Experimental Models Of Heart Failure Research Articles

Cognitive performance of 20 healthy humans supplemented with L-homoarginine for 4 weeks

l-homoarginine (l-hArg) is an endogenous non-proteinogenic amino acid. Low l-hArg concentrations are associated with increased all-cause mortality, fatal strokes, and worse outcome after stroke. On the other hand, oral supplementation with l-hArg in mice improved neurological deficits and preserved cardiac function in experimental models of stroke and heart failure, respectively. Recently, oral supplementation with 125 mg daily l-hArg capsules in healthy volunteers demonstrated increased l-hArg plasma levels. Therefore, oral l-hArg supplementation could represent a potential treatment for patients with cerebrovascular disease. In addition to vascular physiology, animal studies have suggested that l-hArg might play a role in synapse function, neurotransmitter metabolism and cognitive training. However the direct influence of l-hArg on cognitive function has not been studied so far. In this study, cognitive performance in healthy humans was analyzed concerning memory, learning, and attention following supplementation with placebo or l-hArg for 4 weeks. Our results did not reveal any effects on cognition, neither impairment nor improvement, upon l-hArg supplementation. Therefore, potential l-hArg treatment is not expected to cause any acute neurocognitive or behavioral side effects.

Targeting microthrombosis and neuroinflammation with vepoloxamer for therapeutic neuroprotection after traumatic brain injury.

Targeting microthrombosis and neuroinflammation with vepoloxamer for therapeutic neuroprotection after traumatic brain injury.

Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart.

AimsThe Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease.Methods and resultsMice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb postnatally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers.ConclusionThis study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillation.

The role of heat shock proteins and co-chaperones in heart failure.

The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure. One of the critical class of proteins involved in protecting the heart against these threats are molecular chaperones, including the heat shock protein70 (HSP70), HSP90 and co-chaperones CHIP (carboxy terminus of Hsp70-interacting protein, encoded by the Stub1 gene) and BAG-3 (BCL2-associated athanogene 3). Here, we review their emerging roles in the maintenance of cardiomyocytes in human and experimental models of heart failure, including their roles in facilitating the removal of misfolded and degraded proteins, inhibiting apoptosis and maintaining the structural integrity of the sarcomere and regulation of nuclear receptors. Furthermore, we discuss emerging evidence of increased expression of extracellular HSP70, HSP90 and BAG-3 in heart failure, with complementary independent roles from intracellular functions with important therapeutic and diagnostic considerations. While our understanding of these major HSPs in heart failure is incomplete, there is a clear potential role for therapeutic modulation of HSPs in heart failure with important contextual considerations to counteract the imbalance of protein damage and endogenous protein quality control systems.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

Nrf2 at the heart of oxidative stress and cardiac protection.

The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.

Dual interplay between desmin phosphorylation and dysregulated autophagy in heart failure

