While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.

• Keywords
• heart failure, phosphodiesterase-5 inhibition, rats, right ventricle, volume overload,
• MeSH
• Angiotensin-Converting Enzyme Inhibitors * pharmacology   MeSH
• Phosphodiesterase 5 Inhibitors * pharmacology   MeSH
• Cardiomegaly drug therapy   MeSH
• Rats MeSH
• Ventricular Remodeling * MeSH
• Heart Failure * drug therapy   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin-Converting Enzyme Inhibitors * MeSH
• Phosphodiesterase 5 Inhibitors * MeSH

The extracellular matrix (ECM) is a highly dynamic structure controlling the proper functioning of heart muscle. ECM remodeling with enhanced collagen deposition due to hemodynamic overload impairs cardiomyocyte adhesion and electrical coupling that contributes to cardiac mechanical dysfunction and arrhythmias. We aimed to explore ECM and connexin-43 (Cx43) signaling pathways in hemodynamically overloaded rat heart as well as the possible implication of angiotensin (1-7) (Ang (1-7)) to prevent/attenuate adverse myocardial remodeling. Male 8-week-old, normotensive Hannover Spraque-Dawley rats (HSD), hypertensive (mRen-2)27 transgenic rats (TGR) and Ang (1-7) transgenic rats (TGR(A1-7)3292) underwent aortocaval fistula (ACF) to produce volume overload. Five weeks later, biometric and heart tissue analyses were performed. Cardiac hypertrophy in response to volume overload was significantly less pronounced in TGR(A1-7)3292 compared to HSD rats. Moreover, a marker of fibrosis hydroxyproline was increased in both ventricles of volume-overloaded TGR while it was reduced in the Ang (1-7) right heart ventricle. The protein level and activity of MMP-2 were reduced in both ventricles of volume-overloaded TGR/TGR(A1-7)3292 compared to HSD. SMAD2/3 protein levels were decreased in the right ventricle of TGR(A1-7)3292 compared to HSD/TGR in response to volume overload. In parallel, Cx43 and pCx43 implicated in electrical coupling were increased in TGR(A1-7)3292 versus HSD/TGR. It can be concluded that Ang (1-7) exhibits cardio-protective and anti-fibrotic potential in conditions of cardiac volume overload.

• Keywords
• angiotensin (1-7), aortocaval fistula, connexin 43, extracellular matrix, heart failure,
• MeSH
• Angiotensin II MeSH
• Fibrosis MeSH
• Hypertension * metabolism   MeSH
• Connexin 43 MeSH
• Rats MeSH
• Rats, Transgenic MeSH
• Heart MeSH
• Heart Failure * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• angiotensin I (1-7) MeSH Browser
• Angiotensin II MeSH
• Connexin 43 MeSH

Background: Arteriovenous fistulas (AVF) represent a low resistant circuit. It is known that their opening leads to decreased systemic vascular resistance, increased cardiac output and other hemodynamic changes. Possible competition of AVF and perfusion of other organs has been observed before, however the specific impact of AVF has not been elucidated yet. Previous animal models studied long-term changes associated with a surgically created high flow AVF. The aim of this study was to create a simple AVF model for the analysis of acute hemodynamic changes. Methods: Domestic female pigs weighing 62.6 ± 5.2 kg were used. All the experiments were held under general anesthesia. The AVF was created using high-diameter ECMO cannulas inserted into femoral artery and vein. Continuous hemodynamic monitoring was performed throughout the protocol. Near-infrared spectroscopy sensors, flow probes and flow wires were inserted to study brain and heart perfusion. Results: AVF blood flow was 2.1 ± 0.5 L/min, which represented around 23% of cardiac output. We observed increase in cardiac output (from 7.02 ± 2.35 L/min to 9.19 ± 2.99 L/min, p = 0.0001) driven dominantly by increased heart rate, increased pulmonary artery pressure, and associated right ventricular work. Coronary artery flow velocity rose. On the contrary, carotid artery flow and brain and muscle tissue oxygenation measured by NIRS decreased significantly. Conclusions: Our new non-surgical AVF model is reproducible and demonstrated an acute decrease of brain and muscle perfusion.

• Keywords
• animal model, arteriovenous fistula, cerebral oxygenation, coronary artery flow, hyperkinetic circulation, tissue perfusion,
• Publication type
• Journal Article MeSH

Mechanisms of right ventricular (RV) dysfunction in heart failure (HF) are poorly understood. RV response to volume overload (VO), a common contributing factor to HF, is rarely studied. The goal was to identify interventricular differences in response to chronic VO. Rats underwent aorto-caval fistula (ACF)/sham operation to induce VO. After 24 weeks, RV and left ventricular (LV) functions, gene expression and proteomics were studied. ACF led to biventricular dilatation, systolic dysfunction and hypertrophy affecting relatively more RV. Increased RV afterload contributed to larger RV stroke work increment compared to LV. Both ACF ventricles displayed upregulation of genes of myocardial stress and metabolism. Most proteins reacted to VO in a similar direction in both ventricles, yet the expression changes were more pronounced in RV (pslope: < 0.001). The most upregulated were extracellular matrix (POSTN, NRAP, TGM2, CKAP4), cell adhesion (NCAM, NRAP, XIRP2) and cytoskeletal proteins (FHL1, CSRP3) and enzymes of carbohydrate (PKM) or norepinephrine (MAOA) metabolism. Downregulated were MYH6 and FAO enzymes. Therefore, when exposed to identical VO, both ventricles display similar upregulation of stress and metabolic markers. Relatively larger response of ACF RV compared to the LV may be caused by concomitant pulmonary hypertension. No evidence supports RV chamber-specific regulation of protein expression in response to VO.

