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β-blockers are a heterogeneous class of drugs, with varying selectivity/specificity for β vs β receptors, intrinsic sympathomimetic activity (ISA), and vasodilatory properties (through β stimulation, α receptor blockade or nitric oxide release). These drugs are indicated for the management of arterial hypertension, heart failure or ischemic heart disease (IHD; eg angina pectoris or prior myocardial infarction). Most of the benefit of β-blockade in these conditions arises from blockade of the β receptor, and, in practice, the addition of ISA appears to reduce the potential for improved clinical outcomes in people with heart failure or IHD. Aspects of the benefit/risk balance of β-blockers remain controversial, and recent meta-analyses have shed new light on this issue. We have reviewed the current place of cardioselective β-blockade in hypertension, IHD and heart failure, with special reference to the therapeutic profile of a highly selective β -adrenoceptor blocker, bisoprolol.

Background Intra-individual heterogeneity of cardiac exposure is an issue in breast cancer (BC) radiotherapy that was poorly considered in previous cardiotoxicity studies mainly based on mean heart dose (MHD). This dosimetric study analyzes the distribution of individually-determined radiation doses to the heart and its substructures including coronary arteries and evaluate whether MHD is a relevant surrogate parameter of dose for these substructures. Methods Data were collected from the BACCARAT prospective study that included left or right unilateral BC patients treated with 3D-Conformal Radiotherapy (RT) between 2015 and 2017 and followed-up for 2 years with repeated cardiac imaging examinations. A coronary computed tomography angiography (CCTA) was performed before RT for all patients. Registration of the planning CT and CCTA images allowed delineation of the coronary arteries on the planning CT images. Using the 3D dose matrix generated during treatment planning and the added coronary contours, dose distributions were generated for whole heart and the following substructures: left ventricle (LV), left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). A descriptive analysis of the physical doses in Gray (Gy) was performed, Dmean was the volume-weighted mean dose. Results Dose distributions were generated for 89 left-sided BC patients (MHD = 2.9 ± 1.5 Gy, Dmean_LAD = 15.7 ± 3.1 Gy) and 15 right-sided BC patients (MHD = 0.5 ± 0.1 Gy; Dmean_RCA = 1.2 ± 0.4 Gy). For left-sided BC patients, the ratio Dmean_LAD/MHD was around 5. Pearson correlation coefficients between MHD and Dmean for delineated substructures were all statistically significant. However, for all substructures, the coefficient of determination R 2 indicated that the proportion of the variance in Dmean of the substructure predictable from MHD was moderate to low (in particular R 2  = 0.45 for LAD). Among left-sided BC patients with MHD < 3Gy, 56% of patients could nevertheless receive LAD doses above 40Gy (V40 > 0). Conclusion Our study illustrates that MHD is not enough to predict with confidence individual patient dose to the LV and coronary arteries, in particular the LAD. For precise radiotherapy-induced cardiotoxicity studies it would be necessary to consider the distribution of doses within these cardiac substructures rather than just the MHD. Trial registration ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.

BRET probes that monitor activation of multiple G protein isoforms reveal that angiotensin II and a biased agonist of the angiotensin II type 1A receptor stabilize distinct receptor conformations associated with different signaling outputs. Functional selectivity of G protein–coupled receptor (GPCR) ligands toward different downstream signals has recently emerged as a general hallmark of this receptor class. However, pleiotropic and crosstalk signaling of GPCRs makes functional selectivity difficult to decode. To look from the initial active receptor point of view, we developed new, highly sensitive and direct bioluminescence resonance energy transfer–based G protein activation probes specific for all G protein isoforms, and we used them to evaluate the G protein–coupling activity of [ 1 Sar 4 Ile 8 Ile]-angiotensin II (SII), previously described as an angiotensin II type 1 (AT 1 ) receptor–biased agonist that is G protein independent but β-arrestin selective. By multiplexing assays sensing sequential signaling events, from receptor conformations to downstream signaling, we decoded SII as an agonist stabilizing a G protein–dependent AT 1A receptor signaling module different from that of the physiological agonist angiotensin II, both in recombinant and primary cells. Thus, a biased agonist does not necessarily select effects from the physiological agonist but may instead stabilize and create a new distinct active pharmacological receptor entity.

The blood pressure (BP) lowering response to renal denervation (RDN) remains variable with about one-third of patients not responding to ultrasound or radiofrequency RDN. Identification of predictors of the BP response to RDN is needed to optimize patient selection for this therapy. This is a post-hoc analysis of the RADIANCE-HTN SOLO study. BP response to RDN was measured by the change in daytime ambulatory systolic blood pressure (dASBP) at 2 months post procedure. Univariate regression was used initially to assess potential predictors of outcome followed by multivariate regression analysis. In the univariate analysis, predictors of response to RDN were higher baseline daytime ambulatory diastolic blood pressure (dADBP), the use of antihypertensive medications at screening, and presence of orthostatic hypertension (OHTN) whilst the presence of untreated accessory arteries was a negative predictor of response. Multivariate analysis determined that dADBP and use of antihypertensive medications were predictors of response to RDN with a trend for OHTN to predict response. Obese females also appeared to be better responders to RDN in an interaction model. RDN is more effective in patients with elevated baseline dADBP and those with OHTN, suggesting increased peripheral vascular resistance secondary to heightened sympathetic tone. These assessments are easy to perform in clinical setting and may help in phenotyping patients who will respond better to RDN.

