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1.  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
2.  EFFECT OF TRANSFORMING GROWTH FACTOR-β RECEPTOR ANTAGONISM IN MICE WITH CARDIAC RESTRICTED OVEREXPRESSION OF TUMOR NECROSIS FACTOR 
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.
doi:10.1007/s00395-007-0689-5
PMCID: PMC3872069  PMID: 18034274
Tumor necrosis factor; transforming growth factor; myocardial fibrosis; transgenesi
3.  Beneficial Effects of the CorCap Cardiac Support Device: 5 Year results from the Acorn Trial 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.jtcvs.2011.06.014
PMCID: PMC3790142  PMID: 21762937
4.  Repetitive Myocardial Ischemia Promotes Coronary Growth in the Adult Mammalian Heart 
Background
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.
Conclusions
These studies describe a novel model of coronary angiogenesis and implicate the cardiac macrophage as a potential mediator of ischemia‐driven coronary growth.
doi:10.1161/JAHA.113.000343
PMCID: PMC3835243  PMID: 24080909
coronary; collateral; macrophage; repetitive ischemia; coronary angiogenesis
5.  Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction: A Randomized Clinical Trial 
JAMA : the journal of the American Medical Association  2013;309(12):10.1001/jama.2013.2024.
Importance
Studies in experimental and human heart failure suggest that phosphodiesterase type-5 inhibitors may enhance cardiovascular function, and thus, exercise capacity in heart failure with preserved ejection fraction.
Objective
To determine the effect of the phosphodiesterase type-5 inhibitor, sildenafil, in comparison to placebo on exercise capacity and clinical status in heart failure with preserved ejection fraction.
Design, setting, and patients
Multicenter, double-blind, placebo-controlled, parallel design, randomized clinical trial of 216 stable outpatients with heart failure, ejection fraction ≥ 50%, elevated N-terminal pro-brain natriuretic peptide or elevated invasively-measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in the United States and Canada.
Intervention
Sildenafil (n=113) or placebo (n=103) administered orally at 20 mg three times daily for 12 weeks followed by 60 mg three times daily for 12 weeks.
Main outcome measures
Primary endpoint was change in peak oxygen consumption after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance and a three tier hierarchical composite clinical status score where patients were ranked (range 1-N) based on time to death, time to cardiovascular or cardiorenal hospitalization and change in quality of life for participants alive without cardiovascular or cardiorenal hospitalization at 24 weeks.
Results
Median age was 69 years and 48% of patients were female. At baseline, median peak oxygen consumption (11.7 ml/kg/min) and six-minute walk distance (308 meters) were reduced and median E/e′ (16), left atrial volume index (44 ml/m2) and pulmonary artery systolic pressure (41 mmHg) were consistent with chronically-elevated left ventricular filling pressures. At 24 weeks, median (interquartile range) changes in peak oxygen consumption (ml/kg/min) in patients who received placebo [−0.20 (−0.70, 1.00)] or sildenafil [−0.20 (−1.20, 1.10); p=0.90] were not significantly different. The mean clinical status rank score (higher value indicates better status; expected value with no treatment effect = 95) was not significantly different (p=0.85) at 24 weeks in patients who received placebo (95.8) or sildenafil (94.2). Changes in six-minute walk distance (meters) at 24 weeks in patients who received placebo [15.0 (−26.0, 45.0)] or sildenafil [5.0 (−37.0, 55.0); p=0.92] were also not significantly different. Adverse events occurred in 78 (76%) of patients who received placebo and 90 (80%) of patients who received sildenafil. Serious adverse events occurred in 16 (16%) of patients who received placebo and 25 (22%) of patients who received sildenafil.
Conclusion
Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction.
Trial registration
clinicaltrials.gov number, NCT00763867
doi:10.1001/jama.2013.2024
PMCID: PMC3835156  PMID: 23478662
6.  Dysferlin Mediates the Cytoprotective Effects of TRAF2 Following Myocardial Ischemia Reperfusion Injury 
Background
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.
Methods/Results
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.
Conclusion
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.
doi:10.1161/JAHA.113.000662
PMCID: PMC3959693  PMID: 24572254
cytoprotection; dysferlin; TNF receptor associated factor 2; tumor necrosis factor
7.  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.
doi:10.1016/j.jacc.2012.06.062
PMCID: PMC3522780  PMID: 23158527
heart failure; left ventricular remodeling; reverse remodeling; myocardial recovery; myocardial remission
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.
doi:10.1152/ajpheart.00910.2007
PMCID: PMC3873738  PMID: 18223193
Inflammation; innate immunity; myocardial function; sepsis
9.  Communication in the Heart: The Role of the Innate Immune System In Coordinating Cellular Responses to Ischemic Injury 
Journal of cardiovascular translational research  2012;5(6):10.1007/s12265-012-9410-7.
