Exercise Preconditioning Preserves Cardiac Function and Enhances Cardiac Recovery Following Dobutamine Stimulation in Doxorubicin-Treated Rat Hearts.

ABSTRACT: Exercise preconditioning has been shown to protect against doxorubicin (DOX)-induced cardiac dysfunction when hearts are maintained under resting conditions. However, it is unclear whether this exercise-induced protective effect is maintained when the heart is challenged with the ß 1 -adrenergic receptor agonist dobutamine (DOB), which mimics acute exercise stress. Fischer 344 rats were randomly assigned to sedentary (SED) or voluntary wheel running (WR) groups for 10 weeks. At week 11, rats were treated with either 15 mg/kg DOX or saline. Five days later, ex vivo cardiac function was assessed using an isolated working heart model at baseline, during the infusion of 7.5 µg·kg -1 ·min -1 DOB, and during recovery. DOB infusion significantly increased left ventricular developed pressure (LVDP), maximal (dP/dt max ) and minimal (dP/dt min ) rate of left ventricular pressure development, and heart rate in all groups ( P < 0.05). SED + DOX also showed a lower baseline and recovery LVDP than WR + DOX (83 ± 12 vs. 109 ± 6 mm Hg baseline, 76 ± 11 vs. 100 ± 10 mm Hg recovery, P < 0.05). WR + DOX showed higher dP/dt max and lower dP/dt min when compared with SED + DOX during DOB infusion (7311 ± 1481 vs. 5167 ± 1436 mm Hg/s and -4059 ± 1114 vs.-3158 ± 1176 mm Hg/s, respectively). SED + DOX dP/dt max was significantly lower during baseline and during recovery when compared with all other groups ( P < 0.05). These data suggest that exercise preconditioning preserved cardiac function after DOX exposure even when the heart is challenged with DOB, and it appeared to preserve the heart's ability to recover from this functional challenge.

The oxidation-resistant CaMKII-MM281/282VV mutation does not prevent arrhythmias in CPVT1.

Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmogenic disorder caused by missense mutations in the cardiac ryanodine receptors (RyR2), that result in increased ß-adrenoceptor stimulation-induced diastolic Ca2+ leak. We have previously shown that exercise training prevents arrhythmias in CPVT1, potentially by reducing the oxidation of Ca2+ /calmodulin-dependent protein kinase type II (CaMKII). Therefore, we tested whether an oxidation-resistant form of CaMKII protects mice carrying the CPVT1-causative mutation RyR2-R2474S (RyR2-RS) against arrhythmias. Antioxidant treatment (N-acetyl-L-cysteine) reduced the frequency of ß-adrenoceptor stimulation-induced arrhythmogenic Ca2+ waves in isolated cardiomyocytes from RyR2-RS mice. To test whether the prevention of CaMKII oxidation exerts an antiarrhythmic effect, mice expressing the oxidation-resistant CaMKII-MM281/282VV variant (MMVV) were crossed with RyR2-RS mice to create a double transgenic model (RyR2-RS/MMVV). Wild-type mice served as controls. Telemetric ECG surveillance revealed an increased incidence of ventricular tachycardia and an increased arrhythmia score in both RyR2-RS and RyR2-RS/MMVV compared to wild-type mice, both following a ß-adrenoceptor challenge (isoprenaline i.p.), and following treadmill exercise combined with a ß-adrenoceptor challenge. There were no differences in the incidence of arrhythmias between RyR2-RS and RyR2-RS/MMVV mice. Furthermore, no differences were observed in ß-adrenoceptor stimulation-induced Ca2+ waves in RyR2-RS/MMVV compared to RyR2-RS. In conclusion, antioxidant treatment reduces ß-adrenoceptor stimulation-induced Ca2+ waves in RyR2-RS cardiomyocytes. However, oxidation-resistant CaMKII-MM281/282VV does not protect RyR2-RS mice from ß-adrenoceptor stimulation-induced Ca2+ waves or arrhythmias. Hence, alternative oxidation-sensitive targets need to be considered to explain the beneficial effect of antioxidant treatment on Ca2+ waves in cardiomyocytes from RyR2-RS mice.

