Patient-Centered Heart Failure Therapy.

Simultaneous initiation of quadruple therapy with angiotensin receptor-neprilysin inhibitor, beta-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor aims at prompt improvement and prevention of readmission in patients hospitalized for heart failure with reduced ejection fraction. However, titration of quadruple therapy is time consuming. Lengthy up-titration of quadruple therapy may negate the benefit of early initiation. Quadruple therapy should start with a sodium glucose cotransporter 2 inhibition and a mineralocorticoid antagonist, as both enable safe decongestion and require minimal or no titration. Depending on the level of decongestion and clinical characteristics, patients receive an angiotensin receptor-neprilysin inhibitor or a beta-adrenergic receptor blocker to be titrated after hospital discharge. Outpatient addition of an angiotensin receptor-neprilysin inhibitor to a beta-adrenergic receptor blocker or vice versa completes the quadruple therapy scheme. By focusing on decongestion and matching intervention to patients' profile, the present therapeutic sequence allows rapid implementation of quadruple therapy at fully recommended doses.

Utilisation and optimisation of beta-adrenergic receptor blockers over a 6-month period among chronic heart failure patients with reduced ejection fraction.

BACKGROUND: Beta-adrenergic receptor blocker (BARB) drugs are a wide range of medicines that are used in various conditions, including chronic heart failure (HF). Several studies have reported a wide-ranging inappropriate use of evidence-based beta-blockers (EBBBs) in chronic HF in both inpatients and outpatients. OBJECTIVES: To assess the utilisation and optimisation of EBBBs among patients with HF who presented with a reduced ejection fraction (HFrEF). METHODS: A hospital-based retrospective cross-sectional study was carried out at the Adult University Teaching Hospital (AUTH), in Lusaka, Zambia, where patient medical files for the period of 1 July 2018 to 31 July 2021 were reviewed. Patient information, including file number, age, sex, type of BARB and the dose used, was recorded on the developed and validated checklist. Multivariable regression analysis was performed to identify factors associated with utilisation of BARBs. RESULTS: Of the 173 medical records reviewed, BARBs were utilised in 101 (58.4%) patients. Among the patients who utilised BARBs, 96 (95.0%) were taking EBBBs, while the rest (n=5, 5.0 %) were taking atenolol, which is a non-EBBB. Among the patients who were on EBBBs, none of them received the optimal dose. Age ≥65 years (adjusted odds ratio (aOR) 0.3, 95% confidence interval (CI) 0.17 - 0.64), previous hospitalisation (aOR 0.3, 95% CI 0.13 - 0.51) and furosemide dose ≥40 mg (aOR 0.4, 95% CI 0.21 - 0.64) were significantly associated with lower likelihood of BARB utilisation. New York Heart Association (NYHA) class II (aOR 3.4, 95% CI 1.08 - 10.7), NYHA class III (aOR 4.8, 95% CI 1.65 - 13.7) and patients using at least 5 medications (aOR 5.0, 95% CI 2.91 - 8.77) were independent predictors of BARB utilisation. CONCLUSION: This study showed that 95.0% of chronic HF patients were utilising EBBBs, and none received the optimal dose as recommended in the guidelines. Pharmacotherapy with EBBBs should be optimised among patients with chronic HfrEF, as these drugs reduce both morbidity and mortality.

Xinbao Pill attenuated chronic heart failure by suppressing the ubiquitination of ß-adrenergic receptors.

