G Protein-Coupled Receptors: A Century of Research and Discovery.

GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and ß-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of ß-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.

Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.

BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.

Do beta-blockers reduce negative intrusive thoughts and anxiety in cancer survivors? - An emulated trial.

BACKGROUND: High rates of negative intrusive thoughts have been reported among cancer patients. Prevalent users of beta-blocker therapy have reported lower levels of cancer related intrusive thoughts than non-user. The aim of this study is to investigate if initiation of beta-blocker therapy reduces the prevalence and severity of intrusive thoughts (co-primary endpoints) and the prevalence of anxiety, depressed mood, and low quality of life (secondary endpoints) in cancer survivors. METHODS: Data on patient-reported outcomes from three cohort studies of Swedish patients diagnosed with colon, prostate or rectal cancer were combined with data on beta-blocker prescriptions retrieved from the Swedish Prescribed Drug Register. Two randomized controlled trials were emulated. Trial 1 had follow-up 1 year after diagnosis, trial 2 had follow-up 2 years after diagnosis, baseline in both trials was 12 months before follow-up. Those who initiated beta-blocker therapy between baseline and follow-up was assigned Active group, those who did not was assigned Control group. All endpoints were analysed using Bayesian ordered logistic regression. RESULTS: Trial 1 consisted of Active group, n = 59, and Control group, n = 3936. Trial 2 consisted of Active group, n = 87, and Control group, n = 3132. The majority of participants were men, 83% in trial 1 and 94% in trial 2. The prevalence and severity of intrusive thoughts were lower in the Active group in trial 1, but no significant differences between groups were found in either trial. The prevalence of depressed mood, worse quality of life and periods of anxiety were higher in the Active group in both trials with significant differences for quality of life in trial 1 and anxiety in trial 2. CONCLUSIONS: The emulated trials demonstrated no evidence of a protective effect of beta-blocker therapy against intrusive thoughts. The Active group had reduced quality of life and elevated anxiety compared to the Control group. TRIAL REGISTRATION: The three cohort studies were registered at isrctn.com/clinicaltrials.gov (ISRCTN06393679, NCT02530593 and NCT01477229).

Beta-blockers and breastfeeding: a real-life prospective study.

PURPOSE: At Lille University Hospital, a pregnancy heart team including cardiologists, obstetricians, pediatricians, anesthetists, geneticists, and pharmacologists discusses about treatment compatibility taken during breastfeeding in pregnant women (or those wishing to be pregnant) with complex cardiovascular pathologies. Beta-blockers are among the drug most often used in these patients, and data are missing or suggest a risk to the breastfed child. The aim of this study was to evaluate the proportion of women treated with beta-blockers, identified during the multidisciplinary meeting, who breastfed and to monitor adverse effects (AEs) in newborns. METHODS: A prospective descriptive study was conducted from 1 December 2017 to 1 December 2021. All pregnant patients followed up by the pregnancy heart team in Lille University Hospital, treated with beta-blockers and who gave birth, were contacted as part of the pharmacovigilance follow-up. RESULTS: The proportion of women treated with beta-blockers intending to breastfeed was 69.8%. Among the 53 women interviewed, 49% did not breastfeed, including 10 because of the theoretical incompatibility of their beta-blocker with breastfeeding. Among the 27 women who breastfed, 30% breastfed while treated with a theoretically incompatible beta-blocker; 56% was changed from their initial beta-blocker to allow safe breastfeeding. No serious AE was observed. CONCLUSION: To our knowledge, our study is the largest series of patients treated with beta-blockers during breastfeeding. Taking a treatment can be an obstacle to breastfeeding, but for the particular case of beta-blockers, even if the available data are few and sometimes worrying, the data from this study are reassuring.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Early postoperative beta-blockers are associated with improved cardiac output after late complete repair of tetralogy of Fallot: a retrospective cohort study.

