key: cord-0028850-8dg7lzol authors: Vasques‐Nóvoa, Francisco; Angélico‐Gonçalves, António; Alvarenga, José M.G.; Nobrega, João; Cerqueira, Rui J.; Mancio, Jennifer; Leite‐Moreira, Adelino F.; Roncon‐Albuquerque, Roberto title: Myocardial oedema: pathophysiological basis and implications for the failing heart date: 2022-02-11 journal: ESC Heart Fail DOI: 10.1002/ehf2.13775 sha: 875d1087adbc7dfe17d645ae9f5389d17db72e3c doc_id: 28850 cord_uid: 8dg7lzol Myocardial fluid homeostasis relies on a complex interplay between microvascular filtration, interstitial hydration, cardiomyocyte water uptake and lymphatic removal. Dysregulation of one or more of these mechanisms may result in myocardial oedema. Interstitial and intracellular fluid accumulation disrupts myocardial architecture, intercellular communication, and metabolic pathways, decreasing contractility and increasing myocardial stiffness. The widespread use of cardiac magnetic resonance enabled the identification of myocardial oedema as a clinically relevant imaging finding with prognostic implications in several types of heart failure. Furthermore, growing experimental evidence has contributed to a better understanding of the physical and molecular interactions in the microvascular barrier, myocardial interstitium and lymphatics and how they might be disrupted in heart failure. In this review, we summarize current knowledge on the factors controlling myocardial water balance in the healthy and failing heart and pinpoint the new potential therapeutic avenues. The adequate compartmentalization of water in the myocardium is essential to maintain normal cardiac function. 1 Despite several mechanisms known to regulate cardiomyocyte and interstitial volume, 2 the myocardium remains particularly susceptible to oedema formation due to its dense microvascular network and high interstitial flow rate. Myocardial oedema (MO), defined by the accumulation of cardiac water in interstitial and/or intracellular compartments, has been shown to induce cardiomyocyte injury, dysfunction 3-6 and remodelling. 3, 4 The recent introduction of magnetic resonance imaging (MRI) techniques (e.g. myocardial T1 and T2 mapping) has enabled the non-invasive assessment of the extracellular component, namely, the myocardial water content, suggesting that MO negatively affects the prognosis across acute and chronic heart failure (HF). [7] [8] [9] Moreover, advances in the understanding of the myocardial microvascular barrier and lymphatics suggest that myocardial fluid balance disturbances are key determinants of the extent and duration of myocardial injury. These aspects may recast MO as a therapeutic target yet to explore in clinical practice. The present review aims to summarize the current knowledge on the pathophysiological mechanisms of MO formation and their contribution to the disruption of cardiac homeostasis in the failing heart, also discussing future perspectives on therapeutic targeting of MO. To maintain fluid homeostasis, microvascular fluid filtration into the myocardium must be matched by its removal rate via myocardial lymphatic vessels. Microvascular fluid exchange is governed by the Starling principle, expertly reviewed elsewhere, 1,10 summarized by the revised Starling equation: where L P is the hydraulic conductivity, S is the filtration surface area, P C and P I are the intracapillary (C) and interstitial (I) hydrostatic pressures, σ is the protein reflection coefficient and Π C and Π G are the intracapillary and subglycocalyx (G) colloid osmotic pressures, respectively ( Figure 1) . In order to keep a stable interstitial volume (V I ) and defend against oedema formation, several physiological mechanisms counteract primary perturbations in P C , Π C and endothelial barrier function-oedema safety factors. 2 Figure 1 The disruption of myocardial fluid balance in the failing heart. Multiple mechanisms can contribute for oedema formation in the failing heart and are differentially observed in several types of acute and chronic heart failure. Myocardial ischaemia, inflammation and volume overload negatively impact on microvascular barrier function by promoting the glycocalyx degradation and pericyte detachment, resulting in excessive fluid filtration. The resulting increase in interstitial volume and pressure disrupt the extracellular matrix (ECM) architecture, pulling cardiomyocytes away from capillaries and increasing oxygen diffusion distance. Moreover, ECM degradation and high central venous pressure impair lymphatic recruitment and drainage, leading to the accumulation of inflammatory cells, cytokines and metabolic waste products in the myocardial interstitium. Collectively, these mechanisms can impair myocardial contractility and bioenergetics, increase myocardial stiffness and promote cardiomyocyte apoptosis. Myocardial oedema in the failing heart Myocardial oedema develops when fluid filtration rate exceeds lymphatic fluid removal and can be generated by increased ΔP or S, decreased ΔΠ or alterations of microvascular membrane properties (increased L P or decreased σ) (Figure 1) . Increased P C can be driven by high pre-capillary pressure in the setting of acute 11 and chronic 12 arterial hypertension, or high post-capillary pressure in coronary sinus occlusion, 4, 13, 14 pulmonary hypertension 15 or in acute HF with increased central venous pressure. 16 Moreover, increased S, caused by increased capillary recruitment or vasodilation, promotes MO formation and is particularly relevant in inflammatory HF aetiologies (e.g. myocarditis and sepsis). Finally, as albumin is the major determinant of Π C , states of hypoalbuminemia facilitate fluid filtration and global interstitial oedema. 6 This is particularly relevant in crystalloid coronary perfusion during cardiac surgery 17 and in shock management (e.g. septic and cardiogenic) in which, excessive fluid resuscitation worsens prognosis. 18, 19 Myocardial oedema dramatically reduces energetic efficiency, impairing both contraction and relaxation. 1, 20, 21 However, increased V I and P I have been shown to primarily affect myocardial viscoelastic properties, resulting in higher diastolic stiffness. 6, 22 Due to its low interstitial compliance, small interstitial volume expansions create high interstitial pressures, making the myocardium particularly sensitive to oedema formation. The experimental increase in myocardial water content by 3.5% was associated with a 40% drop in cardiac output. 3 In addition, MO directly opposes filtration, by decreasing ΔP and physically compressing the capillaries and disrupting nutrient and oxygen delivery. 23 The disruption of the extracellular matrix structure, increased oxygen diffusion distance and accumulation of metabolic waste products are additional proposed mechanisms of MO-associated functional deterioration ( Figure 2 ). 1, 24 In summary, myocardial fluid balance is largely dependent on microcirculation dynamics, microvascular barrier, interstitial architecture and lymphatic drainage. Disruption of any of these components may disturb myocardial fluid homeostasis. In this review, each factor will be addressed in detail regarding its physiological role and how it may be disrupted in the failing heart. The healthy myocardium is one of the most densely vascularized tissues in human body, possessing a high density capillary network (3.000-4.000/mm 2 ) closely disposed around cardiomyocytes 25, 26 (Figure 2 ). Such proximity between cardiomyocytes and capillaries is of utmost importance to maintain a short diffusion distance not only for oxygen, but also for potentially toxic byproducts of cellular metabolism. 