Down-regulation Of Beta-adrenoceptors Research Articles

Valvular Cardiomyopathy in Aortic Valve Regurgitation Correlates with Myocardial Fibrosis.

Objective: At the tissue level, disruption of the extracellular matrix network leads to irreversible cardiac fibrosis, which contributes to myocardial dysfunction. At the myocyte level, downregulation of beta-adrenoceptors (beta-AR) reduces adaptation to increased workload. The aim of our study was to analyse the correlation between myocardial fibrosis and beta-AR sensitivity in patients with aortic valve (AV) disease. Methods: A total of 92 consecutive patients who underwent elective AV surgery between 2017-2019 were included in our study (51 with aortic regurgitation (AR-group); 41 with aortic stenosis (AS-group) and left ventricular (LV) biopsies were obtained intraoperatively. In vitro force contractility testing was performed by measuring beta-AR sensitivity (-log EC50[ISO]). In parallel, a quantitative analysis of myocardial fibrosis burden was performed. Results: Mean age at the time of AV surgery was not statistically different in both groups (AR: 53.3 ± 15.3 years vs. AS: 58.7 ± 17.0 years; p = 0.116). The LV end-diastolic diameter was significantly enlarged in the AR-group when compared to the AS-group (59.4 ± 15.6 vs. 39.7 ± 21.2; p < 0.001). Analysis of beta-AR sensitivity (AR: -6.769 vs. AS: -6.659; p = 0.316) and myocardial fibrosis (AR: 8.9% vs. AS: 11.3%; p = 0.284) showed no significant differences between patients with AS and AR. There was no correlation between myocardial fibrosis and beta-AR sensitivity in the whole study cohort (R = 0.1987; p = 0.100) or in the AS-subgroup (R = 0.009; p = 0.960). However, significant correlation of fibrosis and beta-AR sensitivity was seen in AR-patients (R = 0.363; p = 0.023). Conclusion: More severe myocardial fibrosis was associated with reduced beta-AR sensitivity in patients presenting with AR but not with AS. Therefore, our results suggest that in patients with AR, cellular myocardial dysfunction is present and correlates with the extent of myocardial fibrosis in the myocardium.

St. John's wort for depression

Depression is a common and serious mood disorder, with nearly 7% of U.S. adults reporting at least one episode of major depression in the past year. The common adverse effects associated with antidepressants cause many patients to turn to alternative treatments like St. John's wort (Hypericum perforatum). This yellow-flowering plant is one of the most popular supplements promoted for depression, menopause symptoms, and mood disorders. St. John's wort blooms in June around the time of the feast of St. John the Baptist, thereby earning its name. This wild-growing plant has been used for centuries in traditional medicine to treat a variety of conditions, including kidney and lung ailments, insomnia, and depression, and to aid in wound healing. Several active components found in the leaves and flowers may be responsible for St. John's wort's healing properties. Many of the pharmacologic activities of St. John's wort appear attributable to hypericin, hyperforin, and several flavonoids. These organic compounds act to improve and regulate mood through inhibition of the uptake of neurotransmitters like serotonin, dopamine, and noradrenaline. St. John's wort leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors. By causing changes in neurotransmitter concentrations implicated in depression, St. John's wort acts on several messengers in the brain, similarly to antidepressants. A 2016 in-depth analysis in Systematic Reviews evaluated the efficacy and safety of St. John's wort for treatment of major depressive order. The researchers examined 35 studies with 6,993 patients prescribed a hypericum extract of 0.3% hypericin and 1% to 4% hyperforin. St. John's wort showed clinical significance and appeared to be more effective compared with placebo. However, it is unclear if this holds true for severe depression or time periods longer than 12 weeks. A 2017 review in Journal of Affective Disorders detailed data from 27 clinical trials including 3,808 patients that compared St. John's wort and SSRIs. Results indicated that St. John's wort improved depression symptoms and was as effective as standard antidepressant medications for symptoms of mild and moderate depression. The authors also found a lower dropout rate for patients using St. John's wort over SSRIs. Lack of research on severe depression, limited study length, and poor reporting on adverse events mean the findings from both studies should be interpreted with caution. St. John's wort grows in the wild, and chopped or powdered forms of the dried herb are available in capsules, tablets, liquid extracts, and teas, all standardized to contain 0.3% hypericin. Because of its anti-inflammatory properties, oil-based topical lotions of St. John's wort are promoted for various skin conditions as well as wounds, bruises, and muscle pain. For mood disorders and mild to moderate depression, St. John's wort extract is well tolerated as 0.3% hypericin or 5% hyperforin at doses of 300 mg three times daily, with meals. For symptoms of menopause, St. John's wort extract may be taken in doses of 300 mg three times daily for 3 to 4 months. Overall, St. John's wort is considered safe, with few reported minor and uncommon adverse effects, including upset stomach, dry mouth, headache, fatigue, dizziness, confusion, sexual dysfunction, or sensitivity to sunlight when taken in large doses. Because St. John's wort is a stimulant, it may worsen feelings of anxiety in some people. Counsel patients that St. John's wort limits the effectiveness of many prescription medicines, including antidepressants, birth control pills, cyclosporine, digoxin, and oxycodone, among others. Caution pregnant or breastfeeding patients that there are insufficient data on the safety of St. John's wort during pregnancy and lactation, and it cannot be recommended. Depression can become a serious and severe illness if effective, professional help is not sought. Encourage patients to speak with their health care provider and not attempt to treat depression on their own.

