the RAS. It is synthesized from deoxycorti-
costerone by a mitochondrial cytochrome P450 enzyme, aldosterone synthase (CYP11B2). Aldosterone
can directly induce myocardial cell hypertrophy and remodeling via activation of the mineralocorticoid
receptors, a member of the steroid/thyroid/retinoid nuclear receptor family of ligand-dependent transcrip-
tion factors (Yoshida et al. 2010). Upregulation of CYP11B2 has been associated with increased
aldosterone production promoting myocardial fibrosis. By this way, progressive myocardial fibrosis
would result in progressive ventricular remodeling. However, aldosterone production is not only regu-
lated by Ang II but also by other factors, such as potassium and corticotrophin (Yoshida et al. 2010). This
raises the possibility that local variations in aldosterone, even under conditions of RAS blockade, may
participate into the control of ECM turnover. Experimental data from animal models and clinical
observations with several mineralocorticoid antagonists highlight the potentially adverse effects of
aldosterone on cardiac structure and function (Delcayre and Silvestre 1999; Pitt et al. 1999). It has been
observed that ventricular density of AGTR1 receptors is increased in rats treated for 1 month with
aldosterone, and this increase was prevented by both spironolactone and losartan (Delcayre and Silvestre
1999). Thus, aldosterone leads to increased responsiveness of cardiac cells to Ang II. This
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cardioprotective effect of spironolactone may explain the survival benefit of anti-aldosterone therapy in
patients with severe chronic heart failure evaluated in the randomized Aldactone Evaluation Study
(RALES) mortality trial (Pitt et al. 1999).
Role of MicroRNAs (MiRNAs) in Cardiac Remodeling

miRNAs represent a sizable subgroup of endogenous, conserved, single-stranded, small, noncoding
RNAs, which degrade or inhibit the translation of their target miRNA, depending upon the overall degree
of complementarity of the binding site, the number of binding sites, and the accessibility of those binding
sites in the target mRNA (Bagga et al. 2005). This way, miRNAs regulate gene expression and play an
important role in a wide range of biologic processes. In Fig. 5, the synthesis process of miRNAs and their
mechanism of action through binding to their target mRNA can be observed.
Recent studies have provided increasing evidence that miRNAs play a significant role in cardiac
remodeling; however, the biology of miRNAs represents a relatively new research area and is still an
emerging field (Orenes-Pinero et al. 2013). It is becoming clear that miRNAs play a pivotal role in cardiac
muscle biology, the interstitial tissue, and also valve development. Noting its importance in
Fig. 5 Schematic process of miRNAs biosynthesis and mechanism of action (From Orenes-Piñero et al. 2013)
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cardiovascular development, using microarray technology, it has been highlighted that almost 50 % of the
differentially expressed miRNAs identified by now have been shown to play diverse functional roles in
the cardiovascular system. Moreover, different meta-analyses have revealed similar miRNA signatures in
the developing cardiac chambers and the differentiating and maturing cardiomyocytes derived from
induced pluripotent stem cells, which are not altered in the adult and aging heart (Chinchilla
et al. 2011). Furthermore, genome-wide association studies (GWAS) have been carried out to identify
scores of genetic variants that appear in miRNAs and may contribute to human disease risk (Richardson
et al. 2011). The most important miRNAs related with cardiac remodeling will be summarized in the next
sections of this chapter.
miRNA-133
This is ranked as the first most abundant miRNA in human heart (Luo et al. 2010). miRNA-133, together
with miRNA-1 and miRNA-208, is a muscle-specific miRNA that regulates protein levels by repressing
translation of genes involved in cardiac contractility, hypertrophy, and electric conductance (Care
Table 1 Biological functions regulated by miRNAs affecting cardiac remodeling

