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.

• Klíčová slova
• heart failure, phosphodiesterase-5 inhibition, rats, right ventricle, volume overload,
• MeSH
• inhibitory ACE * farmakologie   MeSH
• inhibitory fosfodiesterasy 5 * farmakologie   MeSH
• kardiomegalie farmakoterapie   MeSH
• krysa rodu Rattus MeSH
• remodelace komor * MeSH
• srdeční selhání * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory ACE * MeSH
• inhibitory fosfodiesterasy 5 * MeSH

Chronic volume overload induces multiple cardiac remodeling processes that finally result in eccentric cardiac hypertrophy and heart failure. We have hypothesized that chronic angiotensin-converting enzyme (ACE) inhibition by trandolapril might affect various remodeling processes differentially, thus allowing their dissociation. Cardiac remodeling due to chronic volume overload and the effects of trandolapril were investigated in rats with an aortocaval fistula (ACF rats). The aortocaval shunt was created using a needle technique and progression of cardiac remodeling to heart failure was followed for 24 weeks. In ACF rats, pronounced eccentric cardiac hypertrophy and contractile and proarrhythmic electrical remodeling were associated with increased mortality. Trandolapril substantially reduced the electrical proarrhythmic remodeling and mortality, whereas the effect on cardiac hypertrophy was less pronounced and significant eccentric hypertrophy was preserved. Effective suppression of electrical proarrhythmic remodeling and mortality but not hypertrophy indicates that the beneficial therapeutic effects of ACE inhibitor trandolapril in volume overload heart failure might be dissociated from pure antihypertrophic effects.

• Klíčová slova
• aortocaval fistula, cardiac remodeling, rat, renin-angiotensin-aldosterone system, trandolapril, volume overload,
• Publikační typ
• časopisecké články 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
• extracelulární matrix - proteiny genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• molekuly buněčné adheze genetika   metabolismus   MeSH
• myokard metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
• proteom genetika   metabolismus   MeSH
• pyruvátkinasa genetika   metabolismus   MeSH
• remodelace komor * MeSH
• srdeční komory metabolismus   patologie   patofyziologie   MeSH
• srdeční selhání metabolismus   patologie   patofyziologie   MeSH
• tepový objem MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• extracelulární matrix - proteiny MeSH
• molekuly buněčné adheze MeSH
• Pkm protein, rat MeSH Prohlížeč
• protein-glutamin:amin-gama-glutamyltransferasa 2 MeSH
• proteom MeSH
• pyruvátkinasa MeSH
• Tgm2 protein, rat MeSH Prohlížeč

Metabolic interactions between adipose tissue and the heart may play an active role in progression of heart failure (HF). The aim of the study was to examine changes in myocardial and adipose tissue metabolism and gene expression in a rat HF model induced by chronic volume overload. HF was induced by volume overload from aorto-caval fistula (ACF) in 3-month-old male Wistar rats and animals were studied in the phase of decompensated HF (22nd week). HF rats showed marked eccentric cardiac hypertrophy, pulmonary congestion, increased LV end-diastolic pressure, and intraabdominal fat depletion. HF rats had preserved glucose tolerance, but increased circulating free fatty acids (FFA) and attenuated insulin response during oral glucose challenge. Isolated organ studies showed preserved responsiveness of adipose tissue lipolysis and lipogenesis to epinephrine and insulin in ACF. The heart of HF animals had markedly reduced triglyceride content (almost to half of controls), attenuated anti-oxidative reserve (GSH/GSSG), upregulated HF markers (ANP, periostin, thrombospondin-4), specific signaling pathways (Wnt, TGF-β), and downregulated enzymes of mitochondrial fatty acid oxidation, citric acid cycle, and respiratory chain. Adipose tissue transcription profiling showed upregulated receptor for gastric inhibitory polypeptide. In conclusion, ACF-induced HF model displays several deregulations of systemic metabolism. Despite elevation of systemic FFAs, myocardial triglycerides are low and insulin levels are attenuated, arguing against a role of lipotoxicity or insulin resistance in this model. Attenuated postprandial insulin response and relative lack of its antilipolytic effects may facilitate intraabdominal fat depletion observed in ACF-HF animals.

