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Cardiac Physiology of Aging: Extracellular Considerations

Margaux A. Horn

10.1002/cphy.c140063

Source: Volume 5, Issue 3, July 2015

Published online: June 2015

Full Article on Wiley Online Library



ABSTRACT

Aging is a major risk factor for the development of cardiovascular disease, with the majority of affected patients being elderly. Progressive changes to myocardial structure and function occur with aging, often in concert with underlying pathologies. However, whether chronological aging results in a remodeled “aged substrate” has yet to be established. In addition to myocyte contractility, myocardial performance relies heavily on the cardiac extracellular matrix (ECM), the roles of which are as dynamic as they are significant; including providing structural integrity, assisting in force transmission throughout the cardiac cycle and acting as a signaling medium for communication between cells and the extracellular environment. In the healthy heart, ECM homeostasis must be maintained, and matrix deposition is in balance with degradation. Consequently, alterations to, or misregulation of the cardiac ECM has been shown to occur in both aging and in pathological remodeling with disease. Mounting evidence suggests that age‐induced matrix remodeling may occur at the level of ECM control; including collagen synthesis, deposition, maturation, and degradation. Furthermore, experimental studies using aged animal models not only suggest that the aged heart may respond differently to insult than the young, but the identification of key players specific to remodeling with age may hold future therapeutic potential for the treatment of cardiac dysfunction in the elderly. This review will focus on the role of the cardiac interstitium in the physiology of the aging myocardium, with particular emphasis on the implications to age‐related remodeling in disease. © 2015 American Physiological Society. Compr Physiol 5:1069‐1121, 2015.

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Figure 1. Figure 1. Relationship between wall tension, cardiac morphology, and function in aging. The relationship between ventricular dimension, pressure, and wall thickness is described by the Law of LaPlace. Throughout aging, increased workload placed on the heart may occur from age‐related vascular stiffening, or intrinsic changes within the myocardium itself. To maintain a given ventricular pressure (P; and thus systolic function is preserved), myocyte hypertrophy results in increased wall thickness (h) and thus wall tension is normalized when ventricular dimension (R; radius) is maintained. However, ventricular remodeling and concurrent interstitial fibrosis results in ventricular stiffening and prolonged relaxation.
Figure 2. Figure 2. Morphological characteristics of the aged heart. Aging is associated with alterations to cardiac morphology. Vascular and large artery remodeling leads to aortic (Ao) stiffening with age, increasing myocardial afterload. Aging‐induced myocyte cell death by either necrosis or apoptosis leads to myocyte loss and hypertrophy of the remaining myocytes. Collectively, this results in myocardial hypertrophy on both the left and right sides of the heart leading to an increase in cardiac mass to volume ratio. This manifests as an increase in left ventricular (LV) wall thickness. Interstitial fibrosis is prominent and acts alongside LV wall thickening to act as a compensatory mechanism to withstand an increased workload consequence to ventricular‐vascular‐coupled stiffening and myocyte loss. In addition to ventricular remodeling, dilatation and hypertrophy of the left atria (LA) occurs leading to atrial enlargement with age. RA = right atria, RV = right ventricle.
Figure 3. Figure 3. Schematic representation of the cardiac interstitium. (A) Both myocytes and nonmyocyte cells as well as proteins and molecules which make up the extracellular matrix (ECM) are embedded within a hydrous ground substance of glycosaminoglycans and proteoglycans. Fibrillar collagen is the predominant ECM protein in the cardiac intersitium, surrounding myofibrillar bundles in a perimysial collagen network, and interconnecting individual myocytes through the endomysial network. Other cell types including cardiac fibroblasts, macrophages and neutrophils also exist in the extracellular space. (B) Myocytes interact with the interstitial environment though integrins and basement membrane proteins. Integrins span the sarcolemma and bind to the actin cytoskeleton intracellularly. The myocyte basement membrane consists of distinct networks of lattice‐like collagen type IV and laminin. These two networks are then linked by the proteoglycan perlecan. Nidogen is component of both collagen type IV and laminin networks. Both laminin and fibronectin bind to integrins and the fibrillar collagen network.
Figure 4. Figure 4. Role and organization of the cardiac fibroblasts. Cardiac fibroblasts are the principal cell type responsible for maintenance of the ECM in the myocardium. (A) Cross‐sectional histological view of rabbit heart stained with hematoxylin and eosin depicting the lamellar structure of the myocardium. Cardiac muscle (pink), scale bar = 5 mm. (B) Transverse view of a rabbit LV tissue section visualized by confocal microscopy. Fibroblasts stained for vimentin (blue) are organized between myocytes stained for myomesin (red). Connexin‐43, bright green and nuclei stained for DAPI (pale yellow/green). Scale bar = 20 μm. (A) and (B) are reprinted, with permission, from (78). (C) Resident fibroblasts are derived from epicardial mesenchymal cells during development. These fibroblasts are thought to regulate matrix turnover in the healthy myocardium by synthesizing both matrix proteins and matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). However following cardiac insult, pathology, and perhaps in aging, fibroblasts will differentiate into myofibroblasts that express αSMA and thus are able to contract and generate force. Myofibroblasts are more sensitive to both mechanical (e.g., stretch) and chemical (bioactive molecules) stimuli and will increase secretion of matrix proteins and MMPs to increase matrix turnover, as well as being highly proliferative and migratory. New evidence suggests that the resident population of fibroblasts/myofibroblasts may be recruited from different cell populations in both disease and aging.
Figure 5. Figure 5. Collagen organization in the myocardium. Collagen organization of the ovine myocardium stained with picrosirius red and visualized by polarized light microscopy where fibrillar collagen is illuminated in yellow/red/green. The perimysial collagen network (P) surrounds myofibrillar bundles. The endomysium (E) surrounds and connects individual myocytes. Scale bar = 100 μm.
Figure 6. Figure 6. The complexity of ECM homeostasis in the heart. Regulation of the cardiac matrix is brought about by a finely balanced equilibrium between matrix synthesis, maturation and processing, and degradation. However cross‐talk between factors controlling these processes leads to a great deal of complexity—meaning matrix protein concentration and integrity cannot simply be inferred from changes to matrix synthesis, or MMP/TIMP levels alone.
Figure 7. Figure 7. Aging is associated with ventricular fibrosis in a large animal model. The interstitial collagen matrix from both young adult (18 months; A and C), and aged (>8 years; B and D) sheep visualized by picrosirius red staining and light microscopy. Under bright field, (i) the interstitial ECM appears pink/red and the myocytes appear yellow, whereas under polarized light (ii) only the fibrillar collagen matrix illuminates as red/yellow/green against a dark background. Aging in the sheep was associated with an expansion of the perimysial collagen matrix as visualized in sections of longitudinal orientation (A and B), as well as increased collagen surrounding myocytes. The latter of which could be seen where myocytes in the tissue were visualized in cross‐section (C and D). Scale bar = 100 μm. Adapted, with permission, from (218).
Figure 8. Figure 8. Pathways of cardiac fibroblast dysfunction and collagen synthesis which may play a role in aging. Aberrant control of collagen secretion from cardiac fibroblasts can occur through several converging pathways. Increased levels of TGF‐β1 in aging can occur through release of active TGF‐β1 from the latent form by enzymes (including MMPs), matricellular proteins (including TSP‐1) and oxidative stress (elevated levels of ROS). TGF‐β1 enhances cardiac fibroblast proliferation, differentiation to myofibroblasts and stimulates ECM turnover, but also acts as negative regulator for both mesenchymal stem cell (MSC) and myeloid differentiation to fibroblasts which, in addition to resident cardiac fibroblasts, have the ability to secrete collagen. AngII signals through both the AT1R or AT2R, and can also signal via ROS and TGF‐β1.
Figure 9. Figure 9. miRNAs in aging‐induced fibrosis. miR‐22 is important in cardiac fibroblast senescence and aging‐induced fibrosis. (A) Levels of miR‐22 increase with age in the mouse, and are associated with increased collagen content of the LV (Bi) as visualized by picrosirius red staining (Bii). (C) Enrichment of miR‐22 in human cardiac fibroblasts compared to rat cardiac myocytes and human endothelial and smooth muscle cells. (D) Increased miR‐22 expression correlates with decreased protein levels of mimican in the mouse heart. (E) Neonatal rat cardiac fibroblasts transfected with the precursor of miR‐22 (pre‐miR‐22) exhibited premature cellular senescence compared to control miR (pre‐Neg2) as illustrated by increased β‐galactosidase activity. Premature senescence was inhibited by incubation with an antagonist to miR‐22 (anti‐miR‐22). (F) Neonatal rat cardiac fibroblasts transfected with siRNA targeted to mimican (or osteoglycin, OGN) also exhibited increased β‐galactosidase activity. Adapted, with permission, from (240).
Figure 10. Figure 10. Alterations to matricellular proteins with age. Schematic representation of the role of SPARC and TSPs in collagen remodeling with age. SPARC binds to the secreted procollagen molecule and increases its extracellular availability to ADAMTS and BMP‐1 which cleave the N‐ and C‐terminal propeptide regions, respectively. The processed collagen molecule is then rendered insoluble and becomes a mature cross‐linked fibril by activity of LOX or by nonenzymatic formation of AGEs. MMPs can then degrade insoluble collagen, as well as process SPARC to increase its activity. TSP‐1 will increase formation of TGF‐β1 which has profibrotic effects on the cardiac fibroblast. Both TSP‐1 and TSP‐2 inhibit activity of MMPs. TSP‐2 also promotes myocyte survival. Red arrows indicate changes in matricellular protein with age.
Figure 11. Figure 11. Atrial contribution to ventricular function and possible alterations with age. The cardiac atria play an integral role in maintaining ventricular function. During LV systole (A), the LA stretch and fill with blood to accommodate an increase in volume. During ventricular diastole (B), LV filling occurs in two phases. The first phase (Bi; early) is a passive process, and involves blood movement down the atrioventricular pressure gradient (black arrow) and directly from the pulmonary veins (gray arrows). Passive LV filling is governed largely by elastic recoil of the atrial tissue and LV diastolic function. In the second phase (Bii; active), atrial contraction ejects the remainder of the blood to the LV. In aging, LV hypertrophy and fibrosis leads to LV stiffening and diastolic dysfunction while systolic function is relatively preserved. Atrial stiffening may also occur due to changes in properties of the atrial ECM. Due to these changes, there is a proportional decrease in passive‐mediated LV filling (decreased E/A ratio) which may further potentiate LV diastolic dysfunction.
Figure 12. Figure 12. Influence of aging on response of the ECM to cardiac insult. Remodeling of the cardiac ECM following tachypacing‐induced heart failure in the sheep is dependent on age. (A) Interstitial collagen matrix of the ovine LV visualized by picrosirius red staining with bright field (top panel) and polarized (bottom panel) light microscopy. White arrows indicate thickening of the perimysial collagen matrix. Scale bar = 100 μm. (B) Mean collagen content quantified from histochemistry in (A), and depicts an age‐dependent response of the ECM to rapid‐pacing. (C) Using gelatin zymography, MMP‐2 activity was increased following rapid‐pacing and with aging alone, but to no greater extent in the aged, failing hearts. Conversely, both TIMP‐3 (D) and TIMP‐4 (E) protein levels were reduced only in the aged, failing heart. (F) Both aging and rapid pacing led to LV dilatation and systolic dysfunction; however, extent of LV remodeling was greatest in the aged, failing sheep. Solid arrow and open arrow indicate endocardial surfaces of the LV free wall and the septum, respectively. YC, young control; YF, young failure; OC, old control; OF, old failure. * P < 0.05 vs. YC, ** P < 0.01 vs. YC, *** P < 0.001 vs. YC, † P < 0.05 vs. OC, # P < 0.05 vs. YF, ## P < 0.01 vs. YF. Adapted, with permission, from (218).


Figure 1. Relationship between wall tension, cardiac morphology, and function in aging. The relationship between ventricular dimension, pressure, and wall thickness is described by the Law of LaPlace. Throughout aging, increased workload placed on the heart may occur from age‐related vascular stiffening, or intrinsic changes within the myocardium itself. To maintain a given ventricular pressure (P; and thus systolic function is preserved), myocyte hypertrophy results in increased wall thickness (h) and thus wall tension is normalized when ventricular dimension (R; radius) is maintained. However, ventricular remodeling and concurrent interstitial fibrosis results in ventricular stiffening and prolonged relaxation.


Figure 2. Morphological characteristics of the aged heart. Aging is associated with alterations to cardiac morphology. Vascular and large artery remodeling leads to aortic (Ao) stiffening with age, increasing myocardial afterload. Aging‐induced myocyte cell death by either necrosis or apoptosis leads to myocyte loss and hypertrophy of the remaining myocytes. Collectively, this results in myocardial hypertrophy on both the left and right sides of the heart leading to an increase in cardiac mass to volume ratio. This manifests as an increase in left ventricular (LV) wall thickness. Interstitial fibrosis is prominent and acts alongside LV wall thickening to act as a compensatory mechanism to withstand an increased workload consequence to ventricular‐vascular‐coupled stiffening and myocyte loss. In addition to ventricular remodeling, dilatation and hypertrophy of the left atria (LA) occurs leading to atrial enlargement with age. RA = right atria, RV = right ventricle.


Figure 3. Schematic representation of the cardiac interstitium. (A) Both myocytes and nonmyocyte cells as well as proteins and molecules which make up the extracellular matrix (ECM) are embedded within a hydrous ground substance of glycosaminoglycans and proteoglycans. Fibrillar collagen is the predominant ECM protein in the cardiac intersitium, surrounding myofibrillar bundles in a perimysial collagen network, and interconnecting individual myocytes through the endomysial network. Other cell types including cardiac fibroblasts, macrophages and neutrophils also exist in the extracellular space. (B) Myocytes interact with the interstitial environment though integrins and basement membrane proteins. Integrins span the sarcolemma and bind to the actin cytoskeleton intracellularly. The myocyte basement membrane consists of distinct networks of lattice‐like collagen type IV and laminin. These two networks are then linked by the proteoglycan perlecan. Nidogen is component of both collagen type IV and laminin networks. Both laminin and fibronectin bind to integrins and the fibrillar collagen network.


Figure 4. Role and organization of the cardiac fibroblasts. Cardiac fibroblasts are the principal cell type responsible for maintenance of the ECM in the myocardium. (A) Cross‐sectional histological view of rabbit heart stained with hematoxylin and eosin depicting the lamellar structure of the myocardium. Cardiac muscle (pink), scale bar = 5 mm. (B) Transverse view of a rabbit LV tissue section visualized by confocal microscopy. Fibroblasts stained for vimentin (blue) are organized between myocytes stained for myomesin (red). Connexin‐43, bright green and nuclei stained for DAPI (pale yellow/green). Scale bar = 20 μm. (A) and (B) are reprinted, with permission, from (78). (C) Resident fibroblasts are derived from epicardial mesenchymal cells during development. These fibroblasts are thought to regulate matrix turnover in the healthy myocardium by synthesizing both matrix proteins and matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). However following cardiac insult, pathology, and perhaps in aging, fibroblasts will differentiate into myofibroblasts that express αSMA and thus are able to contract and generate force. Myofibroblasts are more sensitive to both mechanical (e.g., stretch) and chemical (bioactive molecules) stimuli and will increase secretion of matrix proteins and MMPs to increase matrix turnover, as well as being highly proliferative and migratory. New evidence suggests that the resident population of fibroblasts/myofibroblasts may be recruited from different cell populations in both disease and aging.


Figure 5. Collagen organization in the myocardium. Collagen organization of the ovine myocardium stained with picrosirius red and visualized by polarized light microscopy where fibrillar collagen is illuminated in yellow/red/green. The perimysial collagen network (P) surrounds myofibrillar bundles. The endomysium (E) surrounds and connects individual myocytes. Scale bar = 100 μm.


Figure 6. The complexity of ECM homeostasis in the heart. Regulation of the cardiac matrix is brought about by a finely balanced equilibrium between matrix synthesis, maturation and processing, and degradation. However cross‐talk between factors controlling these processes leads to a great deal of complexity—meaning matrix protein concentration and integrity cannot simply be inferred from changes to matrix synthesis, or MMP/TIMP levels alone.


Figure 7. Aging is associated with ventricular fibrosis in a large animal model. The interstitial collagen matrix from both young adult (18 months; A and C), and aged (>8 years; B and D) sheep visualized by picrosirius red staining and light microscopy. Under bright field, (i) the interstitial ECM appears pink/red and the myocytes appear yellow, whereas under polarized light (ii) only the fibrillar collagen matrix illuminates as red/yellow/green against a dark background. Aging in the sheep was associated with an expansion of the perimysial collagen matrix as visualized in sections of longitudinal orientation (A and B), as well as increased collagen surrounding myocytes. The latter of which could be seen where myocytes in the tissue were visualized in cross‐section (C and D). Scale bar = 100 μm. Adapted, with permission, from (218).


Figure 8. Pathways of cardiac fibroblast dysfunction and collagen synthesis which may play a role in aging. Aberrant control of collagen secretion from cardiac fibroblasts can occur through several converging pathways. Increased levels of TGF‐β1 in aging can occur through release of active TGF‐β1 from the latent form by enzymes (including MMPs), matricellular proteins (including TSP‐1) and oxidative stress (elevated levels of ROS). TGF‐β1 enhances cardiac fibroblast proliferation, differentiation to myofibroblasts and stimulates ECM turnover, but also acts as negative regulator for both mesenchymal stem cell (MSC) and myeloid differentiation to fibroblasts which, in addition to resident cardiac fibroblasts, have the ability to secrete collagen. AngII signals through both the AT1R or AT2R, and can also signal via ROS and TGF‐β1.


Figure 9. miRNAs in aging‐induced fibrosis. miR‐22 is important in cardiac fibroblast senescence and aging‐induced fibrosis. (A) Levels of miR‐22 increase with age in the mouse, and are associated with increased collagen content of the LV (Bi) as visualized by picrosirius red staining (Bii). (C) Enrichment of miR‐22 in human cardiac fibroblasts compared to rat cardiac myocytes and human endothelial and smooth muscle cells. (D) Increased miR‐22 expression correlates with decreased protein levels of mimican in the mouse heart. (E) Neonatal rat cardiac fibroblasts transfected with the precursor of miR‐22 (pre‐miR‐22) exhibited premature cellular senescence compared to control miR (pre‐Neg2) as illustrated by increased β‐galactosidase activity. Premature senescence was inhibited by incubation with an antagonist to miR‐22 (anti‐miR‐22). (F) Neonatal rat cardiac fibroblasts transfected with siRNA targeted to mimican (or osteoglycin, OGN) also exhibited increased β‐galactosidase activity. Adapted, with permission, from (240).


Figure 10. Alterations to matricellular proteins with age. Schematic representation of the role of SPARC and TSPs in collagen remodeling with age. SPARC binds to the secreted procollagen molecule and increases its extracellular availability to ADAMTS and BMP‐1 which cleave the N‐ and C‐terminal propeptide regions, respectively. The processed collagen molecule is then rendered insoluble and becomes a mature cross‐linked fibril by activity of LOX or by nonenzymatic formation of AGEs. MMPs can then degrade insoluble collagen, as well as process SPARC to increase its activity. TSP‐1 will increase formation of TGF‐β1 which has profibrotic effects on the cardiac fibroblast. Both TSP‐1 and TSP‐2 inhibit activity of MMPs. TSP‐2 also promotes myocyte survival. Red arrows indicate changes in matricellular protein with age.


