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Cardiac Physiology of Aging: Extracellular Considerations

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