Neurohumoral Modulation Research Articles

P275 COMBINED NEURO–HUMORAL MODULATION AND OUTCOME IN PATIENTS WITH CHRONIC HEART FAILURE AND MILDLY REDUCED OR PRESERVED EJECTION FRACTION

Abstract Background Drug therapy of patients with chronic heart failure (HF) with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains a challenge. We aimed to assess whether escalating neuro–humoral–modulation (NHM) (renin–angiotensin system inhibitors (RASI), betablockers (BB), mineralocorticoid receptor antagonists (MRA)) was differentially associated with outcome according to phenotype and age groups. Methods and Results Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n=2298, HFpEF n=2409) and classified them into 3 age groups: young (<65 years), old (65–79 years), oldest–old (80+ years). We analysed clinical characteristics and 1–year all–cause mortality/cardiovascular hospitalization according to none/single (RASI or BB or MRA), double (RASI+BB or RASI+MRA or BB+MRA), or triple (MRA+RASI+BB) NHM. Overall, approximately half of HFmrEF and HFpEF patients had double–NHM. Among HFmrEF, 25.1% received no/single and 26.7% triple NHM. In the HFpEF group, 36.5% had no/single and 17.9% triple NHM. Older age was associated with a higher prescription of no/single NHM among HFmrEF patients (ptrend=0.001); the reverse was observed among HFpEF patients (ptrend =0.005). Prescription of triple NHM increased over time in both phenotypes (all p for trend<0.0001). Compared to no/single NHM, triple, but not double, NHM was associated with better outcome in both HFmrEF (HR 0.700, 95% CI 0.505–0.969, p=0.032) and HFpEF (HR 0.700, 95% CI 0.499–0.983, p=0.039), with no interaction between NHM and age groups (p=0.58, p=0.80, respectively). Conclusions In a cardiology setting, among HF outpatient with EF>40%, prescription rates of triple NHM increased over time and were associated with better patient outcome.

Combined Neuro-Humoral Modulation and Outcomes in Patients with Chronic Heart Failure and Mildly Reduced or Preserved Ejection Fraction.

Pharmacotherapy of chronic heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF) remains challenging. We aimed to assess whether combined neuro-humoral modulation (NHM) (renin-angiotensin system inhibitors, betablockers, mineralocorticoid receptor antagonists) was differentially associated with outcome according to phenotype and age groups. Between 1999 and 2018 we recruited in a nationwide cardiology registry 4707 patients (HFmrEF n = 2298, HFpEF n = 2409) from three age groups: <65, 65-79 and 80+ years old. We analyzed clinical characteristics and 1 year all-cause mortality/cardiovascular hospitalization according to none/single, any double, or triple NHM. Prescription rates of no/single and triple NHM were 25.1% and 26.7% for HFmrEF; 36.5% and 17.9% for HFpEF patients, respectively. Older age was associated with higher prescription of no/single NHM in HFmrEF (ptrend = 0.001); the reverse was observed among HFpEF (ptrend = 0.005). Triple NHM increased over time in both phenotypes (all p for trend < 0.0001). Compared to no/single NHM, triple, but not double, NHM was associated with better outcomes in both HFmrEF (HR 0.700, 95%CI 0.505-0.969, p = 0.032) and HFpEF (HR 0.700, 95%CI 0.499-0.983, p = 0.039), with no interaction between NHM treatment and age groups (p = 0.58, p = 0.80, respectively). In a cardiology setting, among HF outpatients with EF > 40%, triple NHM treatment increased over time and was associated with better patient outcomes.

Shift of conventional paradigm of heart failure treatment: from angiotensin receptor neprilysin inhibitor to sodium-glucose co-transporter 2 inhibitors?

Current clinical guidelines for heart failure (HF) contain a brand new therapeutic strategy for HF with reduced ejection fraction (HFrEF), which is based on neurohumoral modulation through the use of angiotensin receptor neprilysin inhibitors. There is a large body of evidence for the fact that sodium-glucose co-transporter 2inhibitors may significantly improve all-cause mortality, cardiovascular mortality and hospitalization for HF in patients with HFrEF who received renin-angiotensin system blockers including angiotensin receptor neprilysin inhibitors, β-blockers and mineralocorticoid receptor antagonists. The review discusses that sodium-glucose co-transporter 2 inhibitors have a wide spectrum of favorable molecular effects and contribute to tissue protection, improving survival in HFrEF patients.