miRNA Target Gene symbol Biological effect References
miR-133 nPTB PTBP2 Muscle development and maturation Chen et al. 2006
SRF/HDAC4 SRF/HDAC4 Proliferation and differentiation of Chen et al. 2006
skeletal muscle progenitor cells
RhoA/Cdc42/Nelf-A RHOA/ARHGEF6/ Inhibition of cardiac hypertrophy Care et al. 2007
WHSC2
CTGF CTGF Inhibition of cardiac fibrosis Liu et al. 2008; Duisters
et al. 2009
HCN2/HCN4 HCN2/HCN4 Regulation of pacemaker channels Luo et al. 2010
KCNH2/KCNQ1 KCNH2/KCNQ1 QT prolongation Luo et al. 2010
miR-1 Hand2 HAND2 Decrease in cardiomyocyte Zhao et al. 2007
proliferation
Calmodulin/MEF2a/ CALM1/MEF2A/ Inhibition of cardiac hypertrophy Ikeda et al. 2009
GATA4 GATA4
Ras/Cdk9/fibronectin RAS/CDK9/FN Inhibition of cardiac hypertrophy Care et al. 2007
Bcl-2/IGF-1 BCL2/IGF1 Inhibition of anti-apoptotic effect Shan et al. 2009
KCNJ2/Cx43/KCND2 KCNJ2/GJA1/KCND2 QRS and QT prolongation Zhao et al. 2007; Yang
et al. 2007
SPRY1/PTEN SPRY1/PTEN Fibroblast proliferation Thum et al. 2008; Roy
et al. 2009
miR-21 PDCD4/Bcl-2 PDCD4/BCL2 Anti-apoptotic effect Ji et al. 2007
miR-208 Thrap1/myostatin THRAP1/MSTN Induce cardiac hypertrophy van Rooij et al. 2006
Cx40 GJA5 Promotion of arrhythmogenicity Callis et al. 2009
miR-29 ELN/FBN1/COL1A1/ ELN/FBN1/COL1A1/ Decrease of collagen and other van Rooij et al. 2008;
COL1A2/COL3A1 COL1A2/COL3A1 proteins of the ECM Divakaran et al. 2009
nPTB n-terminus polypyrimidine tract-binding protein, SRF serum response factor, HDAC4 histone deacetylase 4, RhoA ras
homolog gene family, member A, Cdc42 cell division control protein 42 homolog, Nelf-A negative elongation factor-A, CTGF
connective tissue growth factor, HCN2, KCNH2, KCNQ1, KCNJ2, KCND2 potassium ion channels, Cx connexin, Hand2 heart
and neural crest derivatives-expressed protein 2, MEF2a myocyte enhancer factor-2a, Ras rat sarcoma, Cdk9 cyclin-dependent
kinase 9, IGF insulin growth factor, Bcl-2 B-cell CLL/lymphoma 2, SPRY sprouty homolog, PTEN phosphatase and tensin
homolog, PDCD4 recombinant human programmed cell death 4, Thrap1 thyroid hormone receptor associated protein 1, ELN
elastin, FBN1 fibrillin-1, COL collagen
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et al. 2007) (Table 1). miRNA-133 and miRNA-1 modulate the proliferation and differentiation of skeletal
muscle progenitor cells (Chen et al. 2006). The impact of miRNA-133 on cardiac hypertrophy has been
extensively studied in animal models. Downregulation of miRNA-133 was sufficient to induce hyper-
trophic gene expression in cell-based experiments. In the same direction, downregulation of miRNA-133
in mouse hearts resulted in increased left ventricle/body weight, diastolic ventricle wall thickness, and
septum thickness. On the other hand, miRNA-133 also regulates cardiac fibrosis by repressing connective
tissue growth factor (CTGF) expression (Duisters et al. 2009). miRNA-133 is downregulated during
cardiac disease, which inversely correlates with the upregulation of CTGF. Inversely, overexpression of
miRNA-133 in cultured fibroblasts decreased the production of collagens by suppressing CTG-
F. Consistent with these results, it was reported that knockout mice lacking miRNA-133 developed
severe fibrosis and heart failure, resulting in cardiomyopathy and sudden death (Liu et al. 2008).
Regarding electrical remodeling of the heart, miRNA-133 regulates pacemaker channels HCN2 and
HCN4 (Luo et al. 2010). miRNA-133 has been observed to mainly control cardiac repolarization through
targeting the two major repolarizing K+ channels in the heart (Table 1). The downregulation of miRNA-
133 contributes to enhance a peacemaker current, inducing abnormal cardiac automaticity (Luo
et al. 2010). These observations suggest that miRNA-133 can provoke cardiac arrhythmias.
miRNA-1
This is the most abundant miRNA in mice heart with about 40 % of total miRNA, but in humans, it is the
second most common, with around one third of the miRNA-133 levels (Luo et al. 2010). The deregulation
of miRNA-1 expression in developing mouse heart causes catastrophic consequences. Analysis of
miRNA-1 null animals in utero results in pericardial edema, consistent with embryonic myocardial
dysfunction (Zhao et al. 2007). With regard to cardiac hypertrophy, miRNA-1 negatively regulates the
expression of hypertrophy-associated calmodulin, MEF2a, and GATA4 and attenuates the calcium-
dependent signaling necessary for induction of cardiomyocyte hypertrophy through the calcineurin-
NFAT pathway (Ikeda et al. 2009). Also, overexpression of miRNA-1 prevented hypertrophic growth
of neonatal cardiac myocytes by inhibiting its growth-related targets (Table 1). Similarly, there is
downregulation of miRNA-1 in three different hypertrophic models, including TAC mice, transgenic
mice with cardiac overexpression of a constitutively active mutant of the Akt kinase, and exercised rats
(Care et al. 2007).
Although miRNA-1 and miRNA-133 are co-transcribed from bicistronic genes and they have similar
functions in regulating cardiac development and hypertrophy, their role in cardiac cell fate is
antagonistic. While miRNA-133 has an anti-apoptotic role, being caspase-9 its putative target, miRNA-
1 has demonstrated to be pro-apoptotic through repression of the anti-apoptosis factor, insulin growth
factor-1 (IGF-1) (Shan et al. 2009).