• MeSH
• Extracellular Matrix Proteins genetics   metabolism   MeSH
• Rats MeSH
• Cell Adhesion Molecules genetics   metabolism   MeSH
• Myocardium metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• Proteome genetics   metabolism   MeSH
• Pyruvate Kinase genetics   metabolism   MeSH
• Ventricular Remodeling * MeSH
• Heart Ventricles metabolism   pathology   physiopathology   MeSH
• Heart Failure metabolism   pathology   physiopathology   MeSH
• Stroke Volume MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Extracellular Matrix Proteins MeSH
• Cell Adhesion Molecules MeSH
• Pkm protein, rat MeSH Browser
• Protein Glutamine gamma Glutamyltransferase 2 MeSH
• Proteome MeSH
• Pyruvate Kinase MeSH
• Tgm2 protein, rat MeSH Browser

OBJECTIVE: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). METHODS: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). RESULTS: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. CONCLUSION: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.

• Keywords
• Acetylcholine, Angiotensin II, Aorto-caval fistula, Bradykinin, Congestive heart failure, Epoxyeicosatrienoic acid, Hypertension, Norepinephrine, Renal blood flow, Renal dysfunction, Renal vascular reactivity,
• MeSH
• Angiotensin II adverse effects   MeSH
• Pulmonary Artery abnormalities   physiopathology   MeSH
• Arterio-Arterial Fistula physiopathology   MeSH
• Hypertension chemically induced   complications   MeSH
• Rats MeSH
• Rats, Transgenic MeSH
• Renal Circulation drug effects   MeSH
• Heart Failure complications   physiopathology   MeSH
• Vasodilation drug effects   MeSH
• Vasoconstriction drug effects   MeSH
• Vasoconstrictor Agents pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin II MeSH
• Vasoconstrictor Agents MeSH

The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Wnt signaling hyperactivation is predominantly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene that encodes the pathway negative regulator. In order to identify genes affected by the Apc loss, we performed expression profiling of intestinal epithelium isolated from mice harboring a conditional Apc allele. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Histological analysis of the Apc-deficient epithelium revealed that in the small intestine, the Msx1 protein was localized exclusively in ectopic crypts, i.e., in pockets of proliferating cells abnormally positioned on the villi. Ablation of the Msx1 gene leads to the disappearance of ectopic crypts and loss of differentiated cells. Moreover, tumors arising from Msx1-deficient cells display altered morphology reminiscent of villous adenomas. In human tumor specimens, MSX1 displayed significantly increased expression in colonic neoplasia with a descending tendency during the lesion progression towards colorectal carcinoma. In summary, the results indicate that Msx1 represents a novel marker of intestinal tumorigenesis. In addition, we described the previously unknown relationship between the Msx1-dependent formation of ectopic crypts and cell differentiation.

• MeSH
• beta Catenin metabolism   MeSH
• Cell Differentiation MeSH
• Colorectal Neoplasms genetics   pathology   MeSH
• Humans MeSH
• Mice, Knockout MeSH
• Colonic Neoplasms genetics   pathology   MeSH
• Adenomatous Polyposis Coli Protein genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Wnt Signaling Pathway MeSH
• Gene Expression Profiling MeSH
• Intestinal Mucosa metabolism   pathology   MeSH
• Intestine, Small pathology   MeSH
• MSX1 Transcription Factor genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• adenomatous polyposis coli protein, mouse MeSH Browser
• APC protein, human MeSH Browser
• beta Catenin MeSH
• MSX1 protein, human MeSH Browser
• Msx1 protein, mouse MeSH Browser
• Adenomatous Polyposis Coli Protein MeSH
• MSX1 Transcription Factor MeSH

We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.

