The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize ß-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

ß-BLOCKERS LOWER FIRST DECOMPENSATION IN PATIENTS WITH CIRRHOSIS AND ENDURING PORTAL HYPERTENSION AFTER ETIOLOGICAL TREATMENT.

BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) can lower the risk of first decompensation in patients with cirrhosis and clinically significant portal hypertension (CSPH) (identified by a hepatic venous pressure gradient ≥10 mmHg) with active etiology. Our aim was to examine the effect of NSBB on first decompensation occurrence in patients with cirrhosis and enduring CSPH after etiological treatment. METHODS: Patients with compensated cirrhosis and clinical evidence of CSPH (gastroesophageal varices -GEV- and/or spontaneous portosystemic collaterals- SPSS) after two years from etiological treatment. Primary endpoint was first decompensation (occurrence of variceal bleeding, ascites, or hepatic encephalopathy) in patients on-NSBB vs. off-NSBB. RESULTS: Final cohort included 406 patients. Baseline characteristics of patients on-NSBB (n=187) and off-NSBB (n=219) were comparable, except for signs of PH that were more pronounced in the on-NSBB group. During a mean follow-up of 32 months, 127 (31%) patients decompensated, with ascites being the most common (77%) decompensating event. Decompensation rates were lower in patients on-NSBB (16% vs 44%, p<0,0001). The benefit of NSBB on decompensation was maintained in patients with small GEV (17% vs 43%, p<0,0001), in those with SPSS only (8% vs 43%, p=0,003) and in each different etiology, including HCV-cured cirrhosis (9% vs 32%, p<0,0001). At Cox regression analysis, Hemoglobin, Child-Pugh, MELD-Na, diabetes at baseline and previous bacterial infections were independent predictors of decompensation, while NSBB-use had a protective effect (HR 0,32, 95% CI 0,20-0,49; p<0,0001). NSBB-use significantly reduced bacterial infection rates (HR 0,36, 95% CI 0,22-0,58; p<0,0001). CONCLUSION: NSBB decrease the risk of first decompensation in patients with cirrhosis and enduring CSPH after etiological treatment.

Use of beta-blockers in patients with ductal carcinoma in situ and risk of invasive breast cancer recurrence: a Swedish retrospective cohort study.

BACKGROUND: Retrospective observational studies suggest a potential role of beta-blockers as a protective strategy against progression and metastasis in invasive breast cancer. In this context, we investigated the impact of beta-blocker exposure on risk for progression to invasive breast cancer after diagnosis of ductal cancer in situ (DCIS). METHODS: The retrospective study population included 2535 women diagnosed with pure DCIS between 2006 and2012 in three healthcare regions in SwedenExposure to beta-blocker was quantified using a time-varying percentage of days with medication available. The absolute risk was quantified using cumulative incidence functions and cox models were applied to quantify the association between beta-blocker exposure and time from DCIS diagnosis to invasive breast cancer, accounting for delayed effects, competing risks and pre-specified confounders. RESULTS: The median follow-up was 8.7 years. One third of the patients in our cohort were exposed to beta-blockers post DCIS diagnosis. During the study period, 48 patients experienced an invasive recurrence, giving a cumulative incidence of invasive breast cancer progression of 1.8% at five years. The cumulative exposure to beta-blocker was associated with a reduced risk in a dose-dependent manner, though the effect was not statistically significant. CONCLUSION: Our observational study is suggestive of a protective effect of beta-blockers against invasive breast cancer after primary DCIS diagnosis. These results provide rationales for experimental and clinical follow-up studies in carefully selected DCIS groups.

Beta-blocker use and breast cancer outcomes: a meta-analysis.