BACKGROUD: Xinbao Pill (XBP) is extensively used in the adjuvant treatment of chronic heart failure in China. However, the pharmacological effect and underlying mechanism on CHF remains unclear. PURPOSE: Our research was performed to investigate the cardioprotective effect of XBP against CHF and uncover the potential mechanism. METHODS: Male Sprague-Dawley (SD) rats were subjected to the left anterior descending (LAD) artery ligation for 8 weeks and were treated with different doses of XBP (from the 4th week to the end). Cardiac function and morphology assessment were performed by using M-mode echocardiography, H&E and Masson staining. Western blotting analysis, co-immunoprecipitation (IP) assays, siRNA transfection were used to evaluate the mechanism of XBP. RESULTS: XBP improved cardiac function and alleviated cardiac fibrosis in LAD-induced chronic heart failure rats. Meanwhile, XBP protected cardiomyocytes against oxygen-glucose deprivation (OGD) injury in AC16 cells and H9c2 cells. Additionally, XBP could increase the expression of ß1-AR and ß2-AR and inhibit their ubiquitanation. Further mechanism study showed that XBP upregulated USP18 expression, while silence of USP18 attenuated the cardioprotective effect of XBP and the increase of ß1-AR by XBP. Moreover, XBP increased MDM2 and ß-arrestin2, and disrupted the interaction between Nedd4 and ß2-AR. After using the inhibitor of MDM2, SP141, the cardioprotective effect of XBP and the inhibitory effect on the ubiquitanation of ß2-AR were also blocked. CONCLUSION: Our study firstly revealed that XBP improved cardiac function against CHF through suppressing USP18 and MDM2/ß-arrestin2/Nedd4-mediated the ubiquitination of ß1-AR and ß2-AR.

Association of Nondihydropyridine Calcium Channel Blockers Versus ß-Adrenergic Receptor Blockers With Risk of Heart Failure Hospitalization.

Heart failure (HF) with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are interrelated and often coexisting conditions in older adults. Although equally recommended, nondihydropyridine calcium channel blockers (non-DHP CCBs), such as diltiazem and verapamil, are less often used than ß blockers. Because recent studies suggested that ß-blocker use in both HFpEF and AF may increase the risk for HF, we tested whether non-DHP CCBs were associated with lower HF hospitalization risk than ß blockers. We examined fee-for-service Medicare beneficiaries who were aged ≥66 years, had HFpEF or AF, and newly initiated a ß blocker (n = 83,458) or non-DHP CCB (n = 18,924) from 2014 to 2018. The outcomes of HF hospitalization and all-cause mortality were analyzed using multivariable-adjusted Cox regression in the full cohort and, separately, in the subset without a recent hospital or skilled nursing discharge. Follow-up was analyzed using 2 frameworks: intention-to-treat and censored-at-drug-switch-or-discontinuation. There was a modestly protective association of non-DHP CCBs for the risk of HF hospitalization. Before drug switch or discontinuation, the use of diltiazem or verapamil was associated with decreased risk of HF hospitalization in the full cohort (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.81 to 1.00, p = 0.05) and in the subgroup (HR 0.70, 95% CI 0.56 to 0.89, p = 0.003). However, the association with all-cause mortality tended to favor ß blockers, including in the intention-to-treat analysis (HR 1.21, 95% CI 1.17 to 1.25, p <0.001). In conclusion, compared with ß blockers, the initiation of diltiazem or verapamil in patients with HFpEF or AF may be associated with fewer HF hospitalization events but also with more all-cause deaths.

Beta-blocker use in patients with heart failure with preserved ejection fraction and sinus rhythm.

INTRODUCTION: Beta-adrenergic receptor blockers (beta-blockers) are frequently used for patients with heart failure (HF) with preserved ejection fraction (HFpEF), although evidence-based recommendations for this indication are still lacking. Our goal was to assess which clinical factors are associated with the prescription of beta-blockers in patients discharged after an episode of HFpEF decompensation, and the clinical outcomes of these patients. METHODS: We assessed 1078 patients with HFpEF and in sinus rhythm who had experienced an acute HF episode to explore whether prescription of beta-blockers on discharge was associated with one-year all-cause mortality or the composite endpoint of one-year all-cause death or HF readmission. We also examined the clinical factors associated with beta-blocker discharge prescription for such patients. RESULTS: At discharge, 531 (49.3%) patients were on beta-blocker therapy. Patients on beta-blockers more often had a prior diagnosis of hypertension and more comorbidity (including ischemic heart disease) and a better functional status, but less often a prior diagnosis of chronic obstructive pulmonary disease. These patients had a lower heart rate on admission and more often used angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors and loop diuretics. One year after the index admission, 161 patients (15%) had died and 314 (29%) had experienced the composite endpoint. After multivariate adjustment, beta-blocker prescription was not associated with either all-cause mortality (HR=0.83 [95% CI 0.61-1.13]; p=0.236) or the composite endpoint (HR=0.98 [95% CI 0.79-1.23]; p=0.882). CONCLUSION: In patients with HFpEF in sinus rhythm, beta-blocker use was not related to one-year mortality or mortality plus HF readmission.

Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma.

BACKGROUND: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of ß-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. METHODS: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between ß-blockers and ionising radiations. Gene expression profiles of ß-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. FINDINGS: Low concentrations of ß-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of ß-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. INTERPRETATION: These data provide the evidence of the efficacy of ß-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. FUNDING: This study was funded by institutional grants and charities.

Efeitos dos receptores adrenérgicos no reparo tecidual cutâneo / Effects of adrenergic receptors in cutaneous tissue repair

Os receptores adrenérgicos regulam diversas funções do sistema tegumentar; entretanto, o papel destes receptores no processo de reparo tecidual cutâneo ainda não é completamente compreendido. O objetivo deste trabalho foi investigar o papel dos receptores alfa- e beta-adrenérgicos no reparo tecidual cutâneo em ratos. Inicialmente observamos que o bloqueio dos receptores beta1- e beta2-adrenérgicos (através da administração de propranolol) reduz a contração, a re-epitelização e a deposição de colágeno em lesões excisionais cutâneas, mas aumenta o infiltrado inflamatório, a proliferação celular, a densidade miofibroblástica e de vasos sanguíneos. Em seguida avaliamos se ambos receptores beta1- e beta2-adrenérgicos participam das alterações causadas pela administração de propranolol no reparo de lesões excisionais cutâneas e se os receptores alfa1- e alfa2-adrenérgicos participam do reparo destas lesões. O bloqueio de ambos receptores beta1- e beta1-adrenérgicos retarda a resposta inflamatória, o desenvolvimento do tecido de granulação e o remodelamento do tecido. Entretanto, o bloqueio do receptor beta1-adrenérgico não altera a re-epitelização. Além disso, o bloqueio dos receptores alfa1- e alfa2-adrenérgicos não compromete o reparo de lesões excisionais cutâneas. Posteriormente investigamos se o retardo induzido pela administração de propranolol no reparo tecidual cutâneo ocorre através da ativação dos receptores alfa-adrenérgicos. O bloqueio simultâneo dos receptores beta1-, beta2-, alfa1- e alfa2-adrenérgicos prejudica o fechamento, a re-epitelização, a mobilização de mastócitos e a proliferação celular de lesões excisionais cutâneas sem um efeito sinérgico ou a ativação dos receptores a-adrenérgicos. Além disso, estudamos os efeitos dos receptores alfa- e beta-adrenérgicos na formação do tecido de granulação em implantes de esponjas de poliuretano. O bloqueio dos receptores beta1- e beta2-adrenérgicos, mas não o bloqueio dos receptores alfa1 e alfa2...

Adrenoceptors regulate several functions of the skin; however, the role of adrenoceptors on cutaneous wound healing is not completely understood yet. The aim of this study was to investigate the role of the alfa- and beta-adrenoceptors on cutaneous wound healing in rats. Firstly, we observe that the blockage of beta1- and beta2-adrenoceptors (through propranolol administration) reduces wound contraction, re-epithelialization, and collagen deposition, but increases inflammatory infiltrate, cellular proliferation, density of myofibroblasts and blood vessels. Subsequently, we evaluate if both beta1- and beta2-adrenoceptors play a role in the propranolol-induced alterations on cutaneous wound healing and if alfa1- and alfa2-adrenoceptors participate in cutaneous wound healing. The blockade of both beta1- e beta2-adrenoceptors delays inflammatory response, granulation tissue formation and tissue remodeling. However, the blockade of beta1-adrenoceptors does not alter re-epithelialization. Moreover, the blockage of the alfa1- and alfa2-adrenoceptors does not compromise tissue repair of the cutaneous excisional lesions. Furthermore, we evaluate if propranolol-induced alterations on cutaneous wound healing occur through alfa1- and alfa2-adrenoceptors activation. The simultaneous blockade of beta1-, beta2-, alfa1- and alfa2-adrenoceptors impairs wound contraction, re-epithelialization, mast cells mobilization, and cellular proliferation of the cutaneous excisional lesions without a synergic effect or alfa-adrenoceptors activation. In addition, we study the effects of alfa- and beta-adrenoceptors blockade on granulation tissue formation in polyurethane sponges implants. The blockade of beta1- and beta2-adrenoceptors, but not alfa1- and alfa2-adrenoceptors, delays inflammatory cells migration, myofibroblastic differentiation, angiogenesis, and collagen fibers organization. Moreover, we also evaluate the effects of administration of a low dose of propranolol ...

