Non-selective beta-blockers in cirrhosis:Current concepts and controversies

Non-selective beta-blockers(NSBBs) have been at the forefront in the management of portal hypertension in liver cirrhosis for the last three decades, a trusty component in the armamentarium of the Hepatologist. The role of beta-blockers has been cemented for years in cardiac disease including angina, hypertension and in heart failure, however NSBBs with their non-selective effects on β1 and β2 receptors have led to them fondly being termed "the hepatologist's aspirin". NSBBs' role in reduction of portal pressure in the setting of primary and secondary prophylaxis for variceal haemorrhage has been well established. NSBBs include propranolol, nadolol and carvedilol- with the latter having been shown to be effective in patients who often fail to demonstrate a haemodynamic response to propranolol. Recent observational studies however have served for the Hepatology community to question the beneficial role of NSBBs in portal hypertension, especially in advanced cases with refractory ascites. The deleterious effect in patients with refractory ascites in a few studies led to a U-turn in clinical practice, with some in the Hepatology community withdrawing their usage in patients with advanced cirrhosis. This also led to the "window hypothesis" suggesting there may be only be a finite time frame when NSBBs have a beneficial effect in portal hypertension. The window hypothesis proposed the window for the benefits of NSBBs is closed in early portal hypertension, opening as portal hypertension progresses with it closing in advanced liver disease. The window was proposed to close in conditions such as refractory ascites or spontaneous bacterial peritonitis when patients may not necessarily mount a compensatory haemodynamic response when on NSBBs. Some centres however have continued the practice of NSBBs in advanced cirrhosis with published data challenging the scepticisms of other groups who stop NSBBs. Thus the debate, like the window hypothesis has opened, with more questions to be answered about NSBB's mechanism of action not only in reducing portal hypertension but also their effects on systemic haemodynamics and on the pro-inflammatory pathways often activated in cirrhosis especially in advanced disease. This article serves to review the role of NSBBs in the management of portal hypertension/cirrhosis and concentrate on current concepts and controversies in this field.

Nonselective β-blockers may induce development of portal vein thrombosis in cirrhosis

Currently, nonselective β-blockers (NSBBs) are commonly used for the prevention of variceal bleeding in liver cirrhosis. The beneficial effects of NSBBs are primarily attributed to the reduction in cardiac output by blockade of β1 receptors and vasoconstriction of the splanchnic circulation by the blockade of β2 receptors. The prognostic value of occlusive portal vein thrombosis (PVT) in cirrhotic patients has been increasingly recognized. The most important risk factor for the development of PVT in liver cirrhosis is the decreased portal vein inflow velocity. Collectively, we propose that the use of NSBBs potentially increases the development of portal vein thrombosis by reducing portal vein inflow velocity. The hypothesis should be confirmed by prospective cohort studies, in which cirrhotic patients without prior PVT treated with and without NSBBs are enrolled, and the development of PVT during follow-up is compared between the two groups. Additionally, subgroup analyses should be performed according to the dosage of NSBBs and the reduction of portal inflow velocity after use of NSBBs.

Beneficial effects of switching from β-blockers to nebivolol on the erectile function of hypertensive patients

Aim： To investigate the effect of substituting β-blockers with nebivolol on the erectile function of patients suffering from essential hypertension. Methods： Forty-four young and middle-aged men （31-65 years） with essential hypertension visited our outpatient clinic and took β-blocker treatment （atenolol, metoprolol or bisoprolol） for more than 6 months. All the patients completed a questionnaire regarding erectile function （International Index for Erectile Function）. Patients were then switched to an equipotent dose of nebivolol for 3 months and, at the end of this time period, filled out the same questionnaire. Results： Twenty-nine out of the 44 （65.9%） patients who took p-blockers （atenolol, metoprolol or bisoprolol） had exhibited erectile dysfunction （ED）. Their systolic and diastolic blood pressure did not change significantly with the treatment switch. In 20 out of these 29 （69%） patients, a significant improvement in the erectile function score was exhibited after 3 months of nebivolol administration, and in 11 of these 20 patients, erectile function was normalized. Conclusion： Nebivolol seems to have a beneficial effect on ED （possibly due to increased nitric oxide availability）; however, further prospective, randomized, placebo-controlled studies are needed to confirm the beneficial effects of nebivolol. （Asian J Androl 2006 Mar; 8： 177-182）

Rapid and sensitive analysis of trace b-blockers by magnetic solidphase extraction coupled with Fourier transform ion cyclotron resonance mass spectrometry