Tetralogy of Fallot is the most common cyanotic congenital heart disease. For decades, our institution has cared for humanitarian patients with late presentation of tetralogy of Fallot. They are characterized by severe right ventricular hypertrophy with consecutive diastolic dysfunction, increasing the risk of postoperative low cardiac output syndrome (LCOS). By right ventricular restrictive physiology, we hypothesized that patients receiving early postoperative beta-blockers (within 48 h after cardiopulmonary bypass) may have better diastolic function and cardiac output. This is a retrospective cohort study in a single-center tertiary pediatric intensive care unit. We included > 1-year-old humanitarian patients with a confirmed diagnosis of tetralogy of Fallot undergoing a complete surgical repair between 2005 and 2019. We measured demographic data, preoperative echocardiographic and cardiac catheterization measures, postoperative mean heart rate, vasoactive-inotropic scores, LCOS scores, length of stay, and mechanical ventilation duration. One hundred sixty-five patients met the inclusion criteria. Fifty-nine patients (36%) received early postoperative beta-blockers, associated with a lower mean heart rate, higher vasoactive-inotropic scores, and lower LCOS scores during the first 48 h following cardiopulmonary bypass. There was no significant difference in lengths of stay and ventilation. Conclusion: Early postoperative beta-blockers lower the prevalence of postoperative LCOS at the expense of a higher need for vasoactive drugs without any consequence on length of stay and ventilation duration. This approach may benefit the specific population of children undergoing a late complete repair of tetralogy of Fallot. What is Known: • Prevalence of low cardiac output syndrome is high following a late complete surgical repair of tetralogy of Fallot. What is New: • Early postoperative beta-blockade is associated with lower heart rate, prolonged relaxation time, and lower prevalence of low cardiac output syndrome. • Negative chronotropic agents like beta-blockers may benefit selected patients undergoing a late complete repair of tetralogy of Fallot, who are numerous in low-income countries.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study.

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

Long-term neurocognitive functioning of children treated with propranolol or atenolol for infantile hemangioma.

The purpose of this study was to compare long-term neurocognitive functioning (working memory, processing speed, and attention) between children who had been treated with either propranolol or atenolol for infantile hemangioma during infancy. All eligible children (n = 158) aged 6 years or older and treated with propranolol or atenolol as infants were invited to participate in this two-center cross-sectional study. The primary outcome was the Wechsler Intelligence Scale for Children-V Cognitive Proficiency Index (CPI), a measure of working memory, processing speed, and attention. Secondary outcomes were general intelligence, auditory, visuospatial, and narrative memory, as well as executive functioning and sleep. A total of 105 children, of whom 36 had been treated with propranolol (age 6.0-11.8 years, follow-up time 1.6-9.7 years, 19% male) and 69 had been treated with atenolol (age 6.9-9.7 years, follow-up time 4.5-8.4 years, 19% male), were analyzed. The CPI and other neurocognitive outcomes did not differ between the propranolol and atenolol groups and were in line with general population test norms. Post hoc analyses revealed lower CPI scores for males, both compared to participating females (10.3 IQ points, medium effect size) and compared to matched test norms (12.4 IQ points, medium effect size). CONCLUSIONS:  Long-term neurocognitive functioning did not differ between children treated with propranolol and those treated with atenolol for IH. Overall, propranolol and atenolol appear to be safe treatments for IH regarding long-term neurocognitive functioning. The substantially lower CPI scores in males warrant further investigation. TRIAL REGISTRATION:  Netherlands Trial Register, NL7703 https://www.trialregister.nl/trial/7703 What is Known: • Infants with infantile hemangioma are effectively treated with propranolol or atenolol. • Parents and professionals are concerned about long-term neurocognitive effects. WHAT IS NEW: • No long-term (≥ 6 years) differences in neurocognitive functioning were found between children treated with propranolol or atenolol. • Males treated with beta-blockers had substantially lower IQ scores than treated females and males from the general population, which is a matter of concern and should be considered when evaluating the risk/benefit ratio in less severe forms of infantile hemangioma.

Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Extended Follow-Up of a 2×2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol.

BACKGROUND: Adjuvant breast cancer therapy containing anthracyclines with or without anti-human epidermal growth factor receptor-2 antibodies and radiotherapy is associated with cancer treatment-related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the ß-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. METHODS: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. RESULTS: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. CONCLUSIONS: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations.

BACKGROUND: We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM). METHODS: The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location. RESULTS: Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01-0.66]; P=0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01-1.07]; P=0.067). CONCLUSIONS: Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM.

In at-risk patients without CVD, polypill plus aspirin reduced a composite of major CV events at 4.6 y.

SOURCE CITATION: Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med. 2021;384:216-28. 33186492.

Beta-blocker use after complete repair of tetralogy of Fallot: an analysis of a national database.

INTRODUCTION: In patients with right ventricular diastolic dysfunction after complete repair of tetralogy of Fallot, some employ the use of beta-blockade. The theoretical benefit of this therapy is felt to be one of the two: 1) reduction in heart rate with subsequent increase in diastolic filling time and stroke volume; 2) halting or reversal of right ventricular remodelling. This study aimed to characterise the use of beta-blockade in paediatric admissions with complete repair of tetralogy of Fallot and characterise the effects of beta-blockade on admission characteristics. METHODS: Admissions from 2004 to 2015 in the Pediatric Health Information System database with complete repair of tetralogy of Fallot were identified. Characteristics between admissions with and without beta-blockade were compared by univariate analysis. Next, regression analyses were conducted to determine the independent association of beta-blockade on length of admission, billed charges, cardiac arrest, and inpatient mortality while controlling for demographic variables and comorbidities. RESULTS: A total of 3594 admissions were included in the final analyses. Of these, 371 employed beta-blockade. Admissions with beta-blockade were more likely to have heart failure and tachyarrhythmias. These admissions also tended to be longer by univariate analysis. Regression analyses demonstrated that beta-blockade was independently associated with a 2.8-day increase in length of stay and no statistically significant change in billed charges, cardiac arrest, or inpatient mortality. CONCLUSIONS: Beta-blockade after complete repair of tetralogy of Fallot is associated with a longer length of stay but did not statistically significantly impact billed charges, cardiac arrest, or inpatient mortality.

Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial.

INTRODUCTION: The migraine-preventive drug propranolol is efficacious in reducing pain from temporomandibular disorder, suggesting potential modifying or mediating effects of comorbid migraine. METHODS: In this randomized controlled trial, myofascial temporomandibular disorder patients were treated with propranolol or placebo for 9 weeks. The primary endpoint was change in a facial pain index derived from daily symptom diaries. Linear and logistic regression models tested for a migraine × treatment-group interaction in reducing facial pain index. Counterfactual models explored changes in headache impact and heart rate as mediators of propranolol's efficacy. RESULTS: Propranolol's efficacy in reducing facial pain index was greater among the 104 migraineurs than the 95 non-migraineurs: For example, for the binary ≥ 30% reduction in facial pain index, odds ratios were 3.3 (95% confidence limits: 1.4, 8.1) versus 1.3 (0.5, 3.2), respectively, although the interaction was statistically non-significant (p = 0.139). Cumulative response curves confirmed greater efficacy for migraineurs than non-migraineurs (differences in area under the curve 26% and 6%, respectively; p = 0.081). While 9% of the treatment effect was mediated by reduced headache impact, 46% was mediated by reduced heart rate. CONCLUSIONS: Propranolol was more efficacious in reducing temporomandibular disorder pain among migraineurs than non-migraineurs, with more of the effect mediated by reduced heart rate than by reduced headache impact. STUDY IDENTIFICATION AND REGISTRATION: SOPPRANO; NCT02437383; https://clinicaltrials.gov/ct2/show/NCT02437383.