Figure 11. Atrial contribution to ventricular function and possible alterations with age. The cardiac atria play an integral role in maintaining ventricular function. During LV systole (A), the LA stretch and fill with blood to accommodate an increase in volume. During ventricular diastole (B), LV filling occurs in two phases. The first phase (Bi; early) is a passive process, and involves blood movement down the atrioventricular pressure gradient (black arrow) and directly from the pulmonary veins (gray arrows). Passive LV filling is governed largely by elastic recoil of the atrial tissue and LV diastolic function. In the second phase (Bii; active), atrial contraction ejects the remainder of the blood to the LV. In aging, LV hypertrophy and fibrosis leads to LV stiffening and diastolic dysfunction while systolic function is relatively preserved. Atrial stiffening may also occur due to changes in properties of the atrial ECM. Due to these changes, there is a proportional decrease in passive‐mediated LV filling (decreased E/A ratio) which may further potentiate LV diastolic dysfunction.


Figure 12. Influence of aging on response of the ECM to cardiac insult. Remodeling of the cardiac ECM following tachypacing‐induced heart failure in the sheep is dependent on age. (A) Interstitial collagen matrix of the ovine LV visualized by picrosirius red staining with bright field (top panel) and polarized (bottom panel) light microscopy. White arrows indicate thickening of the perimysial collagen matrix. Scale bar = 100 μm. (B) Mean collagen content quantified from histochemistry in (A), and depicts an age‐dependent response of the ECM to rapid‐pacing. (C) Using gelatin zymography, MMP‐2 activity was increased following rapid‐pacing and with aging alone, but to no greater extent in the aged, failing hearts. Conversely, both TIMP‐3 (D) and TIMP‐4 (E) protein levels were reduced only in the aged, failing heart. (F) Both aging and rapid pacing led to LV dilatation and systolic dysfunction; however, extent of LV remodeling was greatest in the aged, failing sheep. Solid arrow and open arrow indicate endocardial surfaces of the LV free wall and the septum, respectively. YC, young control; YF, young failure; OC, old control; OF, old failure. * P < 0.05 vs. YC, ** P < 0.01 vs. YC, *** P < 0.001 vs. YC, † P < 0.05 vs. OC, # P < 0.05 vs. YF, ## P < 0.01 vs. YF. Adapted, with permission, from (218).
References
 1. Abrial M , Da Silva CC , Pillot B , Augeul L , Ivanes F , Teixeira G , Cartier R , Angoulvant D , Ovize M , Ferrera R . Cardiac fibroblasts protect cardiomyocytes against lethal ischemia‐reperfusion injury. J Mol Cell Cardiol 68: 56‐65, 2014.
 2. Adam O , Lohfelm B , Thum T , Gupta SK , Puhl SL , Schafers HJ , Bohm M , Laufs U . Role of miR‐21 in the pathogenesis of atrial fibrosis. Basic Res Cardiol 107: 278, 2012.
 3. Ahumada GG , Saffitz JE . Fibronectin in rat heart: A link between cardiac myocytes and collagen. J Histochem Cytochem 32: 383‐388, 1984.
 4. Alberts B , Bray D , Lewis J , Raff M , Roberts K , Watson JD . Cell junctions, cell adhesion and the extracellular matrix. In: Mol Biol Cell. New York, NY: Garland Publishing, 1994, pp. 949‐1009.
 5. Ali MA , Cho WJ , Hudson B , Kassiri Z , Granzier H , Schulz R . Titin is a target of matrix metalloproteinase‐2: Implications in myocardial ischemia/reperfusion injury. Circulation 122: 2039‐2047, 2010.
 6. Ali MA , Fan X , Schulz R . Cardiac sarcomeric proteins: Novel intracellular targets of matrix metalloproteinase‐2 in heart disease. Trends Cardiovasc Med 21: 112‐118, 2011.
 7. Ammarguellat FZ , Gannon PO , Amiri F , Schiffrin EL . Fibrosis, matrix Metalloproteinases, and inflammation in the heart of DOCA‐salt hypertensive rats: Role of ETA receptors. Hypertension 39: 679‐684, 2002.
 8. Amour A , Slocombe PM , Webster A , Butler M , Knight CG , Smith BJ , Stephens PE , Shelley C , Hutton M , Knauper V , Docherty AJ , Murphy G . TNF‐alpha converting enzyme (TACE) is inhibited by TIMP‐3. FEBS Lett 435: 39‐44, 1998.
 9. Annoni G , Luvarà G , Arosio B , Gagliano N , Fiordaliso F , Santambrogio D , Jeremic G , Mircoli L , Latini R , Vergani C , Masson S . Age‐dependent expression of fibrosis‐related genes and collagen deposition in the rat myocardium. Mech Ageing Dev 101: 57‐72, 1998.
 10. Anversa P , Hiler B , Ricci R , Guideri G , Olivetti G . Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol 8: 1441‐1448, 1986.
 11. Anversa P , Olivetti G . Cellular Basis of Physiological and Pathological Myocardial Growth. Compr Physiol. 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 75‐144. First published in print 2002. doi: 10.1002/cphy.cp020102
 12. Anwar AM , Geleijnse ML , Soliman OII , Nemes A , Cate FJ . Left atrial Frank‐Starling law assessed by real‐time, three‐dimensional echocardiographic left atrial volume changes. Heart 93: 1393‐1397, 2007.
 13. Anyukhovsky EP , Sosunov EA , Chandra P , Rosen TS , Boyden PA , Danilo P Jr. , Rosen MR . Age‐associated changes in electrophysiologic remodeling: A potential contributor to initiation of atrial fibrillation. Cardiovasc Res 66: 353‐363, 2005.
 14. Anyukhovsky EP , Sosunov EA , Plotnikov A , Gainullin RZ , Jhang JS , Marboe CC , Rosen MR . Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res 54: 462‐469, 2002.
 15. Arbab‐Zadeh A , Dijk E , Prasad A , Fu Q , Torres P , Zhang R , Thomas JD , Palmer D , Levine BD . Effect of aging and physical activity on left ventricular compliance. Circulation 110: 1799‐1805, 2004.
 16. Aronson D . Cross‐linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens 21: 3‐12, 2003.
 17. Asif M , Egan J , Vasan S , Jyothirmayi GN , Masurekar MR , Lopez S , Williams C , Torres RL , Wagle D , Ulrich P , Cerami A , Brines M , Regan TJ . An advanced glycation endproduct cross‐link breaker can reverse age‐related increases in myocardial stiffness. Proc Natl Acad Sci U S A 97: 2809‐2813, 2000.
 18. Assomull RG , Prasad SK , Lyne J , Smith G , Burman ED , Khan M , Sheppard MN , Poole‐Wilson PA , Pennell DJ . Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol 48: 1977‐1985, 2006.
 19. Ayisi K , Lindner J , Krohn J , Mangold I . Investigations on connective tissue metabolism: Ageing of the human heart. Mech Ageing Dev 14: 325‐331, 1980.
 20. Badenhorst D , Maseko M , Tsotetsi OJ , Naidoo A , Brooksbank R , Norton GR , Woodiwiss AJ . Cross‐linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats. Cardiovasc Res 57: 632‐641, 2003.
 21. Baicu CF , Stroud JD , Livesay VA , Hapke E , Holder J , Spinale FG , Zile MR . Changes in extracellular collagen matrix alter myocardial systolic performance. Am J Physiol Heart Circ Physiol 284: H122‐H132, 2003.
 22. Baicu CF , Zhang Y , Van Laer AO , Renaud L , Zile MR , Bradshaw AD . Effects of the absence of procollagen C‐endopeptidase enhancer‐2 on myocardial collagen accumulation in chronic pressure overload. Am J Physiol Heart Circ Physiol 303: H234‐H240, 2012.
 23. Bailey AJ . Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev 122: 735‐755, 2001.
 24. Balasubramanian S , Quinones L , Kasiganesan H , Zhang Y , Pleasant DL , Sundararaj KP , Zile MR , Bradshaw AD , Kuppuswamy D . Beta3 integrin in cardiac fibroblast is critical for extracellular matrix accumulation during pressure overload hypertrophy in mouse. PLoS One 7: e45076, 2012.
 25. Banerjee I , Yekkala K , Borg TK , Baudino TA . Dynamic interactions between myocytes, fibroblasts, and extracellular matrix. Ann N Y Acad Sci 1080: 76‐84, 2006.
 26. Bapat A , Nguyen TP , Lee JH , Sovari AA , Fishbein MC , Weiss JN , Karagueuzian HS . Enhanced sensitivity of aged fibrotic hearts to angiotensin II‐ and hypokalemia‐induced early afterdepolarization‐mediated ventricular arrhythmias. Am J Physiol Heart Circ Physiol 302: H2331‐H2340, 2012.
 27. Bashey RI , Martinez‐Hernandez A , Jimenez SA . Isolation, characterization, and localization of cardiac collagen type VI. Associations with other extracellular matrix components. Circ Res 70: 1006‐1017, 1992.
 28. Basso N , Cini R , Pietrelli A , Ferder L , Terragno NA , Inserra F . Protective effect of long‐term angiotensin II inhibition. Am J Physiol Heart Circ Physiol 293: H1351‐H1358, 2007.
 29. Batkai S , Rajesh M , Mukhopadhyay P , Hasko G , Liaudet L , Cravatt BF , Csiszar A , Ungvari Z , Pacher P . Decreased age‐related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol 293: H909‐H918, 2007.
 30. Baudino TA , Carver W , Giles W , Borg TK . Cardiac fibroblasts: Friend or foe? Am J Physiol Heart Circ Physiol 291: H1015‐H1026, 2006.
 31. Behrens DT , Villone D , Koch M , Brunner G , Sorokin L , Robenek H , Bruckner‐Tuderman L , Bruckner P , Hansen U . The epidermal basement membrane is a composite of separate laminin‐ or collagen IV‐containing networks connected by aggregated perlecan, but not by nidogens. J Biol Chem 287: 18700‐18709, 2012.
 32. Bein K , Simons M . Thrombospondin type 1 repeats interact with matrix metalloproteinase 2: Regulation of metalloproteinase activity. J Biol Chem 275: 32167‐32173, 2000.
 33. Benigni A , Corna D , Zoja C , Sonzogni A , Latini R , Salio M , Conti S , Rottoli D , Longaretti L , Cassis P , Morigi M , Coffman TM , Remuzzi G . Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119: 524‐530, 2009.
 34. Benjamin IJ , Jalil JE , Tan LB , Cho K , Weber KT , Clark WA . Isoproterenol‐induced myocardial fibrosis in relation to myocyte necrosis. Circ Res 65: 657‐670, 1989.
 35. Berg TJ , Snorgaard O , Faber J , Torjesen PA , Hildebrandt P , Mehlsen J , Hanssen KF . Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetes Care 22: 1186‐1190, 1999.
 36. Bers DM . Altered cardiac myocyte Ca regulation in heart failure. Physiology 21: 380‐387, 2006.
 37. Bhatia RS , Tu JV , Lee DS , Austin PC , Fang J , Haouzi A , Gong Y , Liu PP . Outcome of heart failure with preserved ejection fraction in a population‐based study. N Engl J Med 355: 260‐269, 2006.
 38. Biernacka A , Frangogiannis NG . Aging and cardiac fibrosis. Aging Dis 2: 158‐173, 2011.
 39. Bing OHL , Matsushita S , Fanburg BL , Levine HJ . Mechanical properties of rat cardiac muscle during experimental hypertrophy. Circ Res 28: 234‐245, 1971.
 40. Boengler K , Buechert A , Heinen Y , Roeskes C , Hilfiker‐Kleiner D , Heusch G , Schulz R . Cardioprotection by ischemic postconditioning is lost in aged and STAT3‐deficient mice. Circ Res 102: 131‐135, 2008.
 41. Boixel C , Fontaine V , Rucker‐Martin C , Milliez P , Louedec L , Michel JB , Jacob MP , Hatem SN . Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol 42: 336‐344, 2003.
 42. Boldt A , Wetzel U , Lauschke J , Weigl J , Gummert J , Hindricks G , Kottkamp H , Dhein S . Fibrosis in left atrial tissue of patients with atrial fibrillation with and without underlying mitral valve disease. Heart 90: 400‐405, 2004.
 43. Boluyt MO , O'Neill L , Meredith AL , Bing OHL , Brooks WW , Conrad CH , Crow MT , Lakatta EG . Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Circ Res 75: 23‐32, 1994.
 44. Bonnema DD , Webb CS , Pennington WR , Stroud RE , Leonardi AE , Clark LL , McClure CD , Finklea L , Spinale FG , Zile MR . Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). J Card Fail 13: 530‐540, 2007.
 45. Bonnin CM , Sparrow MP , Taylor RR . Collagen‐synthesis and content in right ventricular hypertrophy in the dog. Am J Physiol 241: H708‐H713, 1981.
 46. Boon RA , Iekushi K , Lechner S , Seeger T , Fischer A , Heydt S , Kaluza D , Treguer K , Carmona G , Bonauer A , Horrevoets AJ , Didier N , Girmatsion Z , Biliczki P , Ehrlich JR , Katus HA , Muller OJ , Potente M , Zeiher AM , Hermeking H , Dimmeler S . MicroRNA‐34a regulates cardiac ageing and function. Nature 495: 107‐110, 2013.
 47. Borer JS , Truter S , Herrold EM , Falcone DJ , Pena M , Carter JN , Dumlao TF , Lee JA , Supino PG . Myocardial fibrosis in chronic aortic regurgitation: Molecular and cellular responses to volume overload. Circulation 105: 1837‐1842, 2002.
 48. Borlaug BA , Paulus WJ . Heart failure with preserved ejection fraction: Pathophysiology, diagnosis, and treatment. Eur Heart J 32: 670‐679, 2011.
 49. Borlaug BA , Redfield MM , Melenovsky V , Kane GC , Karon BL , Jacobsen SJ , Rodeheffer RJ . Longitudinal changes in left ventricular stiffness: A community‐based study. Circ Heart Fail 6: 944‐952, 2013.
 50. Boyd AC , Schiller NB , Leung D , Ross DL , Thomas L . Atrial dilation and altered function are mediated by age and diastolic function but not before the eighth decade. JACC Cardiovasc Imaging 4: 234‐242, 2011.
 51. Bozkurt B , Kribbs SB , Clubb FJ Jr. , Michael LH , Didenko VV , Hornsby PJ , Seta Y , Oral H , Spinale FG , and Mann DL . Pathophysiologically relevant concentrations of tumor necrosis factor‐alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 97: 1382‐1391, 1998.
 52. Bradham WS , Moe G , Wendt KA , Scott AA , Konig A , Romanova M , Naik G , Spinale FG . TNF‐alpha and myocardial matrix metalloproteinases in heart failure: Relationship to LV remodeling. Am J Physiol Heart Circ Physiol 282: H1288‐H1295, 2002.
 53. Bradshaw AD , Baicu CF , Rentz TJ , Van Laer AO , Boggs J , Lacy JM , Zile MR . Pressure overload‐induced alterations in fibrillar collagen content and myocardial diastolic function. Circulation 119: 269‐280, 2009.
 54. Bradshaw AD , Baicu CF , Rentz TJ , Van Laer AO , Bonnema DD , Zile MR . Age‐dependent alterations in fibrillar collagen content and myocardial diastolic function: Role of SPARC in post‐synthetic procollagen processing. Am J Physiol Heart Circ Physiol 298: H614‐H622, 2010.
 55. Bradshaw AD , Graves DC , Motamed K , Sage EH . SPARC‐null mice exhibit increased adiposity without significant differences in overall body weight. Proc Natl Acad Sci USA 100: 6045‐6050, 2003.
 56. Bradshaw AD , Puolakkainen P , Dasgupta J , Davidson JM , Wight TN , Helene Sage E . SPARC‐null mice display abnormalities in the dermis characterized by decreased collagen fibril diameter and reduced tensile strength. J Invest Dermatol 120: 949‐955, 2003.
 57. Brancaccio M , Hirsch E , Notte A , Selvetella G , Lembo G , Tarone G . Integrin signalling: The tug‐of‐war in heart hypertrophy. Cardiovasc Res 70: 422‐433, 2006.
 58. Brett J , Schmidt AM , Yan SD , Zou YS , Weidman E , Pinsky D , Nowygrod R , Neeper M , Przysiecki C , Shaw A , et al. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol 143: 1699‐1712, 1993.
 59. Brew K , Dinakarpandian D , Nagase H . Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochim Biophys Acta 1477: 267‐283, 2000.
 60. Brilla CG , Reams GP , Maisch B , Weber KT . Renin‐angiotensin system and myocardial fibrosis in hypertension: Regulation of the myocardial collagen matrix. Eur Heart J 14(Suppl J): 57‐61, 1993.
 61. Brilla CG , Zhou G , Matsubara L , Weber KT . Collagen metabolism in cultured adult rat cardiac fibroblasts: Response to angiotensin II and aldosterone. J Mol Cell Cardiol 26: 809‐820, 1994.
 62. Briston SJ , Caldwell JL , Horn MA , Clarke JD , Richards MA , Greensmith DJ , Graham HK , Hall MC , Eisner DA , Dibb KM , Trafford AW . Impaired beta‐adrenergic responsiveness accentuates dysfunctional excitation contraction coupling in an ovine model of tachypacing induced heart failure. J Physiol 589: 1367‐1382, 2011.
 63. Bristow MR , Ginsburg R , Minobe W , Cubicciotti RS , Sageman WS , Lurie K , Billingham ME , Harrison DC , Stinson EB . Decreased catecholamine sensitivity and beta‐adrenergic‐receptor density in failing human hearts. N Engl J Med 307: 205‐211, 1982.
 64. Brooks WW , Bing OHL , Robinson KG , Slawsky MT , Chaletsky DM , Conrad CH . Effect of angiotensin‐converting enzyme inhibition on myocardial fibrosis and function in hypertrophied and failing myocardium from the spontaneously hypertensive rat. Circulation 96: 4002‐4010, 1997.
 65. Brooks WW , Conrad CH . Myocardial fibrosis in transforming growth factor beta(1)heterozygous mice. J Mol Cell Cardiol 32: 187‐195, 2000.
 66. Brouri F , Hanoun N , Mediani O , Saurini F , Hamon M , Vanhoutte PM , Lechat P . Blockade of beta 1‐ and desensitization of beta 2‐adrenoceptors reduce isoprenaline‐induced cardiac fibrosis. Eur J Pharmacol 485: 227‐234, 2004.
 67. Brower GL , Gardner JD , Forman MF , Murray DB , Voloshenyuk T , Levick SP , Janicki JS . The relationship between myocardial extracellular matrix remodeling and ventricular function. Eur J Cardiothorac Surg 30: 604‐610, 2006.
 68. Brown L . Cardiac extracellular matrix: A dynamic entity. Am J Physiol Heart Circ Physiol 289: H973‐H974, 2005.
 69. Bruckner P . Suprastructures of extracellular matrices: Paradigms of functions controlled by aggregates rather than molecules. Cell Tissue Res 339: 7‐18, 2010.
 70. Bruel A , Oxlund H . Changes in biomechanical properties, composition of collagen and elastin, and advanced glycation end products of the rat aorta in relation to age. Atherosclerosis 127: 155‐165, 1996.
 71. Bujak M , Frangogiannis NG . The role of TGF‐β signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74: 184‐195, 2007.
 72. Bujak M , Kweon HJ , Chatila K , Li N , Taffet G , Frangogiannis NG . Aging‐related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol 51: 1384‐1392, 2008.
 73. Burgess ML , McCrea JC , Hedrick HL . Age‐associated changes in cardiac matrix and integrins. Mech Ageing Dev 122: 1739‐1756, 2001.
 74. Burstein B , Libby E , Calderone A , Nattel S . Differential behaviors of atrial versus ventricular fibroblasts: A potential role for platelet‐derived growth factor in atrial‐ventricular remodeling differences. Circulation 117: 1630‐1641, 2008.
