Myocardial Remodeling in Hypertension
2018; Lippincott Williams & Wilkins; Volume: 72; Issue: 3 Linguagem: Inglês
10.1161/hypertensionaha.118.11125
ISSN1524-4563
AutoresArantxa González, Susana Ravassa, Begoña López, María U. Moreno, Javier Beaumont, Gorka San José, Ramón Querejeta, Antoni Bayés‐Genís, Javier Dı́ez,
Tópico(s)Heart Failure Treatment and Management
ResumoHomeHypertensionVol. 72, No. 3Myocardial Remodeling in Hypertension Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBMyocardial Remodeling in HypertensionToward a New View of Hypertensive Heart Disease Arantxa González, Susana Ravassa, Begoña López, María U. Moreno, Javier Beaumont, Gorka San José, Ramón Querejeta, Antoni Bayés-Genís and Javier Díez Arantxa GonzálezArantxa González From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) , Susana RavassaSusana Ravassa From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) , Begoña LópezBegoña López From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) , María U. MorenoMaría U. Moreno From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) , Javier BeaumontJavier Beaumont From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) , Gorka San JoséGorka San José From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) , Ramón QuerejetaRamón Querejeta Division of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastián, Spain (R.Q.) , Antoni Bayés-GenísAntoni Bayés-Genís CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) Heart Failure Unit and Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (A.B.-G.) Department of Medicine, Universitat Autònoma de Barcelona, Spain (A.B.-G.) and Javier DíezJavier Díez Correspondence to Javier Díez, Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Ave Pío XII, 55, 31008 Pamplona, Spain. Email E-mail Address: [email protected] From the Program of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra, Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) Instituto de Investigación Sanitaria de Navarra (IDISNA), Pamplona, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., J.D.) CIBERCV, Carlos III Institute of Health, Madrid, Spain (A.G., S.R., B.L., M.U.M., J.B., G.S.J., A.B.-G., J.D.) Department of Cardiology and Cardiac Surgery (J.D.) Department of Nephrology (J.D.), University of Navarra Clinic, University of Navarra, Pamplona, Spain. Originally published23 Jul 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11125Hypertension. 2018;72:549–558Arterial hypertension has been related to multiple outcomes, including cardiac, cerebral, and renal.1 The burden of arterial hypertension remains high, despite the availability of preventive interventions and low-cost, effective antihypertensive medications.2 Therefore, to hypertension burden, beyond new effective health strategies, novel pathophysiological and clinical approaches are also required.Hypertension can cause or is related to various cardiac manifestations, including hypertensive heart disease (HHD) and obstructive coronary heart disease. HHD is defined by the presence of left ventricular (LV) hypertrophy (LVH) or LV systolic and diastolic dysfunction and their clinical manifestations, such as arrhythmias and symptomatic heart failure (HF), appearing in patients with hypertension.3 The classical view of HHD sustains that in conditions of pressure overload because of systemic hypertension and no other cardiac conditions, the LV undergoes extensive growth, leading to LVH, in an attempt to maintain cardiac output, despite the increased afterload imposed by systemic hypertension.4 However, many patients with high blood pressures do not present clinically detectable LVH. Therefore, a new view of HHD is emerging, sustaining that long-term exposure to the hemodynamic stress imposed by hypertension, in combination with the influence of other factors, including comorbidities (eg, obesity, diabetes mellitus, and chronic kidney disease), sex, age, environmental exposures, and genetic factors, eventually leads to LV dysfunction and HF, as well as disturbances of the cardiac rhythm and the myocardial perfusion.5,6 This maladaptive change is likely because of alterations in the structure and the function of the myocardium that result in its remodeling (Figure 1).7,8Download figureDownload PowerPointFigure 1. Pathophysiological continuum of hypertensive heart disease, which describes the progressive process at cardiac and organ tissue levels that manifest as clinical disease in hypertensive patients. BP indicates blood pressure; CFR, coronary flow reserve; CV, cardiovascular; and LVH, left ventricular hypertrophy.This article reviews the major