Dysautonomic responses during percutaneous carotid intervention: principles of physiology and management.

Percutaneous carotid artery stenting (CAS) has emerged as a less invasive alternative to carotid endarterectomy for the treatment of carotid atherosclerotic disease. The main risk of CAS is the occurrence of neuro-vascular complications; however, carotid artery stenting-related dysautonomia (CAS-D) (hypertension, hypotension, and bradycardia) is the most frequently reported problem occurring in the periprocedural period. Alterations in autonomic homeostasis result from baroreceptor stimulation, which occurs particularly at the time of balloon inflation in the region of the carotid sinus. The response can be profound enough to induce asystole or even complete cessation of postganglionic sympathetic nerve activity. Frequency and factors predisposing a patient to CAS-D have been investigated in several studies; however, there are significant discrepancies in results among reports. Lack of consistent findings may arise from using different methods and definitions, as well as other factors discussed in detail in this review. Furthermore, a correlation of CAS-D with short and long-term outcomes has been investigated only in small and mostly retrospective studies, explaining why its prognostic significance remains uncertain. In this manuscript, we have focused on risk factors, pathophysiology and management of periprocedural autonomic dysfunction. As there is no standardized approach to the treatment of CAS-D, we present an algorithm for the periprocedural management of patients undergoing CAS. The proposed algorithm was developed based on our procedural experience as well as data from the available literature. The Yale Algorithm was successfully implemented at our institution and we are currently collecting data for short- and long-term safety. © 2014 Wiley Periodicals, Inc.

Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction.

RATIONALE: Cardiac fibroblasts are key effector cells in the pathogenesis of cardiac fibrosis. Transforming growth factor (TGF)-beta/Smad3 signaling is activated in the border zone of healing infarcts and induces fibrotic remodeling of the infarcted ventricle contributing to the development of diastolic dysfunction. OBJECTIVE: The present study explores the mechanisms responsible for the fibrogenic effects of Smad3 by dissecting its role in modulating cardiac fibroblast phenotype and function. METHODS AND RESULTS: Smad3 null mice and corresponding wild-type controls underwent reperfused myocardial infarction protocols. Surprisingly, reduced collagen deposition in Smad3-/- infarcts was associated with increased infiltration with myofibroblasts. In vitro studies demonstrated that TGF-beta1 inhibited murine cardiac fibroblast proliferation; these antiproliferative effects were mediated via Smad3. Smad3-/- fibroblasts were functionally defective, exhibiting impaired collagen lattice contraction when compared with wild-type cells. Decreased contractile function was associated with attenuated TGF-beta-induced expression of alpha-smooth muscle actin. In addition, Smad3-/- fibroblasts had decreased migratory activity on stimulation with serum, and exhibited attenuated TGF-beta1-induced upregulation of extracellular matrix protein synthesis. Upregulation of connective tissue growth factor, an essential downstream mediator in TGF-beta-induced fibrosis, was in part dependent on Smad3. Connective tissue growth factor stimulation enhanced extracellular matrix protein expression by cardiac fibroblasts in a Smad3-independent manner. CONCLUSIONS: Disruption of Smad3 results in infiltration of the infarct with abundant hypofunctional fibroblasts that exhibit impaired myofibroblast transdifferentiation, reduced migratory potential, and suppressed expression of fibrosis-associated genes.

CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells.

Myocardial infarction triggers an inflammatory reaction that is involved in cardiac remodeling. Cardiac repair is dependent on regulatory mechanisms that suppress inflammation and prevent excessive matrix degradation. Chemokine induction in the infarcted heart mediates recruitment of leukocyte subsets with distinct properties. We demonstrate that signaling through the CC chemokine receptor 5 (CCR5) prevents uncontrolled postinfarction inflammation and protects from adverse remodeling by recruiting suppressive mononuclear cells. CCR5 and its ligands macrophage inflammatory protein (MIP)-1alpha and MIP-1beta were markedly induced in the infarcted mouse myocardium. In addition, almost 40% of the mononuclear cells infiltrating the infarct expressed CCR5. CCR5(-/-) mice exhibited marked upregulation of proinflammatory cytokine and chemokine expression in the infarct. In wild-type infarcts CCR5+ mononuclear cells had anti-inflammatory properties, expressing higher levels of IL-10 than CCR5- cells. In contrast, mononuclear cells isolated from CCR5(-/-) infarcts had reduced IL-10 expression. Moreover, enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of CD4+/foxp3+ regulatory T cells (Tregs). The CCR5+ Treg subset exhibited increased IL-10 expression, reflecting potent anti-inflammatory activity. Accentuated inflammation in CCR5(-/-) infarcts was associated with increased matrix metalloproteinase (MMP) expression, reduced TIMP levels, and enhanced MMP-2 and MMP-9 activity, resulting in worse cardiac dilation. These results suggest that CCR5-mediated Treg recruitment may restrain postinfarction inflammation, preventing excessive matrix degradation and attenuating adverse remodeling.

Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.

RATIONALE: Interferon-gamma-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. OBJECTIVE: To study the role of IP-10 in cardiac repair and remodeling. METHODS AND RESULTS: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10(-/-) hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10(-/-) infarcts had more intense infiltration with CD45(+) leukocytes, Mac-2(+) macrophages, and alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and alpha-SMA(+) cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. CONCLUSIONS: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.

Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling.

The proinflammatory cytokine interleukin (IL)-1 signals exclusively through the type I IL-1 receptor (IL-1RI). IL-1 expression is markedly induced in the infarcted heart; however, its role in cardiac injury and repair remains controversial. We examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI(-/-) mice. After reperfused infarction IL-1RI-null mice exhibited decreased infiltration of the infarcted myocardium with neutrophils and macrophages and reduced chemokine and cytokine expression. In the absence of IL-1 signaling, suppressed inflammation was followed by an attenuated fibrotic response. Infarcted IL-1RI(-/-) mice had decreased myofibroblast infiltration and reduced collagen deposition in the infarcted and remodeling myocardium. IL-1RI deficiency protected against the development of adverse remodeling; however, infarct size was comparable between groups suggesting that the beneficial effects of IL-1RI gene disruption were not attributable to decreased cardiomyocyte injury. Reduced chamber dilation in IL-1RI-null animals was associated with decreased collagen deposition and attenuated matrix metalloproteinase (MMP)-2 and MMP-3 expression in the peri-infarct area, suggesting decreased fibrotic remodeling of the noninfarcted heart. IL-1beta stimulated MMP mRNA synthesis in wild-type, but not in IL-1RI-null cardiac fibroblasts. In conclusion, IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct, playing an important role in the pathogenesis of remodeling after infarction. Thus, interventional therapeutics targeting the IL-1 system may have great benefits in myocardial infarction.

Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling.

BACKGROUND: Postinfarction cardiac repair is regulated through timely activation and repression of inflammatory pathways, followed by transition to fibrous tissue deposition and formation of a scar. The transforming growth factor-beta/Smad3 pathway is activated in healing infarcts and may regulate cellular events critical for the inflammatory and the fibrotic responses. METHODS AND RESULTS: We examined the effects of Smad3 gene disruption on infarct healing and the pathogenesis of cardiac remodeling. In the absence of injury, Smad3-null hearts had comparable function to and similar morphology as wild-type hearts. Smad3-null animals had suppressed peak chemokine expression and decreased neutrophil recruitment in the infarcted myocardium but showed timely repression of inflammatory gene synthesis and resolution of the inflammatory infiltrate. Although myofibroblast density was higher in Smad3-null infarcts, interstitial deposition of collagen and tenascin-C in the remodeling myocardium was markedly reduced. Compared with wild-type animals, Smad3-/- mice exhibited decreased dilative remodeling and attenuated diastolic dysfunction; however, infarct size was comparable between groups. Transforming growth factor-beta-mediated induction of procollagen type III and tenascin-C in isolated cardiac fibroblasts was dependent on Smad3, which suggests that decreased fibrotic remodeling in infarcted Smad3-null hearts may be due to abrogation of the profibrotic transforming growth factor-beta responses. CONCLUSIONS: Smad3 loss does not alter the time course of resolution of inflammation in healing infarcts, but it prevents interstitial fibrosis in the noninfarcted myocardium and attenuates cardiac remodeling. Thus, the Smad3 cascade may be a promising therapeutic target for the treatment of myocardial infarction.

The role of TGF-beta signaling in myocardial infarction and cardiac remodeling.

