Therapeutic Strategy For Heart Failure Research Articles

Generation, Characterization, and Potential Therapeutic Applications of Cardiomyocytes from Various Stem Cells

Heart failure is one of the leading causes of death worldwide. Myocardial cell transplantation emerges as a novel therapeutic strategy for heart failure, but this approach has been hampered by severe shortage of human cardiomyocytes. We have recently induced mouse embryonic stem cells to differentiate into embryoid bodies and eventually, cardiomyocytes. Here, we address recent advancements in cardiomyocyte differentiation from cardiac stem cells and pluripotent stem cells. We highlight the methodologies, using growth factors, endoderm-like cell cocultures, small molecules, and biomaterials, in directing the differentiation of pluripotent stem cells into cardiomyocytes. The characterization and identification of pluripotent stem cell-derived cardiomyocytes by morphological, phenotypic, and functional features are also discussed. Notably, increasing evidence demonstrates that cardiomyocytes may be generated from the stem cells of several tissues outside the cardiovascular system, including skeletal muscles, bone marrow, testes, placenta, amniotic fluid, and adipose tissues. We further address the potential applications of cardiomyocytes derived from various kinds of stem cells. The differentiation of stem cells into functional cardiomyocytes, especially from an extra-cardiac stem cell source, would circumvent the scarcity of heart donors and human cardiomyocytes, and, most importantly, it would offer an ideal and promising cardiomyocyte source for cell therapy and tissue engineering in treating heart failure.

MicroRNAs: um novo paradigma no tratamento e diagnóstico da insuficiência cardíaca?

MicroRNAs (miRNAs) são um grupo recém-descoberto de pequenos RNAs, não codificantes, que representam uma das áreas mais estimulantes da ciência médica moderna por modularem uma enorme e complexa rede regulatória da expressão dos genes.Recentemente, linhas de evidências sugerem que os miRNAs desempenham um papel crucial na patogênese da insuficiência cardíaca. Alguns miRNAs altamente expressos no coração como o miR-1, miR-133 e miR-208 estão fortemente associados ao desenvolvimento da hipertrofia cardíaca, enquanto o exato papel de miR-21 no sistema cardiovascular permanece controverso. Os níveis séricos de miRNAs circulantes como o miR-423-5p estão sendo avaliados como potenciais biomarcadores no diagnóstico e prognóstico da insuficiência cardíaca.Por outro lado, a manipulação dos níveis de miRNAs usando técnicas como os mimetizadores de miRNAs (miRmimics) e miRNAs antagônicos(antagomiRs) está tornando cada vez mais evidente o enorme potencial dos miRNAs como promissoras estratégias terapêutica sna insuficiência cardíaca.

Nitric Oxide Modulation as a Therapeutic Strategy in Heart Failure

Nitric oxide (NO) is recognized as one of the most important cardiovascular signaling molecules, with multiple regulatory effects on myocardial and vascular tissue as well as on other tissues and organ systems. With the growth in understanding of the range and mechanisms of NO effects on the cardiovascular system, it is now possible to consider pharmaceutical interventions that directly target NO or key steps in NO effector pathways. This article reviews aspects of the cardiovascular effects of NO, abnormalities in NO regulation in heart failure, and clinical trials of drugs that target specific aspects of NO signaling pathways.

Ischemia/Infarction

Myocardial infarction (MI) accounts for most incidences of heart failure (HF) and low ejection fraction. Evidence suggests that acute MI leads to early cardiac remodeling, with changes in ventricular geometry and structure that in turn lead to a vicious cycle of ventricular dilation, increased wall stress, hypertrophy and more ventricular dilation and dysfunction, and worsening of HF. The early geometric and structural changes contribute to early mechanical complications and subsequent progressive ventricular remodeling and the development of chronic HF. A clear understanding of the underlying mechanisms is helpful in developing optimal preventive and therapeutic strategies for HF.

