European Heart Journal (2009) 30, 139151 doi:10.

1093/eurheartj/ehn538

REVIEW

Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis
n2, n 1, Vanessa Rolda Francisco Cambronero1, Francisco Mar s1, and Gregory Y.H. Lip 3* ndez-Romero1, Mariano Valde Diana Herna
1 3

n, University of Murcia, Spain; and Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; 2Centro Regional de Hemodonacio Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UK

Received 24 May 2008; revised 6 November 2008; accepted 17 November 2008

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

The study of biomarkers and their signalling pathways has allowed the development of new therapeutic strategies in a range of disorders. The aim of the present systematic review is to provide an overview of different biomarkers in patients with hypertrophic cardiomyopathy that could give some insight into the pathophysiologic mechanism(s) underlying the typical clinical and histological manifestations of the disease. Several pathophysiological models are presented and discussed, including studies that have investigated these biomarkers for diagnostic and prognostic reasons, in relation to disease progression and/or mortality.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Hypertrophic cardiomyopathy Biomarkers Pathophysiology

Introduction
Hypertrophic cardiomyopathy (HCM) has been dened morphologically by unexplained hypertrophy in the absence of haemodynamic stress, and at the histological level by myocyte disarray, brosis, and abnormalities of the intramyocardial small vessels.1 HCM is a monogenic cardiac disease with an autosomal dominant pattern of heritability and different penetrance, with a prevalence in the general population of 1/500.2 Mutations in 11 genes of contractile sarcomeric proteins have been shown to produce the disease, and more than 400 different mutations have been discovered so far, most of them of the missense type.3 In at least 25% of patients, asymmetrical septal hypertrophy leads to a signicant pressure gradient between the apical left ventricular (LV) chamber and the left ventricular outow tract (LVOT), resulting in the so-called hypertrophic obstructive cardiomyopathy (obstructive HCM) presentation. Majority of patients with obstructive HCM are asymptomatic but some can present with heart failure or arrhythmias. Thromboembolic events are frequent and potentially serious causes of mortality and morbidity amongst HCM patients. Indeed, the incidence of stroke is around 3% per patient-year, especially in patients with HCM an atrial brillation, or those with obstructive

HCM.4,5 Arrhythmias and premature sudden cardiac deaths (SCDs) are also common in HCM.6 Ultimately, about 10% of obstructive HCM patients progress to an end-stage dilated phase with LV wall thinning, cavity enlargement, and systolic dysfunction that resembles a dilated cardiomyopathy.7 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. The most active elds in cardiovascular medicine in which biomarkers have shown to be useful are ischaemic heart disease and heart failure. In ischaemic heart disease, for example, multiple biomarkers have helped us to understand the pathophysiology of the atheromatous plaque.8 11 Such biomarkers have also been used to predict the risk for coronary artery disease and its sequelae. For example, B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are useful in the diagnostic and prognostic pathway for patients with heart failure.12 Could biomarkers help in understanding the pathophysiology of HCM? The clinical and pathological characteristics of HCM could involve a number of diverse mechanisms that include inammation, endothelial dysfunction, brosis, and extracellular matrix degradation, as well as coagulation and platelet activation. In each of

* Corresponding author. Tel: 44 121 5075080, Fax: 44 121 554 4083, Email: g.y.h.lip@bham.ac.uk Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

140
these processes, different molecules involved in the different pathophysiological pathways can be detected in the blood, providing us with information on subgroups of patients may be at increased risk for subsequent cardiovascular events. The detection of appropriate biomarkers could potentially provide tools to diagnose and stratify these patients. The aim of the present systematic review is to provide an overview of different biomarkers in patients with HCM that could give some insights into the pathophysiologic mechanism(s) underlying the typical clinical and histological manifestations of the disease.

F. Cambronero et al.

Search strategy
We performed a comprehensive literature search by using electronic bibliographic databases (MEDLINE, EMBASE, The Cochrane Library, and DARE) and combinations of the following keywords: HCM, treatment, hypertrophy, cardiomyopathy, inammation, cytokines, C-reactive protein, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-a), s-Fas, s-FasL, apoptosis, endothelin, Von Willebrand factor (vWf), soluble thrombomodulin (sTM), tissue factor pathway inhibitor (TFPI), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), platelet function, CD40 ligand, soluble CD40 ligand, Beta thromboglobulin (b-TG), P-Selectin, coagulation markers, brinogen, platelet-derived growth factor (PDGF), brinopeptide A, thrombin-antithrombin III complex, brinolysis, thrombotic, prothrombic fragment 1 2 (F1 2), D-Dimer, plasmin-alpha2-plasmin inhibitor complex, aldosterone, brosis, apoptosis, matrix metalloprotreinases (MMPs), tissue inhibitor of matrix metalloproteinases (TIMPs), brain natriuretic peptide (BNP), NT-pro-BNP, atrial natriuretic peptide (ANP), insulin growth factor-1 (IGF-1), transforming growth factor-b (TGF-b), angiotensin 2, and calcineurin. Bibliographies of all selected articles and review articles were reviewed for other relevant articles. Where necessary, study authors were contacted to obtain further data.

For example, brosis is greater beneath the endocardium and is more prominent in the interventricular septum area compared to the free LV wall.17 Abnormalities in small intramural coronary arteries and subendocardial arterioles have also been observed at autopsy in obstructive HCM subjects. The walls of these intramural vessels, especially in the ventricular septum, are thickened and the vessel lumen is frequently narrowed.16,18,19 There is hypertrophy of the intima and an abnormal ultrastructure of endothelial cells, providing a morphological substrate for functional impairment of the endothelium.20,21 These abnormal vessels are usually within the areas of brous tissue or in close proximity to these areas.

Pathophysiology of hypertrophic cardiomyopathy

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Morphological and microscopic characteristics of hypertrophic cardiomyopathy

Macroscopically, HCM is characterized by unexplained left or right ventricular hypertrophy in the absence of an increased external load, which is usually asymmetric in affecting different portions of the ventricles. Microscopic changes in obstructive HCM include myocyte hypertrophy and disarray, as well as increased interstitial brosis and small intramural coronary artery abnormalities.1,7,13 16 Myocyte disarray is a characteristic feature of HCM, seemingly preceding hypertrophy and brosis.7,14 The high degree of disarray observed in obstructive HCM is distinctive1,13 and involves substantial portions of LV wall. Fibrosis is another important component of the pathophysiology of obstructive HCM.1 Histological examination demonstrates an increase of connective tissue between individual cells and deposition of large amounts of collagen and bronectin.15 However, the distribution and severity of brosis can be quite variable.

While the aetiology of HCM has been extensively studied, its pathogenesis is not completely understood. All of the knowledge accumulated has largely been obtained from animal models. Indeed, the initial defects caused by the mutant proteins are diverse and a common mode of pathogenesis is believed to exist, ultimately converging into impaired cardiac myocyte function. In vitro functional studies have shown that HCM mutants alter sarcomere function in two different ways: rst, by decreasing the translocating lament activity and/or force leading to a reduction of power production. It can also increase in vitro motility rates of lament sliding and/or force.22 The molecular changes subjacent to these observations seem to vary, and include reduced crossbridge kinetics,23,24 reduced ATPase activity, altered calcium sensitivity,24 27 reduced myoshortening,28 myocyte atrophy,26 and impaired excitation contraction coupling.29 Altogether these points to the diversity of the molecular and cellular mechanisms could be involved in the pathogenesis of the nal HCM phenotypes seen clinically. It is still unknown how a mutation of a sarcomeric protein, the functional defect observed, and the development of the microscopic characteristics of HCM are linked. Several hypotheses have been proposed.23,30,31 The most accepted one suggests that HCM mutations induce functional defects in myocyte contractility, thus producing diastolic and systolic dysfunction that induces increased wall stress, a reduction of stroke volume, and, consequently, an activation of stress responsive trophic and mitotic factors (such as ACE1, angiotensin II, IGF-1, TGF-b, TNF-a, IL-6, and endothelin).30 These molecules increase the entrance of calcium into the cells and the activation of transcriptional pathways that lead to the diverse histological and structural phenotypes of HCM including cardiac hypertrophy, interstitial brosis, and myocyte disarray. The problem with this hypothesis is that not all the mutations produce hypocontractility, as HCM mutations in some thin lament regulatory proteins (e.g. troponin I and a-tropomyosin) actually increase the force of contraction.24,32 34 Therefore, decreased contractility per se cannot be the sole stimulus to hypertrophy. In an alternative model where there is an increase in the force of

