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1.  Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation 
Immunity  2014;40(1):91-104.
Cardiac macrophages are crucial for tissue repair after cardiac injury but have not been well characterized. Here we identify four populations of cardiac macrophages. At steady state, resident macrophages were primarily maintained through local proliferation. However, after macrophage depletion or during cardiac inflammation, Ly6chi monocytes contributed to all four macrophage populations, whereas resident macrophages also expanded numerically through proliferation. Genetic fate mapping revealed that yolk-sac and fetal monocyte progenitors gave rise to the majority of cardiac macrophages, and the heart was among a minority of organs in which substantial numbers of yolk-sac macrophages persisted in adulthood. CCR2 expression and dependence distinguished cardiac macrophages of adult monocyte versus embryonic origin. Transcriptional and functional data revealed that monocyte-derived macrophages coordinate cardiac inflammation, while playing redundant but lesser roles in antigen sampling and efferocytosis. These data highlight the presence of multiple cardiac macrophage subsets, with different functions, origins and strategies to regulate compartment.
PMCID: PMC3923301  PMID: 24439267
Macrophage; Cardiac; Inflammation; Angiotensin II; Yolk Sac
2.  Epidemiology and Natural History of Recovery of Left Ventricular Function in Recent Onset Dilated Cardiomyopathies 
Current heart failure reports  2013;10(4):10.1007/s11897-013-0157-5.
Although the long term prognosis of patients with dilated cardiomyopathy (DCM) remains poor, approximately 25% of DCM patients with recent onset of heart failure (< 6 months) have a relatively benign clinical course with a spontaneously improvement in symptoms and partial, or in some cases complete, recovery of left ventricular (LV) function. Despite the longstanding recognition of the clinical phenomenon of LV recovery, relatively little attention has been paid to the etiology and natural history of this important group of DCM patients. Accordingly, in the present review we will focus on the epidemiology and natural history of recent onset DCM in patients who undergo spontaneous resolution of symptoms that is accompanied by recovery of LV function.
PMCID: PMC3823811  PMID: 24014141
Left ventricular recovery; reverse remodeling
3.  Rethinking Phase II Clinical Trial Design in Heart Failure 
Clinical investigation  2013;3(1):57-68.
The incidence and economic burden of heart failure continue to rise worldwide, despite implementation of a number of effective heart failure therapies. Although there have been a number phase I–II studies of potential novel heart failure therapies over the past decade, none of these new compounds have been successful in phase III clinical trials. While there are likely a number of reasons for this failure, one of the problems that has become increasingly apparent is the inability of phase II trials to correctly identify novel therapies that will be successful in phase III clinical trials. In the following review, we will discuss the some of the problems inherent with current phase II heart failure clinical trials, as well as discuss possible ways to rethink phase II development of new therapies for heart failure.
PMCID: PMC4204480  PMID: 25343020
Heart failure; clinical trial design; adaptive study design; clinical translation; phase II
5.  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.
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.
These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.
PMCID: PMC3672470  PMID: 23493088
tumor necrosis factor superfamily; dilated cardiomyopathy; inflammation; TNF receptor associated factor 2
6.  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.
PMCID: PMC3982911  PMID: 18988904
heart failure; cardiac remodeling; microRNAs; neurohormonal activation; arrhythmia
7.  Dysferlin Mediates the Cytoprotective Effects of TRAF2 Following Myocardial Ischemia Reperfusion Injury 
We have demonstrated that tumor necrosis factor (TNF) receptor‐associated factor 2 (TRAF2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF2 are not known.
Mice with cardiac‐restricted overexpression of low levels of TRAF2 (MHC‐TRAF2LC) and a dominant negative TRAF2 (MHC‐TRAF2DN) were subjected to ischemia (30‐minute) reperfusion (60‐minute) injury (I/R), using a Langendorff apparatus. MHC‐TRAF2LC mice were protected against I/R injury as shown by a significant ≈27% greater left ventricular (LV) developed pressure after I/R, whereas mice with impaired TRAF2 signaling had a significantly ≈38% lower LV developed pressure, a ≈41% greater creatine kinase (CK) release, and ≈52% greater Evans blue dye uptake after I/R, compared to LM. Transcriptional profiling of MHC‐TRAF2LC and MHC‐TRAF2DN mice identified a calcium‐triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of TRAF2. Mice lacking dysferlin had a significant ≈39% lower LV developed pressure, a ≈20% greater CK release, and ≈29% greater Evans blue dye uptake after I/R, compared to wild‐type mice, thus phenocopying the response to tissue injury in the MHC‐TRAF2DN mice. Moreover, breeding MHC‐TRAF2LC onto a dysferlin‐null background significantly attenuated the cytoprotective effects of TRAF2 after I/R injury.