Clinical Cardiac Magnetic Resonance Spectroscopy

Cardiac magnetic resonance spectroscopy (MRS) is a noninvasive tool for the assessment of myocardial metabolism, without the use of radiation or intravenous contrast agents. Using the intrinsic magnetic resonance signals from nuclei, including 31Phosphorus, 1Hydrogen, 23Sodium, and 13Carbon and, more recently, hyperpolarization techniques, MRS provides a comprehensive metabolic assessment of cardiac muscle. This highly versatile technique has provided insights into the pathophysiology of cardiac metabolism in a wide range of conditions, including ischemic heart disease, heart failure, genetic cardiomyopathies, heart transplantation, hypertensive heart disease, valvular heart disease, and diabetes. In addition, MRS has value in the assessment of prognosis and for monitoring therapeutic strategies in heart failure. However, because of the low temporal and spatial resolution of the technique, MRS has so far been limited to research applications. With higher field strength magnets and novel hyperpolarization techniques, the promise of using MRS for clinical applications may eventually be fulfilled.

Vascularized Atrial Tissue Patch Cardiomyoplasty With Omentopexy Improves Cardiac Performance After Myocardial Infarction

The tissue-engineered cardiac patch can alleviate ventricular remodeling and improve functional recovery in experimental myocardial infarction. However, the size of the engineered patch is limited due to insufficient vascularization. This study evaluated the effects of autologous atrial tissue patch cardiomyoplasty and omentopexy in rats with myocardial infarction. Myocardial infarction was induced by left coronary artery ligation in Sprague-Dawley rats. Three weeks later, either a patch of left atrium (A group) or omentum (O group) or both (OA group) were placed over the infarct zone. The atrial tissue patch was harvested from the autologous left atrial appendage along its long axis. The rats in the Control group received rethoracotomy only. After 4 weeks, the survival of the transplanted atrial tissue patch, ventricular remodeling, and cardiac performance were examined. After 4 weeks, surviving myocardium was only detected in the OA group, as indicated by immunolabeling of cardiac troponin-I. Compared with the Control group, only animals in the OA group showed improved heart function assessed by left ventricular ejection fraction (57.9% ± 5.8% vs 47.5% ± 4.5%, p < 0.05) and left ventricular fractional shortening (25.2% ± 3.6% vs 20.7% ± 2.0%, p < 0.05). The histologic analysis demonstrated increased scar thickness in the OA group. This was accompanied by increased angiogenesis of the border zone but decreased expression and activity of matrix metalloproteinase and endothelin-1 levels. The omentopexy supported the survival of the autologous atrial tissue patch, which resulted in attenuated ventricular remodeling and restoration of heart function in rats with myocardial infarction. Our findings might represent a novel therapeutic strategy for heart failure.

SUMO1-dependent modulation of SERCA2a in heart failure

SR Ca2+ ATPase 2a (SERCA2a) is a critical ATPase responsible for Ca2+ re-uptake during excitation-contraction coupling. Impaired SR Ca2+ uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure (HF)1. Accordingly, restoration of SERCA2a expression by gene transfer has proven to be effective in improving cardiac function in HF patients2 as well as in animal models3. The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins4, which is involved in most cellular process5. Here, we show that SERCA2a is SUMOylated at lysine 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability. The levels of SUMO1 and SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated virus-mediated gene delivery maintained protein abundance of SERCA2a and significantly improved cardiac function in HF mice. This effect was comparable to SERCA2a gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca2+ decay. Transgene-mediated SUMO1 overexpression rescued pressure overload-induced cardiac dysfunction concomitantly with increased SERCA2a function. By contrast, down-regulation of SUMO1 using shRNA accelerated pressure overload-induced deterioration of cardiac function and was accompanied by decreased SERCA2a function. However, knockdown of SERCA2a resulted in severe contractile dysfunction both in vitro and in vivo, which was not rescued by overexpression of SUMO1. Taken together, our data show that SUMOylation is a critical post-translational modification that regulates SERCA2a function and provides a platform for the design of novel therapeutic strategies for HF.

Functional genomics applied to cardiovascular medicine.