PURPOSE: Beta blockers (BBs) are commonly used cardiovascular medications, and their association with breast cancer outcomes has been examined in several previous observational studies and meta-analyses. In this study, an updated meta-analysis was undertaken to ascertain the association between BBs and both breast cancer death (BCD) and breast cancer recurrence (BCR). METHODS: Articles were sourced from various databases up until the 14th of August 2023. Effect estimates were pooled using the random effects model, and the Higgins I2 statistic was computed to ascertain heterogeneity. Subgroup analyses were conducted by the potential for immortal time bias (ITB), the exposure period (prediagnosis vs postdiagnosis), and type of BB (selective vs non-selective). Publication bias was assessed using funnel plots and Egger's regression tests. RESULTS: Twenty-four studies were included. Pooled results showed that there was no statistically significant association between BB use and both BCD (19 studies, hazard ratio = 0.90, 95% CI 0.78-1.04) and BCR (16 studies, HR = 0.87, 95% CI 0.71-1.08). After removing studies with ITB, the associations were attenuated towards the null. There was no effect modification for either outcome when stratifying by the exposure period or type of BB. There was clear evidence of publication bias for both outcomes. CONCLUSION: In this meta-analysis, we found no evidence of an association between BB use and both BCD and BCR. Removing studies with ITB attenuated the associations towards the null, but there was no effect modification by the exposure period or type of BB.

Does Heterogeneity Exist in Treatment Associations With Renin-Angiotensin-System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BACKGROUND: We explored the association between use of renin-angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young-low comorbidity burden (12%), atrial fibrillation-hypertensive (32%), older-atrial fibrillation (24%), obese-diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin-angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young-low comorbidity burden and atrial fibrillation-hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese-diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. CONCLUSIONS: In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design.

Pharmacological management of heart failure in adults with congenital heart disease.

Congenital heart disease (CHD) is the most common global congenital defect affecting over 2.4 million individuals in the United States. Ongoing medical and surgical advancements have improved the survival of children with CHD leading to a shift where, as of 2010, adults constitute two-thirds of the CHD patient population. The increasing number and aging of adult congenital heart disease (ACHD) patients present a clinical challenge due to heightened complexity, morbidity, and mortality. Studies indicate that 1 in 13 ACHD patients will develop heart failure (HF) in their lifetime. ACHD-HF patients experience more frequent emergency department visits, higher hospitalization rates, longer hospital stays, and higher mortality compared to non-ACHD patients with heart failure (non-ACHD-HF). Despite HF being the leading cause of death in ACHD patients, there is a notable gap in evidence regarding treatment. While guideline-directed medical therapy (GDMT) has been extensively studied in non-ACHD-HF, research specific to ACHD-HF individuals is limited. This article aims to comprehensively review available literature addressing the pharmacological treatment of ACHD-HF.

Influence of Weight and Body Size on the Pharmacokinetics of Heart Failure Pharmacotherapy: A Systematic Review.

OBJECTIVE: To conduct a review of studies evaluating the influence of body size and weight (WT) on the pharmacokinetics (PK) of drugs recommended for heart failure (HF) treatment. DATA SOURCES: A systematic search of the MEDLINE (1946 to April 2023) and EMBASE (1974 to April 2023) databases was conducted for articles that focused on the impact of WT or body size on the PK of drugs of interest used in HF patients. STUDY SELECTION AND DATA EXTRACTION: Articles written in English or French related to the aim of our study were retained for analysis. DATA SYNTHESIS: Of 6493 articles, 20 were retained for analysis. Weight was associated with the clearance of digoxin, carvedilol, enalapril, and candesartan as well as the volume of distribution of eplerenone and bisoprolol. There was no documented direct impact of WT on the PK of furosemide, valsartan, and metoprolol, although these studies were limited or confounded by the small sample size, adjustment of PK factors by WT, or the use of the Cockroff-Gault equation for the evaluation of creatinine clearance, which includes WT. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review highlights and summarizes the available data on the importance of WT on the PK of HF treatment. CONCLUSION: Considering the significant impact of WT on most HF drugs in this review, it may be important to further investigate it in the context of personalized therapy, particularly in patients presenting extreme WTs.

Early Beta-Blocker Utilization in Critically Ill Patients With Moderate-Severe Traumatic Brain Injury: A Retrospective Cohort Study.