The study shows that dysferlin, a calcium‐triggered exocytotic membrane repair protein, is required for the cytoprotective effects of TRAF2‐mediated signaling after I/R injury.
PMCID: PMC3959693  PMID: 24572254
cytoprotection; dysferlin; TNF receptor associated factor 2; tumor necrosis factor
8.  Negative Inotropic Effects of High Mobility Box Group 1 Protein in Isolated Contracting Cardiac Myocytes 
American journal of physiology. Heart and circulatory physiology  2008;294(3):10.1152/ajpheart.00910.2007.
HMGB1 released from necrotic cells or macrophages functions as a late inflammatory mediator, and has been shown to induce cardiovascular collapse during sepsis. Thus far, however, the effect(s) of HMGB1 in the heart are not known. We determined the effects of HMGB1 on isolated feline cardiac myocytes by measuring sarcomere shortening in contracting cardiac myocytes, intracellular Ca2+ transients using fluo-3, and L-type calcium currents using whole cell perforate configuration of the patch clamp technique. Treatment of isolated myocytes with HMGB1 (100 ng/ml) resulted in a 70% decrease in sarcomere shortening and a 50% decrease in the height of the peak Ca++ transient within 5 min (p <0.01). The immediate negative inotropic effects HMGB1 on cell contractility and calcium homeostasis were partially reversible upon washout of HMGB1. A significant inhibition of the inward L-type calcium currents also was documented by the patch clamp technique. HMGB1 induced the PKCε translocation and a PKC inhibitor significantly attenuated the negative inotropic effects of HMGB1. These studies show for the first time that HMGB1 impairs sarcomere shortening by decreasing calcium availability in cardiac myocytes through modulating membrane calcium influx, and suggest that HMGB1 maybe act as a novel myocardial depressant factor during cardiac injury.
PMCID: PMC3873738  PMID: 18223193
Inflammation; innate immunity; myocardial function; sepsis
Basic research in cardiology  2007;103(1):10.1007/s00395-007-0689-5.
The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a pro-inflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase levels transforming growth factor-β (TGF-β) mRNA and protein. In order to determine whether TGF-β mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study myocardial collagen content was determined using the picrosirius red technique, and LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness in the MHCsTNF mice when compared to diluent treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.
PMCID: PMC3872069  PMID: 18034274
Tumor necrosis factor; transforming growth factor; myocardial fibrosis; transgenesi
10.  Beneficial Effects of the CorCap Cardiac Support Device: 5 Year results from the Acorn Trial 
The CorCap Cardiac Support Device (Acorn Cardiovascular, Inc.) is the first device that specifically addresses ventricular remodeling in heart failure by reducing wall stress. We previously reported outcomes from the Acorn randomized trial to a common closing date (22.9 months of follow up). This report summarizes results of extended follow up to 5 years.
107 patients were enrolled in the No-Mitral Valve Repair/Replacement stratum including 57 in the CorCap treatment group and 50 in the control (optimal medical therapy alone) group. Patients were assessed every year until completing 5 years of follow up, for survival, adverse events, major cardiac procedures, New York Heart Association (NYHA) functional status and echocardiograms, which were read at a core laboratory.
Overall survival rates were similar between the treatment and control groups demonstrating no late adverse effect on mortality. The treatment group had significant reductions in left ventricular end diastolic volume (p = 0.029) as well as a small increase in sphericity index. More patients in the treatment group improved by at least one NYHA functional class (p= 0.0005). There was no difference in rates of adverse events. In a subgroup of patients with an intermediate left ventricular end diastolic dimension, there was a significant reduction in the Kaplan Meier estimate of the freedom from the composite endpoint of death and major cardiac procedures (p= 0.04).
These cumulative data demonstrate the sustained reverse remodeling of the left ventricle and the long term safety and efficacy of the CorCap Cardiac Support Device as an adjunctive therapy for patients with heart failure who remain symptomatic despite optimal medical therapy.
PMCID: PMC3790142  PMID: 21762937
11.  Repetitive Myocardial Ischemia Promotes Coronary Growth in the Adult Mammalian Heart 
Coronary artery disease and ischemic cardiomyopathy represent the leading cause of heart failure and continue to grow at exponential rates. Despite widespread availability of coronary bypass surgery and percutaneous coronary intervention, subsequent ischemic events and progression to heart failure continue to be common occurrences. Previous studies have shown that a subgroup of patients develop collateral blood vessels that serve to connect patent and occluded arteries and restore perfusion to ischemic territories. The presence of coronary collaterals has been correlated with improved clinical outcomes; however, the molecular mechanisms governing this process remain largely unknown.
Methods and Results
To date, no mouse models of coronary arterial growth have been described. Using a closed‐chest model of myocardial ischemia, we have demonstrated that brief episodes of repetitive ischemia are sufficient to promote the growth of both large coronary arteries and the microvasculature. Induction of large coronary artery and microvascular growth resulted in improvements in myocardial perfusion after prolonged ischemia and protected from subsequent myocardial infarction. We further show that repetitive ischemia did not lead to increased expression of classic proangiogenic factors but instead resulted in activation of the innate immune system and recruitment of macrophages to growing blood vessels.
These studies describe a novel model of coronary angiogenesis and implicate the cardiac macrophage as a potential mediator of ischemia‐driven coronary growth.
PMCID: PMC3835243  PMID: 24080909
coronary; collateral; macrophage; repetitive ischemia; coronary angiogenesis
12.  Myocardial Recovery and The Failing Heart: Myth, Magic or Molecular Target? 
Medical and device therapies that reduce heart failure morbidity and mortality also lead to decreased left ventricular (LV) volume and mass, and a more normal elliptical shape of the ventricle. These are due to changes in myocyte size, structure and organization that have been referred to collectively as “reverse remodeling.” Moreover, there are subsets of patients whose hearts have undergone reverse remodeling either spontaneously, or following medical or device therapies, and whose clinical course is associated with freedom from future heart failure events. This phenomenon has been referred to as “myocardial recovery.” Despite the frequent interchangeable use of the terms myocardial recovery and reverse remodeling to describe the reversal of various aspects of the heart failure phenotype following medical and device therapy, the literature suggests that there are important differences between these two phenomenon, and that myocardial recovery and reverse remodeling are not synonymous. In the following review, we will discuss the biology of cardiac remodeling, cardiac reverse remodeling and myocardial recovery, with the intent of providing a conceptual framework for understanding myocardial recovery.
PMCID: PMC3522780  PMID: 23158527
heart failure; left ventricular remodeling; reverse remodeling; myocardial recovery; myocardial remission
13.  The Development of Myocardial Fibrosis in Transgenic Mice with Targeted Overexpression of Tumor Necrosis Factor Requires Mast Cell-Fibroblast Interactions 
Circulation  2011;124(19):2106-2116.
Transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice) develop progressive myocardial fibrosis, diastolic dysfunction and adverse cardiac remodeling. Insofar as tumor necrosis factor (TNF) does not directly stimulate fibroblast collagen synthesis, we asked whether TNF-induced fibrosis was mediated indirectly through interactions between mast cells and cardiac fibroblasts.
Methods and Results
Cardiac mast cell number increased 2–3-fold (p < 0.001) in MHCsTNF mice compared to littermate (LM) controls. Outcrossing MHCsTNF mice with mast cell deficient (c-kit−/−) mice showed that the 11-fold increase (p < 0.001) in collagen volume fraction in MHCsTNF/c-kit+/− mice was abrogated in MHCsTNF/c-kit−/− mice, and that the leftward shifted LV pressure-volume curve in the MHCsTNF/c-kit+/− mice was normalized in the MHCsTNF/c-kit−/− hearts. Furthermore, the increase in TGF-β1 and type I TGF-β receptor (TβR I) mRNA levels was significantly (p = 0.03, p = 0.01 respectively) attenuated in MHCsTNF/c-kit−/− when compared to MHCsTNF/c-kit+/− mice. Co-culture of fibroblasts with mast cells resulted in enhanced α-smooth muscle actin expression, increased proliferation and collagen mRNA expression, and increased contraction of 3-D collagen gels in MHCsTNF fibroblasts compared to LM fibroblasts. The effects of mast cells were abrogated by TβR I antagonist NP-40208.
