Neurohumoral changes in chronic heart failure

Background: Humoral systems play an important role in the patophysiology and development of chronic heart failure (CHF). Methods: We conducted a search of neurohumoral activation in heart failure and its risk in the development of CHF. Results and conclusion: Neurohumoral factors may be divided into vasoconstrictive, vasodilative and cytokines. The main vasoconstrictive systems are the renin-angiotensin-aldosterone system (RAAS) and the sympathoadrenal system (SAS). Cytokines include tumour necrosis factor (TNF) alpha and interleukins. The systems of actions are interconnected and they mutually influence their secretion and activities. The possibilities of their detection and assessment for clinical purposes depend on their changes and kinetics in the organism and on the activity of individual metabolites. Apart from their vasoactive effects, the majority of humoral actions also interfere in the process of remodelling, function of the endothelium, blood elements, cardiomyocytes, cells of the smooth muscles, and in immunity as well as inflammatory processes. The rapid development of knowledge on the humoral actions in recent years has made possible their utilisation in diagnostics, treatment and prognosis.     

Real-world heart failure management in 10,910 patients with chronic heart failure in the Netherlands

Aims

Data from patient registries give insight into the management of patients with heart failure (HF), but actual data from unselected real-world HF patients are scarce. Therefore, we performed a cross sectional study of current HF care in the period 2013–2016 among more than 10,000 unselected HF patients at HF outpatient clinics in the Netherlands.

Methods

In 34 participating centres, all 10,910 patients with chronic HF treated at cardiology centres were included in the CHECK-HF registry. Of these, most (96%) were managed at a specific HF outpatient clinic. Heart failure was typically diagnosed according to the ESC guidelines 2012, based on signs, symptoms and structural and/or functional cardiac abnormalities. Information on diagnostics, treatment and co-morbidities were recorded, with specific focus on drug therapy and devices. In our cohort, the mean age was 73 years (SD 12) and 60% were male. Frequent co-morbidities reported in the patient records were diabetes mellitus 30%, hypertension 43%, COPD 19%, and renal insufficiency 58%. In 47% of the patients, ischaemia was the origin of HF. In our registry, the prevalence of HF with preserved ejection fraction was 21%.

Conclusion

The CHECK-HF registry will provide insight into the current, real world management of patient with chronic HF, including HF with reduced ejection fraction, preserved ejection fraction and mid-range ejection fraction, that will help define ways to improve quality of care. Drug and device therapy and guideline adherence as well as interactions with age, gender and co-morbidities will receive specific attention.

     

Impact of airflow limitation in chronic heart failure

Background

Comorbidities are common in chronic heart failure (HF) patients, but diagnoses are often not based on objective testing. Chronic obstructive pulmonary disease (COPD) is an important comorbidity and often neglected because of shared symptoms and risk factors. Precise prevalence and consequences are not well known. Therefore, we investigated prevalence, pulmonary treatment, symptoms and quality of life (QOL) of COPD in patients with chronic HF.

Methods

205 patients with stable HF for at least 1 month, aged above 50 years, were included from our outpatient cardiology clinic, irrespective of left ventricular ejection fraction. Patients performed post-bronchodilator spirometry, a six-minute walk test (6-MWT) and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ). COPD was diagnosed according to GOLD criteria. Restrictive lung function was defined as FEV₁/FVC ≥0.70 and FVC <80% of predicted value. The BODE and ADO index, risk scores in COPD patients, were calculated.

Results

Almost 40% fulfilled the criteria of COPD and 7% had restrictive lung disease, the latter being excluded from further analysis. Noteworthy, 63% of the COPD patients were undiagnosed and 8% of those without COPD used inhalation therapy. Patients with COPD had more shortness of breath despite little difference in HF severity and similar other comorbidities. KCCQ was significantly worse in COPD patients. The ADO and BODE indices were significantly different.

Conclusion

COPD is very common in unselected HF patients. It was often not diagnosed and many patients received treatment without being diagnosed with COPD. Presence of COPD worsens symptoms and negatively effects cardiac specific QOL.