Transforming Growth Factor (TGF)-beta is markedly induced and rapidly activated in the infarcted myocardium. However, understanding of the exact role of TGF-beta signaling in the infarcted and remodeling heart has been hampered by the complex and unusual biology of TGF-beta activation and by the diversity of its effects eliciting multiple, and often opposing cellular responses. Experimental studies suggest that TGF-beta signaling may be crucial for repression of inflammatory gene synthesis in healing infarcts mediating resolution of the inflammatory infiltrate. In addition, TGF-beta may play an important role in modulating fibroblast phenotype and gene expression, promoting extracellular matrix deposition in the infarct by upregulating collagen and fibronectin synthesis and by decreasing matrix degradation through induction of protease inhibitors. TGF-beta is also a key mediator in the pathogenesis of hypertrophic and dilative ventricular remodeling by stimulating cardiomyocyte growth and by inducing interstitial fibrosis. In this review we summarize the current knowledge on the role of TGF-beta in infarct healing and cardiac remodeling.

Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling.

OBJECTIVE: Interleukin-10 (IL-10) exerts potent anti-inflammatory actions and modulates matrix metalloproteinase expression. We hypothesized that endogenous IL-10 may regulate infarct healing and left ventricular remodeling by promoting resolution of the post-infarction inflammatory response and by modulating extracellular matrix metabolism. METHODS: IL-10 null and wildtype (WT) mice underwent reperfused infarction protocols. We compared the healing response and remodeling-associated parameters between IL-10-/-and WT infarcts. In addition, we studied the effects of IL-10 on inflammatory gene synthesis by stimulated murine cardiac fibroblasts. RESULTS: Infarcted IL-10-/-mice exhibited comparable mortality rates with WT animals. Although IL-10-/-mice had higher peak tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1/CCL2 mRNA levels in the infarcted heart than WT mice, both groups demonstrated timely repression of pro-inflammatory cytokine and chemokine mRNA synthesis after 24 h of reperfusion and exhibited a similar time course of resolution of the neutrophil infiltrate. IL-10 gene disruption did not alter fibrous tissue deposition and dilative remodeling of the infarcted heart. Pre-incubation with IL-10 did not modulate the pro-inflammatory phenotype of TNF-alpha-stimulated cardiac fibroblasts, failing to inhibit chemokine mRNA synthesis. In contrast, transforming growth factor (TGF)-beta1 pre-incubation suppressed interferon-gamma-inducible protein (IP)-10/CXCL10 synthesis by cardiac fibroblasts exposed to TNF-alpha. CONCLUSIONS: IL-10 signaling plays a non-critical role in suppression of inflammatory mediators, resolution of the inflammatory response, and fibrous tissue deposition following myocardial infarction. This may be due to the relative selectivity of IL-10-mediated anti-inflammatory actions, with respect to cell type and stimulus. Resolution of post-infarction inflammation is likely to involve multiple overlapping regulatory mechanisms controlling various pro-inflammatory pathways activated in the infarcted myocardium.

Management of Atherosclerotic Aortoiliac Occlusive Disease.

Development of aortoiliac occlusive disease (AIOD) is associated with classic risk factors for atherosclerotic disease such as hyperlipidemia, hypertension, diabetes, or smoking. Risk factor modification, smoking cessation, and prevention of cardiovascular events remain the cornerstones of AIOD management. Symptom improvement and limb loss prevention are considered secondary goals of therapy. Continuous technological advances, new devices, as well as new revascularization techniques are constantly changing the landscape of AIOD management. Surgical interventions, which were considered a gold standard therapy for nearly 50 years, currently give way to newer and less invasive endovascular techniques.

CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans.