It has been reported that the expression of miRNA-1 into the myocardium induces arrhythmias in both
healthy normal hearts and a rat model of myocardial infarction (MI). Two miRNA-1 targets were
identified: KCNJ2, which is the channel responsible for the inward rectifier K+ current (IK1), and
connexin 43 (Cx43), which is the primary gap junction protein in the ventricle (Yang et al. 2007).
Thus, miRNA-1 overexpression in normal and infarcted rat hearts results in a slowed conduction velocity,
excessively prolonged repolarization, and the induction of arrhythmias (Table 1). Together, all these data
indicate that alteration in miRNA-1 levels may be a trigger for the production of the arrhythmogenic
substrate.
miR-21
miRNA-21 is one of the most highly upregulated miRNAs during cardiac remodeling, but the precise
functions of miRNA-21 in cardiac stress responses remain unclear. Its role as an anti-apoptotic miRNA
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and the fact of being deregulated in almost all types of cancers have led some to classify it as an
oncomiR. Regarding cardiac hypertrophy, its role is controversial. In contrast, the impact of miRNA-21
on cardiac fibrosis has been well established. miRNA-21 is upregulated in cardiac fibroblasts in the heart
failure (Thum et al. 2008). This upregulation in cardiac fibroblasts enhances ERK/MAP kinase signaling,
leading to fibroblast proliferation and fibrosis and cardiac remodeling (Table 1). Phosphatase and tensin
homolog (PTEN), a suppressor of MMP-2 expression, has also been demonstrated to be a direct target of
miRNA-21 in cardiac fibroblasts. Importantly, blocking of endogenous miRNA-21 by antagomiR-21
reduced genes encoding collagens and extracellular matrix molecules that are highly upregulated during
cardiac fibrosis (Roy et al. 2009).
Interestingly, miRNA-21 has been found to prevent cell damage and cell death. PDCD4 protein
(recombinant human programmed cell death 4 protein) and Bcl-2 have been demonstrated to be a target
of miRNA-21, thus supporting, through a novel pathway, the anti-apoptotic role of this miRNA (Table 1).
Overexpression of chemically synthesized miRNA-21 in mice heart reduced infarct size by inhibition of
pro-apoptotic genes and increasing of anti-apoptotic genes (Ji et al. 2007).
miRNA-208
Two components of miRNA-208 have been described (miRNA-208a and miRNA-208b). However,
miRNA- 208b has not been detectable in the adult heart, indicating that they are expressed at different
developmental stages (Callis et al. 2009). It has been observed that cardiac overexpression of miRNA-
208a is sufficient to activate calcineurin signaling and cardiac pressure overload-induced stress and
induce cardiac hypertrophy. In regard to fibrosis, miRNA-208 appears to be required for cardiac fibrosis
in response to hemodynamic pressure overload (Table 1). Importantly, miRNA-208a expression and
b-MHC upregulation were restricted to areas of myocardial fibrosis. Furthermore, miRNA-208a knock-
out mice have substantially increased transcription of genes encoding antifibrotic molecules, such as,
ANP (atrial natriuretic peptide) and BNP (van Rooij et al. 2006).
The electrocardiograms of approximately 80 % of the miRNA-208a knockout mice lack P waves
preceding QRS complexes, suggesting that miRNA208a / mice suffer from AF. Knockout of miRNA-
208a in mice hearts promotes higher expression of connexin-40 (Cx-40) compared with wild-type mice,
indicating that miRNA-208a is required for Cx40 expression (Callis et al. 2009) (Table 1). Apart from
regulating Cx40 expression, miRNA-208a can directly repress the expression of other transcriptional
cofactors expressed within the cardiac conduction system of the adult heart (Callis et al. 2009). All these
data clearly demonstrate a role for miRNA-208a in repressing antihypertrophic genes and establish
miRNA-208a as a regulator of cardiac conduction system, thus being a potential target for therapeutic
purposes.
miRNA-29
This miRNA is expressed preferentially in fibroblasts. Exposition of cardiac fibroblasts to TGF-b, a
signaling factor implied in the production and deposition of collagens in the heart, revealed a decrease in
miRNA-29 expression, thus suggesting a miRNA-29 regulation effector. Potential targets of miRNA-29
related with cardiac remodeling and fibrosis were analyzed, and it was observed that elastin (ELN);
fibrillin 1 (FBN1); collagen type I, alpha 1 and 2 (COL1A1, COL1A2); and collagen type III, alpha 1
(COL3A1), contained one or more conserved potential seed sequences for miRNA-29 (Tables 1).
Moreover, in vivo downregulation of miRNA-29 correlated with an upregulation of these proteins and
with an amount of collagen deposition (van Rooij et al. 2008). In a more recent study, a novel mechanism
of miRNA-29 regulation was identified. The loss of SMAD3 resulted in increased pressure overload and
induces myocardial fibrosis that is accompanied by the differential expression of miRNA-29 in vivo.
Moreover, transfection of pre-miRNA-29 in cardiac fibroblasts resulted in a significant decrease of
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collagen-1 (COL1A1 and COL1A2) and collagen-3 (COL3A1) gene expression at 48 h (Divakaran
et al. 2009).
Potential Uses and Therapeutic Strategies of miRNAs