Inappropriate sinus tachycardia: a review.

Inappropriate sinus tachycardia (IST) has been defined as a resting heart rate of >100 beats per minute and an average 24-hour heart rate >90 bpm with distressing symptoms resulting from the persistent tachycardia. IST is prevalent in 1% of the middle-aged population, mostly females. Rarely can elderly patients also present with IST. Possible mechanisms of IST include intrinsic sinus node abnormality, beta-adrenergic receptor stimulating autoantibody, beta-adrenergic receptor supersensitivity, muscarinic receptor autoantibody, or hyposensitivity, impaired baroreflex control, depressed efferent parasympathetic/vagal function, nociceptive stimulation, central autonomic overactivity, aberrant neurohumoral modulation, etc. Symptoms associated with IST are palpitations, chest pain, fatigue, shortness of breath, presyncope, and syncope. Despite these distressing symptoms, IST has not been associated with tachycardia-associated cardiomyopathy or increased major cardiovascular events. Various treatment options for patients with IST are ivabradine, beta-adrenergic blockers, calcium channel blockers, psychiatric evaluation, and exercise training. Although, endocardial radiofrequency ablation targeting the sinus node has been used as a treatment modality for otherwise treatment-refractory IST, the results have been dismal. The other modalities used for refractory IST treatment are endocardial modification of the sinus node using radiofrequency energy, combined endo and epicardial ablation of the sinus node, thoracoscopic epicardial ablation of the sinus node, sinus node sparing thoracoscopic and endocardial hybrid ablation. The goal of this review is to provide the readership with the pathophysiological basis of IST and its management options.

Cardiovascular Effects of Three Distinct Anesthetic Approaches in Rats

It is well known that anesthesia affects hemodynamics and leads to marked changes in neurohumoral modulation of the cardiovascular system, affecting results obtained in research protocols conducted during anesthesia. We evaluated the effect of three distinct anesthetic agents on arterial pressure (AP), heart rate (HR), and their variability indexes before and during anesthesia in rats. Conscious freely moving Wistar rats, previously instrumented with catheters in the femoral artery, had their AP recorded during 30 min. Following they were anesthetized with ketamine/xylazine (KX: 50/10 mg/kg, ip, N=7), urethane (URE: 1 g/kg, ip, N=7) or inhalation of isoflurane (ISO: 3–5%, N=10) and the AP recording was maintained for the next 30 min. At the onset of anesthesia with KX, the animals showed a marked rise in AP (D 47±2 mmHg) that slowly returned to normal values within 30 min. URE did not affect AP, while ISO caused a pressure drop of 16±1 mmHg. Overall blood pressure variability, measured by the standard deviation of systolic pressure values, was reduced during anesthesia with KX (D ‐ 1.9±0.5 mmHg) or URE (D −2.3±0.3 mmHg) but was not affected by inhalation of ISO. Likewise, the power of systolic AP spectra, an index of sympathetic vascular modulation, was markedly decreased by anesthesia with KX or URE (D −6.6±1.3 and −4.7±0.6 mmHg2, respectively) but not with ISO. Bradycardia (D −64±10 bpm) and an increase in HR (D 85±12 bpm) were caused by anesthesia with KX and URE, respectively. Inhalation of ISO had no effect on HR. Overall HR variability, measured by the standard deviation of normal cardiac intervals (SDNN), was markedly reduced by all anesthetic agents studied (D −1.1 to −2.0 ms for the three agents used). Spectral analysis showed that low‐frequency power of pulse interval (PI) spectra was decreased during anesthesia with KX (D −10±1 nu) or URE (D −11±3 nu). At the same time, it was not affected by the inhalation of ISO. The high‐frequency power of PI spectra was found reduced during anesthesia with the tree agents used (D −7.7 to −3.1 ms2). Multiscale entropy, an index of complexity of HR variability, showed that anesthesia with KX or URE, but not with ISO, decreased HR complexity at lower scales (1–6). At higher scales (7–20) entropy was markedly decreased by the three anesthetic agents studied. Our results revealed that, despite its hemodynamical effects, anesthesia decreases cardiovascular modulation. However, the inhalation of ISO is the anesthetic approach that preserves the most the characteristics of AP and HR variability, suggesting that this is the anesthesia that has less effect on cardiac and vascular modulation.Support or Funding InformationSupported by FAPESP and CNPq

Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension.