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.

Suppression of beta 2 adrenergic receptor actions prevent UVB mediated cutaneous squamous cell tumorigenesis through inhibition of VEGF-A induced angiogenesis.

Although beta 2 adrenergic receptors (ß2 ADR) are present in the keratinocytes, their role in cutaneous squamous cell tumorigenesis needs to be ascertained. For the first time, we report here that selective ß2 ADR antagonists by inhibiting ß2 ADR actions significantly retarded the progression of ultraviolet B (UVB) induced premalignant cutaneous squamous cell lesions. These antagonists acted by inhibiting vascular endothelial growth factor-A (VEGF) mediated angiogenesis to prevent UVB radiation-induced squamous cell carcinoma of the skin.

Feasibility and functional correlates of left atrial volume changes during stress echocardiography in chronic coronary syndromes.

An enlarged left atrial volume index (LAVI) at rest mirrors increased LA pressure and/or impairment of LA function. A cardiovascular stress may acutely modify left atrial volume (LAV) within minutes. Aim of this study was to assess the feasibility and functional correlates of LAV-stress echocardiography (SE) Out of 514 subjects referred to 10 quality-controlled labs, LAV-SE was completed in 490 (359 male, age 67 ± 12 years) with suspected or known chronic coronary syndromes (n = 462) or asymptomatic controls (n = 28). The utilized stress was exercise in 177, vasodilator in 167, dobutamine in 146. LAV was measured with the biplane disk summation method. SE was performed with the ABCDE protocol. The intra-observer and inter-observer LAV variability were 5% and 8%, respectively. ∆-LAVI changes (stress-rest) were negatively correlated with resting LAVI (r = - 0.271, p < 0.001) and heart rate reserve (r = -.239, p < 0.001). LAV-dilators were defined as those with stress-rest increase ≥ 6.8 ml/m2, a cutoff derived from a calculated reference change value above the biological, analytical and observer variability of LAVI. LAV dilation occurred in 56 patients (11%), more frequently with exercise (16%) and dipyridamole (13%) compared to dobutamine (4%, p < 0.01). At multivariable logistic regression analysis, B-lines ≥ 2 (OR: 2.586, 95% CI = 1.1293-5.169, p = 0.007) and abnormal contractile reserve (OR: 2.207, 95% CI = 1.111-4.386, p = 0.024) were associated with LAV dilation. In conclusion, LAV-SE is feasible with high success rate and low variability in patients with chronic coronary syndromes. LAV dilation is more likely with reduced left ventricular contractile reserve and pulmonary congestion.

The pretreatment of rats with nebivolol ameliorates bladder contractile dysfunction caused by ischemia-reperfusion injury.

OBJECTIVE: The present study aimed to investigate the protective effect of nebivolol in the bladder isolated from rats exposed to ischemia-reperfusion (IR) injury. METHODS: Sprague-Dawley rats were divided into control, IR, and nebivolol+IR groups. In the nebivolol+IR group, nebivolol was administered (0.4 mg/kg, subcutaneous) in rats prior to IR insult. At the end of the experimental protocol, the urinary bladder was rapidly isolated and bladder strips were mounted in an organ bath. After the equilibration period, potassium chloride (KCl, 20-100 mM) or carbachol (0.01-10 µM) was cumulatively added to the organ bath to generate cumulative concentration-response curves (CCRCs). Oxidative stress and interleukin 6 (IL-6) levels were also evaluated in the bladder tissue. RESULTS: The CCRCs of KCl and carbachol were significantly reduced in the IR group compared to those of the control, and this inhibition was reversed by the pretreatment of rats with nebivolol (P < .05). The IR group's total antioxidant status was significantly lower with a concomitant increase in IL-6 levels than that of the control and nebivolol+IR groups (P < .05). CONCLUSIONS: The present study indicates that pretreatment of rats with nebivolol (0.4 mg/kg) could improve bladder contractile dysfunction caused by IR injury through suppression of increased oxidative stress and IL-6 levels.