23 Moreover, the high metabolic rate of the myocardium, which primarily depends on oxidative phosphorylation, translates in an elevated oxygen demand that is matched by a very high oxygen extraction rate (70%-80% in resting conditions). [27] [28] [29] Consequently, in stress conditions, additional increments in oxygen demand are predominantly met by parallel increases in myocardial blood flow (MBF). 27 This metabolic contribution to MBF autoregulation is made possible by the close contact between cardiac muscle and vasculature, enabling cardiomyocyte-derived mediators (CO 2 30 and lactate 31 ) and microenvironmental factors (pH 32 and extracellular K +33 ) to modulate local vasomotor tone and haemoglobin dissociation curve. Therefore, pathological conditions limiting the close communication between cardiomyocytes and vasculature, namely, the expansion of the interstitial space due to oedema or fibrosis, as well as arteriolar and capillary rarefaction, common features in chronic HF, 34 impair diffusional transport and MBF autoregulation, contributing to oxygen supply/demand mismatch ( Figure 2) . Another consequence of the proximity between coronary microvasculature and cardiomyocytes is their mechanical interaction. Previously considered an important modulator of contractility (i.e. Gregg phenomenon), the effect of coronary perfusion was later shown to be negligible within the autoregulatory pressure-flow range. 35,36 Extravascular forces are not uniform across the ventricular wall and a gradual increase in interstitial pressure and vascular compression is observed from the subepicardium to the subendocardium. 37,38 This is partly compensated by a higher arteriolar density at the subendocardium so that, in physiological conditions, MBF is similar in both myocardial layers. 39 ,40 Yet, the distinct mechanical cross-talk between different myocardial layers, makes arterio-venous pressure gradient (i.e. perfusion pressure) at the subendocardium about half of that of subepicardium. 41 Consequently, in the setting of decreased coronary pressure (e.g. coronary artery disease), the subendocardial perfusion is predominantly affected. 42-44 This intricate relation between microcirculation and perfusion may underly, at least partially, the existence of clearly distinct patterns of MO distribution associated with different kinds of myocardial injury: in acute inflammatory conditions (e.g. viral myocarditis, sepsis) oedema is generally evident in the subepicardial layers whereas in acute ischaemia, the oedema is transmural or predominantly affects the subendocardium. 7, [45] [46] [47] Coronary vasculature also influences myocardial tissue properties. Higher coronary perfusion pressure is associated with increased myocardial stiffness, shifting diastolic pressure-volume relationship left and upwards, even in the absence of oedema formation. 48-50 The underlying mechanism resides in the fact that cardiomyocyte contraction increases the cell diameter, which happens at the expense of coronary vascular diameter, contributing to the abovementioned systolic vascular compression. 36,51 Accordingly, higher intravascular volume and pressure, caused by increased coronary perfusion or venous outflow pressure, oppose intravascular fluid displacement, and therefore impair muscle contraction and relaxation. This has been shown to be especially relevant in the setting of increased coronary sinus pressure, seen in acute and chronic HF, where increased intravascular and interstitial volume act cooperatively to impair systolic function and diastolic compliance. 52-54 Overlooked in the past, the cardiac microvascular barrier became increasingly recognized as highly active and complex structure, composed of a continuous non-fenestrated endothelial cell monolayer, which is internally coated with a negatively charged gel-like mesh (i.e. glycocalyx) and externally covered by pericytes and basement membrane ( Figure 3 ). Endothelial cells (EC) are tightly bonded by interendothelial junctions (IEJ), mostly comprised by tight (occludins, claudins and JAMs) and adherens junctions (VE-cadherin), which define endothelial pore size and can be dynamically regulated at the expression level and through internalization, to finely tune endothelial permeability and regulate the passage of macromolecules and cells 55-57 ( Figure 3 ). Accumulating evidence suggests IEJ disruption as a potential pathophysiological mechanism in cardiac diseases. Importantly, endothelial expression of claudin-5, a critical player in size-selective barrier function, is reduced in human end-stage HF hearts. 58 This was also shown in experimental diastolic dysfunction induced by western diet, where claudin-5 and occludin down-regulation was associated with increased vascular permeability, 59 an effect attenuated by amiloride, suggesting an important role for endothelial ENaC expression and sodium overload. Regarding adherens junctions, reduced VEcadherin/β-catenin expression in dilated cardiomyopathy was associated with endothelial cell degeneration, 60 whereas in post-ischaemic MO, Src inhibition prevented VEGF-mediated disruption of Flk/VE-cadherin/β-catenin complex and attenuated post-ischaemic MO, fibrosis and mortality. 61 In addition, key risk factors for HF development and progression have been shown experimentally to promote endothelial hyperpermeability by disrupting EIJ, namely, renin-angiotensin-aldosterone system activation, 62 inflammation, 63,64 hypoxia, 65 cardioplegic arrest, 66 hyperglycaemia, 67 oxidative stress, 68 increased circulating LDL 69,70 and free fatty acid 71 levels. The endothelial glycocalyx (eGC) covers the apical side of endothelial cells and consists of a complex meshwork of varied membrane-associated macromolecules [72] [73] [74] (Figure 3) . These include proteoglycans and glycoproteins, forming a backbone in which soluble proteins, plasma-or endothelial-derived, are incorporated. eGC proteoglycans are constituted by linear core proteins, mostly Syndecan-1, to which multiple glycosaminoglycans (GAGs) side chains can be covalently attached. GAGs are highly polyanionic compounds composed of disaccharide repeating units which can be non-sulfated [hyaluronic acid (HA)] or sulfated (chondroitin sulfate, dermatan sulfate, keratan sulfate and heparan sulfate). Together, they form a negatively charged surface that will enable electrostatic interactions with plasma cations, mostly with divalent metal cations (e.g. Ca 2+ ), but also with Na + due to its high plasma concentration. 75, 76 The resulting high cation concentration at the interface with the plasma enables negatively charged circulating proteins (albumin, antithrombin III and thrombomodulin), that would otherwise not be able to electrically interact with the glycocalyx, to approach and incorporate this layer, forming together the endothelial cell surface layer (ESL). 