Since completion of the draft sequence of the human genome in 2000, the landscape of biomedical research has undergone a rapid transformation. Growing knowledge of genome structure and variation has spawned the development of technologies that allow researchers to study thousands of genes, transcripts, and proteins simultaneously. This has expanded biomedical science beyond reductionist approaches that test the function of individual genes to less biased approaches that study the behavior of many or all genes in homeostasis and disease. Such studies have been grouped under the broad label of functional genomics, which can be defined as the branch of biology that seeks to uncover the properties and function of the entirety of the genes and gene products of an organism.1 Functional genomics is fueling an explosion of new insights in biology and medicine, and many of these insights were completely unanticipated. Because these advances have begun to influence clinical practice,2,3 physicians will be expected to understand the potential uses and limitations of functional genomics in clinical settings. The purpose of this review is to provide a conceptual overview of functional genomics applied to the practice of cardiovascular medicine. We begin with a review of commonly used terms and approaches and then describe examples of their use for screening, diagnosis, and treatment selection in clinical cardiology. We also highlight emerging trends and speculate about where the field is headed in the near term. Although some predictions will be overly optimistic and some major advances unanticipated, we hope this review will help prepare cardiologists for their role in the application of genome science to the diagnosis and treatment of disease. This review is part of a series that introduces several related areas of cardiovascular genetics and genomics.4 We refer to these other contributions to guide further reading …

Synergistic Effect of Combined HMG-CoA Reductase Inhibitor and Angiotensin-II Receptor Blocker Therapy in Patients With Chronic Heart Failure

It is known that HMG-CoA reductase inhibitors (statins) may have a therapeutic benefit in patients with heart failure (HF). However, no studies have yet evaluated the possible interaction of statins and angiotensin-II receptor blockers (ARBs) on left ventricular (LV) function in patients with HF. We hypothesized that statins might alter the effect of ARBs on cardiac function in patients with HF. We prospectively randomized patients with chronic HF who received the ARB, losartan (LOS group), or the statin, simvastatin (SIM), in combination with LOS (SIM+LOS group) at our hospitals and assessed before and after treatment for 6 months. Although no significant improvement of HF symptoms as evaluated by the New York Heart Association (NYHA) classification was observed in the LOS group, HF symptoms in the SIM+LOS group significantly improved. The percent increase of LV ejection fraction after treatment in the SIM+LOS group was significantly larger than in the LOS group. Furthermore, the plasma brain natriuretic peptide level was significantly lower after treatment in the SIM+LOS group than in the LOS group. Combined statin and ARB therapy significantly improves both symptoms and LV function over time in patients with HF. Thus, the combination of an ARB with a statin may be a useful therapeutic strategy for HF.

CD-NP: An Innovative Designer Natriuretic Peptide Activator of Particulate Guanylyl Cyclase Receptors for Cardiorenal Disease

The natriuretic peptide (NP) family consists of structurally similar, although physiologically distinct, peptides that play an important role in cardiorenal homeostasis. CD-NP is a novel chimeric natriuretic peptide developed by the Mayo Clinic, in which the 15-amino acid COOH-terminus of dendroaspis NP is fused to C-type NP. CD-NP is a dual activator of NP receptors A and B, and therefore, possesses the strong antiproliferative and antifibrotic properties of C-type NP with the potent natriuretic, diuretic, and aldosterone-inhibiting properties of dendroaspis NP. CD-NP has favorable cardiorenal properties when compared to recombinant B-type NP (nesiritide), including preservation of glomerular filtration rate with minimal blood pressure-lowering effects. Thus, CD-NP has emerged as an appealing novel therapeutic strategy for heart failure. The endogenous NP system, the development rationale for CD-NP, as well as in vitro, animal, and human studies and future directions will be reviewed.