The biology of miRNAs is a relatively new research area. Deregulation of one particular miRNA is
enough to cause a specific cardiovascular disease, which can be reversed by correcting the aberrant
expressed miRNA, indicating the potential of miRNAs as pharmacological targets. One of the potential
advantages of miRNA-based therapies over conventional therapeutics would be their ability to modulate
multiple target genes or networks related to cardiac remodeling process. To recover the decreased miRNA
levels in a particular cardiovascular disease and thus prevent the pathological process, a miRNA
reexpression strategy can be used to increase miRNA levels. The miRNA mimic (miR-mimic) technology
has been developed to synthesize nonnatural nucleic acids that can bind to target mRNAs in a gene-
specific manner and elicits the same posttranscriptional regulatory effects as a miRNA does. The success
of this technique has been already demonstrated (Xiao et al. 2007), suggesting that miR-mimic strategy
may be effective in vivo. In contrast, for those miRNAs that are upregulated and cause a disease, the anti-
miRNA techniques to block miRNA expression can be employed. One of them is the use of antisense
inhibitor oligonucleotides (AMOs). AMOs are artificially designed oligonucleotides that are fully
complementary to their target miRNAs; they bind to their target miRNA and reduce their activity.
The main limitation of miRNA-based therapies is that a single miRNA may regulate expression of
hundreds of genes, and the modulation of a miRNA of interest can lead to unintended side effects. To
solve this problem, a technique termed miRNA-masking antisense oligodeoxynucleotides (miR-Mask)
was developed. A miR-Mask is designed to be exactly antisense to the binding site in the target mRNA,
thus forming duplex with the target mRNA and not with other potential targets of the selected miRNA
(Xiao et al. 2007).
Future studies aimed at understanding how miRNAs are integrated into heart disease are a prerequisite
for their development as potential therapeutic targets. Thus, there is still a long way to go for miRNA-
based therapeutic strategies in human. However, miRNAs can be a very powerful weapon in our hands to
subjugate cardiac remodeling.
Inflammatory Biomarkers and Cardiac Ischemic Remodeling