77, 78 The ESL, measuring between 0.2 and 2.0 mm in vivo, is therefore a highly complex structure with critical functions in microvascular physiology by (i) physically shielding the underlying endothelium from luminal aggressions; (ii) regulating microvascular flow by transmitting shear-stress forces; (iii) constituting a barrier for plasma proteins and ions, thereby maintaining intravascular oncotic In the myocardial interstitium, fluid entry is limited by type I and type III collagen fibres and GAGs, extracellular matrix components that act as a buffer for Na + and water. Interstitial and intracellular water are in delicate balance, maintained by cardiomyocyte volume regulators. Interstitial fluid (IF) and solutes are collected by initial lymphatic capillaries, enabling a continuous IF renovation, which is returned ultimately to the venous circulation. (A). Cardiomyocyte ionic transporters: cardiomyocytes closely regulate intracellular water entry and extrusion. Water enters through aquaporins or passively diffuses through the cell membrane, according to osmotic gradients established by ionic and solute concentrations. (B). Endothelial cell-pericyte interaction: these cells establish close paracrine and physical (N-cadherin) interactions regulating microvascular stability. Endothelial cells secrete PDGF-BB that binds to PDGFR-β, promoting pericyte recruitment and microvascular integrity, whereas pericytes secrete angiopoietin 1 (Ang-1), which acts on Tie-2 and stabilizes endothelial cells. (C). Endothelial surface layer and interendothelial junction: the endothelial surface layer is composed by endoluminal glycocalyx, which binds plasma proteins and protects endothelial cells. Furthermore, endothelial cells establish varied connections, maintaining cohesiveness and cell survival. (D). Lymph drainage in initial lymphatic capillary: fluid enters the lymphatic vasculature via lymphatic capillaries, which are blunt-ended vessels attached to the extracellular matrix by anchoring filaments. Lymphatic endothelial cells overlap, creating valve-like structures that promote unidirectional lymph flow. These vessels converge progressively from the subendocardium to the subepicardium, forming epicardial lymphatic collectors. ALK-1 and -5, anaplastic lymphoma kinase-1 and 5; Ang-1, angiopoietin-1; AngII, angiotensin II; Aqp, aquaporins; GAG, glycosaminoglycans; HA, hyaluronic acid; JAMs, junctional adhesion molecules; NBS, Na + /HCO 3 À Symporter; NCX, Na + /Ca 2+ exchanger; NHE, Na + /H + exchanger; PDGF-BB, platelet-derived growth factor BB; PDGFR-β, PDGF receptor β; TGF-β, transforming growth factor β; TGFR-β2, TGF receptor β2; Tie-2, angiopoietin-1 receptor. F. Vasques-Nóvoa et al. pressure; (iv) avoiding platelet aggregation by accumulating platelet-inhibitory factors (antithrombin III and thrombomodulin) and physically restricting its interaction with subendothelium at the endothelial gaps; (v) inhibiting endothelial proinflammatory activation (i.e. increased permeability and adhesiveness) by binding circulating cytokines; and (vi) limiting the access and adhesion of circulating immune cells to the EC surface. 79, 80, 81 The ESL structure is maintained by a fragile balance between flow and enzymatically mediated shedding, and de novo production of its components. 82 Not surprisingly, most pathological mechanisms shown to increase microvascular barrier permeability act concomitantly on IEJ and ESL, namely, in inflammation, ischaemia-reperfusion, 83 hypoxia 84 and hyperglycaemia. 85 Importantly, the activity of glycocalyx-degrading enzymes (i.e. hyaluronidases, heparanase and MMPs) is increased in the setting of inflammation, which, in combination with endothelial CAM overexpression, facilitates leukocyte adhesion and diapedesis. 86 The importance of the permissive effect of ESL degradation on cardiac leukocyte infiltration has been shown in myocardial infarction, 87,88 viral myocarditis 89 and sepsis, 90,91 aggravating the myocardial inflammatory injury. Moreover, degradation of eGC components (hyaluronan 92 and heparan sulfate 93 ) has been shown to promote MO by increasing microvascular permeability to water and proteins. Perhaps, the more striking association between eGC and HF is the fact natriuretic peptides (NP), mostly produced by cardiomyocyte stretching in the setting of hypervolemia and ventricular overload, have been repeatedly shown to promote eGC degradation. [94] [95] [96] [97] [98] This effect seems to act concurrently with Na + overload, which also leads to the destabilization and collapse of the eGC, mainly through loss of heparan sulfate residues, an effect attenuated by the use of spironolactone. 99 This can be interpreted essentially as a compensatory mechanism, by enabling the escape of excessive intravascular fluid and sodium to the interstitium, which has a high Na + buffering capacity due to its GAG content, 100 and acting in conjunction with NP-mediated venodilation to reduce cardiac overload. However, eGC degradation in the setting of myocardial functional impairment might also carry some drawbacks. In addition to eGC degradation being an inherently proinflammatory stimuli for EC, 101,102,103 the impairment of glycocalyx Na + buffering capacity may increase the amount of Na + presented to the endothelium, promoting intracellular endothelial Na + overload and increased transport to the interstitium, resulting in endothelial dysfunction and aggravated interstitial oedema, respectively. 104, 105, 106 Furthermore, this combined effect of hypervolemia and Na + overload also has important implications in the critical care setting (e.g. cardiogenic and septic shock), 107, 108 where the frequently excessive crystalloid resuscitation might disrupt microvascular barrier function and complicate haemodynamic management and prognosis. Despite its proposed pathophysiological importance, a direct observation of ESL disruption in HF is still lacking. Cardiac pericytes (CPc) are a highly heterogeneous population of perivascular contractile cells that ensheath and intimately interact with underlying endothelial cells, forming a microvascular syncytium. 109, 110 Despite conflicting reports, recent data suggest that CPc cover up to 99% of the length of the myocardial microvasculature. 111 CPc share the basement membrane with EC and establish numerous physical interactions, ensuring an adequate control of microvascular permeability. Moreover, an intense reciprocal communication between CPc and EC takes place through gap junctions and paracrine factors, which has been shown to be especially relevant for angiogenesis and stabilization of newly formed vessels 101 ( Figure 3) . Importantly, multiple pericyte phenotypes with distinct cell-surface marker signatures and variable expression of contractile proteins have been shown to be differentially distributed across the arteriolar, microvascular and venular sections of coronary vasculature. 99, 112 Such diversity probably underlies distinct pathological roles attributed to pericytes in the context of myocardial injury and remodeling. Extensive evidence supports a key role for CPc in the regulation of myocardial microvascular flow and permeability. Indeed, the disruption of key trophic and homeostatic pathways for CPc, namely, PDGF-BB/PDGFR-β, 113, 114 Ang-1/ Tie2, 115, 116 Sirtuin-3 117, 118 and Notch3, 119, 120 has been shown to decrease CPc density and EC coverage, resulting in increased microvascular permeability in response to injury, MO and functional impairment. Importantly, common observations in genetic and drug-induced CPc dysfunction are increased microvascular tortuosity and decreased coronary reserve in response to vasodilator challenge, with cardiac up-regulation of hypoxia-related genes. 121 In knockout mouse models, the genetic ablation of Notch3 122 and Sirtuin-3 123 impairs microvascular maturation and pericyte/ EC interaction, exacerbating ischaemic injury and hindering post-ischaemic functional recovery. Similar observations were made in experimental models of endotoxemia and diet-induced obesity, in which Sirtuin-3 has been shown to be down-regulated. 124, 125 Accordingly, in the setting of ischaemic injury, cardiomyocyte-derived proNGF activates p75 neurotrophin receptor, causing pericyte process retraction, resulting in a lack of support of the microvascular endothelium and perivascular oedema. 