AIMS: The CXC chemokine CXCL10 is up-regulated in the infarcted myocardium and limits cardiac fibrosis by inhibiting growth factor-mediated fibroblast migration. CXCL10 signals by binding to its receptor CXCR3; however, recently CXCR3-independent CXCL10 actions have been suggested. Our study explores the role of CXCR3 signalling in myocardial infarction and investigates its involvement in mediating the anti-fibrotic effects of CXCL10. METHODS AND RESULTS: Wild-type and CXCR3 null mice underwent reperfused infarction protocols. CXCL10 was markedly induced in the infarct; in contrast, expression of the other two CXCR3 ligands, CXCL9 and CXCL11 was extremely low. CXCR3 loss did not affect scar size, geometric ventricular remodelling, collagen deposition, and systolic dysfunction of the infarcted heart. CXCR3 null mice had increased peak neutrophil recruitment and delayed myofibroblast infiltration in the infarcted heart, but exhibited comparable myocardial expression of pro-inflammatory cytokines and chemokines. In vitro, CXCL10 did not modulate Transforming Growth Factor (TGF)-ß signalling, but inhibited basic fibroblast growth factor (bFGF)-induced cardiac fibroblast migration in both wild-type and CXCR3 null cells. Treatment of fibroblasts with heparinase and chondroitinase to cleave glycosaminoglycan chains abrogated the inhibitory effects of CXCL10 on cell migration. CONCLUSION: CXCR3 signalling does not critically regulate cardiac remodelling and dysfunction following myocardial infarction. The anti-fibrotic effects of CXCL10 in the healing infarct and in isolated cardiac fibroblasts are CXCR3-independent and may be mediated through proteoglycan signalling. Thus, administration of CXCR3-defective forms of CXCL10 may be an effective anti-fibrotic strategy in the remodelling myocardium without activating a potentially injurious, CXCR3-driven T cell response.

Systematic characterization of myocardial inflammation, repair, and remodeling in a mouse model of reperfused myocardial infarction.

Mouse models of myocardial infarction are essential tools for the study of cardiac injury, repair, and remodeling. Our current investigation establishes a systematic approach for quantitative evaluation of the inflammatory and reparative response, cardiac function, and geometry in a mouse model of reperfused myocardial infarction. Reperfused mouse infarcts exhibited marked induction of inflammatory cytokines that peaked after 6 hr of reperfusion. In the infarcted heart, scar contraction and chamber dilation continued for at least 28 days after reperfusion; infarct maturation was associated with marked thinning of the scar, accompanied by volume loss and rapid clearance of cellular elements. Echocardiographic measurements of end-diastolic dimensions correlated well with morphometric assessment of dilative remodeling in perfusion-fixed hearts. Hemodynamic monitoring was used to quantitatively assess systolic and diastolic function; the severity of diastolic dysfunction following myocardial infarction correlated with cardiomyocyte hypertrophy and infarct collagen content. Expression of molecular mediators of inflammation and cellular infiltration needs to be investigated during the first 72 hr, whereas assessment of dilative remodeling requires measurement of geometric parameters for at least four weeks after the acute event. Rapid initiation and resolution of the inflammatory response, accelerated scar maturation, and extensive infarct volume loss are important characteristics of infarct healing in mice.

The role of IL-1 in the pathogenesis of heart disease.

Interleukin (IL)-1 consists of two distinct ligands, IL-1alpha and IL-1beta, with indistinguishable biological activities that signal through the IL-1 type I receptor (IL-1RI). A naturally occurring IL-1 receptor antagonist (IL-1Ra) binds to IL-1RI without initiating signal transduction and prevents IL-1 signaling, competitively inhibiting IL-1-mediated responses. Emerging evidence suggests that the balance between IL-1 agonists and antagonists plays an essential role in a variety of cardiovascular conditions. IL-1 may play a role in atherothrombotic disease by promoting the formation of atheromatous lesions, enhancing vascular inflammation, and triggering plaque destabilization. Following myocardial infarction, IL-1 critically regulates the inflammatory response and is involved in the development of adverse remodeling by enhancing expression of matrix metalloproteinases. IL-1 signaling may also be an essential mediator in the pathogenesis of heart failure by suppressing cardiac contractility, promoting myocardial hypertrophy, and inducing cardiomyocyte apoptosis. The present review summarizes current available data showing the significant role of IL-1 signaling in heart disease and raising the possibility that IL-1 inhibitors (such as anakinra, a nonglycosylated recombinant human IL-1Ra) may be clinically useful agents in patients with certain cardiovascular conditions.

Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction.