Long-term prognosis and predictors of outcomes after negative stress echocardiography.

Negative stress echocardiography (NSE) is associated with low cardiovascular morbidity and overall mortality. We aimed to determine the clinical and echocardiographic predictors of overall and cardiovascular outcomes following NSE. Patients who underwent SE between 2013 and 2017 were reviewed. Patients with a history of solid organ transplant or being evaluated for transplant, history of end-stage renal or liver disease, and positive SE were excluded. NSE results were divided into negative diagnostic if patient reached target heart rate (THR) and had no wall motion abnormality (WMA) at rest or stress; negative non-diagnostic if patient had no WMA but did not reach THR or if image quality was non-diagnostic; and abnormal non-ischemic if patient had a resting WMA not worsened at stress along with a personal history of coronary artery disease (CAD). New CAD lesion at 1 year was defined as ≥ 50% stenosis on cardiac catheterization. Of 4119 patients with SE, 2575 were included. All-cause mortality rate was 1.1%/year and CAD rate was 3.1%/year. Predictors of all-cause mortality were age, male gender, history of smoking and being selected for dobutamine SE. Predictors of a new CAD lesion at 1 year were male gender, diabetes, personal history of CAD and abnormal non-ischemic SE. We identified clinical and echocardiographic characteristics in a subset of NSE patients who are at higher risk for subsequent adverse events. These characteristics should be accounted for during the clinical interpretation of SE, and patients found at increased risk for morbidity and mortality warrant continued follow-up.

Head-to-head comparison of prognostic accuracy in patients undergoing noncardiac surgery of dobutamine stress echocardiography versus computed tomography coronary angiography (PANDA trial): A prospective observational study.

BACKGROUND: Dobutamine stress echocardiography (DSE) and coronary computed tomography angiography (CTA) can provide perioperative prognostic information in risk stratification of patients undergoing noncardiac surgery. This study directly compared the prognostic value of DSE and CTA in patients undergoing noncardiac surgery. METHODS: Between 2014 and 2016, 215 patients with more than one clinical risk factor for perioperative cardiovascular (CV) events were enrolled prospectively. They received both DSE and CTA before noncardiac surgery. Perioperative clinical risk was classified according to the revised cardiac risk index (RCRI), DSE results were categorized as abnormal (inducible ischemia and/or nonviable infarction) or not. CTA results were assessed using the severity of stenosis, with significant stenosis being ≥50% of the luminal diameter). After the exclusion, a total of 206 patients remained. Perioperative CV events were defined as CV death, non-fatal myocardial infarction (MI), myocardial injury, pulmonary edema, non-fatal stroke, and systemic embolism within 30 days after surgery. RESULTS: Twenty-four patients (12%) had perioperative cardiac events (1 cardiac death, 10 non-fatal MI, 8 myocardial injury, 11 pulmonary edema, 1 non-fatal stroke, and 1 pulmonary embolism). Following adjustment for baseline RCRI score, abnormal result on DSE (OR, 6.08, 95% CI, 2.41 to 15.31, P < 0.001), significant CAD on CTA (OR, 18.79; 95% CI, 5.24 to 67.42, P < 0.001), and high CACS (OR, 4.19; 95% CI, 1.39 to 12.60, P = 0.011) remained significant predictors of perioperative CV events. CONCLUSIONS: DSE and CTA are independent predictive factors of events in patients undergoing noncardiac surgery. Among them, assessment of significant CAD using CTA might show a higher prognostic value compared with DSE before noncardiac surgery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02250963.