These results suggest that increased mast cell density with resultant mast cell-cardiac fibroblast cross-talk is required for the development of myocardial fibrosis in inflammatory cardiomyopathy. Cardiac fibroblasts exposed to sustained inflammatory signaling exhibit an increased repertoire of pro-fibrotic phenotypic responses in response to mast cell mediators.
PMCID: PMC3217207  PMID: 22025605
Tumor necrosis factor (TNF); Transforming growth factor-beta (TGF-β); cardiac fibroblasts; mast cells; myocardial fibrosis
Recent studies suggest that the heart possesses an intrinsic system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses within the heart. The extant literature suggests that this intrinsic stress response is mediated, at least in part, by a family of pattern recognition receptors that belong to the innate immune system, including CD14, the soluble pattern recognition receptor for lipopolysaccharide, and Toll like receptors-2, 3, 4, 5, 6, 7 and 9. Although this intrinsic stress response system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if myocardial expression of these molecules either becomes sustained and/or excessive, in which case the salutary effects of activation of these pathways is contravened by the known deleterious effects of inflammatory signaling. Herein we present new information with regard to activation of innate immune gene expression in the failing human heart, as well as review the novel TLR antagonists that are being developed for other indications outside of heart failure.
This review will discuss the interesting possibility that the TLR pathway may represent a new target for the development of novel heart failure therapeutics.
PMCID: PMC3053440  PMID: 21074541
Circulation research  2011;108(9):1133-1145.
Recent studies suggest that the heart possesses an innate immune system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses within the heart. The extant literature suggests that this intrinsic stress response system is mediated, at least in part, by a family of pattern recognition receptors, most notably the Toll-like receptors. Although the innate immune system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if innate immune signaling becomes sustained and/or excessive, in which case the salutary effects of activation of these pathways is contravened by the known deleterious effects of inflammatory signaling. Herein we review the biology of innate immune signaling in the heart, as well as review the literature which suggests that the innate immune system is involved in the pathogenesis of atherosclerosis, acute coronary syndromes, stroke, viral myocarditis, sepsis, ischemia reperfusion injury and heart failure. The review concludes by discussing new therapies that are being developed to modulate the innate immune system.
PMCID: PMC3084988  PMID: 21527743
innate immunity; homeostasis; heart failure
16.  Translational Medicine: Proceed at Your Own Risk 
Nature reviews. Drug discovery  2013;12(5):327-328.
Although investigators are encouraged to translate their laboratory research to impact the care of patients, there is an unappreciated downside to participating in “T1 translation” from the standpoint of the investigator if their translational efforts do not yield positive results in pivotal clinical trials.
PMCID: PMC4283600  PMID: 23629490
Circulation. Heart failure  2009;2(6):633-642.
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.
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.
PMCID: PMC3064555  PMID: 19919989
Fibrosis; microRNA; pressure overload; hypertropy
18.  Soluble Tumor Necrosis Factor Receptors and Heart Failure Risk in Older Adults: The Health, Aging, and Body Composition Study 
Circulation. Heart failure  2013;7(1):5-11.
Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type-1 (sTNF-R1) and type-2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear.
Methods and Results
Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF R2 levels were 3.14 (2.42-4.06) pg/ml, 1.46 (1.25-1.76) ng/ml, and 3.43 (2.95-4.02) ng/ml, respectively. During a median follow-up of 11.4 (6.9, 11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02-1.61 per log2 increase), and sTNF-R1 (HR, 1.68; 95%CI, 1.15-2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95%CI, 0.80-1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2, interaction P=0.531, 0.091 and 0.795, respectively), and in both genders (TNF, sTNF-R1, sTNF-R2, interaction P=0.491, 0.672 and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95%CI, 1.03, 3.18; P=0.038 for preserved vs. HR, 0.90; 95%CI, 0.56, 1.44; P=0.667 for reduced ejection fraction, interaction P=0.05).
In older adults, elevated levels of sTNF-R1 are associated with an increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.