pathological components of myocardial remodeling (MR) in HHD, highlighting their main mechanisms and their impact on cardiac function and the patient's clinical outcome. In addition, we discuss the potential of circulating and imaging biomarkers to recognize diverse phenotypes of MR and track their evolution and review current and future therapies that may allow personalized HHD management targeting MR.Mechanisms and Consequences of MR in HHDMR is a complex process driven by the responses of cardiomyocytes, other resident cells of the myocardium (ie, fibroblasts, endothelial cells, pericytes, and immune cells), and cells recruited from the circulation (eg, immune and inflammatory cells and progenitor cells) to a variety of dynamic stimuli, including mechanical and nonmechanical stimuli, present in conditions of cardiac injury (Figure 1).9 As a consequence, the volume, composition, and biophysiology of cardiomyocytes, the interstitial space, and the coronary microvasculature develop a variety of interrelated alterations, which have a detrimental impact on both cardiac function and clinical outcomes of patients with HHD (Figure 1).9 Therefore, HHD is not just a matter of LVH but the result of complex myocardial, cellular, and tissue arrangements leading to changes in shape or size and function of the LV and other cardiac chambers.10Alterations of CardiomyocytesHypertrophyThe hypertrophic growth of cardiomyocytes is the primary response by which the heart reduces the stress on the LV wall imposed by pressure overload. It entails stimulation of intracellular signaling cascades that activate gene expression and promotes protein synthesis, protein stability, or both, with consequent increases in protein content and in the size and organization of force-generating units (sarcomeres), which, in turn, lead to increased size of individual cardiomyocytes. In many cases, but not necessarily in all, the magnitude of the cardiomyocyte growth will determine that LV mass increases and, thus, LVH develops.11 Moreover, there are changes in sarcomeric proteins that regulate passive cardiomyocyte stiffness (eg, titin).12The mechanisms whereby the mechanical stretch of cardiomyocytes is transduced across the cell membrane are unclear. They probably involve stretch-sensitive ion channels, a Na+/H+ exchanger, integrins and integrin-interacting molecules, and other internal and membrane-bound stretch sensors in a complex network that links the extracellular matrix (ECM), the cytoskeleton, the sarcomere, Ca2+-handling proteins, and the nucleus.13 Local humoral mechanisms activated in conditions of pressure overload, including neurohormones as catecholamines14 and angiotensin II,15 as well as growth factors and cytokines released by noncardiomyocytes, such as fibroblasts, vascular cells, and blood cells,16 can also play a role in activating gene expression and promoting hypertrophy of the cardiomyocyte through specific membrane receptors, although their quantitative importance has not been determined. Because of the inter-relationships of the cardiomyocyte responses to hypertrophic stimuli, they are likely to implicate common mediators. For instance, it has been recently reported that MRTF (myocardin-related transcription factor)-A mediates both mechanical stretch- and neurohormonal stimulation-induced gene and hypertrophic responses in cardiomyocytes.17Experimental evidence supports the notion that the genetic reprogramming associated with cardiomyocyte hypertrophy may no longer be considered as an adaptive process.18 In fact, the genetic changes that accompany cardiomyocyte hypertrophy translate into derangements in energy metabolism, contractile cycle and excitation-contraction coupling, cytoskeleton and membrane properties. These changes determine mechanical dysfunction, which, in turn, provides the basis for the cardiomyocyte malfunction, which is associated with LVH and predisposes the LV to diastolic or systolic dysfunction. For instance, the analysis of experimental findings suggests that the hypertrophic growth of the cardiomyocyte is associated with metabolic changes that result in reduced fatty acid oxidation and increased glucose use, the dysfunction of the mitochondrial electron transport chain, and the subsequent diminution in ATP production.19–21DeathThe hypertrophic response of the cardiomyocyte may be linked to its death. The dysregulation of protein synthesis/processing during the hypertrophic process occurs within the endoplasmic reticulum and, when persistent, causes the accumulation of unfolded proteins, thereby leading to endoplasmic reticulum stress and activation of the unfolded