• MeSH
• aorta chirurgie   MeSH
• arteriovenózní píštěl MeSH
• arteriovenózní zkrat MeSH
• biologické markery metabolismus   MeSH
• epididymis metabolismus   patologie   MeSH
• glukózový toleranční test MeSH
• glutathion metabolismus   MeSH
• hemodynamika MeSH
• inzulin krev   MeSH
• játra patologie   MeSH
• kardiomyocyty metabolismus   patologie   MeSH
• krysa rodu Rattus MeSH
• kyseliny mastné neesterifikované krev   MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• ledviny patologie   MeSH
• metabolismus lipidů MeSH
• myokard metabolismus   patologie   MeSH
• oxidační stres MeSH
• plíce patologie   MeSH
• potkani Wistar MeSH
• remodelace komor MeSH
• srdce patofyziologie   MeSH
• srdeční selhání metabolismus   patologie   patofyziologie   MeSH
• stanovení celkové genové exprese MeSH
• superoxiddismutasa metabolismus   MeSH
• tuková tkáň metabolismus   patologie   MeSH
• velikost orgánu MeSH
• venae cavae chirurgie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• glutathion MeSH
• inzulin MeSH
• kyseliny mastné neesterifikované MeSH
• látky reagující s kyselinou thiobarbiturovou MeSH
• superoxiddismutasa MeSH

Chronic volume overload leads to cardiac hypertrophy and later to heart failure (HF), which are both associated with increased risk of cardiac arrhythmias. The goal of this study was to describe changes in myocardial morphology and to characterize arrhythmogenic substrate in rat model of developing HF due to volume overload. An arteriovenous fistula (AVF) was created in male Wistar rats between the inferior vena cava and abdominal aorta using needle technique. Myocardial morphology, tissue fibrosis, and connexin43 distribution, localization and phosphorylation were examined using confocal microscopy and Western blotting in the stage of compensated hypertrophy (11 weeks), and decompensated HF (21 weeks). Heart to body weight (BW) ratio was 89% and 133% higher in AVF rats at 11 and 21 weeks, respectively. At 21 weeks but not 11 weeks, AVF rats had pulmonary congestion (increased lung to BW ratio) indicating presence of decompensated HF. The myocytes in left ventricular midmyocardium were significantly thicker (+8% and +45%) and longer (+88% and +97%). Despite extensive hypertrophy, there was no excessive fibrosis in the AVF ventricles. Distribution and localization of connexin43 were similar between groups, but its phosphorylation was significantly lower in AVF hearts at 21st week, but not 11th week, suggesting that HF, rather than hypertrophy contributes to the connexin43 hypophosphorylation. In conclusion, volume overload leads to extensive eccentric hypertrophy, but not to myocardial fibrosis. Increased vulnerability to arrhythmia in this HF model is possibly related to gap junction remodeling with hypophosphorylation of connexin43.

• MeSH
• arteriovenózní píštěl komplikace   metabolismus   patologie   MeSH
• chronická nemoc MeSH
• fosforylace MeSH
• kardiomegalie komplikace   metabolismus   patologie   MeSH
• konexin 43 biosyntéza   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech * MeSH
• myokard metabolismus   patologie   MeSH
• potkani Wistar MeSH
• srdeční arytmie etiologie   metabolismus   patologie   MeSH
• srdeční selhání metabolismus   patologie   MeSH
• tepový objem fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• konexin 43 MeSH