The impact of regular bisoprolol on the response to salbutamol in asthma: A double-blind randomized placebo-controlled crossover trial.

BACKGROUND AND OBJECTIVE: Non-selective beta-blockers impair the bronchodilator response to beta2 -agonists. Cardio-selective beta1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta1 -blocker treatment in people with asthma. METHODS: A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 µg) was administered via spacer at 5-min intervals with repeated FEV1 measures. The FEV1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. RESULTS: A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. CONCLUSION: The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta1 -blocker, bisoprolol, compared to placebo. CLINICAL TRIAL REGISTRATION: ACTRN12618000306213 at https://www.anzctr.org.au.

Practical instructions for using drugs in CT and MR cardiac imaging.

The progressive increase in numbers of noninvasive cardiac imaging examinations broadens the spectrum of knowledge radiologists are expected to acquire in the management of drugs during CT coronary angiography (CTCA) and cardiac MR (CMR) to improve image quality for optimal visualization and assessment of the coronary arteries and adequate MR functional analysis. Aim of this review is to provide an overview on different class of drugs (nitrate, beta-blockers, ivabradine, anxiolytic, adenosine, dobutamine, atropine, dipyridamole and regadenoson) that can be used in CTCA and CMR, illustrating their main indications, contraindications, efficacy, mechanism of action, metabolism, safety, side effects or complications, and providing advices in their use.

Pulse Oximeter Plethysmograph Variation During Hemorrhage in Beta-Blocker-Treated Swine.

BACKGROUND: Beta-blockers blunt the stress response to hemorrhage. Our aim was to investigate the feasibility of noninvasive pulse oximeter plethysmographic waveform variation (PoPV) for predicting blood volume loss in an esmolol-treated swine hemorrhagic shock model. MATERIALS AND METHODS: Controlled hemorrhage was induced in eight male domestic pigs. In four pigs, a total of 15% and 30% blood volume was drawn step-by-step over 10 min in each step (controlled hemorrhage-only pigs). In the other four pigs, the heart rate (HR) was reduced and maintained by 30% from baseline by esmolol infusion before controlled hemorrhage (esmolol-treated pigs). Diagnostic abilities of HR, pulse pressure variation (PPV), PoPV, and mean arterial pressure for 15% and 30% blood volume loss were determined by the area under the receiver operating characteristic curve (AUC). RESULTS: PoPV was well correlated with PPV in controlled hemorrhage-only pigs (r = 0.717) and esmolol-treated pigs (r = 0.532). In controlled hemorrhage-only pigs, HR (AUC = 0.841 and 0.864), PPV (0.878 and 0.843), and PoPV (0.779 and 0.793) accurately predicted 15% and 30% of blood volume loss. In esmolol-treated pigs, the diagnostic ability of HR was decreased (AUC = 0.766 and 0.733). However, diagnostic abilities of PPV (0.848 and 0.804) and PoPV (0.808 and 0.842) were not deteriorated. CONCLUSIONS: The diagnostic ability of HR for blood volume loss was blunted by esmolol. However, those of PPV and PoPV were not altered. PoPV may be considered to be a useful noninvasive tool to predict blood volume loss in injured patients taking beta-blockers.

Underuse of beta-blockers by patients with COPD and co-morbid acute coronary syndrome: A nationwide follow-up study in New Zealand.