Biomarkers of pathophysiology in HCM

141

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Figure 1 Schematic demonstrating in summary some of the known hypertrophic and brosis signalling pathways. Calcium plays a central role
in the pathogenesis of hypertrophic cardiomyopathy (HCM). The increase in intracellular calcium could be due to two different mechanisms. On one hand, following the theory of energy depletion, the mutated sarcomeric proteins will use more adenosine triphosphate to produce the same force of contraction. Therefore, it will compromise calcium reuptake by the SERCA transporter into the endoplasmic reticulum and more calcium will be available inside the cells. On the other hand, activation of a number of different receptor classes lead to an increase in intracellular calcium; these include angiotensin II, endothelin-1, TNF-a, and IL-6 and their signalling pathways including the mitogen-activated protein kinase cascade (MAPK), protein kinase C (PKC), the phosphatidyl inositol kinase (PI(3)K)/Akt/glycogen synthase kinase 3b (GSK3b) pathway. This increase in intracellular calcium will modulate transcription via modication of nuclear factors of activated T cells (NFAT), myocyte enhancer factor-2 (MEF2) that will induce hypertrophy through the activation of foetal isoforms of proteins. The same molecules afore mentioned plus aldosterone and TGF-b will activate pathways that will modulate the production of transcription factors such as nuclear factor kappa B (NF-Kb), activating protein-1 (AP-1), small mothers against decapentaplegic (SMAD), signal transducer, and activator of transcription (STAT) that will be integrated and eventually will drive MMPs and TIMPs transcription remodelling the extracellular matrix. Sr, sarcoplasmic reticulum; SERCA, sarcoplasmic reticulum calcium pump; CaM, calmodulin; SHR, steroid hormone receptor, HRE, hormone response element.

contraction, the induced hypertrophy is directly as a consequence of hypercontractility.22 The nal model that can explain the hyper- and hypocontractility observed in both previous models is the energy compromise hypothesis.35 For example, myosin ATPase uses at least 70% of adenosine triphosphate (ATP) hydrolysis in the cardiac myocyte, and perturbation of either the motor itself or its regulation may alter the efciency of ATP usage by the sarcomere.31 In HCM patients, there is a reduction of the phosphocreatine to ATP ratio, which is an indicator of the energetic state of cardiac muscle. Such inefcient utilization of ATP results in the need for more energy to produce the same amount of force. For example, in an a-MHC403/ murine model of HCM, the demand of more ATP to produce myocyte contraction results in ATP depletion, thus affecting a highly ATP-dependent process, the sarcoplasmic reticulum calcium pump (SERCA), leading to accumulation of Ca in the citosol29 (Figure 1).

Support for this hypothesis comes from the study of other human diseases that limit myocardial energy production or cellular energy s homeostasis, such as mitochondrial tRNA mutations,36 Friedreich ataxia,37 defects in fatty acid uptake through CD36 deciency,38 mitochondrial fatty acid oxidation through very-long chain acyl-CoA dehydrogenase deciency,39 and mutations in the g2 regulatory subunit of AMP-activated protein kinase.40,41 Consequently, less ATP is available to maintain normal calcium reuptake, and thus, there is an increase in the citosolic calcium and activation of calciumdependent transcriptional signals [the most important of which seems to be calcineurin, and the downstream transcription factors NFAT (nuclear factor of activated T cells) and MEF-2 (myocyte enhancer factor)] leading to hypertrophy and brosis.42 44 Of note, homeostasis of calcium in the sarcomere is of great importance in the pathogenesis of HCM. Evidence of this role comes from the study of mutations in calcium regulatory proteins showing the development of HCM phenotype.45 The accumulation

142

F. Cambronero et al.

Table 1 Inammatory biomarkers in hypertrophic cardiomyopathy

References

...............................................................................................................................................................................
Zen et al. (2005)47 IL-6, TNF-a, ANP, BNP, 38 HNCM, 11 DHCM s-Fas, s-FasL patients, and 10 normal subjects In HNCM and DHCM, TNF-a and IL-6 were slightly higher compared with normal subjects and sFas increased signicantly. IL-6 was signicantly higher in DHCM compared with HNCM. Thus, IL-6 may play an important role in the status of HCM and its progression to DHCM TNF-alpha was not elevated in HCM. The markedly elevated IL-6 levels did not correlate with the left ventricular function in HCM patients Signicant reduction of TNF-a alters non-surgical septal reduction therapy. TNF-a may play a pathogenetic role in the hypertrophy of pressure overload

Biomarker

Patient population

Findings

Hogye et al. (2004)48

IL-6, TNF-a

19 patients with HCM, 31 patients with DCM, and 20 healthy subjects 15 HOCM patients at baseline and after successful NSRT

Nagueh et al. 200149

TNF-a

Buzas et al. (2004)50

IL-6, TNF-a, sFas, sIL-6R 31 DCM patients, 19 HCM patients, and 20 healthy controls

Penicka et al. (2001)64

sTNFRI

HCM patients have higher IL-6 and sIL-6R levels when compared with healthy individuals. DCM patients exhibit elevated concentrations of TNF-alpha, sFas, IL-6, and sIL-6R. The data indicate the activation of the pro-apoptotic TNF and Fas pathways in DCM patients, and an anti-apoptotic shift in HCM patients 66 patients with HCM and 30 sTNFRI levels were higher in severely symptomatic patients, and in age-matched healthy patients with reduced LV systolic and diastolic reserve during subjects dobutamine stress echocardiography C-reactive protein levels are different between control and HCM patients but only due to the subgroup with LVOT obstruction No relation between C-reactive protein values and brosis, severity of hypertrophy, clinical symptoms nor any of the clinical variables known to be associated to prognosis in HCM, including NT-pro-BNP

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Dimitrow et al. (2007)66 C-reactive protein

42 HCM patients (16 with LVOT obstruction) and 29 controls 120 patients with HCM, 83 HCM with LGE by CMR

et al. (2008)67 Paya

C-reactive protein

ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; DCM, dilated cardiomyiopathy; DHCM, dilated hypertrophic cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; HNCM, hypertrophic non-obstructive cardiomyopathy; HCM, hypertrophic cardiomyopathy; IL-6, interleukin 6; LV, left ventricle; LVOT, left ventricular outow tract; NSRT, non-surgical septal reduction therapy; sFas, soluble Fas; s-FasL, soluble Fas ligand; sIL-6R, soluble interleukin 6 receptor; sTNFRI, soluble tumour necrosis factor receptor 1; TNF-a, tumour necrosis factor a; LGE, late Gadolinium enhancement.

of calcium in the cytosol and the activation of hypertrophic and brosis pathways could be due to a decrease in ATP with the reduction of SERCA activity but also through the regulation of proteins that control calcium release from the sarcoplasmic reticulum or decrease of storage calcium proteins in the sarcoplasmic reticulum. These processes will change the calcium sensitivity as well as the buffering capacity of the sarcomere.46

Biomarkers associated with hypertrophic cardiomyopathy

Inammatory biomarkers
Cytokines are pleiotropic proteins that regulate leukocyte activity. In the acute-phase response, cytokines such as interleukin (IL)-1 and IL-6 drive production of reactant proteins, including C-reactive protein. Inammatory biomarkers that have been most studied in HCM patients are IL-6 and TNF-a47 51 (Table 1). Both can be expressed in the myocardium under various forms of stress and are capable of modulating cardiac function by a variety of mechanisms including the induction of LV hypertrophy, cardiomyopathy, and apoptosis in cardiac myocytes.50,52 56 Indeed, the progressive loss of cardiac myocytes due to apoptosis would contribute to the overall deterioration of myocardial function.56

IL-6 is a pro-inammatory cytokine secreted by all the nucleated cells of the heart. IL-6 is also considered a myokine, which is a cytokine produced in the muscle that is elevated in response to muscle contraction. Indeed, skeletal muscle is a major source of this cytokine. Smooth muscle cells in the tunica media of many blood vessels also produce IL-6, as a pro-inammatory cytokine.57 IL-6 may also induce the expression of MMPs and TNF-a.58 HCM patients have higher levels of IL-6 compared with healthy controls.47,50,51 However, IL-6 levels did not correlate with LV function,48 although the overexpression of IL-6 and IL-6 receptor in mice leads to the development of cardiac hypertrophy.53 TNF-a is a multifunctional cytokine with a broad range of concentration-dependent effects involved in systemic inammation, the regulation of immune cells function, and stimulation of the acute phase reaction. TNF-a has been detected in several human cardiac-related conditions, including congestive heart failure, the hypertrophic growth response in cardiac myocytes, and septal cardiomyopathy.52,59 TNF-a can also participate in different pathways causing apoptosis60 and it is a cytokine capable of producing brosis through the activation of MMPs and TIMPs.61 Various studies in HCM have generally found an increase in TNF-a levels,47,49 with one exception.48 It is plausible that TNF-a may play a pathogenetic role in HCM. While pressure or volume overload contributes to the development of left

Biomarkers of pathophysiology in HCM

143
incidence of worsening heart failure.47 Thus, plasma sFas levels could potentially be a prognostic predictor in dilated HCM patients.

hypertrophy and cardiomyopathy,62 septal ablation of HCM patients leads to a reduction of TNF-a, myocyte size, and collagen content that is accompanied by an increase in LV volumes and a reduction in LV hypertrophy and chamber stiffness.49 Genetic studies show that an uncommon allele of the TNF-a-308G/A polymorphism, which produces more TNF-a, is associated with greater LV mass index and clinical diagnosis at a younger age in patients with HCM.63 Finally, it has been shown that transgenic mice that overexpress TNF-a develop LVH, dilated cardiomyopathy, and premature death.52 There are also signicant differences in soluble TNF receptor 1 (sTNFR1) serum levels between patients with HCM and healthy subjects.64 The levels can be related to functional class, being higher in patients with NYHA III IV and also with reduced LV systolic and diastolic reserve during dobutamine stress echocardiography.64 Importantly, TNF-a may play an important role in the status of HCM and its progression to dilated HCM. Indeed, increases in TNF-a are marked in those patients with the dilated phase of HCM indicating a strong pro-apoptotic activation effect.47 It is possible that the sustained long-term overexpression of TNF-a may induce cardiac myocyte apoptosis.65 An inammatory marker, C-reactive protein has also been studied in HCM. For example, Dimitrow et al.66 showed that C-reactive protein was more elevated in HCM patients than in controls. In our laboratory, we failed to demonstrate a relation between C-reactive protein values with brosis as measured by MRI, the severity of hypertrophy, clinical symptoms nor any of the clinical variables known to be associated to prognosis in HCM, including NT-pro-BNP.67 In summary, TNF-a and IL-6 might be involved in the pathogenesis of HCM, but there is no clear activation mechanism. It is possible that an increase in mechanical overload could be the trigger that stimulates the production of these two cytokines (IL-6 and TNF-a).68 IL-6 may induce the expression of MMPs and TNF-a causing brosis.58 In mice, the overexpression of IL-6 and IL-6 receptor leads to the development of cardiac hypertrophy;53 it is possible that this will work in the same way in humans. Elevated TNF-a levels may identify patients with a more severe cardiomyopathy, as well as early progression to a dilated cardyomyopathy who could benet from more aggressive intervention.

