Resolution of dynamic left ventricular outflow tract obstruction and reversible left ventricular hypertrophy in 4 cats.

This case series describes spontaneous resolution of systolic anterior motion of the mitral valve, cessation of a dynamic left ventricular outflow tract obstruction, and reverse cardiac remodeling in 4 young cats. Following initial presentation with or without congestive heart failure, subsequent rechecks documented resolution of systolic anterior motion of the mitral valve and normalization of left heart dimensions. Those cats originally presented with congestive heart failure were successfully weaned off diuretic medications. Atenolol was prescribed to all 4 cats, and all remained on oral atenolol through the final recheck. There was no documented recurrence of progressive heart disease and heart failure in any of the cats. Consideration is given to transient myocardial thickening, spontaneous resolution of mitral valve dysplasia, and response to beta-1 adrenergic antagonism as possible underlying mechanisms. Key clinical message: When presented with young cats with hypertrophic obstructive cardiomyopathy, veterinarians should consider multiple differential diagnoses, as lifespan in these cases may be longer than typically expected for cats with primary hypertrophic cardiomyopathy, even with concurrent congestive heart failure.

Résolution d'une obstruction dynamique de la voie d'éjection du ventricule gauche et d'une hypertrophie réversible du ventricule gauche chez 4 chatsCette série de cas décrit la résolution spontanée du mouvement antérieur systolique de la valve mitrale, la cessation d'une obstruction dynamique de la voie d'éjection du ventricule gauche et le remodelage cardiaque inverse chez 4 jeunes chats. Après une présentation initiale avec ou sans insuffisance cardiaque congestive, des vérifications ultérieures ont documenté la résolution du mouvement antérieur systolique de la valve mitrale et la normalisation des dimensions du cœur gauche. Les chats initialement présentés avec une insuffisance cardiaque congestive ont été sevrés avec succès des médicaments diurétiques. De l'aténolol a été prescrit aux 4 chats, et tous sont restés sous aténolol oral jusqu'au dernier contrôle. Aucune récidive de maladie cardiaque progressive et d'insuffisance cardiaque n'a été documentée chez aucun des chats. L'épaississement transitoire du myocarde, la résolution spontanée de la dysplasie de la valve mitrale et la réponse à l'antagonisme bêta-1 adrénergique sont pris en compte comme mécanismes sous-jacents possibles.Message clinique clé :Lorsqu'ils sont confrontés à de jeunes chats atteints de cardiomyopathie hypertrophique obstructive, les vétérinaires doivent envisager plusieurs diagnostics différentiels, car la durée de vie dans ces cas peut être plus longue que celle généralement attendue pour les chats atteints de cardiomyopathie hypertrophique primaire, même en cas d'insuffisance cardiaque congestive concomitante.(Traduit par Dr Serge Messier).

Effect of a Cardiovascular Polypill on Poststroke Cognition Among Ghanaians: Secondary Analysis of a Randomized Clinical Trial.

BACKGROUND: Poststroke cognitive impairment is prevalent worldwide, with no satisfactory preventative therapeutic strategies. We report on the effect of a cardiovascular polypill on cognitive performance among recent stroke survivors. METHODS AND RESULTS: The SMAART (Stroke Minimization through Additive Anti-atherosclerotic Agents in Routine Treatment) trial was a phase II randomized trial primarily assessing the polypill versus usual care for secondary prevention after a recent ischemic stroke. Participants allocated to the experimental arm were provided 2 Polycaps taken orally once a day for 12 months. A capsule of Polycap contained aspirin 100 mg, simvastatin 20 mg, hydrochlorothiazide 12.5 mg, ramipril 5 mg, and atenolol 50 mg. Participants in the usual care arm received standard secondary prevention therapy. We compared slopes of the trajectory of raw scores in the executive, language, memory, and visuospatial cognitive domains and aggregated cognitive scores over 12 months via a linear mixed-effects model. We enrolled 148 eligible participants (n=74 in each arm) and 59 versus 64 participants in the polypill and usual care arms, respectively, at month 12. Compared with the usual care arm, the slopes of cognitive performance over 12 months in the polypill arm were steeper by 2.02 units (95% CI, 0.52-3.53), P=0.009 in executive domain, 1.88 units (95% CI, 0.42-3.34), P=0.012 in language domain, 2.60 (0.03-5.17), P=0.049 in memory domain, 0.55 (-0.80 to 1.91), P=0.42 in the visuospatial domain, and global cognitive performance 6.87 units (95% CI, 1.44-12.30), P=0.013. CONCLUSIONS: The cardiovascular polypill is associated with a signal of better cognitive performance over 12 months among stroke survivors. Further definitive trials are warranted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03329599.

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.

