Cardiology
Abstract
Background: Epicardial adipose tissue (EAT) is the visceral fat depot of the heart. Inflammation of EAT is thought to contribute to coronary artery disease (CAD). Therefore, we hypothesized that the EAT of patients with CAD would have increased inflammatory gene expression compared to controls without CAD. Methods: 26 patients referred for cardiac surgery with (n=13) or without CAD (n=13) were consented. Samples of EAT and subcutaneous adipose tissue (SAT) were obtained at the time of surgery. Gene expression analysis was performed using Affymetrix Human Gene 1.0 ST arrays. Differential regulation was defined as a 1.5 fold change (ANOVA p<0.05). Results: When comparing SAT and EAT of controls, 693 genes were differentially expressed. 805 genes were differentially expressed between SAT and EAT in cases. Expression of 326 genes was different between EAT of cases and controls; expression of 14 genes was increased in cases, while 312 were increased in controls. qRT-PCR confirmed that there was no difference in expression of major inflammatory genes (CCL2, CCR2, TNFα, IL6, IL8, PAI1) between cases and controls. Immunohistochemistry demonstrated that there were more macrophages in EAT than SAT, but that there was no difference in the number or activation state between cases and controls. Conclusion: In contrast to prior studies, we did not find increased inflammatory gene expression in the EAT of patients with CAD in comparison to controls without CAD. We conclude that specific adipose tissue organ, rather than CAD status, is responsible for the majority of differential gene expression.
Authors
Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van Tran, Sara Nicoloro, Mark Kelly, Stanley K.C. Tam, Michael P. Czech
Abstract
The cardiac hormone atrial natriuretic peptide (ANP) is a central regulator of blood volume and a therapeutic target in hypertension and heart failure. Enhanced ANP activity in such conditions through inhibition of the degradative enzyme neprilysin has shown clinical efficacy, but is complicated by consequences from simultaneous accumulation of a heterogeneous array of other hormones. Targets for specific ANP enhancement have not been available. Here, we describe a cis-acting antisense transcript (NPPA-AS1) which negatively regulates ANP expression in human cardiomyocytes. We show that NPPA-AS1 regulates ANP expression via facilitating interaction of the NPPA repressor REST (RE1-silencing transcription factor) binding to its promoter, rather than base-pairing with ANP mRNA. Expression of ANP mRNA and NPPA-AS1 was increased and correlated in isolated strained human cardiomyocytes and in hearts from patients with advanced heart failure. Further, inhibition of NPPA-AS1 in vitro and in vivo resulted in increased myocardial expression of ANP, increased circulating ANP, increased renal cGMP and lower blood pressure. The effects of NPPA-AS1 inhibition on NPPA expression in human cardiomyocytes were further marked under cell-strain conditions. Collectively, these results implicate the antisense transcript NPPA-AS1 as part of a physiologic self-regulatory ANP circuit and a viable target for specific ANP augmentation.
Authors
Selvi Celik, Mardjaneh Karbalaei Sadegh, Michael Morley, Carolina Roselli, Patrick T. Ellinor, Thomas Cappola, J. Gustav Smith, Olof Gidlof
Abstract
Atrial fibrillation (AF) is the most common heart rhythm disorder and a major cause of stroke. Unfortunately, current therapies for AF are suboptimal, largely because the molecular mechanisms underlying AF are poorly understood. Since the autonomic nervous system is thought to increase vulnerability to AF, we investigated in a rapid atrial pacing (RAP) canine model the anatomic and electrophysiological characteristics of autonomic remodeling in different regions of the left atrium. RAP led to marked hypertrophy of parent nerve bundles in the posterior left atrium (PLA), resulting in a global increase in parasympathetic and sympathetic innervation throughout the left atrium. Parasympathetic fibers were more heterogeneously distributed in the PLA when compared to other left atrial regions; this led to greater fractionation and disorganization of AF electrograms in the PLA. Computational modeling revealed that heterogeneously distributed parasympathetic activity exacerbates sympathetic substrate for wave break and reentry. We further discovered that levels of Nerve Growth Factor (NGF) were greatest in the left atrial appendage (LAA), where AF was most organized. Preferential NGF release by the LAA - likely a direct function of frequency and regularity of atrial stimulation - may have important implications for creation of a vulnerable AF substrate.