Pulmonary vascular disease, including pulmonary arterial hypertension (PAH), is increasingly recognized to be affected by systemic alterations including up-regulation of the renin-angiotensin-aldosterone system and perturbations to metabolic pathways, particularly glucose and fat metabolism. There is increasing preclinical and clinical data that each of these pathways can promote pulmonary vascular disease and right heart failure and are not simply disease markers. More recently, trials of therapeutics aimed at neurohormonal activation or metabolic dysfunction are beginning to shed light on how interventions in these pathways may affect patients with PAH. This review will focus on underlying mechanistic data that supports neurohormonal activation and metabolic dysfunction in the pathogenesis of PAH and right heart failure as well as discussing early translational data in patients with PAH.

ПСИХОФІЗІОЛОГІЧНІ ЗМІНИ В ОРГАНІЗМІ СТУДЕНТІВ ПІД ВПЛИВОМ НАВЧАЛЬНОГО НАВАНТАЖЕННЯ

Introduction: Preparation of students for professional activity requires significant psycho-physiological stress. Adaptive changes that occur in the body, characterize the level of functioning of systems and their potential capabilities. Purpose: The aim of the artcle was to investigate the changes in mental functions and vegetative reactions in the formation of long-term adaptation of the students organisms to the study load. Methods: A method for studying the properties of attention for correctional tables Anfimova, the method of arrangement of numbers, red-black tables of Schulte, methods of studying short-term arbitrary visual memory; 5-minute Heart Rate Variability (HRV) records. Results: The study load for students of “Physics and Mathematics” (PHM) and “Chemistry and Biology”(CHB) corresponded to their psychological and mental abilities that were decisive when choosing a specialty, and therefore did not cause significant changes in attention and mnemonic processes. Adaptive reactions manifested in vegetative regulation. Changes in HRV showed an increase in parasympathetic regulation and decreased neurohumoral modulation in women, “Foreign Languages” (FL). Reduced memory for words (p ≤ 0.05), caused tensions of regulatory influences and increased central regulation. Under the influence of the educational load in the students of the “Physical Education” (PHE), the indicators of mental activity improved (p ≤ 0.05). Changes in regulatory influences were manifested in lowering the activity of higher super-segmental levels of cardiac rhythm management and increased activity of the respiratory and vasomotor centers. In women, PHM was observed reduction of cerebro-ergotropic activity (p ≤ 0.05) and maintenance of vegetative balance. Low volume and productivity of attention showed a decrease in efficiency, but it did not have a disruptive effect on the body. In students of CHB the activity of both departments of vegetative regulation decreased. This indicated the development of unsatisfactory adaptation mechanisms under the influence of the study load. Originality: The psycho-physiological parameters of students of different specializations of linked samples have been analyzed. Differences in the formation of adaptive changes in an organism depending on the content of educational activity have been established. Conclusion: The tension of regulatory mechanisms was felt by the students of FL and CHB. Women of PHE, psychophysiological parameters have improved as a result of high motor activity. The smallest psychophysiological discomfort was felt by women of PHM, which was manifested in the stability of the studied indicators.

Treatment strategies for the right heart in pulmonary hypertension.

The function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension. While much progress has been made in the treatment of pulmonary hypertension, therapies for the RV are less well established. In this review of treatment strategies for the RV, first we focus on ways to reduce wall stress since this is the main determinant of changes to the ventricle. Secondly, we discuss treatment strategies targeting the detrimental consequences of increased RV wall stress. To reduce wall stress, afterload reduction is the essential. Additionally, preload to the ventricle can be reduced by diuretics, by atrial septostomy, and potentially by mechanical ventricular support. Secondary to ventricular wall stress, left-to-right asynchrony, altered myocardial energy metabolism, and neurohumoral activation will occur. These may be targeted by optimising RV contraction with pacing, by iron supplement, by angiogenesis and improving mitochondrial function, and by neurohumoral modulation, respectively. We conclude that several treatment strategies for the right heart are available; however, evidence is still limited and further research is needed before clinical application can be recommended.