126 Moreover, Hypoxia-Induced Endoplasmic Reticulum Stress Regulating (HypER) lncRNA, which promotes pericyte proliferation, viability and interactions with EC, is down-regulated in human HF, 127 supporting pericyte degeneration as a potentially important pathophysiological mechanism. In line with the diversity of CPc phenotypes and functional roles in the setting of myocardial ischemia, CPc have also been implicated in the no-reflow phenomenon. 128 Importantly, some pericyte subpopulations express variable amounts of myosin and actin isoforms (α-SMA and γ-actin), having the ability to contract and relax in response to multiple paracrine factors (catecholamines and adenosine). 129, 130 Being circumferentially disposed around capillaries, CPc contraction can decrease microvascular flow and theoretically reduce capillary luminal diameter enough to impede the passage of leukocytes. Indeed, in an ischaemia/reperfusion injury model, post-ischaemic capillary blockage sites have been shown to be disproportionally close to pericytes, suggesting ischemic CPc contraction, probably mediated by an increase in intracellular Ca 2+,131 as an important mediator of impaired reoxygenation of ischemic tissue following myocardial revascularization. 132 In inflammatory conditions, CPc detachment from EC surface was associated with differentiation into myofibroblasts and increased production of ECM, potentially contributing to pathological myocardial remodelling. 134, 135 In fact, galectin-3, a well-validated biomarker and mediator of cardiac fibrosis in HF patients, 136 has been shown to stimulate pericyte proliferation and procollagen I secretion. 137 This is in accordance with observations in angiotensin II-induced myocardial hypertrophy model, in which Gli1 + cells were shown to consist in a subpopulation of pericytes that, in the setting of injury, differentiate into myofibroblasts and produce ECM in perivascular and interstitial spaces. 138 Further supporting this role of CPc, in a clinically relevant rat model of HF with preserved ejection fraction (ZSF1 obese rats), decreased EC coverage was associated with subendocardial foci of CPc proliferation, which colocalized with ECM deposition and inflammatory cell infiltration. 139 Consistently with this finding, pericytes have been shown to respond to proinflammatory stimuli with overexpression of cytokines, chemokines and CAMs, 140 regulating immune cell diapedesis. 141 In the setting of experimental sepsis, inflammatory-mediated CPc loss facilitates the infiltration of immune cells in cardiac interstitium. 142 These findings highlight the fact that, beyond being key determinants in the microvascular barrier, pericytes may detach from endothelial cells and promote interstitial remodelling in inflammatory injury. The myocardial interstitium is a highly organized and compact structure, comprised by fibrillar collagen, non-collagen matrix proteins, proteoglycans, GAGs and a wide array of bioactive signalling molecules 143 (Figure 3) . Cardiomyocytes are enclosed in a basement membrane, mostly constituted by integrins, laminin and fibronectin, behaving as anchoring points for fibrillar collagen and other matrix components (proteoglycans and GAG) attachment. Collagens (type I and III) are the predominant components of cardiac ECM, and their high tensile strength is assumed to be the main contributor for ECM structural integrity. 144 Cardiac ECM architecture enables an effective force summation of individually contracting cardiomyocytes, allowing a coordinated myocardial tissue contraction, while at the same time maintaining adequate spatial relationships between cells, which prevents cardiomyocyte overstretching, preserves intercellular connections and opposes microcirculatory collapse. Cardiac ECM composition is an important determinant of interstitial space volume and pressure. The interstitial space is densely crowded with intertwined components, which occupy the available physical space and limit the entrance of plasma proteins or cells, a phenomenon called steric interstitial exclusion. 2 Given their polyanionic nature, interstitial GAGs futher contribute to limit the entrance of plasma proteins, while also binding free ions (mostly Na + ) and annulling their osmotic force. 93 Interestingly, changes in sulfated GAG conformation are associated with decreased Na + buffering capacity and interstitial oedema. 93 Moreover, the high stiffness of cardiac ECM not only preserves cardiomyocyte function by generating passive tension and avoiding tissue overstretching but also confers a low interstitial compliance to the myocardium and opposes interstitial space expansion. 145 Consequently, in the setting of increased transcapillary filtration, interstitial fluid (IF) buildup stretches the ECM, causing a steep increase in interstitial pressure, which, in turn, forces IF into the lymphatic system. 22 Alterations in ECM architecture or composition critically influence myocardial function. Increased ECM deposition, mainly in the form of collagen, has been recognized as an important mechanism of increased stiffness and diastolic dysfunction in most forms of chronic HF. 16 However, mechanical and enzymatic disruption of the ECM also significantly impairs myocardial systolic and diastolic function by compromising force transmission by displacing collagen struts from their anchoring points and breaking intercellular connections. 146, 147 Moreover, inflammation-driven up-regulation of ECM-degrading enzymes promotes both ECM and basement membrane degradation, decreasing interstitial exclusion effect and facilitating the interstitial passage of fluid, proteins and immune cells. 148 ECM degradation has been shown in acute high-grade myocardial inflammation, especially in experimental myocarditis 149 and sepsis, 150 where a significant acute decrease in total myocardial collagen content and collagen degradation were observed and associated with MO, systolic and diastolic dysfunction. Further supporting this experimental observation, post-mortem evaluation of human septic myocardium found significant ECM disruption and interstitial oedema at the subepicardium, which colocalized with macrophage infiltration and cardiomyocyte apoptosis. 45 Importantly, disruption of collagen struts may also increase coronary microvasculature suscepti-964 F. Vasques-Nóvoa et al. bility to external compression, which might compromise MBF in the setting of oedema-associated increased interstitial pressure. 36, 123 Interestingly, chronic oedematous states produced by increased microvascular filtration or decreased lymphatic drainage are associated with increased myocardial collagen deposition. 3, 4 The interstitial remodelling may be interpreted as a compensatory mechanism, by decreasing interstitial compliance and preventing interstitial expansion, therefore minimizing the disruption of cardiac architecture. However, increased collagen deposition also causes long-term detrimental effects on overall myocardial compliance and function. 151 Impaired turnover of non-collagen ECM elements can also promote fibrosis and have detrimental effects on myocardial function. HA is observed in healthy cardiac ECM in its highmolecular-weight HA form and has a unique capacity to bind and retain water molecules. 152 Interestingly, while eGC HA degradation has been consistently associated with endothelial dysfunction, increased microvascular permeability and MO, 85, 153 cardiac interstitial accumulation of HA, has similarly been shown to promote MO and structural remodelling. 