Should Propranolol Remain the Gold Standard for Treatment of Infantile Hemangioma? A Systematic Review and Meta-Analysis of Propranolol Versus Atenolol.

BACKGROUND: Although propranolol has been established as the gold standard when treatment is sought for infantile hemangioma, concerns over its side effect profile have led to increasing usage of atenolol, a beta-1 selective blocker. METHODS: A systematic review of PubMed, Scopus, CINAHL, Google Scholar, and Cochrane was conducted following PRISMA guidelines using MeSH terms and keywords for the terms propranolol, atenolol, and infantile hemangioma, including alternative spellings. All randomized control trials (RCTs) or cohort studies directly comparing outcomes of hemangioma treatment with atenolol and propranolol were included. A meta-analysis with pooled mean differences, pooled odds ratios, and analysis of proportions was performed. RESULTS: A total of 669 participants in 7 studies (3 RCTs and 4 cohort) were included. Propranolol showed a significantly higher rate of complete response compared to atenolol (73.3% vs 85.4%, P = .0004). The pooled mean difference of 0.07 (95% CI -0.12, 0.27) in Hemangioma Activity Score (HAS) was not statistically significant. In terms of side effects, there were significantly more agitation and bronchial hyperreactivity events in the propranolol group (P = .0245 and P < .0001, respectively). Overall, there was a significantly greater number of adverse events in the propranolol group compared to the atenolol group (185 vs 117, P < .00001). The overall pooled odds ratio was 2.70 (95% CI 1.90, 3.84), indicating that there is 2.7 times higher odds of adverse events in the propranolol group. CONCLUSION: Propranolol treatment leads to a significantly higher rate of complete response than atenolol. However, its use must be weighed against its greater side effect profile.

Β-blockers activate autophagy on infantile hemangioma-derived endothelial cells in vitro.

The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether ß-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro. MATERIAL AND METHODS: Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 µM to 150 µM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy. RESULTS: Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in ß-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to ß-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by ß-blockers in Hem-ECs. CONCLUSION: Our data suggest that autophagy may be ascribed among the mechanisms of action of ß-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis.

Comparative cardioprotective effects of carvedilol versus atenolol in a rat model of cardiorenal syndrome type 4.

The incidence of chronic kidney disease is escalating; cardiorenal syndrome (CRS) type 4 is gaining a major health concern causing significant morbidity and mortality, putting major burdens on the healthcare system. This study was designed to compare the cardioprotective effects of carvedilol versus atenolol against CRS type 4 induced by subtotal 5/6 nephrectomy in rats and to explore the underlying mechanisms. Immediately after surgery, carvedilol (20 mg/kg/day) or atenolol (20 mg/kg/day) was added to drinking water for 10 weeks. Carvedilol was more effective than atenolol in improving kidney functions, decreasing elevated blood pressures, attenuating cardiac hypertrophy, reducing serum brain natriuretic peptide, and diminished cardiac fibrous tissue deposition. However, carvedilol was equivalent to atenolol in modulating ß1-adrenergic receptors (ß1ARs) and cardiac diacylglycerol (DAG) signaling, but carvedilol was superior in modulating ß-arrestin2, phosphatidyl inositol 4,5 bisphosphates (PIP2), and caspase 3 levels. Carvedilol has superior cardioprotective effects than atenolol in a rat model of CRS type 4. These protective effects are mediated through modulating cardiac ß1ARs/ß-arrestin2/PIP2/DAG as well as abating cardiac apoptotic signaling pathways (caspase3/pS473 protein kinase B (Akt)).

Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas: A Randomized Clinical Trial.