Cardiac β-Adrenergic Receptor Downregulation, Evaluated by Cardiac PET, in Chronotropic Incompetence.

The mechanism of chronotropic incompetence (CTI), which has been associated with autonomic dysfunction, has not been elucidated in patients without heart failure (HF). Methods: Cardiac PET using 11C-CGP12177 was performed to investigate the cardiac β-adrenergic receptor density (β-ARD) in 13 patients with CTI without HF and 6 healthy controls. The maximum number of available specific 11C-CGP12177 binding sites per gram of tissue was calculated in regions of interest using an established graphical method. Results: Peak heart rate was significantly lower in CTI patients than in controls (116.9 ± 11.0 vs. 154.8 ± 14.4 beats/min, P < 0.001). β-ARD of the total myocardium was significantly lower in CTI patients than in controls (4.3 ± 1.7 vs. 7.0 ± 1.7 pmol/mL, P = 0.005). Conclusion: β-adrenergic receptor downregulation was demonstrated in patients with CTI without HF. Decreased β-ARD is a common feature in patients with CTI, with or without HF.

Abstract 469: Targeting Beta Adrenergic Receptor Resensitization Aids in Preservation of Receptor Function

Beta adrenergic receptor (βAR) down-regulation and desensitization are hallmarks of heart failure. Traditionally, it has been considered that increased desensitization mechanisms underlie βAR dysfunction in heart failure but it is not known whether resensitization of βARs is altered and is an integral contributor to heart failure. We have previously shown that resensitization is regulated by inhibition of PP2A by I2PP2A via PI3Kγ (Vasudevan et. al., 2011), the underlying mechanisms of I2PP2A binding to PP2A are not well understood. We used PyMOL software to find the binding interaction between PP2A and I2PP2A. Based on in silico predictions, we generated a mutant PP2A that when expressed would compete out I2PP2A and inhibit I2PP2A from binding to endogenous PP2A. Expression of PP2A mutant in β2AR expressing cells showed preservation of β2AR function following stimulation as measured by reduced β2AR phosphorylation, increased cAMP generation and increased phosphatase function. We also generated a small molecule from our in silico predictions that could target the interface of I2PP2A and PP2A binding to find that disruption of the PP2A/I2PP2A interaction underlies receptor function. We will use this small molecule to look at preservation of βAR function and amelioration of cardiac function. To test whether resensitization is altered in heart failure we used plasma membrane and endosomal fractions from non-failing and paired pre- and post-LVAD samples to show PI3K activity, PP2A activity, β2AR phosphorylation and adenylyl cyclase activity as a measure of recovery in βAR function. Our studies showed that endosomal fractions from human heart failure samples had elevated PI3K activity associated with reduced PP2A activity supporting the idea that βAR resensitization is inhibited in human heart failure samples. Since human heart failure samples have inhibited resensitization we tested the underlying mechanisms regulating βAR resensitization. Thus ongoing studies suggest that targeting the resensitization of βAR could provide beneficial cardiac remodeling in conditions of chronic mechanical overload and will be further discussed.