Markers of endothelial function

Microvascular dysfunction is a common nding in HCM patients and its extent is an important prognostic marker.73 Impairment of endothelium-dependent coronary vasodilatation has been shown in patients with HCM.74 77 These patients had an abnormal vasoconstrictor response of the coronary artery to acetylcholine,74 the cold pressor test,77 and pacing stimulation,76 which are various stressor tests that measure endothelium-dependent vasomotor reactivity. Extravascular compressive forces may play an important role in the microvascular dysfunction in HCM.78 In addition, hyperaemic myocardial blood ow as measured by PET scan is severely blunted, with particularly pronounced hypoperfusion at the subendocardial layer, indicative of microvascular dysfunction (Table 1).73,78 Plasma vWf is an established marker of endothelial damage/ dysfunction.79,80 Only two published articles have compared vWF levels between patients with HCM and age- and gendermatched controls. There were no statistically signicant differences between both groups and vWf levels were not related to functional class.81,82 Recently, Dimitrow et al.82 found that other markers of endothelial dysfunction, such as soluble thrombomodulin (sTM) and tissue factor pathway inhibitor (TFPI) were elevated in HCM compared to healthy individuals. Also, there was an elevation of markers related to the nitric oxide pathways, including asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA).82 The obstructive HCM subgroup displayed higher values of ADMA, SDMA, and sTM compared with the nonobstructive HCM subgroup.82 These ndings suggest that endothelium in HCM could well be functionally abnormal. Endothelin-1 (ET-1) is a potent vasoconstrictor produced by vascular endothelial cells and causes hypertrophy in cultured heart muscle cells,84 perhaps by activating the reexpression of cardiac-specic foetal genes.84 In HCM patients, ET-1 levels are signicantly increased by more than two-fold compared with controls.85,86 ET-1 mRNA synthesis in the heart is also upregulated in hypertrophied hearts by pressure overload.87,88 It is uncertain whether the increase of ET is the cause of the hypertrophy or it contributes to the pathophysiology of HCM. However, there is a report showing that ETA (receptor antagonist A) blockade can cause LV hypertrophy by pressure overload in vivo, suggesting a role of ET-1 in the development of cardiac hypertrophy.87 HCM patients have well-documented evidence of endothelial dysfunction, which can be detected in peripheral blood as elevation of endothelial-related biomarkers, as well as impaired endothelium-dependent coronary vasodilatation. The precise mechanisms of endothelial dysfunction in HCM are unknown, but the impaired hyperaemic myocardial blood ow correlates independently with LV mass. It is possible that a thickened ventricle could generate extravascular compressive forces that play a role in the microvascular dysfunction seen in HCM. Another possibility is the induction of structurally abnormal and altered endothelial

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Apoptotic biomarkers
Fas is an apoptosis-signalling receptor molecule on the surface of a number of cell types including the myocardium. Fas antigen is expressed in various tissues, and its soluble form, sFas, lacks the transmembrane domain.69 Binding of sFas to Fas inhibits apoptosis (Table 1).70 A related molecule, Fas ligand (Fas-L) is a type II transmembrane protein that belongs to the TNF family. The binding of Fas-L, sFas-L, or agonistic anti-Fas antibodies to Fas induces apoptosis in the targeted cell.71,72 Plasma sFas-L levels in patients from HCM group are signicantly decreased compared to normals and this reduction was even more marked in patients with dilated HCM.47 sFas is also increased signicantly in HCM compared to normal subjects, and dilated HCM patients with high sFas levels demonstrated deterioration of mitral E wave deceleration time, an index of LV diastolic function, as well as a high

144

F. Cambronero et al.

Table 2 Endothelial, platelet function, and coagulation biomarkers in hypertrophic cardiomyopathy patients
References

..............................................................................................................................................................................
Dimitrow et al. 200766 TAT; F1 2, sCD40L, b-TG; P-sel; IL-6; TNF-a 42 HCM patients (16 with LVOT obstruction is independently associated with enhanced LVOT obstruction) thrombin generation and platelet activity in HCM and 29 controls vWf 29 HCM and 29 control vWf levels are not increased in patients with hypertrophic subjects cardiomyopathy and there is no relation to functional class sTM, TFPI, ADMA, and SDMA were elevated in HCM patients sTM, vWF, TFPI, ADMA, SDMA 29 HCM patients compared with controls. vWF levels were similar in both including 11 with groups. In LVOT subgroup, higher values of ADMA, SDMA, LVOT obstruction and sTM were found compared with the HNCM. In and 29 controls conclusion, HCM patients show specic features of endothelial dysfunction Endothelin-1 Endothelin-1 26 HCM and 6 control subjects 40 patients with HCM, 35 with hypertension, and 15 controls 5 HCM patients 45 HCM and 15 healthy controls Endothelin-1 was more than two-fold higher in hypertrophic cardiomyopathy patients than in control subject Endothelin-1 concentrations were only slightly higher in HCM patients than in hypertensive and control patients

Biomarker

Patient population

Findings

Varol et al. 200581 Dimitrow et al. 200782

Hasegawa et al. (1996)85 Ogino et al. (2004)86

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Yarom et al. (1982)89 Riazanov et al. 200090

Platelet Platelet aggregation

Increased cell size, decreased phosphorus concentrations, and increased permeability to cations in HCM patients

Yamamoto et al. (1995)94 PF-4; b-TG; PLN-a2PI complex; brinopeptide A; TAT, D-dimer

HCM patients have higher induced with thromboxane A2 analogue and spontaneous platelet aggregation. There is a positive correlation between platelet aggregation and the degree of LVH 13 patients with HCM, 17 Plasma levels of brinopeptide A and TAT in both patient DCM, and 20 normal groups were signicantly higher than those in normal subjects subjects. Plasma levels of D-dimer were higher in DCM patients

ADMA, asymmetric dimethylarginine; b-TG, beta-thromboglobulin; DCM, dilated cardiomyopathy; F1 2, prothrombin fragment 1 2; HCM, hypertrophic cardiomyopathy; HNCM, hypertrophic non-obstructive cardiomyopathy; IL-6, interleukin 6; LVOT, left ventricular outow tract; PLN- a2PI complex, plasmin-alpha 2-plasmin inhibitor complex; PF4, platelet factor 4; P-sel, P-selectin; sCD40-L, soluble CD 40 ligand; SDMA, symmetric dimethylarginine; sTM, soluble thrombomodulin; TAT, thrombin-antithrombin III complex; TFPI, tissue factor pathway inhibitor; TNF-a, tumour necrosis factor a; vWF, von Willebrand factor.

hypertrophy by platelet derived growth factor (PDGF), which is produced by disturbed platelets (see below).

Platelets and platelet function

Yarom et al.89 were the rst to show morphometric and chemical differences in platelets in HCM patients that consisted in increased cell size, decreased phosphorus concentration, and increased permeability to cations, suggesting membrane and energy metabolism aberrations in such patients. Patients with HCM had high induced and spontaneous platelet aggregation which was positively correlated with LVH mass.90 Moreover, platelets were especially sensitive to the aggregation with a thromboxane A2 analogue (Table 2).90 In a recent study, Dimitrow et al.66 found an increase of three platelet activation markerssoluble CD40 ligand (sCD40L), b-thromboglobulin (b-TG), and P-Selectinin HCM patients, but non-obstructive patients had only higher levels of plasma P-Selectin compared with controls. The accelerated ow due to LVOT obstruction may stimulate platelets through an increase in shear stress. Do platelet abnormalities in HCM go beyond thrombogenesis? One of the pathological characteristics of HCM is intimal and/or medial hyperplasia of intramyocardial small vessels, and given

that PDGF has the potential to induce the proliferation of vascular smooth muscle cells, broblasts, and endothelial cells,91,92 PDGF may have a role in the development of intramyocardial vasculopathy.93 Although no studies have investigated the production of this molecule in the platelets of HCM patients, the abnormal platelets could drive the increase production of PDGF. We can not rule out the possibility that PDGF production in HCM patients could originate from other cells, including myocytes.93 The inhibition of PDGF signalling using receptors antagonists could open a new future eld in the treatment of HCM, but many more studies are required.