Importance: Propranolol has become the first-line therapy for problematic infantile hemangiomas (IHs) that require systemic therapy. However, different adverse events have been reported during propranolol treatment. The positive efficacy and safety of atenolol raise the question of whether it could be used as a promising therapy for IH. Objective: To compare the efficacy and safety of propranolol vs atenolol in infants (between age 5 and 20 weeks) with problematic IHs who required systemic therapy. Design, Setting, and Participants: This was a prospective, multicenter, randomized, controlled, open-label clinical trial conducted in collaboration among 6 separate investigation sites in China from February 1, 2015, to December 31, 2018. A total of 377 patients met the criteria for inclusion and were randomized to the propranolol (190 [50.4%]) and atenolol (187 [49.6%]) groups. Data were analyzed in June 2020. Interventions: Participants were randomized to receive either propranolol or atenolol for at least 6 months. They completed efficacy assessments at 2 years after the initial treatment. Main Outcomes and Measures: The primary outcome was any response or nonresponse at 6 months. The key secondary outcome was changes in the hemangioma activity score. Results: Of 377 participants, 287 (76.1%) were female, and the mean (SD) age was 10.2 (4.0) weeks in the propranolol group and 9.8 (4.1) weeks in the atenolol group. After 6 months of treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and 92.5%, respectively (difference, 1.2%; 95% CI, -4.1% to 6.6%). At 1 and 4 weeks after treatment, and thereafter, the hemangioma activity score in the atenolol group aligned with the propranolol group (odds ratio, 1.034; 95% CI, 0.886-1.206). No differences between the propranolol group and atenolol group were observed in successful initial responses, quality of life scores, complete ulceration healing times, or the rebound rate. Both groups presented a similar percentage of complete/nearly complete responses at 2 years (82.1% vs 79.7%; difference, 2.4%; 95% CI, -5.9% to 10.7%). Adverse events were more common in the propranolol group (70.0% vs 44.4%; difference, 25.6%; 95% CI, 15.7%-34.8%), but the frequency of severe adverse events did not differ meaningfully between the groups. Conclusions and Relevance: In this randomized clinical trial, when compared with propranolol, atenolol had similar efficacy and fewer adverse events in the treatment of infants with problematic IHs. The results suggest that oral atenolol can be used as an alternative treatment option for patients with IH who require systemic therapy. Trial Registration: ClinicalTrial.gov Identifier: NCT02342275.

A survey on the application of oral propranolol and atenolol for the management of infantile hemangiomas in mainland China: Survey on propranolol atenolol hemangiomas.

ABSTRACT: Since 2008, oral propranolol has evolved as the first-line therapy for infantile hemangiomas (IHs). Meanwhile, oral atenolol gradually shows comparative effectiveness versus oral propranolol with few side effects. Here, we conducted a mobile internal survey among a group of Chinese clinicians about how they choose the dosage, dose regimen, and dose escalation methods of propranolol and atenolol for the treatment of IH.A mobile-ready internal survey on the application of oral propranolol and oral atenolol for IH in mainland China was performed and distributed to 333 potential clinicians from different levels of healthcare institutions in mainland China. Eighty-one doctors responded to the survey. All the respondents had the experience of treating IH with oral propranolol and 32 had the experience with oral atenolol.Most of the doctors from tertiary hospitals chose 2 mg/kg/d twice daily, while most of those with the experience of propranolol from private hospitals chose 1 mg/kg/d once daily. More doctors from tertiary hospitals had the experience of atenolol than those from private hospitals.Oral atenolol has become another medication intervention option for IH in mainland China. This survey is helpful to standardize and develop a guideline of oral atenolol therapy for IH.

Traumatic brain injury induced temperature dysregulation: What is the role of ß blockers?

BACKGROUND: Traumatic brain injury (TBI) is associated with sympathetic discharge that leads to posttraumatic hyperthermia (PTH). Beta blockers (ßß) are known to counteract overactive sympathetic discharge. The aim of our study was to evaluate the effect of ßß on PTH in critically-ill TBI patients. METHODS: We performed retrospective cohort analysis of the Medical Information Mart for Intensive Care database. We included all critically ill TBI patients with head Abbreviated Injury Scale (AIS) score of 3 or greater and other body region AIS score less than 2 who developed PTH (at least one febrile episode [T > 38.3°C] with negative microbiological cultures (blood, urine, and bronchoalveolar lavage). Patients on preinjury ßß were excluded. Patients were stratified into (ßß+) and (ßß-) groups. Propensity score matching was performed (1:1 ratio) controlling for patient demographics, injury parameters and other medications that influence temperature. Outcomes were the number of febrile episodes, maximum temperature, and the time interval between febrile episodes. Multivariate linear regression was performed. RESULTS: We analyzed 4,286 critically ill TBI patients. A matched cohort of 1,544 patients was obtained: 772 ßß + (metoprolol, 60%; propranolol, 25%; and atenolol, 15%) and 772 ßß-. Mean age was 63.4 ± 15.4 years, median head AIS score of 3 (3-4), and median Injury Severity Score of 10 (9-16). Patients in the ßß+ group had a lower number of febrile episodes (8 episodes vs. 12 episodes; p = 0.003), lower median maximum temperature (38.0°C vs. 38.5°C; p = 0.025), and a longer median time between febrile episodes (3 hours vs. 1 hour; p = 0.013). On linear regression, propranolol was found to be superior in terms of reducing the number of febrile episodes and the maximum temperature. However, there was no significant difference between the three ßß in terms of reducing the time interval between febrile episodes (p = 0.582). CONCLUSION: Beta blockers attenuate PTH by decreasing the frequency of febrile episodes, increasing the time interval between febrile episodes, and reducing the maximum rise in temperature. ßß may be a potential therapeutic modality in PTH. LEVEL OF EVIDENCE: Therapeutic, level IV.