Post-translational modifications (PTMs) of sarcomeric proteins could participate to left ventricular (LV) remodeling and contractile dysfunction leading in advanced heart failure (HF) with altered ejection fraction.Using an experimental rat model of HF (ligation of left coronary artery) and phosphoproteomic analysis, we highlighted an increase of phosphorylated desmin on serine residues in LV of 2 month-HF rats, dependent of PKCζ and GSK3β. We verified the desmin phosphorylation profile by Phos-Tag™ gel and observed that desmin is mainly expressed in insoluble fraction of LV of HF rats. Electron microscopy shows alteration of sarcomere in LV of HF rats due to desmin filaments desorganisation and immunofluorescence accumulation of desmin aggregates that could be toxic in cardiomyocytes. We then analyzed whether the autophagic pathways (macro-autophagy and chaperone-mediated autophagy (CMA)) may be involved in phosphorylated desmin clearance in our experimental model of HF. We found a decrease of macroautophagy processes (LC3II/LC3I, p62, beclin-1) throughout LV remodeling that may participate to hyperphosphorylated desmin accumulation. We identified that CMA is activated throughout the LV remodelling post-MI with increased CMA markers (Lamp-2a, hsc70, hsp90) in LV of HF rats suggesting that CMA may be involved in the clearance of aggregates of phosphorylated desmin. Bioinformatical analysis identified desmin as a new CMA substrate with 4 KFERQ motifs conserved in the aminoacid sequence of rat, mouse, bovine, pig, danio Rerio and human species. We then developed an in vitro model of CMA induction in neonate cardiomyocytes with geldanamycin. We observed increased levels of hsc70 and hsp90 and colocalization of desmin and Lamp2a that suggests desmin lysosomal sequestration by PLA technique. CMA activation did not induce changes in insoluble desmin but decreased levels of soluble desmin and phosphorylated soluble desmin. Conversely, preliminary data on inhibition of CMA with Lamp2a siRNA only induced increase of soluble desmin and phosphorylated soluble desmin. Our data suggest for the first time that CMA is able to clear monomeric phosphorylated soluble desmin but is not sufficient for intracellular clearance of phosphorylated desmin aggregates in the experimental model of ischemic HF. We could speculate that induction of early CMA activation in post-infarction might be a therapeutic approach to fight against desmin aggregates in order to maintain cardiomyocyte survival.

DWORF overexpression prevents heart failure in an experimental mouse model of dilated cardiomyopathy

Background: Defective intracellular Ca2+ homeostasis is a hallmark feature of heart failure. Increasing the expression level or activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) pump can normalize Ca2+-handling and rescue several genetic and experimental models of heart failure. Results: Our lab has recently identified and characterized a novel transmembrane protein named DWORF (DWarf Open Reading Frame) that binds to SERCA and enhances its activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Transgenic mice with cardiac-specific DWORF over-expression (αMHC-DWORF) have a cellular phenotype that mimics that of PLN KO mice, exhibiting an increase in peak Ca2+-transient amplitude, faster cytosolic Ca2+ decay rates, higher SR Ca2+ load and enhanced cardiomyocyte contractility. Using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to deletion of the muscle-specific LIM protein (MLP KO), other laboratories have previously shown that genetic ablation of PLN leads to a restoration of SERCA activity and prevention of DCM in the hearts of MLP KO mice. Invoking a similar scientific rationale here, we generated αMHC-DWORF Tg/MLP KO mice and observed that DWORF overexpression in the heart of MLP KO mice resulted in a complete rescue of in vivo cardiac function and prevented the pathological remodeling, development of fibrosis and ultrastructural defects that are all characteristic features of MLP KO hearts. At the cellular level, cardiomyocytes isolated from αMHC-DWORF Tg/MLP KO displayed enhanced Ca2+-cycling and contractile properties that contrasted sharply with MLP KO cardiomyocytes, which exhibited depressed contractility. Conclusion: Cardiac-specific over-expression of DWORF prevents the development of the DCM phenotype characteristic of MLP KO mice and provides an attractive candidate for a novel heart failure therapeutic.

Abstract P317: Sex Differences in the Hemodynamic and Sympathetic Responses to Centrally Administered Tumor Necrosis Factor-α in Rats