Authors
Georg Gussak, Anna Pfenniger, Lisa M. Wren, Mehul Gilani, Wenwei Zhang, Shin Yoo, David A. Johnson, Amy Burrell, Brandon Benefield, Gabriel M. Knight, Bradley P. Knight, Rod Passman, Jeffrey J. Goldberger, Gary Aistrup, J. Andrew Wasserstrom, Yohannes Shiferaw, Rishi Arora
Abstract
The mechanisms contributing to heart failure remain incompletely understood. d-dopachrome tautomerase (DDT) is a member of the macrophage migration inhibitory factor family of cytokines and is highly expressed in cardiomyocytes. This study examined the role of cardiomyocyte DDT in the setting of heart failure. Patients with advanced heart failure undergoing transplantation demonstrated decreased cardiac DDT expression. To understand the effect of loss of cardiac DDT in experimental heart failure, cardiomyocyte-specific DDT-KO (DDT-cKO) and littermate control mice underwent surgical transverse aortic constriction (TAC) to induce cardiac pressure overload. DDT-cKO mice developed more rapid cardiac contractile dysfunction, greater cardiac dilatation, and pulmonary edema after TAC. Cardiomyocytes from DDT-cKO mice after TAC had impaired contractility, calcium transients, and reduced expression of the sarcoplasmic reticulum calcium ATPase. The DDT-cKO hearts also exhibited diminished angiogenesis with reduced capillary density and lower VEGF-A expression after TAC. In pharmacological studies, recombinant DDT (rDDT) activated endothelial cell ERK1/2 and Akt signaling and had proangiogenic effects in vitro. The DDT-cKO hearts also demonstrated more interstitial fibrosis with enhanced collagen and connective tissue growth factor expression after TAC. In cardiac fibroblasts, rDDT had an antifibrotic action by inhibiting TGF-β–induced Smad-2 activation. Thus, endogenous cardiomyocyte DDT has pleiotropic actions that are protective against heart failure.
Authors
Yina Ma, Kevin N. Su, Daniel Pfau, Veena S. Rao, Xiaohong Wu, Xiaoyue Hu, Lin Leng, Xin Du, Marta Piecychna, Kenneth Bedi, Stuart G. Campbell, Anne Eichmann, Jeffrey M. Testani, Kenneth B. Margulies, Richard Bucala, Lawrence H. Young
Abstract
Left ventricular noncompaction (LVNC) is one of the most common forms of genetic cardiomyopathy characterized by excessive trabeculation and impaired myocardial compaction during fetal development. Patients with LVNC are at higher risk of developing left/right ventricular failure or both. Although the key regulators for cardiac chamber development are well studied, the role of semaphorin (Sema)/plexin signaling in this process remains poorly understood. In this article, we demonstrate that genetic deletion of Plxnd1, a class-3 Sema receptor in endothelial cells, leads to severe cardiac chamber defects. They were characterized by excessive trabeculation and noncompaction similar to patients with LVNC. Loss of Plxnd1 results in decreased expression of extracellular matrix proteolytic genes, leading to excessive deposition of cardiac jelly. We demonstrate that Plxnd1 deficiency is associated with an increase in Notch1 expression and its downstream target genes. In addition, inhibition of the Notch signaling pathway partially rescues the excessive trabeculation and noncompaction phenotype present in Plxnd1 mutants. Furthermore, we demonstrate that Semaphorin 3E (Sema3E), one of PlexinD1’s known ligands, is expressed in the developing heart and is required for myocardial compaction. Collectively, our study uncovers what we believe to be a previously undescribed role of the Sema3E/PlexinD1 signaling pathway in myocardial trabeculation and the compaction process.