Use of beta-blocker types and risk of incident prostate cancer in a multiethnic population.

PURPOSE: Increased adrenergic innervation is observed in prostate cancer (CaP) and is associated with aggressive disease. Emerging evidence suggests that beta-adrenergic blockade inhibits CaP progression. However, the association between type of beta-blocker use and risk of incident CaP on initial prostate biopsy has not been investigated in multiethnic populations. MATERIALS AND METHODS: A retrospective study of racially/ethnically diverse men (64% African-American and Hispanic), who underwent initial prostate biopsy between 2006 and 2016 in a large healthcare system was performed. Oral use of beta-blocker type was assessed by reviewing active prescriptions within the 5-year period preceding initial biopsy. Patient demographics and clinical factors were collected. RESULTS: Of 4,607 men who underwent initial prostate biopsy, 4,516 met criteria and 2,128 had a biopsy positive for CaP; 20% high-risk, 41% intermediate-risk, and 39% low or very-low risk (National Comprehensive Cancer Network classification). Overall, 15% of patients were taking a beta-blocker prior to initial biopsy, with Metoprolol, Atenolol, and Carvedilol accounting for the majority. Of beta-blocker types, Atenolol alone was associated with a 38% reduction in odds of incident CaP (P= 0.01), with a 40% and 54% reduction in risks of National Comprehensive Cancer Network intermediate and high-risk CaP (P = 0.03 and P = 0.03, respectively) compared to men not taking a beta-blocker. Furthermore, longer duration of Atenolol use (3-5 years) was associated with a 54% and 72% reduction in intermediate and high-risk disease, (P = 0.03 and P = 0.03, respectively). CONCLUSIONS: Among beta blocker types, long-term Atenolol use is associated with a significant reduction in incident CaP risk on initial prostate biopsy for clinically-significant intermediate and high-risk disease compared to men not taking a beta-blocker.

Clinical evaluation of infantile hemangiomas treated with atenolol.

Currently, propranolol, is the first line treatment for problematic infantile hemangioma (IH) management. However, serious side effects have been reported. For that reason, atenolol, a hydrophilic selective beta-1 blocker with the potential for fewer side effects, has been explored. A descriptive, observational case series study of 30 patients between the ages one to 5 months with superficial, deep, or mixed IH was conducted between January 2016 and December 2017. Oral atenolol was administered using a single once daily dose of 1mg/kg, which was adjusted for weight gain each month. The IH was assessed using the Hemangioma Activity Score (HAS) at initiation of treatment, four months, and 9 months of age and improvement percentage was calculated at four and nine months of age. A total of 25 patients completed three evaluations. The baseline, four-month, and 9-month HAS were 4.6, 2.39, and 0.65, respectively. Mean improvement percentage at four months of age was 46.76% and at 9 months of age was 85.65%. No side effects were reported. This study suggests atenolol as an effective treatment for IH in almost all cases, especially in patients who initiated treatment before three months of age. It was well tolerated in all our cases.

Cardiac Inflammation after Ischemia-Reperfusion of the Kidney: Role of the Sympathetic Nervous System and the Renin-Angiotensin System.

BACKGROUND/AIMS: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. METHODS: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ß1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. RESULTS: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of ß1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. CONCLUSION: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.

Genome-Wide Meta-Analysis of Blood Pressure Response to ß1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to ß1-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing ß1-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to ß1-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta-analysis and single nucleotide polymorphisms (SNPs) with P<10-4 were tested for replication in 2 independent randomized clinical trials of ß1-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a ß1-blocker-treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to ß1-blockers in the discovery meta-analysis (P=9.33×10-5, ß=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10-4, ß=-4.86 mm Hg) in the replication meta-analysis with combined meta-analysis approaching genome-wide significance (P=2.18×10-7). This SNP in BST1 is in linkage disequilibrium with several SNPs with putative regulatory functions in nearby genes, including CD38, FBXL5, and FGFBP1, all of which have been implicated in BP regulation. SNPs in this genetic region were also associated with BP response in the black cohort.ConclusionsData from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with ß1-blocker BP response. Given the previous associations of this region with BP, this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.

Atenolol as an alternative to propranolol for the management of sleep disturbances in the treatment of infantile hemangiomas.

Infantile hemangiomas are the most common tumors of infancy and are often managed with oral beta-blockers to address or prevent associated complications. However, treatment with propranolol can occasionally be associated with sleep disturbances, which in some cases are severe enough to warrant discontinuation or replacement with another agent. We herein report four cases in which treatment with propranolol resulted in significant sleep disturbances prompting substitution with atenolol, which in some cases resolved these issues.