Abstract 207: Left Ventricular Assist Device (LVAD) Reverses Inhibition on Beta-adrenergic Receptor Resensitization

Beta-adrenergic receptor (βAR) down-regulation and desensitization are hallmarks of heart failure. Agonist occupied βAR undergo desensitization through phosphorylation by G-protein coupled receptor kinases leading to βAR internalization. Phosphorylated βAR becomes resensitized following dephosphorylation by protein phosphatase 2A (PP2A) in the endosomes and we have shown previously shown that PP2A activity is regulated by phosphoinositide3-kinaseγ (PI3Kγ). Traditionally, it has been considered that increased desensitization mechanisms underlie βAR dysfunction in heart failure but it is not known whether resensitization of βARs is altered and an integral contributor to heart failure. To test whether resensitization mechanisms are altered in heart failure and could play a role in recovery of βAR function post-LVAD, we used paired pre- and post-LVAD human heart samples along with non-failing hearts. Since resensitization occurs in endosomes, plasma membranes and endosomes were isolated from these human heart samples and assessed for PI3K activity, PP2A activity, β2AR phosphorylation and adenylyl cyclase (AC) activity as a measure of recovery in βAR function by G-protein coupling. Significant PI3Kγ activity was observed in the endosomes of pre-LVAD compared post-LVAD and non-failing human heart samples while plasma membrane PI3K activity remained similar across all samples. Similarly, AC activity was markedly reduced in plasma membranes and endosomes of pre-LVAD samples compared to post-LVAD and non-failing showing reduced ability of receptors to couple to G-proteins indicating reduced recovery of receptor function in post-LVAD heart samples. Consistent with the reduced recovery in βAR function in pre-LVAD samples, significant β2AR phosphorylation was observed in the endosomes and plasma membranes of pre-LVAD compared to post-LVAD and non-failing. Correspondingly, we observed significant reduction in endosomal PP2A activity in the pre-LVAD samples which was remarkably reversed in post-LVAD samples similar to the activity in non-failing. These studies suggest that resensitization is inhibited in end-stage human heart failure and may critically contribute to cardiac remodeling and hypertrophic response upon cardiac stress.

Salbutamol and around

Short-acting beta agonists (SABAs) such as salbutamol are well known as the first-line therapy for the treatment of acute exacerbations, exercise-induced asthma and childhood intermittent asthma. As needed, SABAs with no controller should be considered only if symptoms are rare and there is no awakening due to asthma. Salbutamol, through its effects of relaxing airway smooth muscle and increasing airflow, provides rapid relief of acute asthma symptoms. Treatment's effects begin in about 10-15 minutes and peak effect is usually within 30 minutes. Patient experience prompt benefit with reduction in coughing, wheezing, chest tightness and shortness of breath. The treatment dose includes 4-10 puffs by pMDI+spacer every 20 minutes for 1 hour [1]. The rapid relief provided by salbutamol may invite misuse and overuse, particularly in adolescents. SABAs should not be prescribed on a regular schedule as it may lead to a beta receptor downregulation. Moreover, frequent use of salbutamol is an indication of poor asthma control and an increased use of controller therapy should be considered. An heterogenous response to beta agonist therapy has been described and individual response is related to many factors, including: the relative contribution of bronchoconstriction versus airway inflammation and edema in producing the airway obstruction, different triggering mechanisms, the duration of symptoms, the patient's age and the route of medication delivery. Salbutamol is normally delivered through the inhaled route while intravenous salbutamol is used when children are unresponsive to inhaled treatment [A]. Less common are the oral and subcutaneous routes. Inhaled SABAs, administered through a MDI with attached spacer device along with infant- or child-sized mask or by nebulization, have the advantages of smaller doses and fewer side effects [3]. Inhaled SABAs allow selectivity for beta-2 receptors on bronchial smooth muscle to achieve bronchodilation without significant tachycardia associated with activation of beta-1 receptors on cardiac muscle. The incidence of adverse effects is dependent upon age of patient, dose, and route of administration. Examples of possible mild or moderate side effects in children and adolescents, not very common at recommended doses, include: palpitations, tachycardia, excitement, hyperactivity, insomnia, nervousness, shakiness and unpleasant taste (inhalation site) [4].