 75. Burstein B , Nattel S . Atrial fibrosis: Mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 51: 802‐809, 2008.
 76. Burstein B , Qi XY , Yeh YH , Calderone A , Nattel S . Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling. Cardiovasc Res 76: 442‐452, 2007.
 77. Cai H , Yuan Z , Fei Q , Zhao J . Investigation of thrombospondin‐1 and transforming growth factor‐beta expression in the heart of aging mice. Exp Ther Med 3: 433‐436, 2012.
 78. Camelliti P , Borg TK , Kohl P . Structural and functional characterisation of cardiac fibroblasts. Cardiovasc Res 65: 40‐51, 2005.
 79. Campa JS , Greenhalgh RM , Powell JT . Elastin degradation in abdominal aortic aneurysms. Atherosclerosis 65: 13‐21, 1987.
 80. Campbell DJ , Somaratne JB , Jenkins AJ , Prior DL , Yii M , Kenny JF , Newcomb AE , Schalkwijk CG , Black MJ , Kelly DJ . Diastolic dysfunction of aging is independent of myocardial structure but associated with plasma advanced glycation end‐product levels. PLoS One 7: e49813, 2012.
 81. Candido R , Forbes JM , Thomas MC , Thallas V , Dean RG , Burns WC , Tikellis C , Ritchie RH , Twigg SM , Cooper ME , Burrell LM . A breaker of advanced glycation end products attenuates diabetes‐induced myocardial structural changes. Circ Res 92: 785‐792, 2003.
 82. Cao J , Drews M , Lee HM , Conner C , Bahou WF , Zucker S . The propeptide domain of membrane type 1 matrix metalloproteinase is required for binding of tissue inhibitor of metalloproteinases and for activation of pro‐gelatinase A. J Biol Chem 273: 34745‐34752, 1998.
 83. Cao L , Gardner DG . Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. Hypertension 25: 227‐234, 1995.
 84. Cao XJ , Li YF . Alteration of messenger RNA and protein levels of cardiac alpha(1)‐adrenergic receptor and angiotensin II receptor subtypes during aging in rats. Can J Cardiol 25: 415‐420, 2009.
 85. Capasso JM , Palackal T , Olivetti G , Anversa P . Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts. Am J Physiol Heart Circ Physiol 259: H1086‐H1096, 1990.
 86. Carlson S , Trial J , Soeller C , Entman ML . Cardiac mesenchymal stem cells contribute to scar formation after myocardial infarction. Cardiovasc Res 91: 99‐107, 2011.
 87. Carver W , Terracio L , Borg TK . Expression and accumulation of interstitial collagen in the neonatal rat heart. Anat Rec 236: 511‐520, 1993.
 88. Casaclang‐Verzosa G , Gersh BJ , Tsang TSM . Structural and functional remodeling of the left atrium: Clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol 51: 1‐11.
 89. Caulfield JB , Borg TK . The collagen network of the heart. Lab Invest 40: 364‐372, 1979.
 90. Caulfield JB , Norton P , Weaver RD . Cardiac dilatation associated with collagen alterations. Mol Cell Biochem 118: 171‐179, 1992.
 91. Chan V , Fenning A , Hoey A , Brown L . Chronic beta‐adrenoceptor antagonist treatment controls cardiovascular remodeling in heart failure in the aging spontaneously hypertensive rat. J Cardiovasc Pharmacol 58: 424‐431, 2011.
 92. Chen CH , Nakayama M , Nevo E , Fetics BJ , Maughan WL , Kass DA . Coupled systolic‐ventricular and vascular stiffening with age: Implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 32: 1221‐1227, 1998.
 93. Chen H , Huang XN , Stewart AFR , Sepulveda JL . Gene expression changes associated with fibronectin‐induced cardiac myocyte hypertrophy. Physiol Genomics 18: 273‐283, 2004.
 94. Chen MA . Heart failure with preserved ejection fraction in older adults. Am J Med 122: 713‐723, 2009.
 95. Chen W , Frangogiannis NG . The role of inflammatory and fibrogenic pathways in heart failure associated with aging. Heart Fail Rev 15: 415‐422, 2010.
 96. Chen X , Li Z , Feng Z , Wang J , Ouyang C , Liu W , Fu B , Cai G , Wu C , Wei R , Wu D , Hong Q . Integrin‐linked kinase induces both senescence‐associated alterations and extracellular fibronectin assembly in aging cardiac fibroblasts. J Gerontol A Biol Sci Med Sci 61: 1232‐1245, 2006.
 97. Cheng S , Xanthakis V , Sullivan LM , Vasan RS . Blood pressure tracking over the adult life course: Patterns and correlates in the Framingham heart study. Hypertension 60: 1393‐1399, 2012.
 98. Cherubini A , Oristrell J , Pla X , Ruggiero C , Ferretti R , Diestre G , Clarfield AM , Crome P , Hertogh C , Lesauskaite V , Prada GI , Szczerbinska K , Topinkova E , Sinclair‐Cohen J , Edbrooke D , Mills GH . The persistent exclusion of older patients from ongoing clinical trials regarding heart failure. Arch Intern Med (Chic) 171: 550‐556, 2011.
 99. Chiao YA , Dai Q , Zhang J , Lin J , Lopez EF , Ahuja SS , Chou YM , Lindsey ML , Jin YF . Multi‐analyte profiling reveals matrix metalloproteinase‐9 and monocyte chemotactic protein‐1 as plasma biomarkers of cardiac aging. Circ Cardiovasc Genet 4: 455‐462, 2011.
 100. Chiao YA , Ramirez TA , Zamilpa R , Okoronkwo SM , Dai Q , Zhang J , Jin YF , Lindsey ML . Matrix metalloproteinase‐9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res 96: 444‐455, 2012.
 101. Choi DJ , Koch WJ , Hunter JJ , Rockman HA . Mechanism of beta‐adrenergic receptor desensitization in cardiac hypertrophy is increased beta‐adrenergic receptor kinase. J Biol Chem 272: 17223‐17229, 1997.
 102. Chua CC , Chua BH , Zhao ZY , Krebs C , Diglio C , Perrin E . Effect of growth factors on collagen metabolism in cultured human heart fibroblasts. Connect Tissue Res 26: 271‐281, 1991.
 103. Chung CS , Hutchinson KR , Methawasin M , Saripalli C , Smith JE, 3rd , Hidalgo CG , Luo X , Labeit S , Guo C , Granzier HL . Shortening of the elastic tandem immunoglobulin segment of titin leads to diastolic dysfunction. Circulation 128: 19‐28, 2013.
 104. Cieslik KA , Taffet GE , Carlson S , Hermosillo J , Trial J , Entman ML . Immune‐inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. J Mol Cell Cardiol 50: 248‐256, 2011.
 105. Cieslik KA , Trial J , Carlson S , Taffet GE , Entman ML . Aberrant differentiation of fibroblast progenitors contributes to fibrosis in the aged murine heart: Role of elevated circulating insulin levels. FASEB J 27: 1761‐1771, 2013.
 106. Cieslik KA , Trial J , Crawford JR , Taffet GE , Entman ML . Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts. J Mol Cell Cardiol 70c: 56‐63, 2014.
 107. Cieslik KA , Trial J , Entman ML . Defective myofibroblast formation from mesenchymal stem cells in the aging murine heart rescue by activation of the AMPK pathway. Am J Pathol 179: 1792‐1806, 2011.
 108. Clegg A , Young J , Iliffe S , Rikkert MO , Rockwood K . Frailty in elderly people. Lancet 381: 752‐762, 2013.
 109. Cleutjens JP , Verluyten MJ , Smiths JF , Daemen MJ . Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol 147: 325‐338, 1995.
 110. Cleutjens JPM . Regulation of cardiac extracellular matrix remodeling following myocardial infarction. In: Villarreal FJ , editor. Interstitial Fibrosis in Heart Failure. New York: Springer, 2005, pp. 239‐251.
 111. Cohn JN , Levine TB , Olivari MT , Garberg V , Lura D , Francis GS , Simon AB , Rector T . Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311: 819‐823, 1984.
 112. Coker ML , Doscher MA , Thomas CV , Galis ZS , Spinale FG . Matrix metalloproteinase synthesis and expression in isolated LV myocyte preparations. Am J Physiol Heart Circ Physiol 277: H777‐H787, 1999.
 113. Coker ML , Jolly JR , Joffs C , Etoh T , Holder JR , Bond BR , Spinale FG . Matrix metalloproteinase expression and activity in isolated myocytes after neurohormonal stimulation. Am J Physiol Heart Circ Physiol 281: H543‐H551, 2001.
 114. Crawford DC , Chobanian AV , Brecher P . Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat. Circ Res 74: 727‐739, 1994.
 115. Cucoranu I , Clempus R , Dikalova A , Phelan PJ , Ariyan S , Dikalov S , Sorescu D . NAD(P)H oxidase 4 mediates transforming growth factor‐β1–induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res 97: 900‐907, 2005.
 116. Dai D‐F , Santana LF , Vermulst M , Tomazela DM , Emond MJ , MacCoss MJ , Gollahon K , Martin GM , Loeb LA , Ladiges WC , Rabinovitch PS . Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119: 2789‐2797, 2009.
 117. Dai DF , Chiao YA , Marcinek DJ , Szeto HH , Rabinovitch PS . Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan 3: 6, 2014.
 118. Dannenberg AL , Levy D , Garrison RJ . Impact of age on echocardiographic left ventricular mass in a healthy population (the Framingham Study). Am J Cardiol 64: 1066‐1068, 1989.
 119. Dart AM , Kingwell BA . Pulse pressure–a review of mechanisms and clinical relevance. J Am Coll Cardiol 37: 975‐984, 2001.
 120. Davies L , Jin J , Shen W , Tsui H , Shi Y , Wang Y , Zhang Y , Hao G , Wu J , Chen S , Fraser JA , Dong N , Christoffels V , Ravens U , Huang CLH , Zhang H , Cartwright EJ , Wang X , Lei M . Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age. J Am Heart Assoc 3: e000340, 2014.
 121. Davies P , Dewar J , Tynan M , Ward R . Post‐natal developmental changes in the length‐tension relationship of cat papillary muscles. J Physiol 253: 95‐102, 1975.
 122. Davis J , Molkentin JD . Myofibroblasts: Trust your heart and let fate decide. J Mol Cell Cardiol 70c: 9‐18, 2014.
 123. Davis KM , Fish LC , Minaker KL , Elahi D . Atrial natriuretic peptide levels in the elderly: Differentiating normal aging changes from disease. J Gerontol A Biol Sci Med Sci 51A: M95‐M101, 1996.
 124. Dawson K , Wakili R , Ordog B , Clauss S , Chen Y , Iwasaki Y , Voigt N , Qi XY , Sinner MF , Dobrev D , Kaab S , Nattel S . MicroRNA29: A mechanistic contributor and potential biomarker in atrial fibrillation. Circulation 127: 1466‐1475, 1475e1461‐1428, 2013.
 125. de Castro Bras LE , Toba H , Baicu CF , Zile MR , Weintraub ST , Lindsey ML , Bradshaw AD . Age and SPARC change the extracellular matrix composition of the left ventricle. Biomed Res Int 2014: 810562, 2014.
 126. De Jong AM , Maass AH , Oberdorf‐Maass SU , van Veldhuisen DJ , van Gilst WH , Van Gelder IC . Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res 89: 754‐765, 2011.
 127. de Souza RR . Aging of myocardial collagen. Biogerontology 3: 325‐335, 2002.
 128. Debessa CRG , Maifrino LBM , de Souza RR . Age related changes of the collagen network of the human heart. Mech Ageing Dev 122: 1049‐1058, 2001.
 129. Derynck R , Zhang YE . Smad‐dependent and Smad‐independent pathways in TGF‐beta family signalling. Nature 425: 577‐584, 2003.
 130. DeSantiago J , Ai X , Islam M , Acuna G , Ziolo MT , Bers DM , Pogwizd SM . Arrhythmogenic effects of beta2‐adrenergic stimulation in the failing heart are attributable to enhanced sarcoplasmic reticulum Ca load. Circ Res 102: 1389‐1397, 2008.
 131. Deschamps AM , Spinale FG . Extracellular matrix. In: Walsh RA , editor. Molecular Mechanisms Of Cardiac Hypertrophy And Failure. Taylor & Francis Ltd., 2005, pp. 101‐117.
 132. Deschamps AM , Spinale FG . Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation. Cardiovasc Res 69: 666‐676, 2006.
 133. Desmouliere A , Geinoz A , Gabbiani F , Gabbiani G . Transforming growth factor‐beta 1 induces alpha‐smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122: 103‐111, 1993.
 134. Dibb KM , Rueckschloss U , Eisner DA , Isenberg G , Trafford AW . Mechanisms underlying enhanced cardiac excitation contraction coupling observed in the senescent sheep myocardium. J Mol Cell Cardiol 37: 1171‐1181, 2004.
 135. Dietz JR . Mechanisms of atrial natriuretic peptide secretion from the atrium. Cardiovasc Res 68: 8‐17, 2005.
 136. Dimmeler S , Nicotera P . MicroRNAs in age‐related diseases. EMBO Mol Med 5: 180‐190, 2013.
 137. Dobaczewski M , Gonzalez‐Quesada C , Frangogiannis NG . The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 48: 504‐511, 2010.
 138. Dong S , Ma W , Hao B , Hu F , Yan L , Yan X , Wang Y , Chen Z , Wang Z . microRNA‐21 promotes cardiac fibrosis and development of heart failure with preserved left ventricular ejection fraction by up‐regulating Bcl‐2. Int J Clin Exp Pathol 7: 565‐574, 2014.
 139. Du XJ , Gao XM , Wang B , Jennings GL , Woodcock EA , Dart AM . Age‐dependent cardiomyopathy and heart failure phenotype in mice overexpressing beta(2)‐adrenergic receptors in the heart. Cardiovasc Res 48: 448‐454, 2000.
 140. Ducharme A , Frantz S , Aikawa M , Rabkin E , Lindsey M , Rohde LE , Schoen FJ , Kelly RA , Werb Z , Libby P , Lee RT . Targeted deletion of matrix metalloproteinase‐9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 106: 55‐62, 2000.
 141. Eckhouse SR , Purcell BP , McGarvey JR , Lobb D , Logdon CB , Doviak H , O'Neill JW , Shuman JA , Novack CP , Zellars KN , Pettaway S , Black RA , Khakoo A , Lee T , Mukherjee R , Gorman JH , Gorman RC , Burdick JA , Spinale FG . Local hydrogel release of recombinant TIMP‐3 attenuates adverse left ventricular remodeling after experimental myocardial infarction. Sci Transl Med 6: 223ra221, 2014.
 142. Eeckhout Y , Vaes G . Further studies on the activation of procollagenase, the latent precursor of bone collagenase. Effects of lysosomal cathepsin B, plasmin and kallikrein, and spontaneous activation. Biochem J 166: 21‐31, 1977.
 143. Eghbali M , Blumenfeld OO , Seifter S , Buttrick PM , Leinwand LA , Robinson TF , Zern MA , Giambrone MA . Localization of types I, III and IV collagen mRNAs in rat heart cells by in situ hybridization. J Mol Cell Cardiol 21: 103‐113, 1989.
 144. Eghbali M , Czaja MJ , Zeydel M , Weiner FR , Zern MA , Seifter S , Blumenfeld OO . Collagen chain mRNAs in isolated heart cells from young and adult rats. J Mol Cell Cardiol 20: 267‐276, 1988.
 145. Eghbali M , Eghbali M , Robinson TF , Seifter S , Blumenfeld OO . Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res 23: 723‐729, 1989.
 146. Eghbali M , Weber KT . Collagen and the myocardium: Fibrillar structure, biosynthesis and degradation in relation to hypertrophy and its regression. Mol Cell Biochem 96: 1‐14, 1990.
 147. Eiras S , Narolska NA , van Loon RB , Boontje NM , Zaremba R , Jimenez CR , Visser FC , Stooker W , van der Velden J , Stienen GJM . Alterations in contractile protein composition and function in human atrial dilatation and atrial fibrillation. J Mol Cell Cardiol 41: 467‐477, 2006.
 148. Engel J , Odermatt E , Engel A , Madri JA , Furthmayr H , Rohde H , Timpl R . Shapes, domain organizations and flexibility of laminin and fibronectin, two multifunctional proteins of the extracellular matrix. J Mol Biol 150: 97‐120, 1981.
 149. Everett TH , Li H , Mangrum JM , McRury ID , Mitchell MA , Redick JA , Haines DE . Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation. Circulation 102: 1454‐1460, 2000.
 150. Factor SM , Robinson TF , Dominitz R , Cho S . Alterations of the myocardial skeletal framework in acute myocardial infarction with and without ventricular rupture. A preliminary report. Am J Cardiovasc Pathol 1: 91‐97, 1986.
 151. Fan D , Creemers EE , Kassiri Z . Matrix as an interstitial transport system. Circ Res 114: 889‐902, 2014.
 152. Fan F , Sun A , Zhao H , Liu X , Zhang W , Jin X , Wang C , Ma X , Shen C , Zou Y , Hu K , Ge J . MicroRNA‐34a promotes cardiomyocyte apoptosis post myocardial infarction through down‐regulating aldehyde dehydrogenase 2. Curr Pharm Des 19: 4865‐4873, 2013.
 153. Farhadian F , Contard F , Sabri A , Samuel JL , Rappaport L . Fibronectin and basement membrane in cardiovascular organogenesis and disease pathogenesis. Cardiovasc Res 32: 433‐442, 1996.
 154. Fedak PW , Altamentova SM , Weisel RD , Nili N , Ohno N , Verma S , Lee TY , Kiani C , Mickle DA , Strauss BH , Li RK . Matrix remodeling in experimental and human heart failure: A possible regulatory role for TIMP‐3. Am J Physiol Heart Circ Physiol 284: H626‐H634, 2003.
 155. Fedak PWM , Smookler DS , Kassiri Z , Ohno N , Leco KJ , Verma S , Mickle DAG , Watson KL , Hojilla CV , Cruz W , Weisel RD , Li RK , Khokha R . TIMP‐3 deficiency leads to dilated cardiomyopathy. Circulation 110: 2401‐2409, 2004.
 156. Frangogiannis NG . Matricellular proteins in cardiac adaptation and disease. Physiol Rev 92: 635‐688, 2012.
 157. Frangogiannis NG . The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 11: 255‐265, 2014.
 158. Frangogiannis NG , Ren G , Dewald O , Zymek P , Haudek S , Koerting A , Winkelmann K , Michael LH , Lawler J , Entman ML . Critical role of endogenous thrombospondin‐1 in preventing expansion of healing myocardial infarcts. Circulation 111: 2935‐2942, 2005.
 159. Frangogiannis NG , Smith CW , Entman ML . The inflammatory response in myocardial infarction. Cardiovasc Res 53: 31‐47, 2002.
 160. Franklin SS , Gustin WIV , Wong ND , Larson MG , Weber MA , Kannel WB , Levy D . Hemodynamic patterns of age‐related changes in blood pressure: The Framingham Heart Study. Circulation 96: 308‐315, 1997.
 161. Frazier SB , Roodhouse KA , Hourcade DE , Zhang L . The quantification of glycosaminoglycans: A comparison of HPLC, carbazole, and Alcian Blue Methods. Open Glycosci 1: 31‐39, 2008.
 162. Friedman WF . The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 15: 87‐111, 1972.
 163. Friedrichs K , Klinke A , Baldus S . Inflammatory pathways underlying atrial fibrillation. Trends Mol Med 17: 556‐563, 2011.
 164. Frustaci A , Chimenti C , Bellocci F , Morgante E , Russo MA , Maseri A . Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96: 1180‐1184, 1997.
 165. Fujimoto N , Hastings JL , Bhella PS , Shibata S , Gandhi NK , Carrick‐Ranson G , Palmer D , Levine BD . Effect of ageing on left ventricular compliance and distensibility in healthy sedentary humans. J Physiol 590: 1871‐1880, 2012.