     

PPAR gamma agonist normalizes glomerular filtration rate, tissue levels of homocysteine, and attenuates endothelial-myocyte uncoupling in alloxan induced diabetic mice

Background: Homocysteine (Hcy) is an independent cardiovascular risk factor; however, in diabetes, the role of tissue Hcy leading to cardiac dysfunction is unclear.Aims: To determine whether tissue Hcy caused endothelial-myocyte uncoupling and ventricular dysfunction in diabetes.Methods: Diabetes was created in C57BL/6J male mice by injecting 65 mg/kg alloxan. To reverse diabetic complications, ciglitazone (CZ) was administered in the drinking water. Plasma glucose, Hcy, left ventricular (LV) tissue levels of Hcy and nitric oxide (NO) were measured. Glomerular filtration rate (GFR) was measured by inulin-FITC. Endothelial-myocyte coupling was measured in cardiac rings. In vivo diastolic relaxation and LV diameters were measured by a Millar catheter in LV and by M-mode echocardiography, respectively.Results: Plasma glucose, GFR and LV tissue Hcy were increased in diabetic mice and were normalized after CZ treatment; whereas, elevated plasma Hcy level remained unchanged with or without CZ treatment. NO levels in the LV were found inversely related to tissue Hcy levels. Attenuated endothelial-myocyte function in diabetic mice was ameliorated by CZ treatment. Cardiac relaxation, the ratio of LV wall thickness to LV diameter was decreased in diabetes, and normalized after CZ treatment.Conclusion: CZ normalized LV tissue levels of Hcy and ameliorated endothelial-myocyte coupling; therefore, specifically suggest the association of LV tissue Hcy levels with impair endothelial-myocyte function in diabetes.     

Renal denervation modulates angiotensin receptor expression in the renal cortex of rabbits with chronic heart failure

Excessive sympathetic drive is a hallmark of chronic heart failure (HF). Disease progression can be correlated with plasma norepinephrine concentration. Renal function is also correlated with disease progression and prognosis. Because both the renal nerves and renin-angiotensin II system are activated in chronic HF we hypothesized that excessive renal sympathetic nerve activity decreases renal blood flow in HF and is associated with changes in angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) expression. The present study was carried out in conscious, chronically instrumented rabbits with pacing-induced HF. We found that rabbits with HF showed a decrease in mean renal blood flow (19.8±1.6 in HF vs. 32.0±2.5 ml/min from prepace levels; P<0.05) and an increase in renal vascular resistance (3.26±0.29 in HF vs. 2.21±0.13 mmHg·ml(-1)·min in prepace normal rabbits; P<0.05) while the blood flow and resistance was not changed in HF rabbits with the surgical renal denervation. Renal AT1R expression was increased by ～67% and AT2R expression was decreased by ～87% in rabbits with HF; however, kidneys from denervated rabbits with HF showed a near normalization in the expression of these receptors. These results suggest renal sympathetic nerve activity elicits a detrimental effect on renal blood flow and may be associated with alterations in the expression of angiotensin II receptors.     

Oxidative stress and ischemia-modified albumin in chronic ischemic heart failure

Abstract

Objectives

Knowledge about the role of oxidative stress in human diseases, including cardiovascular system disorders, emphasizes the need for reliable markers of oxidative stress. Here, we evaluated the levels of the novel marker ischemia-modified albumin (IMA), albumin-adjusted IMA (adj-IMA), and the IMA/serum albumin ratio (IMAR) in patients with chronic ischemic heart failure (CIHF).

Methods

A total of 55 patients with CIHF and 40 age- and sex-matched healthy individuals were included in the study. Serum levels of IMA, total antioxidant status, and total oxidant status were analyzed, and the adj-IMA level, IMAR, and oxidative stress index were calculated.

Results

Serum IMA, IMAR, total oxidant status levels, and oxidative stress index were significantly higher in patients with CIHF than in the controls (all P < 0.0001), whereas albumin and total antioxidant status levels were significantly lower in the CIHF patients (P < 0.0001 and P = 0.0004, respectively). However, there was no significant difference in serum adj-IMA levels between the groups (P = 0.8).

Discussion

We observed impaired oxidant/antioxidant status in favor of oxidative stress in CIHF patients. Oxidative stress may be a key factor in the development of hypoalbuminemia in CIHF. Further studies are needed to establish the relationships among IMA, albumin, and redox balance in CIHF.     