BACKGROUND: There is limited evidence that beta-blockers may provide benefit for patients with moderate-severe traumatic brain injury (TBI) during the acute injury period. Larger studies on utilization patterns and impact on outcomes in clinical practice are lacking. OBJECTIVE: The present study uses a large, national hospital claims-based dataset to examine early beta-blocker utilization patterns and its association with clinical outcomes among critically ill patients with moderate-severe TBI. METHODS: We conducted a retrospective cohort study of the administrative claims Premier Healthcare Database of adults (≥17 years) with moderate-severe TBI admitted to the intensive care unit (ICU) from 2016 to 2020. The exposure was receipt of a beta-blocker during day 1 or 2 of ICU stay (BB+). The primary outcome was hospital mortality, and secondary outcomes were: hospital length of stay (LOS), ICU LOS, discharge to home, and vasopressor utilization. In a sensitivity analysis, we explored the association of beta-blocker class (cardioselective and noncardioselective) with hospital mortality. We used propensity weighting methods to address possible confounding by treatment indication. RESULTS: A total of 109 665 participants met inclusion criteria and 39% (n = 42 489) were exposed to beta-blockers during the first 2 days of hospitalization. Of those, 42% received cardioselective only, 43% received noncardioselective only, and 14% received both. After adjustment, there was no association with hospital mortality in the BB+ group compared to the BB- group (adjusted odds ratio [OR] = 0.99, 95% confidence interval [CI] = 0.94, 1.04). The BB+ group had longer hospital stays, lower chance of discharged home, and lower risk of vasopressor utilization, although these difference were clinically small. Beta-blocker class was not associated with hospital mortality. CONCLUSION: In this retrospective cohort study, we found variation in use of beta-blockers and early exposure was not associated with hospital mortality. Further research is necessary to understand the optimal type, dose, and timing of beta-blockers for this population.

Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer.

AIM: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks. METHOD: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68-1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31-1.92). CONCLUSION: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.

Beta-blocker use and survival after pancreatic cancer surgery: A nationwide population-based cohort study.

PURPOSE: We examined the association between use of beta-blockers and survival in pancreatic cancer patients after curative-intent surgery. METHODS: Using Danish healthcare registries, we conducted a population-based cohort study of all patients undergoing curative-intent surgery for pancreatic cancer in Denmark 1997-2021. We defined beta-blocker use according to exposure before surgery as current (≤90 days), recent (91-365 days), or former (366-730 days) use, requiring at least one filled prescription. Patients were followed from the date of surgery for up to 5 years. We used Cox regression to compute hazard ratios (HRs) of deaths with 95% confidence intervals (CIs), adjusting for age, sex, year of diagnosis, cardiovascular disease, diabetes, liver disease, alcohol, and smoking. We also conducted an active comparator analysis, where we used angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers as comparators instead of nonusers. RESULTS: We included 2592 patients, of which 16.7% were beta-blocker users. Median survival for the entire population was 24.4 months. Beta-blocker use was associated with increased mortality (adjusted HR: 1.18; 95% CI: 1.04-1.34). This was evident in current (adjusted HR: 1.19; 95% CI: 1.02-1.38) and recent (adjusted HR: 1.29; 95% CI: 1.04-1.59) but not former (adjusted HR: 0.91; 95% CI: 0.64-1.43) users. In the active comparator analysis, the association between beta-blocker exposure and mortality attenuated slightly (adjusted HR: 1.12; 95% CI: 0.93-1.35). CONCLUSIONS: We observed an association between beta-blocker use and increased mortality in patients operated for pancreatic cancer. Findings are likely explained by confounding by indication.

The heart rate response to the 6-min walk test in atrial fibrillation patients with or without beta-blockers: Referring to patients with sinus rhythm.

BACKGROUND: The aim was to evaluate the effect of beta-blockers (BB) on the response of heart rate (HR) to 6-min walk test (6MWT) in atrial fibrillation (AF) and whether the AF patients treated with BB have a similar HR response to 6MWT as the AF and sinus rhythm (SR) patients without BB treatment at the same resting HR level. METHODS: The before-after study involving 74 AF patients was to evaluate the effect of BB treatment (pre-BB and with BB). The comparison study included 74 BB-treated AF patients (with BB), 74 matched AF patients without BB (no BB), and 74 SR patients. The percentage increase amplitude of HR (HR-PIA) in 6MWT was calculated: [(the exercise HR - the resting HR)/(the resting HR)] × 100%. RESULTS: The before-after study showed that BB treatment decreased the resting and mean exercise HR (98.6 ± 15.2 vs. 85.5 ± 11.2 bpm and 121.3 ± 17.3 vs. 109.0 ± 16.7 bpm) during 6MWT. The comparison study demonstrated that against the SR, the AF with BB and no BB groups have higher mean exercise HR-PIA (28.2 ± 17.1% and 22.0 ± 9.6%, vs. 6.9 ± 3.7%) when their resting HR is similar. Moreover, the mean exercise HR-PIA was also significantly higher in the with BB group than in the no BB group. CONCLUSION: In AF patients with relatively higher resting HR, BB treatment could decrease the resting and exercise HR during 6MWT. However, BB treatment could not effectively attenuate the exercise HR rise as compared with AF without BB treatment, even with similar resting HR levels.