Effect of a 6-month pedometer-based walking intervention on functional capacity in patients with chronic heart failure with reduced (HFrEF) and with preserved (HFpEF) ejection fraction: study protocol for two multicenter randomized controlled trials

BackgroundRegular physical activity is recommended for patients with chronic heart failure to improve their functional capacity, and walking is a popular, effective, and safe form of physical activity. Pedometers have shown potential to increase the amount of walking across a range of chronic diseases, but it is unknown whether a pedometer-based intervention improves functional capacity and neurohumoral modulation in heart failure patients.MethodsTwo multicenter randomized controlled trials will be conducted in parallel: one in patients with chronic heart failure with reduced ejection fraction (HFrEF), the other in patients with chronic heart failure with preserved ejection fraction (HFpEF). Each trial will consist of a 6-month intervention with an assessment at baseline, at 3 months, at the end of the intervention, and 6 months after completing the intervention. Each trial will aim to include a total of 200 physically inactive participants with chronic heart failure who will be randomly assigned to intervention or control arms. The 6-month intervention will consist of an individualized pedometer-based walking program with weekly step goals, behavioral face-to-face sessions with a physician, and regular telephone calls with a research nurse. The intervention will be based on effective behavioral principles (goal setting, self-monitoring, personalized feedback). The primary outcome is the change in 6-min walk distance at the end of the 6-month intervention. Secondary outcomes include changes in serum biomarkers levels, pulmonary congestion assessed by ultrasound, average daily step count measured by accelerometry, anthropometric measures, symptoms of depression, health-related quality of life, self-efficacy, and MAGGIC risk score.DiscussionTo our knowledge, these are the first studies to evaluate a pedometer-based walking intervention in patients with chronic heart failure with either reduced or preserved ejection fraction. The studies will contribute to a better understanding of physical activity promotion in heart failure patients to inform future physical activity recommendations and heart failure guidelines.Trial registration The trials are registered in ClinicalTrials.gov, identifiers: NCT03041610, registered 29 January 2017 (HFrEF), NCT03041376, registered 1 February 2017 (HFpEF)

Sacubitril/valsartan, a new and effective treatment for heart failure with reduced ejection fraction

Despite significant therapeutic advances, patients with chronic heart failure and reduced ejection fraction (HFrEF) remain at high risk for heart failure progression and death. The PARADIGM-HF study, the largest outcome trial in HFrEF, has shown improved cardiovascular outcomes with sacubitril/valsartan (Entresto®, Novartis), previously known as LCZ696, compared with angiotensin-converting enzyme (ACE) inhibitor therapy, possibly leading us to a new era for heart failure treatment. Sacubitril/valsartan represents a first-in-class drug acting through inhibition of angiotensin receptor and neprilysin, thus modulating the renin-angiotensin-aldosterone system and vasoactive substances such as natriuretic peptides. This approach can be considered a "paradigm shift" from neurohumoral inhibition to neurohumoral modulation. Based on the PARADIGM-HF results, the European Society of Cardiology and the American Heart Association/American College of Cardiology guidelines proposed a substitution of ACE-inhibitor/angiotensin receptor blocker therapy rather than an "add-on" strategy in HFrEF. Sacubitril/valsartan can be considered a milestone in cardiovascular therapy, like aspirin, statins, beta-blockers. Of course there are many questions that arise spontaneously from this trial, three recognized experts can help us to answer them.

Role of PTHrP and Sensory Nerve Peptides in Regulating Contractility of Muscularis Mucosae and Detrusor Smooth Muscle in the Guinea Pig Bladder

We investigated the neurohumoral modulation of the contractility of bladder muscularis mucosae (mucosa) compared with that of detrusor smooth muscle. Changes in the contractility of mucosal and detrusor bundles from guinea pig bladders were measured using isometric tension recording. The morphological relationship between the muscularis mucosae and blood vessels, and their sensory innervation was examined by fluorescence immunohistochemistry. Meshworks of muscularis mucosae with numerous branches and anastomosis preferentially ran parallel with suburothelial blood vessels. Although PTHrPRs (parathyroid hormone-related peptide receptors) were expressed in detrusor and mucosa, the endogenous detrusor relaxant PTHrP (parathyroid hormone-related peptide) (1 nM) suppressed spontaneous contractions in detrusor but not in mucosa. A higher concentration of PTHrP (10 nM) was required to inhibit mucosal contractility. Capsaicin (1 μM) abolished spontaneous contractions in mucosa but had an excitatory action on detrusor contractility. hCGRP (human calcitonin gene-related peptide) (1 nM) attenuated spontaneous mucosal contractions. Pretreatment with the CGRP (calcitonin gene-related peptide) antagonist hCGRP 8-37 (2 μM) inhibited CGRP or capsaicin induced suppression of spontaneous contractions. Consistently, CGRP immunoreactive primary afferent nerves were abundant in muscularis mucosae. Co-localization of muscularis mucosae with the suburothelial microvasculature suggests that spontaneous contractions of mucosa might function to prevent microvasculature stretching upon bladder wall distension during the storage phase. It is likely that PTHrP selectively suppresses spontaneous contractions in detrusor but not in mucosa. Thus, endogenous PTHrP may well increase bladder compliance without an associated distension induced deformation of mucosal elements. Excessive stimulations of sensory nerves may suppress mucosal contractility by releasing CGRP.

