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Sodium isoascorbate is one of the most popular antioxidants in food industry. Russia imports it from abroad. Thus, import substitution requires a thorough research into the patterns of isoascorbate technology production and development. The mass fraction of the main substance in the solution and crystals of the target product was determined by iodometric titration. It was established that the rate of oxidative degradation of sodium isoascorbate solutions is from 0.01%/h at 25°C to 0.80%/h at 82°C, depending on the temperature and duration of the process, as well as contact with metal and oxygen of the air. The experiment substantiated the choice of metal equipment and the temperature limit of 60°C. The equivalent pH values during the interaction of isoascorbic acid solutions with sodium hydroxide, carbonate, and sodium bicarbonate solutions were 7.5, 7.0, and 5.6, respectively. The author also defined the influence of equilibrium concentrations of aqueous solutions of isoascorbic acid and sodium isoascorbate on temperature. The optimal method was to add a solution of sodium hydroxide into a solution of isoascorbic acid with a ratio between the masses of sodium hydroxide solution, crystalline isoascorbic acid, and prepared water, respectively, 1:2.11:6.13. The solution obtained at such ratios had a supersaturation coefficient of 1.05 at a temperature of 60°C. The experiment revealed the time required to establish equilibrium in the crystallizing system and the dependence of the solubility of sodium isoasorbate on the mass fraction of ethyl alcohol in solution. It was proposed to separate the target product from the solution by isohydric crystallization followed by isothermal crystallization, followed by washing the crystals with ethyl alcohol. According to the proposed technology, sodium isoascorbate was obtained with a mass fraction of the basic substance of at least 99.0%. The obtained data can be used in the development of industrial technology for the production of sodium isoascorbate.

Production of functional foods containing such functional ingredients as pectin and anthocyanins is particularly important nowadays. The goal of the given research was to study the effect of high esterified pectin obtained from apples at a dosage of 0.3% on the changes of viscosity and color of drinks based on cherry juice and anthocyanin colourant obtained from black carrot, apple juice and sugar color IV during storage in a dark place at 22 ± 3 °C for 180 days. Optical density was measured using spectrophotometric method at a wavelength of 350 to 700 nm. Mass fraction of solid matter was adjusted using sucrose to reach 10.1 ± 0.7 %, pH for drinks based on cherry juice and anthocyanin colourant obtained from black carrot was adjusted to reach 3.0, and for drinks based on apple juice and sugar color IV – to reach 3.5 in the prepared beverages. The author shows that pectin does not have any significant effect on colour retention in drinks based on cherry juice and anthocyanin obtained from black carrot, and that anthocyanin colourant from black carrots is more stable during storage than the colourant that cherry juice contains. The color of the drinks based on apple juice and sugar color IV without pectin remains almost the same during storage. In the visible spectrum region they have a monotonous graph of the change in optical density, and pectin makes a significant contribution to the final color. It is established that for 180 days of storage kinematic viscosity of the beverages with pectin decreased not more than 12%, that indicates a high level of pectin preservation. According to the results of the research, the author makes a conclusion that the use of pectin to preserve the color of beverages with natural colourants is not practical. It makes sense to use pectin in order to give the beverages functional properties, as well as to increase their viscosity and stability.