Cardiac β-adrenergic receptor density and myocardial systolic function in the remote noninfarcted region after prior myocardial infarction with left ventricular remodelling

After myocardial infarction (MI), left ventricular (LV) remodelling is observed in noninfarcted LV myocardium. LV remodelling is closely associated with systolic heart failure. Since myocardial dysfunction is related to the downregulation of cardiac postsynaptic beta-adrenergic receptors (β-AR), we hypothesized that a reduction in β-AR density may be manifested in the remote noninfarcted region and such reduction may be related to myocardial systolic dysfunction. Accordingly, we assessed β-AR density with a focus on the remote noninfarcted region. Cardiac PET was performed in 15 patients with a prior MI and 10 age-matched healthy controls using (11)C-CGP 12177, a radioligand for β-receptors. The maximum number of available specific (11)C-CGP 12177 binding sites per gram of tissue was calculated in regions of interest using an established graphical method. LV regional systolic function was assessed based on peak systolic myocardial strain on the LV wall in the longitudinal direction using two-dimensional ultrasound speckle tracking imaging. LV volumes and LV ejection fraction (EF) were also measured. The LV end-diastolic volume index was significantly larger in patients than in controls (67.8 ± 16.9 vs. 49.1 ± 12.3 ml/m(2), p < 0.01). Significant differences in β-AR density were observed among three areas: the apical area in controls (where the lowest β-AR density was observed), the remote noninfarcted region of patients and LVEF ≥ 55 %, and the remote noninfarcted region of patients and LVEF <55 % (5.8 ± 2.1 vs. 4.2 ± 0.7 vs. 3.3 ± 0.7 pmol/ml, p < 0.01, ANOVA). Peak systolic myocardial strain was significantly reduced in the remote noninfarcted LV wall in patients with a prior anterior wall MI compared with that in the corresponding wall in controls (-15.5 ± 2.5 vs. -20.1 ± 2.2 %, p < 0.001). A similar finding was also observed in patients with a prior inferior wall MI. In the remote noninfarcted region in patients, β-AR downregulation was observed, which was related to deterioration of local myocardial systolic function.

Chronic treatment with electroconvulsive shock prevents the salbutamol-induced hypoactivity in rats.

Several lines of evidence (binding studies, reduced responsiveness of brain adenylate cyclase to noradrenergic stimulation) indicate that chronic treatment with electroconvulsive shock (ECS) induces down-regulation of central beta-adrenoceptors. The effect of acute and chronic (10 days) treatment with ECS on salbutamol-induced suppression of exploratory activity in rats has been examined. This effect was prevented by chronic but not by acute treatment with ECS. Chronic treatment with ECS did not affect exploratory activity. The salbutamol-induced hypoactivity is mediated through central beta-adrenoceptors (antagonistic effect of (-)-propranolol but not (+)-propranolol or practolol), so the results may be regarded as functional evidence at the behavioral level for the down-regulation of beta-adrenoceptors produced by chronic treatment with ECS.

558 Alterations in Muscarinic Receptors in Human Heart Failure and Effects of LVAD Support

It is well established that the sympathetic nervous system (SNS) is over stimulated in the failing human heart, resulting in down regulation of beta-adrenergic receptors on cardiac myocytes. The goal of the current study was to test the hypothesis that the parasympathetic nervous system (PNS) may be concomitantly dysregulated in human heart failure (HF).