Impact of preoperative nonselective beta-blocker use on acute kidney injury after living donor liver transplantation: Propensity score analysis.

INTRODUCTION AND OBJECTIVES: Acute kidney injury (AKI) is prevalent and has deleterious effects on postoperative outcomes following liver transplantation (LT). The impact of nonselective beta-blockers (NSBBs) in patients with liver cirrhosis remains controversial. This study investigated the association between preoperative NSBB use and AKI after living donor LT (LDLT). PATIENTS AND METHODS: We evaluated 2,972 adult LDLT recipients between January 2012 and July 2022. The patients were divided into two groups based on the preoperative NSBB use. Propensity score matched (PSM) and inverse probability of treatment weighting (IPTW) analyses were performed to evaluate the association between preoperative NSBB use and postoperative AKI. Multiple logistic regression analyses were also used to identify the risk factors for AKI. RESULTS: The overall incidence of AKI was 1,721 (57.9%) cases. The NSBB group showed a higher incidence of AKI than the non-NSBB group (62.4% vs. 56.7%; P = 0.011). After PSM and IPTW analyses, no significant difference in the incidence of AKI was found between the two groups (Odds ratio, OR 1.13, 95% confidence interval, CI 0.93-1.37, P = 0.230, PSM analysis; OR 1.20, 95% CI 0.99-1.44, P = 0.059, IPTW analysis). In addition, preoperative NSBB use was not associated with AKI after multivariate logistic regression analysis (OR 1.16, 95% CI 0.96-1.40, P = 0.118). CONCLUSIONS: Preoperative NSBB use was not associated with AKI after LDLT. Further studies are needed to validate our results.

Evolving portal hypertension through Baveno VII recommendations.

The Baveno VII consensus workshop has provided several novel recommendations regarding the management of patients with clinically significant portal hypertension (CSPH). The expert panel summarized the existing data into simple clinical rules to aid clinicians in their clinical practice. The use of non-invasive tests (NITs), especially liver stiffness measurement (LSM), have gain an important role in daily practice. The use of LSM alone or in combination with platelet count can be used to rule-in and rule-out compensated advanced chronic liver disease (cACLD) and CSPH. Further decompensation events were defined as a prognostic stage associated with an even higher mortality than that associated with first decompensation. Moreover, the term hepatic recompensation was introduced in Baveno VII consensus implying a partial or complete regression of the functional and structural changes of cirrhosis after the removal of the underlying etiology. This review will summarize the reader main aspects of Baveno VII consensus regarding the use of NITs in cACLD, analyze further decompensation events, and evaluate recent recommendations for prophylaxis and management of liver decompensation events.

Evaluating the Prevalence of Cardiac Surgery-associated Acute Kidney Injury After Septal Myectomy Combined With Concomitant Procedures in Obstructive Hypertrophic Cardiomyopathy.

OBJECTIVES: Hypertrophic obstructive cardiomyopathy (HOCM) may be treated by septal myectomy. Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication, but little is known about its incidence after septal myectomy. The objectives of this work were to evaluate the prevalence of CSA-AKI after septal myectomy and identify potential perioperative and phenotype-related factors contributing to CSA-AKI. DESIGN: This was a retrospective database analysis with new data analysis. SETTING: The study occurred in a single university academic expertise center for septal myectomy HOCM patients. PARTICIPANTS: Data from 238 HOCM patients with septal myectomy operated on between 2005 and 2022 were collected. INTERVENTIONS: CSA-AKI was stratified according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines using measurement of creatinine and urine production. Important HOCM phenotype-related and perioperative factors were analyzed for their possible associations with CSA-AKI. MEASUREMENTS AND MAIN RESULTS: CSA-AKI occurred in 45% of patients; of these, 55% were classified as KDIGO stage I and the remaining 45% as stage II, with no chronic kidney damage observed. Moreover, there were no phenotypical or perioperative characteristics that were more prevalent in the CSA-AKI cohort. However, the use of beta-blockers and coronary artery disease were more prevalent in the CSA-AKI cohort. CONCLUSIONS: CSA-AKI is a common complication after septal myectomy but was transient, and kidney function recovered in all patients.