BACKGROUND AND OBJECTIVE: Clinical guidelines recommend the use of beta-blockers and other cardiovascular prevention drugs in patients with acute coronary syndrome (ACS). Studies in several countries have found that beta-blockers are underused in patients with chronic obstructive pulmonary disease (COPD) and co-morbid heart disease, although most have only examined use in subgroups of patients. We undertook a nationwide follow-up study in New Zealand to describe the use of beta-blockers and other cardiovascular prevention drugs in patients with COPD and ACS. METHODS: National health and pharmaceutical dispensing data were used to derive the study cohort, identify patients who were admitted to hospital with ACS and/or heart failure before cohort entry and during follow-up, and ascertain drug use. RESULTS: The study cohort included 83 435 patients aged ≥45 years, with 290 400 person-years of follow-up. Among 2637 patients with ≥1 ACS admission during follow-up, only 56.6% received a beta-blocker in the 6 months following the first admission, while 87.7% and 81%, respectively, received aspirin and a statin. Patients with higher COPD severity were less likely to receive a beta-blocker than those with lower severity, as were those with no history of previous ACS and/or heart failure. CONCLUSION: Use of beta-blockers following an ACS admission was much lower than expected based on the findings of general audits of ACS management in New Zealand. Along with the higher proportions using aspirin and statins, and the differences in beta-blocker dispensing by COPD severity, this suggests a particular reluctance to prescribe beta-blockers to patients with COPD.

Beta-Blockade in Aneurysmal Subarachnoid Hemorrhage: a Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVE: Sympathetic nervous system activation after aneurysmal subarachnoid hemorrhage (aSAH) is associated with complications and poor outcome. In this systematic review and meta-analysis, we investigate the effect of beta-blockers on outcome after aSAH. METHODS: The review was prospectively registered with PROSPERO (CRD42019111784). We performed a systematic literature search of MEDLINE, EMBASE, the Cochrane Library, published conference proceedings, and abstracts. Eligible studies included both randomized controlled trials and observational studies up to October 2018, reporting the effect of beta-blocker therapy on the following outcomes in aSAH: mortality, vasospasm, delayed cerebral ischemia, infarction or stroke, cardiac dysfunction, and functional outcomes. Studies involving traumatic SAH were excluded. Citations were reviewed, and data extracted independently by two investigators using a standardized proforma. RESULTS: We identified 819 records with 16 studies (four were randomized controlled trials) including 6702 patients selected for analysis. Exposure to beta-blockade either before or after aSAH was associated with a significant reduction in unadjusted mortality (RR 0.63, 95% CI 0.42-0.93, p = 0.02). A significant reduction in unadjusted mortality was also seen in prospective trials of post-event beta-blockade (RR 0.51, 95% CI 0.28-0.93, p = 0.03). Statistically significant differences were not seen for other outcomes investigated. CONCLUSIONS: In adult patients with aSAH, beta-blocker therapy is associated with a mortality benefit. Studies are generally of a low quality with considerable clinical heterogeneity. Prospective large interventional trials with patient centered outcomes are required to validate this finding.

High-Dose Insulin for Toxin Induced Cardiogenic Shock: Experience at a New High and Overview of the Evidence.

BACKGROUND: High-dose insulin therapy is an effective treatment for cardiogenic shock caused by the overdose of particular medications. Other treatment options are usually of limited benefit. Consensus suggests that early initiation improves efficacy. No ceiling effect has been established at doses in the general range of 0.5-10 units/kg/hour. CASE REPORT: A 79-year-old man presented in cardiogenic shock after an intentional overdose of numerous cardioactive medications 10 days after experiencing myocardial infarction. A high-dose insulin infusion was commenced. This was titrated up to a maximum of 20 units/kg/hour (1600 units/hour) and sustained for 32 h (61,334 units total). Minimal adverse events were seen despite this exceptional infusion rate (3 episodes of hypoglycemia and 2 episodes of hypokalemia). Concurrent catecholamine support was used, and cardiovascular function was maintained until all support was withdrawn 5 days after admission. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians are pivotal to the successful initiation/up-titration of high-dose insulin therapy. They must balance the potential for treatment failure with other treatment options, mitigate against adverse events in the initial phase of therapy, and coordinate care between other hospital specialties. This case shows that the relative safety and efficacy was extended to an infusion rate of 20 units/kg/hour, the highest recorded in the published literature. This information may help guide treatment of similar cases in the future.