Effects of Beta; 1-adrenoceptors in the Basolateral Amygdala on Spatial Memory, Passive Avoidance, Long-term Potentiation and Neuronal Arborization in the Hippocampal CA1 Region in Response to Unavoidable Stress

Abstract Norepinephrine in the basolateral amygdala (BLA) plays a pivotal role in mediating the effects of stress on memory functions in the hippocampus, however, the functional contribution of β1-adrenergic receptors on the BLA inputs to the CA1 region of hippocampus and memory function are not well understood. In the present study the role of β1-adrenoreceptor in the BLA on memory, neuronal arborization and long-term potentiation (LTP) in the CA1 region of hippocampus was examined by infusion the β1-adrenoreceptor agonist (Dobutamine; 0.5µl/side) or antagonist (Atenolol; 0.25µL/side) bilaterally into the BLA before foot-shock stress. Passive avoidance test results showed that Step-through latency time was significantly decreased in the stress group rats one, four and seven days after the stress, which intra-BLA injection of Atenolol or Dobutamine before stress couldn't attenuate this reduction. Barnes-maze results revealed that infusion of Dobutamine and Atenolol significantly reduced spatial memory indicators such as increased latency time, the number of errors and the distance traveling to achieve the target hole in the stress group. These learning impairments in stress rats correlated with a reduction of LTP in hippocampal CA1 synapses in-vivo, which infusion of Dobutamine and Atenolol couldn't attenuate the population spike amplitude and mean-field excitatory postsynaptic potentials (fEPSP) slope reduction induced by stress. Also, the Golgi-Cox staining demonstrated that infusion of Atenolol attenuated stress decreased CA1 region dendritic and axonal arborization. These results suggest that β1-adrenergic receptors activation or block seem to exacerbate stress-induced hippocampal memory deficits and this effect is independent of CA1 LTP modulation.

Beta1- and Beta2-Adrenoceptors Expression Patterns in Human Non-small Cell Lung Cancer: Relationship with Cancer Histology.

Assessment of Beta-AR protein expression on tumour tissues might be a plausible strategy to select cancer patients who can benefit from Beta-blockers therapy. The aim of this study is to evaluate the differences between resected tissue specimens from primary lung cancer (adenocarcinoma (ADC) and squamous cell carcinoma (SCC)) in terms of expression pattern of Beta1- and Beta2-AR in both tumour and adjacent surrounding non-tumour tissue. This retrospective study was based on the analysis of 80 patients with histologically confirmed diagnosis of primary Non-Small Cell Lung Cancer (NSCLC) who received surgical treatment. The cases were carefully selected in order to obtain the most homogeneous sample in terms of histologic subtype (40 ADCs and 40 SCCs) and clinical stage (10 each). Beta1- and Beta2-AR expression was determined by immunohistochemistry and the staining evaluated by semi-quantitative scoring using the H-score method. In our NSCLC series, Beta1- and Beta2-AR are differentially expressed. Beta1-AR expression is present at low levels in both SCC and ADC. Likewise, when compared with the matched surrounding non-tumour tissues, Beta1-AR expression level was significantly lower in both histologic subtypes. Conversely, Beta2-AR is highly expressed in both histologic subtypes, but clearly highly expressed in ADC when compared with SCC and with their matched surrounding non-tumour tissue. Overall, this clinicopathological study highlights the differential expression of Beta1- and Beta2-AR in ADC and SCC. Repurposing non-selective Beta-blockers in oncologic setting might be a suitable therapeutic strategy for lung ADC. Graphical abstract.

Effective dose of dobutamine in augmenting free flap blood flow during reconstructive surgery of the lower extremity.

Success of surgical free flap transfer depends on achieving and maintaining adequate perfusion across the microvascular anastomosis. The purpose of this prospective study was to determine the optimal infusion rate of dobutamine to augment duplex ultrasound measured blood flow to the tissue flap during surgery.Twenty-one patients undergoing general anesthesia for lower limb reconstructive surgery were recruited. The optimal dobutamine dose was evaluated using the modified Dixon's up-and-down method, starting at 6 µg·kg·min, and then titrated in increments of 1 µg·kg·min.The optimal dose of dobutamine for improving blood flow to the tissue flap was 3.50 ±â€Š0.57 µg·kg·min in 50% of patients. The 95% effective dose of dobutamine calculated by probit analysis was 4.46 µg·kg·min (95% confidence interval: 3.99-7.00 µg·kg·min).The results of our study suggest that a dobutamine infusion rate less than 5 µg·kg·minprovides significant improvement of blood flow to the tissue flap, while minimizing cardiovascular side effects.