154 Cardiac interstitial accumulation of HA is normally associated with increased interstitial water content and MO, and is observed in myocardial infarction, 155 hypertrophic cardiomyopathy, 156 myocarditis 157 and experimental cardiac transplant rejection. 158, 159 Curiously, hyaluronidase treatment was able to decrease MO in rejected heterotopic transplants, 160 whereas accumulation of low-molecularweight HA (LMWHA) in hypertrophic cardiomyopathy is not associated with increased water content, 161 raising the possibility of distinct contributions of high-molecular-weight HA and LMWHA for oedema generation. Indeed, in the setting of inflammation and myocardial injury, production of LMWHA is preponderant and has been shown to stimulate TLR inflammatory signalling pathways. 127 Collectively, these results underscore the importance of GAG structure, composition and regional distribution for IF balance. The cardiac lymphatic system is essential in maintaining myocardial fluid balance and immunological homeostasis. 139 It represents the main route for the removal of cellular metabolites, allowing the continuous IF renewal while avoiding the buildup of interstitial volume and pressure. 2 Additionally, an immunomodulatory role has also been attributed to cardiac lymphatics due to the washout of proinflammatory mediators and immune cells from the myocardial interstitium in the setting of myocardial injury. 162, 163 Lymphatic capillaries are highly specialized blind-ended structures, composed by oak-leaf shaped lymphatic endothelial cells (LEC), which mostly lack basement membrane and are connected by permeable flap-like intercellular junctions that favour unidirectional passage of IF, solutes and immune cells 164, 165 (Figure 3) . Moreover, cardiac LEC are connected to the surrounding ECM and cardiomyocytes by structures designated as anchoring filaments, constituted by type VII collagen projections, integrins and focal adhesion kinases. Anchoring filaments maintain lymphatic patency by exerting tensile forces and opening the lumen of lymphatic capillaries, facilitating lymphatic flow. 166, 167 Anatomically, the lymphatic capillary plexus progressively converges from the subendocardium to the subepicardium, suffering structural alterations along the way, namely, the appearance of a continuous basement membrane, intraluminal valves to promote unidirectional flow, tight junctions, and, in larger trunks outside the myocardium, an adventitial layer and surrounding smooth muscle cells to help pump lymph. 168, 169 Subepicardial lymphatic pre-collectors converge to form epicardial lymphatic collectors that transport cardiac lymph via lymph nodes towards thoracic ducts, ultimately draining into the superior vena cava. 170 Several factors influence cardiac lymph flow, most of which known to be unique to the heart. A distinctive feature of the intramyocardial lymphatic system is the absence of smooth muscle in intramyocardial vessels. Therefore, lymph flow is highly dependent on external forces, namely, muscle contraction and deformation along the cardiac cycle, heart rate and contractility. 1 However, factors not intrinsic the heart function also impact lymph drainage. By concentrating interstitial metabolic products and proteins, lymph oncotic pressure exceeds interstitial oncotic pressure, promoting water osmotic dragging and fluid drainage. 1 Coronary venous pressure is also an important regulator of lymph flow. Experimental coronary sinus blockade increases capillary hydrostatic pressure and promotes fluid filtration upstream, which requires compensatory lymphatic dilation and increased lymph flow to maintain fluid homeostasis. 13, 14, 147 On the other hand, downstream, because lymph is ultimately drained into the venous circulation, increased central venous pressure acts synergically with decreased contractility to impair lymph flow in acute HF, promoting MO. 16, 93 The frequent observation of MO in several aetiologies of HF suggests that cardiac lymphatic inability to respond to increased filtration is a rather common finding. Despite the recognized ability of the healthy heart to respond to an increased capillary filtration by increasing lymph drainage severalfold, 1 multiple disease mechanisms may render the cardiac lymphatic system incapable to cope. In this setting, lymphatic dysfunction will not only promote accumulation of a protein-rich IF, which contributes to microvascular and cardiomyocyte stress, but will also have a proinflammatory effect by decreasing the clearance of proinflammatory cytokines and immune cells. 171 Prolonged residence of cellular debris, inflammatory mediators and cells in myocardial interstitium will aggravate and prolong myocardial inflammation, especially in the setting of myocardial infarction and myocarditis. 172 Furthermore, the distortion of interstitial architecture mediated by oedema and the activation of collagen and GAG-degrading enzymes may have a negative impact on anchoring filaments and initial lymphatics, further compromising lymphatic patency and function. Whereas acute lymphatic obstruction leads to oedema, chronic obstruction is associated with interstitial fibrosis and ECM remodelling. 125 Moreover, given the close proximity of the lymphatic and electrical conduction system, lymphatic dysfunction has also been shown to be associated with electrical disturbances. 173 Lymphangiogenesis, the process of producing new lymphatic vessels is known to be a dynamic process mainly regulated by VEGF-C and VEGF-D binding to lymphatic-specific receptor VEGFR3, and to be affected by inflammation and other cardiovascular factors (diabetes and obesity). 146 In acute inflammation 174 and in myocardial infarction, 175 higher fluid filtration increases the need for lymph drainage, with resulting up-regulation of lymphangiogenic factors. However, this endogenous response appears to be insufficient and to result in deficient lymphangiogenesis, with a predominance of lymphatic capillaries and lack of pre-collectors. In fact, in post-infarct mouse models, stimulating lymphangiogenesis with exogenous VEGF-C or adrenomedullin increases lymph flow, decreases MO, attenuates myocardial inflammation and fibrosis and improves cardiac function. [176] [177] [178] [179] [180] Still, this promising therapeutic avenue has been recently questioned by the absent impact of genetic blockade of lymphangiogenesis on cardiac function after experimental myocardial infarction. 181 The cardiomyocyte membrane is highly permeable to water, which moves passively according to osmotic gradients and directly sets cell volume. 182 Normal cell function requires a stable volume and excessive water entry may disrupt membrane and cytoskeleton integrity. To prevent abrupt cell volume alterations, intracellular osmolarity is highly controlled, either with active ionic fluxes or the synthesis/degradation of osmotically active solutes 39,183 (Figure 3) . In the isotonic steady-state, intracellular osmotic pressure exceeds extracellular osmotic pressure due to celullar concentration of organic phosphates and proteins, thus favouring passive water entry. To maintain the volume constant, the membrane Na + /K + ATPase promotes the exit of 3 Na + and entry of 2 K + ions, a phenomenon known as the 'Pump and Leak' concept. Together with low Na + membrane permeability, both mechanisms contribute to maintain a low intracellular [Na + ] and a constant transmembrane gradient, on which many ionic transporters that regulate cell volume are highly dependent. In myocardial ischaemia, Na + /K + ATPase dysfunction results in extracellular accumulation of K + , intracellular accumulation of lactate, Na + and Cland consequent cell swelling and membrane depolarization. 