 166. Fujiu K , Nagai R . Fibroblast‐mediated pathways in cardiac hypertrophy. J Mol Cell Cardiol 70: 64‐73, 2014.
 167. Gerstenblith G , Frederiksen J , Yin FCP , Fortuin NJ , Lakatta EG , Weisfeldt ML . Echocardiographic assessment of a normal adult aging population. Circulation 56: 273‐278, 1977.
 168. Giancotti FG , Ruoslahti E . Integrin signaling. Science 285: 1028‐1033, 1999.
 169. Gingrich JA , Hen R . The broken mouse: The role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice. Curr Opin Neurobiol 10: 146‐152, 2000.
 170. Go AS , Mozaffarian D , Roger VL , Benjamin EJ , Berry JD , Blaha MJ , Dai S , Ford ES , Fox CS , Franco S , Fullerton HJ , Gillespie C , Hailpern SM , Heit JA , Howard VJ , Huffman MD , Judd SE , Kissela BM , Kittner SJ , Lackland DT , Lichtman JH , Lisabeth LD , Mackey RH , Magid DJ , Marcus GM , Marelli A , Matchar DB , McGuire DK , Mohler ER III , Moy CS , Mussolino ME , Neumar RW , Nichol G , Pandey DK , Paynter NP , Reeves MJ , Sorlie PD , Stein J , Towfighi A , Turan TN , Virani SS , Wong ND , Woo D , Turner MB . Heart disease and stroke statistics–2014 update: A report from the american heart association. Circulation 129: e28‐e292, 2014.
 171. Goddeeris MM , Wu B , Venzke D , Yoshida‐Moriguchi T , Saito F , Matsumura K , Moore SA , Campbell KP . LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy. Nature 503: 136‐140, 2013.
 172. Goldsmith EC , Bradshaw AD , Spinale FG . Cellular mechanisms of tissue fibrosis. 2. Contributory pathways leading to myocardial fibrosis: Moving beyond collagen expression. Am J Physiol Cell Physiol 304: C393‐C402, 2013.
 173. Goldsmith EC , Bradshaw AD , Zile MR , Spinale FG . Myocardial fibroblast‐matrix interactions and potential therapeutic targets. J Mol Cell Cardiol 70c: 92‐99, 2014.
 174. Gonzalez‐Quesada C , Cavalera M , Biernacka A , Kong P , Lee DW , Saxena A , Frunza O , Dobaczewski M , Shinde A , Frangogiannis NG . Thrombospondin‐1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin‐2 upregulation. Circ Res 113: 1331‐1344, 2013.
 175. Gonzalez A , Lopez B , Querejeta R , Diez J . Regulation of myocardial fibrillar collagen by angiotensin II. A role in hypertensive heart disease? J Mol Cell Cardiol 34: 1585‐1593, 2002.
 176. Gordon M , Hahn R . Collagens. Cell Tissue Res 339: 247‐257, 2010.
 177. Gorman RC , Jackson BM , Gorman JH , Edmunds LHJ . The mechanics of the fibrosed/remodeled heart. In: Villarreal FJ , editor. Interstitial Fibrosis in Heart Failure. New York: Springer, 2005, pp. 149‐163.
 178. Gottdiener JS , Kitzman DW , Aurigemma GP , Arnold AM , Manolio TA . Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons > or =65 years of age (the cardiovascular health study). Am J Cardiol 97: 83‐89, 2006.
 179. Graham HK , Akhtar R , Kridiotis C , Derby B , Kundu T , Trafford AW , Sherratt MJ . Localised micro‐mechanical stiffening in the ageing aorta. Mech Ageing Dev 132: 459‐467, 2011.
 180. Graham HK , Horn M , Trafford AW . Extracellular matrix profiles in the progression to heart failure. Acta Physiol 194: 3‐21, 2008.
 181. Graham HK , Trafford AW . Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure. Am J Physiol Heart Circ Physiol 292: H1364‐H1372, 2007.
 182. Gramley F , Lorenzen J , Knackstedt C , Rana OR , Saygili E , Frechen D , Stanzel S , Pezzella F , Koellensperger E , Weiss C , Munzel T , Schauerte P . Age‐related atrial fibrosis. Age (Dordr) 31: 27‐38, 2009.
 183. Grande‐Allen KJ , Calabro A , Gupta V , Wight TN , Hascall VC , Vesely I . Glycosaminoglycans and proteoglycans in normal mitral valve leaflets and chordae: Association with regions of tensile and compressive loading. Glycobiology 14: 621‐633, 2004.
 184. Gray MO , Long CS , Kalinyak JE , Li HT , Karliner JS . Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF‐beta 1 and endothelin‐1 from fibroblasts. Cardiovasc Res 40: 352‐363, 1998.
 185. Gray WR , Sandberg LB , Foster JA . Molecular model for elastin structure and function. Nature 246: 461‐466, 1973.
 186. Greene J , Wang M , Liu YE , Raymond LA , Rosen C , Shi YE . Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 271: 30375‐30380, 1996.
 187. Greenwald SE . Ageing of the conduit arteries. J Pathol 211: 157‐172, 2007.
 188. Gregorevic P , Ryall JG , Plant DR , Sillence MN , Lynch GS . Chronic beta‐agonist administration affects cardiac function of adult but not old rats, independent of beta‐adrenoceptor density. Am J Physiol Heart Circ Physiol 289: H344‐H349, 2005.
 189. Grimes KM , Lindsey ML , Gelfond JA , Buffenstein R . Getting to the heart of the matter: Age‐related changes in diastolic heart function in the longest‐lived rodent, the naked mole rat. J Gerontol A Biol Sci Med Sci 67: 384‐394, 2012.
 190. Groban L , Pailes NA , Bennett CD , Carter CS , Chappell MC , Kitzman DW , Sonntag WE . Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. J Gerontol A Biol Sci Med Sci 61: 28‐35, 2006.
 191. Gross J , Lapiere CM . Collagenolytic activity in amphibian tissues: A tissue culture assay. Proc Natl Acad Sci U S A 48: 1014‐1022, 1962.
 192. Gu Z , Kaul M , Yan B , Kridel SJ , Cui J , Strongin A , Smith JW , Liddington RC , Lipton SA . S‐Nitrosylation of matrix metalloproteinases: Signaling pathway to neuronal cell death. Science 297: 1186‐1190, 2002.
 193. Hafner AV , Dai J , Gomes AP , Xiao CY , Palmeira CM , Rosenzweig A , Sinclair DA . Regulation of the mPTP by SIRT3‐mediated deacetylation of CypD at lysine 166 suppresses age‐related cardiac hypertrophy. Aging (Albany NY) 2: 914‐923, 2010.
 194. Halper J . Proteoglycans and diseases of soft tissues. Adv Exp Med Biol 802: 49‐58, 2014.
 195. Hamdani N , Franssen C , Lourenco A , Falcao‐Pires I , Fontoura D , Leite S , Plettig L , Lopez B , Ottenheijm CA , Becher PM , Gonzalez A , Tschope C , Diez J , Linke WA , Leite‐Moreira AF , Paulus WJ . Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circ Heart Fail 6: 1239‐1249, 2013.
 196. Hanna N , Cardin S , Leung TK , Nattel S . Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing‐induced congestive heart failure. Cardiovasc Res 63: 236‐244, 2004.
 197. Harris BS , Zhang Y , Card L , Rivera LB , Brekken RA , Bradshaw AD . SPARC regulates collagen interaction with cardiac fibroblast cell surfaces. Am J Physiol Heart Circ Physiol 301: H841‐H847, 2011.
 198. Hartog JWL , Voors AA , Bakker SJL , Smit AJ , van Veldhuisen DJ . Advanced glycation end‐products (AGEs) and heart failure: Pathophysiology and clinical implications. Eur J Heart Fail 9: 1146‐1155, 2007.
 199. Hasenfuss G . Alterations of calcium‐regulatory proteins in heart failure. Cardiovasc Res 37: 279‐289, 1998.
 200. Haudek SB , Xia Y , Huebener P , Lee JM , Carlson S , Crawford JR , Pilling D , Gomer RH , Trial J , Frangogiannis NG , Entman ML . Bone marrow‐derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci U S A 103: 18284‐18289, 2006.
 201. Hauser J , Michel‐Behnke I , Zervan K , Pees C . Noninvasive measurement of atrial contribution to the cardiac output in children and adolescents with congenital complete atrioventricular block treated with dual‐chamber pacemakers. Am J Cardiol 107: 92‐95, 2011.
 202. Hayashi H , Wang C , Miyauchi Y , Omichi C , Pak HN , Zhou S , Ohara T , Mandel WJ , Lin SF , Fishbein MC , Chen PS , Karagueuzian HS . Aging‐related increase to inducible atrial fibrillation in the rat model. J Cardiovasc Electrophysiol 13: 801‐808, 2002.
 203. Hayashidani S , Tsutsui H , Ikeuchi M , Shiomi T , Matsusaka H , Kubota T , Imanaka‐Yoshida K , Itoh T , Takeshita A . Targeted deletion of MMP‐2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. Am J Physiol Heart Circ Physiol 285: H1229‐H1235, 2003.
 204. Heeringa J , van der Kuip DA , Hofman A , Kors JA , van HG , Stricker BH , Stijnen T , Lip GY , Witteman JC . Prevalence, incidence and lifetime risk of atrial fibrillation: The Rotterdam study. Eur Heart J 27: 949‐953, 2006.
 205. Hein S , Schaper J . The extracellular matrix in normal and diseased myocardium. J Nucl Cardiol 8: 188‐196, 2001.
 206. Heinke MY , Yao M , Chang D , Einstein R , dos Remedios CG . Apoptosis of ventricular and atrial myocytes from pacing‐induced canine heart failure. Cardiovasc Res 49: 127‐134, 2001.
 207. Heinsimer JA , Lefkowitz RJ . The impact of aging on adrenergic receptor function: Clinical and biochemical aspects. J Am Geriatr Soc 33: 184‐188, 1985.
 208. Hellman U , Hellstrom M , Morner S , Engstrom‐Laurent A , Aberg AM , Oliviero P , Samuel JL , Waldenstrom A . Parallel up‐regulation of FGF‐2 and hyaluronan during development of cardiac hypertrophy in rat. Cell Tissue Res 332: 49‐56, 2008.
 209. Hellman U , Morner S , Engstrom‐Laurent A , Samuel JL , Waldenstrom A . Temporal correlation between transcriptional changes and increased synthesis of hyaluronan in experimental cardiac hypertrophy. Genomics 96: 73‐81, 2010.
 210. Hellstrom M , Johansson B , Engstrom‐Laurent A . Hyaluronan and its receptor CD44 in the heart of newborn and adult rats. Anat Rec A Discov Mol Cell Evol Biol 288: 587‐592, 2006.
 211. Henry WL , Morganroth J , Pearlman AS , Clark CE , Redwood DR , Itscoitz SB , Epstein SE . Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 53: 273‐279, 1976.
 212. Hermida N , Lopez B , Gonzalez A , Dotor J , Lasarte JJ , Sarobe P , Borras‐Cuesta F , Diez J . A synthetic peptide from transforming growth factor‐beta1 type III receptor prevents myocardial fibrosis in spontaneously hypertensive rats. Cardiovasc Res 81: 601‐609, 2009.
 213. Herrera AP , Snipes SA , King DW , Torres‐Vigil I , Goldberg DS , Weinberg AD . Disparate inclusion of older adults in clinical trials: Priorities and opportunities for policy and practice change. Am J Public Health 100(Suppl 1): S105‐S112, 2010.
 214. Herrmann KL , McCulloch AD , Omens JH . Glycated collagen cross‐linking alters cardiac mechanics in volume‐overload hypertrophy. Am J Physiol Heart Circ Physiol 284: H1277‐H1284, 2003.
 215. Heymes C , Silvestre JS , Llorens‐Cortes C , Chevalier B , Marotte F , Levy BI , Swynghedauw B , Samuel JL . Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology 139: 2579‐2587, 1998.
 216. Heymes C , Swynghedauw B , Chevalier B . Activation of angiotensinogen and angiotensin‐converting enzyme gene expression in the left ventricle of senescent rats. Circulation 90: 1328‐1333, 1994.
 217. Hinescu ME , Gherghiceanu M , Mandache E , Ciontea SM , Popescu LM . Interstitial Cajal‐like cells (ICLC) in atrial myocardium: Ultrastructural and immunohistochemical characterization. J Cell Mol Med 10: 243‐257, 2006.
 218. Horn MA , Graham HK , Richards MA , Clarke JD , Greensmith DJ , Briston SJ , Hall MCS , Dibb KM , Trafford AW . Age‐related divergent remodeling of the cardiac extracellular matrix in heart failure: Collagen accumulation in the young and loss in the aged. J Mol Cell Cardiol 53: 82‐90, 2012.
 219. Hosoda Y , Kawano K , Yamasawa F , Ishii T , Shibata T , Inayama S . Age‐dependent changes of collagen and elastin content in human aorta and pulmonary artery. Angiology 35: 615‐621, 1984.
 220. Houser SR , Margulies KB . Is depressed myocyte contractility centrally involved in heart failure? Circ Res 92: 350‐358, 2003.
 221. Howlett SE , Rockwood K . New horizons in frailty: Ageing and the deficit‐scaling problem. Age Ageing 42: 416‐423, 2013.
 222. Hsia TY , Ringewald JM , Stroud RE , Forbus GA , Bradley SM , Chung WK , Spinale FG . Determinants of extracellular matrix remodelling are differentially expressed in paediatric and adult dilated cardiomyopathy. Eur J Heart Fail 13: 271‐277, 2011.
 223. Huang XR , Chung AC , Yang F , Yue W , Deng C , Lau CP , Tse HF , Lan HY . Smad3 mediates cardiac inflammation and fibrosis in angiotensin II‐induced hypertensive cardiac remodeling. Hypertension 55: 1165‐1171, 2010.
 224. Huebener P , Abou‐Khamis T , Zymek P , Bujak M , Ying X , Chatila K , Haudek S , Thakker G , Frangogiannis NG . CD44 is critically involved in infarct healing by regulating the inflammatory and fibrotic response. J Immunol 180: 2625‐2633, 2008.
 225. Hulbert AJ , Pamplona R , Buffenstein R , Buttemer WA . Life and death: Metabolic rate, membrane composition, and life span of animals. Physiol Rev 87: 1175‐1213, 2007.
 226. Humphries MJ . Integrin structure. Biochem Soc Trans 28: 311‐339, 2000.
 227. Hurle JM , Kitten GT , Sakai LY , Volpin D , Solursh M . Elastic extracellular matrix of the embryonic chick heart: An immunohistological study using laser confocal microscopy. Dev Dyn 200: 321‐332, 1994.
 228. Huynh MB , Morin C , Carpentier G , Garcia‐Filipe S , Talhas‐Perret S , Barbier‐Chassefiere V , van Kuppevelt TH , Martelly I , Albanese P , Papy‐Garcia D . Age‐related changes in rat myocardium involve altered capacities of glycosaminoglycans to potentiate growth factor functions and heparan sulfate‐altered sulfation. J Biol Chem 287: 11363‐11373, 2012.
 229. Ichihara S , Senbonmatsu T , Price E , Ichiki T , Gaffney FA , Inagami T . Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin ii–induced hypertension. Circulation 104: 346‐351, 2001.
 230. Ikonomidis JS , Hendrick JW , Parkhurst AM , Herron AR , Escobar PG , Dowdy KB , Stroud RE , Hapke E , Zile MR , Spinale FG . Accelerated LV remodeling after myocardial infarction in TIMP‐1‐deficient mice: Effects of exogenous MMP inhibition. Am J Physiol Heart Circ Physiol 288: H149‐H158, 2005.
 231. Inserra F , Romano L , Ercole L , de Cavanagh EMV , Ferder L . Cardiovascular changes by long‐term inhibition of the renin‐angiotensin system in aging. Hypertension 25: 437‐442, 1995.
 232. Isoyama S , Wei JY , Izumo S , Fort P , Schoen FJ , Grossman W . Effect of age on the development of cardiac hypertrophy produced by aortic constriction in the rat. Circ Res 61: 337‐345, 1987.
 233. Israeli‐Rosenberg S , Manso AM , Okada H , Ross RS . Integrins and integrin‐associated proteins in the cardiac myocyte. Circ Res 114: 572‐586, 2014.
 234. Ito A , Yamagiwa H , Sasaki R . Effects of aging on hydroxyproline in human heart muscle. J Am Geriatr Soc 28: 398‐404, 1980.
 235. Jackson M , Connell MG , Smith A . Development of the collagen network of the human fetal myocardium: An immunohistochemical study. Int J Cardiol 41: 77‐86, 1993.
 236. Jacoby JJ , Kalinowski A , Liu MG , Zhang SS , Gao Q , Chai GX , Ji L , Iwamoto Y , Li E , Schneider M , Russell KS , Fu XY . Cardiomyocyte‐restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci U S A 100: 12929‐12934, 2003.
 237. Jacot JG , Martin JC , Hunt DL . Mechanobiology of cardiomyocyte development. J Biomech 43: 93‐98, 2010.
 238. Jalil JE , Doering CW , Janicki JS , Pick R , Shroff SG , Weber KT . Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 64: 1041‐1050, 1989.
 239. Jane‐Lise S , Corda S , Chassagne C , Rappaport L . The extracellular matrix and the cytoskeleton in heart hypertrophy and failure. Heart Fail Rev 5: 239‐250, 2000.
 240. Jazbutyte V , Fiedler J , Kneitz S , Galuppo P , Just A , Holzmann A , Bauersachs J , Thum T . MicroRNA‐22 increases senescence and activates cardiac fibroblasts in the aging heart. AGE 35: 747‐762, 2013.
 241. Johar S , Cave AC , Narayanapanicker A , Grieve DJ , Shah AM . Aldosterone mediates angiotensin II‐induced interstitial cardiac fibrosis via a Nox2‐containing NADPH oxidase. FASEB J 20: 1546‐1548, 2006.
 242. Jones ES , Black MJ , Widdop RE . Angiotensin AT2 receptor contributes to cardiovascular remodelling of aged rats during chronic AT1 receptor blockade. J Mol Cell Cardiol 37: 1023‐1030, 2004.
 243. Judd JT , Wexler BC . Prolyl hydroxylase and collagen metabolism after experimental mycardial infarction. Am J Physiol Heart Circ Physiol 228: 212‐216, 1975.
 244. Judge S , Jang YM , Smith A , Hagen T , Leeuwenburgh C . Age‐associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: Implications for the mitochondrial theory of aging. FASEB J 19: 419‐421, 2005.
 245. Jugdutt BI. Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets Cardiovasc Haematol Disord 3: 1‐30, 2003.
 246. Jugdutt BI. Ventricular remodeling after infarction and the extracellular collagen matrix: When is enough enough? Circulation 108: 1395‐1403, 2003.
 247. Jugdutt BI. Aging and heart failure: Changing demographics and implications for therapy in the elderly. Heart Fail Rev 15: 401‐405, 2010.
 248. Jugdutt BI. Aging and remodeling of the RAS and RAAS and related pathways: Implications for heart failure therapy. In: Jugdutt BI , editor. Aging and Heart Failure Mechanisms and Management. New York, NY: Springer, 2014, pp. 259‐289.
 249. Jugdutt BI. Changing demographics of the aging population with heart failure and implications for therapy. In: Jugdutt BI , editor. Aging and Heart Failure: Mechanisms and Management. New York: Springer, 2014, pp. 1‐14.
 250. Jugdutt BI , Jelani A , Palaniyappan A , Idikio H , Uweira RE , Menon V , Jugdutt CE. Aging‐related early changes in markers of ventricular and matrix remodeling after reperfused ST‐segment elevation myocardial infarction in the canine model: Effect of early therapy with an angiotensin II type 1 receptor blocker. Circulation 122: 341‐351, 2010.
 251. Jugdutt BI , Palaniyappan A , Uwiera RR , Idikio H. Role of healing‐specific‐matricellular proteins and matrix metalloproteinases in age‐related enhanced early remodeling after reperfused STEMI in dogs. Mol Cell Biochem 322: 25‐36, 2009.