Novel device-based interventional strategies for advanced heart failure.

While heart failure is one of the leading causes of mortality and morbidity, our tools to provide ultimate treatment solutions are still limited. Recent developments in new devices are designed to fill this therapeutic gap. The scope of this review is to focus on two particular targets, namely (1) left ventricular geometric restoration and (2) atrial depressurization. (1) Reduction of the wall stress by shrinking the ventricular cavity has been traditionally attempted surgically. Recently, the Parachute device (CardioKinetix Inc., Menlo Park, CA, USA) has been introduced to restore ventricular geometry and cardiac mechanics. The intervention aims to partition distal dysfunctional segments that are non-contributory to the ventricular mechanics and forward cardiac output. (2) Diastolic heart failure is characterized by abnormal relaxation and chamber stiffness. The main therapeutic goal achieved should be the reduction of afterload and diastolic pressure load. Recently, new catheter-based approaches were proposed to reduce left atrial pressure and ventricular decompression: the InterAtrial Shunt Device (IASD™) (Corvia Medical Inc., Tewksbury, MA, USA) and the V-Wave Shunt (V-Wave Ltd, Or Akiva, Israel). Both are designed to create a controlled atrial septal defect in symptomatic patients with heart failure. While the assist devices are aimed at end-stage heart failure, emerging device-based percutaneous or minimal invasive techniques comprise a wide spectrum of innovative concepts that target ventricular remodeling, cardiac contractility or neuro-humoral modulation. The clinical adoption is in the early stages of the initial feasibility and safety studies, and clinical evidence needs to be gathered in appropriately designed clinical trials.

Heart Failure Pharmacotherapy: Differences Between Adult and Paediatric Patients

During the last decades, the introduction of new, more efficient drugs, has significantly improved the heart failure (HF) therapy of adults. Therapeutic focus has shifted from simple hemodynamic manipulation to include neurohumoral modulation as a consequence of the better understanding of mechanisms of HF formation, in particular at the cellular level. The aetiologies of HF in children are remarkably different and more varied than in the adult population. Cardiac failure is usually caused by congenital heart disease and cardiomyopathy in children, whereas in adults, coronary artery disease, hypertension and myocardial infarction are the most common causes. Despite this fact, pharmacotherapy of children is based on the same drugs, usually extrapolated from adult HF regimens. A recently published study in children treated with the drugs known to be efficient in adult HF therapy, provides encouragement that the outcomes might be similarly beneficial. On the other hand, some reports outline that children with HF, especially patients with systemic right ventricles or single ventricle physiology, require specific drug guidelines. A general characteristic of HF pharmacotherapy in children is the lack of paediatrically designed drugs. Drugs currently used in the treatment of HF in paediatric patients are designed for adults, and their efficacy, safety and quality have generally not been confirmed by clinical studies of children. Aside from this, availability of commercial paediatric drug formulations labelled for treatment of HF in children significantly influences the quality and efficacy of therapy.

Modulation of Myocardial Stiffness by β-Adrenergic Stimulation - Its Role in Normal and Failing Heart

The acute effects of beta-adrenergic stimulation on myocardial stiffness were evaluated. New-Zealand white rabbits were treated with saline (control group) or doxorubicin to induce heart failure (HF) (DOXO-HF group). Effects of isoprenaline (10(-10)-10(-5) M), a non-selective beta-adrenergic agonist, were tested in papillary muscles from both groups. In the control group, the effects of isoprenaline were also evaluated in the presence of a damaged endocardial endothelium, atenolol (beta(1)-adrenoceptor antagonist), ICI-118551 (beta(2)-adrenoceptor antagonist), KT-5720 (PKA inhibitor), L-NNA (NO-synthase inhibitor), or indomethacin (cyclooxygenase inhibitor). Passive length-tension relations were constructed before and after adding isoprenaline (10(-5) M). In the control group, isoprenaline increased resting muscle length up to 1.017+/-0.006 L/L(max). Correction of resting muscle length to its initial value resulted in a 28.5+/-3.1 % decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the isoprenaline-induced right-downward shift of the passive length-tension relation. These effects were modulated by beta(1)- and beta(2)-adrenoceptors and PKA. In DOXO-HF group, the effect on myocardial stiffness was significantly decreased. We conclude that beta-adrenergic stimulation is a relevant mechanism of acute neurohumoral modulation of the diastolic function. Furthermore, this study clarifies the mechanisms by which myocardial stiffness is decreased.