protein response, which, in turn, may induce cardiomyocyte apoptosis.22 For instance, in cardiomyocytes isolated from spontaneously hypertensive rats, which present LVH and dysfunction, an association was found between the activation of unfolded protein response and stimulation of apoptosis.23 Additionally, clinical evidence suggests that in the hypertensive myocardium, there is a deficient activity of the factors that prevent cardiomyocyte apoptosis (eg, gp130/leukemia inhibitory factor receptor survival pathway).24 Therefore, cardiomyocyte apoptosis is abnormally stimulated in patients with HHD, namely in those with HF with reduced ejection fraction (Figure 2).25Download figureDownload PowerPointFigure 2. Distribution of the cardiomyocyte apoptotic index in normotensive subjects and in hypertensive patients classified according to stages of heart failure (HF). Box plots show the 5th and 95th (vertical lines), 25th and 75th (boxes), and 50th (horizontal line) percentile values. Adapted from Ravassa et al25 with permission. Copyright © 2007, The Author.The apoptosis of cardiomyocytes may contribute to the development of LV dysfunction or failure of the hypertensive myocardium through 3 different pathways. First, it has been reported that the loss of cardiomyocytes caused by apoptosis increases in parallel with the deterioration of systolic function in spontaneously hypertensive rats,26 suggesting that apoptosis may serve as one mechanism involved in the loss of contractile mass and function in patients with HHD. Second, some mechanisms that are activated during the apoptotic process may also interfere with the function of viable cardiomyocytes before death.27 Caspase-3 cleaves cardiac myofibrillar proteins, resulting in an impaired force/Ca2+ relationship and myofibrillar ATPase activity. In addition, the release of cytochrome C from mitochondria during apoptosis may impair oxidative phosphorylation and ATP production, thus leading to energetic compromise and functional impairment. Third, in addition to contributing to histological remodeling of the myocardium, cardiomyocyte apoptosis may also contribute to geometric remodeling of the LV chamber. In fact, severe cardiomyocyte apoptosis may lead to side-to-side slippage of cells, mural thinning, and chamber dilatation. Thus, wall restructuring secondary to severe cardiomyocyte apoptosis may create an irreversible state of the myocardium, conditioning progressive dilatation and the continuous deterioration of LV hemodynamics and performance with time.28Although apoptosis is characteristic of HHD, it is important to point out that in the response to any given cardiac injury, various modalities of cell death, including apoptosis, necrosis, and autophagy, are stimulated because they are interconnected by common cellular pathways at multiple points.29 In fact, autophagy is activated during hypertensive LVH, serving to maintain cellular homeostasis.30 Excessive autophagy, however, eliminates essential cellular elements and possibly provokes cardiomyocyte death, which further contributes to MR.Alterations of the Interstitial SpaceInflammationRecent advances clearly show that inflammation and activation of immunity are central drivers in the pathogenesis of hypertension-induced target organ damage.31–33 For instance, experimental evidence supports a substantial involvement of the inflammatory component in hypertensive animal model-dependent cardiac damage, particularly in response to administration of exogenous angiotensin II,34 aldosterone35 and other mineralocorticoids,36 stimulation of the sympathetic nervous system,37 and induction of pressure overload.38 These models are associated in a variable degree with increased permeability of the capillary wall, induction of cytokines and chemokines, and recruitment of inflammatory cells that will infiltrate the myocardium. More recently, cardiomyocytes have emerged as additional key players in orchestrating the inflammatory response in experimental HHD.39 Injured cardiomyocytes release damage-associated molecular pattern molecules, DNA fragments, heat shock proteins, and matricellular proteins, instructing surrounding healthy cardiomyocytes to produce inflammatory mediators (eg, IL [interleukin]-1β, IL-6, macrophage chemoattractant protein-1, and TNF-α [tumor necrosis factor α]), which in turn activate versatile signaling networks within surviving cardiomyocytes and trigger leukocyte activation and recruitment.Recently published studies suggested that the myocardial proinflammatory cytokine milieu, as well as changes in the composition of the ECM, are crucial in the differentiation