Fenestration in the Fontan circulation as a strategy for chronic cardioprotection.

BACKGROUND: Fenestration in the Fontan circulation potentially liberates patients from factors leading to cardiovascular remodelling, through stable haemodynamics with attenuated venous congestion. We hypothesised that a fenestrated Fontan procedure would possess chronic haemodynamic advantages beyond the preload preservation. METHODS: We enrolled 35 patients with fenestrated Fontan with a constructed pressure-volume relationship under dobutamine (DOB) infusion and/or transient fenestration occlusion (TFO). Despite the use of antiplatelets and anticoagulants, natural closure of fenestration was confirmed in 11 patients. Cardiovascular properties in patients with patent fenestration (P-F) were compared with those in patients with naturally closed fenestration (NC-F). To further delineate the roles of fenestration, paired analysis in patients with P-F was performed under DOB or rapid atrial pacing with/without TFO. RESULTS: As compared with P-F, patients with NC-F had a higher heart rate (HR), smaller ventricular end-diastolic area, better ejection fraction and higher central venous pressure, with higher pulmonary resistance. While this was similarly observed after DOB infusion, DOB markedly augmented diastolic and systolic ventricular stiffness in patients with NC-F compared with patients with P-F. As a mirror image of the relationship between patients with P-F and NC-F, TFO markedly reduced preload, suppressed cardiac output, and augmented afterload and diastolic stiffness. Importantly, rapid atrial pacing compromised these haemodynamic advantages of fenestration. CONCLUSIONS: As compared with patients with NC-F, patients with P-F had robust haemodynamics with secured preload reserve, reduced afterload and a suppressed beta-adrenergic response, along with a lower HR at baseline, although these advantages had been overshadowed, or worsened, by an increased HR.

Continuous exposure of isoprenaline inhibits myoblast differentiation and fusion through PKA/ERK1/2-FOXO1 signaling pathway.

AIM: The objective of this study is to determine if exuberant sympathetic nerve activity is involved in muscle satellite cell differentiation and myoblast fusion. METHODS AND RESULTS: By using immunoassaying and western blot analyses, we found that ß1 and ß2-adrenergic receptors (AdR) were expressed in C2C12 cells. The differentiated satellite cells exhibited an increased expression of ß2-AdR, as compared with the proliferating cells. Continuous exposure of isoprenaline (ISO), a ß-AdR agonist, delayed C2C12 cell differentiation, and myoblast fusion in time- and dose-dependent manner. ISO also increased short myotube numbers while decreasing long myotube numbers, consistent with the greater reduction in MyHC1, MyHC2a, and MyHC2x expression. Moreover, continuous exposure of ISO gradually decreased the ratio of PKA RI/RII, and PKA RI activator efficiently reversed the ISO effect on C2C12 cell differentiation and myoblast fusion while PKA inhibitor H-89 deteriorated the effects. Continuous single-dose ISO increased ß1-AdR expression in C2C12 cells. More importantly, the cells showed enhanced phospho-ERK1/2 levels, resulting in increasing phospho-ß2-AdR levels while decreasing ß2-AdR levels, and the specific effects could be abolished by ERK1/2 inhibitor. Furthermore, continuous exposure of ISO induced FOXO1 nuclear translocation and increased the levels of FOXO1 in nuclear extracts while reducing pAKT, p-p38MAPK, and pFOXO1 levels. Conversely, blockade of ERK1/2 signaling partially abrogated ISO effects on AKT, p38MAPK, and FOXO1signaling, which partially restored C2C12 cell differentiation and myoblast fusion, leading to an increase in the numbers of medium myotube along with the increased expression of MyHC1 and MyHC2a. CONCLUSION: Continuous exposure of ISO impedes satellite cell differentiation and myoblast fusion, at least in part, through PKA-ERK1/2-FOXO1 signaling pathways, which were associated with the reduced ß2-AdR and increased ß1-AdR levels.

Low-Gradient Aortic Stenosis: Solving the Conundrum Using Multi-Modality Imaging.