Acute MI starts a cytokine cascade in both infarcted and non-infarcted myocardium via complement
activation and reactive oxygen species (Frangogiannis et al. 2002). Upregulation of pro-inflammatory
cytokines, such as TNF-a, interleukin-1beta (IL-1b), and IL-6, usually unexpressed in the normal heart,
has been clearly shown both in animal and human models during MI; the acute intramyocardial gene
expression of TNF-a, IL-1b, and IL-6 involves both the infarct area and the non-infarcted myocardium,
but it begins to decrease toward baseline after 1 week. If the infarct size is large or if there are ongoing
myocardial stress factors, the cytokine gene expression may remain elevated or may recrudesce as a
second wave of cytokine activation; the levels of late cytokine activation in the non-infarcted region
correlate the best with the eventual LV end-diastolic diameter measured at 20 weeks after infarction
(Frangogiannis et al. 2002).
Published data analyzing the cytokine network in the complex processes of postischemic LV
remodeling have confirmed important disturbances in the cell production of pro- and anti-inflammatory
mediators; in particular, the increase of pro-inflammatory cytokine TNF-a is associated with the decrease
of IL-10 which could exert a protective/regulatory role (Pasqui et al. 2010). It is not clear why the same
ischemic stress induces in patients with similar characteristics more TNF-a and less IL-10 production than
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in others. However, they observed that a marked imbalance between pro-inflammatory and protective
mechanism was generated in patients undergoing LV remodeling, suggesting that the lack of homeostatic
mechanism could influence the activation and the extent of inflammatory reaction which leads to the
progression of ventricular remodeling and consequent myocardial dysfunction and HF.
Furthermore, a critical regulatory element in the coordinated activation of cytokine and adhesion
molecule genes is the dimeric transcription factor NF-kB (Ghosh and Karin 2002). A variety of stimuli
including cytokines, ischemic and mechanical stress, reactive oxygen species, and growth factors activate
IkappaB kinase, a kinase complex which leads to degradation of inhibitor kappa B (IkB) (Ghosh and
Karin 2002). NF-kB activity is significantly upregulated within minutes after MI and can be further
increased by following reperfusion. A study by Trescher et al. showed how reducing NF-kB activity via
IkB overexpression after MI positively influences ECM remodeling by reducing MMP-2 and MMP-9
levels while increasing TIMP-1, TIMP-2, TIMP-3, and TIMP-4 levels. Therefore, IkB overexpression
prevents ventricular dilation and consequently preserves cardiac function (Trescher et al. 2006).
Summary Points
– Cardiac troponins (TnI and TnT) have more advantages over other cardiac biomarkers for the detection
of acute MI; that is why it has led to their adoption as the new gold standard for myonecrosis.
Furthermore, due to the improved analytical performance of the new high-sensitivity TnT assays
have permitted the detection of more acute, subacute, and chronic cardiac diseases not related to ACS,
such as HF or cardiomyopathies.
– It is demonstrated how TGF-b appears increased during HF and contributes to the hypertrophy of
myocytes and fibrosis. GDF-15, a member of the TGF-b superfamily, has been related to long-standing
hypertension, a common secondary cause of hypertrophy, and also has been linked to poor functional
class. Furthermore, Galectin-3, a biomarker directly related to be a mediator of profibrotic pathways,
also demonstrated the clear link of fibrotic pathway and their potential biomarkers with adverse cardiac
remodeling.
– The evaluation of collagen peptides and MMP, as potential biomarkers representing a turnover
presented in HF or HCM, could report some slides of the pathogenesis of myocardial remodeling
and demonstrated a continuous ECM turnover, leading to an increase of interstitial fibrosis due to the
higher levels of collagen type I/III deposited. But published data in different types of pathologies and
cohorts have shown controversial data that force to continue in the study of this group of biomarkers in
cardiac remodeling.
– RAS contributes to the remodeling process through indirect effects such as interactions with other
neurohormonal systems and by direct effects on cardiac cells.
– Recent studies have provided increasing evidence that miRNAs play a significant role in cardiac
remodeling; however, the biology of miRNAs represents a relatively new research area and is still an
emerging field.
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Table 2 Abbreviations
Main abbreviations
ACE: angiotensin-converting ACS: acute coronary AF: atrial fibrillation AGT1R: Ang II type
enzyme syndromes 1 receptor
AMI: acute myocardial Ang: angiotensin AST: aspartate BNP: B-type natriuretic
infarction aminotransferase peptide
CK: creatine kinase CK-MB: creatine kinase MB CLcr: creatine clearance CYP11B2: aldosterone
isoenzyme synthase
CTGF: connective tissue ERK: extracellular signal- ECM: extracellular matrix GDF-15: growth
growth factor regulated kinase differentiation factor-15
GHL: tripeptide glycyl- GWAS: genome-wide HCM: hypertrophic HF: heart failure
histidyl-lysine association studies cardiomyopathy
HDAC4: histone deacetylase 4 hs-TnT: high-sensitivity TnT IL-6: interleukin-6 ICTP: procollagen
carboxyterminal telopeptide
type I
LAP: TGFb-1 latency- LDH: lactate dehydrogenase LGE: late gadolinium LV: left ventricular
associated peptide enhancement
MAP: mitogen-activated MI: myocardial infarction miRNAs: microRNAs MMPs: matrix
protein metalloproteinases
MRI: magnetic resonance NSVT: nonsustained NT-proBNP: N-terminal NYHA: New York Heart
imaging ventricular tachycardia proBNP Association
PICP: carboxyterminal PINP: amino-terminal PIIINP: N-terminal RAS: renin-angiotensin
propeptide of procollagen propeptide of procollagen propeptide of procollagen system
type I type I type III
ROS: reactive oxygen species SCD: sudden cardiac death SPRY1: sprouty homolog1 SRF: serum response factor
TGF: the transforming growth TIMPs: tissue inhibitors of TnT: troponin T
factor matrix metalloproteinases
Acknowledgments
JA Vílchez holds a research grant “Río Hortega” by the Instituto de Salud Carlos III, Madrid, Spain.
Dr. Orenes-Piñero is supported by a postdoctoral contract from Fundación para la Formación e
Investigación Sanitarias de la Región de Murcia, Murcia, Spain.
D Hernandez-Romero holds a research grant “Sara Borrell” by the Instituto de Salud Carlos III, Madrid,
Spain.
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Biomarkers of Necrosis and Myocardial Remodeling