A rapid and sensitive method for analyzing trace b-blockers in complex biological samples,which involved magnetic solid-phase extraction(MSPE)coupled with Fourier transform ion cyclotron resonance mass spectrometry(FTICR-MS),was developed.Novel nanosilver-functionalized magnetic nanoparticles with an interlayer of poly(3,4-dihydroxyphenylalanine)(polyDOPA@Ag-MNPs)were synthesized and used as MSPE adsorbents to extract trace b-blockers from biological samples.After extraction,the analytes loaded on the polyDOPA@Ag-MNPs were desorbed using an organic solvent and analyzed by FTICR-MS.The method was rapid and sensitive,with a total detection procedure of less than 10 min as well as limits of detection and quantification in the ranges of 3.5-6.8 pg/mL and 11.7-22.8 pg/mL,respectively.The accuracy of the method was also desirable,with recoveries ranging from 80.9%to 91.0%following the detection of analytes in human blood samples.All the experimental results demonstrated that the developed MSPE-FTICR-MS method was suitable for the rapid and sensitive analysis of trace b-blockers in complex biological samples.

Flow-injection-enhanced chemiluminescence method for the determination of three β-blockers

Objective To develop a rapid,simple and sensitive chemiluminescence method for the determination of three β-blockers (bisoprolol,atenolol and propranolol). Methods The chemiluminescence of cerium (Ⅳ)-sulfite system was obviously sensitized by adding anyone of three β-blockers in acid media. A new chemiluminescence method was set up by combining with flow-injection technique and used to determine the three β-blockers. Results Good linear ranges were obtained at the concentrations of 2.0×10-7g/mL-4.0×10-5g/mL,1.0×10-7g/mL-3.0×10-5g/mL and 7.0×10-7g/mL-1.0×10-5g/mL,respectively,with the detection limits of 5.0×10-8g/mL,7.0×10-8g/mL and 5.0×10-8g/mL (S/N=3),respectively,and the relative standard deviations for 11 times consecutive injections of 1.0×10-6g/mL bisoprolol,atenolol and propranolol were 3.57%,2.21% and 2.26%,respectively. Conclusion The developed method is sensitive,accurate,rapid and of low cost. And it can be applied to determine bisoprolol,atenolol and propranolol in pharmaceutical preparations.

Minimising non-selective defects in ultrathin reduced graphene oxide membranes with graphene quantum dots for enhanced water and NaCl separation

Reduced graphene oxide(rGO)membranes have been intensively evaluated for desalination and ionic sieving applications,benefiting from their stable and well-confined interlayer channels.However,rGO membranes generally suffer from low permeability due to the high transport resistance resulting from the narrowed two-dimensional(2D)channels.Although high permeability can be realized by reducing membrane thickness,membrane selectivity normally declines because of the formation of nonselective defects,in particular pinholes.In this study,we demonstrate that the non-selective defects in ultrathin rGO membranes can be effectively minimised by a facile posttreatment via surfacedeposition of graphene quantum dots(GQDs).The resultant GQDs/rGO membranes obtained a good trade-off between water permeance(14 L·m^(-2)·h^(-1).MPa^(-1))and NaCl rejection(91%).This work provides new insights into the design of high quality ultrathin 2D laminar membranes for desalination,molecular/ionic sieving and other separation applications.

Non-Selective SiGe Graphic Epitaxial by MBE

To handle the thermal budget in SiGe BiCMOS process, a non-selective graphic epitaxial technology using molecular beam epitaxial （MBE） has been developed. SEM, AFM, XRD, and dislocation density measurements are carried out. The SiGe film＇s RMS roughness is 0.45nm, and dislocation density is 0.3×10^3cm^-2-1.2×10^3cm^-2. No dislocation accumulation exists on the boundary of the windows; this indicates the high quality of the SiGe film. The experiment results show that the technology presented in this paper meets the fabrication requirements of SiGe BiCMOS.

Research Progress in Preparation of Oxidized Cellulose

Cellulose is the most abundant natural polymer material in the world.Cellulose is diffi-cult to dissolve because it contains a large number of inter molecular hydrogen bonds.Therefore,the modification of natural cellulose by chemical oxidation can expand its application field.The oxidation process of cellulose is focused on,the oxidation methods and research progress of cellulose are introduced,and further development direction of oxidized cellulose is prospected.