Ischemic cardiac injury is the leading cause of heart failure and mortality in the US, and a major expense to health care systems. Once the heart is injured, a highly dynamic and coordinated immune response is initiated, which is dependent on both resident and recruited leukocytes. The goal of the inflammatory response is to remove ischemic and necrotic material, and to promote infarct healing. If this system is perturbed, the myocardium heals poorly, leading to significant left ventricular dysfunction. Understanding how inflammatory cells coordinate and interact with each other is required prior to designing therapeutic interventions that target pathological processes at play, and leave untouched those processes that are protective. This review will discuss the intercellular cross talk between cells of the innate immune system following myocardial ischemic injury and how that response is coordinated over time.
doi:10.1007/s12265-012-9410-7
PMCID: PMC3847667  PMID: 23054658
Myocardial infarction; innate immunity; monocyte; T cell; neutrophil
10.  THERAPEUTIC TARGETING OF INNATE IMMUNITY IN THE FAILING HEART 
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.
doi:10.1016/j.yjmcc.2010.11.003
PMCID: PMC3053440  PMID: 21074541
11.  THE EMERGING ROLE OF INNATE IMMUNITY IN THE HEART AND VASCULAR SYSTEM: FOR WHOM THE CELL TOLLS 
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.
doi:10.1161/CIRCRESAHA.110.226936
PMCID: PMC3084988  PMID: 21527743
innate immunity; homeostasis; heart failure
12.  Diabetic Cardiomyopathy: Bench to Bedside 
Heart failure clinics  2012;8(4):619-631.
The study of diabetic cardiomyopathy (diabetic CM) is an area of significant interest given the strong association between diabetes and the risk of heart failure. Many unanswered questions remain regarding the clinical definition and pathogenesis of this metabolic cardiomyopathy. This article reviews the current understanding of diabetic CM with a particular emphasis on the unresolved issues that have limited translation of scientific discovery to patient bedside.
doi:10.1016/j.hfc.2012.06.007
PMCID: PMC3457018  PMID: 22999244
diabetic cardiomyopathy; mitochondria; heart failure; metabolism
13.  Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm 
The New England journal of medicine  2012;366(20):1859-1869.
BACKGROUND
It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm.
METHODS
We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause.
RESULTS
The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82).
CONCLUSIONS
Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.
doi:10.1056/NEJMoa1202299
PMCID: PMC3723382  PMID: 22551105
14.  Effects of Phosphodiesterase Type 5 Inhibition on Systemic and Pulmonary Hemodynamics and Ventricular Function in Patients with Severe Symptomatic Aortic Stenosis 
Circulation  2012;125(19):2353-2362.
Background
Pressure overload due to aortic stenosis (AS) causes maladaptive ventricular and vascular remodeling that can lead to pulmonary hypertension, heart failure symptoms, and adverse outcomes. Retarding or reversing this maladaptive remodeling and its unfavorable hemodynamic consequences has potential to improve morbidity and mortality. Preclinical models of pressure overload have shown that phosphodiesterase type 5 (PDE5) inhibition is beneficial, however the use of PDE5 inhibitors in patients with AS is controversial because of concerns about vasodilation and hypotension.
Methods and Results
We evaluated the safety and hemodynamic response of 20 subjects with severe symptomatic AS (mean aortic valve area 0.7±0.2 cm2, ejection fraction 60±14%) who received a single oral dose of sildenafil (40mg or 80mg). Compared to baseline, after 60 minutes sildenafil reduced systemic (−12%, p<0.001) and pulmonary (−29%, p=0.002) vascular resistance, mean pulmonary artery (−25%, p<0.001) and wedge (−17%, p<0.001) pressure, and increased systemic (+13%, p<0.001) and pulmonary (+45%, p<0.001) vascular compliance and stroke volume index (+8%, p=0.01). These changes were not dose dependent. Sildenafil caused a modest decrease in mean systemic arterial pressure (−11%, p<0.001), but was well-tolerated with no episodes of symptomatic hypotension.