Prothrombotic markers
Thromboembolic events in patients with HCM are very frequent. Alterations in the plasma levels of molecular markers of the prothrombotic and brinolytic status have been reported in patients with HCM (Table 2). In small studies, plasma levels of brinopeptide A, thrombinantithrombin III complex (TAT), and F1 2 levels, as markers of brin generation and reecting thrombotic status, are signicantly increased in patients with HCM compared with normal subjects.66,94 Plasma brinopeptide A and plasma TAT levels have a signicantly positive correlation with left atrial diameter, but not

Biomarkers of pathophysiology in HCM

145

Table 3 Fibrosis biomarkers and hormones in hypertrophic cardiomyopathy patients

References

...............................................................................................................................................................................
Stroud et al. 200583 TIMP-4 18 normal and 16 HCM after alcohol-induced MI 26 HCM patients and 38 controls Plasma TIMP-4 levels increased by 250% in the HCM patients when compared with normal controls TIMP-1 and PICP were elevated in HCM. Free MMP-1 was lower in HCM. Inhibition of collagenolysis by means of reduction of TIMP-1 and the increased production of PICP indicate collagen accumulation (brosis) Patients had higher levels of PIIINP, ICTP, MMP-2, MMP-9, and TIMP-1. Collagen turnover is enhanced in HCM patients MMP-2 and TIMP-2 were higher in DHCM. MMP-2 concentrations increased with NYHA functional class. TIMP-1 was higher in HCM patients than in control MMP-2 was associated with dyspnoea. MMP-9 was and independent factor associated with the presence of brosis in CMR. NT-pro-BNP was associated with brosis Plasma aldosterone was similar between both groups. Myocardial aldosterone and aldosterone synthase mRNA levels were elevated by four- to six-fold in humans with HCM IGF-1 levels were higher in patients with HCM and lower in patients with DHCM. IGFBP-1 levels were signicantly higher in patients with DHCM than in the other two groups

Biomarker

Patient population

Findings

Fassbach and Schwartzkopff (2005)98 Lombardi et al. (2003)99 Noji et al. (2004)100

PICP; ICTP; MMP-1; TIMP-1

PIIINP; PICP; PINP; ICTP; MMP-1; MMP-2; MMP-9; TIMP-1 MMP-2; MMP-3; MMP-9; TIMP-1; TIMP-2 NT-pro-BNP; MMP-1; MMP-2 and MMP-9; TIMP-1 Aldosterone

36 HCM patients and 14 controls 11 DHCM, 17 HCM, and 50 age-matched control subjects 67 HCM patients

n et al. 2008102 Rolda

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Tsybouleva et al. (2004)107 Saeki et al. (2002)114

11 HCM patients and 8 controls 39 HOCM, 67 HNCM, and 18 DHCM

IGF-1 and IGFBP-1

CMR, cardiac magnetic resonance; DHCM, dilated hypertrophic cardiomyopathy; HCM, hypertrophic cardiomyopathy; HNCM, hypertrophic non-obstructive cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; ICTP, type I collagen degradation product; IGF-1, insulin growth factor 1; IGFBP-1, insulin growth factor binding protein 1; MI, myocardial infarction; MMP, metalloproteinases; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide; PICP, procollagen type I C-terminal peptide; PIIINP, N-terminal pro-peptide of collagen type III; PINP, procollagen type 1 N-terminal propeptide; TIMP, metalloproteinase inhibitors.

with LV diastolic volume.94 Dimitrow et al.66 found increased TAT and F1 2 levels in obstructive HCM, correlating positively with the LVOT gradient. Indeed, the turbulent ow in obstructive HCM might be involved in the prothrombotic state through an increase of shear stress.66

Matrix metalloproteinases
Matrix metalloproteinases (MMPs) are zinc-dependant endopeptidases with collagenase and/or gelatinase activity. Collectively they are capable of degrading various extracellular matrix proteins, but also can process a number of bioactive molecules. They play an important role in cardiac remodelling and brosis in other cardiovascular diseases, for example, myocardial infarction and development of dilated cardiomyopathy. MMPs are inhibited by specic endogenous tissue inhibitors of metalloproteinases (TIMPs) that comprises a family of four protease inhibitors (TIMP-1 through 4).95,96 The various molecules that inuence the expression of MMPs and TIMPs in HCM patients are varied, including the renin angiotensin aldosterone system, oxidative stress, endothelin-1, TNF-a, sympathetic activation markers, and TGF-b1.97 The high grade of brosis seen in HCM could be due to an imbalance between MMPs and TIMPs with the accumulation of brous tissue (Table 3). Impaired collagenolysis and an increased deposition of collagen have been seen in patients with HCM. In HCM, there is a reduction of MMP-1 to undetectable levels, with an increase of TIMP-1, TIMP -2, TIMP-4, MMP-2, and MMP-9.83,98 100 These changes result in enhanced collagen turnover, with an increase of collagen type I98

and a shift of collagen I to collagen III.99 This shift is not easy to explain because collagen I is apparently stiffer than collagen III,101 but could well be a compensatory mechanism due to the increase in wall stiffness. MMP-2 correlates negatively with systolic function100 and levels signicantly increase with higher NYHA functional class.100,102 TIMP-2 correlates positively with LV dimensions100 and diastolic dysfunction can be related to MMP-1 and MMP-2.99 In our group, we have shown that MMP-2 levels correlate with functional class and MMP-9 is an independent factor associated with late Gadolinium enhancement in cardiac magnetic resonance imaging,102 an established non-invasive method to assess the presence of brosis. This is important as an increase in cardiac collagen content has been associated with SCD in young patients with an 8-fold (14.1 + 8.8 vs. 1.8 + 1% of the tissue section; P , 0.0001) and three-fold (4.5 + 1.3%; P , 0.001) increase compared with controls and systemic hypertensive patients, respectively.103 This raises the possibility of using treatments that could reduce the interstitial brosis and consequently reduce SCD. Interestingly, several authors have proposed the measurement of MMPs for the follow-up of HCM patients in order to analyse the benecial effects of different therapies.104,105 Understanding how upstream molecules regulate MMP may provide clues to develop important therapeutic interventions. In animal models, several treatments have shown potential to reverse or attenuate interstitial brosis. Treatment with drugs that can block the activators of MMPs as losartan, spirinolactone, and N-acetilcysteine reduce the expression of collagen 1 alpha

146
(I) and TGF-b in a TnT mutant mouse, that in turn reduce interstitial brosis and improve diastolic dysfunction.105 107 In humans, the effects of atorvastatin on LV mass in patients with HCM have been investigated in a randomized placebo-controlled double-blind pilot study, but this did not demonstrate any effect of 9-month treatment with atorvastatin on LV mass reduction.104 Also in humans, the angiotensin blocker, losartan, has been shown to improve diastolic LV dysfunction in HCM, but no signicant changes in LV wall and cavity measurements were observed.108 It is possible that some of the benecial effects of ACE inhibitors in remodelling may be mediated through MMPs, at least in hypertensive patients.106 For now, the available data suggest a disturbed balance of collagen synthesis and degradation with a predominance of inhibition of collagenolysis and collagen accumulation (brosis), which could explain passive diastolic dysfunction in patients with HCM. MMPs are probably associated with mechanisms of remodelling in patients with HCM and the progression to systolic dysfunction and heart failure, increase of LV dimension and wall thinning.

F. Cambronero et al.

levels are also signicantly higher in HCM patients with heart failure compared to the other three groups (Table 3).114

Myonecrosis markers: troponin

Troponins I and T are very sensitive and specic indicators of cardiac myocyte injury, and have been used in the diagnosis and prognosis of acute coronary syndromes. Sato et al.115 compared HCM patients with normal and altered troponin levels and correlated the differences with echocardiographic ndings, and higher troponin levels were associated with a signicantly lower fractional shortening and thicker interventricular septum. Of note, 4 of 12 patients with increased troponin T experienced end stage dilated HCM, suggesting that an increase in troponin T concentration in HCM may be an indicator of subclinical myocyte injury and/or progression to dilated HCM. In another paper, Pop et al.116 showed that increased troponin release may be present in patients with HCM secondary to exercise, which is reduced with b-blockade (Table 4). The mechanism of myocyte injury in HCM is unknown. Abnormal troponin levels may be caused by relative myocardial ischaemia due to the imbalance between a hypertrophic heart and the insufcient coronary blood supply due to abnormal vessels. The other possibility is that myocyte abnormalities determined by gene mutation are causing myocyte injury. Troponins could be useful in determining the patients with higher risk to develop dilated phase of HCM and the effects of drug treatment on the evolution of HCM, but further studies are necessary.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Hormones
Aldosterone is a steroid hormone produced by the glomerulosa zone of adrenal cortex in response to several factors, the most important of which is angiotensin II. Aldosterone has been implicated in several functions including the regulation of sodium and potassium plasma concentrations as well as in cardiac hypertrophy, brosis, and heart failure (Table 3).109,110 Tsybouleva et al.107 showed that aldosterone is a major link between sarcomeric mutations and cardiac phenotype in HCM, although mean serum aldosterone levels were not signicantly different between HCM and control subjects; however, myocardial aldosterone and cardiac aldosterone synthase (CYP11B2) mRNA levels were increased four- and seven-fold respectively, when compared with normal hearts. Aldosterone induced expression of cardiac hypertrophic markers in rat cardiomyocytes and has a probrotic response in rat cardiac broblasts, inducing the expression of TGF-b1, a major probrotic factor and in turn, the production of collagens.107 Blockade of mineral corticoid receptor with spironolactone in a cTnTQ92 mutant mouse model of HCM normalized myocardial collagen content, attenuated myocyte disarray, and improved diastolic function.107 Myocyte disarray, the pathological hallmark of HCM, seems to be due to the disruption of cadherin-mediated myocytemyocyte adhesion at the adherens junction, which is reduced by spironolactone treatment.107