Benefit of combination β-blocker and endoscopic treatment to prevent variceal rebleeding: A meta-analysis

AIM: To determine whether the association of β-blockers with endoscopic treatment is superior to endoscopic treatment alone for the secondary prophylaxis of oesophageal variceal bleeding. METHODS: Randomised controlled trials comparing sclerotherapy (SCL) with SCL plus β-blockers (BB) or banding ligation (BL) with BL plus BB were identif ied.Main outcomes were overall and 6, 12 and 24 mo rebleeding rates, as well as overall and 6, 12 and 24 mo mortality. Two statistical methods were used: Yusuf-Peto, and Der Simonian and Laird. Inter-trial heterogeneity was systematically taken into account. RESULTS: Seventeen randomised controlled trials were included, 14 with SCL and 3 with BL. Combination β-blocker and endoscopic treatment signif icantly reduced rebleeding rates at 6, 12 and 24 mo and overall [odds ratio (OR): 2.20, 95% conf idence interval (CI): 1.69-2.85, P<0.0001] compared to endoscopic treatment alone. Mortality at 24 mo was signif icantly lower for the combined treatment group (OR: 1.83, 95% CI:1.16-2.90, P= 0.009), as well as overall mortality (OR: 1.43, 95% CI:1.03-1.98, P= 0.03). CONCLUSION: Combination therapy should thus be recommended as the fi rst line treatment for secondary prophylaxis of oesophageal variceal bleeding.

Effect of β-blocker therapy in diabetic patients with stable coronary heart disease: a meta-analysis

Background β-blocker (BB) therapy is a cornerstone for the treatment of coronary heart disease (CHD).The evidence of the benefit from long-term BB therapy in diabetic patients with stable CHD is scarce.This meta-analysis summarizes the evidence relating to the BB therapy in diabetic patients with stable CHD.Methods A meta-analysis was performed according to PRISMA and MOOSE guidelines for reporting of systematic reviews of observational studies.PubMed,Embase,and Cochrane central were searched and two authors independently screened studies for eligibility.The quality of studies was assessed with the Newcastle Ottawa scale.The primary outcome of interest was all-cause mortality,cardiovascular (CV) mortality and major adverse cardiovascular events (MACE) in diabetic patients with and without BB therapy.A generic inverse variance model was used to pool odds ratio or hazards ratio from included studies to calculate the overall effect estimate.The significance threshold was set at P-value < 0.05.Heterogeneity was assessed by I2.Results Four non-randomized studies with 9515 participants were selected for the analyses.Four studies were post-hoc analyses of randomized controlled trials,and one article was an analysis of a nationally representative survey.In a fixed effects model,BB therapy in diabetic patients with stable CHD was found to be associated with increased risk of CV mortality,and MACE (27% and 32% respectively;P-value < 0.05) and was not associated with a reduction in all-cause mortality (HR 1.12;95% CI: 0.94–1.33;P-value = 0.22).Conclusion BB therapy in diabetic patients with stable CHD appears to be linked to higher mortality.Large randomized trials are needed in this population to confirm these findings.

Association of Hypertension and <i>β</i>-Blocker Use with Depression during Pregnancy

Objective: To evaluate the association between hypertension and β-blocker (BB) use and antepartum depression risk. Patients and Methods: We conducted a retrospective cohort study of women who delivered within our integrated health system between 2009 and 2015, and completed an Edinburgh Postnatal Depression Scale (EPDS) during pregnancy. Increased depression risk was defined as EPDS score ≥ 10, or an affirmative answer to question ten, endorsing self-harm. Antepartum hypertension was determined by blood pressure measurements and provider ICD-9 codes. Regression analyses examined the independent associations of BB use and hypertension on antepartum depression risk. Results: Of 9192 deliveries during the study time frame, 5% were hypertensive. Within the hypertensive group, 103 (22%) used a single agent BB (BB Group), 325 (68%) required no antihypertensive medication (No-Med Group), and 48 (10%) used a non-BB single agent or multi-agent therapy (All-Other Group). After adjusting for covariates, compared to normotensive pregnancies, antepartum hypertension was significantly associated with both EPDS score ≥ 10 (adjusted odds ratio [aOR] 1.61, 95% confidence interval [CI] 1.17 - 2.21) and endorsement of self-harm (aOR 1.76, 95% CI 1.05 - 2.95). In further analyses of depression risk in hypertensive pregnancies, there was no difference between the BB Group and No-Med Group (EPDS score ≥ 10, aOR 1.22, 95% CI 0.56 - 2.63;self-harm, aOR 0.84, 95% CI 0.32 - 2.21), or between the All-Other Group and No-Med Group (EPDS ≥ 10, aOR 1.42, 95% CI 0.57 - 3.54;self-harm, aOR 1.04, 95% CI 0.29 - 3.74). Conclusion: Women with antepartum hypertension have increased risk for depression and thoughts of self-harm. β-Blocker use is not associated with further increased risk.