Study Objective: To evaluate the hemodynamic effects of the antiarrhythmic drug, encainide, in patients with severe chronic heart failure.Design: Unblinded, before-after study.Setting: Referral center for patients with heart failure.Patients: Thirty patients with severe chronic heart failure and a left ventricular ejection fraction less than 40%.Interventions: Invasive hemodynamic measurements were done (using a balloon-tipped thermodilution catheter) before and for 3 hours after a single oral dose of 50 mg of encainide.Measurements and Main Results: Ninety to one hundred and twenty minutes after its administration, encainide produced a significant deterioration in cardiac performance, as reflected by a fall in cardiac index from 2.3 to 1.8 L/min.m2 body surface (mean change 0.5 +/- 0.1; P less than 0.001), a fall in stroke work index from 26 to 18 g.m/m2 (mean change 8 +/- 2; P less than 0.001), and an increase in left ventricular filling pressure from 19 to 22 mm Hg (mean change 3 +/- 2; P less than 0.05). These deleterious hemodynamic effects were accompanied by worsening symptoms of heart failure in 8 of the 30 patients. Serum levels of encainide and its metabolites, O-desmethylencainide and 3-methoxy-O-desmethylencainide, were within the therapeutic range in most patients.Conclusions: Encainide can cause adverse hemodynamic and clinical effects in patients with severe chronic heart failure. [ABSTRACT FROM AUTHOR]

We sought to determine the effect of race in response to metoprolol in patients with dilated cardiomyopathy. We found no difference in exercise, hemodynamic, and neurohormonal responses to metoprolol based on race in patients with cardiomyopathy. [ABSTRACT FROM AUTHOR]

There remains an ongoing controversy regarding the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of developing heart failure (HF). In addition, none of the animal studies suggested a mechanism for the DPP-4 inhibitors and HF risk. To date, advances in pharmacogenomics have enabled the identification of genetic variants in DPP-4 gene. Studies have shown that genetic polymorphisms in the gene encoding DPP-4 may be associated with potential pathways involved in HF risk. This review discusses the contradictory findings of DPP-4 inhibitors and HF and a potential role for pharmacogenomics. Pharmacogenomics of DPP-4 inhibitors is promising, and genetic information from randomized control trials is urgently needed to gain a full understanding of the safety of DPP-4 inhibitors and the risk of HF.

Aims: Hospitalization for worsening heart failure (HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint., Methods and Results: MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio (HR) 12.4, 95% confidence interval (CI) 9.1-16.9 for inpatient HF; HR 10.7, 95% CI 6.1-18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF., Conclusion: Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials., Trial Registration: NCT01294449., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Recent studies have provided new insights into the pathophysiology of congestive heart failure. Organ-specific responses to circulatory disturbances may differ via a hypoperfusion state and a venous congestion state. The liver and the kidneys serve as a good example of a differential injury pattern based on the predominant circulatory insult. Cardiorenal syndrome appears to be a kidney-specific response to predominantly right-sided backward heart failure ("congestive state"), rather than forward heart failure. Despite significant progress in our understanding of cardiorenal interactions, there is no specific therapy for the cardiorenal syndrome, which is a marker of the severity of the heart failure state., (© 2011 Wiley Periodicals, Inc.)

Introduction: Furosemide is a potent loop diuretic that is widely used in the management of heart failure. Several reports have suggested that continuous intravenous administration of loop diuretics may be superior to intermittent administration. In addition the effect of low-dose dopamine to improve renal perfusion might be of benefit to this patient cohort., Methods: We retrospectively evaluated 116 consecutive cardiac care unit patients, who were admitted with acute decompensated heart failure and were divided into two equal groups according to diuretic protocol. Group A patients received furosemide by continuous infusion combined with low-dose dopamine infusion. Group B patients received bolus therapy of intravenous furosemide. The effect on renal function and readmission rate was recorded., Results: Among 116 patients (60% males, average age 71, range 46-96 years) 41% had ischemic cardiomyopathy, NYHA functional Class was 3.5 ± 0.5 and average EF was 21% ± 7%. On admission, patients in Group A had creatinine (Cr) 2.3 ± 0.2 mg/dL, blood urea nitrogen (BUN) 49.2 ± 25 mg/100 ml and median b-type natriuretic peptid (BNP) 1340 pg/mL, compared to group B patients with Cr 1.7 ± 1.2 mg/dL, BUN 32 ± 22 mg/100 ml and median BNP 1106 pg/mL. The average furosemide dose in group A was 7.9 ± 3.5 mg/hr compared to 7.6 ± 2.7 mg/hr for group B (p=NS). At the end of the study, patients in group A had lower Cr 1.8 ± 0.9 (p=0.0001), lower BUN 43.6 ± 22.9 (p=NS), an increase in estimated glomerular filtration rate 57.4 ± 27.4, a shorter hospital stay (p=0.015) and lower readmission rates at 30 days (p=0.0003)., Conclusions: Continuous infusion of furosemide in addition to low-dose dopamine is safe, effective and less nephrotoxic than intermittent boluses in patients admitted with acute decompensated heart failure and portends a shorter hospital stay and lower readmission rates at 30 days.

