Combination of chronic kidney disease (CKD) and heart failure (HF) results in extremely high morbidity and mortality. The current guideline-directed medical therapy is rarely effective and new therapeutic approaches are urgently needed. The study was designed to examine if renal denervation (RDN) will exhibit long-standing beneficial effects on the HF- and CKD-related morbidity and mortality. Fawn-hooded hypertensive rats (FHH) served as a genetic model of CKD and fawn-hooded low-pressure rats (FHL) without CKD served as controls. HF was induced by creation of aorto-caval fistula (ACF). RDN was performed 28 days after creation of ACF and the follow-up period was 70 days. ACF FHH subjected to sham-RDN had survival rate of 34 % i.e. significantly lower than 79 % observed in sham-denervated ACF FHL. RDN did not improve the condition and the final survival rate, both in ACF FHL and in ACF FHH. In FHH basal albuminuria was markedly higher than in FHL, and further increased throughout the study. RDN did not lower albuminuria and did not reduce renal glomerular damage in FHH. In these rats creation of ACF resulted in marked bilateral cardiac hypertrophy and alterations of cardiac connexin-43, however, RDN did not modify any of the cardiac parameters. Our present results further support the notion that kidney damage aggravates the HF-related morbidity and mortality. Moreover, it is clear that in the ACF FHH model of combined CKD and HF, RDN does not exhibit any important renoprotective or cardioprotective effects and does not reduce mortality. Key words Chronic kidney disease, Heart failure, Renal denervation, Fawn-hooded hypertensive rats.

• MeSH
• Denervation methods   MeSH
• Hypertension * physiopathology   complications   MeSH
• Cardio-Renal Syndrome * physiopathology   surgery   etiology   MeSH
• Rats MeSH
• Kidney * innervation   MeSH
• Disease Models, Animal MeSH
• Sympathectomy * methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Left ventricular noncompaction cardiomyopathy is associated with heart failure, arrhythmia, and sudden cardiac death. The developmental mechanism underpinning noncompaction in the adult heart is still not fully understood, with lack of trabeculae compaction, hypertrabeculation, and loss of proliferation cited as possible causes. To study this, we utilised a mouse model of aberrant Rho kinase (ROCK) signalling in cardiomyocytes, which led to a noncompaction phenotype during embryogenesis, and monitored how this progressed after birth and into adulthood. The cause of the early noncompaction at E15.5 was attributed to a decrease in proliferation in the developing ventricular wall. By E18.5, the phenotype became patchy, with regions of noncompaction interspersed with thick compacted areas of ventricular wall. To study how this altered myoarchitecture of the heart influenced impulse propagation in the developing and adult heart, we used histology with immunohistochemistry for gap junction protein expression, optical mapping, and electrocardiography. At the prenatal stages, a clear reduction in left ventricular wall thickness, accompanied by abnormal conduction of the ectopically paced beat in that area, was observed in mutant hearts. This correlated with increased expression of connexin-40 and connexin-43 in noncompacted trabeculae. In postnatal stages, left ventricular noncompaction was resolved, but the right ventricular wall remained structurally abnormal through to adulthood with cardiomyocyte hypertrophy and retention of myocardial crypts. Thus, this is a novel model of self-correcting embryonic hypertrabeculation cardiomyopathy, but it highlights that remodelling potential differs between the left and right ventricles. We conclude that disruption of ROCK signalling induces both morphological and electrophysiological changes that evolve over time, highlighting the link between myocyte proliferation and noncompaction phenotypes and electrophysiological differentiation.

• Keywords
• ROCK, cardiomyocyte proliferation, compaction, conduction, mouse embryonic heart, myocardial trabeculae, ventricular wall,
• Publication type
• Journal Article MeSH

Valvular heart disease leads to ventricular pressure and/or volume overload. Pressure overload leads to fibrosis, which might regress with its resolution, but the limits and details of this reverse remodeling are not known. To gain more insight into the extent and nature of cardiac fibrosis in valve disease, we analyzed needle biopsies taken from the interventricular septum of patients undergoing surgery for valve replacement focusing on the expression and distribution of major extracellular matrix protein involved in this process. Proteomic analysis performed using mass spectrometry revealed an excellent correlation between the expression of collagen type I and III, but there was little correlation with the immunohistochemical staining performed on sister sections, which included antibodies against collagen I, III, fibronectin, sarcomeric actin, and histochemistry for wheat germ agglutinin. Surprisingly, the immunofluorescence intensity did not correlate significantly with the gold standard for fibrosis quantification, which was performed using Picrosirius Red (PSR) staining, unless multiplexed on the same tissue section. There was also little correlation between the immunohistochemical markers and pressure gradient severity. It appears that at least in humans, the immunohistochemical pattern of fibrosis is not clearly correlated with standard Picrosirius Red staining on sister sections or quantitative proteomic data, possibly due to tissue heterogeneity at microscale, comorbidities, or other patient-specific factors. For precise correlation of different types of staining, multiplexing on the same section is the best approach.