 252. Jung JP , Squirrell JM , Lyons GE , Eliceiri KW , Ogle BM . Imaging cardiac extracellular matrices: A blueprint for regeneration. Trends Biotechnol 30: 233‐240, 2012.
 253. Junqueira LC , Montes GS , Sanchez EM . The influence of tissue section thickness on the study of collagen by the Picrosirius‐polarization method. Histochemistry 74: 153‐156, 1982.
 254. Kandalam V , Basu R , Abraham T , Wang X , Soloway PD , Jaworski DM , Oudit GY , Kassiri Z . TIMP2 deficiency accelerates adverse post‐myocardial infarction remodeling because of enhanced MT1‐MMP activity despite lack of MMP2 activation. Circ Res 106: 796‐808, 2010.
 255. Kannel WB . Incidence and epidemiology of heart failure. Heart Fail Rev 5: 167‐173, 2000.
 256. Kannel WB , Benjamin EJ . Status of the epidemiology of atrial fibrillation. Med Clin North Am 92: 17‐40, ix, 2008.
 257. Karayannis G , Kitsios G , Kotidis H , Triposkiadis F . Left atrial remodelling contributes to the progression of asymptomatic left ventricular systolic dysfunction to chronic symptomatic heart failure. Heart Fail Rev 13: 91‐98, 2008.
 258. Kato S , Spinale FG , Tanaka R , Johnson W , Cooper Gt , Zile MR . Inhibition of collagen cross‐linking: Effects on fibrillar collagen and ventricular diastolic function. Am J Physiol 269: H863‐H868, 1995.
 259. Katwa LC , Campbell SE , Tyagi SC , Lee SC , Cicila GT , Weber KT . Cultured nyofibroblasts generate angiotensin peptides de novo. J Mol Cell Cardiol 29: 1375‐1386, 1997.
 260. Katz AM . The heart as a muscular pump. In: Physiology of the Heart. Philadelphia: Lippincott Williams & Wilkins, 2006, pp. 317‐336.
 261. Kawaguchi M , Takahashi M , Hata T , Kashima Y , Usui F , Morimoto H , Izawa A , Takahashi Y , Masumoto J , Koyama J , Hongo M , Noda T , Nakayama J , Sagara J , Taniguchi S , Ikeda U . Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123: 594‐604, 2011.
 262. Kawano H , Do YS , Kawano Y , Starnes V , Barr M , Law RE , Hsueh WA . Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts. Circulation 101: 1130‐1137, 2000.
 263. Keller RS , Shai SY , Babbitt CJ , Pham CG , Solaro RJ , Valencik ML , Loftus JC , Ross RS . Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac performance. Am J Pathol 158: 1079‐1090, 2001.
 264. Kempf T , Zarbock A , Widera C , Butz S , Stadtmann A , Rossaint J , Bolomini‐Vittori M , Korf‐Klingebiel M , Napp LC , Hansen B , Kanwischer A , Bavendiek U , Beutel G , Hapke M , Sauer MG , Laudanna C , Hogg N , Vestweber D , Wollert KC . GDF‐15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 17: 581‐588, 2011.
 265. Khan A , Moe GW , Nili N , Rezaei E , Eskandarian M , Butany J , Strauss BH . The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure. J Am Coll Cardiol 43: 68‐76, 2004.
 266. Kielty CM . Elastic fibres in health and disease. Expert Rev Mol Med 8: 1‐23, 2006.
 267. Kielty CM , Sherratt MJ , Shuttleworth CA . Elastic fibres. J Cell Sci 115: 2817‐2828, 2002.
 268. Kim H , Yoon CS , Kim H , Rah B . Expression of extracellular matrix components fibronectin and laminin in the human fetal heart. Cell Struct Funct 24: 19‐26, 1999.
 269. King TE , Pardo A , Selman M . Idiopathic pulmonary fibrosis. The Lancet 378: 1949‐1961, 2011.
 270. Kirkland JL , Peterson C . Healthspan, translation, and new outcomes for animal studies of aging. J Gerontol A Biol Sci Med Sci 64: 209‐212, 2009.
 271. Kitamura M , Shimizu M , Ino H , Okeie K , Yamaguchi M , Funjno N , Mabuchi H , Nakanishi I . Collagen remodeling and cardiac dysfunction in patients with hypertrophic cardiomyopathy: The significance of type III and VI collagens. Clin Cardiol 24: 325‐329, 2001.
 272. Kitzman DW , Gardin JM , Gottdiener JS , Arnold A , Boineau R , Aurigemma G , Marino EK , Lyles M , Cushman M , Enright PL . Importance of heart failure with preserved systolic function in patients > or =65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol 87: 413‐419, 2001.
 273. Knowlton AA , Connelly CM , Romo GM , Mamuya W , Apstein CS , Brecher P . Rapid expression of fibronectin in the rabbit heart after myocardial infarction with and without reperfusion. J Clin Invest 89: 1060‐1068, 1992.
 274. Kobayashi K , Luo M , Zhang Y , Wilkes DC , Ge G , Grieskamp T , Yamada C , Liu TC , Huang G , Basson CT , Kispert A , Greenspan DS , Sato TN . Secreted Frizzled‐related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nat Cell Biol 11: 46‐55, 2009.
 275. Kohl P , Camelliti P , Burton FL , Smith GL . Electrical coupling of fibroblasts and myocytes: Relevance for cardiac propagation. J Electrocardiol 38: 45‐50, 2005.
 276. Komosinska‐Vassev K , Olczyk P , Winsz‐Szczotka K , Kuznik‐Trocha K , Klimek K , Olczyk K . Age‐ and gender‐dependent changes in connective tissue remodeling: Physiological differences in circulating MMP‐3, MMP‐10, TIMP‐1 and TIMP‐2 level. Gerontology 57: 44‐52, 2011.
 277. Kono T , Sabbah HN , Rosman H , Alam M , Stein PD , Goldstein S . Left atrial contribution to ventricular filling during the course of evolving heart failure. Circulation 86: 1317‐1322, 1992.
 278. Konstandin MH , Volkers M , Collins B , Quijada P , Quintana M , De La Torre A , Ormachea L , Din S , Gude N , Toko H , Sussman MA . Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth. Basic Res Cardiol 108: 375, 2013.
 279. Koshy SKG , Reddy HK , Shukla HH . Collagen cross‐linking: New dimension to cardiac remodeling. Cardiovasc Res 57: 594‐598, 2003.
 280. Koskivirta I , Kassiri Z , Rahkonen O , Kiviranta R , Oudit GY , McKee TD , Kyto V , Saraste A , Jokinen E , Liu PP , Vuorio E , Khokha R . Mice with Tissue Inhibitor of Metalloproteinases 4 (Timp4) deletion succumb to induced myocardial infarction but not to cardiac pressure overload. J Biol Chem 285: 24487‐24493, 2010.
 281. Kovacic JC , Moreno P , Nabel EG , Hachinski V , Fuster V . Cellular senescence, vascular disease, and aging: Part 2 of a 2‐Part Review: Clinical vascular disease in the elderly. Circulation 123: 1900‐1910, 2011.
 282. Kranstuber AL , Del Rio C , Biesiadecki BJ , Hamlin RL , Ottobre J , Gyorke S , Lacombe VA . Advanced glycation end product cross‐link breaker attenuates diabetes‐induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling. Front Physiol 3: 292, 2012.
 283. Kruger M , Kohl T , Linke WA . Developmental changes in passive stiffness and myofilament Ca2+ sensitivity due to titin and troponin‐I isoform switching are not critically triggered by birth. Am J Physiol Heart Circ Physiol 291: H496‐H506, 2006.
 284. Kubo H , Margulies KB , Piacentino V, III , Gaughan JP , Houser SR . Patients with end‐stage congestive heart failure treated with beta‐ adrenergic receptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation 104: 1012‐1018, 2001.
 285. Kucukler N , Kurt IH , Topaloglu C , Gurbuz S , Yalcin F . The effect of valsartan on left ventricular myocardial functions in hypertensive patients with left ventricular hypertrophy. J Cardiovasc Med (Hagerstown) 13: 181‐186, 2012.
 286. Kulkarni AB , Huh CG , Becker D , Geiser A , Lyght M , Flanders KC , Roberts AB , Sporn MB , Ward JM , Karlsson S . Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 90: 770‐774, 1993.
 287. Kumarswamy R , Thum T . Non‐coding RNAs in cardiac remodeling and heart failure. Circ Res 113: 676‐689, 2013.
 288. Kuo LC , Quinones MA , Rokey R , Sartori M , Abinader EG , Zoghbi WA . Quantification of atrial contribution to left ventricular filling by pulsed Doppler echocardiography and the effect of age in normal and diseased hearts. Am J Cardiol 59: 1174‐1178, 1987.
 289. Kuroda J , Ago T , Matsushima S , Zhai P , Schneider MD , Sadoshima J . NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci U S A 107: 15565‐15570, 2010.
 290. Kurt M , Wang J , Torre‐Amione G , Nagueh SF . Left atrial function in diastolic heart failure. Circ Cardiovasc Imaging 2: 10‐15, 2009.
 291. Kyriakides TR , Zhu YH , Smith LT , Bain SD , Yang Z , Lin MT , Danielson KG , Iozzo RV , LaMarca M , McKinney CE , Ginns EI , Bornstein P . Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol 140: 419‐430, 1998.
 292. Lahmers S , Wu Y , Call DR , Labeit S , Granzier H . Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res 94: 505‐513, 2004.
 293. Lakatta EG . Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part III: Cellular and molecular clues to heart and arterial aging. Circulation 107: 490‐497, 2003.
 294. Lakatta EG . Alterations in the cardiovascular system that occur in advanced age. Fed Proc 38: 163‐167, 1979.
 295. Lakatta EG . Deficient neuroendocrine regulation of the cardiovascular system with advancing age in healthy humans. Circulation 87: 631‐636, 1993.
 296. Lakatta EG , Levy D . Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A “set up” for vascular disease. Circulation 107: 139‐146, 2003a.
 297. Lakatta EG , Levy D . Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part II: The aging heart in health: Links to heart disease. Circulation 107: 346‐354, 2003b.
 298. Lam CS , Roger VL , Rodeheffer RJ , Bursi F , Borlaug BA , Ommen SR , Kass DA , Redfield MM . Cardiac structure and ventricular‐vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 115: 1982‐1990, 2007.
 299. Lamparter S , Sun Y , Weber KT . Angiotensin II receptor blockade during gestation attenuates collagen formation in the developing rat heart. Cardiovasc Res 43: 165‐172, 1999.
 300. Lapiere CM , Nusgens B , Pierard GE . Interaction between collagen type I and type III in conditioning bundles organization. Connect Tissue Res 5: 21‐29, 1977.
 301. Laser M , Willey CD , Jiang W , Cooper G , Menick DR , Zile MR , Kuppuswamy D . Integrin activation and focal complex formation in cardiac hypertrophy. J Biol Chem 275: 35624‐35630, 2000.
 302. Laurent GJ . Dynamic state of collagen: Pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. Am J Physiol Heart Circ Physiol 252: C1‐C9, 1987.
 303. Lee AA , Dillmann WH , McCulloch AD , Villarreal FJ . Angiotensin II stimulates the autocrine production of transforming growth factor‐beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol 27: 2347‐2357, 1995.
 304. Lee MH , Atkinson S , Murphy G . Identification of the extracellular matrix (ECM) binding motifs of tissue inhibitor of metalloproteinases (TIMP)‐3 and effective transfer to TIMP‐1. J Biol Chem 282: 6887‐6898, 2007.
 305. LeGrice IJ , Smaill BH , Chai LZ , Edgar SG , Gavin JB , Hunter PJ . Laminar structure of the heart: Ventricular myocyte arrangement and connective tissue architecture in the dog. Am J Physiol Heart Circ Physiol 269: H571‐H582, 1995.
 306. LeGrice IJ , Takayama Y , Covell JW . Transverse shear along myocardial cleavage planes provides a mechanism for normal systolic wall thickening. Circ Res 77: 182‐193, 1995.
 307. Leicht M , Briest W , Zimmer HG . Regulation of norepinephrine‐induced proliferation in cardiac fibroblasts by interleukin‐6 and p42/p44 mitogen activated protein kinase. Mol Cell Biochem 243: 65‐72, 2003.
 308. Leicht M , Greipel N , Zimmer H . Comitogenic effect of catecholamines on rat cardiac fibroblasts in culture. Cardiovasc Res 48: 274‐284, 2000.
 309. Levin ER , Gardner DG , Samson WK . Natriuretic peptides. N Engl J Med 339: 321‐328, 1998.
 310. LeWinter MM , Granzier H . Cardiac titin: A multifunctional giant. Circulation 121: 2137‐2145, 2010.
 311. Li PF , Dietz R , von Harsdorf R . Superoxide induces apoptosis in cardiomyocytes, but proliferation and expression of transforming growth factor‐beta1 in cardiac fibroblasts. FEBS Lett 448: 206‐210, 1999.
 312. Li YY , Feng YQ , Kadokami T , McTiernan CF , Draviam R , Watkins SC , Feldman AM . Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti‐ tumor necrosis factor alpha therapy. Proc Natl Acad Sci U S A 97: 12746‐12751, 2000.
 313. Li YY , McTiernan CF , Feldman AM . Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells. Cardiovasc Res 42: 162‐172, 1999.
 314. Lieber SC , Aubry N , Pain J , Diaz G , Kim SJ , Vatner SF . Aging increases stiffness of cardiac myocytes measured by atomic force microscopy nanoindentation. Am J Physiol 287: H645‐H651, 2004.
 315. Lijnen P , Papparella I , Petrov V , Semplicini A , Fagard R . Angiotensin II‐stimulated collagen production in cardiac fibroblasts is mediated by reactive oxygen species. J Hypertens 24: 757‐766, 2006.
 316. Lijnen P , Petrov V , van Pelt J , Fagard R . Inhibition of superoxide dismutase induces collagen production in cardiac fibroblasts. Am J Hypertens 21: 1129‐1136, 2008.
 317. Lijnen PJ , Petrov VV , Fagard RH . Angiotensin II‐induced stimulation of collagen secretion and production in cardiac fibroblasts is mediated via angiotensin II subtype 1 receptors. J Renin Angiotensin Aldosterone Syst 2: 117‐122, 2001.
 318. Lim JH , Kim EN , Kim MY , Chung S , Shin SJ , Kim HW , Yang CW , Kim YS , Chang YS , Park CW , Choi BS . Age‐associated molecular changes in the kidney in aged mice. Oxid Med Cell Longev 2012: 171383, 2012.
 319. Lin J , Lopez EF , Jin Y , Van Remmen H , Bauch T , Han HC , Lindsey ML . Age‐related cardiac muscle sarcopenia: Combining experimental and mathematical modeling to identify mechanisms. Exp Gerontol 43: 296‐306, 2008.
 320. Lindsey ML , Goshorn DK , Squires CE , Escobar GP , Hendrick JW , Mingoia JT , Sweterlitsch SE , Spinale FG . Age‐dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function. Cardiovasc Res 66: 410‐419, 2005.
 321. Linke WA . Sense and stretchability: The role of titin and titin‐associated proteins in myocardial stress‐sensing and mechanical dysfunction. Cardiovasc Res 77: 637‐648, 2008.
 322. Little CD , Rongish BJ . The extracellular matrix during heart development. Experientia 51: 873‐882, 1995.
 323. Lockhart M , Wirrig E , Phelps A , Wessels A . Extracellular matrix and heart development. Birth Defects Res A Clin Mol Teratol 91: 535‐550, 2011.
 324. Lohi J , Wilson CL , Roby JD , Parks WC . Epilysin, a novel human matrix metalloproteinase (MMP‐28) expressed in testis and keratinocytes and in response to injury. J Biol Chem 276: 10134‐10144, 2001.
 325. Lopez B , Querejeta R , Gonzalez A , Beaumont J , Larman M , Diez J . Impact of treatment on myocardial lysyl oxidase expression and collagen cross‐linking in patients with heart failure. Hypertension 53: 236‐242, 2009.
 326. Lovelock JD , Baker AH , Gao F , Dong JF , Bergeron AL , McPheat W , Sivasubramanian N , Mann DL . Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts. Am J Physiol Heart Circ Physiol 288: H461‐H468, 2005.
 327. Lu TY , Lin B , Kim J , Sullivan M , Tobita K , Salama G , Yang L . Repopulation of decellularized mouse heart with human induced pluripotent stem cell‐derived cardiovascular progenitor cells. Nat Commun 4: 2307, 2013.
 328. Lundgren E , Gullberg D , Rubin K , Borg TK , Terracio MJ , Terracio L . In vitro studies on adult cardiac myocytes: Attachment and biosynthesis of collagen type IV and laminin. J Cell Physiol 136: 43‐53, 1988.
 329. Luo T , Chang CX , Zhou X , Gu SK , Jiang TM , Li YM . Characterization of atrial histopathological and electrophysiological changes in a mouse model of aging. Int J Mol Med 31: 138‐146, 2013.
 330. Ma Y , Chiao YA , Zhang J , Manicone AM , Jin YF , Lindsey ML . Matrix metalloproteinase‐28 deletion amplifies inflammatory and extracellular matrix responses to cardiac aging. Microsc Microanal 18: 81‐90, 2012.
 331. Ma Y , Halade GV , Zhang J , Ramirez TA , Levin D , Voorhees A , Jin YF , Han HC , Manicone AM , Lindsey ML . Matrix metalloproteinase‐28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Circ Res 112: 675‐688, 2013.
 332. MacFarlane N , Northridge DB , Wright AR , Grant S , Dargie HJ . A comparative study of left ventricular structure and function in elite athletes. Br J Sports Med 25: 45‐48, 1991.
 333. MacKenna D , Summerour SR , Villarreal FJ . Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc Res 46: 257‐263, 2000.
 334. Maggioni AP , Maseri A , Fresco C , Franzosi MG , Mauri F , Santoro E , Tognoni G . Age‐related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. The Investigators of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI‐2). N Engl J Med 329: 1442‐1448, 1993.
 335. Magnusson MK , Mosher DF . Fibronectin: Structure, assembly, and cardiovascular implications. Arterioscler Thromb Vasc Biol 18: 1363‐1370, 1998.
 336. Maki T , Horio T , Yoshihara F , Suga S , Takeo S , Matsuo H , Kangawa K . Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts. Br J Pharmacol 131: 1204‐1210, 2000.
 337. Malmqvist UP , Aronshtam A , Lowey S . Cardiac myosin isoforms from different species have unique enzymatic and mechanical properties. Biochemistry 43: 15058‐15065, 2004.
 338. Mamuya W , Chobanian A , Brecher P . Age‐related changes in fibronectin expression in spontaneously hypertensive, Wistar‐Kyoto, and Wistar rat hearts. Circ Res 71: 1341‐1350, 1992.
 339. Manabe I , Shindo T , Nagai R . Gene expression in fibroblasts and fibrosis: Involvement in cardiac hypertrophy. Circ Res 91: 1103‐1113, 2002.
 340. Mangiafico S , Costello‐Boerrigter LC , Andersen IA , Cataliotti A , Burnett JC, Jr . Neutral endopeptidase inhibition and the natriuretic peptide system: An evolving strategy in cardiovascular therapeutics. Eur Heart J 34: 886‐893c, 2013.
 341. Manhenke C , Ueland T , Jugdutt BI , Godang K , Aukrust P , Dickstein K , Orn S . The relationship between markers of extracellular cardiac matrix turnover: Infarct healing and left ventricular remodelling following primary PCI in patients with first‐time STEMI. Eur Heart J 35: 395‐402, 2014.