Therapeutic potential of targeting the renin angiotensin system in portal hypertension

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells.The second approach is to reduce mesenteric and portal blood flow.Non-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis.However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients.Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding.This review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this condition.It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

Is it time to replace propranolol with carvedilol for portal hypertension?

Beta-adrenergic receptor antagonists(β-blockers) have been well established for use in portal hypertension for more than three decades. Different Non-selective β-blockers like propranolol, nadolol, timolol, atenolol, metoprolol and carvedilol have been in clinical practice in patients with cirrhosis. Carvedilol has proven 2-4 times more potent than propranolol as a beta-receptor blocker in trials conducted testing its efficacy for heart failure. Whether the same effect extends to its potency in the reduction of portal venous pressures is a topic of on-going debate. The aim of this review is to compare the hemodynamic and clinical effects of carvedilol with propranolol, and attempt assess whether carvedilol can be used instead of propranolol in patients with cirrhosis. Carvedilol is a promising agent among the beta blockers of recent time that has shown significant effects in portal hypertension hemodynamics. It has also demonstrated an effective profile in its clinical application specifically for the prevention of variceal bleeding. Carvedilol has more potent desired physiological effects when compared to Propranolol. However, it is uncertain at the present juncture whether the improvement in hemodynamics also translates into a decreased rate of disease progression and complications when compared to propranolol. Currently Carvedilol shows promise as a therapy for portal hypertension but more clinical trials need to be carried out before we can consider it as a superior option and a replacement for propranolol.

Parallel effects of β-adrenoceptor blockade on cardiac function and fatty acid oxidation in the diabetic heart: Confronting the maze

Diabetic cardiomyopathy is a disease process in which diabetes produces a direct and continuous myocardial insult even in the absence of ischemic, hypertensive or valvular disease. The β-blocking agents bisoprolol, carvedilol and metoprolol have been shown in large-scale randomized controlled trials to reduce heart failure mortality. In this review, we summarize the results of our studies investigating the effects of β-blocking agents on cardiac function and metabolism in diabetic heart failure, and the complex inter-related mechanisms involved. Metoprolol inhibits fatty acid oxidation at the mitochondrial level but does not prevent lipotoxicity; its benefi cial effects are more likely to be due to prosurvival effects of chronic treatment. These studies have expanded our understanding of the range of effects produced by β-adrenergic blockade and showhow interconnected the signaling pathways of function and metabolism are in the heart. Although our initial hypothesis that inhibition of fatty acid oxidation would be a key mechanism of action was disproved, unexpected results led us to some intriguing regulatory mechanisms of cardiac metabolism. The fi rst was upstream stimulatory factor-2-mediated repression of transcriptional master regulator PGC-1α, most likely occurring as a consequence of the improved function; it is unclear whether this effect is unique to β-blockers, although repression of carnitine palmitoyltransferase (CPT)-1 has not been reported with other drugs which improve function. The second was the identif ication of a range of covalent modifications which can regulate CPT-1 directly, mediated by a signalome at the level of the mitochondria. We also identif ied an important interaction between β-adrenergic signaling and caveolins, which may be a key mechanism of action of β-adrenergic blockade. Our experience with this labyrinthine signaling web illustrates that initial hypotheses and anticipat-ed directions do not have to be right in order to open up meaningful directions or reveal new information.

Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis

Portal hypertension(PH),a common complication of liver cirrhosis,results in development of esophageal varices.When esophageal varices rupture,they cause significant upper gastrointestinal bleeding with mortality rates up to 20%despite state-of-the-art treatment.Thus,prophylactic measures are of utmost importance to improve outcomes of patients with PH.Several high-quality studies have demonstrated that non-selective beta blockers(NSBBs)or endoscopic band ligation(EBL)are effective for primary prophylaxis of variceal bleeding.In secondary prophylaxis,a combination of NSBB+EBL should be routinely used.Once esophageal varices develop and variceal bleeding occurs,standardized treatment algorithms should be followed to minimize bleeding-associated mortality.Special attention should be paid to avoidance of overtransfusion,early initiation of vasoconstrictive therapy,prophylactic antibiotics and early endoscopic therapy.Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding,and potentially in Child B patients with active bleeding at endoscopy.The use of carvedilol,safety of NSBBs in advanced cirrhosis(i.e.with refractory ascites)and assessment of hepatic venous pressure gradient response to NSBB is discussed.In the present review,we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