• Keywords
• Collagen, Fibronectin, Fibrosis, Pressure overload, Valvular heart disease,
• MeSH
• Aortic Valve Insufficiency metabolism   pathology   surgery   MeSH
• Aortic Valve Stenosis * metabolism   pathology   surgery   MeSH
• Extracellular Matrix Proteins * metabolism   analysis   MeSH
• Fibrosis * metabolism   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Ventricular Septum pathology   metabolism   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Extracellular Matrix Proteins * MeSH

No information is available about sex-related differences in unloading-induced cardiac atrophy. We aimed to compare the course of unloading-induced cardiac atrophy in intact (without gonadectomy) male and female rats, and in animals after gonadectomy, to obtain insight into the influence of sex hormones on this process. Heterotopic heart transplantation (HT((x)) was used as a model for heart unloading. Cardiac atrophy was assessed as the weight ratio of heterotopically transplanted heart weight (HW) to the native HW on days 7 and 14 after HTx in intact male and female rats. In separate experimental groups, gonadectomy was performed in male and female recipient animals 28 days before HT(x) and the course of cardiac atrophy was again evaluated on days 7 and 14 after HT(x). In intact male rats, HT(x) resulted in significantly greater decreases in whole HW when compared to intact female rats. The dynamics of the left ventricle (LV) and right ventricle (RV) atrophy after HT(x) was quite similar to that of whole hearts. Gonadectomy did not have any significant effect on the decreases in whole HW, LV, and RV weights, with similar results in male and female rats. Our results show that the development of unloading-induced cardiac atrophy is substantially reduced in female rats when compared to male rats. Since gonadectomy did not alter the course of cardiac atrophy after HTx, similarly in both male and female rats, we conclude that sex-linked differences in the development of unloading-induced cardiac atrophy are not caused by the activity of sex hormones.

• MeSH
• Atrophy pathology   MeSH
• Rats MeSH
• Myocardium pathology   MeSH
• Gonadal Steroid Hormones MeSH
• Heart * MeSH
• Heart Ventricles pathology   MeSH
• Heart Transplantation * adverse effects   methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Gonadal Steroid Hormones MeSH

Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore a dual impact of pressure, and volume overload due to aorto-caval fistula (ACF) on Cx43 and ECM as well as effect of renin-angiotensin blockade. Hypertensive Ren-2 transgenic rats (TGR) and normotensive Hannover Sprague-Dawley rats (HSD) that underwent ACF were treated for 15-weeks with trandolapril or losartan. Blood serum and heart tissue samples of the right (RV) and left ventricles (LV) were used for analyses. ACF-HF increased RV, LV and lung mass in HSD and to lesser extent in TGR, while treatment attenuated it and normalized serum ANP, BNP-45 and TBARS. Cx43 protein and its ser368 variant along with PKCε were lower in TGR vs HSD and suppressed in both rat strains due to ACF but prevented more by trandolapril. Pro-hypertrophic PKCδ, collagen I and hydroxyproline were elevated in TGR and increased due to ACF in both rat strains. While SMAD2/3 and MMP2 levels were lower in TGR vs HSD and reduced due to ACF in both strains. Findings point out the strain-related differences in response to volume overload. Disorders of Cx43 and ECM signalling may contribute not only to HF but also to the formation of arrhythmogenic substrate. There is benefit of treatment with trandolapril and losartan indicating their pleiotropic anti-arrhythmic potential. It may provide novel input to therapy.

• MeSH
• Extracellular Matrix MeSH
• Hypertension * MeSH
• Connexin 43 genetics   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Losartan pharmacology   MeSH
• Fistula * MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Renin MeSH
• Heart Failure * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Connexin 43 MeSH
• Losartan MeSH
• Renin MeSH
• trandolapril MeSH Browser

The aim of the present study was to assess the autoregulatory capacity of renal blood flow (RBF) and of the pressure-natriuresis characteristics in the early phase of heart failure (HF) in rats, normotensive and with angiotensin II (ANG II)-dependent hypertension. Ren-2 transgenic rats (TGR) were employed as a model of ANG II-dependent hypertension. HF was induced by creating the aorto-caval fistula (ACF). One week after ACF creation or sham-operation, the animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. In ACF TGR the basal mean arterial pressure, RBF, urine flow (UF), and absolute sodium excretion (UNaV) were all significantly lower tha n in sham-operated TGR. In the latter, reductions in renal arterial pressure (RAP) significantly decreased RBF whereas in ACF TGR they did not change. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Our data show that compared with sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and improved slope of the pressure-natriuresis relationship. Thus, even though in the very early HF stage renal dysfunction was demonstrable, in the HF model of ANG II-dependent hypertensive rat such dysfunction and the subsequent HF decompensation cannot be simply ascribed to impaired renal autoregulation and pressure-natriuresis relationship.

• Keywords
• Ren-2 transgenic hypertensive rat, Renal autoregulation, Renal blood flow, Sodium excretion, Volume-overload heart failure,
• MeSH
• Angiotensin II pharmacology   MeSH
• Homeostasis MeSH
• Hypertension * MeSH
• Blood Pressure MeSH
• Rats MeSH
• Kidney MeSH
• Natriuresis MeSH
• Rats, Transgenic MeSH
• Renal Circulation MeSH
• Sodium MeSH
• Heart Failure * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin II MeSH
• Sodium 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.