Heart of the matter: coronary dysfunction in metabolic syndrome.

Metabolic syndrome (MetS) is a collection of risk factors including obesity, dyslipidemia, insulin resistance/impaired glucose tolerance, and/or hypertension. The incidence of obesity has reached pandemic levels, as ~20-30% of adults in most developed countries can be classified as having MetS. This increased prevalence of MetS is critical as it is associated with a two-fold elevated risk for cardiovascular disease. Although the pathophysiology underlying this increase in disease has not been clearly defined, recent evidence indicates that alterations in the control of coronary blood flow could play an important role. The purpose of this review is to highlight current understanding of the effects of MetS on regulation of coronary blood flow and to outline the potential mechanisms involved. In particular, the role of neurohumoral modulation via sympathetic α-adrenoceptors and the renin-angiotensin-aldosterone system (RAAS) are explored. Alterations in the contribution of end-effector K(+), Ca(2+), and transient receptor potential (TRP) channels are also addressed. Finally, future perspectives and potential therapeutic targeting of the microcirculation in MetS are discussed. This article is part of a Special Issue entitled "Coronary Blood Flow".

Modulation of peripheral chemoreflex by neurohumoral adaptations after kidney transplantation

BackgroundPeripheral chemoreceptors residing predominantly in the carotid body monitor changes in arterial blood oxygen and are mechanistically linked to the cardiorespiratory control by the autonomic nervous system. Enhanced sympathetic activation is common in end-stage renal disease and kidney transplantation has been shown to improve cardiorespiratory reflex measures of autonomic function.ObjectiveThe aim of the present study was to test whether improvement in renal function following kidney transplantation is related to an improvement in chemosensory function.Methods and ResultsWe compared hyperoxic chemoreflex sensitivity (CHRS) in patients after renal transplantation (RTX) to that in patients on maintenance hemodialysis (HD), and that of age- and gender-matched healthy controls. In addition, we investigated the impact of common confounding factors including pharmacological neurohumoral modulation and diabetes mellitus. The difference in the R-R intervals divided by the difference in the oxygen pressures before and after deactivation of the chemoreceptors by 5-min inhalation of 7 L oxygen was calculated as the hyperoxic CHRS. Autonomic activity was characterized by 24-h time-domain heart rate variability (HRV) parameters. CHRS was improved in RTX patients as compared to HD patients being related to HRV. CHRS was related to the concomitant presence of diabetes and medication with cyclosporine.ConclusionOur findings indicate that chemosensory activity following kidney transplantation is related to cardiac autonomic control, but functional testing might only be useful to characterize the time course and extent of sympathetic activation in selected patients due to existing co-morbidities and immunosuppressive medication in this population.

Heart rate variability in weightlifters

On the basis of the literature and original data, heart rate variability (HRV) in weightlifters has been studied. The results showed that the distribution mode (a parameter of mathematical analysis that is equal to the most frequent length of RR intervals) indicates the intensity of physical exercise. Specific changes in the autonomic balance in athletes as dependent on their degree of training and sports qualification are important characteristics of adaptations to physical loads. For example, the degree of training of weightlifters is reflected by the level of the respiratory component as an index of the activity of the parasympathetic nervous system. Adaptation to physical exercise leads to an increase in the power of the spectrum of neurohumoral modulation and to changes in the ratio between the levels of the total spectral power of HRV.