Wall stress markers: natriuretic peptides (Table 4)

Atrial (ANP) and BNP are stable peptides that are synthesized predominantly in the atria and left ventricle, respectively, in response to elevated wall tension. Plasma levels of the peptides correlate positively with cardiac lling pressures, making them excellent markers for the presence of LV dysfunction and abnormal LV wall stress.117,118 In various studies, plasma ANP119,120 and BNP47,121 123 levels were signicantly increased in HCM compared with normal subjects. ANP does not correlate with symptoms or echocardiographically derived indices of LV structure or diastolic function.120 On the other hand, BNP levels correlate positively with symptoms of heart failure, hypertrophy severity, and Doppler echocardiographic signs of LV diastolic dysfunction.86,120,124,125,126 BNP has been used to predict clinical course (being worse with higher levels),127 peak oxygen consumption, and functional impairment.128 In HCM patients, both BNP and ANP are signicantly higher in the subgroup that shows evidence of obstruction, and both correlate positively with left intraventricular pressure gradient.121,129 BNP in obstructive and non-obstructive HCM is 85-fold and 23-fold times elevated, respectively, compared with controls.121,129 Khan and Talwar130 have even proposed the measurement of BNP as an effective measure for screening of HCM, especially in children where the sensitivity of ECG and echocardiography alone is relatively low. As prognostic factors, plasma levels of NT-pro-BNP and ANP are independent predictors of cardiovascular events in patients with HCM.127,131 Elevated NT-pro-BNP levels are associated with incipient LV remodelling and brosis assessed by cardiac magnetic resonance, could be

Growth factors
IGF-1 has short-term insulin-like metabolic effects and long-term growth factor-like effects on cell proliferation and differentiation of various cell types. IGF-1 is produced in different cell types and it acts locally in both autocrine and paracrine fashions.111,112 Several reports have shown that the expressions of the mRNA and protein levels for IGF-1 are increased in the myocardium of HCM.113 IGF-1 levels were signicantly higher in patients with obstructive or non-obstructive HCM, and lower in patients with heart failure-HCM when compared with healthy control subjects.113 IGFBP-1 (insulin-like growth factor binding protein 1)

Biomarkers of pathophysiology in HCM

147

Table 4 Wall stress and necrosis biomarkers

References

...............................................................................................................................................................................
et al. (2008)67 Paya Ogino et al. 200486 NT-pro-BNP ANP, BNP 120 patients with HCM: 83 HCM with LGE by CMR 40 patients with HCM, 35 with hypertension, and 15 controls 30 HCM patients HCM patients with LGE have higher levels of NT-pro-BNP ANP and BNP were signicantly higher in HCM than hypertensive and controls. BNP concentration signicantly correlated with left intraventricular pressure gradient in HCM Patients with positive troponin levels ( . 0.02 ng/mL) had a FS signicantly lower and interventricular septum signicantly thicker. FS and VST decreased signicantly between baseline and the end of a mean follow up in patients with positive troponin levels Elevated troponin levels after physical exercise that was diminished after the use of a b-blocker In HCM patients, NT-pro-BNP levels correlate directly with NYHA functional class, septal thickness, maximal wall thickness, left ventricular hypertrophy score, left atrial size, and mitral deceleration time and inversely with left atrial fractional shortening The concentration of ANP was signicantly higher in patients with HCM than controls Elevation of the BNP plasma level vs. control subjects, even higher in HCM. Elevation of the ANP plasma level vs. control subjects was mild Increased levels of BNP and ANP in HCM patients compared with controls and patients with left ventricular hypertrophy Elevated NT-pro-BNP levels in HCM patients compared to controls that are associated with incipient LV remodelling Plasma BNP is independently related to the presence and magnitude of heart failure symptoms in patients with HCM The plasma BNP level correlated with Tei index in non-obstructive HCM In HCM, plasma NT-pro-BNP levels are elevated and correlate positively with symptoms of heart failure, hypertrophy severity, and Doppler echocardiographic signs of left ventricular diastolic dysfunction NT-pro-BNP identies patients at risk of cardiovascular death and hospitalization for worsening heart failure symptoms NT-pro-BNP levels correlate with peak oxygen consumption in HCM Plasma BNP levels were higher in the HOCM patients compared with HNCM, hypertensive heart disease, AS, and normal groups PAF and CAF groups showed signicantly higher plasma BNP levels than the NSR group. PAF is independently associated with high levels of BNP Progression to end-stage of HCM is characterized by further increase of myocardial and plasma BNP

Biomarker

Patient population

Findings

Sato et al. (2003)115

Troponin T

Pop et al. (2006)116 Brito et al. (2004)117

Troponin T NT-pro-BNP

7 HCM patients 53 patients with HCM, 92 healthy relatives with no disease expression, 46 healthy volunteers

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Fahy et al. (1996)120 Hasegawa et al. (1993)121

ANP BNP, ANP

14 HCM patients and 17 healthy controls. 39 HCM and 10 control subjects

Yoshibayashi et al. (1993)122 Magga et al. (2008)123 Maron et al. (2004)124 Okawa et al. (2005)125 Arteaga et al. (2005)126

BNP, ANP NT-pro-BNP BNP BNP NT-pro-BNP

15 HNCM, 35 patients with LV hypertrophy, and 10 normal controls 17 healthy controls and 24 patients HNCM 107 consecutive HCM patients 45 HCM patients and 20 normal control subjects 71 HCM patients and 40 healthy subjects.

Mutlu et al. (2006)127 Thaman et al. (2006)128 Nishigaki et al. (1996)129

NT-pro-BNP NT-pro-BNP BNP and ANP BNP

80 HCM patients 171 HCM patients 15 HOCM, 15 HNCM, 10 AS, 10 hypertensive, and 10 normal subjects 94 HNCM: 14 CAF, 18 PAF, and 65 NSR

Matsuura et al. (2008)132

Pieroni et al. (2007)135

BNP

40 HCM patients

ANP, atrial natriuretic peptide; AS, aortic stenosis; BNP, brain natriuretic peptide; CAF, chronic atrial brillation; CMR, cardiac resonance magnetic; FS, fractional shortening; HCM, hypertrophic cardiomyopathy; HOCM, hypertrophic obstructive cardiomyopathy; HNCM, hypertrophic non-obstructive cardiomyopathy; LGE, late Gadolinium enhancement; NSR, normal sinus rhythm; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide; PAF, paroxysmal atrial brillation.

used to diagnose insidious unfavourable LV remodelling and higher risk of sudden death in HCM.67,123 A recent paper132 proposes the clinical use of plasma BNP levels to identify non-obstructive HCM patients who are at risk of paroxysmal atrial brillation. As BNP is a marker of disease progression in non-obstructive HCM, serial assessment may provide non-invasive recognition of haemodynamic deterioration.105,132

A proposed pathophysiological model linking biomarkers in hypertrophic cardiomyopathy

Trophic and mitotic factors as angiotensin II, IGF-1, TGF-b, endothelin 1, and IL-6 produced in the patients will activate

148
downstream signalling cascade that converge upon intracellular Ca and its downstream phosphatase Ca sensor protein calcineurin (Figure 1). This protein dephosphorylates a variety of cellular substrates, including nuclear factors of activated T cells (NFAT) and myocyte enhancer factor-2 (MEF2) that in turn will activate transcriptional processes inducing hypertrophy through the activation of foetal isoforms of proteins133 (Figure 1). The study of promoter regions of MMPs and TIMPs has allowed us to identify transcription factors that control the expression of these two families of proteins.134 The same trophic and mitotic factors mentioned in the previous paragraph plus aldosterone and TNF-a, through parallel pathways (Figure 1), activate transcription factors (AP-1, STATs, NF-k b, and SMADs) that control the expression via activation/inhibition of MMPs and TIMPS. The hypothesis of energy depletion with the consequent accumulation of Ca inside the cells by-pass all, therefore, mentioned signalling pathways and activate directly the calciumdependent nal common pathway. It is possible that all the trophic and mitotic molecules are induced and mediate further development of phenotypic characteristics, thus increasing the incidence of brosis and hypertrophy but without being the primary mechanism of the disease. Only small improvements in the phenotypic manifestations of the disease have been observed in animals treated with losartan,108 simvastatin,134 and spironolactone.105 It will be more important and effective to treat the calciumdependent nal common pathway.

F. Cambronero et al.

Conclusions
The study of biomarkers in experimental models and clinical studies of HCM has given insight to possible disease mechanisms, but many more studies are clearly required. Moreover, the study of biomarkers in animal models and in patients with HCM-related mutations before and after all the phenotypic characteristics of the disease have appeared, will help identify molecules that could be active and trigger hypertrophy and/or brosis. Currently, biomarkers can be used as a diagnostic tool in HCM as well as to determine prognosis factors or progression of the disease. Finally, the study of biomarkers and their signalling pathways in HCM has enabled the investigation of new therapeutic strategies with the aim of altering phenotype rather than simply targeting the palliation of symptoms.

