Abstract-Although there is a correlation between hypertension and levels of interleukin (IL) 6, the exact role this cytokine plays in myocardial remodeling is unknown. This is complicated by the variable tissue and circulating levels of IL-6 reported in numerous experimental models of hypertension. Accordingly, we explored the hypothesis that elevated levels of IL-6 mediate adverse myocardial remodeling. To this end, adult male Sprague-Dawley rats were infused with IL-6 (2.5 g ⅐ kg Ϫ1 ⅐ h Ϫ1 , IP) for 7 days via osmotic minipump and compared with vehicle-infused, aged-matched controls. Left ventricular function was evaluated using a blood-perfused isolated heart preparation. Myocardial interstitial collagen volume fraction and isolated cardiomyocyte size were also assessed. Isolated adult cardiac fibroblast experiments were performed to determine the importance of the soluble IL-6 receptor in mediating cardiac fibrosis. IL-6 infusions in vivo resulted in concentric left ventricular hypertrophy, increased ventricular stiffness, a marked increase in collagen volume fraction (6.2% versus 1.7%; PϽ0.001), and proportional increases in cardiomyocyte width and length, all independent of blood pressure. The soluble IL-6 receptor in combination with IL-6 was found to be essential to producing increased collagen concentration by isolated cardiac fibroblasts and also played a role in mediating a phenotypic conversion to myofibroblasts. These novel observations demonstrate that IL-6 induces a myocardial phenotype almost identical to that of the hypertensive heart, identifying IL-6 as potentially important in this remodeling process. (Hypertension. 2010;56:225-231.)

In this nonhuman primate trial, treatment with BZA alone, CEE alone, and combined BZA and CEE does not have significant effects on plasma lipid profiles. CEE markedly inhibits the progression and complications of both coronary and iliac artery atheroscleroses. BZA has no adverse effects on atherosclerosis but attenuates the atheroprotective effects of CEE.

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed.

Background Cardiovascular magnetic resonance (CMR) T1 mapping characteristics are elevated in adult cancer survivors; however, it remains unknown whether these elevations are related to age or presence of coincident cardiovascular comorbidities. Methods and Results We performed blinded CMR analyses of left ventricular (LV) T1 and extracellular volume fraction (ECV) in 327 individuals (65% women, aged 64±12 years). Thirty-seven (37) individuals had breast cancer or a hematologic malignancy but had not yet initiated their treatment, and 54 cancer survivors that received either anthracycline-based (n=37) or non-anthracycline-based (n=17) chemotherapy 2.8±1.3 years earlier were compared to 236 cancer-free participants. Multivariable analyses were performed to determine the association between T1/ECV measures and variables associated with myocardial fibrosis. Age-adjusted native T1 was elevated pre- (1058±7 ms) and post- (1040±7 ms) receipt of anthracycline chemotherapy versus comparators (965±3 ms, p<0.0001 for both). Age-adjusted ECV, a marker of myocardial fibrosis, was elevated in anthracycline-treated cancer participants (30.4±0.7%) compared with either pre-treatment cancer (27.8±0.7%, p<0.01) or cancer-free comparators (26.9±0.2%, p<0.0001). T1 and ECV of non-anthracycline survivors was no different than pre-treatment survivors (p=0.17 and p=0.16, respectively). Native T1 and ECV remained elevated in cancer survivors after accounting for demographics (including age), myocardial fibrosis risk factors, and LV ejection fraction or myocardial mass index (p<0.0001 for all). Conclusions Three years after anthracycline-based chemotherapy, elevations in myocardial T1 and ECV occur independent of underlying cancer or cardiovascular comorbidities suggesting that imaging biomarkers of interstitial fibrosis in cancer survivors are related to prior receipt of a potentially cardiotoxic cancer treatment regimen.

The mast cell product, tryptase, has recently been implicated in fibrosis in the hypertensive heart. Tryptase has been shown to mediate non-cardiac fibroblast function via activation of protease activated receptor-2 and subsequent activation of the mitogen-activated protein kinase pathway, including extracellular signal-regulated kinase1/2. Therefore, we hypothesized that this pathway may be a mechanism leading to fibrosis in the hypertensive heart. Isolated adult cardiac fibroblasts were treated with tryptase, which induced activation of extracellular signal-regulated kinase1/2 via protease activated receptor-2. Blockade of protease activated receptor-2 with FSLLRY (10 μM) and inhibition of the extracellular signal-regulated kinase pathway with PD98059 (10 μM) prevented collagen synthesis in isolated cardiac fibroblasts stimulated with tryptase. p38 mitogen activated protein kinase and stress-activated protein/c-Jun N-terminal kinase were not activated by tryptase. Cardiac fibroblasts isolated from spontaneously hypertensive rats showed this same pattern of activation and treatment of spontaneously hypertensive rats with FSLLRY prevented fibrosis in these animals indicating the in vivo applicability of the cultured fibroblast findings. Also, tryptase induced a myofibroblastic phenotype indicated by elevations in α smooth muscle actin and ED-A fibronectin. Thus, the results from this study demonstrate the importance of tryptase for inducing a cardiac myofibroblastic phenotype, ultimately leading to the development of cardiac fibrosis through the activation of the extracellular signal-regulated kinase pathway. Specifically, tryptase causes cardiac fibroblasts to increase collagen synthesis via a mechanism involving activation of protease activated receptor-2 and subsequent induction of extracellular signal-regulated kinase signaling.

Our studies suggest that substance P may be important in mediating adverse myocardial remodelling secondary to volume overload by activating cardiac mast cells, leading to increased TNF-α and MMP activation with subsequent degradation of the extracellular matrix.

Early after Anth-bC, LV mass reductions associate with worsening HF symptomatology independent of LVEF. These data suggest an alternative mechanism whereby anthracyclines may contribute to HF symptomatology and raise the possibility that surveillance strategies during Anth-bC should also assess LV mass.

Jobe LJ, Meléndez GC, Levick SP, Du Y, Brower GL, Janicki JS. TNF-␣ inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. Am J Physiol Heart Circ Physiol 297: H1462-H1468, 2009. First published August 7, 2009 doi:10.1152/ajpheart.00442.2009.-Tumor necrosis factor (TNF)-␣ is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-␣ are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-␣ with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-␣ inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-␣ antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-␣ has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure. diastolic function; intrinsic contractility; myocyte dimensions; etanercept; extracellular matrix; ventricular pressure-volume relationship THE PROINFLAMMATORY CYTOKINE tumor necrosis factor-␣ (TNF-␣) has been documented to elicit a variety of responses in the heart ranging from cardioprotective to pathological (3,4,14,23,(32)(33)(34). However, chronically elevated levels of TNF-␣ have been identified as a risk factor for coronary heart disease and congestive heart failure (12,22,23). Consistent with this, Bozkurt et al. (3) demonstrated that a chronic infusion of rats with pathological levels of TNF-␣ was sufficient to induce myocardial remodeling consisting of left ventricular (LV) wall thinning, dilatation, and collagen degradation, resulting in reduced myocardial function. Furthermore, collagen degradation due to increased matrix metalloproteinase (MMP) activity and a reduction in tissue inhibitor of metalloproteinases-1 (TIMP-1) in mice with cardiac-restricted overexpression of TNF-␣ has been imp...