Effects of adrenomedullin on systolic and diastolic myocardial function

Adrenomedullin (AM) effects were studied in rabbit papillary muscles by adding increasing concentrations (10 −10 to 10 −6 M) either alone or after pre-treatment with l-NNA, indomethacin, AM22–52 (AM receptor antagonist), CGRP(8–37) (CGRP receptors antagonist), KT5720 (PKA inhibitor), as well as after endocardial endothelium (EE) removal. Passive length–tension relations were constructed before and after a single concentration of AM (10 −6 M). AM concentration-dependently induced negative inotropic and lusitropic effects, and increased resting muscle length (RL). At 10 −6 M, AT, d T/d t max and d T/d t min decreased 20.9 ± 4.9%, 18.3 ± 7.3% and 16.7 ± 7.8%, respectively, and RL increased to 1.010 ± 0.004 L/ L max. Correcting RL to its initial value resulted in a 26.6 ± 6.4% decrease of resting tension, indicating decreased muscle stiffness, also patent in the down and rightward shift of the passive length–tension relation. The negative inotropic effect of AM was dependent on its receptor, CGRP receptor, PKA, the EE and NO, while the effects of AM on myocardial stiffness were abolished by EE damage and NO inhibition. This latter effect represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that AM is an important regulator of cardiac filling.

Urotensin II acutely increases myocardial length and distensibility: potential implications for diastolic function and ventricular remodeling

Urotensin II (U-II) is a cyclic peptide that may be involved in cardiovascular dysfunction. In the present study, the acute effects of U-II on diastolic properties of the myocardium were investigated. Increasing concentrations of U-II (10(-8) to 10(-6) M) were added to rabbit papillary muscles in the absence (n = 15) or presence of: (1) damaged endocardial endothelium (EE; n = 9); (2) U-II receptor antagonist, urantide (10(-5) M; n = 7); (3) nitric oxide (NO) synthase inhibitor, N(G)-Nitro-L-Arginine (10(-5) M; n = 9); (4) cyclooxygenase inhibitor, indomethacin (10(-5) M; n = 8); (5) NO synthase and cyclooxygenase inhibitors, N(G)-Nitro-L-Arginine (10(-5) M) and indomethacin (10(-5) M), respectively, (n = 8); or (6) protein kinase C (PKC) inhibitor, chelerythrine (10(-5) M; n = 9). Passive length-tension relations were constructed before and after a single concentration of U-II (10(-6) M; n = 3). U-II concentration dependently decreased inotropy and increased resting muscle length (RL). At 10(-6) M, active tension decreased 13.8 +/- 5.4%, and RL increased to 1.007 +/- 0.001 L/L (max). Correcting RL to its initial value resulted in an 18.1 +/- 3.0% decrease in resting tension, indicating decreased muscle stiffness, which was also suggested by the down and rightward shift of the passive length-tension relation. This effect remained unaffected by EE damage and PKC inhibition. In contrast, the presence of urantide and NO inhibition abolished the effects of U-II on myocardial stiffness, while cyclooxygenase inhibition significantly attenuated them. U-II decreases myocardial stiffness, an effect that is mediated by the urotensin-II receptor, NO, and prostaglandins. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that U-II is an important regulator of cardiac filling.

β-Agonist enhances type 2 T-cell survival and accumulation

Neurohumoral modulation of immune system function is poorly understood. beta-Adrenergic receptor ligands (beta-agonists) subserve numerous physiologic processes but also function as pathogenic or therapeutic agents in numerous diseases with inflammatory components. We sought to establish the effects of beta-agonists and prostaglandin E(2) (PGE(2)) on antigen-dependent and antigen-independent accumulation of IL-13(+) (type 2) and IFN-gamma(+) (type 1) T cells. We also sought to clarify the mechanisms mediating the effects of these G protein-coupled receptor agonists. Effects of beta-agonists or PGE(2) on T-cell subtype accumulation were assessed in peripheral blood lymphocytes cultured with alphaCD3/CD28 or IL-2 by using flow cytometry. The role of cyclic AMP-dependent protein kinase (PKA) in mediating agonist effects was assessed by means of characterization of (1) phosphorylation of an intracellular PKA substrate and (2) T cells from patients with lupus possessing a natural defect in PKA activation. beta-Agonists, in contrast to PGE(2), increased IL-2-induced accumulation of human type 2 T cells, an effect attributable to differential activation of PKA affecting regulation of cell proliferation and apoptosis. In T cells from patients with lupus exhibiting defective PKA activation, both beta-agonists and PGE(2) promoted an increase in type 2 T-cell accumulation. G(s)-coupled receptors have the capacity to elicit prosurvival signaling in type 2 T cells, which, in most instances, is obscured by concomitant and antimitogenic PKA activation. beta-Agonists and other G(s)-coupled receptor agonists have the potential to regulate T-cell development to affect disease pathogenesis or the efficacy of therapies, and variability of effect relates to the ability to stimulate PKA activity.