Exercise training in chronic heart failure: mechanisms and therapies

Decreased exercise capacity negatively affects the individuals’ ability to adequately perform activities required for normal daily life and, therefore, the independence and quality of life. Regular exercise training is associated with improved quality of life and survival in healthy individuals and in cardiovascular disease patients. Also in patients with stable heart failure, exercise training can relieve symptoms, improve exercise capacity and reduce disability, hospitalisation and probably mortality. Physical inactivity can thus be considered a major cardiovascular risk factor, and current treatment guidelines recommend exercise training in patients with heart failure in NYHA functional classes II and III. Exercise training is associated with numerous pulmonary, cardiovascular, and skeletal muscle metabolic adaptations that are beneficial to patients with heart failure. This review discusses current knowledge of mechanisms by which exercise training is beneficial in these patients.     

Protease-activated receptor mediated RhoA signaling and cytoskeletal reorganization in LNCaP cells

Thrombin and trypsin induce cell signaling through a subclass of G-protein-coupled receptors called the protease-activated receptors (PARs). In many cells, PAR signaling results in the activation of RhoA and other members of the Rho family of small GTPases which are involved in cytoskeletal reorganization. The expression of PARs and their role in the activation of Rho GTPases in prostate cancer cells are not clearly known. FACS analysis demonstrated that the androgen-dependent LNCaP cells express PAR1, PAR2, and PAR4 but not PAR3. Stimulation with thrombin and trypsin resulted in the rapid activation of RhoA in a dose-dependent manner with an EC(50) of 1.0 and 5 nM, respectively. Activation of RhoA was enhanced by, but not dependent on, the presence of 1 nM dihydrotestosterone. Inhibition of the proteolytic properties of thrombin by hirudin and trypsin by diisopropyl fluorophosphate abolished the observed RhoA activation. Stimulation with 150 microM PAR-activating peptides TFFLRN (PAR1), SLIGKV (PAR2), and AYPGKF (PAR4) demonstrated that PAR1 and PAR2 mediated protease-activated RhoA signaling. Fluorescent microscopy studies showed that LNCaP cells treated with either thrombin (10 nM) or trypsin (10 nM) developed an increased number of filopodia, stress fibers, and focal adhesions relative to untreated cells. These observations represent the first report of PAR signaling in prostate cancer cells as well as the ability of PAR2 to mediate RhoA activation. Since the activation of RhoA is important for cytoskeletal reorganization, we postulate that PAR-mediated RhoA activation may be a major signaling pathway in the biology of prostate cancer.     

Protease-activated receptor signaling increases epithelial antimicrobial peptide expression

Epithelial tissues provide both a physical barrier and an antimicrobial barrier. Antimicrobial peptides of the human beta-defensin (hBD) family are part of the innate immune responses that play a role in mucosal defense. hBDs are made in epithelia including oral epithelium where the bacterial load is particularly great. hBD-2 and hBD-3 are up-regulated in response to bacterial stimuli. Previous studies show that hBD-2 expression in human gingival epithelial cells (GEC) is stimulated by both nonpathogenic and pathogenic bacteria, including Porphyromonas gingivalis, a Gram-negative pathogen associated with periodontitis. Present evidence suggests that hBD-2 expression in GEC uses several signaling pathways, including an NF-kappaB-mediated pathway but without apparent LPS-TLR4 signaling. Protease-activated receptors (PAR) are G-protein-coupled receptors that mediate cellular responses to extracellular proteinases. P. gingivalis secretes multiple proteases that contribute to its virulence mechanisms. To determine whether PAR signaling is used in hBD-2 induction, GEC were stimulated with wild-type P. gingivalis or mutants lacking one or more proteases. hBD-2 mRNA expression was reduced in GEC stimulated with single protease mutants (11-67% compared with wild type), strongly reduced in double mutants (0.1-16%), and restored to wild-type levels (93%) in mutant with restored protease activity. Stimulation by wild type was partially blocked by inhibitors of phospholipase C, a main signaling pathway for PARs. Expression of hBD-3 was unaffected. Peptide agonist of PAR-2, but not PAR-1 activator, also induced hBD-2 in GEC. Thus, P. gingivalis proteases are directly involved in regulation of hBD-2 in cultured GEC, and this induction partially uses the PAR-2 receptor and signaling pathway.     

Adrenergic and muscarinic receptor regulation and therapeutic implications in heart failure

In end-stage heart failure the expression of different myocardial regulatory proteins involved in the -adrenergic cAMP signalling pathway is altered. The downregulation of -adrenoceptors and their uncoupling from the effector as well as an increased expression of the inhibitory GTP-binding protein seem to be the most important alterations. Since catecholamine levels are elevated in these patients and since some alterations can be restored after treatment with -adrenoceptor antagonists it was hypothesized that excessive -adrenergic stimulation could be involved in these alterations.In this article the changes of -adrenergic receptors, GTP-binding proteins, sarcoplasmic reticulum Ca²⁺-ATPase and of phospholamban found in heart failure are addressed with its possible therapeutic implications.     

