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The balance between matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), plays a critical role in cardiac remodeling. Although a number of studies have characterized the pathophysiological role of MMPs in the heart, very little is known with respect to the role of TIMPs in the heart. To delineate the role of TIMPs in the heart we examined the effects of adenovirus-mediated overexpression of TIMP-1, -2, -3, and -4 in cardiac fibroblasts. Infection of cardiac fibroblasts with adenoviral constructs containing human recombinant TIMP (AdTIMP-1, -2, -3, and -4) provoked a significant (P < 0.0001) 1.3-fold in increase in bromodeoxyuridine (BrdU) incorporation. Similarly, treatment of cardiac fibroblasts with AdTIMP-1-, -2-, -3-, and -4-conditioned medium led to a 1.2-fold increase in BrdU incorporation (P < 0.0001) that was abolished by pretreatment with anti-TIMP- 1, -2, -3, and -4 antibodies. The effects of TIMPs were not mimicked by treating the cells with RS-130830, a broad-based MMP inhibitor, suggesting that the effects of TIMPs were independent of their ability to inhibit MMPs. Infection with AdTIMP-1, -2, -3, and -4 led to a significant increase in a-smooth muscle actin staining, consistent with TIMP-induced phenotypic differentiation into myofibroblasts. Finally, infection with AdTIMP-2 resulted in a significant increase in collagen synthesis, whereas infection with AdTIMP-3 resulted in a significant increase in fibroblast apoptosis. TIMPs exert overlapping as well as diverse effects on isolated cardiac fibroblasts. The observation that TIMPs stimulate fibroblast proliferation as well as phenotypic differentiation into myofibroblasts suggests that TIMPs may play an important role in tissue repair in the heart that extends beyond their traditional role as MMP inhibitors. matrix metalloproteinase; proliferation; apoptosis; phenotypic differentiation

Background Lead malfunction is an important cause of morbidity and mortality in patients with an implantable cardioverter-defibrillator (ICD). We have shown that the failure of recalled high-voltage leads significantly increases after ICD generator replacement. However, generator replacement has not been recognized as a predictor of lead failure in general. Objective The purpose of this study is to assess the effect of ICD generator exchange on the rate of ICD lead alerts. Methods A time-dependent Cox proportional hazards model was used to analyze a database of remotely monitored ICDs. The model assessed the impact of generator exchange on the rate of lead alerts after ICD generator replacement. Results The analysis included 60,219 patients followed for 37 ± 19 months. The 5-year lead survival was 99.3% (95% confidence interval 99.2%–99.4%). Of 60,219 patients, 7458 patients (12.9%) underwent ICD generator exchange without lead replacement. After generator replacement, the rate of lead alerts was more than 5-fold higher than in controls with leads of the same age without generator replacement (hazard ratio 5.19; 95% confidence interval 3.45–7.84). A large number of lead alerted within 3 months of generator replacement. Lead alerts were more common in patients with single- vs dual-chamber ICDs and in younger patients. Sex was not associated with lead alerts. Conclusion Routine generator replacement is associated with a 5-fold higher risk of lead alert compared to age-matched leads without generator replacement. This suggests the need for intense surveillance after generator replacement and the development of techniques to minimize the risk of lead damage during generator replacement. [ABSTRACT FROM AUTHOR]

Background: The Medtronic Sprint Fidelis defibrillator lead is at an increased risk for failure and was recalled in October 2007. Approximately 268,000 leads were implanted, and more than 100,000 patients still have active Fidelis leads. A number of studies have examined the rate and clinical predictors of lead failure, but none has addressed the effect of an implantable cardioverter-defibrillator generator exchange on subsequent lead failure. Although the manufacturer asserts that “Sprint Fidelis performance after device change-out is similar to lead performance without device change-out,” published data are lacking. Objective: To assess the effect of implantable cardioverter-defibrillator generator exchange on the rate of Fidelis lead failure. Methods: A chart review was conducted in patients who underwent implantation of a Fidelis lead. Patients with a functioning Fidelis lead at generator exchange were compared with controls with leads implanted for a comparable amount of time not undergoing ICD replacement. Results: A total of 1366 patients received a Fidelis lead prior to the recall, of which 479 were still actively followed. Seventy-two patients with a functioning lead underwent generator exchange without lead replacement. Following generator replacement, 15 leads failed. Sixty percent of the Fidelis leads failed within 3 months. Generator exchange increased the rate of lead failure compared with matched controls (20.8% vs 2.54%; P < .001). Conclusions: Generator exchange is associated with a higher than expected rate of Fidelis lead failure, often within 3 months. The risk-benefit ratio of Fidelis lead replacement at the time of generator exchange may be greater than appreciated. [Copyright &y& Elsevier]

Summary: It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, we show that a thyroid hormone surge activates the IGF-1/IGF-1-R/Akt pathway on postnatal day 15 and initiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ∼40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day 15 is intermediate between that observed at postnatal days 2 and 21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases. [ABSTRACT FROM AUTHOR]