Beta-Adrenergic Blockers for Chronic Heart Failure

Systolic dysfunction and heart failure are major public health problems associated with a significant risk of morbidity and mortality. During the past 2 decades, considerable progress has been made in defining the underlying pathophysiology and the appropriate therapies in heart failure. In patients with chronic heart failure (CHF), sustained sympathetic overactivation leads to down-regulation of beta receptors and uncoupling of the receptors from adenylate cyclase. The clear understanding of the pivotal role of sympathetic overactivation in CHF has led to the evaluation of beta- blocker therapy in CHF. A number of large randomized clinical trials have been conducted with a variety of beta-blockers, and although most of them have shown benefit, there have been differing findings with different molecules. beta-blockers are now considered part of the standard therapy for all patients with symptomatic CHF. Despite the strong evidence supporting their use, beta-blockers continue to be underutilized in CHF.

Involvement of β3-Adrenoceptor in Altered β-Adrenergic Response in Senescent Heart

In senescent heart, beta-adrenergic response is altered in parallel with beta1- and beta2-adrenoceptor down-regulation. A negative inotropic effect of beta3-adrenoceptor could be involved. In this study, the authors tested the hypothesis that beta3-adrenoceptor plays a role in beta-adrenergic dysfunction in senescent heart. beta-Adrenergic responses were investigated in vivo (echocardiography-dobutamine, electron paramagnetic resonance) and in vitro (isolated left ventricular papillary muscle, electron paramagnetic resonance) in young adult (3-month-old) and senescent (24-month-old) rats. Nitric oxide synthase (NOS) immunolabeling (confocal microscopy), nitric oxide production (electron paramagnetic resonance) and beta-adrenoceptor Western blots were performed in vitro. Data are mean percentages of baseline +/- SD. An impaired positive inotropic effect (isoproterenol) was confirmed in senescent hearts in vivo (117 +/- 23 vs. 162 +/- 16%; P < 0.05) and in vitro (127 +/- 10 vs. 179 +/- 15%; P < 0.05). In the young adult group, the positive inotropic effect was not significantly modified by the nonselective NOS inhibitor N-nitro-L-arginine methylester (L-NAME; 183 +/- 19%), the selective NOS1 inhibitor vinyl-L-N-5(1-imino-3-butenyl)-L-ornithine (L-VNIO; 172 +/- 13%), or the selective NOS2 inhibitor 1400W (183 +/- 19%). In the senescent group, in parallel with beta3-adrenoceptor up-regulation and increased nitric oxide production, the positive inotropic effect was partially restored by L-NAME (151 +/- 8%; P < 0.05) and L-VNIO (149 +/- 7%; P < 0.05) but not by 1400W (132 +/- 11%; not significant). The positive inotropic effect induced by dibutyryl-cyclic adenosine monophosphate was decreased in the senescent group with the specific beta3-adrenoceptor agonist BRL 37344 (167 +/- 10 vs. 142 +/- 10%; P < 0.05). NOS1 and NOS2 were significantly up-regulated in the senescent rat. In senescent cardiomyopathy, beta3-adrenoceptor overexpression plays an important role in the altered beta-adrenergic response via induction of NOS1-nitric oxide.

Exercise promotes angiogenesis and improves β-adrenergic receptor signalling in the post-ischaemic failing rat heart

We investigated whether exercise training could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodelling of the post-myocardial infarction (MI) failing heart. We also explored the contribution of ameliorated beta-adrenergic receptor signalling and function on the overall improvement of cardiac contractility reserve induced by exercise. Adult Wistar male rats were randomly assigned to one of four experimental groups. Sham-operated and post-MI heart failure (HF) rats were housed under sedentary conditions or assigned to 10-weeks of a treadmill exercise protocol. At 4 weeks after MI, sedentary HF rats showed LV eccentric hypertrophy, marked increase of LV diameters associated with severely impaired fractional shortening (14 +/- 5%), increased LV end diastolic pressure (20.9 +/- 2.6 mmHg), and pulmonary congestion. In addition, cardiac contractile responses to adrenergic stimulation were significantly blunted. In trained HF rats, exercise was able to (i) reactivate the cardiac vascular endothelial growth factor pathway with a concurrent enhancement of myocardial angiogenesis, (ii) significantly increase myocardial perfusion and coronary reserve, (iii) reduce cardiac diameters, and (iv) improve LV contractility in response to adrenergic stimulation. This latter finding was also associated with a significant improvement of cardiac beta-adrenergic receptor downregulation and desensitization. Our data indicate that exercise favourably affects angiogenesis and improves LV remodelling and contractility reserve in a rat model of severe chronic HF.