of resident cardiac fibroblasts to activated myofibroblasts, which initiate the process leading to myocardial fibrosis and its detrimental consequences.40 Accordingly, experimental findings support a substantial role of inflammation in myocardial fibrosis and diastolic dysfunction in hypertensive hearts.41,42 Additionally, a positive correlation between myocardial fibrosis, as well as the amount of myocardial inflammatory cells, and passive myocardial stiffness and diastolic dysfunction was reported in patients (mostly hypertensive) with HF with preserved ejection fraction (HFpEF).43The role of systemic inflammation in MR in hypertension also deserves to be considered. Evidence from experimental models of hypertension and hypertensive patients suggests an imbalance of T effector and regulatory subsets of lymphocytes in hypertension, causing low-grade inflammation and contributing to blood pressure elevation and progression of end-organ damage.44 It has been demonstrated in numerous clinical trials that hypertensive patients commonly have increased plasma concentrations of C-reactive protein45 and proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α.46,47 In addition, circulating levels of CXCR3 (C-X-C chemokine receptor type 3) chemokines, which induce T-cell tissue homing, have been reported to be elevated in hypertensive patients.48 On the other hand, inverse correlations have been reported between regulatory T-cell and C-reactive protein levels in hypertensive patients.49Recent findings in patients and rats with HFpEF support that systemic inflammation induces oxidative stress in the coronary microvascular endothelium that results in reduced myocardial NO availability, leading to reduced protein kinase G in cardiomyocytes, which, therefore, become stiff and hypertrophied.50 A high cardiomyocyte stiffness has been related to a diminished distensibility of the giant cytoskeletal protein titin, whose elastic properties are dynamically modulated by isoform shifts, phosphorylation, and oxidation.51 Of interest, it has been reported that hypertensive patients with HFpEF have markedly increased passive myocardial stiffness because of increases in the contribution of both titin and collagen (Figure 3).12Download figureDownload PowerPointFigure 3. Collagen-dependent and titin-dependent myocardial stress at a sarcomere length (SL) of 2.6 μm for referent control patients (green bars), patients with hypertension but without heart failure (HF; orange bars), and patients with hypertension and HF with preserved ejection fraction (red bars). Total stress is the numeric sum of collagen- and titin-specific data. LV indicates left ventricular. *P<0.01 vs referent control patients, †P<0.01 vs patients with hypertension but without HF. Adapted from Zile et al12 with permission. Copyright © 2015, American Heart Association, Inc.FibrosisMyocardial fibrosis, secondary to the diffuse accumulation of collagen type I and type III fibers within the interstitium and surrounding intramural coronary arteries and arterioles, is one of the key features of hypertensive MR.52 The excess of collagen relative to the mass of cardiomyocytes within the myocardium in HHD is suggested to be the result of a process with several consecutive steps:53 (1) the differentiation of resident fibroblasts and other cell types into myofibroblasts; (2) an increased synthesis and secretion of procollagen, procollagen processing enzymes, and profibrotic growth factors and cytokines by myofibroblasts; (3) an increased extracellular conversion of procollagen into microfibril-forming collagen by the action of specific proteinases; (4) an increased spontaneous microfibril assembly to form fibrils; (5) an enhanced cross-linking of fibrils to form fibers through chemical reactions catalyzed by lysyl oxidases and other enzymes; and (6) an unchanged or decreased fiber degradation by matrix metalloproteinases and other enzymes. This process can be triggered either to replace small foci of dead cardiomyocytes or as a reaction to a diversity of mechanical (eg, stretch), humoral (eg, aldosterone), and chemical (eg, advanced glycation end products and reactive oxygen species) stimuli acting on any of these steps.Fibrosis may contribute to the pathophysiological changes of HHD through diverse pathways. First, a linkage between fibrosis and LV dysfunction may be established.54 Initially, the accumulation of collagen fibers compromises the rate of relaxation, diastolic suction, and passive stiffness, thereby contributing to impaired diastolic function. Continued accumulation of collagen fibers, accompanied by changes in their