Atrial fibrosis is considered as the basis in the development of long-standing atrial fibrillation (AF). However, in advanced heart failure (HF), the independent role of fibrosis for AF development is less clear since HF itself leads to atrial scarring. Our study aimed to differentiate patients with AF from patients without AF in a population consisting of patients with advanced HF. Myocardial samples from the right atrial and the left ventricular wall were obtained during he art transplantation from the explanted hearts of 21 male patients with advanced HF. Long- standing AF was present in 10 of them and the remaining 11 patients served as sinus rhythm controls. Echocardiographic and hemodynamic measurements were recorded prior to heart transplantation. Collagen volume fraction (CVF), transforming growth factor-beta (TGF- β ), and connective tissue growth factor (CTGF) expression in myocardial specimens were assessed histologically and immunohistochemically. The groups were well matched according to age (51. 9±8.8 vs. 51.3±9.3 y) and co- morbidities. The AF group had high er blood pressure in the right atrium (13.6±7.7 vs. 6.0±5.0 mmHg; p=0.02), larger left atrium diameter (56.1±7.7 vs. 50±5.1 mm; p=0.043), higher left atrium wall stress (18.1±2.1 vs. 16.1±1.7 kdynes/m 2 ; p=0.04), and longer duration of HF (5.0±2.9 vs. 2.0±1.6 y, p=0.008). There were no significant differences in CVF (p=0.12), in CTGF (p=0.60), and in TGF- β expression (p=0.66) in the atrial myocardium between the two study groups. In conclusions, in advanced HF, atrial fibrosis expressed by CVF is invariably present regardless of occurrence of AF. In addition to atrial wall fibrosis, increased wall stress might contribute to AF development in long-standing AF., B. Aldhoon, ... [et al.]., and Obsahuje seznam literatury
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 followup period was 50 weeks. RAS was blocked using angiotensinconverting 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., P. Kala, L. Sedláková, P. Škaroupková, L. Kopkan, Z. Vaňourková, M. Táborský, A. Nishiyama, S. H. Hwang, B. D. Hammock, J. Sadowski, V. Melenovský, J. D. Imig, L. Červenka., and Obsahuje bibliografii
The present experiments were performed to evaluate if increased heart tissue concentration of fatty acids, specifically myristic, palmitic and palmitoleic acids that are believed to promote physiological heart growth, can attenuate the progression of unloading-induced cardiac atrophy in rats with healthy and failing hearts. Heterotopic abdominal heart transplantation (HTx) was used as a model for heart unloading. Cardiac atrophy was assessed from the ratio of the native- to-transplanted heart weight (HW). The degree of cardiac atrophy after HTx was determined on days 7, 14, 21 and 28 after HTx in recipients of either healthy or failing hearts. HTx of healthy hearts resulted in 23±3, 46±3, 48±4 and 46±4 % HW loss at the four time-points. HTx of the failing heart resulted in even greater HW losses, of 46±4, 58±3, 66±2 and 68±4 %, respectively (P<0.05). Activation of “fetal gene cardiac program” (e.g. beta myosin heavy chain gene expression) and “genes reflecting cardiac remodeling” (e.g. atrial natriuretic peptide gene expression) after HTx was greater in failing than in healthy hearts (P<0.05 each time). Exposure to isocaloric high sugar diet caused significant increases in fatty acid concentrations in healthy and in failing hearts. However, these increases were not associated with any change in the course of cardiac atrophy, similarly in healthy and post-HTx failing hearts. We conclude that increasing heart tissue concentrations of the fatty acids allegedly involved in heart growth does not attenuate the unloading-induced cardiac atrophy., M. Pokorný, I. Mrázová, J. Malý, J. Pirk, I. Netuka, Z. Vaňourková, Š. Doleželová, L. Červenková, H. Maxová, V. Melenovský, J. Šochman, J. Sadowski, L. Červenka., and Seznam literatury
Previous studies revealed altered levels of the circulating insulin-like growth factor-I (IGF-I) and of its binding protein-3 (IGFBP-3) in subjects with coronary atherosclerosis, metabolic syndrome and premature atherosclerosis. Hyperlipidemia is a powerful risk factor of atherosclerosis. We expected IGF-I and IGFBP-3 alterations in subjects with moderate/severe hyperlipidemia but without any clinical manifestation of atherosclerosis. Total IGF-I and IGFBP-3 were assessed in 56 patients with mixed hyperlipidemia (MHL; cholesterol>6.0 mmol/l, triglycerides>2.0 mmol/l), in 33 patients with isolated hypercholesterolemia (IHC; cholesterol>6.0 mmol/l, triglycerides<2.0 mmol/l), and in 29 healthy controls (cholesterol<6.0 mmol/l, triglycerides<2.0 mmol/l). The molar ratio of IGF-I/IGFBP-3 was used as a measure of free IGF-I. IHC subjects differed from controls by lower total IGF-I (164±60 vs. 209±73 ng/ml, p=0.01) and IGF-I/IGFBP-3 ratio (0.14±0.05 vs. 0.17±0.04, p=0.04). Compared to controls, MHL subjects had lower total IGF-I (153±54 ng/ml, p=0.0002) and IGFBP-3 (2.8±0.6 mg/ml, p<0.0001), but higher IGF-I/IGFBP-3 ratio (0.25±0.06, p<0.0001). Differences remained significant after the adjustment for clinical and biochemical covariates, except for triglycerides. Patients with both IHC and MHL have lower total IGF-I compared to controls. The mechanism is presumably different in IHC and MHL. Because of prominent reduction of IGFBP-3 in patients with MHL, they have reduced total IGF-I despite the actual elevation IGF-I/IGFBP-3 ratio as a surrogate of free IGF-I., J. Malík, T. Štulc, D. Wichterle, V. Melenovský, E. Chytilová, Z. Lacinová, J. Marek, R. Češka., and Obsahuje bibliografii a bibliografické odkazy