007 The tumour suppressor Ras-association domain family 1 isoform A (RASSF1A): a novel modulator of hypertrophic signalling pathway in the heart

Myocardial hypertrophy is an important pathological process that can lead to heart failure, therefore understanding the molecular mechanisms of cardiac hypertrophy is key in elucidating the pathogenesis of this disease. One important signalling pathway which has been associated with cardiac hypertrophy is the Ras pathway. It is known that mutations in genes of the Ras signalling pathway are associated with syndromes (eg, Noonan and Costelloe) that are characterised by tumour formation and cardiac hypertrophy. This lead us to hypothesise that negative regulators of the Ras pathway may also limit cardiac growth in common conditions such as pressure overload. One such negative regulator of tumour growth is the recently described tumour suppressor protein RASSF1A (Ras-association domain family 1 isoform A). Although we and others have detected RASSF1A expression in the heart, little is known about its functions. Here we investigate the role of this molecule in regulating myocardial hypertrophy. We used mice with genetic ablation of the Rassf1a gene and isolated neonatal rat cardiomyocytes with adenoviral mediated overexpression of RASSF1A to investigate the role of RASSF1A in the heart. Induction of pressure overload hypertrophy by transverse aortic constriction (TAC) resulted in enhanced myocardial hypertrophy in knock out (KO) mice compared to wild type (WT) controls (64.7% increase in heart weight/body weight ratio in RASSF1A KO mice compared to 30.6% in WT, n=10, p In conclusion, our data establish RASSF1A as a potent inhibitor of cardiac hypertrophy by modulating the Ras-Raf1-ERK1/2 pathway. This may provide opportunities for the development of novel therapeutic strategies for heart failure in the future.

Control of autocrine and paracrine myocardial signals: an emerging therapeutic strategy in heart failure

A growing body of evidence supports the hypothesis that autocrine and paracrine mechanisms, mediated by factors released by the resident cardiac cells, could play an essential role in the reparative process of the failing heart. Such signals may influence the function of cardiac stem cells via several mechanisms, among which the most extensively studied are cardiomyocyte survival and angiogenesis. Moreover, besides promoting cytoprotection and angiogenesis, paracrine factors released by resident cardiac cells may alter cardiac metabolism and extracellular matrix turnover, resulting in more favorable post-injury remodeling. It is reasonable to believe that critical intracellular signals are activated and modulated in a temporal and spatial manner exerting different effects, overall depending on the microenvironment changes present in the failing myocardium. The recent demonstration that chemically, mechanically or genetically activated cardiac cells may release peptides to protect tissue against ischemic injury provides a potential route to achieve the delivery of specific proteins produced by these cells for innovative pharmacological regenerative therapy of the heart. It is important to keep in mind that therapies currently used to treat heart failure (HF) and leading to improvement of cardiac function fail to induce tissue repair/regeneration. As a matter of facts, if specific autocrine/paracrine cell-derived factors that improve cardiac function will be identified, pharmacological-based therapy might be more easily translated into clinical benefits than cell-based therapy. This review will focus on the recent development of potential pharmacologic targets to promote and drive at molecular level the cardiac repair/regeneration in HF.

NO Way to Relax

The roles of nitric oxide (NO) in the heart have been studied intensely ever since the first report nearly 2 decades ago showing that endogenous NO modulates cardiac myocyte function.1 All 3 NO synthase (NOS) isoforms have been found in mammalian heart tissues (see reviews in Massion et al2 and Belge et al3). A complex array of myocyte and nonmyocyte cells in the heart express NOS isoforms, and the local generation of NO2,3 and reactive oxygen species (ROS)4 may exert both autocrine and paracrine effects on cellular function. Not only is the endothelial isoform of NOS (eNOS, or NOS3) robustly expressed in the endothelial cells of the cardiac vasculature, but eNOS is also present within cardiac myocytes, where the enzyme associates with the scaffolding/regulatory protein caveolin-3 in T tubules in plasmalemmal caveolae.5 The neuronal NOS (nNOS, or NOS1) is also expressed in cardiac myocytes, where the enzyme appears to be localized in the sarcoplasmic reticulum and modulates phospholamban phosphorylation.6 Although both eNOS and nNOS appear to be physiologically expressed in cardiac tissues, the inflammation-related NOS isoform (iNOS, or NOS2) only appears in the heart after immunoactivation; iNOS may modulate the decline in myocardial function seen in sepsis.7 There have been innumerable studies of the cardiac effects of various NOS inhibitors, NO-donating drugs, and NO itself.2 The cardiac phenotypes of NOS “knockout” mouse models have been characterized extensively, and mice lacking 1, 2, or all 3 NOS isoforms have been generated and characterized.8 In addition, the roles of NOS substrates, cofactors, and allosteric modulators have been explored exhaustively in diverse cardiac model systems. Emerging from this broad range of experimental evidence is an increasingly clear view that NO and NOS are key determinants of cardiac function. Yet the molecular mechanisms and …

IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure

Objective This study was designed to investigate whether IL-17 can regulate the expression of the MMP/TIMP system, the OPG/RANK/RANKL system, or type-I and type-III collagen fibers in a rat model of isoproterenol-induced heart failure (HF). We also investigated the effect of IL-17 on myocardial fibrosis in this model. Methods HF was induced in Wistar–Kyoto rats by hypodermic injection of isoproterenol (ISO) twice every 24 h. After 2 months, the surviving rats were divided into three groups: monoclonal Anti-IL-17 Ab (100 μg/day), IgG (100 μg/day) or PBS were injected five times every 48 h (i.p.). One day after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluate myocardial fibrosis, and immunohistochemistry was used to measure the levels of MMP-1, TIMP-1, TIMP-4, OPG, RANKL, type-I and type-III collagen fibers. We also treated adult rat cardiac fibroblasts with IL-17 (10 ng/ml), IL-17 (10 ng/ml) + OPG (10 ng/ml), IL-17 (10 ng/ml) + anti-RANKL Ab (100 ng/ml), or PBS for 24 h, realtime RT-PCR was used to measure the expressions of MMP-1. Results The expressions of MMP-1, RANKL, and type-I and -III collagen fibers decreased, and the expressions of TIMP-1, TIMP-4, and OPG increased in the Anti-IL-17 group compared to controls. H&E and Masson staining revealed that blockade of IL-17 can improve myocardial fibrosis in HF. IL-17 increased the expression of MMP-1 in cardiac fibroblasts, and OPG and anti-IL-17 Ab could inhibit this function partly. Thus, IL-17 was dependent on the RANKL/OPG system to induce MMP-1 partly. Conclusion Our study demonstrates the contribution of IL-17 to myocardial fibrosis in isoproterenol-induced HF. IL-17 can regulate the RANKL/OPG and MMP/TIMP systems in this model. The RANKL/OPG system is one of intermediaries between IL-17 and MMP-1 in cardiac fibroblasts. As a harmful cytokine, anti-IL-17 treatment is a potential therapeutic strategy in HF.

Soluble Guanylate Cyclase

Arthur Kornberg, who shared with Severo Ochoa the 1959 Nobel Prize for Physiology or Medicine, stated in his autobiography that he had never met a dull enzyme.1 We strongly believe that soluble guanylate cyclase (sGC; E.C.4.6.1.2) is no exception to this. Article see p 2781 Nitric oxide (NO) plays an important physiological role as a signaling molecule as well as a cytotoxic agent. It is produced by 3 distinct NO synthases, specifically endothelial, neuronal, and inducible NO synthase. In the vasculature, endothelial NO synthase plays an important role in vascular homeostasis because NO generated in endothelial cells promotes vascular smooth muscle cell relaxation and inhibits platelet aggregation. Importantly, bioavailability of NO can be reduced in cardiovascular diseases, a condition which has been termed “endothelial dysfunction.” This phenomenon provides a rationale for therapeutic intervention. The primary target of NO is sGC, which is a heterodimeric enzyme consisting of an α- and β-subunit and a prosthetic heme group, which is located in the β-subunit. The heme group contains a ferrous iron atom (Fe2+). Binding of NO to this iron changes the conformation of the enzyme and leads to a >100-fold increase in catalytic rate (ie, the conversion of guanosine triphosphate to the second messenger cyclic guanosine monophosphate [cGMP]). The NO-induced cGMP signal modulates intracellularly the activity of several effector molecules: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cGMP-gated ion channels. Of note, both heme iron oxidation (Fe3+) and heme removal render sGC unresponsive to NO (Figure). These 2 conditions could therefore provide a mechanism for “vascular smooth muscle cell dysfunction” in cardiovascular disease states, which are often characterized by marked vasoconstriction either systemically or in specific organs. Figure. Schematic illustrating 3 different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, sGC stimulators (eg, BAY 41–2272), and sGC …