Conclusions
This study shows for the first time that a single dose of a PDE5 inhibitor is safe and well-tolerated in patients with severe AS and is associated with acute improvements in pulmonary and systemic hemodynamics resulting in biventricular unloading. These findings support the need for longer-term studies to evaluate the role of PDE5 inhibition as adjunctive medical therapy in patients with AS.
doi:10.1161/CIRCULATIONAHA.111.081125
PMCID: PMC3485404  PMID: 22447809
aortic valve stenosis; heart failure; phosphodiesterase type 5 inhibitors; pulmonary hypertension; hemodynamics
16.  TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways 
The Journal of Clinical Investigation  2007;117(9):2692-2701.
Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl-2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t-Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.
doi:10.1172/JCI29134
PMCID: PMC1937497  PMID: 17694177
17.  The Treatment of Heart Failure in the 21st Century: Is the Glass Half Empty or Half Full? 
The field of heart failure has seen striking advances during the past 50 years, yet the overall economic and social burden imposed by heart failure continues to rise. While neurohormonal models provide many insights in terms of explaining disease progression and informing drug development, mounting clinical evidence suggests that this model provides only a partial explanation of the disease. This paper evaluates the emerging models of heart failure and their potential to reverse the disturbing trends in heart failure morbidity and mortality.
PMCID: PMC3600876  PMID: 23518696
heart failure; acute decompensated HF; Winters Center for Heart Failure Research
18.  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.
Background
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.
Conclusions
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.
doi:10.1161/CIRCULATIONAHA.111.052399
PMCID: PMC3217207  PMID: 22025605
Tumor necrosis factor (TNF); Transforming growth factor-beta (TGF-β); cardiac fibroblasts; mast cells; myocardial fibrosis
19.  IN SEARCH OF NEW THERAPEUTIC TARGETS AND STRATEGIES FOR HEART FAILURE: RECENT ADVANCES IN BASIC SCIENCE 
Lancet  2011;378(9792):704-712.
doi:10.1016/S0140-6736(11)60894-5
PMCID: PMC3486638  PMID: 21856484
20.  Lifestyle Modification with Diet and Exercise in Obese Patients with Heart Failure – A Pilot Study 
Objective
There is a paucity of data regarding intentional weight loss in obese heart failure patients. This study sought to ascertain the safety and effectiveness of a lifestyle modification program in patients with systolic heart failure and metabolic syndrome.
Methods
Patients (n=20) with systolic heart failure (ejection fraction < 50%) and metabolic syndrome were randomized to standard medical therapy (Control) versus medical therapy and lifestyle modification (Lifestyle) and followed prospectively for 3 months. Lifestyle modification involved a walking program and reduced calorie diet with 2 meal replacement products (Slim Fast®) daily. Patients attended weekly meetings with a dietitian for 12 weeks. Endpoints were obtained at baseline and 3 months and included physical exam, laboratory values, quality of life questionnaire, 6 minute walk, and brachial ultrasound.
Results
At 3 months, 5 patients in each group had lost weight. Excluding 1 patient in each group who had increased diuretic dosing, the overall change in weight was −0.84 ± 3.82 and −0.50 ± 3.64 kg (p=0.85) in the control versus lifestyle groups respectively. No significant differences in the defined endpoints were noted. None of the patients had an adverse event that was related to weight loss or exercise.
Conclusions
This study is the first to assess the effects of a comprehensive program of dietary, behavioral, and exercise modifications in this population. Institution of lifestyle modification in patients with systolic heart failure and metabolic syndrome was well tolerated, but did not result in significant weight loss.
doi:10.4172/2165-7904.1000118
PMCID: PMC3484982  PMID: 23125955
Weight loss; Heart failure; Metabolic syndrome; Obesity
21.  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
22.  Inflammation and treatment response to sertraline in patients with coronary heart disease and comorbid major depression 
Objective
Treatment-resistant depression has recently emerged as a marker of increased risk for morbidity and mortality in patients with coronary heart disease (CHD). Studies in depressed patients without CHD suggest that elevated markers of inflammation predict poor response to treatment. This may help to explain the increased risk of cardiac events associated with depression. We therefore studied the relationship between pre-treatment markers of inflammation and treatment response in patients with CHD and major depression.
Methods
This was a planned, secondary analysis of a clinical trial in which 122 patients with CHD and comorbid major depression were randomly assigned to 50mg of sertraline plus 2g/day omega-3 fatty acids or to 50mg of sertraline plus 2g/day corn oil placebo capsules for ten weeks. Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II). Blood samples were collected at baseline to determine levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). The primary outcome was the post-treatment BDI-II depression score.