Funding
n para la Dr Hernandez-Romero is supported by a grant from Fundacio n e Investigacio n Sanitarias de la Regio n de Murcia, Murcia, Spain. Formacio Conict of interest: none declared.

References
1. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic cardiomyopathy: the interrelation of disarray, brosis, and small vessel disease. Heart 2000;84:476 482. 2. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 1995;92:785789.

3. Ho CY, Seidman CE. A contemporary approach to hypertrophic cardiomyopathy. Circulation 2006;113:e858 e862. 4. Hardarson T, De la Calzada CS, Curiel R, Goodwin JF. Prognosis and mortality of hypertrophic obstructive cardiomyopathy. Lancet 1973;2:1462 1467. 5. Furlan AJ, Craciun AR, Raju NR, Hart N. Cerebrovascular complications associated with idiopathic hypertrophic subaortic stenosis. Stroke 1984;15:282 284. 6. Maron BJ. Sudden death in young athletes. N Engl J Med 2003;349:1064 1075. 7. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287: 1308 1320. 8. Armstrong EJ, Morrow DA, Sabatine MS. Inammatory biomarkers in acute coronary syndromes: part I: introduction and cytokines. Circulation 2006;113: e72 e75. 9. Armstrong EJ, Morrow DA, Sabatine MS. Inammatory biomarkers in acute coronary syndromes: part II: acute-phase reactants and biomarkers of endothelial cell activation. Circulation 2006;113:e152 e155. 10. Armstrong EJ, Morrow DA, Sabatine MS. Inammatory biomarkers in acute coronary syndromes: part III: biomarkers of oxidative stress and angiogenic growth factors. Circulation 2006;113:e289 e292. 11. Armstrong EJ, Morrow DA, Sabatine MS. Inammatory biomarkers in acute coronary syndromes: part IV: matrix metalloproteinases and biomarkers of platelet activation. Circulation 2006;113:e382e385. 12. Moe GW. B-type natriuretic peptide in heart failure. Curr Opin Cardiol 2006;21: 208 214. 13. Ferrans VJ, Morrow AG, Roberts WC. Myocardial ultrastructure in idiopathic hypertrophic subaortic stenosis. A study of operatively excised left ventricular outow tract muscle in 14 patients. Circulation 1972;45:769 792. 14. Maron BJ. Hypertrophic cardiomyopathy. Lancet 1997;350:127 133. 15. Factor SM, Butany J, Sole MJ, Wigle ED, Williams WC, Rojkind M. Pathologic brosis and matrix connective tissue in the subaortic myocardium of patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1991;17:1343 1351. 16. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (small vessel) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol 1986;8: 545 557. 17. Tanaka M, Fujiwara H, Onodera T, Wu DJ, Hamashima Y, Kawai C. Quantitative analysis of myocardial brosis in normals, hypertensive hearts, and hypertrophic cardiomyopathy. Br Heart J 1986;55:575581. 18. Schwartzkopff B, Mundhenke M, Strauer BE. Alterations of the architecture of subendocardial arterioles in patients with hypertrophic cardiomyopathy and impaired coronary vasodilator reserve: a possible cause for myocardial ischemia. J Am Coll Cardiol 1998;31:1089 1096. 19. Tanaka M, Fujiwara H, Onodera T, Wu DJ, Matsuda M, Hamashima Y, Kawai C. Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy. Circulation 1987;75:1130 1139. 20. Takemura G, Takatsu Y, Fujiwara H. Luminal narrowing of coronary capillaries in human hypertrophic hearts: an ultrastructural morphometrical study using endomyocardial biopsy specimens. Heart 1998;79:78 85. 21. Suzuki H, Koba S, Katagiri T, Takeyama Y, Suwa Y. Ultrastructural changes of blood capillaries in patients with microvascular angina, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Am J Cardiovasc Pathol 1995;5:19 26. 22. Bonne G, Carrier L, Richard P, Hainque B, Schwartz K. Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ Res 1998;83:580 593. 23. Blanchard E, Seidman C, Seidman JG, LeWinter M, Maughan D. Altered crossbridge kinetics in the alphaMHC403/ mouse model of familial hypertrophic cardiomyopathy. Circ Res 1999;84:475 483. 24. Lin D, Bobkova A, Homsher E, Tobacman LS. Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy. J Clin Invest 1996;97:2842 2848. 25. Yang Q, Sanbe A, Osinska H, Hewett TE, Klevitsky R, Robbins J. A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy. J Clin Invest 1998;102:1292 1300. 26. Tardiff JC, Factor SM, Tompkins BD, Hewett TE, Palmer BM, Moore RL, Schwartz S, Robbins J, Leinwand LA. A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. J Clin Invest 1998;101:2800 2811. 27. Yang Q, Sanbe A, Osinska H, Hewett TE, Klevitsky R, Robbins J. In vivo modeling of myosin binding protein C familial hypertrophic cardiomyopathy. Circ Res 1999; 85:841 847. 28. Kim SJ, Iizuka K, Kelly RA, Geng YJ, Bishop SP, Yang G, Kudej A, McConnell BK, Seidman CE, Seidman JG, Vatner SF. An alpha-cardiac myosin heavy chain gene mutation impairs contraction and relaxation function of cardiac myocytes. Am J Physiol 1999;276:H1780 H1787. 29. Spindler M, Saupe KW, Christe ME, Sweeney HL, Seidman CE, Seidman JG, Ingwall JS. Diastolic dysfunction and altered energetics in the alphaMHC403/

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Biomarkers of pathophysiology in HCM

149
53. Hirota H, Yoshida K, Kishimoto T, Taga T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci USA 1995;92: 4862 4866. 54. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJ, Sabbadini RA. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 1996;98:2854 2865. 55. Mann DL, Young JB. Basic mechanisms in congestive heart failure. Recognizing the role of proinammatory cytokines. Chest 1994;105:897 904. 56. Narula J, Haider N, Arbustini E, Chandrashekhar Y. Mechanisms of disease: apoptosis in heart failure-seeing hope in death. Nat Clin Pract Cardiovasc Med 2006;3:681 688. 57. Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 2005;33: 114 119. 58. Schieffer B, Schieffer E, Hilker-Kleiner D, Hilker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inammation and plaque instability. Circulation 2000;101:1372 1378. 59. Yokoyama T, Nakano M, Bednarczyk JL, McIntyre BW, Entman M, Mann DL. Tumor necrosis factor-a provokes a hypertrophic growth response in adult cardiac myocytes. Circulation 1997;95:1247 1252. 60. Tartaglia LA, Ayres TM, Wong GH, Goeddel DV. A novel domain within the 55 kd TNF receptor signals cell death. Cell 1993;74:845 853. 61. Li YY, Feng YQ, Kadokami T, McTiernan CF, Draviam R, Watkins SC, Feldman AM. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy. Proc Natl Acad Sci USA 2000;97:12746 12751. 62. Kapadia SR, Oral H, Lee J, Nakano M, Taffet GE, Mann DL. Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res 1997;81:187 195. 63. Patel R, Lim DS, Reddy D, Nagueh SF, Lutucuta S, Sole MJ, Zoghbi WA, Quin ones MA, Roberts R, Marian AJ. Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. J Mol Cell Cardiol 2000;32:2369 2377. 64. Penicka M, Gregor P, Krupicka J, Jira M. Tumour necrosis factor-alpha soluble receptors type I are related to symptoms and left ventricular function in hypertrophic cardiomyopathy. Can J Cardiol 2001;17:777 784. 65. Packer M. Is tumor necrosis factor an important neurohormonal mechanism in chronic heart failure? Circulation 1995;92:1379 1382. 66. Dimitrow PP, Undas A, Bober M, Tracz W, Dubiel JS. Obstructive hypertrophic cardiomyopathy is associated with enhanced thrombin generation and platelet activation. Heart 2008;94:e21. E, Mar n F, Gonza lez J, Gimeno J, Feliu E, Romero A, Ruiz-Espejo F, 67. Paya n V, Climent V, de la Morena G, Valde s M. Variables associated with conRolda trast enhanced cardiovascular magnetic resonance in hypertrophic cardiomyopathy: clinical implications. J Card Fail 2008;14:414 419. 68. Sun M, Chen M, Dawood F, Zurawska U, Li JY, Parker T, Kassiri Z, Kirshenbaum LA, Arnold M, Khokha R, Liu PP. Tumor necrosis factor-alpha mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation 2007;115:1398 1407. 69. Watanabe-Fukunaga R, Brannan CI, Itoh N, Yonehara S, Copeland NG, Jenkins NA, Nagata S. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 1992;148:1274 1279. 70. Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 1994;263:1759 1762. 71. Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, Motoyoshi K, Mizuki M, Tagawa S, Ohga S, Hatake K, Drummond AH, Nagata S. Fas ligand in human serum. Nat Med 1996;2:317 322. 72. Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993;75: 1169 1178. 73. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356: 830 840. 74. Kodama K, Shigematsu Y, Hamada M, Hiwada K, Kazatani Y, Matsuzaki K, Murakami E. The effect of coronary vasospasm on the direction of ST-segment deviation in patients with both hypertrophic cardiomyopathy and vasospastic angina. Chest 2000;117:1300 1308. 75. Misawa K, Nitta Y, Matsubara T, Oe K, Kiyama M, Shimizu M, Mabuchi H. Difference in coronary blood ow dynamics between patients with hypertension and those with hypertrophic cardiomyopathy. Hypertens Res 2002;25:711 716. 76. Dimitrow PP, Krzanowski M, Grodecki J, Malecka B, Lelakowski J, Kawecka-Jaszcz K, Szczeklik A, Dubiel JS. Verapamil improves the pacing-induced

30. 31.