Background: Loop diuretics are considered first-line therapy for patients with acute decompensated heart failure (ADHF). Adding nitroglycerin (NTG) to diuretic therapy for alleviation of acute shortness of breath has been advocated in our institution. We evaluated the benefits of adding NTG to diuretics in the emergency department for patients with ADHF and chronic kidney disease (CKD)., Methods: 430 consecutive patients with ADHF who were admitted with a chief complaint of dyspnea were included in this retrospective study. Patients were divided into 3 groups. Group A patients were treated with neither diuretics nor NTG; Group B patients were treated with diuretics only; and Group C patients were treated with both diuretics and NTG. Estimated glomerular filtration rate (GFR) was calculated according to the Cockcroft-Gault formula. Follow-up was 36 ± 9 (mean ± standard deviation [SD]) months. Primary endpoints were readmission rate at 30 days and mortality at 24 months., Results: 430 patients were included in this study (42% men; age, 69 ± 14 [mean ± SD] years); mean New York Heart Association class was 2.4 ± 0.7 (mean ± SD) and mean ejection fraction was 28% ± 17% (mean ± SD). Group A included 257 (59%) patients, Group B had 127 (29%) patients, and Group C had 46 (11%) patients. Group C patients were older (mean age, 72 ± 13 years) with lower body mass index (26 ± 7 kg/m2), lower estimated GFR (55.8 ± 38 mL/min per 1.73 m2), higher B-type natriuretic peptide levels (1112 ± 876 pg/mL; P = nonsignificant [NS]), and higher systolic and diastolic blood pressures on admission (P = 0.001). The primary endpoint was assessed as a composite of all-cause mortality and ADHF readmission seen in 143 (56%) Group A patients, 68 (53%) Group B patients, and 22 (48%) Group C patients (P = NS). At 30 days there were 53 (12%) readmissions--26 in Group A, 20 in Group B, and 7 in Group C (P = NS). However, survival at 24 months was higher in Group C (87%) compared with Groups A (79%) and B (82%) (P = 0.002). Using the Cox proportional-hazards regression module, early administration of NTG and Lasix (95% confidence interval [CI], 1.06-1.62; P = 0.01) followed by CKD stage (95% CI, 1.00-1.35; P = 0.04) were the only predictors for survival., Conclusion: There is a role for early administration of NTG in addition to diuretic therapy in patients admitted to the emergency department with ADHF, with resultant decreased length of stay and a trend toward a decrease in the composite endpoint of all-cause mortality and ADHF readmission. The mortality benefit at 2 years reported in our study is thought-provoking and raises a premise to be proven in randomized clinical trials.

Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V(2) -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double-blind, placebo-controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital-free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30-day safety follow-up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure., (© 2010 Wiley Periodicals, Inc.)