spatial orientation, further impairs diastolic filling. In particular, an association of myocardial fibrosis with LV stiffness has been described in patients with HHD without HF55 and in patients with HFpEF (mostly hypertensives)56 and also that collagen contributes to increased myocardial passive stiffness in these patients.12 Additionally, these changes compromise cardiomyocyte contraction and myocardial force development, thus impairing systolic performance. Of interest, it has been reported that acute chamber stiffening is the main mechanism responsible for rising late-diastolic pressures when patients with HFpEF undergo hypertension transients.57 This stiffening is related to impaired dynamic systolic-diastolic interactions and correlates with the quantity and degree of cross-linking of collagen deposits. Second, perivascular fibrosis may contribute to impaired coronary flow reserve (CFR) through the external compression of intramural coronary arteries.58 Because the amount of perivascular collagen has been correlated inversely with CFR in hypertensive animals59 and patients60 with LVH. Third, interstitial fibrosis may also contribute to ventricular arrhythmias in hypertension.61 Patients with HHD and arrhythmias exhibit higher values of myocardial collagen than patients without arrhythmias, despite the finding that ejection fraction and the frequency of coronary vessels with significant stenosis may be similar in the 2 groups of patients. Fibrosis induces conduction abnormalities thereby promoting local reentry arrhythmias. Additionally, the myofibroblasts may alter the electric activity of the cardiomyocyte through either direct intercellular interactions or secretion of paracrine factors.62Of interest, myocardial fibrosis may also adversely influence the clinical outcome in patients with HHD, namely in those with HF. For instance, it has been shown that whereas increased collagen type I cross-linking is associated per se with HF hospitalization in patients with HHD and HF,63 the coincidence of increased collagen type I cross-linking with extensive collagen type I deposition is associated with HF hospitalization and cardiovascular and all-cause death.64Alterations of the Coronary MicrovasculatureTogether with alterations in the coronary macrocirculation (eg, obstructive disease of the epicardial coronary arteries), several structural alterations develop in the coronary microvasculature (ie, prearterioles 100–500 μm in diameter and arterioles <100 μm in diameter that make up the coronary microcirculation, capillaries, and venules) as part of MR. In combination with reduced diastolic myocardial perfusion pressure because of increased arterial stiffness, they render the hypertensive heart an ischemic organ.65.66 On one hand, hyperplasia or hypertrophy and altered vascular smooth muscle cellular alignment may promote encroachment of the tunica media into the lumen, thereby causing both increased medial thickness/lumen ratio or reduced maximal cross-sectional area of prearterioles and arterioles. On the other hand, vascular density in LVH becomes relatively decreased. This seems to result from capillary rarefaction or inadequate vascular growth in response to the increasing muscle mass. These alterations may depend, in part, on the abnormal transmission of highly pulsatile blood pressure into microvascular networks, especially in highly perfused organs with low vascular resistance, such as the heart. Additionally, alterations in pericytes (ie, smooth muscle-like cells of mesenchymal origin that surround capillary endothelial cells) may be involved in the paucity of microvessels in HHD as it has been demonstrated in other cardiac diseases.67 Finally, deposition of fibrotic tissue around prearterioles and arterioles (ie, perivascular fibrosis) increases oxygen diffusion distance leading to impairment of oxygen supply to cardiomyocytes.68These structural alterations, namely those of the coronary microcirculation, together with endothelial dysfunction,69 contribute to reduction of CFR in patients with HHD.70 Interestingly, associations between decreased CFR and LV systolic and diastolic dysfunction71,72 and mortality73 have been found in patients with HHD (Figure 4). In addition, it has been proposed that the combination of microvascular ischemia and myocardial fibrosis may be involved in the facilitation of ventricular tachyarrythmias and sudden cardiac death in patients with HHD.74,75 Of interest, it has been recently reported that the proportion of sudden cardiac deaths attributable to HHD in the absence of coronary artery disease has increased during the last years.76Download