159, 160 Furthermore, anaerobic metabolites accumulate in extracellular and intracellular spaces. Following reperfusion of the coronary vessels will re-establish water delivery and wash out extracellular, but not intracellular, metabolic products, creating an osmotic gradient that promotes cell swelling. Highlighting the pathophysiological importance of cardiomyocyte oedema in ischaemia/reperfusion injury, reperfusion with a hypertonic solution limited MO and infarct size, when compared with isotonic solution. 184, 185 Cell swelling depolymerizes actin filaments and disrupts cytoskeleton interactions with membrane proteins. 159 Of note, cardiomyocyte swelling induced by ischaemia-reperfusion injury was associated with variable degrees of mitochondrial damage, cytoskeleton abnormalities and significant increases in sarcomere length, radial distance between myofibrils and distance between mitochondria and myofibrils, repercussing on maximal tension and calcium sensitivity. 186 Accordingly, swelling of isolated cardiomyocytes induced by hypotonic medium was associated with lower contractility and activated NO/cGMP/PKG pathway. 158 Despite most of myocardial water being confined to the intracellular compartment, few studies have addressed the pathophysiological role of cardiomyocyte swelling in HF. In clinical research and practice, MRI stands out as the gold-standard method for non-invasive MO evaluation, based on its ability to identify the tissue 'free' water pool. 'Free' water molecules rotate very rapidly when subjected to a magnetic field and produce long T1 and T2 relaxation times, whereas 'bound' water molecules have their motion restricted due to hydrogen bonding with macromolecules, producing short T2 relaxation time values. The recent introduction of parametric mapping techniques-T1, T2 and extracellular volume, has enabled the detection of subtle changes in myocardial free water content and precise estimation of the interstitial fraction volume and composition. 187 Making use of aforementioned MRI capabilities, evidence supporting the disruption of myocardial water balance has been shown in a broad range of cardiac and systemic diseases ( Table 1) . Overall, the increase in myocardial free water content is generally associated with depressed left ventricular function, increased NP plasma levels, disease progression and severity, and poor prognosis ( Table 1) . Nevertheless, due to the observational nature of these studies, a causal association between the presence of MO, LV dysfunction and cardiac prognosis could not yet be drawn. Myocardial oedema has been particularly well-studied in the acute setting of ischemic heart disease, in which it may have a role on early injury during reperfusion and also late tissue healing. [165] [166] [167] [168] [169] [170] [171] During the initial phase of reperfusion, MO may contribute to the pathophysiological process of microcirculation compression and perfusion defects underlying the 'no-reflow' phenomenon. 171, 172 MO is also detectable later, at the time of tissue healing and collagen deposition, 166 which discloses the complex interplay between myocardial fluid balance and inflammation and underscores the need for a cautious interpretation of MRI assessment of infarcted and at-risk myocardium. 171, 173 Interestingly, patient comorbidities might impact on the development of MO in a disease-specific and somewhat unpredicted way, underscoring the lack of clinical knowledge on this topic. As an illustration, diabetes was shown to aggravate post-ischaemic MO, 174, 175 whereas the opposite effect may be present in Takotsubo cardiomyopathy. 176 Myocardial oedema has not been evaluated as an endpoint in HF randomized clinical trials, and the effect of most drugs on myocardial fluid balance is currently unknown. However, pre-clinical evidence supports the beneficial effect of spironolactone 92 and SGLT2 inhibitors 177 by protecting endothelial glycocalyx. Interestingly, these two drug classes were shown to provide clinical benefit across a wide ejection fraction range in HF, 178-181 supporting a possible role for myocardial fluid balance among their mechanisms of action. Other drugs have proved useful to protect microvascular barrier in distinct clinical scenarios and may oppose MO formation. Of note, aprotinin, a fibrinolysis inhibitor, preserves adherens junctions and reduces MO in experimental cardioplegic arrest, 65 whereas in sepsis, hydrocortisone 182 and sulodexide, a mixture of GAGs (heparan and dermatan sulfates), 183 may protect the glycocalyx and diminish oedema formation. In contrast, some drugs may facilitate the development of MO by impacting on microvascular filtration and ESL preservation. NP are known disruptors of the ESL 89,91 and BNP levels correlate with myocardial water content across several clinical scenarios (Table 1) , an association not yet known to be causal. However, it is tempting to speculate that this effect might have contributed to the somewhat disappointing results of BNP analogue nesiritide in the setting of acute HF treatment. 184 In line with this, neprilysin is a known regulator of microvascular permeability by increasing the half-life of NP and bradykinin, 185 suggesting that sacubitril may also perturb microvascular barrier function. 230 Preclinical evidence suggests that beta-blockers 186 and calcium channel blockers 187 may increase microvascular permeability, an effect not yet observed in the myocardium. Finally, experimental data suggest that stimulators of lymphangiogenesis (e.g. VEGF-C and adrenomedullin) may accelerate oedema resolution after myocardial infarction, 152, 231 but clinical studies are needed before considering this therapeutic pathway in HF. In the failing heart, myocardial fluid balance is disrupted due to alterations in microcirculation dynamics, microvascular barrier, extracellular matrix composition and lymphatic function. Experimental data suggest that MO significantly impairs cardiac performance, affecting systolic and diastolic properties and promoting long-term adverse remodelling. In the last decade, CMR has been increasingly used for HF phenotyping and data suggest the increase in myocardial free water content as relevant pathophysiological mechanism of cardiac injury and dysfunction, also representing an important prognosticator across multiple cardiac and systemic diseases. Oncotarget Myocardial microvascular permeability, interstitial oedema, and compromised cardiac function Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer Lymph flow, interstitial fibrosis, and cardiac function Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema Effect of acute edema on left ventricular function and coronary vascular resistance in the isolated rat heart Effects of hypoproteinemia-induced myocardial edema on left ventricular function Myocardial edema-a new clinical entity? Cardiac magnetic resonance with edema imaging identifies myocardium at risk and predicts worse outcome in patients with non-ST-segment elevation acute coronary syndrome Cardiac Magnetic Resonance Working Group of the Italian Society of C. Prognostic value of repeating cardiac magnetic resonance in patients with acute myocarditis Microvascular fluid exchange and the revised Starling principle Myocardial fluid balance in acute hypertension Microvascular changes in the heart during chronic arterial hypertension A murine model of increased coronary sinus