Background: Heart failure and atrial fibrillation (AFib) are the twin epidemics of modern cardiovascular disease. The incidence of new-onset AFib in acute decompensated heart failure (ADHF) patients is difficult to predict and the short- and long-term outcomes of AFib in a cohort of patients admitted with ADHF are unknown., Methods and Results: A total of 904 patients admitted with ADHF were studied. Incidence of AFib on admission was recorded and a multivariate analysis was performed using echocardiographic parameters to specify the predictors of AFib incidence in this cohort. In 904 ADHF patients (57% male, mean age 69 ± 14 years), 81% had history of hypertension, 40% were diabetics, and 51% were smokers. A total of 63% of the patients had known heart failure (HF) with mean ejection fraction of 34% ± 21%, and 33% of the patients had ischemic cardiomyopathy as the etiology of HF. Echocardiographic parameters were: left atrial (LA) diameter 4.5 ± 0.8 cm, left ventricular end-systolic 4.1 ± 1.3 cm, left ventricular end-diastolic 5.3 ± 1.1 cm. Right ventricular dysfunction (RVD) was present in 34% of the patients. A total of 191 (21%) patients subsequently developed AFib with two thirds of the cases occurring in patients with RVD. Using a univariate analysis, older age (OR 1.02; P < .0001), history of HF (OR 2.93; P < .0001), LA dilation (OR 1.58; P < .0001), the presence of left ventricular hypertrophy (OR 3.01, P < .0001), and RVD (OR 4.93; P < .00001) were the strongest predictors for AFib. Controlling for LA size and left ventricular hypertrophy using a forward stepwise regression, RVD remained the strongest predictor (OR 4.45; P < .0001). Patients with RVD had more events (cardiac readmission and mortality) than those with normal RV (56% versus 38%; P < .00001), notably; all-cause mortality was 4.7%/year in the abnormal RV group versus 2.9%/year in the normal RV group; P < .05. RV function analyses by echocardiography further risk stratified these patients based on their rhythm categorizing those patients with abnormal RV and AFib as the ones with the worse prognosis., Conclusion: RV dysfunction is a strong predictor for developing AFib in acutely decompensated systolic failure patients. Patients with AFib and RVD have the worse outcome specially when is combined with LV dysfunction, therefore; evaluation of RV function may substantiate the difference in HF prognosis., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Heart failure due to systolic dysfunction has enormous global impact. Medical management based on an understanding of the pathophysiology of the disease as well as its neurohormonal mechanisms has greatly advanced over the past 25 years. Below is a review of recent and emerging data on epidemiology and diagnosis of heart failure due to systolic dysfunction and the current and future management techniques to ameliorate this disease. At the end, we will highlight three significant trials in the field in 2009 that will impact heart failure care: STICH, MADIT-CRT, and HeartMate II.

Small, single-center studies suggest that catheter ablation of atrial fibrillation (AF) can improve ventricular function and reduce symptoms in patients with left ventricular (LV) dysfunction. However, ablation has not been compared with a pharmacologic strategy for AF. The authors evaluated patients with AF and symptomatic LV dysfunction (ejection fraction < or =45%) referred for pulmonary vein isolation (PVI). They compared these patients with a matched cohort treated medically for AF and LV dysfunction via a retrospective case-control method. Fifteen patients (14 men, 56+/-11 years, 10 [67%] paroxysmal AF) with AF for 4+/-3 years underwent PVI. Baseline ejection fraction was 37%+/-6% and New York Heart Association (NYHA) class was 2.0+/-1.0. Fifteen controls (13 men, 63+/-14 years, 11 [73%] paroxysmal AF) with AF for 5+/-4 years were treated medically for AF. Baseline ejection fraction was 34%+/-11% and NYHA class was 2.0+/-0.7. The groups were similar in all respects. During a follow-up of 16+/-13 months after complete PVI, ejection fraction improved (P=.001) to 50%+/-13% and normalized in 8 patients (53%). NYHA class improved to 1.3+/-0.5 (P=.01). In the medically treated group, after follow-up of 16+/-12 months, no improvement in ejection fraction (36%+/-12%) or NYHA class (1.8+/-0.7) was seen. Compared with pharmacologic therapy, PVI significantly improved LV function and NYHA class in patients with AF and symptomatic LV dysfunction. These provocative findings provide potent rationale for a randomized clinical trial comparing ablation with pharmacologic therapy., (2009 Wiley Periodicals, Inc.)