Authors
Reddemma Sandireddy, Dasan Mary Cibi, Priyanka Gupta, Anamika Singh, Nicole Tee, Akiyoshi Uemura, Jonathan A. Epstein, Manvendra K. Singh
Abstract
Mesenchymal stem cells (MSCs) can suppress pathological inflammation. However, the mechanisms underlying the association between MSCs and inflammation remain unclear. Under coculture conditions with macrophages, MSCs highly expressed angiopoietin-like 4 (ANGPTL4) to blunt the polarization of macrophages toward the proinflammatory phenotype. ANGPTL4-deficient MSCs failed to inhibit the inflammatory macrophage phenotype. In inflammation-related animal models, the injection of coculture medium or ANGPTL4 protein increased the antiinflammatory macrophages in both peritonitis and myocardial infarction. In particular, cardiac function and pathology were markedly improved by ANGPTL4 treatment. We found that retinoic acid–related orphan receptor α (RORα) was increased by inflammatory mediators, such as IL-1β, and bound to ANGPTL4 promoter in MSCs. Collectively, RORα-mediated ANGPTL4 induction was shown to contribute to the antiinflammatory activity of MSCs against macrophages under pathological conditions. This study suggests that the capability of ANGPTL4 to induce tissue repair is a promising opportunity for safe stem cell–free regeneration therapy from a translational perspective.
Authors
Dong Im Cho, Hye-jin Kang, Ju Hee Jeon, Gwang Hyeon Eom, Hyang Hee Cho, Mi Ra Kim, Meeyoung Cho, Hye-yun Jeong, Hyen Chung Cho, Moon Hwa Hong, Yong Sook Kim, Youngkeun Ahn
Abstract
Calorie restriction (CR) improved healthspan in two longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce cardiac fibrosis relative to controls. However, there was a 5.9-fold increase of total fibrosis in UW hearts, compared to NIA. Diet composition was a prominent difference between the studies; therefore, we used the NHP diets to characterize diet-associated molecular and functional changes in the hearts of mice. Consistent with the findings from the NHP samples, mice fed UW or a modified NIA diet with increased sucrose and fat developed greater cardiac fibrosis compared to the NIA diet, and transcriptomics analysis revealed diet-induced activation of myocardial oxidative phosphorylation and cardiac muscle contraction pathways.
Authors
Niranjana Natarajan, Ana Vujic, Jishnu Das, Annie C. Wang, Krystal K. Phu, Spencer H. Kiehm, Elisabeth M. Ricci-Blair, Anthony Y. Zhu, Kelli L. Vaughan, Ricki J. Colman, Julie A. Mattison, Richard T. Lee
Abstract
It has been hypothesized that interleukin-1alpha (IL-1α) is released from damaged cardiomyocytes following myocardial infarction (MI) and activates cardiac fibroblasts via its receptor (IL-1R1) to drive the early stages of cardiac remodeling. This study aimed to definitively test this hypothesis using cell type-specific IL-1α and IL-1R1 knockout (KO) mouse models. A floxed Il1α mouse was created and used to generate a cardiomyocyte-specific IL-1α KO mouse line (MIL1AKO). A tamoxifen-inducible fibroblast-specific IL-1R1 hemizygous KO mouse line (FIL1R1KO) was also generated. Mice underwent experimental MI (permanent left anterior descending coronary artery ligation) and cardiac function was determined 4 weeks later by conductance pressure-volume catheter analysis. Molecular markers of remodeling were evaluated at various time points by real-time RT-PCR and histology. MIL1AKO mice showed no difference in cardiac function or molecular markers of remodeling post-MI compared with littermate controls. In contrast, FIL1R1KO mice showed improved cardiac function and reduced remodeling markers post-MI compared with littermate controls. In conclusion, these data highlight a key role for the IL-1R1/cardiac fibroblast signaling axis in regulating post-MI remodeling and provide support for the continued development of anti-IL-1 therapies for improving cardiac function after MI. Cardiomyocyte-derived IL-1α was not an important contributor to post-MI remodeling in this model.