32.

33.

34.

35. 36.

37.

38. 39.

40.

41.

42. 43. 44. 45. 46. 47.

48.

49.

50.

51.

52.

mouse model of familial hypertrophic cardiomyopathy. J Clin Invest 1998;101: 17751783. Marian AJ. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy. Lancet 2000;355:58 60. Crilley JG, Boehm EA, Blair E, Rajagopalan B, Blamire AM, Styles P, McKenna WJ, Ostman-Smith I, Clarke K, Watkins H. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol 2003;41:1776 1782. Elliott K, Watkins H, Redwood CS. Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy. J Biol Chem 2000;275:22069 22074. Michele DE, Albayya FP, Metzger JM. Direct, convergent hypersensitivity of calcium-activated force generation produced by hypertrophic cardiomyopathy mutant alpha-tropomyosins in adult cardiac myocytes. Nat Med 1999;5: 14131417. Muthuchamy M, Pieples K, Rethinasamy P, Hoit B, Grupp IL, Boivin GP, Wolska B, Evans C, Solaro RJ, Wieczorek DF. Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction. Circ Res 1999;85:47 56. Ashraan H, Redwood C, Blair E, Watkins H. Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion. Trends Genet 2003;19:263 268. Merante F, Tein I, Benson L, Robinson BH. Maternally inherited hypertrophic cardiomyopathy due to a novel T-to-C transition at nucleotide 9997 in the mitochondrial tRNA(glycine) gene. Am J Hum Genet 1994;55:437 446. Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, Schapira AH. Decit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA 1999;96:11492 11495. Tanaka T, Sohmiya K, Kawamura K. Is CD36 deciency an etiology of hereditary hypertrophic cardiomyopathy? J Mol Cell Cardiol 1997;29:121 127. Aoyama T, Souri M, Ushikubo S, Kamijo T, Yamaguchi S, Kelley RI, Rhead WJ, Uetake K, Tanaka K, Hashimoto T. Purication of human very-long-chain acylcoenzyme A dehydrogenase and characterization of its deciency in seven patients. J Clin Invest 1995;95:2465 2473. Blair E, Redwood C, Ashraan H, Oliveira M, Broxholme J, Kerr B, Salmon A, Ostman-Smith I, Watkins H. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 2001;10:1215 1220. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, Ahmad F, Lozado R, Shah G, Fananapazir L, Bachinski LL, Roberts R. Identication of a gene responsible for familial WolffParkinson White syndrome. N Engl J Med 2001;344:1823 1831. Frey N, McKinsey TA, Olson EN. Decoding calcium signals involved in cardiac growth and function. Nat Med 2000;6:1221 1227. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 2003;65:45 79. Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation 2004;109:1580 1589. Chiu C et al. Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 2007;43:337 343. Tsoutsman T, Lam L, Semsarian C. Genes, calcium and modifying factors in hypertrophic cardiomyopathy. Clin Exp Pharmacol Physiol 2006;33:139 145. Zen K, Irie H, Doue T, Takamiya M, Yamano T, Sawada T, Azuma A, Matsubara H. Analysis of circulating apoptosis mediators and proinammatory cytokines in patients with idiopathic hypertrophic cardiomyopathy: comparison between nonobstructive and dilated-phase hypertrophic cardiomyopathy. Int Heart J 2005;46:231 244. Hogye M, Mandi Y, Csanady M, Sepp R, Buzas K. Comparison of circulating levels of interleukin-6 and tumor necrosis factor-alpha in hypertrophic cardiomyopathy and in idiopathic dilated cardiomyopathy. Am J Cardiol 2004;94:249 251. Nagueh SF, Stetson SJ, Lakkis NM, Killip D, Perez-Verdia A, Entman ML, Spencer WH 3rd, Torre-Amione G. Decreased expression of tumor necrosis factor-alpha and regression of hypertrophy after nonsurgical septal reduction therapy for patients with hypertrophic obstructive cardiomyopathy. Circulation 2001;103:1844 1850. Buzas K, Megyeri K, Hogye M, Csanady M, Bogats G, Mandi Y. Comparative study of the roles of cytokines and apoptosis in dilated and hypertrophic cardiomyopathies. Eur Cytokine Netw 2004;15:53 59. Mandi Y, Hogye M, Talha EM, Skolak E, Csanady M. Cytokine production and antibodies against heat shock protein 60 in cardiomyopathies of different origins. Pathobiology 2000;68:150 158. Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, Thompson M, Giroir B. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 1998;97:1375 1381.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

150
vasodilatation in symptomatic patients with hypertrophic cardiomyopathy. Int J Cardiol 2002;83:239 247. Dimitrow PP, Krzanowski M, Nizankowski R, Szczeklik A, Dubiel JS. Verapamil improves the response of coronary vasomotion to cold pressor test in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy. Cardiovasc Drugs Ther 1999;13:259 264. Knaapen P, Germans T, Camici PG, Rimoldi OE, ten Cate FJ, ten Berg JM, Dijkmans PA, Boellaard R, van Dockum WG, Gotte MJ, Twisk JW, van Rossum AC, Lammertsma AA, Visser FC. Determinants of coronary microvascular dysfunction in symptomatic hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 2008;294:H986 H993. Lip GY, Foster W, Blann AD. Plasma von Willebrand factor levels and surrogates of atherosclerosis. J Thromb Haemost 2005;3:659661. Lip GY, Blann A. von Willebrand factor: a marker of endothelial dysfunction in vascular disorders? Cardiovasc Res 1997;34:255 265. Varol E, Ozaydin M, Sahin M, Altinbas A, Kosar F. vWf levels as a circulating marker of endothelial dysfunction in patients with hypertrophic cardiomyopathy. Indian Heart J 2005;57:655657. Dimitrow PP, Undas A, Bober M, Tracz W, Dubiel JS. Plasma biomarkers of endothelial dysfunction in patients with hypertrophic cardiomyopathy. Pharmacol Rep 2007;59:715 720. Stroud RE, Deschamps AM, Lowry AS, Hardin AE, Mukherjee R, Lindsey ML, Ramamoorthy S, Zile MR, Spencer WH, Spinale FG. Plasma monitoring of the myocardial specic tissue inhibitor of metalloproteinase-4 after alcohol septal ablation in hypertrophic obstructive cardiomyopathy. J Card Fail 2005;11: 124 130. Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specic genes in cultured neonatal rat cardiomyocytes. Circ Res 1991; 69:209 215. Hasegawa K, Fujiwara H, Koshiji M, Inada T, Ohtani S, Doyama K, Tanaka M, Matsumori A, Fujiwara T, Shirakami G, Hosoda K, Nakao K, Sasayama S. Endothelin-1 and its receptor in hypertrophic cardiomyopathy. Hypertension 1996;27:259 264. Ogino K, Ogura K, Kinugawa T, Osaki S, Kato M, Furuse Y, Kinugasa Y, Tomikura Y, Igawa O, Hisatome I, Shigemasa C. Neurohumoral proles in patients with hypertrophic cardiomyopathy: differences to hypertensive left ventricular hypertrophy. Circ J 2004;68:444 450. Ito H, Hiroe M, Hirata Y, Fujisaki H, Adachi S, Akimoto H, Ohta Y, Marumo F. Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload. Circulation 1994;89:2198 2203. Yorikane R, Sakai S, Miyauchi T, Sakurai T, Sugishita Y, Goto K. Increased production of endothelin-1 in the hypertrophied rat heart due to pressure overload. FEBS Lett 1993;332:31 34. Yarom R, Lewis BS, Lijovetzky G, Havivi Y, Chandler JA. Platelet studies in patients with hypertrophic cardiomyopathy. Cardiovasc Res 1982;16:324 330. Riazanov AS, Gabbasov ZA, Iurenev AP. Platelet aggregation in patients with hypertrophic cardiomyopathy. Ter Arkh 2000;72:36 38. Heldin CH, Westermark B. Platelet-derived growth factor: mechanism of action and possible in vivo function. Cell Regul 1990;1:555 566. Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell 1986;46:155169. Suzuki J, Baba S, Ohno I, Endoh M, Nawata J, Miura S, Yamamoto Y, Sekiguchi Y, Takita T, Ogata M, Tamaki K, Ikeda J, Shirato K. Immunohistochemical analysis of platelet-derived growth factor-B expression in myocardial tissues in hypertrophic cardiomyopathy. Cardiovasc Pathol 1999;8:223 231. Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K. The coagulation system is activated in idiopathic cardiomyopathy. J Am Coll Cardiol 1995;25:1634 1640. Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995;77:863 868. Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991;5:2145 2154. Deschamps AM, Spinale FG. Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res 2006;69:666 676. Fassbach M, Schwartzkopff B. Elevated serum markers for collagen synthesis in patients with hypertrophic cardiomyopathy and diastolic dysfunction. Z Kardiol 2005;94:328 335. Lombardi R, Betocchi S, Losi MA, Tocchetti CG, Aversa M, Miranda M, DAlessandro G, Cacace A, Ciampi Q, Chiariello M. Myocardial collagen turnover in hypertrophic cardiomyopathy. Circulation 2003;108:1455 1460. Noji Y, Shimizu M, Ino H, Higashikata T, Yamaguchi M, Nohara A, Horita T, Shimizu K, Ito Y, Matsuda T, Namura M, Mabuchi H. Increased circulating

F. Cambronero et al.

77.