Results
Baseline levels of hs-CRP, IL-6, and TNF-α were not associated with the 10-week post-treatment depression score (p=0.89, p=0.88, and p=0.31, respectively). Treatment responders (>50% reduction from baseline BDI-II score) did not differ from non-responders in either baseline hs-CRP, IL-6, or TNF-α (p=0.83, p=0.93, and p=0.24, respectively). Similarly, depression remitters (BDI-II ≤8 at post-treatment) did not differ from non-remitters on the three baseline inflammation markers.
Conclusion
These findings do not support the hypothesis that elevated baseline inflammatory markers predict poor response to sertraline in patients with CHD and major depression. The explanation for the increased risk of cardiac events associated with poor response to depression treatment remains unclear.
doi:10.1016/j.jpsychores.2010.11.006
PMCID: PMC3115530  PMID: 21665007
depression; treatment response; inflammation; coronary heart disease
23.  The Adverse Impact of Diabetes Mellitus on Left Ventricular Remodeling and Function in Patients with Severe Aortic Stenosis 
Circulation. Heart failure  2011;4(3):286-292.
Background
The diabetic heart exhibits increased left ventricular (LV) mass and reduced ventricular function. However, this relationship has not been studied in patients with aortic stenosis (AS), a disease process that causes LV hypertrophy and dysfunction through a distinct mechanism of pressure overload. The aim of this study was to determine how diabetes mellitus (DM) impacts LV remodeling and function in patients with severe AS.
Methods and Results
Echocardiograms were performed on 114 patients with severe AS [mean aortic valve area (AVA) 0.6 cm2] and included measures of LV remodeling and function. Multivariable linear regression models investigated the independent effect of DM on these aspects of LV structure and function. Compared to non-diabetics (n=60), diabetics (n=54) had increased LV mass, LV end-systolic dimension, LV end-diastolic dimension, and decreased LV ejection fraction (EF) and longitudinal systolic strain (p<0.01 for all). In multivariable analyses adjusting for age, sex, systolic BP, AVA, BSA, and coronary disease, DM was an independent predictor of increased LV mass (β=26g, p=0.01), LV end-systolic dimension (β=0.5cm, p=0.008), and LV end-diastolic dimension (β=0.3cm, p=0.025). After additionally adjusting for LV mass, DM was associated with reduced longitudinal systolic strain (β=1.9%, p=0.023) and a trend toward reduced EF (β=−5%, p=0.09). Among diabetics, insulin use (as a marker of disease severity) was associated with larger LV end-systolic dimension and worse LV function. LV mass was a strong predictor of reduced EF and systolic strain (p<0.001 for both).
Conclusions
DM has an additive adverse effect on hypertrophic remodeling—increased LV mass and larger cavity dimensions—and is associated with reduced systolic function in patients with AS beyond known factors of pressure overload.
doi:10.1161/CIRCHEARTFAILURE.110.960039
PMCID: PMC3100796  PMID: 21357546
aortic stenosis; diabetes mellitus; LV hypertrophy; LV remodeling; echocardiography
24.  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
25.  NHLBI’s Program for VAD Therapy for Moderately Advanced Heart Failure: The REVIVE-IT Pilot Trial 
Journal of cardiac failure  2010;16(11):855-858.
Background
VADs are used to bridge heart failure patients to transplantation, to allow their own hearts to recover, or as permanent (“destination”) therapy. To date, the use of VADs has been limited to late-stage heart failure patients because of the associated device risks. In 2008, an NHLBI working group met to evaluate the treatment of heart failure using VADs and to advise the institute on how therapy for heart failure may be best advanced by clinical trials involving the devices.
Discussion and Recommendations
Recognizing the improvements in VAD technology and in patient care and selection over the past decade, the working group recommended that a trial be performed to assess the use of chronic VAD therapy in patients who are less ill than those currently eligible for destination therapy. The hypothesis proposed for the trial is that VAD therapy may improve both survival and quality of life in moderately advanced heart failure patients who are neither inotrope-dependent nor exercise-intolerant and have not yet developed serious consequences such as malnourishment, end-organ damage, and immobility. Based on the group’s recommendations, NHLBI issued an RFP in 2009 for the REVIVE-IT Pilot Trail which will serve to test the hypothesis and inform the pivotal trial.
doi:10.1016/j.cardfail.2010.06.414
PMCID: PMC2994073  PMID: 21055648

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