Aspectos terapêuticos peculiares para o tratamento medicamentoso da ICC de causa hipertensiva. Liçöes extraíveis dos grandes estudos recentes / Peculiar therapeutic strategies of heart failure due to hypertension. Lessons from recent randomized studies

A insuficiência cardíaca é um problema grave de saúde pública. É a única doença cardiovascular cuja prevalência aumentou nos últimos anos e será uma das principais causas de morbimortalidade no futuro. Os dois principais fatores de risco para insuficiência cardíaca säo o infarto do miocárdio e a hipertensäo arterial. A hipertensäo arterial predispöe o aparecimento de hipertrofia ventricular esquerda, causa disfunçäo ventricular esquerda diastólica e sistólica, e diminui a reserva de fluxo coronário. Esse complexo de anormalidades, conhecido como cardiopatia hipertensiva, freqüentemente resulta em insuficiência cardíaca. Lesöes estruturais responsáveis por esse processo incluem um aumento no tamanho dos miócitos cardíacos (remodelamento), com excesso de deposiçäo de colágeno e infiltraçäo celular, e lesöes arteriolares que podem comprometer o fluxo coronário. A hipertrofia ventricular esquerda também constitui fator de risco para o infarto do miocárdio, que, uma vez superposto, contribui para o agravamento da funçäo contrátil do ventrículo esquerdo. Embora nenhum estudo clínico randomizado tenha sido realizado com o objetivo de testar terapias farmacológicas em pacientes com insuficiência cardíaca congestiva de etiologia exclusivamente hipertensiva, todos eles incluíram pacientes com história de hipertensäo arterial, correspondendo a 15 por cento a 59 por cento do total de pacientes randomizados nos diferentes estudos. Os resultados de grandes estudos randomizados e controlados em pacientes com insuficiência cardíaca congestiva revelaram que a inibiçäo da enzima conversora da angiotensina e o bloqueio beta-adrenérgico säo as estratégias terapêuticas mais eficazes, pois, além de diminuir a morbidade, säo capazes de aumentar a sobrevivência.

Apoptosis in cardiac disease--what is it--how does it occur.

This review will present a summary of a description of apoptotic pathways in the heart, followed by ways to measure it and the experimental and clinical evidence for the role of apoptosis in cardiac disease. An evaluation of the effectiveness of pharmacological and other therapeutic interventions in the prevention of apoptosis in the context of cardiac disease will also be presented.

Simpaticomiméticos / The therapeutic use of catecolaminic drugs

São discutidas as ações farmacológicas principais das substâncias catecolamínicas disponíveis para uso clínico. As principais situações em que estas drogas podem ser usadas são relacionadas. É avaliada a pertinência de administração dessas substâncias em uma série de situações clinicas específicas.

The pharmacological, clinical and therapeutic approach of catecolaminic drugs is object of this article.

Tratamiento farmacológico del paciente obeso / Pharmacotherapy of obesity

Se revisa la farmacoterapia como coadyuvante del tratamiento de obesidad, tanto en la reducción de peso como en la mantención de peso reducido. Se presentan los diferentes fármacos clasificados de acuerdo a su mecanismo de acción en anorexígenos y/o sacietógenos, termogénicos y drogas que provocan malabsorción de macronutrientes. Se entrega información sobre eficacia en el largo plazo, destacándose que entre los medicamentos actualmente en uso, solo la sibutramina y el orlistat han podido demostrar un promedio de reducción del 10 por ciento del peso inicial. En un segundo plano están la fenilpropanolamina, efedrina/cafeína y fluoxetina que, si bien no están aprobados para el tratamiento de la obesidad, en estudios controlados presentan resultados que justifican su indicación en algunos pacientes obesos. Se revisan productos comercializados para el tratamiento de la obesidad sin evidencia científica de su utilidad (picolinato de cromo, ácido hidroxicítrico, l-carnitina, chitosan) y se mencionan las drogas no recomendables por el riesgo de efectos adversos, especialmente cardiovasculares y psiquiátricos o por el potencial adictivo tales como la anfetamina, dietilpropion y fenproporex, hormonas tiroideas, fármacos diuréticos y laxantes. Finalmente, a la luz del descubrimiento de los mecanismos biológicos y moleculares involucrados en la patogénesis de la obesidad, se plantea la aparición futura de nuevos agentes farmacológicos que estimulen el gasto energético y lipídico (estimulantes B3-adrenérgicos), o que modulen el apetito y la saciedad, como los análogos de leptina y CCK, e inhibidores del neuropéptido