Up to 1/3 of patients with both reduced or preserved left ventricular ejection fraction (LVEF), harbor a mean pressure gradient (MPG) < 40 mm Hg (peak velocity (PV) < 4 m/s), suggesting moderate aortic stenosis (AS) and an aortic valve area (AVA) < 1 cm2 suggesting severe AS raising uncertainties regarding AS severity and appropriate management. In patients with reduced LVEF, increased transvalvular flow and stroke volume ≥ 20% (i.e. contractile reserve) during low-dose dobutamine echocardiography enables distinguishing patients with "true-severe AS" (severe AS with secondary LV dysfunction, PV ≥ 4 m/s or MPG > 30-40 mm Hg at peak while AVA remains <1 cm2) from patients with "pseudo-severe AS" (moderate AS with associated LV dysfunction due to ischemic or dilated cardiomyopathy, AVA at peak ≥1 cm2 with a MPG < 30-40 mm Hg). However, interpretation of dobutamine stress echocardiography is often challenging, and absence of contractile reserve is observed in 20 to 30% of patients. Measurement of the degree of calcification (AVC) using computed tomography is an accurate and flow-independent method for the assessment of AS severity. A score > 1250 AU in women and >2000 UA in men strongly suggest severe AS. Combination of dobutamine echocardiography and AVC scoring enables assessment of AS severity with high confidence. The subset of patients with discordant grading and preserved LVEF is heterogenous and encompasses various conditions. A minority harbor a low flow state related to a reduced myocardial performance, an increased arterial afterload or combination of both. A low flow state is an important prognostic factor but does not provide any information regarding AS severity. Similarly to patients with reduced LVEF, assessment of the degree of AVC seems the best method to differentiate patients with pseudo-severe AS from patients with true severe AS. The latter should be referred for an intervention if symptomatic whereas the optimal management of the former subset remains uncertain.

Cardiac Dysfunction in the Sigma 1 Receptor Knockout Mouse Associated With Impaired Mitochondrial Dynamics and Bioenergetics.

Background The Sigma 1 receptor (Sigmar1) functions as an interorganelle signaling molecule and elicits cytoprotective functions. The presence of Sigmar1 in the heart was first reported on the basis of a ligand-binding assay, and all studies to date have been limited to pharmacological approaches using less-selective ligands for Sigmar1. However, the physiological function of cardiac Sigmar1 remains unknown. We investigated the physiological function of Sigmar1 in regulating cardiac hemodynamics using the Sigmar1 knockout mouse (Sigmar1-/-). Methods and Results Sigmar1-/- hearts at 3 to 4 months of age showed significantly increased contractility as assessed by left ventricular catheterization with stimulation by increasing doses of a ß1-adrenoceptor agonist. Noninvasive echocardiographic measurements were also used to measure cardiac function over time, and the data showed the development of cardiac contractile dysfunction in Sigmar1 -/- hearts as the animals aged. Histochemistry demonstrated significant cardiac fibrosis, collagen deposition, and increased periostin in the Sigmar1 -/- hearts compared with wild-type hearts. Ultrastructural analysis of Sigmar1-/- cardiomyocytes revealed an irregularly shaped, highly fused mitochondrial network with abnormal cristae. Mitochondrial size was larger in Sigmar1-/- hearts, resulting in decreased numbers of mitochondria per microscopic field. In addition, Sigmar1-/- hearts showed altered expression of mitochondrial dynamics regulatory proteins. Real-time oxygen consumption rates in isolated mitochondria showed reduced respiratory function in Sigmar1-/- hearts compared with wild-type hearts. Conclusions We demonstrate a potential function of Sigmar1 in regulating normal mitochondrial organization and size in the heart. Sigmar1 loss of function led to mitochondrial dysfunction, abnormal mitochondrial architecture, and adverse cardiac remodeling, culminating in cardiac contractile dysfunction.

Dobutamine and Nitroglycerin Versus Milrinone for Perioperative Management of Pulmonary Hypertension in Mitral Valve Surgery. A Randomized Controlled Study.