Introduction: Accumulating evidence indicates that sex differences exist in the clinical and experimental outcomes of various cardiovascular diseases. In addition to its protective effect on renin-angiotensin system activity, estrogen has an anti-inflammatory influence. The central actions of pro-inflammatory cytokines (PICs) contribute significantly to cardiovascular and autonomic dysfunction in hypertension and heart failure. In male adult rat, central administration of PICs induces substantial increases in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA), and blocking PICs reduces sympathetic excitation in experimental models of hypertension and heart failure. Whether PICs have similar central sympatho-excitatory effects in the female rat remains unknown. Hypothesis: We hypothesized that female rats may be protected from the central cardiovascular and autonomic effects of PICs. Methods: Urethane anesthetized male and female Sprague Dawley rats (10-12 weeks) underwent an intracerebrovascular (ICV) injection of the prototypical PIC tumor necrosis factor-α (TNF-α, 100 ng). BP (mmHg), HR (beats/min) and RSNA (% change) responses were continuously recorded for 4-5 hours. Results: In male rats (n=6), ICV TNF-α induced a dramatic and long-lasting increase (*p<0.001 vs. baseline) in BP (23.1 ± 2.5*), HR (82 ± 8*) and RSNA (109.5 ± 4.3 %*), that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In the female rats (n=6), ICV TNF-α elicited significantly (p<0.05) smaller increases (*p<0.001 vs. baseline) in BP (14.8 ± 1.8*), HR (55 ± 6*) and RSNA (78.5 ± 6.3*), compared with the male rats. Conclusion: These data demonstrate a sex difference in the cardiovascular and sympathetic responses to centrally administered PICs. Whether the observed differences can be explained by an estrogen effect on TNF-α signaling per se or by an estrogen effect on TNF-α-induced renin-angiotensin activity remains to be determined. However, a reduced response of female rats to central inflammation may be an important contributor to sex differences in pathophysiology of hypertension and heart failure.

Alpha2-adrenoceptors in adrenomedullary chromaffin cells: functional role and pathophysiological implications.

Chromaffin cells from the adrenal medulla participate in stress responses by releasing catecholamines into the bloodstream. Main control of adrenal catecholamine secretion is exerted both neurally (by the splanchnic nerve fibers) and humorally (by corticosteroids, circulating noradrenaline, etc.). It should be noted, however, that secretory products themselves (catecholamines, ATP, opioids, ascorbic acid, chromogranins) could also influence the secretory response in an autocrine/paracrine manner. This form of control is activity-dependent and can be either inhibitory or excitatory. Among the inhibitory influences, it stands out the one mediated by α2-adrenergic autoreceptors activated by released catecholamines. α2-adrenoceptors are G protein-coupled receptors capable to inhibit exocytotic secretion through a direct interaction of Gβγ subunits with voltage-gated Ca2+ channels. Interestingly, upon intense and/or prolonged stimulation, α2-adrenergic receptors become desensitized by the intervention of G protein-coupled receptor kinase 2 (GRK2). In several experimental models of heart failure, there has been reported the up-regulation of GRK2 and the loss of functioning of inhibitory α2-adrenoceptors resulting in enhanced release of adrenomedullary catecholamines. Given the importance of circulating catecholamines in the pathophysiology of heart failure, the recovery of α2-adrenergic modulation of the secretory response from chromaffin cells appears as a novel strategy for a better control of the patients with this cardiac disease.

P1485Changes of regional myocardial deformation induced by serelaxin reflect gene regulation in experimental heart failure model

P1485Changes of regional myocardial deformation induced by serelaxin reflect gene regulation in experimental heart failure model

Na+-H+ exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies.

Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (δ-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na+ overload and early death due to HF. Our previous work also showed that another proton transporter, the voltage-gated proton channel (Hv1), exists in many cell types including heart cells and skeletal muscle fibers. The Hv1 could be indirectly implicated in the beneficial effect of blocking NHE-1.

Role of Hypoxia‐Inducible‐Factor‐2α in Transcriptional Regulation of Heme Oxygenase‐1 in Hypoxic Cardiomyocytes