beta-blockers have been well-studied in the treatment of the symptomatic stages of chronic heart failure. Frequently physicians treat patients with asymptomatic left ventricular (LV) dysfunction and patients with hypertension on beta-blockers without clear evidence that there is value in doing so. Chronic heart failure poses an extraordinary economic burden; any effective therapy that limits the progression to symptomatic heart failure can probably reduce monetary expenditures in addition to potentially reducing morbidity and mortality. In this article, we review the available literature on using beta-blockers in stage A and B heart failure to prevent progression to the symptomatic stages. The literature reveals that there is no benefit in using beta-blockers to treat essential hypertension. In patients who experience LV dysfunction post-myocardial infarction, even if asymptomatic, there is improved mortality and a trend toward a reduction in progression to symptomatic heart failure. In patients with asymptomatic chronic LV dysfunction there are data that beta-blockers reduce LV dimensions and improve ejection fraction. Patients with hypertension should not be given beta-blockers as primary treatment. All patients with asymptomatic LV dysfunction should be treated with a beta-blocker, regardless of whether they experienced myocardial infarction.

We have recently developed and published 2 care pathways: 1 for the management of acute coronary syndrome and the other for acute heart failure. Our pathways are designed to optimize care for patients using clinical evidence models and to teach physicians in training consensus evaluation and management strategies. To implement our pathways to improve our patient care, we have developed unique admission and discharge forms derived from these pathways. These forms serve as reminders of key points of the pathways, as data collection devices, and most importantly as a health care agreement on discharge between patients and their healthcare providers.

Acute heart failure poses a major healthcare problem. Recent guidelines for heart failure address management of outpatient chronic heart failure but do not address inpatient management. We present a unique, simple, yet comprehensive pathway that focuses on the differential diagnosis of new-onset heart failure and acute decompensation of chronic heart failure. An algorithm is presented for the optimal management of the patient with chronic heart failure who presents to the emergency room with acute symptomatic decompensation. The treatment algorithm provides recommendations for daily management and adjustments of therapy, which is primarily focused on a safe and rapid diuresis to the point of discharge from the acute care setting.

Objectives: We conducted a prospective multicenter registry in a large metropolitan area to define the clinical characteristics, hospital course, treatment, and factors precipitating decompensation in patients hospitalized for heart failure with a normal ejection fraction (HFNEF)., Background: The clinical profile of patients hospitalized for HFNEF has been characterized by retrospective analyses of hospital records and state data banks, with few prospective single-center studies., Methods: Patients hospitalized for heart failure (HF) at 24 medical centers in the New York metropolitan area and found to have a left ventricular (LV) ejection fraction of > or 50% within seven days of admission were included in this registry. Patient demographics, signs and symptoms of HF, coexisting and exacerbating cardiovascular and medical conditions, treatment, laboratory tests, procedures, and hospital outcomes data were collected. Analysis by gender and race was prespecified., Results: Of 619 patients, 73% were women, who were on average four years older than men (72.8 +/- 14.1 years vs. 68.6 +/- 13.8 years, p < 0.001). Black non-Hispanic patients comprised 30% of the study population. They were eight years younger than other patients (66.0 +/- 14.2 years vs. 74 +/- 13.5 years p < 0.001). Co-morbid conditions and their prevalence were: hypertension, 78%; increased LV mass, 82%; diabetes, 46%; and obesity, 46%. Before clinical decompensation that precipitated hospitalization, 86% of patients had chronic symptoms compatible with New York Heart Association functional classes II to IV. Factors precipitating clinical decompensation were identified in 53% of patients. In-hospital mortality was 4.2%., Conclusions: Patients hospitalized for HFNEF are most often chronically incapacitated elderly women with a history of hypertension and increased LV mass. Reasons for clinical decompensation are identified in only one-half of patients.