OBJECTIVE: To compare the effects of dobutamine and nitroglycerin to milrinone in young patients with severe pulmonary hypertension undergoing mitral valve replacement. DESIGN: A prospective randomized, double-blinded, controlled study. SETTING: Single university hospital. PARTICIPANTS: Forty patients had systolic pulmonary arterial pressure ≥60 mmHg and were scheduled for elective mitral valve replacement. The patients were divided randomly into 2 equal groups according to the drugs given during the study. INTERVENTIONS: The patients in group I received 5 to 20 µg/kg/min of dobutamine and 0.5 to 3 µg/kg/min of nitroglycerin, and patients in group II received a loading dose of milrinone, 50 µg/kg over 10 minutes, followed by a maintenance dose of 0.25 to 0.75 µg/kg/min. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the effects of interventional drugs on mean pulmonary artery pressure. The secondary outcomes were the effects of interventional drugs on systemic and pulmonary hemodynamic parameters measured from induction of anesthesia until the first 12 hours in the intensive care unit stay. There was a more significant decrease in mean pulmonary artery pressure, pulmonary capillary wedge pressure, and central venous pressure in group II than group I at all time points after cardiopulmonary bypass. There were more significant increases in heart rate, mean arterial pressure, cardiac output, and mixed venous oxygen tension in group I than group II, which became more obvious in time. In both groups, there was a significant decrease in systemic vascular resistance and pulmonary vascular resistance at all times. CONCLUSION: Milrinone provides adequate cardiac performance, causing a greater reduction in pulmonary artery pressure and pulmonary capillary wedge pressure.

PDE4 and mAKAPß are nodal organizers of ß2-ARs nuclear PKA signalling in cardiac myocytes.

Aims: ß1- and ß2-adrenergic receptors (ß-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which ß1- and ß2-ARs regulate nuclear PKA activity in cardiomyocytes. Methods and results: We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective ß1- or ß2-ARs stimulation. Both ß1- and ß2-AR stimulation increased cAMP and activated PKA in the cytoplasm. Although the two receptors also increased cAMP in the nucleus, only ß1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP early repressor (ICER). Inhibition of phosphodiesterase (PDE)4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by ß2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by ß1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by ß2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPß partially inhibited nuclear PKA activation upon ß1-AR stimulation, and drastically decreased nuclear PKA activation upon ß2-AR stimulation in the presence of PDE4 inhibition. Conclusions: ß1- and ß2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPß-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon ß2-AR stimulation.

An Alternative Method to Calculate Simplified Projected Aortic Valve Area at Normal Flow Rate / Um Método Alternativo para o Cálculo da Área Valvular Aórtica Projetada Simplificada em Uma Taxa de Fluxo Normal

Abstract Background: Simplified projected aortic valve area (EOAproj) is a valuable echocardiographic parameter in the evaluation of low flow low gradient aortic stenosis (LFLG AS). Its widespread use in clinical practice is hampered by the laborious process of flow rate (Q) calculation. Objetive: This study proposes a less burdensome, alternative method of Q calculation to be incorporated in the original formula of EOAproj and measures the agreement between the new proposed method of EOAproj calculation and the original one. Methods: Retrospective observational single-institution study that included all consecutive patients with classic LFLG AS that showed a Q variation with dobutamine infusion ≥ -15-% by both calculation methods. Results: Twenty-two consecutive patients with classical LFLG AS who underwent dobutamine stress echocardiography were included. Nine patients showed a Q variation with dobutamine infusion calculated by both classical and alternative methods ≥ -15-% and were selected for further statistical analysis. Using the Bland-Altman method to assess agreement we found a systematic bias of 0,037 cm2 (95% CI 0,004 - 0,066), meaning that on average the new method overestimates the EOAproj in 0,037 cm2 compared to the original method. The 95% limits of agreement are narrow (from -0,04 cm2 to 0,12 cm2), meaning that for 95% of individuals, EOAproj calculated by the new method would be between 0,04 cm2 less to 0,12 cm2 more than the EOAproj calculated by the original equation. Conclusion: The bias and 95% limits of agreement of the new method are narrow and not clinically relevant, supporting the potential interchangeability of the two methods of EOAproj calculation. As the new method requires less additional measurements, it would be easier to implement in clinical practice, promoting an increase in the use of EOAproj.