BACKGROUND: There are only few studies documenting the long-term outcome of aorto-caval fistula (ACF) in rats, a model of volume overload heart failure (HF). The aim of the present study was to describe HF-related morbidity and mortality, and to examine the relation between cardiac hypertrophy and survival. METHODS: Adult male Wistar rats underwent needle ACF or sham operation and 71 animals surviving the acute procedure with patent ACF were followed for 52 weeks. RESULTS: By the end of the study, 72% of the ACF animals deceased and 82% developed HF signs. Of the HF rats, 65% died (median: 3 weeks after HF onset). Before death, body weight increased by 9% followed by a final drop. 28% ACF rats died suddenly, without preceding HF. Sudden death occurred earlier and in the rats with a trend to larger hearts (p = 0.07). In the whole ACF cohort, heart weight (heart weight/body weight ratio) was inversely associated with the length of survival (r = -0.51, p < 0.001). CONCLUSION: The median survival of ACF Wistar rats is 43 weeks, longer than reported in other rat strains. Increased heart weight is associated with higher mortality and a significant number of animals die suddenly.

• MeSH
• aorta abdominalis abnormality   MeSH
• arteriovenózní píštěl komplikace   mortalita   patofyziologie   MeSH
• kardiomegalie etiologie   mortalita   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• míra přežití trendy   MeSH
• potkani Wistar MeSH
• srdeční selhání etiologie   mortalita   patofyziologie   MeSH
• vena cava inferior abnormality   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Heart failure (HF) is a leading cause of morbidity and mortality, often driven by prolonged exposure to pathological stimuli such as pressure and volume overload. These factors contribute to excessive oxidative stress, adverse cardiac remodeling, and dysregulation of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway. Given the urgent need for effective treatments, this study investigated the potential of sGC stimulators to mitigate HF progression. We utilized male hypertensive Ren-2 transgenic (TGR) rats and a volume-overload HF model induced by an aortocaval fistula (ACF). Rats received the sGC stimulator BAY 41-8543 (3 mg/kg/day) for 30 weeks, while normotensive Hannover Sprague-Dawley rats served as controls. At the study endpoint (40 weeks of age), left ventricular tissue was analyzed using mass spectrometry, Western blotting, and histological assessment. TGR rats treated with sGC stimulators exhibited a significant increase in key antioxidant proteins (SOD1, CH10, ACSF2, NDUS1, DHE3, GSTM2, and PCCA), suggesting enhanced resistance to oxidative stress. However, sGC stimulator treatment also upregulated extracellular matrix remodeling markers (MMP-2, TGF-β, and SMAD2/3), which are typically associated with fibrosis. Despite this, Masson's trichrome staining revealed reduced collagen deposition in both TGR and TGR-ACF rats receiving sGC stimulators. Notably, all untreated TGR-ACF rats succumbed before the study endpoint, preventing direct assessment of sGC stimulator effects in advanced HF. These findings highlight the therapeutic potential of sGC stimulators in HF, particularly through their antioxidant effects. However, their concurrent influence on fibrosis warrants further investigation to optimize treatment strategies.

• Klíčová slova
• heart failure with reduced ejection fraction, reactive oxygen/nitrogen species, renin‐angiotensin system, soluble guanylate cyclase stimulator,
• MeSH
• agonisté guanylátcyklasy * farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• morfoliny MeSH
• oxidační stres účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• pyrazoly * farmakologie   terapeutické užití   MeSH
• pyrimidiny * farmakologie   terapeutické užití   MeSH
• remodelace komor účinky léků   MeSH
• rozpustná guanylátcyklasa * metabolismus   MeSH
• srdeční selhání * farmakoterapie   etiologie   patofyziologie   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agonisté guanylátcyklasy * MeSH
• BAY 41-8543 MeSH Prohlížeč
• morfoliny MeSH
• pyrazoly * MeSH
• pyrimidiny * MeSH
• rozpustná guanylátcyklasa * MeSH