How antidepressants work: cautionary conclusions based on clinical and laboratory studies of the longer-term consequences of antidepressant drug treatment.

Time-dependent alterations in the functional activity of adrenergic and serotonergic neurotransmitter systems and, in particular, a frequently observed down-regulation of brain beta-adrenoceptors have been implicated in antidepressant drug effects. Current studies of catecholamine and serotonin neurotransmitter systems suggest that the net physiological output changes in neuroendocrine responses, blood pressure, sleep and motor activity which follow various antidepressant treatments in psychiatric patients, normal controls and different experimental animals are not indicative of a common response pattern to all therapeutically effective agents. Rather, antidepressant treatment effects differ according to many variables, including the pre-existing state of the organism (e.g. depressed, stressed or normal), the species, the duration of treatment and the particular brain or peripheral circuits investigated. Examples are cited from our studies of the effects of monoamine oxidase inhibitors and other antidepressants on noradrenergic-serotonergic interactions that affect melatonin release and other neuroendocrine responses, on some additional functional end-points, and on depressive mood and other symptoms in patients with depression or other tricyclic-responsive disorders. These examples illustrate the complexity found in attempts to identify a unitary mechanism of antidepressant drug action.

Mechanisms of sepsis-induced cardiac dysfunction

To review mechanisms underlying sepsis-induced cardiac dysfunction in general and intrinsic myocardial depression in particular. MEDLINE database. Myocardial depression is a well-recognized manifestation of organ dysfunction in sepsis. Due to the lack of a generally accepted definition and the absence of large epidemiologic studies, its frequency is uncertain. Echocardiographic studies suggest that 40% to 50% of patients with prolonged septic shock develop myocardial depression, as defined by a reduced ejection fraction. Sepsis-related changes in circulating volume and vessel tone inevitably affect cardiac performance. Although the coronary circulation during sepsis is maintained or even increased, alterations in the microcirculation are likely. Mitochondrial dysfunction, another feature of sepsis-induced organ dysfunction, will also place the cardiomyocytes at risk of adenosine triphosphate depletion. However, clinical studies have demonstrated that myocardial cell death is rare and that cardiac function is fully reversible in survivors. Hence, functional rather than structural changes seem to be responsible for intrinsic myocardial depression during sepsis. The underlying mechanisms include down-regulation of beta-adrenergic receptors, depressed postreceptor signaling pathways, impaired calcium liberation from the sarcoplasmic reticulum, and impaired electromechanical coupling at the myofibrillar level. Most, if not all, of these changes are regulated by cytokines and nitric oxide. Integrative studies are needed to distinguish the hierarchy of the various mechanisms underlying septic cardiac dysfunction. As many of these changes are related to severe inflammation and not to infection per se, a better understanding of septic myocardial dysfunction may be usefully extended to other systemic inflammatory conditions encountered in the critically ill. Myocardial depression may be arguably viewed as an adaptive event by reducing energy expenditure in a situation when energy generation is limited, thereby preventing activation of cell death pathways and allowing the potential for full functional recovery.