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 m yocardial 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 o verload. 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., L. Červenka, V. Melenovský, Z. Husková, A. Sporková, M. Bürgelová, P. Škaroupková, S. H. Hwang, B. D. Hammock, J. D. Imig, J. Sadowski., and Obsahuje bibliografii
Pulmonary hypertension (PH) unresponsive to pharmacological intervention is considered a contraindication for orthotopic heart transplantation (OHTX) due to risk of postoperative right-heart failure. In this prospective study, we describe our experience with a treatment strategy of improving severe PH in heart transplant candidates by means of ventricular assist device (VAD) implantation and subs equent OHTX. In 11 heart transplantation candidates with severe PH unresponsive to pharmacological intervention we implanted VAD with the aim of achieving PH to values acceptable for OHTX. In all patients we observed significant drop in pulmonary pr essures, PVR and TPG (p<0.001 for all) 3 months after VAD implantation to values sufficient to allow OHTX. Seven patients underwent transplantation (mean duration of support 216 days) while none of patients suffered right-side heart failure in postoperative period. Two patients died after transplantation and five patients are living in very good condition with a mean duration of 286 days after OHTX. In our opinion, severe PH is not a contraindication for orthotopic heart transplantation any more., J. Kettner ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Chronic hypoxia induces an increased production of nitric oxide (NO) in pulmonary prealveolar arterioles. Bioavailability of the NO in the pulmonary vessels correlates with concentration of L-arginine as well as ac tivity of phosphodiesterase-5 enzyme (PDE- 5). We tested a hypothesis whet her a combination of L-arginine and PDE-5 inhibitor sildenafil has an additive effect in reduction of the hypoxic pulmonary hypertension (HPH) in rats. Animals were exposed to chronic normobaric hypoxia for 3 weeks. In the AH group, rats were administered L-arginine during chronic hypoxic exposure. In the SH group, rats were administered sildenafil during chronic hypoxic exposure. In the SAH group, rats were treated by the combination of L-arginine as well as sildenafil during exposure to chronic hypoxia. Mean PAP, structural remodeling of peripheral pu lmonary arterioles (%DL) and RV/LV+S ratio was significantl y decreased in the SAH group compared to hypoxic controls even decreased compared to the AH and the SH groups in first two measured parameters. Plasmatic concentration of cGMP and NOx were significantly lower in the SAH group compared to hypoxic controls. We demonstrate that NO synthase substrate L-arginine and phosphodiesterase-5 inhibitor sildenafil administered in combination are more potent in attenuation of the HPH compared to a treatment by substances given alone., H. Al-Hiti ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Although atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, precise mechanisms that lead to the onset and persistence of AF have not completely been elucidated. Over the last decade, outstanding progress has been made in understanding the complex pathophysiology of AF. The key role of ectopic foci in pulmonary veins as a trigger of AF has been recognized. Furthermore, structural remodeling was identified as the main mechanism for AF persistence, confirming predominant role of atrial fibrosis. Systemic inflammatory state, oxidative stress injury, autonomic balance and neurohormonal activation were discerned as important modifiers that affect AF susceptibility. This new understanding of AF pathophysiology has led to the emergence of novel therapies. Ablative interventions, renin-angiotensin system blockade, modulation of oxidative stress and targeting tissue fibrosis represent new approaches in tackling AF. This review aims to provide a brief summary of novel insights into AF mechanisms and consequent therapeutic strategies., B. Aldhoon ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
In some patients, heart failure (HF) is associated with increased pulmonary vascular resistance (PVR). The magnitude and the reversibility of PVR elevation affect the HF management. Sildenafil has been recently recognized as potent PVR-lowering drug in HF. The aim of the study was to compare hemodynamic effects and pulmonary selectivity of sildenafil to prostaglandin E1(PGE1). Right-heart catheterization was performed in 13 euvolemic advanced HF patien ts with elevated PVR (6.3±2 Wood's units). Hemodynamic parameters were measured at the baseline, during i.v. infusion of PGE1 (alprostadil 200 ng·kg-1·min-1 ) and after 40 mg oral do se of sildenafil. Both drugs similarly reduced systemic vascular resistance (SVR), but sildenafil had higher effect on PVR (-28 % vs. -49 %, p=0.05) and transpulmonary pressu re gradient than PGE1. The PVR/SVR ratio - an index of pulmonary se lectivity, did not change after PGE1(p=0.7) but it decreased by -32 % (p=0.004) after sildenafil. Both drugs similarly reduced pulmonary artery mean and wedge pressures and increa sed cardiac index (+27 % and +28 %). Sildenafil led more often to transplant-acceptable PVR while causing smaller drop of mean systemic pressure than PGE1. In conclusion, vasodilatatory effects of sildenafil in patients with heart failure are more pronounced in pulmonary than in systemic circulation., H. Al-Hiti ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy