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Joseph S Janicki

Publications and source records attributed to Joseph S Janicki.

18 recordsLinked to original sources
PubMed2007

Arachidonic acid metabolism as a potential mediator of cardiac fibrosis associated with inflammation.

An increase in left ventricular collagen (cardiac fibrosis) is a detrimental process that adversely affects heart function. Strong evidence implicates the infiltration of inflammatory cells as a critical part of the process resulting in cardiac fibrosis. Inflammatory cells are capable of releasing arachidonic acid, which may be further metabolized by cyclooxygenase, lipoxygenase, and cytochrome P450 monooxygenase enzymes to biologically active products, including PGs, leukotrienes, epoxyeicosatrienoic acids, and hydroxyeicosatetraenoic acids. Some of these products have profibrotic properties and may represent a pathway by which inflammatory cells initiate and mediate the development of cardiac fibrosis. In this study, we critically review the current literature on the potential link between this pathway and cardiac fibrosis.

Animals↗
PubMed2006

The relationship between myocardial extracellular matrix remodeling and ventricular function.

Elevations in myocardial stress initiate structural remodeling of the heart in an attempt to normalize the imposed stress. This remodeling consists of cardiomyocyte hypertrophy and changes in the amount of collagen, collagen phenotype and collagen cross-linking. Since fibrillar collagen is a relatively stiff material, a decrease in collagen can result in a more compliant ventricle while an increase in collagen or collagen cross-linking results in a stiffer ventricle. If continued elevations in wall stress exceed the ability of the heart to compensate, then the ventricular wall thickness is disproportionately reduced compared to chamber volume and diastolic and systolic dysfunction ensues. This review describes the structural organization of collagen within the myocardium, discusses its effect on ventricular function and considers whether therapy aimed at reducing fibrosis is efficacious in heart failure. The evidence indicates that chamber stiffness can clearly be affected by alterations in both collagen quantity and quality, with the effect of changes in collagen concentration being modified by the extent of collagen cross-linking. The limited evidence available regarding the effects of collagen on systolic function indicates that pharmacological attempts to reduce interstitial collagen have a negative impact. Accordingly, a shift in treatment strategies directed more specifically at affecting collagen cross-linking, rather than reducing the concentration of collagen, may be warranted in the prevention of the adverse impact of collagen alterations on myocardial remodeling.

Cardiomegaly↗
PubMed2005

Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload.

The chronic elevation in ventricular wall stress secondary to ventricular volume or pressure overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. While initially a compensatory response, the progressive hypertrophy and ventricular dilatation induced by this condition ultimately have a detrimental effect on ventricular function, resulting in heart failure. Fibrillar collagen provides the skeletal framework which interconnects the cardiomyocytes, thereby maintaining ventricular shape and size and contributing to tissue stiffness. Accordingly, these myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. The presence of an abundant, latent matrix metalloproteinase (MMP) population which coexists with myocardial fibrillar collagen has been documented. Thus, the potential for collagen degradation to exceed synthesis exists should there be significant activation of this latent MMP system. Mast cells are known to store and release a variety of biologically active mediators including TNF-alpha and proteases such as tryptase and chymase, which can induce MMP activation. Increased cardiac mast cell density has been implicated in the pathophysiology of human end-stage cardiomyopathy and experimental myocardial infarction, hypertension and chronic volume overload secondary to mitral regurgitation and aorto-caval fistula. The potential role of cardiac mast cells in activating MMPs, which then results in fibrillar collagen degradation and adverse myocardial remodeling secondary to chronic volume and pressure overload will be the subject of this review.

Extracellular Matrix↗
PubMed2005

Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats.

Previously, we demonstrated that intact female rats fed a standard rodent diet containing soybean products exhibit essentially no adverse left ventricular (LV) remodeling in response to aortocaval fistula-induced chronic volume overload. We hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection. To test this hypothesis, four groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(-)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats. Fistula groups developed LV hypertrophy, which was not reduced by dietary phytoestrogens [1,184 +/- 229 mg Fist-P(-) and 1,079 +/- 199 mg Fist-P(+) vs. 620 +/- 47 mg for combined Sham groups, P < 0.05]. Unstressed LV volume increased in Fist-P(-) rats (428 +/- 16 vs. 300 +/- 14 microl Sham, P < 0.0001), but it was not different from Sham for Fist-P(+) animals (286 +/- 17 microl). Fist-P(-) rats developed increased ventricular compliance (5.3 +/- 0.8 vs. 2.3 +/- 0.3 microl/mmHg Sham, P < 0.01), whereas Fist-P(+) rats had no change in compliance (2.8 +/- 0.4 mul/mmHg). Intrinsic ventricular contractility was maintained in the Fist-P(+) rats, but it was reduced (P < 0.001) in the Fist-P(-) rats [systolic pressure-volume slope: 1.04 +/- 0.03, 0.60 +/- 0.06, and 0.99 +/- 0.08 mmHg/microl, for Fist-P(+), Fist-P(-), and Sham, respectively]. These data indicate that dietary phytoestrogens contribute significantly to female cardioprotection against volume overload-induced adverse ventricular remodeling and that studies evaluating gender differences in cardiovascular remodeling must consider the influence of dietary phytoestrogens.

Animals↗
PubMed2005

Modulation of cardiac mast cell-mediated extracellular matrix degradation by estrogen.

There are fundamental differences between males and females with regard to susceptibility to heart disease. Although numerous animal models of heart failure have demonstrated that premenopausal females are afforded cardioprotection and, therefore, fare better in the face of cardiac disease than their male counterparts, many questions as to how this occurs still exist. Recently, we showed that 1) increased mast cell density is associated with adverse ventricular remodeling and 2) chemically induced mast cell degranulation using compound 48/80 resulted in remarkable changes in matrix metalloproteinase (MMP) activity, cardiac collagen structure, and cardiac diastolic function in normal male rats. With the known gender differences in cardiac disease in mind, we sought to examine the effects of chemically induced cardiac mast cell degranulation in isolated, blood-perfused hearts of intact female rats, ovariectomized female rats, and ovariectomized female rats treated with 17beta-estradiol. In response to mast cell degranulation, no significant differences in cardiac function, MMP-2 activity, or collagen volume fraction were observed between intact female rats and ovariectomized female rats treated with estrogen. In the ovariectomized female group, a significant rightward shift in the left ventricular pressure-volume relation, accompanied by a marked 133% increase in active MMP-2 values over that in the intact female group, was noted after treatment with compound 48/80 (P < or = 0.05), along with a significant reduction in collagen volume fraction below control (0.46 +/- 0.23 vs. 0.73 +/- 0.13%, P < or = 0.05). These findings indicate that estrogen's cardioprotective role can be partially mediated by its effects on cardiac mast cells, MMPs, and the extracellular matrix.

Animals↗
PubMed2005

Pharmacologic inhibition of mast cell degranulation prevents left ventricular remodeling induced by chronic volume overload in rats.

BACKGROUND: Left ventricular (LV) hypertrophy and dilation are important compensatory responses to chronic volume overload; however, the mechanisms responsible for this LV remodeling have not been well characterized. Previous observations that the number of myocardial mast cells are increased in congestive heart failure (CHF) suggested the hypothesis that mast cells might be involved in the ventricular remodeling induced by a chronic volume overload. METHODS AND RESULTS: Accordingly, the intent of this study was to determine the contribution of mast cells to LV remodeling, dysfunction, and morbidity/mortality secondary to CHF in the infrarenal aortocaval fistula model of sustained volume overload. To this end, LV end-diastolic pressure, size, and function (ie, isovolumetric pressure-volume relations in the blood-perfused isolated heart) were assessed in both nedocromil sodium treated and untreated rats at 8 weeks after fistula and compared with age-matched controls. Nedocromil, a mast cell-stabilizing drug, effectively prevented the LV dilation and decreased contractility seen in the untreated fistula group in a dose-dependent fashion, resulting in a significant reduction in the incidence of morbidity/mortality from CHF. CONCLUSION: The ability of mast cell stabilization to prevent ventricular dilation induced by chronic volume overload identifies a key role for mast cells in the regulation of myocardial remodeling.

Animals↗
PubMed2004

Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats.

The objective of this study was to determine whether elevated circulating levels of endothelin (ET)-1 are capable of mediating left ventricular (LV) mast cell degranulation and thereby induce matrix metalloproteinase (MMP) activation. After the administration of 20 pg/ml ET-1 to blood-perfused isolated rat hearts, LV tissue was analyzed for signs of mast cell degranulation and MMP activation. Relative to control, ET-1 produced extensive mast cell degranulation as well as a significant increase in myocardial water content (78.8 +/- 1.5% vs. 74.2 +/- 2.2%, P <0.01), a marked 107% increase in MMP-2 activity (P <0.05), and a substantial decrease in collagen volume fraction (0.69 +/- 0.09% vs. 0.99 +/- 0.04%, P <0.001). Although the myocardial edema would be expected to increase ventricular stiffness, compliance was not altered, and moderate ventricular dilatation was observed (end-diastolic volume at end-diastolic pressure of 0 mmHg of 330.2 +/- 22.1 vs. 298.9 +/- 17.4 microl in ET-1 treated vs. control, respectively, P=0.07). Additionally, pretreatment with the mast cell stabilizer nedocromil prevented ET-1-induced changes in MMP-2 activity, myocardial water content, collagen volume fraction, and end-diastolic volume. These findings demonstrate that ET-1 is a potent cardiac mast cell secretogogue and further indicate that ET-1-mediated mast cell degranulation is a potential mechanism responsible for myocardial remodeling.

Animals↗
PubMed2004

The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling.

The process of cardiac remodeling in response to cardiac injury and/or persistent elevations in wall stress generally relates to the progressive changes that occur in ventricular chamber dimensions and the various components of the myocardium, in particular the cardiomyocytes and the extracellular matrix. Volume overload, pressure overload or myocardial injury produces a sustained abnormal elevation in myocardial wall stress which initiates cardiac remodeling that frequently results in ventricular decompensation and heart failure. Regardless of the inciting cause, there appear to be three distinct phases to this process. In the initial phase, fibrillar collagen is partially degraded secondary to increased matrix metalloproteinase (MMP) activity. Following this, there is a chronic compensatory phase during which MMP activity and collagen concentration return to normal while cardiomyocyte size continues to progressively increase. The final phase is attained once the compensatory hypertrophic mechanisms are exhausted and is characterized by elevated MMP activity, marked ventricular dilatation and prominent fibrosis. Details of this progressive, dynamic remodeling process and its effect on ventricular function during chronic volume overload, chronic pressure overload and following myocardial infarction will be the focus of this article.

Cardiomegaly↗
PubMed2004

Expression of matrix metalloproteinase activity in idiopathic dilated cardiomyopathy: a marker of cardiac dilatation.

BACKGROUND: Idiopathic dilated cardiomyopathy (DCM), ventricular systolic dysfunction and chamber dilatation are accompanied by architectural remodeling, wall thinning and cardiac myocyte slippage. Recent work has demonstrated an association between collagen degradation and an increased expression of matrix metalloproteinases (MMPs). Accordingly, we have sought to correlate (a) collagen degradation with MMP elevations and, (b) assay the neutralizing potential of a known inhibitor of MMP, tetracycline on MMPs in DCM. METHODS: Assessment of LV volume and shape by 2-D echocardiography was performed. Light microscopic assessment of histopathology in picrosirius red stained biopsy samples of 11 DCM patients and six post-transplant patients was performed. Zymographic estimation of MMP activity and influence of tetracycline on MMP activity was assessed. RESULTS: Small amount of interstitial collagen was noted in the control group, whereas in the DCM hearts, chamber dilatation was associated with areas of scanty myocyte necrosis, islands of excess collagen, and focal areas of absent or scanty collagen with intact myocytes. In cardiomyopathic tissue, collagenase activity was markedly elevated at 63% compared with 8% in post-transplant tissue. Tetracycline at a concentration of 285+/-10 microM (IC50) inhibited collagenase activity by 50% in cardiomyopathic tissue. CONCLUSIONS: Areas of focal interstitial collagen accumulation were accompanied by collagen fiber lysis and increased collagenase activity in dilated cardiomyopathy. This enhanced collagenolytic activity found in endomyocardial biopsy tissue was inhibited by tetracycline. The non-antibiotic property of tetracycline may be of potential value in the prevention of ventricular dilatation in idiopathic dilated cardiomyopathy.

Adult↗
PubMed2003

Cardiac mast cell- and chymase-mediated matrix metalloproteinase activity and left ventricular remodeling in mitral regurgitation in the dog.

The present study tested the hypothesis that cardiac mast cells and chymase are associated with matrix metalloproteinase (MMP) activation and extracellular matrix (ECM) degradation in the evolution of left ventricular (LV) chamber remodeling secondary to experimental mitral regurgitation (MR) in dogs. LV mast cell density, chymase activity, and angiotensin II (ANG II) levels were significantly increased 2 and 4 weeks post-MR, while an increase in angiotensin-converting enzyme (ACE) activity was not seen prior to the chronic 24 week stage. As early as 2 and 4 weeks, there was a significant decrease in interstitial myocardial collagen content that was associated with an increase in LV end-diastolic diameter (LVEDD) but a normal LVEDD/wall thickness ratio. While mast cell density decreased to normal at 24 weeks, both chymase and MMP-2 activity remained increased throughout the entire 24-week period post-MR. By 24 weeks a transition to an adverse pattern of LV remodeling characterized by a 2-fold increase in the LVEDD/wall thickness ratio had occurred. Thus, this study supports the hypothesis that mast cells and chymase are important modulators of MMP activity and ECM degradation, contributing to adverse LV remodeling in chronic volume overload secondary to MR.