Improved left ventricular function after transplantation of microspheres and fibroblasts in a rat model of myocardial infarction

As a novel and promising therapeutic strategy for heart failure, the application of different cell types is the subject of increasing research interest. In this study we investigated the effect of several cell types and microspheres (uniform polystyrene microspheres, 10 microm diameter) transplanted 4 weeks after induction of myocardial infarction in a rat model. Eight weeks after intramyocardial application of fibroblasts and microspheres, left ventricular function was significantly improved as demonstrated by isolated heart studies (Langendorff) and echocardiographic findings (LVDP fibroblasts 129 +/- 32.9 mmHg, LVDP microspheres 119.2 +/- 24.1 mmHg, fractional shortening (FS) microspheres 38.9 +/- 4.6%, FS fibroblasts 36.84 +/- 6.05%) in contrast to injection of macrophages or medium alone (LVDP medium 67 +/- 22.6 mmHg, LVDP macrophages 75.9 +/- 24.8 mmHg, FS macrophages 29.16 +/- 8.7%, FS medium 27.2 +/- 7.2%, P < 0.05). Signals of Bromodesoxy-Uridine (BrdU) labeled transplanted fibroblasts were detected in infarcted areas. Microspheres were recorded abundantly by autofluorescence. Significantly more apoptotic cells were observed in infarcted areas of macrophage (328.6 +/- 37.4 cells/mm(2)) and medium (338.7 +/- 16.5 cells/mm(2); P < 0.05) treated hearts compared to microsphere (233.2 +/- 16.8 cells/mm(2)) and fibroblast (232.2 +/- 19.1 cells/mm(2)) injected hearts. Neovascularization, as reflected by the density of CD 31 positive vessels in the infracted area, did not differ between the four groups studied. The increased number of macrophages in infarcted areas after fibroblast and microsphere injection (fibroblasts 94.7 +/- 7.1 cells/mm(2), microspheres 82.2 +/- 3.0 cells/mm(2), macrophages 56.02 +/- 9.93 cells/mm(2), medium 46.35 +/- 9.03 cells/mm(2), P < 0.05) suggests that the underlying mechanism of augmented left ventricular function might be based on inflammatory processes.

Role of PP1 in the regulation of Ca cycling in cardiac physiology and pathophysiology

Type 1 protein phosphatase (PP1) is a critical regulator of several cellular processes. In the heart, it mediates restoration of contractility to basal levels by dephosphorylating key phospho-proteins, after beta-adrenergic stimulation. PP1 is a holoenzyme consisting of its catalytic and regulatory subunits, which anchor the catalytic subunit to desired subcellular locations, define substrate specificity and modulate catalytic activity. At the level of the cardiac sarcoplasmic reticulum (SR), PP1 is regulated by Inhibitor-1 (I-1) and Inhibitor-2 (I-2), which modulate its activity, and the striated muscle-specific glycogen-targeting subunit, GM/RGL, which targets it to the SR vicinity. PP1 regulation is highly important in maintaining cardiac function under physiological conditions. In fact, aberrant Ca handling and depressed contractility in heart failure have been, at least partly, attributed to increases in PP1 activity, mediated by impaired regulation via its inhibitors. Importantly, increases in the level and activity of I-1 and I-2 in animal models have been successful in ameliorating dysfunction and remodeling in heart failure, suggesting that PP1 inhibition may be a plausible therapeutic strategy in heart failure.