INTRODUCTIONThe heme metabolism pathway is a novel therapeutic target in the management of heart failure, with cytoprotection mediated through induction of heme oxygenase‐1 (HMOX1). However, translation of HMOX1‐targeted therapeutics to the clinic has not occurred. Understanding of heme bioavailability regulation in cardiomyocytes, particularly during hypoxia or heart failure, is incomplete. The molecular response to hypoxia is largely regulated by hypoxia inducible transcription factors (HIFs). HIF1α transcriptionally regulates HMOX1 in acute, severe hypoxia but the role of HIF2α in heme metabolism is unknown. A detailed understanding of the differences in molecular regulation between acute or chronic and severe or moderate hypoxia in cardiomyocytes is required.HYPOTHESISHypoxia‐inducible factor 2α (HIF2α) contains heme‐regulatory motifs that are sensitized by heme bioavailability at various degrees of hypoxia in cardiomyocytes to regulate the acute expression of HMOX1 in vitro and in experimental models of heart failure in vivo.METHODSAcute myocardial infarction (AMI)‐induced heart failure was modeled through permanent surgical ligation of the left anterior descending coronary artery in mice. Hypertensive heart failure was modeled through transverse aortic constriction (TAC). Expression of heme regulatory enzymes and hypoxia inducible factors were measured via Western Blot, qPCR and heme content assay. In vitro, hypoxia was established by incubating H9C2 and neonatal rat cardiomyocytes in an adjustable‐oxygen chamber. HIF1α and HIF2α were knocked down or overexpressed through adenoviral vectors. To investigate the role of heme bioavailability in HIF2α sensitization, cells were incubated with the heme surrogate, hemin.RESULTSIn vivo, heme levels were increased in both AMI and TAC‐induced heart failure progressively, however not due to increased heme synthesis enzymes. In vitro, HMOX1 was increased by HIF2α more than by HIF1α overexpression. This response was synergistically increased in heme‐replete hypoxia with HIF2α, but not HIF1α, overexpression.CONCLUSIONSWe have shown for the first time that HIF2α is a novel regulator of HMOX1. Further understanding of heme homeostasis in the heart is necessary to optimize therapeutic targeting of the heme metabolic pathway in heart failure. Further, we show that HIF2α has a distinct role from HIF1α as it is sensitive to heme bioavailability and not an exclusive oxygen sensor.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada

A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure

Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (P<0.05). In myocardial infarction-induced chronic heart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR-36996 treatment (25 and 50mg/kg/day, p.o.) for 12 weeks. Moreover, KR-36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications.

Epigenetic Mechanisms: New Targets for Heart Failure Pharmacopuncture.

Pharmacopuncture treatments are proposed for cardiovascular disease and heart failure [1]. Heart failure results from complex environment-gene interactions. β-adrenergic receptors and protein kinase A (PKA) interact with histones and related segments of deoxyribonucleic acid (DNA) at promoter regions of genes for messenger ribo nucleic acid (mRNA) transcription. This increases cardiac muscle mass and contractility in normal hearts. In heart failure, activation of β-adrenergic receptors and PKA promote pathological hypertrophy and decreased contractility. Experimental models show that prenatal exposure to hypoxia, cocaine, or nicotine increases susceptibility to heart failure when animals reach adulthood. Hypermethylation of DNA is an epigenetic mechanism associated with downregulation of the protein kinase C (PKC) gene in such models of heart failure. Downregulation of PKC is also produced by the stress-related hormone norepinephrine with upregulation of the hypoxia-inducible differentiation regulator Nix in norepinephrine-induced cardiac fibrosis [2]. Norepinephrine is also the main mediator of sympathetic neural activity. Sympathetic neural overactivity, a significant cofactor in human heart failure, is, therefore, implicated as a cofactor in this epigenetic mechanism for heart failure. Other epigenetic mechanism for cardiac hypertrophy and heart failure involve endothelin- 1 induced downregulation of the cardiac myocyte differentiation factor RE1-silencing transcription signaler (REST) and GATA zinc-finger domain-containing protein-1 (GATAD1) induced inhibition of histone deacetylase (HDAC-2) in cardiac myocytes harvested from autosomal-recessive dilated cardiac myopathy patients with heart failure [3]. In contrast, both the HDAC-2 in cardiac myocytes and the HDAC-1 in cardiac fibroblasts are upregulated in experimental animal models of congestive heart failure [4]. A prominent role for inflammation in heart failure is suggested by tumor necrosis factor (TNF-α), a proinflammatory cytokine, inducing hypermethylation of the sarcoplasmic reticulum calcium ATPase (SERCA-2A) gene in cardiac myocytes, associated with diastolic dysfunction and heart failure. An important role for epigenetic mechanisms in heart failure is also suggested by HDAC-dependent stimulation of the stress-apoptosis intracellular signaling pathway, which induces hypertrophy of both cardiac and vascular smooth muscle [5].

