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1.  Tumor Necrosis Factor Receptor Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian Heart 
Circulation. Heart failure  2013;6(3):535-543.
Background
Tumor necrosis factor (TNF) superfamily ligands that provoke a dilated cardiac phenotype signal through a common scaffolding protein termed TNF receptor associated factor 2 (TRAF2); however, virtually nothing is known with regard to TRAF2 signaling in the adult mammalian heart.
Methods and Results
We generated multiple founder lines of mice with cardiac restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (MHC-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, LV dilation and adverse LV remodeling, and a significant decrease in LV +dP/dt and −dP/dt when compared to littermate (LM) controls (p < 0.05 compared to LM). During the early phases of LV remodeling there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total MMP activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in NF-κB activation at 4 – 12 weeks and JNK activation at 4 weeks in the MHCs TRAF2HC mice. Transciptional profiling revealed that > 95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained κB elements in their promoters.
Conclusions
These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.
doi:10.1161/CIRCHEARTFAILURE.112.000080
PMCID: PMC3672470  PMID: 23493088
tumor necrosis factor superfamily; dilated cardiomyopathy; inflammation; TNF receptor associated factor 2
2.  The Emerging Role of MicroRNAs in Cardiac Remodeling and Heart Failure 
Circulation research  2008;103(10):1072-1083.
Recent studies have suggested a potentially important role for a family of tiny regulatory RNAs, known as microRNAs (miRNAs or miRs), in the control of diverse aspects of cardiac function in health and disease. Although the field of miRNA biology is relatively new, there is emerging evidence that miRNAs may play an important role in the pathogenesis of heart failure through their ability to regulate the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodeling. Here we review the biology of miRNAs in relation to their role in modulating various aspects of the process of cardiac remodeling, as well as discuss the potential application of miRNA biology to the field of heart failure.
doi:10.1161/CIRCRESAHA.108.183087
PMCID: PMC3982911  PMID: 18988904
heart failure; cardiac remodeling; microRNAs; neurohormonal activation; arrhythmia
3.  Digoxin Treatment in Heart Failure -- Unveiling Risk by Cluster analysis of DIG data 
International journal of cardiology  2010;150(3):264-269.
Background
Digoxin has been shown to reduce heart failure (HF) hospitalizations with no overall effect on mortality in HF patients. We used cluster analysis to delineate the clinical characteristics of HF patients in whom digoxin therapy was associated with improved or worsened clinical outcomes.
Methods
The Digitalis Investigation Group (DIG) database was partitioned into 20 clusters. Multivariate Cox regression analyses was used, to identify clusters in which digoxin was associated with either an increase (MortalitydigHR>1), decrease (MortalitydigHR<1), or no association with all cause mortality (MortalitydigHR-NS); and separately, with an increase (HFAdigHR>1), decrease (HFAdigHR<1), or no association (HFAdigHR-NS) with HF admissions (HFA).
Results
We identified 938 patients in the MortalitydigHR>1 group, 6,818 patients in the MortalitydigHR-NS group, and none in MortalitydigHR<1 group. The MortalitydigHR>1 group had a higher prevalence of females, diabetes mellitus, hypertension, higher age, systolic blood pressure (SBP), heart rate and ejection fraction (EF), compared to the MortalitydigHR-NS group.
Similarly, 6,325 patients clustered in the HFAdigHR<1 group, 1,431 patients in the HFAdigHR-NS group, and none in the HFAdigHR>1 group. The HFAdigHR-NS group had a higher prevalence of females and hypertension, higher SBP, body mass index and EF; and lower prevalence of peripheral edema and third heart sound, compared with the HFAdigHR<1 group.
Conclusion
Thus, the baseline characteristics of patients who did not have reduction in HF hospitalization or who had increased mortality were very similar and included females with hypertension, higher EF and higher SBP. Thus, use of digoxin in patients with this profile may need to be avoided.
doi:10.1016/j.ijcard.2010.04.021
PMCID: PMC2923690  PMID: 20471706
Cluster analysis; digoxin; heart failure
4.  Hepcidin in anemia of chronic heart failure 
American journal of hematology  2011;86(1):107-109.
Anemia is a common finding among patients with chronic heart failure. Although co-morbidities, such as kidney failure, might contribute to the pathogenesis of anemia, many patients with heart failure do not have any other obvious etiology for their anemia. We investigated whether anemia in heart failure is associated with an elevation in hepcidin concentration.
We used time-of-flight mass spectrometry to measure hepcidin concentration in urine and serum samples of patients with heart failure and in control subjects. We found that the concentration of hepcidin was lower in urine samples of patients with heart failure compared to those of control subjects. Serum hepcidin was also reduced in heart failure but was not significantly lower than that in controls. There were no significant differences between hepcidin levels in patients with heart failure and anemia compared to patients with heart failure and normal hemoglobin. We concluded that hepcidin probably does not play a major role in pathogenesis of anemia in patients with chronic heart failure.
doi:10.1002/ajh.21902
PMCID: PMC3076004  PMID: 21080339
Anemias; Cytokines; Iron
5.  ADAPTIVE AND MALADPTIVE EFFECTS OF SMAD3 SIGNALING IN THE ADULT HEART FOLLOWING HEMODYNAMIC PRESSURE OVERLOADING 
Circulation. Heart failure  2009;2(6):633-642.
Background
Previous studies suggest that transforming growth factor- beta (TGF-∃) provokes cardiac hypertrophy and myocardial fibrosis; however, it is unclear whether the deleterious effects of TGF-∃ signaling are conveyed through SMAD-dependent or SMAD-independent signaling pathways.
Methods and Results
To determine the contribution of SMAD dependent signaling to cardiac remodeling, we performed transaortic constriction (TAC) in SMAD3 null (SMAD3−/−) and littermate control mice (age 10–12 weeks). Cumulative survival 20 days post-TAC was significantly less in the SMAD3 −/− mice when compared to littermate controls (43.6% vs 90.9%, p<0.01). TAC resulted in a significant increase in cardiac hypertrophy in the SMAD3 −/− mice, denoted by an increase in the heart-weight-to-tibial length ratio and increased myocyte cross-sectional area. Loss of SMAD3 signaling also resulted in a significant 60% decrease in myocardial fibrosis (p < 0.05). A microRNA microarray showed that 55 microRNAs were differentially expressed in littermate and SMAD3−/− mice, and that 10 of these microRNAs were predicted to bind to genes that regulate the extracellular matrix. Of these 10 candidate microRNAs, both miR-25 and miR-29a were sufficient to decrease collagen gene expression when transfected into isolated cardiac fibroblasts in vitro.
Conclusions
The results suggest that SMAD3 signaling plays dual roles in the heart: one beneficial role by delimiting hypertrophic growth, and the other deleterious by modulating myocardial fibrosis, possibly through a pathway that entails accumulation of microRNAs that decrease collagen gene expression.
doi:10.1161/CIRCHEARTFAILURE.108.823070
PMCID: PMC3064555  PMID: 19919989
Fibrosis; microRNA; pressure overload; hypertropy

Results 1-5 (5)