Based on impressive morbidity and mortality data using beta blockers in heart failure, this therapy has now become part of the standard of care for patients with New York Heart Association II/III symptoms. The question remains whether there are clinically relevant differences between the beta blockers that have shown beneficial effects. This review summarizes the major mortality trials, and examines the smaller comparative trials of second and third generation beta blockers.

Background: A preliminary study suggested that the long-acting late-generation calcium-channel blocker amlodipine has favorable effects on exercise tolerance and is safe to use in heart failure, in contrast to earlier generation agents. The goal of 2 multicenter studies was to assess the effect of adjunctive therapy with amlodipine in addition to standard therapy on exercise capacity, quality of life, left ventricular function, and safety parameters in patients with heart failure and left ventricular systolic dysfunction., Methods: Two large multicenter trials examining the effects of amlodipine on these parameters over a 12-week period of therapy were undertaken in patients with mild to moderate heart failure and left ventricular systolic dysfunction. A total of 437 patients with stable heart failure were studied in a randomized, double-blind, placebo-controlled prospective design., Results: Amlodipine at a dose of 10 mg/day in addition to standard therapy in such patients was associated with no significant difference in change in exercise tolerance on a Naughton protocol compared with placebo in each trial. Among all patients taking amlodipine, exercise time increased 53 +/- 9 (SE) seconds; exercise time for those taking placebo increased 66 +/- 9 seconds (P = not significant). There were no significant differences in changes of quality of life parameters between amlodipine- and placebo-treated patients, and there were no significant differences in symptom scores or New York Heart Association classification between groups. Left ventricular function (measured as ejection fraction) improved 3. 4% +/- 0.5% in amlodipine-treated patients and 1.5% +/- 0.5% in placebo-treated patients (P =.007). There was no statistically significant excess of important adverse events (episodes of worsening heart failure in 10% amlodipine-treated vs 6.3% of placebo-treated patients) or differences in need for changes in background medication between groups., Conclusions: The addition of 10 mg of amlodipine per day to standard therapy in patients with heart failure is associated with no significant improvement in exercise time compared with placebo therapy over a 12-week period, and there was no increased incidence of adverse events. These data suggest that the addition of amlodipine to standard therapy in heart failure will not result in additional efficacy per se beyond standard therapy.

Neurohormonal antagonism is now recognized as an essential treatment modality for heart failure. As a prime example, the benefits of blocking the renin-angiotensin system with angiotensin converting enzyme inhibitors are clearly established for all four New York Heart Association classes. In this clinical trials review, we discuss two other therapies with neurohormonal targets: beta-blockers and the sympathetic nervous system, and the aldosterone antagonist spironolactone.

Background: Ventricular arrhythmias are a frequent finding in congestive heart failure (CHF) patients and a cause of concern for physicians caring for them. Previous studies have reached conflicting conclusions regarding the importance of ventricular arrhythmias as predictors of sudden death in patients with CHF. This study examined the independent predictive value of ventricular arrhythmias for sudden death and all-cause mortality in PROMISE (Prospective Randomized Milrinone Survival Evaluation)., Methods and Results: Ventricular arrhythmias were analyzed and quantified by use of prespecified criteria on baseline ambulatory ECGs from 1080 patients with New York Heart Association (NYHA) class III/IV symptoms and a left ventricular ejection fraction