 342. Marijianowski MMH , Teeling P , Mann J , Becker AE . Dilated cardiomyopathy is associated with an increase in the type I/type III collagen ratio: A quantitative assessment. J Am Coll Cardiol 25: 1263‐1272, 1995.
 343. Martos R , Baugh J , Ledwidge M , O'Loughlin C , Conlon C , Patle A , Donnelly SC , McDonald K . Diastolic heart failure: Evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 115: 888‐895, 2007.
 344. Masson S , Arosio B , Fiordaliso F , Gagliano N , Calvillo L , Santambrogio D , D'Aquila S , Vergani C , Latini R , Annoni G . Left ventricular response to beta‐adrenergic stimulation in aging rats. J Gerontol A Biol Sci Med Sci 55: B35‐B41; discussion B42‐B33, 2000.
 345. Masur SK , Dewal HS , Dinh TT , Erenburg I , Petridou S . Myofibroblasts differentiate from fibroblasts when plated at low density. Proc Natl Acad Sci U S A 93: 4219‐4223, 1996.
 346. Maurer P , Gohring W , Sasaki T , Mann K , Timpl R , Nischt R . Recombinant and tissue‐derived mouse BM‐40 bind to several collagen types and have increased affinities after proteolytic activation. Cell Mol Life Sci 53: 478‐484, 1997.
 347. Mays PK , Bishop JE , Laurent GJ . Age‐related changes in the proportion of types I and III collagen. Mech Ageing Dev 45: 203‐212, 1988.
 348. Mays PK , McAnulty RJ , Campa JS , Lauquin GJ . Age‐related changes in collagen synthesis and degradation in rat tissues: Importance of degradation of newly synthesized collagen in regulating collagen production. Biochem J 276: 307‐313, 1991.
 349. McCurdy S , Baicu CF , Heymans S , Bradshaw AD . Cardiac extracellular matrix remodeling: Fibrillar collagens and Secreted Protein Acidic and Rich in Cysteine (SPARC). J Mol Cell Cardiol 48: 544‐549, 2010.
 350. McMurray J , Pfeffer MA . New therapeutic options in congestive heart failure: Part I. Circulation 105: 2099‐2106, 2002.
 351. Medugorac I . Collagen type distribution in the mammalian left ventricle during growth and aging. Res Exp Med(Berl) 180: 255‐262, 1982.
 352. Medugorac I , Jacob R . Characterisation of left ventricular collagen in the rat. Cardiovasc Res 17: 15‐21, 1983.
 353. Meran S , Thomas DW , Stephens P , Enoch S , Martin J , Steadman R , Phillips AO . Hyaluronan facilitates transforming growth factor‐beta1‐mediated fibroblast proliferation. J Biol Chem 283: 6530‐6545, 2008.
 354. Milliez P , Deangelis N , Rucker‐Martin C , Leenhardt A , Vicaut E , Robidel E , Beaufils P , Delcayre C , Hatem SN . Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. Eur Heart J 26: 2193‐2199, 2005.
 355. Mirkovic S , Seymour AM , Fenning A , Strachan A , Margolin SB , Taylor SM , Brown L . Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA‐salt hypertensive rats. Br J Pharmacol 135: 961‐968, 2002.
 356. Mirsky I , Parmley WW . Assessment of passive elastic stiffness for isolated heart muscle and the intact heart. Circ Res 33: 233‐243, 1973.
 357. Mitchell GF . Effects of central arterial aging on the structure and function of the peripheral vasculature: Implications for end‐organ damage. J Appl Physiol 105: 1652‐1660, 2008.
 358. Miyamoto S , Teramoto H , Gutkind JS , Yamada KM . Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: Roles of integrin aggregation and occupancy of receptors. J Cell Biol 135: 1633‐1642, 1996.
 359. Mizutani K , Ikeda K , Yamori Y . Resveratrol inhibits AGEs‐induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke‐prone spontaneously hypertensive rats. Biochem Biophys Res Commun 274: 61‐67, 2000.
 360. Mogford JE , Tawil N , Chen A , Gies D , Xia Y , Mustoe TA . Effect of age and hypoxia on TGFbeta1 receptor expression and signal transduction in human dermal fibroblasts: Impact on cell migration. J Cell Physiol 190: 259‐265, 2002.
 361. Mohammed SF , Borlaug BA , McNulty S , Lewis GD , Lin G , Zakeri R , Semigran MJ , LeWinter M , Hernandez AF , Braunwald E , Redfield MM . Resting ventricular–vascular function and exercise capacity in heart failure with preserved ejection fraction: A RELAX Trial Ancillary Study. Circ Heart Fail 7: 580‐589, 2014.
 362. Mohan S , Radha E . Age related changes in muscle connective tissue: Acid mucopolysaccharides and structural glycoprotein. Exp Gerontol 16: 385‐392, 1981.
 363. Molkentin JD . Calcineurin–NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res 63: 467‐475, 2004.
 364. Moore‐Morris T , Guimaraes‐Camboa N , Banerjee I , Zambon AC , Kisseleva T , Velayoudon A , Stallcup WB , Gu Y , Dalton ND , Cedenilla M , Gomez‐Amaro R , Zhou B , Brenner DA , Peterson KL , Chen J , Evans SM . Resident fibroblast lineages mediate pressure overload‐induced cardiac fibrosis. J Clin Invest 124: 2921‐2934, 2014.
 365. Moretti A , Whitehouse MW . Changes in the mucopolysaccharide composition of bovine heart valves with age. Biochem J 87: 396‐402, 1963.
 366. Mori Y , Hatamochi A , Arakawa M , Ueki H . Reduced expression of mRNA for transforming growth factor beta (TGF beta) and TGF beta receptors I and II and decreased TGF beta binding to the receptors in in vitro‐aged fibroblasts. Arch Dermatol Res 290: 158‐162, 1998.
 367. Morita N , Sovari AA , Xie Y , Fishbein MC , Mandel WJ , Garfinkel A , Lin SF , Chen PS , Xie LH , Chen F , Qu Z , Weiss JN , Karagueuzian HS . Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress. Am J Physiol Heart Circ Physiol 297: H1594‐H1605, 2009.
 368. Morris DA , Gailani M , Vaz PA , Blaschke F , Dietz R , Haverkamp W , Ozcelik C . Left atrial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. J Am Soc Echocardiogr 24: 651‐662, 2011.
 369. Mudhasani R , Zhu Z , Hutvagner G , Eischen CM , Lyle S , Hall LL , Lawrence JB , Imbalzano AN , Jones SN . Loss of miRNA biogenesis induces p19Arf‐p53 signaling and senescence in primary cells. J Cell Biol 181: 1055‐1063, 2008.
 370. Mukherjee R , Herron AR , Lowry AS , Stroud RE , Stroud MR , Wharton JM , Ikonomidis JS , Crumbley AJ III , Spinale FG , Gold MR . Selective induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation. Am J Cardiol 97: 532‐537, 2006.
 371. Murakami M , Kusachi S , Nakahama M , Naito I , Murakami T , Doi M , Kondo J , Higashi T , Ninomiya Y , Tsuji T . Expression of the alpha 1 and alpha 2 chains of type IV collagen in the infarct zone of rat myocardial infarction. J Mol Cell Cardiol 30: 1191‐1202, 1998.
 372. Murata K . Acidic glycosaminoglycans in human heart valves. J Mol Cell Cardiol 13: 281‐292, 1981.
 373. Murdoch CE , Zhang M , Cave AC , Shah AM . NADPH oxidase‐dependent redox signalling in cardiac hypertrophy, remodelling and failure. Cardiovasc Res 71: 208‐215, 2006.
 374. Murphy‐Ullrich JE , Poczatek M . Activation of latent TGF‐beta by thrombospondin‐1: Mechanisms and physiology. Cytokine Growth Factor Rev 11: 59‐69, 2000.
 375. Nabeebaccus A , Zhang M , Shah AM . NADPH oxidases and cardiac remodelling. Heart Fail Rev 16: 5‐12, 2011.
 376. Nagase H , Visse R , Murphy G . Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562‐573, 2006.
 377. Nagueh SF , Shah G , Wu Y , Torre‐Amione G , King NM , Lahmers S , Witt CC , Becker K , Labeit S , Granzier HL . Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110: 155‐162, 2004.
 378. Nakajima H , Nakajima HO , Salcher O , Dittie AS , Dembowsky K , Jing S , Field LJ . Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor‐beta transgene in the heart. Circ Res 86: 571‐579, 2000.
 379. Nattel S , Harada M . Atrial remodeling and atrial fibrillation: Recent advances and translational perspectives. J Am Coll Cardiol 63: 2335‐2345, 2014.
 380. Nattel S , Maguy A , Le BS , Yeh YH . Arrhythmogenic ion‐channel remodeling in the heart: Heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 87: 425‐456, 2007.
 381. Naugle JE , Olson ER , Zhang X , Mase SE , Pilati CF , Maron MB , Folkesson HG , Horne WI , Doane KJ , Meszaros JG . Type VI collagen induces cardiac myofibroblast differentiation: Implications for postinfarction remodeling. Am J Physiol Heart Circ Physiol 290: H323‐H330, 2005.
 382. Nelson OL , Robbins CT , Wu Y , Granzier H . Titin isoform switching is a major cardiac adaptive response in hibernating grizzly bears. Am J Physiol Heart Circ Physiol 295: H366‐H371, 2008.
 383. Nguyen DT , Ding C , Wilson E , Marcus GM , Olgin JE . Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart Rhythm 7: 1438‐1445, 2010.
 384. Nichols WW , O'Rourke MF . Aging. In: McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles. New York: Oxford University Press Inc., 2005.
 385. Nikitin NP , Witte KK , Thackray SD , Goodge LJ , Clark AL , Cleland JG . Effect of age and sex on left atrial morphology and function. Eur J Echocardiogr 4: 36‐42, 2003.
 386. Nishimura M , Kumsta C , Kaushik G , Diop SB , Ding Y , Bisharat‐Kernizan J , Catan H , Cammarato A , Ross RS , Engler AJ , Bodmer R , Hansen M , Ocorr K . A dual role for integrin‐linked kinase and beta1‐integrin in modulating cardiac aging. Aging Cell 13: 431‐440, 2014.
 387. Norton GR , Tsotetsi J , Trifunovic B , Hartford C , Candy GP , Woodiwiss AJ . Myocardial stiffness is attributed to alterations in cross‐linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats. Circulation 96: 1991‐1998, 1997.
 388. O'Brien DW , Fu Y , Parker HR , Chan SY , Idikio H , Scott PG , Jugdutt BI . Differential morphometric and ultrastructural remodelling in the left atrium and left ventricle in rapid ventricular pacing‐induced heart failure. Can J Cardiol 16: 1411‐1419, 2000.
 389. O'Hara T , Rudy Y . Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. Am J Physiol Heart Circ Physiol 302: H1023‐H1030, 2012.
 390. O'Rourke MF , Hashimoto J . Mechanical factors in arterial aging: A clinical perspective. J Am Coll Cardiol 50: 1‐13, 2007.
 391. O'Sullivan GJ , O'Tuathaigh CM , Clifford JJ , O'Meara GF , Croke DT , Waddington JL . Potential and limitations of genetic manipulation in animals. Drug Disc Today Technol 3: 173‐180, 2006.
 392. Ogata Y , Itoh Y , Nagase H . Steps involved in activation of the pro‐matrix metalloproteinase 9 (progelatinase B)‐tissue inhibitor of metalloproteinases‐1 complex by 4‐aminophenylmercuric acetate and proteinases. J Biol Chem 270: 18506‐18511, 1995.
 393. Olivetti G , Melissari M , Capasso JM , Anversa P . Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 68: 1560‐1568, 1991.
 394. Oliviero P , Chassagne C , Salichon N , Corbier A , Hamon G , Marotte F , Charlemagne D , Rappaport L , Samuel JL . Expression of laminin alpha2 chain during normal and pathological growth of myocardium in rat and human. Cardiovasc Res 46: 346‐355, 2000.
 395. Olson ER , Naugle JE , Zhang X , Bomser JA , Meszaros JG . Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. Am J Physiol Heart Circ Physiol 288: H1131‐H1138, 2005.
 396. Opie LH , Commerford PJ , Gersh BJ , Pfeffer MA . Controversies in ventricular remodelling. The Lancet 367: 356‐367, 2006.
 397. Orlandi A , Francesconi A , Marcellini M , Ferlosio A , Spagnoli LG . Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit. Cardiovasc Res 64: 544‐552, 2004.
 398. Ostrom RS , Naugle JE , Hase M , Gregorian C , Swaney JS , Insel PA , Brunton LL , Meszaros JG . Angiotensin II enhances adenylyl cyclase signaling via Ca2+/calmodulin: Gq‐Gs cross‐talk regulates collagen production in cardiac fibroblasts. J Biol Chem 278: 24461‐24468, 2003.
 399. Overall CM , Wrana JL , Sodek J . Transcriptional and post‐transcriptional regulation of 72‐kDa gelatinase/type IV collagenase by transforming growth factor‐beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem 266: 14064‐14071, 1991.
 400. Owan TE , Hodge DO , Herges RM , Jacobsen SJ , Roger VL , Redfield MM . Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355: 251‐259, 2006.
 401. Oxenham H , Sharpe N . Cardiovascular aging and heart failure. Eur J Heart Fail 5: 427‐434, 2003.
 402. Paulsson M , Aumailley M , Deutzmann R , Timpl R , Beck K , Engel J . Laminin‐nidogen complex. Extraction with chelating agents and structural characterization. Eur J Biochem 166: 11‐19, 1987.
 403. Paulus WJ , Tschope C , Sanderson JE , Rusconi C , Flachskampf FA , Rademakers FE , Marino P , Smiseth OA , De KG , Leite‐Moreira AF , Borbely A , Edes I , Handoko ML , Heymans S , Pezzali N , Pieske B , Dickstein K , Fraser AG , Brutsaert DL . How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 28: 2539‐2550, 2007.
 404. Pauschinger M , Doerner A , Remppis A , Tannhauser R , Kuhl U , Schultheiss HP . Differential myocardial abundance of collagen type I and type III mRNA in dilated cardiomyopathy: Effects of myocardial inflammation. Cardiovasc Res 37: 123‐129, 1998.
 405. Pauschinger M , Knopf D , Petschauer S , Doerner A , Poller W , Schwimmbeck PL , Kuhl U , Schultheiss HP . Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99: 2750‐2756, 1999.
 406. Pearlman ES , Weber KT , Janicki JS , Pietra GG , Fishman AP . Muscle‐fiber orientation and connective‐tissue content in the hypertrophied human‐heart. Lab Invest 46: 158‐164, 1982.
 407. Pellman J , Lyon RC , Sheikh F . Extracellular matrix remodeling in atrial fibrosis: Mechanisms and implications in atrial fibrillation. J Mol Cell Cardiol 48: 461‐467, 2010.
 408. Petrov VV , Fagard RH , Lijnen PJ . Stimulation of collagen production by transforming growth factor‐beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension 39: 258‐263, 2002.
 409. Petrova R , Yamamoto Y , Muraki K , Yonekura H , Sakurai S , Watanabe T , Li H , Takeuchi M , Makita Z , Kato I , Takasawa S , Okamoto H , Imaizumi Y , Yamamoto H . Advanced glycation endproduct‐induced calcium handling impairment in mouse cardiac myocytes. J Mol Cell Cardiol 34: 1425‐1431, 2002.
 410. Philbin EF , Rocco TA Jr . Use of angiotensin‐converting enzyme inhibitors in heart failure with preserved left ventricular systolic function. Am Heart J 134: 188‐195, 1997.
 411. Philips N , Bashey RI , Jimenez SA . Collagen and fibronectin expression in cardiac fibroblasts from hypertensive rats. Cardiovasc Res 28: 1342‐1347, 1994.
 412. Pick R , Jalil JE , Janicki JS , Weber KT . The fibrillar nature and structure of isoproterenol‐induced myocardial fibrosis in the rat. Am J Pathol 134: 365‐371, 1989.
 413. Plank DM , Yatani A , Ritsu H , Witt S , Glascock B , Lalli MJ , Periasamy M , Fiset C , Benkusky N , Valdivia HH , Sussman MA . Calcium dynamics in the failing heart: Restoration by beta‐adrenergic receptor blockade. Am J Physiol Heart Circ Physiol 285: H305‐H315, 2003.
 414. Platonov PG , Mitrofanova LB , Orshanskaya V , Ho SY . Structural abnormalities in atrial walls are associated with presence and persistency of atrial fibrillation but not with age. J Am Coll Cardiol 58: 2225‐2232, 2011.
 415. Pluim BM , Lamb HJ , Kayser HWM , Leujes F , Beyerbacht HP , Zwinderman AH , van der Laarse A , Vliegen HW , de Roos A , van der Wall EE . Functional and metabolic evaluation of the athlete's heart by magnetic resonance imaging and dobutamine stress magnetic resonance spectroscopy. Circulation 97: 666‐672, 1998.
 416. Polyakova V , Hein S , Kostin S , Ziegelhoeffer T , Schaper J . Matrix metalloproteinases and their tissue inhibitors in pressure‐overloaded human myocardium during heart failure progression. J Am Coll Cardiol 44: 1609‐1618, 2004.
 417. Pope AJ , Sands GB , Smaill BH , LeGrice IJ . Three‐dimensional transmural organization of perimysial collagen in the heart. Am J Physiol Heart Circ Physiol 295: H1243‐H1252, 2008.
 418. Popescu LM , Gherghiceanu M , Hinescu ME , Cretoiu D , Ceafalan L , Regalia T , Popescu AC , Ardeleanu C , Mandache E . Insights into the interstitium of ventricular myocardium: Interstitial Cajal‐like cells (ICLC). J Cell Mol Med 10: 429‐458, 2006.
 419. Porter KE , Turner NA . Cardiac fibroblasts: At the heart of myocardial remodeling. Pharmacol Ther 123: 255‐278, 2009.
 420. Porter KE , Turner NA , O'Regan DJ , Ball SG . Tumor necrosis factor alpha induces human atrial myofibroblast proliferation, invasion and MMP‐9 secretion: Inhibition by simvastatin. Cardiovasc Res 64: 507‐515, 2004.
 421. Potts JR , Campbell ID . Structure and function of fibronectin modules. Matrix Biol 15: 313‐320, 1996.
 422. Querejeta R , Lopez B , Gonzalez A , Sanchez E , Larman M , Martinez Ubago JL , Diez J . Increased collagen type I synthesis in patients with heart failure of hypertensive origin: Relation to myocardial fibrosis. Circulation 110: 1263‐1268, 2004.
 423. Rahmutula D , Marcus GM , Wilson EE , Ding CH , Xiao Y , Paquet AC , Barbeau R , Barczak AJ , Erle DJ , Olgin JE . Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor‐beta. Cardiovasc Res 99: 769‐779, 2013.
 424. Ranga V , Kleinerman J , Ip MP , Sorensen J . Age‐related changes in elastic fibers and elastin of lung. Am Rev Respir Dis 119: 369‐376, 1979.
 425. Ravichandran LV , Puvanakrishnan R . In vivo labeling studies on the biosynthesis and degradation of collagen in experimental myocardial infarction. Biochem Int 24: 405‐414, 1991.
 426. Raya TE , Gaballa M , Anderson P , Goldman S . Left ventricular function and remodeling after myocardial infarction in aging rats. Am J Physiol Heart Circ Physiol 273: H2652‐H2658, 1997.
 427. Reed AL , Tanaka A , Sorescu D , Liu H , Jeong EM , Sturdy M , Walp ER , Dudley SC, Jr. , and Sutliff RL . Diastolic dysfunction is associated with cardiac fibrosis in the senescence‐accelerated mouse. Am J Physiol Heart Circ Physiol 301: H824‐H831, 2011.
 428. Reed MJ , Vernon RB , Abrass IB , Sage EH . TGF‐beta 1 induces the expression of type I collagen and SPARC, and enhances contraction of collagen gels, by fibroblasts from young and aged donors. J Cell Physiol 158: 169‐179, 1994.