Authors
Sumia A. Bageghni, Karen E. Hemmings, Nadira Y. Yuldasheva, Azhar Maqbool, Filomena O. Gamboa-Esteves, Neil E. Humphreys, Maj Simonsen Jackson, Christopher P. Denton, Sheila Francis, Karen E. Porter, Justin F. X. Ainscough, Emmanuel Pinteaux, Mark J. Drinkhill, Neil A. Turner
Abstract
BACKGROUND. Lewy body diseases, a family of aging-related neurodegenerative disorders, entail loss of the catecholamine dopamine in the nigrostriatal system and equally severe deficiency of the closely related catecholamine norepinephrine in the heart. The myocardial noradrenergic lesion is associated with major non-motor symptoms and decreased survival. Numerous mechanisms determine norepinephrine stores, and which of these are altered in Lewy body diseases has not been examined in an integrated way. We used a computational modeling approach to assess comprehensively pathways of cardiac norepinephrine synthesis, storage, release, reuptake, and metabolism in Lewy body diseases. Application of a novel kinetic model identified a pattern of dysfunctional steps contributing to norepinephrine deficiency. We then tested predictions from the model in a new cohort of Parkinson disease patients. METHODS. Rate constants were calculated for 17 reactions determining intra-neuronal norepinephrine stores. Model predictions were tested by measuring post-mortem apical ventricular concentrations and concentration ratios of catechols in controls and patients with Parkinson disease. RESULTS. The model identified low rate constants for three types of processes in the Lewy body group—catecholamine biosynthesis via tyrosine hydroxylase and L-aromatic-amino-acid decarboxylase, vesicular storage of dopamine and norepinephrine, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter. Post-mortem catechols and catechol ratios confirmed this triad of model-predicted functional abnormalities. CONCLUSION. Denervation-independent impairments of neurotransmitter biosynthesis, vesicular sequestration, and norepinephrine recycling contribute to the myocardial norepinephrine deficiency attending Lewy body diseases. A proportion of cardiac sympathetic nerves are “sick but not dead,” suggesting targeted disease-modification strategies might retard clinical progression. TRIAL REGISTRATION. This study was not a clinical trial. FUNDING. The research reported here was supported by the Division of Intramural Research, NINDS.
Authors
David S. Goldstein, Mark J. Pekker, Graeme Eisenhofer, Yehonatan Sharabi
Abstract
Cardiac pressure overload (for example due to aortic stenosis) induces irreversible myocardial dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis in patients. In contrast to adult, neonatal mice can efficiently regenerate the heart after injury in the first week after birth. To decipher whether insufficient cardiac regeneration contributes to the progression of pressure overload dependent disease, we established a transverse aortic constriction protocol in neonatal mice (nTAC). nTAC in the non-regenerative stage (at postnatal day P7) induced cardiac dysfunction, myocardial fibrosis and cardiomyocyte hypertrophy. In contrast, nTAC in the regenerative stage (at P1) largely prevented these maladaptive responses and was in particular associated with enhanced myocardial angiogenesis and increased cardiomyocyte proliferation, which both supported adaptation during nTAC. A comparative transcriptomic analysis between hearts after regenerative versus non-regenerative nTAC suggested the transcription factor GATA4 as master regulator of the regenerative gene-program. Indeed, cardiomyocyte specific deletion of GATA4 converted the regenerative nTAC into a non-regenerative, maladaptive response. Our new nTAC model can be used to identify mediators of adaptation during pressure overload and to discover novel potential therapeutic strategies.
Authors
Mona Malek Mohammadi, Aya Abouissa, Azizah Isyatul, Yinuo Xie, Julio Cordero, Amir Shirvani, Anna Gigina, Maren Engelhardt, Felix A. Trogisch, Robert Geffers, Gergana Dobreva, Johann Bauersachs, Joerg Heineke
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