Resumo Fundamento: A área valvular aórtica projetada simplificada (AEOproj) é um parâmetro ecocardiográfico valioso na avaliação da estenose aórtica de baixo fluxo e baixo gradiente (EA BFBG). Sua utilização na prática clínica é limitada pelo trabalhoso processo de cálculo da taxa de fluxo (Q). Objetivos: Este estudo propõe um método alternativo, menos complexo, para o cálculo da Q para ser incorporado na fórmula original da AEOproj, e mede a concordância entre o novo método proposto para o cálculo da AEOproj em comparação ao método original. Métodos: Estudo retrospectivo, observacional, unicêntrico que incluiu todos os pacientes com AE BFBG clássica com variação da Q com infusão de dobutamina ≥ -15-% por ambos os métodos. Resultados: Foram incluídos 22 pacientes consecutivos com AE BFBG clássico, que se submeteram à ecocardiografia sob estresse com dobutamina. Nove pacientes apresentaram uma variação da Q com infusão de dobutamina calculada tanto pelo método clássico como pelo método alternativo ≥ -15-%, e foram selecionados para análise estatística. Utilizando método Bland-Altman para avaliar a concordância, encontramos um viés sistemático de 0,037 cm2 (IC 95% 0,004 - 0,066), o que significa que, em média, o novo método superestima a AEOproj em 0m037 cm2 em comparação ao método original. Os limites de concordância de 95% são estreitos (de -0,04 cm2 a 0,12 cm2), o que significa que para 95% dos indivídios, a AEOproj calculada pelo novo método estaria entre 0,04 cm2 menos a 0,12 cm2 mais que a AEOproj calculada pela equação original. Conclusão: O viés e os limites de 95% de concordância do novo método são estreitos e não são clinicamente relevantes, o que corrobora a intercambialidade dos dois métodos de cálculo da AEOproj. Uma vez que o novo método requer menos medidas, seria mais fácil de ser implementado na prática clínica, promovendo um aumento na utilização da AEOproj.

Protective effect of nebivolol on gentamicin-induced nephrotoxicity in rats.

OBJECTIVE: Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe Gram-negative infections. As we know, treatment with nebivolol has been shown to decrease renal fibrosis and glomerular injury as well as improve endothelial dysfunction. Therefore, we evaluated the potential protective effect of nebivolol (NBV) against GEN-induced nephrotoxicity in rats. MATERIAL AND METHOD: Twenty-four rats were randomly divided into four groups: control group (Group 1); rats intraperitoneally injected with GEN (100 mg/kg/day; Group 2); rats treated with GEN plus distilled water (Group 3); and rats treated with GEN plus NBV (10 mg/kg/day; Group 4). After 15 days, the rats were sacrificed, their kidneys taken, and blood analysis performed. Tubular necrosis and interstitial fibrosis scores were determined histopathologically in a part of kidneys; nitric oxide (NO), malondialdehyde (MDA), and reduced glutathione (GSH) levels were determined in other part of kidneys. RESULTS: The GSH levels in renal tissue of only GEN-treated rats were significantly lower than those in control group, and administration of NBV to GEN-treated rats significantly increased the level of GSH. The group that was given GEN and NBV had significantly lower MDA and NO levels in kidney cortex tissue than that given GEN alone. Despite the presence of mild tubular degeneration, the rats treated with GEN+NBV showed a less severe tubular necrosis, and their glomeruli maintained a better morphology compared to GEN group. CONCLUSION: NBV exerts antioxidant, anti-inflammatory and antifibrotic effects on GEN-induced kidney damage by reducing oxidative stress in rat model (Tab. 3, Fig. 2, Ref. 68).

ß2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease.

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the ß2-adrenoreceptor (ß2AR) is a regulator of the α-synuclein gene (SNCA). ß2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the ß2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a ß2AR antagonist correlated with increased risk. ß2AR activation protected model mice and patient-derived cells. Thus, ß2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.