• MeSH
• Arteriovenous Fistula MeSH
• Benzoates pharmacology   therapeutic use   MeSH
• Epoxide Hydrolases antagonists & inhibitors   MeSH
• Indoles therapeutic use   MeSH
• Angiotensin-Converting Enzyme Inhibitors therapeutic use   MeSH
• Drug Therapy, Combination MeSH
• Rats MeSH
• Urea analogs & derivatives   pharmacology   therapeutic use   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Drug Evaluation, Preclinical MeSH
• Renal Insufficiency etiology   prevention & control   MeSH
• Heart Failure complications   drug therapy   mortality   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Browser
• Benzoates MeSH
• Epoxide Hydrolases MeSH
• Indoles MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• Urea MeSH
• trandolapril MeSH Browser

BACKGROUND: The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure (HF) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. METHODS AND RESULTS: In total, 140 advanced HF patients without known diabetes mellitus and 21 sex-, age-, and body mass index-matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose-regulating hormones to model pancreatic β-cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio-a signature of starvation. The insulin/C-peptide ratio was decreased in HF, indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome (P=0.01). Patients in the lowest quartile of fasting plasma glucose (3.8-5.1 mmol·L-1, 68-101 mg·dL-1) had 3-times higher event risk than in the top quartile (6.0-7.9 mmol·L-1, 108-142 mg·dL-1; relative risk: 3.05 [95% confidence interval, 1.46-6.77]; P=0.002). CONCLUSIONS: Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF. Pancreatic insulin secretion is preserved in advanced HF, but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia.

• Keywords
• cachexia, glucagon/glucagon‐like peptide, glucose, heart failure, insulin, metabolism, obesity paradox, right ventricular dysfunction, starvation,
• MeSH
• Biomarkers blood   MeSH
• Time Factors MeSH
• Ventricular Dysfunction, Right blood   diagnosis   physiopathology   MeSH
• Ventricular Function, Right MeSH
• Glucagon blood   MeSH
• Glucose Tolerance Test MeSH
• Homeostasis MeSH
• Insulin blood   MeSH
• Cachexia blood   diagnosis   physiopathology   MeSH
• Kaplan-Meier Estimate MeSH
• Blood Glucose metabolism   MeSH
• Islets of Langerhans metabolism   physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prognosis MeSH
• Risk Factors MeSH
• Aged MeSH
• Heart Failure blood   diagnosis   physiopathology   MeSH
• Case-Control Studies MeSH
• Severity of Illness Index MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• Glucagon MeSH
• Insulin MeSH
• Blood Glucose MeSH

Volume overload leads to development of eccentric cardiac hypertrophy and heart failure. In our previous report, we have shown myocyte hypertrophy with no fibrosis and decrease in gap junctional coupling via connexin43 in a rat model of aorto-caval fistula at 21 weeks. Here we set to analyze the electrophysiological and protein expression changes in the left ventricle and correlate them with phenotypic severity based upon ventricles to body weight ratio. ECG analysis showed increased amplitude and duration of the P wave, prolongation of PR and QRS interval, ST segment elevation and decreased T wave amplitude in the fistula group. Optical mapping showed a prolongation of action potential duration in the hypertrophied hearts. Minimal conduction velocity (CV) showed a bell-shaped curve, with a significant increase in the mild cases and there was a negative correlation of both minimal and maximal CV with heart to body weight ratio. Since the CV is influenced by gap junctional coupling as well as the autonomic nervous system, we measured the amounts of tyrosine hydroxylase (TH) and choline acetyl transferase (ChAT) as a proxy for sympathetic and parasympathetic innervation, respectively. At the protein level, we confirmed a significant decrease in total and phosphorylated connexin43 that was proportional to the level of hypertrophy, and similarly decreased levels of TH and ChAT. Even at a single time-point, severity of morphological phenotype correlates with progression of molecular and electrophysiological changes, with the most hypertrophied hearts showing the most severe changes that might be related to arrhythmogenesis.

• Keywords
• aorto-caval fistula, autonomic heart innervation, conduction velocity, connexin43, hypertrophy,
• Publication type
• Journal Article MeSH

The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment with cis-4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/l in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/l in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue.

• MeSH
• Angiotensin I blood   MeSH
• Angiotensin II blood   MeSH
• Benzoates pharmacology   therapeutic use   MeSH
• Epoxide Hydrolases antagonists & inhibitors   MeSH
• Epoxy Compounds metabolism   MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• Rats MeSH
• 8,11,14-Eicosatrienoic Acid analogs & derivatives   blood   metabolism   MeSH
• Kidney metabolism   MeSH
• Urea analogs & derivatives   pharmacology   therapeutic use   MeSH
• Disease Models, Animal MeSH
• Myocardium metabolism   MeSH
• Random Allocation MeSH
• Peptide Fragments blood   MeSH
• Drug Evaluation, Preclinical MeSH
• Renal Insufficiency blood   etiology   prevention & control   MeSH
• Renin-Angiotensin System drug effects   MeSH
• Heart Failure blood   complications   diagnostic imaging   drug therapy   MeSH
• Ultrasonography MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Browser
• angiotensin I (1-7) MeSH Browser
• Angiotensin I MeSH
• Angiotensin II MeSH
• Benzoates MeSH
• Epoxide Hydrolases MeSH
• Epoxy Compounds MeSH
• Angiotensin-Converting Enzyme Inhibitors MeSH
• 8,11,14-Eicosatrienoic Acid MeSH
• Urea MeSH
• Peptide Fragments MeSH