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.
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.
coronary; collateral; macrophage; repetitive ischemia; coronary angiogenesis
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.
Myocardial infarction; innate immunity; monocyte; T cell; neutrophil
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.
heart failure; left ventricular remodeling; reverse remodeling; myocardial recovery; myocardial remission
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.
diabetic cardiomyopathy; mitochondria; heart failure; metabolism
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.
It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm.
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.
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).
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.
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.
innate immunity; homeostasis; heart failure
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.
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.
aortic valve stenosis; heart failure; phosphodiesterase type 5 inhibitors; pulmonary hypertension; hemodynamics
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.
heart failure; acute decompensated HF; Winters Center for Heart Failure Research
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.
Tumor necrosis factor (TNF); Transforming growth factor-beta (TGF-β); cardiac fibroblasts; mast cells; myocardial fibrosis
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.
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.
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.
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.
Weight loss; Heart failure; Metabolic syndrome; Obesity
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.
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.
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).
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.
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.
Cluster analysis; digoxin; heart failure
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.
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.
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.
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.
depression; treatment response; inflammation; coronary heart disease
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).
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.
aortic stenosis; diabetes mellitus; LV hypertrophy; LV remodeling; echocardiography
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.
Anemias; Cytokines; Iron
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.
MicroRNAs (miRNAs or miRs) are short, highly conserved noncoding RNAs that regulate gene expression at the post-transcriptional level by inhibiting translation or promoting the degradation of target mRNA. Even though the field of miRNA biology is relatively young, growing lines of evidence suggest that miRNAs play a key role pathogenesis of heart failure through their ability to regulate genes that govern the process of adaptive and maladaptive cardiac remodeling. Herein, we review the biology of miRNAs in relation to their role in modulating various aspects of the cardiac remodeling process, as well as discuss the potential applications of miRNA biology to the field of heart failure.
cardiac remodeling; gene silencing; miRNAs; personalized medicine
Atrogin1/MAFbx is an ubiquitin ligase that mediates muscle atrophy in a variety of catabolic states. We recently found that H2O2 stimulates atrogin1/MAFbx gene expression. Since the cytokine tumor necrosis factor-α (TNF-α) stimulates both reactive oxygen production and general activity of the ubiquitin conjugating pathway, we hypothesized that TNF-α would also increase atrogin1/MAFbx gene expression. As with H2O2, we found that TNF-α exposure up-regulates atrogin1/MAFbx mRNA within 2 h in C2C12 myotubes. Intraperitoneal injection of TNF-α increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF-α or H2O2 also produced general activation of the mitogen-activated protein kinases (MAPKs): p38, ERK1/2, and JNK The increase in atrogin1/MAFbx gene expression induced by TNF-α was not altered significantly by ERK inhibitor PD98059 or the JNK inhibitor SP600125. In contrast, atrogin1/MAFbx up-regulation and the associated increase in ubiquitin conjugating activity were both blunted by p38 inhibitors, either SB203580 or curcumin. These data suggest that TNF-α acts via p38 to increase atrogin1/MAFbx gene expression in skeletal muscle.
tumor necrosis factor; muscle wasting; ubituitin conjugating activity
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.
Fibrosis; microRNA; pressure overload; hypertropy
Heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and diabetes commonly co-exist, but the impact of diabetes on HF outcomes in individuals with HF and preserved LVEF has not been well studied. We assessed the risk of HF death or hospitalization for worsening HF associated with diabetes by studying 987 patients with HF and preserved LVEF enrolled in the Digitalis Investigation Group (DIG) ancillary study. Diabetic individuals (n=285, 28.9%) were younger, had a larger body mass index, faster heart rate, and higher pulse pressure than non-diabetic individuals. Diabetic individuals were also more likely to be female, have a prior history of hypertension, ischemic etiology for HF, and were more likely to be treated with diuretics. During the mean follow-up of 37 months, 88 (30.9%) diabetic individuals and 133 (19.0%) non-diabetic individuals experienced the primary outcome of HF hospitalization or HF death. After adjustments for baseline differences, diabetes was associated with a 68% increased risk of HF hospitalization or HF death (adjusted HR 1.68, 95% CI 1.26 to 2.25, p<0.001). In conclusion, in individuals with HF and preserved LVEF, diabetes is associated with significantly increased risk of developing adverse HF outcomes.
Diabetes; Diastolic Heart Failure; Prognosis
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.
ischemia reperfusion injury; tumor necrosis factor; tumor necrosis factor receptor associated factor 2