Massive spinal epidural infantile hemangioma, image findings, and treatment: a case report and review of literature.

Spinal involvement of infantile hemangiomas is rare with the predilection to involve the epidural space. A proper diagnosis might be challenging due to the atypical location and variable/inconsistent use of the International Society for the Study of Vascular Anomalies (ISSVA) classification by radiologists, pathologists, and clinicians. A proper diagnosis of epidural infantile hemangioma is key due to the different aggressiveness of the treatment options with inconstant literature regarding the best available treatment. Herein, we present a case of a massive epidural infantile hemangioma successfully treated with only beta-blocker. We discuss the clinical, MRI, CT, ultrasound, and histological features of this lesion as we review the literature with the objective of addressing some of the confusion surrounding the subject.

Beta-blockers for the treatment of infantile haemangiomas in premature infants.

Beta-blockers have been established as a treatment of infantile haemangiomas (IH) since its serendipitous discovery for use in IH in 2008. However, data on the safety of these beta-blockers for use in IH in preterm infants are scarce. A retrospective study was performed to review the safety of oral propranolol and topical timolol in the treatment of IH in a cohort of preterm infants treated at our tertiary paediatric hospital. It was observed that there was an increased risk of adverse events amongst the preterm infants with chronic lung disease, retinopathy of prematurity and gastroesophageal reflux, when treated with oral propranolol.

Conventional heart failure therapy in cardiac ATTR amyloidosis.

AIMS: The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). METHODS AND RESULTS: A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.66-0.89), P < .001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% [HR 0.75 (95% CI 0.63-0.90), P = .002]; and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% [HR 0.61 (95% CI 0.45-0.83), P = .002]. No convincing differences were found for treatment with ACEi/ARBs. CONCLUSION: Conventional heart failure medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.

Beta-Blockers as an Immunologic and Autonomic Manipulator in Critically Ill Patients: A Review of the Recent Literature.

The autonomic nervous system plays a key role in maintaining body hemostasis through both the sympathetic and parasympathetic nervous systems. Sympathetic overstimulation as a reflex to multiple pathologies, such as septic shock, brain injury, cardiogenic shock, and cardiac arrest, could be harmful and lead to autonomic and immunologic dysfunction. The continuous stimulation of the beta receptors on immune cells has an inhibitory effect on these cells and may lead to immunologic dysfunction through enhancing the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), and inhibiting the production of pro-inflammatory factors, such as interleukin-1B IL-1B and tissue necrotizing factor-alpha (TNF-alpha). Sympathetic overstimulation-induced autonomic dysfunction may also happen due to adrenergic receptor insensitivity or downregulation. Administering anti-adrenergic medication, such as beta-blockers, is a promising treatment to compensate against the undesired effects of adrenergic surge. Despite many misconceptions about beta-blockers, beta-blockers have shown a promising effect in decreasing mortality in patients with critical illness. In this review, we summarize the recently published articles that have discussed using beta-blockers as a promising treatment to decrease mortality in critically ill patients, such as patients with septic shock, traumatic brain injury, cardiogenic shock, acute decompensated heart failure, and electrical storm. We also discuss the potential pathophysiology of beta-blockers in various types of critical illness. More clinical trials are encouraged to evaluate the safety and effectiveness of beta-blockers in improving mortality among critically ill patients.

Therapies for Cirrhotic Cardiomyopathy: Current Perspectives and Future Possibilities.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment.

Sequencing Quadruple Therapy for Heart Failure with Reduced Ejection Fraction: Does It Really Matter?

The conventional sequence of guideline-directed medical therapy (GDMT) initiation in heart failure with reduced ejection fraction (HFrEF) assumes that the effectiveness and tolerability of GDMT agents mirror their order of discovery, which is not true. In this review, the authors discuss flexible GDMT sequencing that should be permitted in special populations, such as patients with bradycardia, chronic kidney disease, or atrial fibrillation. Moreover, the initiation of certain GDMT medications may enable tolerance of other GDMT medications. Most importantly, the achievement of partial doses of all four pillars of GDMT is better than achievement of target dosing of only a couple.