Neuroimmunoendocrine interaction in the pathogenesis of chronic heart failure

Chronic heart failure (CHF) is a common complication of patients with heart dysfunction and of those suffering from various chronic illnesses. Although recently developed therapies revolutionized treatment of CHF, life expectancy of the survivors is still significantly reduced. Proposed neurohoromonal approach in CHF treatment is on the whole rather unsatisfactory. Recently the interest of clinical investigators has been focused on immune mechanisms in the pathogenesis of CHF. In this review we tried to summarize data concerning contribution of inflammatory cytokines to pathogenesis of CHF. The source and site of action of pro- and antiinflammatory cytokines and number of interactions among cytokines and neuroendocrine systems under CHF are considered. Finally we discuss novel therapies managing correction of both immune and neurohormonal status of the patient.     

AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure

Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT(1)R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT(1)R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT(1)R mRNA. AT(1)R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT(1)R mRNA antisense reduces expression of AT(1)R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.     

Cytokines as new treatment targets in chronic heart failure

Inflammatory cytokines may negatively influence contractility and contribute to the remodelling process in the failing myocardium. Traditional cardiovascular drugs appear to have little influence on the overall cytokine network in chronic heart failure (CHF). Increased interest in anticytokine therapy has therefore evolved. Several small studies have used tumour necrosis factor (TNF)-α as a target, resulting in improved functional capacity and myocardial performance. Intravenous immunoglobulin (IVIG) represents another therapeutic approach in which the impact on myocardial performance appears to be correlated with anti-inflammatory effects. These studies demonstrate potential for immunomodulation as a therapy in addition to conventional cardiovascular treatment in CHF, but the most effective drugs in this regard have yet to be identified.     

Calcium-regulating peptide hormones and blood electrolytic balance in chronic heart failure

Calcium-regulating system is important for the functional activity of myocardium. However, little is known about the role of this system in the pathogenesis of cardiovascular diseases. Blood samples from the patients with chronic heart failure (CHF) caused by ischaemic disease (coronary artery disease) (NYHA class I-IV) were used to analyze the levels of calcium, inorganic phosphate, sodium, potassium, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). The heart beat rate and arterial blood pressure were chosen as additional tests for the functional status of cardiovascular system. The alteration of electrolytes homeostasis was found dependent on the severity of the pathology being maximally expressed in the NYHA class IV patients. Similar tendency was demonstrated for circulating PTH and PTHrP with the highest blood concentrations observed in patients of the NYHA class III and IV. The extent of these changes was found more pronounced in the female patients. It is suggested that the calcium-regulating hormonal system is involved in the pathogenesis of the ischaemic heart disease; however the sharp increase of PTH and PTHrP at the severe stages of pathology may play a compensatory role in maintaining the heart function.     

RXRA introne polymorphism and ABO blood groups in chronic heart failure

Retinoic X receptor alpha (RXRA), a member of nuclear receptor superfamily, plays a key role in development, metabolism, glucose homeostasis, and intestinal cholesterol balance. The aim of this study was to examine an association of RXR alpha introne 5 A(39526)AA polymorphism and ABO blood groups with chronic heart failure (CHF) in the Czech population. A total of 238 patients with chronic heart failure and a control group of 246 subjects were included in the study. The RXR alpha gene polymorphism and ABO blood groups were detected by PCR and RFLP methods. Significant differences in distributions of RXRA A(39526)AA alleles and genotypes between CHF patients and controls were observed (P_g=0.03, P_a=0.02). The RXRA gene polymorphism differences of within blood group A between CHF patients and controls were highly significant in genotype distributions (P_g=0.002) and in allele frequency comparisons (P_a=0.0001). The prevalence of AA allele in CHF patients with A blood group was four-fold lower than in controls with the same blood group (OR=0.24; P_corr=0.0001). A highly significant association of RXRA introne single-nucleotide insertion polymorphism and A blood group in chronic heart failure was observed. Our results suggest close linkage between RXRA A(39526)AA polymorphism and ABO blood groups.