Animals↗
PubMed2003

Gender mediated cardiac protection from adverse ventricular remodeling is abolished by ovariectomy.

Gender differences in the prevalence of cardiovascular disease have been observed both clinically and experimentally. These cardioprotective effects have frequently been attributed to female hormones, however, the underlying mechanisms responsible for this cardioprotection are still poorly understood. Accordingly, this study sought to determine the contribution of ovarian hormones to the prevention of adverse ventricular remodeling and congestive heart failure in chronic volume overload (i.e. aortocaval fistula in intact or ovariectomized female rats). Ovariectomized rats developed more extensive cardiac remodeling than intact females at 21 weeks post-fistula, characterized by significantly greater left ventricular (LV) hypertrophy (167 vs. 86%, respectively, p < 0.05) and a substantial increase in LV dilatation (71%, p < 0.05) relative to control. In contrast to the eccentric hypertrophy in ovariectomized females post-fistula, the hypertrophic response in the intact female hearts was essentially concentric. While neither fistula group suffered significant mortality, there was a marked increase in the lung weight of ovariectomized rats (87%, p < 0.05) consistent with the development of pulmonary edema. Overall, the extent of myocardial remodeling and decrease in LV function in the ovariectomized females was comparable to those changes reported for males with symptomatic heart failure, while intact females maintained chronic compensated ventricular function similar to that of controls. The marked ventricular dilatation and symptoms of congestive heart failure seen at 21 weeks post-fistula in the ovariectomized females clearly demonstrate the influence of circulating ovarian hormones on the pattern of myocardial remodeling resulting from a chronic volume overload.

Animals↗
PubMed2002

Effects of matrix metalloproteinase inhibition on ventricular remodeling due to volume overload.

BACKGROUND: Left ventricular (LV) hypertrophy and dilatation are important compensatory responses to chronic volume overload. Although LV function is initially preserved by these responses, the continued structural remodeling of the myocardium ultimately becomes maladaptive, leading to the development of heart failure. We have shown previously that increased myocardial matrix metalloproteinase (MMP) activity precedes LV dilatation induced by a chronic volume overload. Accordingly, this study focused on the effects of MMP inhibition therapy (PD 166793, 1 mg x kg(-1) x d(-1)) on LV size and function in a rat model of volume overload-induced heart failure. METHODS AND RESULTS: Rats were divided into the following groups: treated and untreated infrarenal abdominal aortocaval fistula and treated and untreated sham-operated (control). LV weights of both fistula groups were increased above that of the control group (868+/-79 mg; P< or =0.001); LV weights in the treated fistula group, however, were lower than in the untreated fistula group at 8 weeks (1447+/-186 versus 1715+/-279 mg, respectively; P< or =0.012). The marked ventricular dilatation seen in the untreated fistula group was significantly diminished in the treated fistula group, although the increase in LV compliance was similar in both treated and untreated fistula hearts. CONCLUSIONS: MMP inhibition significantly attenuates the myocardial remodeling associated with chronic volume overload, as evidenced by prevention of dilatation, a marked reduction in LV hypertrophy, and preservation of ventricular function.

Animals↗
PubMed2002

Effects of mast cells on the behavior of isolated heart fibroblasts: modulation of collagen remodeling and gene expression.

The extracellular matrix plays a critical role in the development and maintenance of the vertebrate heart. Changes in the accumulation, composition, or organization of the extracellular matrix are known to deleteriously affect heart function. Mast cells are thought to stimulate collagen expression and fibroblast proliferation accompanying fibrosis in some organs; however, the effects of mast cells on the heart interstitium are largely unexplored. The present studies were carried out to determine the effects of mast cells on isolated heart fibroblasts. Several in vitro assays were used including collagen gel contraction to examine the effects of mast cells on the function of isolated fibroblasts. Neonatal heart fibroblasts were cultured either with mast cells, mast cell-conditioned medium, or mast cell extracts, and their ability to contract collagen gels measured. Results from these experiments indicated that mast cells inhibit heart fibroblast migration and contraction of 3-dimensional collagen gels. Further experiments indicated that incubation of neonatal heart fibroblasts with extracts of mast cells altered the expression of collagen, matrix metalloproteases, and matrix receptors of the integrin family. These studies suggest that mast cells play an important role in the regulation of the cardiac interstitial matrix. Further studies are warranted to determine the mechanisms whereby mast cells modulate fibroblast activity.

Animals↗
PubMed2002

The role of myocardial fibrillar collagen in ventricular remodeling and function.

The myocardial extracellular matrix (ECM) surrounds and interconnects cardiac myocytes, myofibrils, muscle fibers, and the coronary microcirculation. Because of the high tensile strength of fibrillar collagen and its close association with the functioning components of the myocardium, alterations in interstitial collagen can significantly influence the size and shape of the cardiac chambers as well as ventricular function. Typically, an increase in interstitial collagen concentration secondary to pressure overload results in both the myocardium and the ventricle becoming stiffer. In contrast, a reduction in collagen concentration characterized by a disruption and disappearance of fibrillar collagen leads to a markedly dilated left ventricle that is significantly more compliant. However, the effects of myocardial ECM alterations on systolic function remain to be determined. This article provides a brief summary of the structural and functional consequences of alterations to the myocardial ECM and discusses gaps in our knowledge and future research directions.

Extracellular Matrix↗
PubMed2002

Gender differences in cardiac remodeling secondary to chronic volume overload.

BACKGROUND: Gender differences in the prevalence of cardiovascular disease, both clinical and experimental, led us to evaluate the influence of gender on ventricular remodeling induced by chronic volume overload. METHODS AND RESULTS: Chronic volume overload was induced in male and female rats via infrarenal aortocaval fistula. Ventricular function was assessed 8 weeks after fistula surgery in surviving rats. Left ventricular, right ventricular, and lung weights were measured. Mortality in female rats was 10-fold less than in male rats after 8 weeks of volume overload. Both sexes had significant increases in left ventricular weights relative to controls (77% increase for female v 114% for male rats; P <.05). Corresponding increases were also observed in right ventricular weight (134% for female v 161% for male rats; P <.05). However, lung weight was significantly increased only in males. In contrast to males, female rats had no indications of congestive heart failure. Male rats had marked dilatation and increased compliance, whereas female rats had no significant change in left ventricular dilatation or compliance. CONCLUSIONS: There are clear gender-specific differences in ventricular function, structural remodeling, and mortality induced by chronic volume overload in this model of heart failure.

Adaptation, Physiological↗
PubMed2002

Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity.

The objectives of this study were to investigate the temporal response of left ventricular (LV) matrix metalloproteinase (MMP) activity and collagen volume fraction (CVF) induced by an aortocaval fistula and the role of cardiac mast cells in regulating MMP activity. LV tissue was analyzed for MMP activity, CVF, and mast cell number in rats euthanized at 0.5, 1, 2, 3, 5, 14, 21, 35, and 56 days. Additional rats treated with the mast cell membrane-stabilizing drug cromolyn sodium were euthanized 1, 2, and 3 days postfistula. Marked increases in MMP activity occurred rapidly and remained significantly elevated for 5 days before returning toward normal. A significant decrease in CVF occurred by day 5, but thereafter CVF rebounded to normal or above normal values. The number of myocardial mast cells also significantly increased postfistula, and there was a close association between mast cell density and MMP activity. Cromolyn treatment prevented the increase in mast cell number and MMP activity. Thus it is concluded that cardiac mast cells play a major role in the regulation of MMP activity.

Animals↗
PubMed2002

Cardiac mast cell-mediated activation of gelatinase and alteration of ventricular diastolic function.

Mast cells contain proteases capable of activating matrix metalloproteinases (MMPs). However, given the relatively low density of mast cells in the myocardium (i.e., 1.5-5.3 cells/mm(2)), it is unknown whether these enzymes are present in sufficient quantities in the normal heart to mediate MMP activation. Accordingly, this study sought to determine whether chemically induced degranulation of cardiac mast cells (with compound 48/80) would have an effect in isolated, blood-perfused, functioning rat hearts. Mast cell degranulation produced a 15% increase in histamine levels present in the coronary efflux, a significant increase in myocardial water (i.e., edema) relative to normal values (80.1 +/- 3.4% vs. 77.4 +/- 1.08%, P < or = 0.03), a substantial activation of MMP-2 (126% increase relative to controls, P < or = 0.02), and a marked decrease in myocardial collagen volume fraction (0.46 +/- 0.10% vs. 0.97 +/- 0.33%, P < or = 0.001). Furthermore, although an increase in ventricular stiffness was expected due to the extent of edema resulting from mast cell degranulation, modest ventricular dilatation was observed. These findings clearly demonstrate that the number of mast cells present in normal hearts is sufficient to mediate activation of MMPs and produce extracellular matrix degradation, thereby potentially causing subsequent ventricular dilatation.

Animals↗