 429. Rienks M , Papageorgiou AP , Frangogiannis NG , Heymans S . Myocardial extracellular matrix: An ever‐changing and diverse entity. Circ Res 114: 872‐888, 2014.
 430. Rietz A , Spiers J . The relationship between the MMP system, adrenoceptors and phosphoprotein phosphatases. Br J Pharmacol 166: 1225‐1243, 2012.
 431. Rietz A , Volkov Y , Davies A , Hennessy M , Spiers JP . Okadaic acid induces matrix metalloproteinase‐9 expression in fibroblasts: Crosstalk between protein phosphatase inhibition and beta‐adrenoceptor signalling. Br J Pharmacol 165: 274‐288, 2012.
 432. Robert V , Besse S , Sabri A , Silvestre JS , Assayag P , Nguyen VT , Swynghedauw B , Delcayre C . Differential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart. Lab Invest 76: 729‐738, 1997.
 433. Robinson TF , Factor SM , Capasso JM , Wittenberg BA , Blumenfeld OO , Seifter S . Morphology, composition, and function of struts between cardiac myocytes of rat and hamster. Cell Tissue Res 249: 247‐255, 1987.
 434. Robinson TF , Factor SM , Sonnenblick EH . The heart as a suction pump. Sci Am 254: 84‐91, 1986.
 435. Robinson TF , Geraci MA , Sonnenblick EH , Factor SM . Coiled perimysial fibers of papillary muscle in rat heart: Morphology, distribution, and changes in configuration. Circ Res 63: 577‐592, 1988.
 436. Rockwood K , Andrew M , Mitnitski A . A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol Sci Med Sci 62: 738‐743, 2007.
 437. Rodriguez‐Manzaneque JC , Lane TF , Ortega MA , Hynes RO , Lawler J , Iruela‐Arispe ML . Thrombospondin‐1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase‐9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A 98: 12485‐12490, 2001.
 438. Romanic AM , Burns‐Kurtis CL , Gout B , Berrebi‐Bertrand I , Ohlstein EH . Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. Life Sci 68: 799‐814, 2001.
 439. Roncarati R , Viviani Anselmi C , Losi MA , Papa L , Cavarretta E , Da Costa Martins P , Contaldi C , Saccani Jotti G , Franzone A , Galastri L , Latronico MV , Imbriaco M , Esposito G , De Windt L , Betocchi S , Condorelli G . Circulating miR‐29a, among other up‐regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 63: 920‐927, 2014.
 440. Rosenkranz S . TGF‐[beta]1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 63: 423‐432, 2004.
 441. Ross RS . Molecular and mechanical synergy: Cross‐talk between integrins and growth factor receptors. Cardiovasc Res 63: 381‐390, 2004.
 442. Ross RS , Borg TK . Integrins and the myocardium. Circ Res 88: 1112‐1119, 2001.
 443. Ross RS , Pham C , Shai SY , Goldhaber JI , Fenczik C , Glembotski CC , Ginsberg MH , Loftus JC . Beta1 integrins participate in the hypertrophic response of rat ventricular myocytes. Circ Res 82: 1160‐1172, 1998.
 444. Rossi A , Cicoira M , Zanolla L , Sandrini R , Golia G , Zardini P , Enriquez‐Sarano M . Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy. J Am Coll Cardiol 40: 1425, 2002.
 445. Rueckschloss U , Isenberg G . Contraction augments L‐type Ca2+ currents in adherent guinea‐pig cardiomyocytes. J Physiol 560: 403‐411, 2004.
 446. Sadoshima J , Izumo S . Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 73: 413‐423, 1993.
 447. Samuel JL , Barrieux A , Dufour S , Dubus I , Contard F , Koteliansky V , Farhadian F , Marotte F , Thiery JP , Rappaport L . Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload. J Clin Invest 88: 1737‐1746, 1991.
 448. Sanchez‐Quintana D , Garcia‐Martinez V , Macias D , Hurle JM . Structural arrangement of the extracellular matrix network during myocardial development in the chick embryo heart. Anat Embryol (Berl) 184: 451‐460, 1991.
 449. Sanghi S , Kumar R , Smith M , Baker KM , Dostal DE . Activation of protein kinase A by atrial natriuretic peptide in neonatal rat cardiac fibroblasts: Role in regulation of the local renin‐angiotensin system. Regul Pept 132: 1‐8, 2005.
 450. Sariahmetoglu M , Crawford BD , Leon H , Sawicka J , Li L , Ballermann BJ , Holmes C , Berthiaume LG , Holt A , Sawicki G , Schulz R . Regulation of matrix metalloproteinase‐2 (MMP‐2) activity by phosphorylation. FASEB J 21: 2486‐2495, 2007.
 451. Sasaki T , Gohring W , Mann K , Maurer P , Hohenester E , Knauper V , Murphy G , Timpl R . Limited cleavage of extracellular matrix protein BM‐40 by matrix metalloproteinases increases its affinity for collagens. J Biol Chem 272: 9237‐9243, 1997.
 452. Sasisekharan R , Venkataraman G . Heparin and heparan sulfate: Biosynthesis, structure and function. Curr Opin Chem Biol 4: 626‐631, 2000.
 453. Sato H , Takino T , Okada y , Cao J , Shinagawa A , Yamamoto E , Seiki M . A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61‐65, 1994.
 454. Sawada M , Carlson JC . Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech Ageing Dev 41: 125‐137, 1987.
 455. Sawicki G , Leon H , Sawicka J , Sariahmetoglu M , Schulze CJ , Scott PG , Szczesna‐Cordary D , Schulz R . Degradation of myosin light chain in isolated rat hearts subjected to ischemia‐reperfusion injury: A new intracellular target for matrix metalloproteinase‐2. Circulation 112: 544‐552, 2005.
 456. Saygili E , Rana O , Meyer C , Gemein C , Andrzejewski M , Ludwig A , Weber C , Schotten U , Kruttgen A , Weis J , Schwinger R , Mischke K , Rassaf T , Kelm M , Schauerte P . The angiotensin‐calcineurin‐NFAT pathway mediates stretch‐induced up‐regulation of matrix metalloproteinases‐2/‐9 in atrial myocytes. Basic Res Cardiol 104: 435‐448, 2009.
 457. Schelbert EB , Fonarow GC , Bonow RO , Butler J , Gheorghiade M . Therapeutic targets in heart failure: Refocusing on the myocardial interstitium. J Am Coll Cardiol 63: 2188‐2198, 2014.
 458. Schellings MW , Vanhoutte D , Swinnen M , Cleutjens JP , Debets J , van Leeuwen RE , d'Hooge J , Van de Werf F , Carmeliet P , Pinto YM , Sage EH , Heymans S . Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction. J Exp Med 206: 113‐123, 2009.
 459. Schriner SE , Linford NJ , Martin GM , Treuting P , Ogburn CE , Emond M , Coskun PE , Ladiges W , Wolf N , Van Remmen H , Wallace DC , Rabinovitch PS . Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308: 1909‐1911, 2005.
 460. Schroen B , Heymans S , Sharma U , Blankesteijn WM , Pokharel S , Cleutjens JP , Porter JG , Evelo CT , Duisters R , van Leeuwen RE , Janssen BJ , Debets JJ , Smits JF , Daemen MJ , Crijns HJ , Bornstein P , Pinto YM . Thrombospondin‐2 is essential for myocardial matrix integrity: Increased expression identifies failure‐prone cardiac hypertrophy. Circ Res 95: 515‐522, 2004.
 461. Schultz‐Cherry S , Murphy‐Ullrich JE . Thrombospondin causes activation of latent transforming growth factor‐beta secreted by endothelial cells by a novel mechanism. J Cell Biol 122: 923‐932, 1993.
 462. Schultz Jel J , Witt SA , Glascock BJ , Nieman ML , Reiser PJ , Nix SL , Kimball TR , Doetschman T . TGF‐beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 109: 787‐796, 2002.
 463. Seeland U , Haeuseler C , Hinrichs R , Rosenkranz S , Pfitzner T , Scharffetter‐Kochanek K , Bohm M . Myocardial fibrosis in transforming growth factor‐beta(1) (TGF‐beta(1)) transgenic mice is associated with inhibition of interstitial collagenase. Eur J Clin Invest 32: 295‐303, 2002.
 464. Seeland U , Selejan S , Engelhardt S , Muller P , Lohse MJ , Bohm M . Interstitial remodeling in beta1‐adrenergic receptor transgenic mice. Basic Res Cardiol 102: 183‐193, 2007.
 465. Sell DR , Monnier VM . Aging of Long‐Lived Proteins: Extracellular Matrix (Collagens, Elastins, Proteoglycans) and Lens Crystallins. Compr Physiol. 2011, Supplement 28: Handbook of Physiology, Aging: 235‐305. First published in print 1995. doi: 10.1002/cphy.cp110110
 466. Sengupta P . The laboratory rat: Relating its age with human's. Int J Prev Med 4: 624‐630, 2013.
 467. Senni M , Paulus WJ , Gavazzi A , Fraser AG , Díez J , Solomon SD , Smiseth OA , Guazzi M , Lam CSP , Maggioni AP , Tschöpe C , Metra M , Hummel SL , Edelmann F , Ambrosio G , Stewart Coats AJ , Filippatos GS , Gheorghiade M , Anker SD , Levy D , Pfeffer MA , Stough WG , Pieske BM . New strategies for heart failure with preserved ejection fraction: The importance of targeted therapies for heart failure phenotypes. Eur Heart J 35: 2797‐2815, 2014.
 468. Shai SY , Harpf AE , Babbitt CJ , Jordan MC , Fishbein MC , Chen J , Omura M , Leil TA , Becker KD , Jiang M , Smith DJ , Cherry SR , Loftus JC , Ross RS . Cardiac myocyte‐specific excision of the beta1 integrin gene results in myocardial fibrosis and cardiac failure. Circ Res 90: 458‐464, 2002.
 469. Shearer F , Lang CC , Struthers AD . Renin‐angiotensin‐aldosterone system inhibitors in heart failure. Clin Pharmacol Ther 94: 459‐467, 2013.
 470. Sherratt MJ . Tissue elasticity and the ageing elastic fibre. AGE 31: 305‐325, 2009.
 471. Shivakumar K , Dostal DE , Boheler K , Baker KM , Lakatta EG . Differential response of cardiac fibroblasts from young adult and senescent rats to ANG II. Am J Physiol Heart Circ Physiol 284: H1454‐H1459, 2003.
 472. Silver MA , Pick R , Brilla CG , Jalil JE , Janicki JS , Weber KT . Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: Two experimental models of myocardial fibrosis. Cardiovasc Res 24: 741‐747, 1990.
 473. Silvestre J‐S , Heymes C , Oubénaïssa A , Robert V , Aupetit‐Faisant B , Carayon A , Swynghedauw B , Delcayre C . Activation of cardiac aldosterone production in rat myocardial infarction: Effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 99: 2694‐2701, 1999.
 474. Simpson RM , Meran S , Thomas D , Stephens P , Bowen T , Steadman R , Phillips A . Age‐related changes in pericellular hyaluronan organization leads to impaired dermal fibroblast to myofibroblast differentiation. Am J Pathol 175: 1915‐1928, 2009.
 475. Siwik D , Colucci W . Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium. Heart Fail Rev 9: 43‐51, 2004.
 476. Siwik DA , Chang DL‐F , Colucci WS . Interleukin‐1β and tumor necrosis factor‐α decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res 86: 1259‐1265, 2000.
 477. Siwik DA , Pagano PJ , Colucci WS . Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280: C53‐C60, 2001.
 478. Skjot‐Arkil H , Clausen R , Nguyen Q , Wang Y , Zheng Q , Martinez F , Hogaboam C , Han M , Klickstein L , Larsen M , Nawrocki A , Leeming D , Karsdal M . Measurement of MMP‐9 and ‐12 degraded elastin (ELM) provides unique information on lung tissue degradation. BMC Pulm Med 12: 1‐12, 2012.
 479. Smaill BH , Zhao J , Trew ML . Three‐dimensional impulse propagation in myocardium: Arrhythmogenic mechanisms at the tissue level. Circ Res 112: 834‐848, 2013.
 480. Solomon SD , Skali H , Bourgoun M , Fang J , Ghali JK , Martelet M , Wojciechowski D , Ansmite B , Skards J , Laks T , Henry D , Packer M , Pfeffer MA . Effect of angiotensin‐converting enzyme or vasopeptidase inhibition on ventricular size and function in patients with heart failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) echocardiographic study. Am Heart J 150: 257‐262, 2005.
 481. Solomon SD , Zile M , Pieske B , Voors A , Shah A , Kraigher‐Krainer E , Shi V , Bransford T , Takeuchi M , Gong J , Lefkowitz M , Packer M , McMurray JJ . The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double‐blind randomised controlled trial. Lancet 380: 1387‐1395, 2012.
 482. Sorsa T , Salo T , Koivunen E , Tyynela J , Konttinen YT , Bergmann U , Tuuttila A , Niemi E , Teronen O , Heikkila P , Tschesche H , Leinonen J , Osman S , Stenman UH . Activation of type IV procollagenases by human tumor‐associated trypsin‐2. J Biol Chem 272: 21067‐21074, 1997.
 483. Souders CA , Bowers SLK , Baudino TA . Cardiac fibroblast: The renaissance cell. Circ Res 105: 1164‐1176, 2009.
 484. Spinale FG . Matrix metalloproteinases: Regulation and dysregulation in the failing heart. Circ Res 90: 520‐530, 2002.
 485. Spinale FG . Myocardial matrix remodeling and the matrix metalloproteinases: Influence on cardiac form and function. Physiol Rev 87: 1285‐1342, 2007.
 486. Spinale FG . Epilysin (Matrix Metalloproteinase‐28) Joins the Matrix Metalloproteinase Team on the field of postmyocardial infarction remodeling. Circ Res 112: 579‐582, 2013.
 487. Spinale FG , Coker ML , Heung LJ , Bond BR , Gunasinghe HR , Etoh T , Goldberg AT , Zellner JL , Crumbley AJ . A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 102: 1944‐1949, 2000.
 488. Spinale FG , Coker ML , Krombach SR , Mukherjee R , Hallak H , Houck WV , Clair MJ , Kribbs SB , Johnson LL , Peterson JT , Zile MR . Matrix metalloproteinase inhibition during the development of congestive heart failure : Effects on left ventricular dimensions and function. Circ Res 85: 364‐376, 1999.
 489. Spinale FG , Coker ML , Thomas CVT , Walker JD , Mukherjee R , Hebbar L . Time dependent changes in matrix metaloproteinase activity and expression during the progression of congestive heart failure: Relation to ventricular and myocyte function. Circ Res 82: 482‐495, 1998.
 490. Spinale FG , Escobar GP , Mukherjee R , Zavadzkas JA , Saunders SM , Jeffords LB , Leone AM , Beck C , Bouges S , Stroud RE . Cardiac‐restricted overexpression of membrane type‐1 matrix metalloproteinase in mice: Effects on myocardial remodeling with aging. Circ Heart Fail 2: 351‐360, 2009.
 491. Spinale FG , Janicki JS , Zile MR . Membrane‐associated matrix proteolysis and heart failure. Circ Res 112: 195‐208, 2013.
 492. Spinale FG , Mukherjee R , Zavadzkas JA , Koval CN , Bouges S , Stroud RE , Dobrucki LW , Sinusas AJ . Cardiac restricted overexpression of membrane type‐1 matrix metalloproteinase causes adverse myocardial remodeling following myocardial infarction. J Biol Chem 285: 30316‐30327, 2010.
 493. Spiro MJ , Crowley TJ . Increased rat myocardial type VI collagen in diabetes mellitus and hypertension. Diabetologia 36: 93‐98, 1993.
 494. Springman EB , Angleton EL , Birkedal‐Hansen H , Van Wart HE . Multiple modes of activation of latent human fibroblast collagenase: Evidence for the role of a Cys73 active‐site zinc complex in latency and a “cysteine switch” mechanism for activation. Proc Natl Acad Sci U S A 87: 364‐368, 1990.
 495. St John Sutton M , Pfeffer MA , Moye L , Plappert T , Rouleau JL , Lamas G , Rouleau J , Parker JO , Arnold MO , Sussex B , Braunwald E . Cardiovascular death and left ventricular remodeling two years after myocardial infarction: Baseline predictors and impact of long‐term use of captopril: Information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation 96: 3294‐3299, 1997.
 496. Stefanadis C , Dernellis J , Toutouzas P . A clinical appraisal of left atrial function. Eur Heart J 22: 22‐36, 2001.
 497. Stein M , Boulaksil M , Jansen JA , Herold E , Noorman M , Joles JA , van Veen TA , Houtman MJ , Engelen MA , Hauer RN , de Bakker JM , van Rijen HV . Reduction of fibrosis‐related arrhythmias by chronic renin‐angiotensin‐aldosterone system inhibitors in an aged mouse model. Am J Physiol Heart Circ Physiol 299: H310‐H321, 2010.
 498. Stern S , Behar S , Gottlieb S . Aging and diseases of the heart. Circulation 108: e99‐e101, 2003.
 499. Stewart AF , Rokosh DG , Bailey BA , Karns LR , Chang KC , Long CS , Kariya K , Simpson PC . Cloning of the rat alpha 1C‐adrenergic receptor from cardiac myocytes. alpha 1C, alpha 1B, and alpha 1D mRNAs are present in cardiac myocytes but not in cardiac fibroblasts. Circ Res 75: 796‐802, 1994.
 500. Strain JE , Grose RM , Factor SM , Fisher JD . Results of endomyocardial biopsy in patients with spontaneous ventricular tachycardia but without apparent structural heart disease. Circulation 68: 1171‐1181, 1983.
 501. Strandjord TP , Madtes DK , Weiss DJ , Sage EH . Collagen accumulation is decreased in SPARC‐null mice with bleomycin‐induced pulmonary fibrosis. Am J Physiol 277: L628‐L635, 1999.
 502. Striker LJ , Striker GE . Administration of AGEs in vivo induces extracellular matrix gene expression. Nephrol Dial Transplant 11(Suppl 5): 62‐65, 1996.
 503. Sullivan KE , Black LD . The role of cardiac fibroblasts in extracellular matrix‐mediated signaling during normal and pathological cardiac development. J Biomech Eng 135: 71001, 2013.
 504. Sun M , Opavsky MA , Stewart DJ , Rabinovitch M , Dawood F , Wen WH , Liu PP . Temporal response and localization of integrins beta1 and beta3 in the heart after myocardial infarction: Regulation by cytokines. Circulation 107: 1046‐1052, 2003.
 505. Sun Y , Weber KT . Infarct scar: A dynamic tissue. Cardiovasc Res 46: 250‐256, 2000.
 506. Swaney JS , Roth DM , Olson ER , Naugle JE , Meszaros JG , Insel PA . Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci U S A 102: 437‐442, 2005.
 507. Swinnen M , Vanhoutte D , Van Almen GC , Hamdani N , Schellings MW , D'Hooge J , Van der Velden J , Weaver MS , Sage EH , Bornstein P , Verheyen FK , VandenDriessche T , Chuah MK , Westermann D , Paulus WJ , Van de Werf F , Schroen B , Carmeliet P , Pinto YM , Heymans S . Absence of thrombospondin‐2 causes age‐related dilated cardiomyopathy. Circulation 120: 1585‐1597, 2009.
 508. Takeda N , Manabe I , Uchino Y , Eguchi K , Matsumoto S , Nishimura S , Shindo T , Sano M , Otsu K , Snider P , Conway SJ , Nagai R . Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J Clin Invest 120: 254‐265, 2010.
 509. Takemoto Y , Barnes ME , Seward JB , Lester SJ , Appleton CA , Gersh BJ , Bailey KR , Tsang TSM . Usefulness of left atrial volume in predicting first congestive heart failure in patients > or =65 years of age with well‐preserved left ventricular systolic function. Am J Cardiol 96: 832‐836, 2005.