Therapeutic Strategies in Heart Failure

Clyde W. Yancy and James B. Young, eds 256 pages. Oxford, UK: Clinical Publishing; 2008. $77.00. ISBN 1–904392–40–7 The sobering statistics on heart failure in the United States are often repeated: the incidence approaches 10 per 1000 population after 65 years of age; the lifetime risk for both men and women over age 40 is 1 in 5; 1.1 million hospital discharges occur per year, with estimated costs of $35 billion.1 To address this major health problem and optimize patient care, the American College of Cardiology and American Heart Association have published extensive evidenced-based guidelines that are readily available to cardiologists and primary care providers.2 In addition, these guidelines have been abbreviated in executive statements, major textbooks, and online support tools for rapid clinical application.3 So is there really a need for another textbook on heart failure? The answer, according to the editors of Therapeutic Strategies in Heart Failure , is definitely yes but with an acknowledgement of what their book is and what it is not. As noted in the preface, Therapeutic Strategies is not meant to be an in-depth review of heart failure pathophysiology or a recapitulation of published guidelines; rather, the aim of the textbook is to provide “topical, contemporary and relevant reviews” of selected treatments. Toward this end, Therapeutic Strategies succeeds in providing clinicians with renewed and practical perspectives on current and emerging therapies …

The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats

Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes. A key signaling event in this process is nuclear acetylation by histone deacetylases and p300, an intrinsic histone acetyltransferase (HAT). It has been previously shown that curcumin, a polyphenol responsible for the yellow color of the spice turmeric, possesses HAT inhibitory activity with specificity for the p300/CREB-binding protein. We found that curcumin inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex and repressed agonist- and p300-induced hypertrophic responses in these cells. Both the acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly increased in rat hypertensive hearts in vivo. The effects of curcumin were examined in vivo in 2 different heart failure models: hypertensive heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats. In both models, curcumin prevented deterioration of systolic function and heart failure-induced increases in both myocardial wall thickness and diameter. From these results, we conclude that inhibition of p300 HAT activity by the nontoxic dietary compound curcumin may provide a novel therapeutic strategy for heart failure in humans.

Abstract 2494: Beneficial Actions of Co-Targeting Particulate and Soluble Guanylate Cyclase Dependent cGMP Pools in Experimental Heart Failure

Background: B-type natriuretic peptide (BNP) signals via particulate guanylyl cyclase (pGC) and cyclic guanosine monophosphate (cGMP). In heart failure (HF), BNP reduces cardiac filling pressures and in selected patients augments sodium excretion and glomerular filtration rate (GFR). Studies have established that pGC and soluble guanylyl cyclase (sGC), the main target of nitric oxide (NO), can be compartmentalized with both enzymes affecting distinct intracellular cGMP pools, resulting in different biological actions. Importantly, sGC may be oxidized in disease states like HF making it unresponsive to NO and nitrovasodilators. BAY 58 –2667 (BAY) is a novel NO and heme independent sGC activator that preferentially stimulates oxidized sGC. We hypothesized that adding direct sGC stimulation with BAY to pGC activation with BNP in HF would enhance vasodilation and cardiac unloading without attenuating the distinct renal actions of BNP. Methods: Severe HF was induced by tachypacing in 13 dogs. On day 11, cardiorenal function was assessed in an acute study under anesthesia at baseline and with intravenous BNP (50 ng/kg/min) alone or in combination with BAY (0.3 ug/kg/min). Results: BNP significantly increased urine flow (UV), urinary sodium excretion (UNaV), GFR, renal blood flow (RBF) and systemic vascular resistance (SVR) and decreased cardiac output (CO), mean arterial pressure (MAP), right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP). Despite a greater decrease in MAP compared to BNP, BAY+BNP resulted in similar increases in UNaV, UV and GFR. Dual pGC and sGC stimulation resulted in greater decreases in SVR, RAP and PCWP together with an augmentation of CO compared to BNP alone. Conclusion: Particulate GC activation with BNP in experimental HF enhances renal function and leads to renal but not systemic vasodilation. Addition of the sGC stimulator BAY provides systemic vasodilation, greater cardiac unloading, and augmented CO. Despite a larger decrease in MAP, additional sGC stimulation does not impair the renal actions observed with pGC stimulation alone. These findings support coactivation of sGC with BAY and pGC with BNP as a novel and beneficial therapeutic strategy in HF to optimize activation of distinct GC enzymes and cGMP.