OBJECTIVES: The purpose of this study was to study aging-associated alterations in the inflammatory and reparative response after myocardial infarction (MI) and their involvement in adverse post-infarction remodeling of the senescent heart. BACKGROUND: Advanced age is a predictor of death and ventricular dilation in patients with MI; however, the cellular mechanisms responsible for increased remodeling of the infarcted senescent heart remain poorly understood. METHODS: Histomorphometric, molecular, and echocardiographic end points were compared between young and senescent mice undergoing reperfused infarction protocols. The response of young and senescent mouse cardiac fibroblasts to transforming growth factor (TGF)-beta stimulation was examined. RESULTS: Senescence was associated with decreased and delayed neutrophil and macrophage infiltration, markedly reduced cytokine and chemokine expression in the infarcted myocardium, and impaired phagocytosis of dead cardiomyocytes. Reduced inflammation in senescent mouse infarcts was followed by decreased myofibroblast density and markedly diminished collagen deposition in the scar. The healing defects in senescent animals were associated with enhanced dilative and hypertrophic remodeling and worse systolic dysfunction. Fibroblasts isolated from senescent mouse hearts showed a blunted response to TGF-beta1. CONCLUSIONS: Although young mice exhibit a robust post-infarction inflammatory response and form dense collagenous scars, senescent mice show suppressed inflammation, delayed granulation tissue formation, and markedly reduced collagen deposition. These defects might contribute to adverse remodeling. These observations suggest that caution is necessary when attempting to therapeutically target the post-infarction inflammatory response in patients with reperfused MI. The injurious potential of inflammatory mediators might have been overstated, owing to extrapolation of experimental findings from young animals to older human patients.

CD44 is critically involved in infarct healing by regulating the inflammatory and fibrotic response.

Infarct healing is dependent on an inflammatory reaction that results in leukocyte infiltration and clearance of the wound from dead cells and matrix debris. However, optimal infarct healing requires timely activation of "stop signals" that suppress inflammatory mediator synthesis and mediate resolution of the inflammatory infiltrate, promoting formation of a scar. A growing body of evidence suggests that interactions involving the transmembrane receptor CD44 may play an important role in resolution of inflammation and migration of fibroblasts in injured tissues. We examined the role of CD44 signaling in infarct healing and cardiac remodeling using a mouse model of reperfused infarction. CD44 expression was markedly induced in the infarcted myocardium and was localized on infiltrating leukocytes, wound myofibroblasts, and vascular cells. In comparison with wild-type mice, CD44(-/-) animals showed enhanced and prolonged neutrophil and macrophage infiltration and increased expression of proinflammatory cytokines following myocardial infarction. In CD44(null) infarcts, the enhanced inflammatory phase was followed by decreased fibroblast infiltration, reduced collagen deposition, and diminished proliferative activity. Isolated CD44(null) cardiac fibroblasts had reduced proliferation upon stimulation with serum and decreased collagen synthesis in response to TGF-beta in comparison to wild-type fibroblasts. The healing defects in CD44(-/-) mice were associated with enhanced dilative remodeling of the infarcted ventricle, without affecting the size of the infarct. Our findings suggest that CD44-mediated interactions are critically involved in infarct healing. CD44 signaling is important for resolution of the postinfarction inflammatory reaction and regulates fibroblast function.

The role of the thrombospondins in healing myocardial infarcts.

The five current members of the thrombospondin (TSP) family can be divided in two subgroups according to their molecular architecture. TSP-1 and -2 (subgroup A) are trimeric matricellular proteins that do not contribute directly to tissue integrity, but influence cell function by modulating cell-matrix interactions, whereas TSP-3, -4 and -5 (subgroup B) are pentameric proteins. TSP-1 and TSP-2 are markedly induced in healing wounds and may regulate cellular responses important for tissue repair. TSP-1 is a crucial activator of TGF-beta, whereas both TSP-1 and TSP-2 inhibit angiogenesis. This manuscript reviews our current knowledge on the expression and role of the TSPs in healing myocardial infarcts. In both canine and murine infarcts, TSP-1 shows a strikingly selective localization in the infarct border zone. In the absence of injury, TSP-1 -/- mice exhibit normal cardiac morphology and show no evidence of myocardial inflammation. Infarcted TSP-1 -/- mice have an enhanced and protracted inflammatory response with subsequent expansion of granulation tissue in the non-infarcted area, resulting in myofibroblast infiltration into the viable myocardium neighboring the infarct. Infarcted TSP-1 -/- animals have enhanced left ventricular remodeling compared with their wildtype littermates. We suggest that TSP-1 is a critical component of the protective mechanisms induced in the infarct border zone in order to limit expansion of fibrosis into the non-infarcted myocardium. Localized TSP-1 expression may suppress expansion of the inflammatory process by activating TGF-beta or by inhibiting local angiogenesis. In addition, TSP-1-mediated inhibition of MMP activity may decrease adverse remodeling. TSP-2, on the other hand, appears to be a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading. The expression and potential role of the pentameric TSPs in the infarcted heart remain unknown. Understanding the specific mechanisms responsible for the protective effects of TSP-1 and TSP-2 in healing infarcts may lead to novel therapeutic interventions aiming at attenuating adverse left ventricular remodeling.