PMCID: PMC3990649  PMID: 24323631
heart failure; tumor necrosis factor; inflammation
Circulation. Heart failure  2009;3(1):157-164.
Activation of both the type 1 (TNFR1) and type 2 (TNFR2) tumor necrosis factor (TNF) receptor confers cytoprotection in cardiac myocytes. Noting that the scaffolding protein tumor necrosis factor receptor associated factor 2 (TRAF2) is common to both TNF receptors, we hypothesized that the cytoprotective responses of TNF were mediated through TRAF2.
Methods and Results
Mice with cardiac-restricted overexpression of low levels of TNF (MHCsTNF3) and TRAF2 (MHC-TRAF2LC), and mice lacking TNFR1, TNFR2 and TNFR1/TNFR2 were subjected to ischemia (30 min) reperfusion (30 min) injury (I/R) ex vivo, using a Langendorff apparatus. MHC-sTNF3 mice were protected against I/R injury as shown by a significant ~ 30 % greater LV developed pressure, and ~ 80% lower creatine kinase (CK) release and Evans blue dye uptake compared to littermates (LM). The extent of I/R induced injury was similar in wild-type, TNFR1 and TNFR2 deficient mice; however, mice lacking TNFR1/TNFR2 had a significant ~ 40% lower LV developed pressure, a ~ 65 % greater CK release and ~ 40% greater Evans blue dye uptake compared to LM. Interestingly, MHC-TRAF2LC mice had a significant ~ 50 % lower LV developed pressure, a ~ 70% lower CK release and ~ 80% lower Evans blue dye uptake compared to LM controls following I/R injury. Biochemical analysis of the MHC-TRAF2LC hearts showed that there was activation of NF-κB but not JNK activation.
Taken together these results suggest that TNF confers cytoprotection in the heart through TRAF2 mediated activation of NF-κB.
PMCID: PMC2910515  PMID: 19880804
ischemia reperfusion injury; tumor necrosis factor; tumor necrosis factor receptor associated factor 2
20.  Stroke in Heart Failure in Sinus Rhythm: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial 
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses.
We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions.
Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3–5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups.
The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.
PMCID: PMC4256381  PMID: 23921215
Aspirin; Cardiac embolism; Heart failure; Stroke prevention
21.  Cognitive Function in Ambulatory Patients with Systolic Heart Failure: Insights from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial 
PLoS ONE  2014;9(11):e113447.
We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE <24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (β-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.
PMCID: PMC4245133  PMID: 25426862
22.  Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm 
Circulation. Heart failure  2013;6(5):988-997.
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.
Methods and Results
We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03).
In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.
Clinical Trial Registration
URL: Unique identifier: NCT00041938.
PMCID: PMC4242511  PMID: 23881846
aspirin; heart failure; sinus rhythm; stroke; warfarin
24.  Spectrum of Pleiotropic Effects of Statins in Heart Failure 
Heart failure clinics  2008;4(2):153-161.
PMCID: PMC2692470  PMID: 18433695
Statins; HMG-CoA reductase inhibitors; Heart Failure; Pleiotropic
25.  Positioning of Inflammatory Biomarkers in the Heart Failure Landscape 
Journal of cardiovascular translational research  2013;6(4):10.1007/s12265-013-9467-y.
The clinical syndrome of heart failure is characterized by a systemic inflammatory response that contributes to end organ damage in the heart and circulation and can thus lead to worsening heart failure. The ensemble of inflammatory mediators that have been detected in heart failure patients include pro-inflammatory cytokines and their cognate receptors, as well as molecules secreted/released by macrophages (galectin-3 and pentraxin-3). Inflammatory biomarkers correlate with disease severity and prognosis across the broad spectrum of heart failure syndromes. Given the proliferation of new biomarkers that predict disease severity and prognosis in heart failure, it is reasonable to ask whether there is a current role for measuring inflammatory mediators in heart failure. This review will attempt to address this question, as well as review several novel approaches that have utilized inflammatory biomarkers to enhance risk stratification and prognosis in heart failure patients.
PMCID: PMC3811018  PMID: 23666808
Inflammation; Heart failure; Biomarkers; Pro-inflammatory cytokines; Cytokine receptors; Tumor necrosis factor; Interleukins; C-reactive protein (CRP); sST2; Galectin-3; Pentraxin-3

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