Advanced HF (heart failure) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. The antihyperglycaemic drug MET (metformin) affects substrate metabolism, and its use might be associated with improved outcome in diabetic HF. The aim of the present study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Volume-overload HF was induced in male Wistar rats by creating ACF (aortocaval fistula). Animals were randomized to placebo/MET (300 mg·kg(-1) of body weight·day(-1), 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (week 21). A separate cohort served for survival analysis (n=10-90/group). The ACF group had marked cardiac hypertrophy, increased LVEDP (left ventricular end-diastolic pressure) and lung weight confirming decompensated HF, increased circulating NEFAs (non-esterified 'free' fatty acids), intra-abdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triacylglycerol (triglyceride) content and attenuated myocardial (14)C-glucose and (14)C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum NEFAs, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK (AMP-activated protein kinase) signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival, despite reaching therapeutic serum levels (2.2±0.7 μg/ml). In conclusion, MET-induced enhancement of myocardial fatty acid oxidation had a neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF.

• MeSH
• analýza přežití MeSH
• glykogen metabolismus   MeSH
• hemodynamika účinky léků   MeSH
• hypoglykemika krev   terapeutické užití   MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• krevní glukóza metabolismus   MeSH
• krysa rodu Rattus MeSH
• metabolismus lipidů účinky léků   MeSH
• metformin krev   terapeutické užití   MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   patologie   MeSH
• plíce patologie   MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• proteinkinasy metabolismus   MeSH
• srdeční mitochondrie fyziologie   MeSH
• srdeční selhání diagnostické zobrazování   farmakoterapie   patofyziologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• ultrasonografie MeSH
• velikost orgánu účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glykogen MeSH
• hypoglykemika MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• krevní glukóza MeSH
• metformin MeSH
• proteinkinasy 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.

• Klíčová slova
• aorto-caval fistula, autonomic heart innervation, conduction velocity, connexin43, hypertrophy,
• Publikační typ
• časopisecké články MeSH

The role of hypertension and the renin-angiotensin system (RAS) in sex-related differences in the course of chronic kidney disease (CKD) and congestive heart failure (CHF) remain unclear, especially when the two diseases are combined. In male and female Ren-2 transgenic rats (TGR), a model of hypertension with activation of endogenous RAS, CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of an aorto-caval fistula (ACF). The primary aim of the study was to examine long-term CKD- and CHF-related mortality, especially in animals with CKD and CHF combined, with particular interest in the potential sex-related differences. The follow-up period was 23 weeks after the first intervention (5/6 NX). We found, first, that TGR did not exhibit sexual dimorphism in the course of 5/6 NX-induced CKD. Second, in contrast, TGR exhibited important sex-related differences in the course of ACF-induced CHF-related mortality: intact female TGR showed higher survival rate than male TGR. This situation is reversed in the course of combined 5/6 NX-induced CKD and ACF-induced CHF-related mortality: intact female TGR exhibited poorer survival than male TGR. Third, the survival rate in animals with combined 5/6 NX-induced CKD and ACF-induced CHF was significantly worsened as compared with rat groups that were exposed to 'single organ disease'. Collectively, our present results clearly show that CKD aggravates long-term mortality of animals with CHF. In addition, TGR exhibit remarkable sexual dimorphism with respect to CKD- and CHF-related mortality, especially in animals with combined CKD and CHF.

• Klíčová slova
• 5/6 nephrectomy, aorto-caval fistula, chronic kidney disease, congestive heart failure, hypertension, renin-angiotensin system, sex differences in rats,
• MeSH
• aorta metabolismus   patofyziologie   MeSH
• hypertenze metabolismus   mortalita   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• míra přežití trendy   MeSH
• nefrektomie škodlivé účinky   MeSH
• píštěle komplikace   metabolismus   patofyziologie   MeSH
• pohlavní dimorfismus * MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• renin * metabolismus   MeSH
• srdeční selhání metabolismus   mortalita   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Ren2 protein, rat MeSH Prohlížeč
• renin * MeSH