Dipeptidyl Peptidase IV Inhibition Exerts Renoprotective Effects in Rats with Established Heart Failure.

Circulating dipeptidyl peptidase IV (DPPIV) activity is associated with worse cardiovascular outcomes in humans and experimental heart failure (HF) models, suggesting that DPPIV may play a role in the pathophysiology of this syndrome. Renal dysfunction is one of the key features of HF, but it remains to be determined whether DPPIV inhibitors are capable of improving cardiorenal function after the onset of HF. Therefore, the present study aimed to test the hypothesis that DPPIV inhibition by vildagliptin improves renal water and salt handling and exerts anti-proteinuric effects in rats with established HF. To this end, male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were randomly divided into two groups and treated for 4 weeks with vildagliptin (120 mg/kg/day) or vehicle by oral gavage. Echocardiography was performed before (pretreatment) and at the end of treatment (post-treatment) to evaluate cardiac function. The fractional area change (FAC) increased (34 ± 5 vs. 45 ± 3%, p < 0.05), and the isovolumic relaxation time decreased (33 ± 2 vs. 27 ± 1 ms; p < 0.05) in HF rats treated with vildagliptin (post-treatment vs. pretreatment). On the other hand, cardiac dysfunction deteriorated further in vehicle-treated HF rats. Renal function was impaired in vehicle-treated HF rats as evidenced by fluid retention, low glomerular filtration rate (GFR) and high levels of urinary protein excretion. Vildagliptin treatment restored urinary flow, GFR, urinary sodium and urinary protein excretion to sham levels. Restoration of renal function in HF rats by DPPIV inhibition was associated with increased active glucagon-like peptide-1 (GLP-1) serum concentration, reduced DPPIV activity and increased activity of protein kinase A in the renal cortex. Furthermore, the anti-proteinuric effect of vildagliptin treatment in rats with established HF was associated with upregulation of the apical proximal tubule endocytic receptor megalin and of the podocyte main slit diaphragm proteins nephrin and podocin. Collectively, these findings demonstrate that DPPIV inhibition exerts renoprotective effects and ameliorates cardiorenal function in rats with established HF. Long-term studies with DPPIV inhibitors are needed to ascertain whether these effects ultimately translate into improved clinical outcomes.

Long-term administration of tolvaptan increases myocardial remodeling and mortality via exacerbation of congestion in mice heart failure model after myocardial infarction

BackgroundIn contrast to loop diuretics, tolvaptan does not cause neurohormonal activation in several animal heart failure models. However, it remains unknown whether chronic vasopressin type 2 receptor blockade exerts beneficial effects on mortality in murine heart failure after myocardial infarction (MI). In an experimental heart failure model, we tested the hypothesis that tolvaptan reduces myocardial remodeling and mortality. Methods and resultsMI was induced in 9-week-old male C57Bl6/J by the left coronary artery ligation. In study 1, animals were randomly assigned to treatment with placebo or tolvaptan starting 14days post-MI. In study 2, animals were randomized to tolvaptan or furosemide+tolvaptan starting 14days post-MI. Interestingly, results showed lower survival rate in tolvaptan group compared to placebo. Tolvaptan group had higher serum osmolality, heavier body weight, more severe myocardial remodeling, and lung congestion at day 28 of drug administration compared to placebo. In study 2, addition of furosemide significantly reduced mortality rate seen with tolvaptan, and presented with decreased osmolality, myocardial remodeling, and lung congestion compared to tolvaptan-treated mice. Increase in proximal tubular expression of aquaporin 1, Angiotensin II, and vasopressin seen with tolvaptan treatments were normalized to basal levels, similar to levels in placebo-treated mice. ConclusionsContrary to our hypothesis, tolvaptan was associated with increased mortality in murine heart failure after MI. This increase in lung congestion, myocardial remodeling, could be prevented by co-administration of furosemide, which resulted in normalized serum osmolality, neurohormonal activation, and renal aquaporin 1 expression, and hence decreased mortality post-MI.