Acute severe asthma: recent advances

Acute severe asthma is challenging to the clinician both in terms of recognition and appropriate treatment. About 30% of these episodes need admission to the medical intensive care unit with a mortality of 8%. Relapse rates vary from 7 to 15% depending on how well the patient is managed. The purpose of this review is to discuss recent advances in identification of risk factors, pathophysiology and management of acute severe asthma. Although the exact mechanism for acute severe asthma is unclear, some that are implicated include inflammation, airway remodeling and downregulation of beta-receptors. None of the environmental factors have been clearly related to the development of near fatal attacks. Genetic polymorphisms have been associated with severe asthma. Lack of steroid responsiveness has been linked to severe asthma attacks. Chemokines and basement membrane changes characteristic of severe asthma are reported in a few studies. Lack of symptom perception in a certain group of patients with acute severe asthma leads to delayed interventions. Specific treatment modalities and ventilator management is reviewed. Severe asthma is a phenotype of asthma with variable pathology and clinical presentation. Early recognition and timely intervention is needed to prevent significant mortality and morbidity.

Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease

Recent evidence suggests that mutant huntingtin protein-induced energetic perturbations contribute to neuronal dysfunction in Huntington's disease (HD). Given the ubiquitous expression of huntingtin, other cell types with high energetic burden may be at risk for HD-related dysfunction. Early-onset cardiovascular disease is the second leading cause of death in HD patients; a direct role for mutant huntingtin in this phenomenon remains unevaluated. Here we tested the hypothesis that expression of mutant huntingtin is sufficient to induce cardiac dysfunction, using a well-described transgenic model of HD (line R6/2). R6/2 mice developed cardiac dysfunction by 8 weeks of age, progressing to severe failure at 12 weeks, assessed by echocardiography. Limited evidence of cardiac remodeling (e.g. hypertrophy, fibrosis, apoptosis, beta(1) adrenergic receptor downregulation) was observed. Immunogold electron microscopy demonstrated significant elevations in nuclear and mitochondrial polyglutamine presence in the R6/2 myocyte. Significant alterations in mitochondrial ultrastructure were seen, consistent with metabolic stress. Increased cardiac lysine acetylation and protein nitration were observed and were each significantly associated with impairments in cardiac performance. These data demonstrate that mutant huntingtin expression has potent cardiotoxic effects; cardiac failure may be a significant complication of this important experimental model of HD. Investigation of the potential cardiotropic effects of mutant huntingtin in humans may be warranted.

Chronic Direct Stimulation of Adenylyl Cyclase Induces Cardiac Desensitization to Catecholamine and Beta-Adrenergic Receptor Downregulation in Rabbits

Chronic stimulation of beta-adrenergic receptors (betaARs) induces betaAR downregulation. However, it is not known whether continuous activation of adenylyl cyclase without direct stimulation of betaARs leads to receptor downregulation. This study investigated the effects of chronic stimulation of adenylyl cyclase with colforsin, on hemodynamic variables, and on myocardial betaAR density. In all, 55 rabbits received intravenous colforsin (1.6 microg/kg/min, n = 20), isoproterenol (ISO; 0.4 microg/kg/min, n = 16), or saline (n = 19) for two weeks. After chronic drug administration, responses of systolic (Delta% peak LV +dP/dt) and diastolic function (Delta% peak LV -dP/dt), and heart rate (Delta% heart rate), to acute administration of ISO (0.05 to 0.2 microg/kg/min) or colforsin (5 to 20 nmol/kg/min) were decreased compared to those before chronic administration. betaAR density in the colforsin group (69.8 +/- 13.8 fmol/ml protein) was less than that in the saline group (79.8 +/- 15.0 fmol/ml protein, P < 0.05), but was greater than that in the ISO group (56.3 +/- 8.4 fmol/ml protein, P < 0.05). Thus, chronic direct stimulation of adenylyl cyclase elicited systolic and diastolic functional desensitization to betaAR stimulation or adenylyl cyclase stimulation, and myocardial betaAR downregulation.