Determination of 23 β_2-agonists and 5 β-blockers in animal muscle by high performance liquid chromatography-linear ion trap mass spectrometry

A high performance liquid chromatography-linear ion trap mass spectrometry method using isotope dilution technique has been developed for the simultaneous determination of 23 β2-agonists and 5 β-blockers in animal muscle tissues. Pork and chicken muscle samples were acid hydrolyzed and extracted with 5% trichloracetic acid in water, and then cleaned up using MCX solid phase extraction (SPE) cartridge. Methanol and 0.1% formic acid were used as mobile phases for gradient elution. A Waters AtlantisT3 column was used for separation. ESI positive ion scan mode was used with selective reaction monitoring. 9 β2-Agonists labeled by the deuterium isotope were used as internal standards for quantification. The linear ranges of 23 β2-agonists and 5 β-blockers were 5-200 μg/L, the coefficient of correlation was not less than 0.995, and the limit of detection for each compound in the muscle tissue was below 0.2 μg/kg. The recoveries of each compound in the spiked samples at three levels 5, 10, 20 μg/kg were in the range of 47.3%-123.7%, and the relative standard deviations were in the range of 3.2%-25.7%. The developed method is sensitive and specific for the determination of β2-agonists and β-blockers in pork and chicken muscle samples.

Primary prevention of bleeding from esophageal varices in patients with liver cirrhosis

Variceal bleeding is a life threatening situation with mortality rates of at least 20%. Prophylactic treatment with non-selective beta blockers(NSBBs) is recommended for patients with small varices that have not bled but with increased risk for bleeding. The recommended treatment strategies on primary prevention of variceal bleeding in patients with medium and largesized varices are NSBBs or endoscopic band ligation. Nitrates, shunt surgery and sclerotherapy are not recommended in this setting. In this review, the most recent data on prevention of esophageal variceal bleeding are presented. Available data derived from randomized-controlled trials suggest both treatment strategies, and according to Baveno V consensus in portal hypertension "the choice of treatment should be based on local resources and expertise, patient preference and characteristics, side-effects and contra-indications".

Primary prophylaxis of variceal bleeding in patients with cirrhosis:A comparison of different strategies

Patients with cirrhosis and esophageal varices bleed at a yearly rate of 5%-15%,and,when variceal hemorrhage develops,mortality reaches 20%.Patients are deemed at high risk of bleeding when they present with medium or large-sized varices,when they have red signs on varices of any size and when they are classified as Child-Pugh C and have varices of any size.In order to avoid variceal bleeding and death,individuals with cirrhosis at high risk of bleeding must undergo primary prophylaxis,for which currently recommended strategies are the use of traditional non-selective beta-blockers(NSBBs)(i.e.,propranolol or nadolol),carvedilol(a NSBB with additional alpha-adrenergic blocking effect)or endoscopic variceal ligation(EVL).The superiority of one of these alternatives over the others is controversial.While EVL might be superior to pharmacological therapy regarding the prevention of the first bleeding episode,either traditional NSBBs or carvedilol seem to play a more prominent role in mortality reduction,probably due to their capacity of preventing other complications of cirrhosis through the decrease in portal hypertension.A sequential strategy,in which patients unresponsive to pharmacological therapy would be submitted to endoscopic treatment,or the combination of pharmacological and endoscopic strategies might be beneficial and deserve further investigation.

Adherence to treatment guidelines in the pharmacological management of chronic heart failure in an Australian population

Background To document the pharmacotherapy of chronic heart failure （CHF） and to evaluate the adherence to treatment guidelines in Australian population. Methods The pharmacological management of 677 patients （female 46.7%, 75.5 ±11.6 years） with CHF was retrospectively analyzed. Results The use of angiotensin converting enzyme （ACE） inhibitors/angiotensin receptor blockers （ARB） and β-blockers were 58.2 % and 34.7 %, respectively. Major reasons for non-use of ACE inhibitors/ARBs were hyperkalemia and elevated serum creatinine level. For patients who did not receive β-blockers, asthma and chronic obstructive pulmonary disease were the main contraindications. Treatment at or above target dosages for ACE inhibitors/ARBs and β-blockers was low for each medication （40.3% and 28.9%, respectively）. Conclusions Evidenced-based medical therapies for heart failure were under used in a rural patient population. Further studies are required to develop processes to improve the optimal use of heart failure medications.