Objectives: To compare the hemodynamic effects of twice daily metoprolol tartrate (MT) and once daily metoprolol succinate (MS) in congestive heart failure patients., Background: Adverse hemodynamic effects with MT demonstrated during initiation persist with drug readministration during chronic therapy., Methods: Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally and the dose was gradually increased to a target of 50 mg twice a day or 100 mg once a day, respectively. Hemodynamic measurements were obtained at baseline and after three months of therapy--both before and after drug readministration., Results: Long term metoprolol therapy produced significant functional, exercise and hemodynamic benefits with no difference in response between either metoprolol preparation in the 27 patients (MT [14], MS [13]). When full dose metoprolol was readministered during chronic therapy, there were parallel adverse hemodynamic effects in both drug groups. Cardiac index decreased by 0.6 liters/min/m2 (p < 0.0001) with MT and by 0.5 liters/min/m2 (p < 0.0001) with MS. Systematic vascular resistance increased by 253 dyne-sec-cm(-5) (p < 0.001) with MT and by 267 dyne-sec-cm(-5) (p < 0.0005) with MS. Stroke volume index decreased by 7.0 ml/m2 (p < 0.0005) with MT and by 6.5 ml/m2 (p < 0.0001) with MS, while SWI decreased by 6.2 g-m/m2 (p < 0.0005) with MT and by 6.0 g-m/m2 (p < 0.001) with MS., Conclusion: Metoprolol tartrate and MS produce similar hemodynamic and clinical effects acutely and chronically despite the fourfold greater starting dose of MS used in this study. A more rapid initiation with readily available starting doses of MS may offer distinct advantages compared with MT in treating chronic heart failure patients with beta-adrenergic blocking agents.

The management of heart failure has evolved in parallel with advances in the understanding of the disease process. Inotropes and diuretics are used to combat pump failure and fluid overload. While no convincing data has emerged regarding the long-term safety of inotropes, new exciting data concerning the role of diuretics, especially aldactone, has led to a renewed interest in this class of drug therapy. Angiotensin converting enzyme inhibitors (ACE inhibitors) were noted to not only affect symptomatology but also decrease mortality by interfering with the renin-angiotensin-aldosterone system. Recent research has focused on more complete blockade of the renin-angiotensin system than that achieved with ACE inhibitors alone with the addition of direct angiotensin II receptor blockers. This new class of drugs may become not only a reasonable alternative to ACE inhibitors in patients intolerant of the drug but also a possible addition to ACE inhibitors in the battle to prevent progression of remodelling and disease. beta-blockers are the most exciting new class of drugs used to combat heart failure. They appear not only to combat the remodelling process that occurs in the progression of disease but also other pathological events such as apoptosis and cellular oxidation. New medical therapies currently being investigated include novel agents such as endothelin antagonists, natriuretic peptides, vasopressin antagonists and anticytokine agents--all part of a new era in drug management of heart failure that has evolved with continued advances in the understanding of chronic heart failure (CHF).

Recent advances in the understanding of the basic mechanisms underlying congestive heart failure (CHF) have focused on the role of neurohormonal activation. Chronic adrenergic overstimulation is directly toxic to myocardial cells, impairs function, causes peripheral vasoconstriction and may induce programmed cell death via apoptosis. beta-Adrenergic blockade can interrupt this pathological process. Accumulating evidence now points to a clear role for beta-blocking agents in the management of heart failure, reducing both the morbidity and mortality associated with CHF. This report will review the recent clinical trials supporting the use of beta-blockers in CHF, briefly highlight some practical considerations in the use of these drugs in patients with CHF and discuss several areas of controversy in which further study is needed.

Background: Initiation of beta-blocker therapy is often limited by worsening congestive heart failure, which may manifest as worsening hemodynamics. Deleterious hemodynamic effects might be mitigated with the vasodilation of combined calcium channel/beta-blocker therapy., Methods and Results: This prospective, randomized study assessed the safety and efficacy of metoprolol alone or combined with amlodipine on hemodynamic parameters at baseline, 2 hours after the first dose of study medication, and after 12 weeks of therapy in patients receiving background triple therapy for mild to severe heart failure. Functional, exercise, and hormonal status were assessed at baseline and end of study. Twenty-nine patients (mean age 50 +/- 12.1 years) were enrolled; 21 completed 12 weeks of treatment. Mean ejection fraction at baseline was 13.4% +/- 5.7%; 79% of patients had heart failure classified as New York Heart Association class III, and 66% had heart failure of idiopathic origin. Heart rate and blood pressure did not change with short-term therapy in either group. The first dose of both regimens produced significant increases in systemic vascular resistance and significant decreases in cardiac output and index and stroke volume and stroke work indexes; combination therapy acutely yielded small but statistically significant increases in pulmonary artery, pulmonary capillary wedge, and right atrial pressures. Long-term therapy with both regimens produced significant decreases in heart rate, systemic vascular resistance, and pulmonary capillary wedge pressure and significant increases in cardiac output and index and stroke volume and stroke work indexes. Combination therapy produced significant long-term decreases in blood pressure., Conclusions: There was no further measurable benefit with the addition of amlodipine to metoprolol compared with the effects of metoprolol alone. Therapy with metoprolol alone and the combination of metoprolol and amlodipine was well tolerated in patients with mild to severe heart failure, as evidenced by a lack of adverse effects on hemodynamic parameters over the short term and clinical and hemodynamic improvement with long-term treatment.