pressure induces myocardial edema with cardiac lymphatic dilation and fibrosis Effect of experimental coronary sinus ligation on myocardial structure and function in the presence or absence of structural heart disease: an insight for the interventional electrophysiologist Effects of myocardial edema on the development of myocardial interstitial fibrosis Global myocardial oedema in advanced decompensated heart failure Myocardial fluid balance Serum albumin as a risk factor for death in patients with prolonged sepsis: an observational study Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality Acute transient coronary sinus hypertension impairs left ventricular function and induces myocardial edema Impact of acute myocardial edema on left ventricular function The role of myocardial edema in the left ventricular diastolic stiffness Capillary Fluid Exchange: Regulation, Functions, and Pathology Cardiogenic shock: failure of oxygen delivery and oxygen utilization The extent of the capillary bed of the heart Myocardial capillarity and maximal capillary diffusion capacity in exercise-trained dogs Myocardial oedema in the failing heart 969 Endothelial glycocalyx and coronary vascular permeability: the fringe benefit Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases Endothelial glycocalyx The structure of glycosaminoglycans and their interactions with proteins Modulation of endothelial glycocalyx structure under inflammatory conditions The endothelial glycocalyx: composition, functions, and visualization Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury Hypoxia induced disruption of the cardiac endothelial glycocalyx: implications for capillary permeability Acute hyperglycemia exacerbates trauma-induced endothelial and glycocalyx injury: an in vitro model CD44 is critically involved in infarct healing by regulating the inflammatory and fibrotic response Increased expression of syndecan-1 protects against cardiac dilatation and dysfunction after myocardial infarction SPARC preserves endothelial glycocalyx integrity, and protects against adverse cardiac inflammation and injury during viral myocarditis Loss of microvascular negative charges accompanied by interstitial edema in septic rats' heart Nanomechanics of the Endothelial Glycocalyx in Experimental Sepsis Exogenous nitric oxide requires an endothelial glycocalyx to prevent postischemic coronary vascular leak in guinea pig hearts Atrial natriuretic peptide induces shedding of endothelial glycocalyx in coronary vascular bed of guinea pig hearts Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx Atrial natriuretic peptide: an essential physiological regulator of transvascular fluid, protein transport, and plasma volume Increased capillary hydraulic conductivity induced by atrial natriuretic peptide Physiological levels of A-, B-and C-type natriuretic peptide shed the endothelial glycocalyx and enhance vascular permeability Salt overload damages the glycocalyx sodium barrier of vascular endothelium The pathophysiological role of interstitial sodium in heart failure Heparan sulfate depletion amplifies TNF-α-induced protein leakage in an in vitro model of protein-losing enteropathy Plasma sodium stiffens vascular endothelium and reduces nitric oxide release Glycocalyx and sepsis-induced alterations in vascular permeability The glycocalyx: a novel diagnostic and therapeutic target in sepsis Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises Pericytes in the heart Isolation, bulk cultivation, and characterization of coronary microvascular pericytes: the second most frequent myocardial cell type in vitro Myocardial oedema in the failing heart 971 Endothelial/Pericyte interactions Discovering cardiac pericyte biology: from physiopathological mechanisms to potential therapeutic applications in ischemic heart disease Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity LPS causes pericyte loss and microvascular dysfunction via disruption of Sirt3/angiopoietins/Tie-2 and HIF-2alpha/Notch3 pathways Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss Hempstead BL. ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes Capillary pericytes mediate coronary no-reflow after myocardial ischaemia Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex Bidirectional control of CNS capillary diameter by pericytes Origins of fibrosis: pericytes take centre stage Mechanisms of fibrosis: the role of the pericyte Galectin-3: a novel blood test for the evaluation and management of patients with heart failure Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis Distinct endothelial cell responses in the heart and kidney microvasculature characterize the progression of heart failure with preserved ejection fraction in the obese ZSF1 rat with cardiorenal metabolic syndrome Lipopolysaccharide activates Toll-like receptor 4 (TLR4)-mediated NF-kappaB signaling pathway and proinflammatory response in human pericytes Role and molecular mechanisms of pericytes in regulation of leukocyte diapedesis in inflamed tissues Changes in the myocardial interstitium and contribution to the progression of heart failure Effect of interconnecting collagen fibres on left ventricular function and intramyocardial compression Hydrostatic forces limit swelling of rat ventricular myocardium Acute and specific collagen type I degradation increases diastolic and developed tension in perfused rat papillary muscle Changes in extracellular collagen matrix alter myocardial systolic performance The impact of the extracellular matrix on inflammation Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction Myocardial collagen changes and edema in rats with hyperdynamic sepsis Cardiac remodeling: concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment Hyaluronan in tissue injury and repair Hyaluronidase 1 deficiency preserves endothelial function and glycocalyx integrity in early streptozotocin-induced diabetes Murine hyaluronidase 2 deficiency results in extracellular hyaluronan accumulation and severe cardiopulmonary dysfunction Accumulation of hyaluronan and tissue edema in experimental myocardial infarction Low molecular mass myocardial hyaluronan in human hypertrophic cardiomyopathy Coxsackie B3 myocarditis induces a decrease in energy charge and accumulation of hyaluronan in the mouse heart Hyaluronidase ameliorates rejection-induced edema Hyaluronidase can be used to reduce interstitial edema in the presence of heparin Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities Leucocyte trafficking via the lymphatic vasculature-mechanisms and consequences Inflammation and lymphatic function Ultrastructural studies on the lymphatic anchoring filaments The evolving cardiac lymphatic vasculature in development, repair and regeneration The structure of lymphatic capillaries in lymph formation Cardiac lymphatics in health and disease Lymphatic system in cardiovascular medicine AWARD ARTICLE: Microcirculatory Society Award for Excellence in Lymphatic ResearchTime Course of Myocardial Interstitial Edema Resolution and Associated Left Ventricular Dysfunction The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction IL-1β reduces cardiac lymphatic muscle contraction via COX-2 and PGE2 induction: potential role in myocarditis Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D Lymphatic and immune cell cross-talk regulates cardiac recovery after experimental myocardial infarction Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction Adrenomedullin induces cardiac lymphangiogenesis after myocardial infarction and regulates cardiac edema via Connexin 43 Impact of lymphangiogenesis