figureDownload PowerPointFigure 4. Survival curves of hypertensive patients with heart failure classified according to coronary flow reserve (CFR) threshold values recorded in healthy controls. Adapted from Pereira et al73 with permission. Copyright © 2010, American Society of Hypertension.Diagnosis and Treatment of MR in HHDAs MR negatively influences the clinical evolution of patients with HHD, integrating its assessment into the evaluation and management of these patients may be warranted. Therefore, it has been proposed that beyond the current clinical protocols based on detecting LVH and LV dysfunction and LVH regression,77 the time has come for additional strategies, aimed at both the noninvasive biochemical or imaging diagnosis78,79 and therapeutic repair80,81 of hypertensive MR, to be considered.Phenotyping MRWhereas cardiovascular magnetic resonance (CMR) is the gold standard for the diagnosis of LVH, echocardiography is the most frequently used in clinical practice because of its low cost and availability. However, a recent analysis of 39 studies focusing on LVH in hypertension reveals that LVH was variably defined according to as many as 19 different echocardiographic criteria,82 thus making the assessment of this entity highly imprecise and, more importantly, limiting the possibility to discriminate phenotypes truly representative of the diversity of mechanistic pathways and alterations underlying HHD.As regards the phenotyping of MR, although the endomyocardial biopsy is relatively safe and might serve to this purpose taking advantage of the use of both histopathologic and molecular methodologies,83 alternative noninvasive methods are needed for routine practice. In this regard, it is desirable that circulating or imaging biomarkers of MR are useful for classifying and staging HHD (Table 1).Table 1. Proposed Biomarkers for the Phenotyping of Myocardial RemodelingType of BiomarkerCardiomyocyte AlterationsInterstitial AlterationsMicrovascular AlterationsHypertrophyInjury DeathInflammationFibrosisEndothelial Activation DysfunctionCoronary Flow DysregulationCirculatingCT-1hs-TnTGal-3PICPVCAM-1Annexin A5sST-2PIIINPP-selectinCRPCITP:MMP-1E-selectinIL-6Gal-3GDF-15sST-2ImagingLV mass: (1.05×[1−ECV]) (assessed by CMR)99 m Tc-annexin A5 (assessed by SPECT)VEGF receptors (assessed by PET)ECV (assessed by CMR)αvβ3 integrins (assessed by PET and SPECT)Coronary flow reserveLV mass: (1.05×ECV) (assessed by CMR)Late gadolinium enhancement (assessed by CMR)Backscatter amplitude (assessed by ultrasound)Perfusable tissue index (assessed by PET)See references for each proposed biomarker in Table S1 in the online-only Data Supplement. CITP indicates carboxy-terminal telopeptide of collagen type I; CMR, cardiac magnetic resonance; CRP, C-reactive protein; CT-1, cardiotrophin-1; ECV, extracellular volume; Gal-3, galectin-3; GDF-15, growth/differentiation factor 15; hs-TnT, high-sensitivity troponin T; IL, interleukin; LV, left ventricular; MMP-1, matrix metalloproteinase-1; PET, positron emission tomography; PICP, carboxy-terminal propeptide of procollagen type I; PIIINP, amino-terminal propeptide of procollagen type III; SPECT, single photon emission computed tomography; sST-2, soluble suppressor of tumorigenicity-2; VCAM-1, vascular cell adhesion molecule-1; and VEGF, vascular endothelial growth factor.Circulating BiomarkersThe investigation of circulating biomarkers for MR detectable in blood by immunochemical methods has been accelerating at a remarkable pace. These investigations have deluged the clinical and research communities with numerous candidates, few of which are, however, likely to survive as useful clinical tools in terms of diagnosis, prognosis, and therapy monitoring. One possible explanation for this failure is that most of the proposed biomarkers lack proof that they actually reflect the structural, functional, or molecular alterations associated with MR in patients with HHD. As shown in Table 1, several circulating parameters have been proposed as biomarkers of MR in HHD. However, a strong evidence of association with MR alterations has not been demonstrated for all of them.The clinical usefulness of circulating biomarkers of HHD can be inferred from considering some examples. Recent findings demonstrate that the presence of echocardiographic LVH in conjunction with elevated circulating biomarkers for cardiomyocyte injury/stress (high-sensitivity cardiac troponin T and amino-terminal pro-B-type natriuretic peptide) can identify a malignant phenotype of LVH more likely to progress to LV dysfunction,
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