Oxygen free radicals, produced by the reduction of oxygen during many cellular reactions, have been implicated in the pathogenesis of a variety of cardiovascular diseases. Extremely reactive, free radicals damage many cellular structures and interfere with multiple cell functions. Clinically, free radicals have been associated with coronary atherosclerosis, ischemia, and reperfusion injury (“stunning”), and other processes related to chronic myocardial dysfunction. Several studies have reported elevated markers of free radical mediated injury in patients with congestive heart failure (CHF), and the link between oxidative stress and the genesis and progression of chronic CHF is being increasingly explored. This review briefly highlights free radical biology and examines the rationale and evidence for the role of oxidative stress in chronic heart failure. (c)1999 by CHF, Inc.

Background: With beta-blocker use becoming more prevalent in treating chronic heart failure (CHF), the choice of drugs raises important theoretical and practical questions. Although the second-generation compound metoprolol is beta1-selective, the third-generation compound carvedilol is beta-nonselective, with ancillary pharmacological properties including alpha-blockade and antioxidant effects. A prospective comparison of these 2 agents can address the issue of optimal adrenergic blockade in selecting agents for therapy in CHF., Methods and Results: Sixty-seven patients with symptomatic stable heart failure were randomly assigned to receive either carvedilol or metoprolol in addition to standard therapy for CHF. Measured variables included symptoms, exercise, ejection fraction, and thiobarbituric acid-reactive substances (TBARS) as an indirect marker of free radical activity. Metoprolol and carvedilol were well tolerated, and both patient groups showed beneficial effects of beta-blocker therapy in each of the measured parameters, with no between-group differences. Ejection fraction increased over 6 months from 18+/-6.3% to 23+/-8.7% (P<0.005) with metoprolol and from 19+/-8.5% to 25+/-9.9% (P<0.0005) with carvedilol (P=NS between groups). With metoprolol, TBARS values decreased from 4.7+/-0.9 nmol/mL at baseline to 4.2+/-1.5 nmol/mL at month 4 to 3.9+/-1.0 nmol/mL at month 6 (P<0.0001). With carvedilol, there was a parallel decline from 4.7+/-1.4 to 4.2+/-1.3 to 4.1+/-1.2 nmol/mL over the same time frame (P<0.025), with no between-group difference in these changes., Conclusions: Carvedilol and metoprolol showed parallel beneficial effects in the measured parameters over 6 months, with no relevant between-group differences in this heart failure population.

Neurohormonal activation and chronic adrenergic overstimulation appear to play important roles in mediating the progressive pathophysiology of congestive heart failure (CHF), and the beneficial effects of beta-blockade in the management of chronic heart failure have been demonstrated by multiple clinical trials over the last decade. Nevertheless, the initiation and maintenance of beta-blocker therapy in CHF may initially precipitate a deterioration in clinical function, and numerous questions regarding the appropriate use of these agents in patients with heart failure remain. This report examines the practicalities of beta-adrenergic blockade in heart failure, focusing on patient selection, nonselective versus selective blockade, management of adverse effects, and indications for withdrawal of therapy.