Background Breast cancer (BC) radiotherapy (RT) can induce cardiotoxicity, with adverse events often observed many years after BC RT. Subclinical left ventricular (LV) dysfunction can be detected early after BC RT with global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography. This 6-month follow-up analysis from the BACCARAT prospective study aimed to investigate the association between cardiac radiation doses and subclinical LV dysfunction based on GLS reduction. Methods The patient study group consisted of 79 BC patients (64 left-sided BC, 15 right-sided BC) treated with RT without chemotherapy. Echocardiographic parameters, including GLS, were measured before RT and 6 months post-RT. The association between subclinical LV dysfunction, defined as GLS reduction > 10%, and radiation doses to whole heart and the LV were performed based on logistic regressions. Non-radiation factors associated with subclinical LV dysfunction including age, BMI, hypertension, hypercholesterolemia and endocrine therapy were considered for multivariate analyses. Results A mean decrease of 6% in GLS was observed (− 15.1% ± 3.2% at 6 months vs. − 16.1% ± 2.7% before RT, p  = 0.01). For left-sided patients, mean heart and LV doses were 3.1 ± 1.3 Gy and 6.7 ± 3.4 Gy respectively. For right-sided patients, mean heart dose was 0.7 ± 0.5 Gy and median LV dose was 0.1 Gy. Associations between GLS reduction > 10% (37 patients) and mean doses to the heart and the LV as well as the V20 were observed in univariate analysis (Odds Ratio = 1.37[1.01–1.86], p  = 0.04 for Dmean Heart; OR = 1.14 [1.01–1.28], p  = 0.03 for Dmean LV; OR = 1.08 [1.01–1.14], p  = 0.02 for LV V20). In multivariate analysis, these associations did not remain significant after adjustment for non-radiation factors. Further exploratory analysis allowed identifying a subgroup of patients (LV V20 > 15%) for whom a significant association with subclinical LV dysfunction was found (adjusted OR = 3.97 [1.01–15.70], p  = 0.048). Conclusions This analysis indicated that subclinical LV dysfunction defined as a GLS decrease > 10% is associated with cardiac doses, but adjustment for non-radiation factors such as endocrine therapy lead to no longer statistically significant relationships. However, LV dosimetry may be promising to identify high-risk subpopulations. Larger and longer follow-up studies are required to further investigate these associations. Trial registration ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered

Technologies that bias GPCR expression for formation of heterodimers show that, when heterodimerized, α 2C -AR and AT-1R exhibit atypical G s -cAMP-PKA signaling upon ligand stimulation compared to either parent receptor expressed alone and mimic activation associated with arterial hypertension. Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT 1 receptor (AT1-R) and NE α 2C -adrenergic receptor (α 2C -AR) could underlie their functional cross-talk to control NE secretion. Multiple bioluminescence resonance energy transfer and protein complementation assays allowed us to accurately probe the structures and functions of the α 2C -AR–AT1-R dimer promoted by ligand binding to individual protomers. We found that dual agonist occupancy resulted in a conformation of the heterodimer different from that induced by active individual protomers and triggered atypical G s -cAMP–PKA signaling. This specific pharmacological signaling unit was identified in vivo to promote not only NE hypersecretion in sympathetic neurons but also sympathetic hyperactivity in mice. Thus, we uncovered a new process by which GPCR heterodimerization creates an original functional pharmacological entity and that could constitute a promising new target in cardiovascular therapeutics.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s11095-020-02971-0

The exact pathophysiology of Tako-Tsubo cardiomyopathy (TTC) remains unknown but a role for sympathetic hyperactivity has been suggested. Up to now, no direct evidence of sympathetic nerve hyperactivity has been established nor involvement of sympathetic baroreflex identified. The aim of our study was to determine, by direct sympathetic nerve activity (SNS) recording if sympathetic nervous system activity is increased and spontaneous baroreflex control of sympathetic activity reduced in patients with TTC. We included 13 patients who presented with TTC and compared their SNS activity and spontaneous baroreflex control of sympathetic activity with that of 13 control patients with acutely decompensated chronic heart failure. SNS activity was evaluated by microneurography, a technique assessing muscle sympathetic nerve activity (MSNA). Spontaneous baroreflex control of sympathetic activity was evaluated as the absolute value of the slope of the regression line representing the relationship between spontaneous diastolic blood pressure values and concomitant SNS activity. Control patients were matched for age, sex, left ventricular ejection fraction and creatinine clearance. The mean age of the patients with TTC was 80 years, all patients were women. There were no significant differences between the two groups of patients for blood pressure, heart rate or oxygen saturation level. TTC patients presented a significant increase in sympathetic nerve activity (MSNA median 63.3 bursts/min [interquartile range 61.3 to 66.0] vs median 55.7 bursts/min [interquartile range 51.0 to 61.7]; p = 0.0089) and a decrease in spontaneous baroreflex control of sympathetic activity compared to matched control patients (spontaneous baroreflex control of sympathetic activity median 0.7%burst/mmHg [interquartile range 0.4 to 1.9] vs median 2.4%burst/mmHg [interquartile range 1.8 to 2.9]; p = 0.005). We report for the first time, through direct measurement of sympathetic nerve activity, that patients with TTC exhibit elevated SNS activity associated with a decrease in spontaneous baroreflex control of sympathetic activity. These data may explain the pathophysiology and clinical presentation of patient with TTC.