Pathophysiologic Mechanisms in Heart Failure: Role of the Sympathetic Nervous System

The syndrome of heart failure involves complex pathophysiologic mechanisms and is associated with extremely high-morbidity, mortality and economic costs. This growing global epidemic has diverse etiologies and is fundamentally characterized by dyshomeostasis between heart and kidneys, leading to development and progression of the cardiorenal syndrome. Excessive and sustained sympathoexcitation has emerged as a single prominent factor involved in the structural and functional dysfunction of multiple organ systems during this disease. Studies in experimental models of heart failure indicate that ablation of the renal nerves may help restore renal sodium and water equilibrium as well as the attenuation of adverse cardiac remodeling. With the recent development of minimally invasive endovascular renal denervation in humans, it is anticipated that this technology would become a novel and important paradigm shift in the management of heart failure.

Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights

Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.

Old dog, new tricks: novel cardiac targets and stress regulation by protein kinase G.

The second messenger cyclic guanosine 3'5' monophosphate (cGMP) and its downstream effector protein kinase G (PKG) have been discovered more than 40 years ago. In vessels, PKG1 induces smooth muscle relaxation in response to nitric oxide signalling and thus lowers systemic and pulmonary blood pressure. In platelets, PKG1 stimulation by cGMP inhibits activation and aggregation, and in experimental models of heart failure (HF), PKG1 activation by inhibiting cGMP degradation is protective. The net effect of the above-mentioned signalling is cardiovascular protection. Yet, while modulation of cGMP-PKG has entered clinical practice for treating pulmonary hypertension or erectile dysfunction, translation of promising studies in experimental HF to clinical success has failed thus far. With the advent of new technologies, novel mechanisms of PKG regulation, including mechanosensing, redox regulation, protein quality control, and cGMP degradation, have been discovered. These novel, non-canonical roles of PKG1 may help understand why clinical translation has disappointed thus far. Addressing them appears to be a requisite for future, successful translation of experimental studies to the clinical arena.

Long-term administration of ranolazine attenuates diastolic dysfunction and adverse myocardial remodeling in a model of heart failure with preserved ejection fraction

BackgroundTo investigate the effects of chronic administration of ranolazine (RAN) on experimental model of heart failure with preserved ejection fraction. MethodsSeven-weeks old Dahl salt-sensitive rats were fed a high salt diet for 5weeks to induce hypertension. Afterwards, rats continued with a high salt diet and were administered either with vehicle or RAN (20mg/kg/die, ip) for the following 8weeks. Control rats were maintained on a low salt diet. ResultsWhile systolic parameters were not altered, diastolic parameters were changed in high salt animals. Hemodynamic analysis showed a decreased dP/dt min, increased LVEDP, longer time constant and steeper slope of the end-diastolic pressure–volume relationship. Treatment with RAN attenuated these alterations and determined a reduction in mortality. Additionally, the magnitude of myocardial hypertrophy and activation of PI3K/Akt pathway were reduced. Alteration in diastolic compliance as a consequence of elevated myocardial stiffness was confirmed by an increase of collagen deposition and activation of pro-fibrotic TGF-β/SMAD3/CTGF signaling. These effects were counteracted by RAN. High salt rats had a decrease in SERCA2 and an increase in Na+/Ca2+ exchanger (NCX). Treatment with RAN reduced NCX expression and determined an increment of SERCA2. Moreover, the levels of nitrotyrosine and oxidized dyhydroethidium were higher in high salt rats. RAN induced a decrement of oxidative stress, supporting the concept that reduction in ROS may mediate beneficial effects. ConclusionsOur findings support the possibility that diastolic dysfunction can be attenuated by RAN, indicating its ability to affect active relaxation and passive diastolic compliance.