• Keywords
• aortocaval fistula, cardiac remodeling, rat, renin-angiotensin-aldosterone system, trandolapril, volume overload,
• Publication type
• Journal Article MeSH

Cardiac atrophy is the most common complication of prolonged application of the left ventricle (LV) assist device (LVAD) in patients with advanced heart failure (HF). Our aim was to evaluate the course of unloading-induced cardiac atrophy in rats with failing hearts, and to examine if increased isovolumic loading obtained by intraventricular implantation of an especially designed spring expander would attenuate this process. Heterotopic abdominal heart transplantation (HTx) was used as a rat model of heart unloading. HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). The degree of cardiac atrophy was assessed as the weight ratio of the heterotopically transplanted heart (HW) to the control heart. Isovolumic loading was increased by intraventricular implantation of a stainless steel three-branch spring expander. The course of cardiac atrophy was evaluated on days 7, 14, 21, and 28 after HTx Seven days unloading by HTx in failing hearts sufficed to substantially decrease the HW (-59 ± 3%), the decrease progressed when measured on days 14, 21, and 28 after HTx Implantation of the spring expander significantly reduced the decreases in whole HW at all the time points (-39 ± 3 compared with -59 ± 3, -52 ± 2 compared with -69 ± 3, -51 ± 2 compared with -71 ± 2, and -44 ± 2 compared with -71 ± 3%, respectively; P<0.05 in each case). We conclude that the enhanced isovolumic heart loading obtained by implantation of the spring expander attenuates the development of unloading-induced cardiac atrophy in the failing rat heart.

• Keywords
• Cardiac atrophy, heart failure, heterotopic heart transplantation, mechanical heart unloading, spring expander,
• MeSH
• Aorta surgery   MeSH
• Atrial Natriuretic Factor genetics   metabolism   MeSH
• Atrophy metabolism   physiopathology   prevention & control   surgery   MeSH
• Biomarkers metabolism   MeSH
• Equipment Design MeSH
• Implants, Experimental MeSH
• Gene Expression MeSH
• Fibroblast Growth Factor 2 genetics   metabolism   MeSH
• Transplantation, Heterotopic MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Fistula MeSH
• Rats, Inbred Lew MeSH
• Glucose Transporter Type 1 genetics   metabolism   MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases genetics   metabolism   MeSH
• Heart physiopathology   MeSH
• Heart Ventricles physiopathology   surgery   MeSH
• Heart Failure metabolism   physiopathology   surgery   therapy   MeSH
• Tissue Expansion Devices * MeSH
• Heart Transplantation * MeSH
• Vena Cava, Superior surgery   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Atp2a1 protein, rat MeSH Browser
• Atrial Natriuretic Factor MeSH
• Biomarkers MeSH
• Fibroblast Growth Factor 2 MeSH
• Glucose Transporter Type 1 MeSH
• Sarcoplasmic Reticulum Calcium-Transporting ATPases MeSH
• Slc2a1 protein, rat MeSH Browser

BACKGROUND: Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart. METHODS AND RESULTS: In a mouse model, we demonstrated that haploinsufficient (Hif1a+/-) offspring from a diabetic pregnancy developed left ventricle dysfunction at 12 weeks of age, as manifested by decreased fractional shortening and structural remodeling of the myocardium. Transcriptional profiling by RNA-seq revealed significant transcriptome changes in the left ventricle of diabetes-exposed Hif1a+/- offspring associated with development, metabolism, apoptosis, and blood vessel physiology. In contrast, both wild type and Hif1a+/- offspring from diabetic pregnancies showed changes in immune system processes and inflammatory responses. Immunohistochemical analyses demonstrated that the combination of haploinsufficiency of Hif1a and exposure to maternal diabetes resulted in impaired macrophage infiltration, increased levels of advanced glycation end products, and changes in vascular homeostasis in the adult offspring heart. CONCLUSIONS: Together our findings provide evidence that a global reduction in Hif1a gene dosage increases predisposition of the offspring exposed to maternal diabetes to cardiac dysfunction, and also underscore Hif1a as a critical factor in the fetal programming of adult cardiovascular disease.

• Keywords
• Echocardiography, Fetal programming, Heart remodelling, Hif1a haploinsufficiency, Maternal diabetes,
• MeSH
• Diabetes Mellitus, Experimental complications   metabolism   pathology   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit genetics   metabolism   MeSH
• Ventricular Function, Left MeSH
• Diabetes, Gestational * metabolism   pathology   MeSH
• Haploinsufficiency MeSH
• Gene-Environment Interaction MeSH
• Cardiovascular Diseases genetics   metabolism   pathology   physiopathology   MeSH
• Mutation * MeSH
• Myocardium metabolism   pathology   MeSH
• Mice, Knockout MeSH
• Ventricular Remodeling MeSH
• Risk Factors MeSH
• Pregnancy MeSH
• Gene Expression Regulation, Developmental MeSH
• Prenatal Exposure Delayed Effects * MeSH
• Animals MeSH
• Check Tag
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• Hif1a protein, mouse MeSH Browser

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