Parallel gene expressions of IL-6 and BNP during cardiac hypertrophy complicated with diastolic dysfunction in spontaneously hypertensive rats

There is increasing evidence showing that inflammation is involved in heart failure. However, heart failure may differ greatly due to different aetiologies. The role of inflammation in hypertensive heart failure, particularly in the early stage of cardiac dysfunction, has not been studied completely. This study aims at finding out whether inflammation is involved in the early stage of heart dysfunction due to hypertension. Methods Ten spontaneously hypertensive rats (SHR) and ten age-matched Whistar rats were used. Cardiac morphology and function, as well as coronary flow reserve, were examined by echocardiography. mRNAs for cytokines and brain natriuretic peptide were determined by RT-PCR. Results The results demonstrate cardiac hypertrophy with increased heart/body weight ratio in SHR. Echocardiographic examination has shown that SHR developed diastolic heart dysfunction as determined by tissue Doppler without decrease in systolic function. In heart biopsies, there were increased mRNA levels for interleukin-6 and brain natriuretic peptide whereas decreased mRNA for interleukin-2, beta adrenergic receptor, interferon and NFkb in SHR as compared to WKY group. Coronary flow remained unchanged in both groups. Conclusion SHR developed cardiac hypertrophy complicated with diastolic heart dysfunction with increased expression of brain natriuretic peptide, down-regulation of beta adrenergic receptors and simultaneous up-regulation of IL-6, which indicates active proinflammatory process as, at least partly, underlying mechanism during the early stage when cardiac hypertrophy associated with diastolic dysfunction occurs.

Noninvasive Imaging of Heart Failure: Neuronal Dysfunction and Risk Stratification

Congestive heart failure (CHF) is a clinical syndrome of impaired cardiac contractile function resulting from structural damage, and is characterized by a vicious cycle in which reduced cardiac output results in neurohumoral activation. The plasma norepinephrine level, which acts as a major neurotransmitter of the sympathetic nervous system, has been shown to increase in heart failure patients in response to decreased systemic pressure [1]. This hyperadrenergic state in turn causes desensitization and downregulation of cardiac beta-adrenergic receptors and alterations in postsynaptic signal transduction, which causes further impairment of myocardial performance [2]. The close relationship between these alterations of the cardiac autonomic nervous system in heart failure and disease progression, and prognosis, including pump failure and sudden death, has been discussed intensively [3]. Nuclear medicine techniques, such as single photon emission tomography (SPECT) and positron emission tomography (PET), are unique methods of evaluating global and regional myocardial autonomic innervation [4]. These techniques have facilitated and refined substantially the study of the nervous system in both healthy and diseased hearts and have contributed significantly to an improved understanding of heart failure pathophysiology. Radiolabeled catecholamine and catecholamine analogs are available and their tracer physiologic properties are well under-

Pathophysiologie der chronischen Herzinsuffizienz

Heart failure is a progressive and often fatal disease process. In general, the pathophysiologic mechanisms responsible for progressive myocyte dysfunction and cell loss, cardiac remodeling and arrhythmias involve signaling mechanisms that alter myocardial gene expression. These changes in gene expression are complex and involve contractile proteins, ion channels, Ca(++) handling, apoptosis, cell metabolism, the extracellular matrix, signal transduction pathways and growth factors. In the failing heart, several changes occur in cardiac adrenergic receptor-signal transduction pathways. The most striking of these changes occur in beta-adrenergic receptors, and of the changes in beta-adrenergic receptors beta1-receptor down-regulation is the most prominent. Other changes include uncoupling of beta2-adrenergic receptors and increased activity of the inhibitory G-protein. Most of these changes appear to be related to increased activity of the adrenergic nervous system, i.e. increased exposure to norepinephrine. Antagonists of the adrenergic nervous system may improve left ventricular function and outcome in patients with heart failure. This fact supports the notion that activation of these neurohormonal systems exerts a net long-term detrimental effect on the natural history of chronic heart failure and that myocardial adrenergic desensitization phenomena are at least partially maladaptive in the setting of left ventricular dysfunction. In addition to functional alterations structural remodeling plays a major role in the progression of various heart diseases to congestive heart failure. Major contributors to this remodeling process in the heart include alterations in myocyte shape, myocyte number and extracellular matrix. However, it is unclear as to which of these changes is most critical in the development of congestive heart failure, and this may vary by etiology.