on cardiac remodeling after ischemia and reperfusion injury Enhancement of cardiac lymphangiogenesis by transplantation of CD34+VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction Physiology of cell volume regulation in vertebrates Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes: impact on swelling-induced negative inotropic effect Functional significance of cell volume regulatory mechanisms Mechanisms and significance of cell volume regulation Favorable effects of hyperosmotic reperfusion on myocardial edema and infarct size Treatment of myocardial ischemia/reperfusion injury by ischemic and pharmacological postconditioning Increase in myofilament separation in the "stunned" myocardium Cardiovascular magnetic resonance in nonischemic myocardial inflammation Pathophysiology underlying the bimodal edema phenomenon after myocardial ischemia/reperfusion Dynamic Edematous Response of the Human Heart to Myocardial Infarction The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection Intravenous metoprolol during ongoing STEMI ameliorates markers of ischemic injury: a METOCARD-CNIC trial electrocardiographic study Myocardial oedema in the failing heart 973 Myocardial stunning and hibernation revisited Coronary microvascular obstruction: the new frontier in cardioprotection Microvascular compression during myocardial ischemia: mechanistic basis for no-reflow phenomenon Is MRI really the gold standard for the quantification of salvage from myocardial infarction? Diabetes is associated with increased and persistent myocardial edema in infarct segment post acute myocardial infarction Comparison of the frequencies of myocardial edema determined by cardiac magnetic resonance in diabetic versus nondiabetic patients having percutaneous coronary intervention for ST elevation myocardial infarction Diabetes paradox in Tako-Tsubo cardiomyopathy: beneficial effect of diabetes on myocardial edema Empagliflozin restores the integrity of the endothelial glycocalyx in vitro EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction The effect of spironolactone on morbidity and mortality in patients with severe heart failure Spironolactone for heart failure with preserved ejection fraction Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus Effect of Nesiritide in Patients with Acute Decompensated Heart Failure The control of microvascular permeability and blood pressure by neutral endopeptidase Propranolol increases vascular permeability through pericyte apoptosis and exacerbates oxygen-induced retinopathy Nifedipine increases microvascular permeability via a direct local effect on postcapillary venules Myocardial edema by noncontrast T2 mapping is increased in acute decompensated heart failure Cardiac magnetic resonance evaluation of edema after ST-elevation acute myocardial infarction Relationship between myocardial edema and regional myocardial function after reperfused acute myocardial infarction: an MR imaging study Myocardial T1 and T2 mapping in severe aortic stenosis: potential novel insights into the pathophysiology of myocardial remodelling Evidence of myocardial edema in patients with nonischemic dilated cardiomyopathy Cardiovascular magnetic resonance T2 mapping can detect myocardial edema in idiopathic dilated cardiomyopathy Distribution and clinical significance of high signal intensity of the myocardium on T2-weighted images in 2 phenotypes of hypertrophic cardiomyopathy Myocardial T2 mapping in patients with hypertrophic cardiomyopathy mapping and T1-mapping detect myocardial involvement in Tako-Tsubo cardiomyopathy: a preliminary experience Myocardial and systemic inflammation in acute stress-induced (Takotsubo) cardiomyopathy Left ventricular function recovery in peripartum cardiomyopathy: a cardiovascular magnetic resonance study by myocardial T1 and T2 mapping Myocardial edema and prognosis in amyloidosis Cardiac sarcoidosis-state of the art review T1 and T2 mapping in recognition of early cardiac involvement in systemic sarcoidosis Myocardial edema, myocyte injury, and disease severity in Fabry disease Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis Abnormal T2 mapping cardiovascular magnetic resonance correlates with adverse clinical outcome in patients with suspected acute myocarditis Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): a systematic review of cardiac magnetic resonance imaging findings in 199 patients Myocardial inflammation and dysfunction in COVID-19-associated myocardial injury T2-mapping increase is the prevalent imaging biomarker of myocardial involvement in active COVID-19: a cardiovascular magnetic resonance study Nonischemic myocardial changes detected by cardiac magnetic resonance in critical care patients with sepsis HIV-1-related cardiovascular disease is associated with chronic inflammation, frequent pericardial effusions, and probable myocardial edema Myocardial tissue characterization in Chagas' heart disease by cardiovascular magnetic resonance Diffuse myocardial fibrosis and inflammation in rheumatoid arthritis: insights from CMR T1 mapping T1 and T2 mapping for evaluation of myocardial involvement in patients with ANCA-associated vasculitides Magnetic resonance imaging of the cardiac manifestations of Churg-Strauss Early myocardial damage and microvascular dysfunction in asymptomatic patients with systemic sclerosis: a cardiovascular magnetic resonance study with cold pressor test Subclinical myocardial inflammation and diffuse fibrosis are common in systemic sclerosis-a clinical study using myocardial T1-mapping and extracellular volume quantification Myocardial tissue characterization in systemic lupus erythematosus: value of a comprehensive cardiovascular magnetic resonance approach Myocardial T2 mapping by cardiovascular magnetic resonance reveals subclinical myocardial inflammation in patients with systemic lupus erythematosus Rapidly reversible myocardial edema in patients with acromegaly: assessment with ultrafast T2 mapping in a singlebreath-hold MRI sequence Native magnetic resonance T1-mapping identifies diffuse myocardial injury in hypothyroidism Myocardial oedema in the failing heart 975 Detection and prediction of acute heart transplant rejection with the myocardial T2determination provided by a black-blood magnetic resonance imaging sequence Cardiovascular magnetic resonance in heart transplant patients: diagnostic value of quantitative tissue markers: T2 mapping and extracellular volume fraction, for acute rejection diagnosis Myocardial T1-mapping and extracellular volume in pulmonary arterial hypertension: a systematic review and meta-analysis Cardiac biomarkers in chronic kidney disease are independently associated with myocardial edema and diffuse fibrosis by cardiovascular magnetic resonance Acute changes in cardiac structural and tissue characterisation parameters following haemodialysis measured using cardiovascular magnetic resonance Early effects of kidney transplantation on the heart-a cardiac magnetic resonance multi-parametric study Birmingham Cardio-Renal Group. Defining myocardial abnormalities across the stages of chronic kidney disease: a cardiac magnetic resonance imaging study Regional myocardial edema detected by T2 mapping is a feature of cardiotoxicity in breast cancer patients receiving sequential therapy with anthracyclines and trastuzumab Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure This study was funded by national funds through FCT -Portuguese Foundation for Science and Technology, under the scope of the Cardiovascular R&D Center -UnIC (UIDB/ 00051/2020 and UIDP/00051/2020).