 510. Tchougounova E , Lundequist A , Fajardo I , Winberg JO , Abrink M , Pejler G . A key role for mast cell chymase in the activation of pro‐matrix metalloprotease‐9 and pro‐matrix metalloprotease‐2. J Biol Chem 280: 9291‐9296, 2005.
 511. Templeton GH , Platt MR , Willerson JT , Weisfeldt ML . Influence of aging on left ventricular hemodynamics and stiffness in beagles. Circ Res 44: 189‐194, 1979.
 512. Terracio L , Rubin K , Gullberg D , Balog E , Carver W , Jyring R , Borg TK . Expression of collagen binding integrins during cardiac development and hypertrophy. Circ Res 68: 734‐744, 1991.
 513. Terracio L , TingstrÖM A , Peters WH , Borg TK . A potential role for mechanical stimulation in cardiac development. Ann N Y Acad Sci 588: 48‐60, 1990.
 514. Thannickal VJ . Mechanistic links between aging and lung fibrosis. Biogerontology 14: 609‐615, 2013.
 515. Thomas DP , McCormick RJ , Zimmerman SD , Vadlamudi RK , Gosselin LE . Aging‐ and training‐induced alterations in collagen characteristics of rat left ventricle and papillary muscle. Am J Physiol Heart Circ Physiol 263: H778‐H783, 1992.
 516. Thomas DP , Zimmerman SD , Hansen TR , Martin DT , McCormick RJ . Collagen gene expression in rat left ventricle: Interactive effect of age and exercise training. J Appl Physiol (1985) 89: 1462‐1468, 2000.
 517. Thomas L , Levett K , Boyd A , Leung DY , Schiller NB , Ross DL . Compensatory changes in atrial volumes with normal aging: Is atrial enlargement inevitable? J Am Coll Cardiol 40: 1630‐1635, 2002.
 518. Thum T , Gross C , Fiedler J , Fischer T , Kissler S , Bussen M , Galuppo P , Just S , Rottbauer W , Frantz S , Castoldi M , Soutschek J , Koteliansky V , Rosenwald A , Basson MA , Licht JD , Pena JT , Rouhanifard SH , Muckenthaler MU , Tuschl T , Martin GR , Bauersachs J , Engelhardt S . MicroRNA‐21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456: 980‐984, 2008.
 519. Tokuda K , Kai H , Kuwahara F , Yasukawa H , Tahara N , Kudo H , Takemiya K , Koga M , Yamamoto T , Imaizumi T . Pressure‐independent effects of angiotensin II on hypertensive myocardial fibrosis. Hypertension 43: 499‐503, 2004.
 520. Tomanek RJ . Effects of age and exercise on the extent of the myocardial capillary bed. Anat Rec 167: 55‐62, 1970.
 521. Townsend N , Wickramasinghe K , Bhatnager P , Smolina K , Nichols M , Leal J , Luengo‐Fernandez R , Rayner M . In: Coronary Heart Disease Statistics. London: British Heart Foundation, 2012.
 522. Trombetta‐eSilva J , Eadie EP , Zhang Y , Norris RA , Borg TK , Bradshaw AD . The effects of age and the expression of SPARC on extracellular matrix production by cardiac fibroblasts in 3‐D cultures. PLoS One 8: e79715, 2013.
 523. Turner NA , O'Regan D J , Ball SG , Porter KE . Endothelin‐1 is an essential co‐factor for beta2‐adrenergic receptor‐induced proliferation of human cardiac fibroblasts. FEBS Lett 576: 156‐160, 2004.
 524. Turner NA , Porter KE . Regulation of myocardial matrix metalloproteinase expression and activity by cardiac fibroblasts. IUBMB Life 64: 143‐150, 2012.
 525. Turner NA , Porter KE , Smith WHT , White HL , Ball SG , Balmforth AJ . Chronic beta2‐adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism. Cardiovasc Res 57: 784‐792, 2003.
 526. Uitto J . The role of elastin and collagen in cutaneous aging: Intrinsic aging versus photoexposure. J Drugs Dermatol 7: s12‐s16, 2008.
 527. Ulrich MMW , Janssen AMH , Daemen MJAP , Rappaport L , Samuel JL , Contard F , Smits JFM , Cleutjens JPM . Increased expression of fibronectin isoforms after myocardial infarction in rats. J Mol Cell Cardiol 29: 2533‐2543, 1997.
 528. van Almen GC , Verhesen W , van Leeuwen RE , van de Vrie M , Eurlings C , Schellings MW , Swinnen M , Cleutjens JP , van Zandvoort MA , Heymans S , Schroen B . MicroRNA‐18 and microRNA‐19 regulate CTGF and TSP‐1 expression in age‐related heart failure. Aging cell 10: 769‐779, 2011.
 529. van den Berg MP , Tjeerdsma G , Jan de Kam P , Boomsma F , Crijns HJ , van Veldhuisen DJ . Longstanding atrial fibrillation causes depletion of atrial natriuretic peptide in patients with advanced congestive heart failure. Eur J Heart Fail 4: 255‐262, 2002.
 530. van der Rest M , Garrone R . Collagen family of proteins. FASEB J 5: 2814‐2823, 1991.
 531. van der Velden J , Papp Z , Zaremba R , Boontje NM , De Jong JW , Owen VJ , Burton PB , Goldmann P , Jaquet K , Stienen GJ . Increased Ca2+‐sensitivity of the contractile apparatus in end‐stage human heart failure results from altered phosphorylation of contractile proteins. Cardiovasc Res 57: 37‐47, 2003.
 532. van Heerebeek L , Borbely A , Niessen HWM , Bronzwaer JGF , van der Velden J , Stienen GJM , Linke WA , Laarman GJ , Paulus WJ . Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113: 1966‐1973, 2006.
 533. van Rooij E . The art of microRNA research. Circ Res 108: 219‐234, 2011.
 534. Vanhoutte D , Heymans S . TIMPs and cardiac remodeling: ‘Embracing the MMP‐independent‐side of the family’. J Mol Cell Cardiol 48: 445‐453, 2010.
 535. Varagic J , Frohlich ED . Local cardiac renin‐angiotensin system: Hypertension and cardiac failure. J Mol Cell Cardiol 34: 1435‐1442, 2002.
 536. Vardeny O , Tacheny T , Solomon SD . First‐in‐class angiotensin receptor neprilysin inhibitor in heart failure. Clin Pharmacol Ther 94: 445‐448, 2013.
 537. Vasan RS , Larson MG , Benjamin EJ , Evans JC , Reiss CK , Levy D . Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a population‐based cohort. J Am Coll Cardiol 33: 1948‐1955, 1999.
 538. Vaziri SM , Larson MG , Benjamin EJ , Levy D . Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 89: 724‐730, 1994.
 539. Viappiani S , Nicolescu AC , Holt A , Sawicki G , Crawford BD , León H , van Mulligen T , Schulz R . Activation and modulation of 72 kDa matrix metalloproteinase‐2 by peroxynitrite and glutathione. Biochem Pharmacol 77: 826‐834, 2009.
 540. Villarreal FJ , Dillmann WH . Cardiac hypertrophy‐induced changes in mRNA levels for TGF‐beta 1, fibronectin, and collagen. Am J Physiol Heart Circ Physiol 262: H1861‐H1866, 1992.
 541. Villarreal FJ , Kim NN , Ungab GD , Printz MP , Dillmann WH . Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 88: 2849‐2861, 1993.
 542. Visse R , Nagase H . Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ Res 92: 827‐839, 2003.
 543. von Knorring J . The mucopolysaccharides in the myocardium of growing rats. Acta Physiol Scand 79: 226‐237, 1970.
 544. von Lueder TG , Wang BH , Kompa AR , Huang L , Webb R , Jordaan P , Atar D , Krum H . The angiotensin‐receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail 2014 [Epub ahead of print].
 545. von Marschall Z , Fisher LW . Dentin sialophosphoprotein (DSPP) is cleaved into its two natural dentin matrix products by three isoforms of bone morphogenetic protein‐1 (BMP1). Matrix Biol 29: 295‐303, 2010.
 546. Wagenseil JE , Mecham RP . New insights into elastic fiber assembly. Birth Defects Res C Embryo Today 81: 229‐240, 2007.
 547. Waldenstrom A , Martinussen HJ , Gerdin B , Hallgren R . Accumulation of hyaluronan and tissue edema in experimental myocardial infarction. J Clin Invest 88: 1622‐1628, 1991.
 548. Wang B , Tedder M , Perez C , Wang G , Jongh Curry A , To F , Elder S , Williams L , Simionescu D , Liao J . Structural and biomechanical characterizations of porcine myocardial extracellular matrix. J Mater Sci Mater Med 23: 1835‐1847, 2012.
 549. Wang J , Chen H , Seth A , McCulloch CA . Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 285: H1871‐H1881, 2003.
 550. Wang J , Hoshijima M , Lam J , Zhou Z , Jokiel A , Dalton ND , Hultenby K , Ruiz‐Lozano P , Ross J , Tryggvason K , Chien KR . Cardiomyopathy associated with microcirculation dysfunction in laminin alpha4 chain‐deficient mice. J Biol Chem 281: 213‐220, 2006.
 551. Wang M , Zhang J , Walker SJ , Dworakowski R , Lakatta EG , Shah AM . Involvement of NADPH oxidase in age‐associated cardiac remodeling. J Mol Cell Cardiol 48: 765‐772, 2010.
 552. Wang P , Zhou S , Xu L , Lu Y , Yuan X , Zhang H , Li R , Fang J , Liu P . Hydrogen peroxide‐mediated oxidative stress and collagen synthesis in cardiac fibroblasts: Blockade by tanshinone IIA. J Ethnopharmacol 145: 152‐161, 2013.
 553. Wang W , Schulze CJ , Suarez‐Pinzon WL , Dyck JRB , Sawicki G , Schulz R . Intracellular action of matrix metalloproteinase‐2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 106: 1543‐1549, 2002.
 554. Wang Y , Wu Y , Chen J , Zhao S , Li H . Pirfenidone attenuates cardiac fibrosis in a mouse model of TAC‐induced left ventricular remodeling by suppressing NLRP3 inflammasome formation. Cardiology 126: 1‐11, 2013.
 555. Wang YG , Samarel AM , Lipsius SL . Laminin acts via beta 1 integrin signalling to alter cholinergic regulation of L‐type Ca(2+) current in cat atrial myocytes. J Physiol 526(Pt 1): 57‐68, 2000.
 556. Webber J , Jenkins RH , Meran S , Phillips A , Steadman R . Modulation of TGFbeta1‐dependent myofibroblast differentiation by hyaluronan. Am J Pathol 175: 148‐160, 2009.
 557. Webber J , Meran S , Steadman R , Phillips A . Hyaluronan orchestrates transforming growth factor‐beta1‐dependent maintenance of myofibroblast phenotype. J Biol Chem 284: 9083‐9092, 2009.
 558. Weber KT . Cardiac interstitium in health and disease: The fibrillar collagen network. J Am Coll Cardiol 13: 1637‐1652, 1989.
 559. Weber KT , Brilla CG . Pathological hypertrophy and cardiac interstitium. Fibrosis and renin‐ angiotensin‐aldosterone system. Circulation 83: 1849‐1865, 1991.
 560. Weber KT , Pick R , Jalil JE , Janicki JS , Carroll EP . Patterns of myocardial fibrosis. J Mol Cell Cardiol 21(Suppl 5): 121‐131, 1989.
 561. Wei S , Chow LT , Shum IO , Qin L , Sanderson JE . Left and right ventricular collagen type I/III ratios and remodeling post‐myocardial infarction. J Card Fail 5: 117‐126, 1999.
 562. Wenzel S , Taimor G , Piper HM , Schlüter K‐D . Redox‐sensitve intermediates mediate angiotensin II‐induced p38 MAP kinase activation, AP‐1 binding activity, and TGF‐b expression in adult ventricular cardiomyocytes. FASEB J 15(12): 2291‐2293, 2001.
 563. Werner SR , Mescher AL , Neff AW , King MW , Chaturvedi S , Duffin KL , Harty MW , Smith RC . Neural MMP‐28 expression precedes myelination during development and peripheral nerve repair. Dev Dyn 236: 2852‐2864, 2007.
 564. White M , Rouleau JL , Hall C , Arnold M , Harel F , Sirois P , Greaves S , Solomon S , Ajani U , Glynn R , Hennekens C , Pfeffer M . Changes in vasoconstrictive hormones, natriuretic peptides, and left ventricular remodeling soon after anterior myocardial infarction. Am Heart J 142: 1056‐1064, 2001.
 565. Whitehead JC , Hildebrand BA , Sun M , Rockwood MR , Rose RA , Rockwood K , Howlett SE . A clinical frailty index in aging mice: Comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci 69: 621‐632, 2014.
 566. WHO. Causes of death, 2000‐2011 [Online]. World Health Organization. http://www.who.int/gho/mortality_burden_disease/causes_death/2000_2011/en/. [2014].
 567. WHO. Interesting facts about ageing [Online]. World Health Organization. http://www.who.int/ageing/about/facts/en./ [2014].
 568. Wilson CG , Stone JW , Fowlkes V , Morales MO , Murphy CJ , Baxter SC , Goldsmith EC . Age‐dependent expression of collagen receptors and deformation of type I collagen substrates by rat cardiac fibroblasts. Microsc Microanal 17: 555‐562, 2011.
 569. Wohlgemuth SE , Calvani R , Marzetti E . The interplay between autophagy and mitochondrial dysfunction in oxidative stress‐induced cardiac aging and pathology. J Mol Cell Cardiol 71c: 62‐70, 2014.
 570. Woodiwiss AJ , Tsotetsi OJ , Sprott S , Lancaster EJ , Mela T , Chung ES , Meyer TE , Norton GR . Reduction in myocardial collagen cross‐linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction. Circulation 103: 155‐160, 2001.
 571. Wu S‐Q , Kwan C‐Y , Tang F . The effect of aging on ANP levels in the plasma, heart, and brain of rats. J Gerontol A Biol Sci Med Sci 52A: B250‐B254, 1997.
 572. Xia Y , Dobaczewski M , Gonzalez‐Quesada C , Chen W , Biernacka A , Li N , Lee DW , Frangogiannis NG . Endogenous thrombospondin 1 protects the pressure‐overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. Hypertension 58: 902‐911, 2011.
 573. Xiao RP , Tomhave ED , Wang DJ , Ji X , Boluyt MO , Cheng H , Lakatta EG , Koch WJ . Age‐associated reductions in cardiac beta1‐ and beta2‐adrenergic responses without changes in inhibitory G proteins or receptor kinases. J Clin Invest 101: 1273‐1282, 1998.
 574. Xu J , Cui G , Esmailian F , Plunkett M , Marelli D , Ardehali A , Odim J , Laks H , Sen L . Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation. Circulation 109: 363‐368, 2004.
 575. Yamamoto K , Masuyama T , Sakata Y , Nishikawa N , Mano T , Yoshida J , Miwa T , Sugawara M , Yamaguchi Y , Ookawara T , Suzuki K , Hori M . Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc Res 55: 76‐82, 2002.
 576. Yan L , Vatner DE , O'Connor JP , Ivessa A , Ge H , Chen W , Hirotani S , Ishikawa Y , Sadoshima J , Vatner SF . Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130: 247‐258, 2007.
 577. Yan RT , White M , Yan AT , Yusuf S , Rouleau JL , Maggioni AP , Hall C , Latini R , Afzal R , Floras J , Masson S , McKelvie RS . Usefulness of temporal changes in neurohormones as markers of ventricular remodeling and prognosis in patients with left ventricular systolic dysfunction and heart failure receiving either candesartan or enalapril or both. Am J Cardiol 96: 698‐704, 2005.
 578. Yang H , Borg TK , Wang z , Ma Z , Gao BZ . Role of the basement membrane in regulation of cardiac electrical properties. Ann Biomed Eng 42: 1148‐1157, 2014.
 579. Yang Y , Ma Y , Han W , Li J , Xiang Y , Liu F , Ma X , Zhang J , Fu Z , Su YD , Du XJ , Gao XM . Age‐related differences in postinfarct left ventricular rupture and remodeling. Am J Physiol Heart Circ Physiol 294: H1815‐H1822, 2008.
 580. Yang Z , Strickland DK , Bornstein P . Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein‐related scavenger receptor and thrombospondin 2. J Biol Chem 276: 8403‐8408, 2001.
 581. Yin F , Wang YY , Du JH , Li C , Lu ZZ , Han C , Zhang YY . Noncanonical cAMP pathway and p38 MAPK mediate beta2‐adrenergic receptor‐induced IL‐6 production in neonatal mouse cardiac fibroblasts. J Mol Cell Cardiol 40: 384‐393, 2006.
 582. Yoshihara F , Nishikimi T , Sasako Y , Hino J , Kobayashi J , Minatoya K , Bando K , Kosakai Y , Horio T , Suga S , Kawano Y , Matsuoka H , Yutani C , Matsuo H , Kitamura S , Ohe T , Kangawa K . Plasma atrial natriuretic peptide concentration inversely correlates with left atrial collagen volume fraction in patients with atrial fibrillation: Plasma ANP as a possible biochemical marker to predict the outcome of the maze procedure. J Am Coll Cardiol 39: 288‐294, 2002.
 583. Young AA , LeGrice IJ , Young MA , Smaill BH . Extended confocal microscopy of myocardial laminae and collagen network. J Microsc 192: 139‐150, 1998.
 584. Yuan W , Ginsburg KS , Bers DM . Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes. J Physiol 493: 733‐746, 1996.
 585. Yurchenco PD , Schittny JC . Molecular architecture of basement membranes. FASEB J 4: 1577‐1590, 1990.
 586. Zarich SW , Arbuckle BE , Cohen LR , Roberts M , Nesto RW . Diastolic abnormalities in young asymptomatic diabetic patients assessed by pulsed Doppler echocardiography. J Am Coll Cardiol 12: 114‐120, 1988.
 587. Zavadzkas JA , Plyler RA , Bouges S , Koval CN , Rivers WT , Beck CU , Chang EI , Stroud RE , Mukherjee R , Spinale FG . Cardiac‐restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice. Am J Physiol Heart Circ Physiol 295: H1394‐H1402, 2008.
 588. Zavadzkas JA , Stroud RE , Bouges S , Mukherjee R , Jones JR , Patel RK , McDermott PJ , Spinale FG . Targeted overexpression of tissue inhibitor of matrix metalloproteinase‐4 modifies post‐myocardial infarction remodeling in mice. Circ Res 114: 1435‐1445, 2014.
 589. Zeisberg EM , Kalluri R . Origins of cardiac fibroblasts. Circ Res 107: 1304‐1312, 2010.
 590. Zellner JL , Spinale FG , Eble DM , Hewett KW , Crawford FA Jr . Alterations in myocyte shape and basement membrane attachment with tachycardia‐induced heart failure. Circ Res 69: 590‐600, 1991.
 591. Zhang X , Chen X , Hong Q , Lin H , Zhu H , Liu Q , Wang J , Xie Y , Shang X , Shi S , Lu Y , Yin Z . TIMP‐1 promotes age‐related renal fibrosis through upregulating ICAM‐1 in human TIMP‐1 transgenic mice. J Gerontol A Biol Sci Med Sci 61: 1130‐1143, 2006.
 592. Zhang Y , Yin H , Lu H . Recent progress in quantitative glycoproteomics. Glycoconj J 29: 249‐258, 2012.
 593. Zile MR , Brutsaert DL . New concepts in diastolic dysfunction and diastolic heart failure: Part II: Causal mechanisms and treatment. Circulation 105: 1503‐1508, 2002.
 594. Zou Y , Komuro I , Yamazaki T , Kudoh S , Aikawa R , Zhu W , Shiojima I , Hiroi Y , Tobe K , Kadowaki T , Yazaki Y . Cell type specific angiotensin II evoked signal transduction pathways: Critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts. Circ Res 82: 337‐345, 1998.

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Article Title: Cardiac Physiology of Aging: Extracellular Considerations
 

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Margaux A. Horn. Cardiac Physiology of Aging: Extracellular Considerations. Compr Physiol 2015, 5: 1069-1121. doi: 10.1002/cphy.c140063