Chapter · August 2015

Juan Antonio Vílchez Esteban Orenes-Piñero

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Diana Hernández-Romero Mariano Valdes

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Biomarkers of Necrosis and Myocardial Remodeling

Biomarkers in Cardiovascular Disease

Pathophysiology of Cardiac Remodeling: Structural Remodeling

Biomarkers Related to Necrosis

Biomarkers Related to Cardiac Remodeling

Myocardial Necrosis Biomarkers: Cardiac Troponins

Profibrotic Biomarkers: Growth Factors

Growth Differentiation Factor-15 (GDF-15)

Collagen Peptides as Fibrotic Biomarkers

PINP Collagen type I PICP

Amino-terminal telopeptide CITP

GHL Other matrikines and degradation products

PINP GHL CITP PICP

Matrix Metalloproteinases and Their Inhibitors Related to Cardiac Remodeling

Role of the Renin-Angiotensin System (RAS) in Cardiac Remodeling

an octapeptide, is generated by angiotensin-converting enzyme (ACE) from Ang I (a decapeptide), which

Role of MicroRNAs (MiRNAs) in Cardiac Remodeling

Table 1 Biological functions regulated by miRNAs affecting cardiac remodeling

Potential Uses and Therapeutic Strategies of miRNAs

Inflammatory Biomarkers and Cardiac Ischemic Remodeling

Bogdanov DV. Spherical remodeling of left atrium in hypertrophic nonobstructive cardiomyopathy.

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