Epidemiology and treatment of left ventricular hypertrophy in the elderly.

Left ventricular hypertrophy (LVH) is an important independent risk factor for cardiovascular disease and is associated with an increased risk of ventricular dysrhythmia, coronary artery disease, myocardial infarction, stroke, heart failure and peripheral artery disease. The prevalence of LVH increases strongly with advancing age and, consequently, the prevention or reduction of LVH should be an important consideration in the older age-group. This review summarises current knowledge on LVH and discusses management issues with particular reference to the elderly. Evidence suggests that antihypertensive treatment can reverse or prevent LVH. There have been few studies of LVH in the elderly, but since age does not appear to be a factor in the regression of LVH, results of studies among younger hypertensive patients can be extrapolated to the elderly population. Meta-analyses of clinical studies have not established conclusively that angiotensin-converting enzyme inhibitors and calcium antagonists are necessarily more effective than diuretics and beta-adrenoceptor antagonists in reducing LVH.

The incidence of nephropathy in type 1 diabetic patients with proliferative retinopathy: a 10-year follow-up study.

Patients with type 1 diabetes mellitus and with proliferative retinopathy often have a concomitant diabetic nephropathy. However, in cross-sectional studies it has been shown that 35% of patients with proliferative retinopathy do not show signs of diabetic nephropathy. The aim of the present study was to examine the incidence of diabetic nephropathy in type 1 diabetic patients with proliferative retinopathy but without signs of nephropathy. To that end, out of 102 consecutive patients with proliferative retinopathy attending the University Hospital, Lund, in 1986, 24 patients did not show any clinical signs of nephropathy, and were followed for 10 years regarding the development of nephropathy. Their age was 36.7 +/- 9.8 years, age at onset 11.8 +/- 7.5 years, diabetes duration 25.7 +/- 6.9 years and duration of proliferative retinopathy 4.6 +/- 3.8 years (mean +/- S.D.). At entry, no patient had albuminuria (< 30 mg/l), and albumin creatinine clearance ratio was < 0.01 x 10(-3). During the 10-year follow-up period, two of the patients showed isolated higher peaks of elevated urinary albumin, but none of the 24 patients developed persistent microalbuminuria (> or = 30 mg/l). Two patients died before follow-up, but none of these had developed microalbuminuria at the time for death. Based on mean annual measurements, there were no increases in HbA1c, systolic and diastolic blood pressure, and serum creatinine levels. At entry, seven of the patients were treated with antihypertensive drugs and another three patients received such treatment during the study period. In conclusion, in a subgroup of patients with proliferative retinopathy, i.e. without clinical signs of diabetic nephropathy, no patient developed persistent microalbuminuria during a 10-year follow-up period. These results indicate further evidence for at least partly different pathogenic mechanisms behind diabetic retinopathy and nephropathy.

Cardiomiopatia hipertrófica: apresentaçäo de quatro casos / Hypertrophic cardiomyophaty: report of four cases

O aparecimento de fibrilaçäo atrial em portadores de cardiomiopatia hipertrófica foi associado com deteriorizaçäo clínica significativa em 04 (quatro) pacientes estudados. Uma paciente evoluiu da classe funcional II (New York Heart Association), para classe funcional IV e posteriormente óbito; outro evoluiu para fibrilaçäo atrial apresentando acidente vascular encefálico e morte súbita; outra paciente evoluiu da classe funcional I para classe funcional III, e o último, desenvolveu fibrilaçäo atrial e acidente vascular encefálico.