The role of platelet-derived growth factor signaling in healing myocardial infarcts.

OBJECTIVES: This study sought to examine the role of platelet-derived growth factor (PDGF) signaling in healing myocardial infarcts. BACKGROUND: Platelet-derived growth factor isoforms exert potent fibrogenic effects through interactions with PDGF receptor (PDGFR)-alpha and PDGFR-beta. In addition, PDGFR-beta signaling mediates coating of developing vessels with mural cells, leading to the formation of a mature vasculature. We hypothesized that PDGFR activation may regulate fibrosis and vascular maturation in healing myocardial infarcts. METHODS: Mice undergoing reperfused infarction protocols were injected daily with a neutralizing anti-PDGFR-beta antibody (APB5), an anti-PDGFR-alpha antibody (APA5), or control immunoglobulin G, and were killed after 7 days of reperfusion. RESULTS: The PDGF-B, PDGFR-alpha, and PDGFR-beta mRNA expression was induced in reperfused mouse infarcts. Perivascular cells expressing phosphorylated PDGFR-beta were identified in the infarct after 7 days of reperfusion, indicating activation of the PDGF-BB/PDGFR-beta pathway. The PDGFR-beta blockade resulted in impaired maturation of the infarct vasculature, enhanced capillary density, and formation of dilated uncoated vessels. Defective vascular maturation in antibody-treated mice was associated with increased and prolonged extravasation of red blood cells and monocyte/macrophages, suggesting increased permeability. These defects resulted in decreased collagen content in the healing infarct. In contrast, PDGFR-alpha inhibition did not affect vascular maturation, but significantly decreased collagen deposition in the infarct. CONCLUSIONS: Platelet-derived growth factor signaling critically regulates postinfarction repair. Both PDGFR-beta- and PDGFR-alpha-mediated pathways promote collagen deposition in the infarct. Activation of PDGF-B/PDGFR-beta is also involved in recruitment of mural cells by neovessels, regulating maturation of the infarct vasculature. Acquisition of a mural coat and maturation of the vasculature promotes resolution of inflammation and stabilization of the scar.

Effects of diet-induced obesity on inflammation and remodeling after myocardial infarction.

Epidemiological studies indicate that obesity, insulin resistance, and diabetes are important comorbidities of patients with ischemic heart disease and increase mortality and development of congestive heart failure after myocardial infarction. Although ob/ob and db/db mice are commonly used to study obesity with insulin resistance or diabetes, mutations in the leptin gene or its receptor are rarely the cause of obesity in humans, which is, instead, primarily a consequence of dietary and lifestyle factors. Therefore, we used a murine model of diet-induced obesity to examine the physiological effects of obesity and the inflammatory and healing response of diet-induced obese (DIO) mice after myocardial ischemia-reperfusion injury. DIO mice developed hyperinsulinemia and insulin resistance and hepatic steatosis, with significant ectopic lipid deposition in the heart and cardiac hypertrophy in the absence of significant changes in blood pressure. The mRNA levels of chemokines at 24 h and cytokines at 24 and 72 h of reperfusion were higher in DIO than in lean mice. In granulation tissue at 72 h of reperfusion, macrophage density was significantly increased, whereas neutrophil density was reduced, in DIO mice compared with lean mice. At 7 days of reperfusion, collagen deposition in the scar was significantly reduced and left ventricular (LV) dilation and cardiac hypertrophy were increased, indicative of adverse LV remodeling, in infarcted DIO mice. Characterization of a murine diet-induced model of obesity and insulin resistance that satisfies many aspects commonly observed in human obesity allows detailed examination of the adverse cardiovascular effects of diet-induced obesity at the molecular level.