101. 102.

78.

103.

79. 80. 81.

104.

105.

82.

106.

83.

107.

84.

108.

85.

109.

86.

110.

87.

111. 112.

88.

113.

89. 90. 91. 92. 93.

114.

115.

116.

117.

94.

118.

95. 96. 97.

119.

120.

98.

121.

99.

122.

100.

matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction. Circ J 2004;68:355 360. Burlew BS, Weber KT. Cardiac brosis as a cause of diastolic dysfunction. Herz 2002;27:9298. n V, Mar n F, Gimeno J, Ru z-Espejo F, Gonzalez J, Feliu J, Rolda a-Honrubia A, Saura D, de la Morena G, Valde s M, Vicente V. Matrix metalGarc loproteinases and tissue remodelling in hypertrophic myocardiopathy. Am Heart J 2008;156:85 91. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and signicance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol 2000;35:36 44. Bauersachs J, Stork S, Kung M, Waller C, Fidler F, Hoyer C, Frantz S, Weidemann F, Ertl G, Angermann CE. HMG CoA reductase inhibition and left ventricular mass in hypertrophic cardiomyopathy: a randomized placebocontrolled pilot study. Eur J Clin Invest 2007;37:852 859. Marian AJ, Senthil V, Chen SN, Lombardi R. Antibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation. J Am Coll Cardiol 2006;47:827 834. Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ. Angiotensin II blockade reverses myocardial brosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 2001;103: 789 791. Tsybouleva N, Zhang L, Chen S, Patel R, Lutucuta S, Nemoto S, DeFreitas G, Entman M, Carabello BA, Roberts R, Marian AJ. Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation 2004; 109:1284 1291. Araujo AQ, Arteaga E, Ianni BM, Buck PC, Rabello R, Mady C. Effect of Losartan on left ventricular diastolic function in patients with nonobstructive hypertrophic cardiomyopathy. Am J Cardiol 2005;96:1563 1567. Le Menuet D, Isnard R, Bichara M, Viengchareun S, Muffat-Joly M, Walker F, Zennaro MC, Lombes M. Alteration of cardiac and renal functions in transgenic mice overexpressing human mineralocorticoid receptor. J Biol Chem 2001;276: 38911 38920. Qin W, Rudolph AE, Bond BR, Rocha R, Blomme EA, Goellner JJ, Funder JW, McMahon EG. Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res 2003;93:69 76. Le Roith D. Insulin-like growth factors. N Engl J Med 1997;336:633 640. Ren J, Samson WK, Sowers JR. Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. J Mol Cell Cardiol 1999;31:2049 2061. Li G, Li RK, Mickle DA, Weisel RD, Merante F, Ball WT, Christakis GT, Cusimano RJ, Williams WG. Elevated insulin-like growth factor-I and transforming growth factor-beta 1 and their receptors in patients with idiopathic hypertrophic obstructive cardiomyopathy. A possible mechanism. Circulation 1998; 98:II144 II149. discussion II149 II150. Saeki H, Hamada M, Hiwada K. Circulating levels of insulin-like growth factor-1 and its binding proteins in patients with hypertrophic cardiomyopathy. Circ J 2002;66:639 644. Sato Y, Taniguchi R, Nagai K, Makiyama T, Okada H, Yamada T, Matsumori A, Takatsu Y. Measurements of cardiac troponin T in patients with hypertrophic cardiomyopathy. Heart 2003;89:659660. Pop GA, Cramer E, Timmermans J, Bos H, Verheugt FW. Troponin I release at rest and after exercise in patients with hypertrophic cardiomyopathy and the effect of betablockade. Arch Cardiol Mex 2006;76:415 418. Brito D, Matias JS, Sargento L, Cabral MJ, Madeira HC. Plasma N-terminal probrain natriuretic peptide: a marker of left ventricular hypertrophy in hypertrophic cardiomyopathy. Rev Port Cardiol 2004;23:1557 1582. Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain natriuretic peptide as an indicator for angiotensin-converting-enzyme inhibition after myocardial infarction. Lancet 1993;341:1109 1113. Derchi G, Bellone P, Chiarella F, Randazzo M, Zino V, Vecchio C. Plasma levels of atrial natriuretic peptide in hypertrophic cardiomyopathy. Am J Cardiol 1992; 70:1502 1504. Fahy GJ, McCreery CJ, Osullivan F, Keenan AK, Quigley PJ, Maurer BJ. Plasma atrial natriuretic peptide is elevated in patients with hypertrophic cardiomyopathy. Int J Cardiol 1996;55:149155. Hasegawa K, Fujiwara H, Doyama K, Miyamae M, Fujiwara T, Suga S, Mukoyama M, Nakao K, Imura H, Sasayama S. Ventricular expression of brain natriuretic peptide in hypertrophic cardiomyopathy. Circulation 1993;88: 372 380. Yoshibayashi M, Kamiya T, Saito Y, Matsuo H. Increased plasma levels of brain natriuretic peptide in hypertrophic cardiomyopathy. N Engl J Med 1993;329: 433 434.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013

Biomarkers of pathophysiology in HCM

151
peptide is a special feature of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 1996;28:1234 1242. Khan K, Talwar S. Screening for familial hypertrophic cardiomyopathy using brain natriuretic peptide. Eur Heart J 1999;20:550. Kitaoka H, Hitomi N, Yabe T, Furuno T, Doi YL. Cardiovascular events and plasma atrial natriuretic peptide level in patients with hypertrophic cardiomyopathy. Am J Cardiol 2001;87:1318 1320. Matsuura H, Murakami T, Hina K, Yamamoto K, Kawamura H, Sogo T, Shinohata R, Usui S, Ninomiya Y, Kusachi S. Association of elevated plasma B-type natriuretic peptide levels with paroxysmal atrial brillation in patients with nonobstructive hypertrophic cardiomyopathy. Clin Biochem 2008;41: 134 139. Kai H, Muraishi A, Sugiu Y, Nishi H, Seki Y, Kuwahara F, Kimura A, Kato H, Imaizumi T. Expression of proto-oncogenes and gene mutation of sarcomeric proteins in patients with hypertrophic cardiomyopathy. Circ Res 1998;83: 594 601. Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, Quinones MA, Zoghbi WA, Entman ML, Roberts R, Marian AJ. Simvastatin induces regression of cardiac hypertrophy and brosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 2001;104:317324. Pieroni M, Bellocci F, Sanna T, Verardo R, Ierardi C, Maseri A, Frustaci A, Crea F. Increased brain natriuretic peptide secretion is a marker of disease progression in nonobstructive hypertrophic cardiomyopathy. J Card Fail 2007;13:380 388.

123. Magga J, Sipola P, Vuolteenaho O, Risteli J, Ja a skela inen P, Peuhkurinen K, Kuusisto J. Signicance of plasma levels of N-Terminal pro-B-type natriuretic peptide on left ventricular remodeling in non-obstructive hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the tropomyosin gene. Am J Cardiol 2008;101:1185 1190. 124. Maron BJ, Tholakanahalli VN, Zenovich AG, Casey SA, Duprez D, Aeppli DM, Cohn JN. Usefulness of B-type natriuretic peptide assay in the assessment of symptomatic state in hypertrophic cardiomyopathy. Circulation 2004;109: 984 989. 125. Okawa M, Kitaoka H, Matsumura Y, Kubo T, Yamasaki N, Furuno T, Doi Y. Functional assessment by myocardial performance index (Tei index) correlates with plasma brain natriuretic peptide concentration in patients with hypertrophic cardiomyopathy. Circ J 2005;69:951 957. 126. Arteaga E, Araujo AQ, Buck P, Ianni BM, Rabello R, Mady C. Plasma aminoterminal pro-B-type natriuretic peptide quantication in hypertrophic cardiomyopathy. Am Heart J 2005;150:1228 1232. 127. Mutlu B, Bayrak F, Kahveci G, Degertekin M, Eroglu E, Basaran Y. Usefulness of N-terminal pro-B-type natriuretic peptide to predict clinical course in patients with hypertrophic cardiomyopathy. Am J Cardiol 2006;98:1504 1506. 128. Thaman R, Esteban MT, Barnes S, Gimeno JR, Mist B, Murphy R, Collinson PO, McKenna WJ, Elliott PM. Usefulness of N-terminal pro-B-type natriuretic peptide levels to predict exercise capacity in hypertrophic cardiomyopathy. Am J Cardiol 2006;98:515519. 129. Nishigaki K, Tomita M, Kagawa K, Noda T, Minatoguchi S, Oda H, Watanabe S, Morita N, Nakao K, Fujiwara H. Marked expression of plasma brain natriuretic

130. 131.

132.

133.

134.

135.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on June 29, 2013