Sustainable (-)-Ambrox Production: Chemistry Meets Biocatalysis.

(-)-Ambrox, the most prominent olfactive component of ambergris, is one of the most widely used biodegradable fragrance ingredients. It is traditionally produced from the diterpene sclareol chemically modified and cyclized into (-)-ambrox. The availability of the new feedstock (E)-ß-farnesene produced by fermentation opened new routes to (E,E)-homofarnesol as a precursor to (-)-ambrox. Combining the chemical transformation of (E)-ß-farnesene to (E,E)-homofarnesol and its enzymatic cyclization with an engineered Squalene Hopene Cyclase provided a new sustainable route for the production of (-)-ambrox at industrial scale. Compared to the traditional synthesis from sclareol, the new and innovative route from (E)-ß-farnesene improves atom and step economy, reduces waste production, solvent and energy consumption.

Biotechnology - A Tool to Transform Givaudan's Fragrance Ingredients Palette.

To support perfumers in their creation of olfactive signatures resulting in unique and instantly recognizable perfumes, there is a constant demand for the development of new odorant molecules and of novel processes for their production. Increasing the sustainability of both the molecules and the processes is a crucial activity at Givaudan. Biocatalysis has the potential to positively influence metrics applied at Givaudan that drive and measure our ambition to innovate responsibly, which is summarized in the FiveCarbon Path™. It targets an increased use of renewable carbon, carbon efficiency in synthesis, and the production of powerful and biodegradable odorant molecules while maximizing the use of upcycled carbon available from waste and side streams. This review illustrates with some examples how enzymes selected from the oxidoreductase and isomerase enzyme classes are applied at Givaudan for the preparation of odorant molecules both at laboratory and industrial scale.

From Ambergris to (-)-Ambrox: Chemistry Meets Biocatalysis for Sustainable (-)-Ambrox Production.

(-)-Ambrox, the most prominent olfactive component of ambergris is one of the most widely used biodegradable fragrance ingredients. Traditionally it is produced from the diterpene sclareol, modified and cyclized into (-)-ambrox by classical chemistry steps. The availability of the new feedstock (E)-ß-farnesene produced by fermentation opened new pathways to (E,E)-homofarnesol as a precursor to (-)-ambrox. Combining chemical transformation of (E)-ß-farnesene to (E,E)-homofarnesol and its enzymatic cyclization at the industrial scale to (-)-ambrox with an engineered squalene hopene cyclase illustrates the potential of biotechnology for a more sustainable process, thus meeting the increasing consumers' demand for sustainably produced high quality perfumery and consumer goods. This review traces back to the origin of ambergris and the search for the source of its mysterious odor, leading to the discovery of (-)-ambrox as its main olfactive principle. It discusses the plethora of ways explored for its synthesis from diverse starting materials and presents the development of a process with significantly improved carbon efficiency for the industrial production of (-)-ambrox as 100% renewable Ambrofix.

Asymmetric Cation-Olefin Monocyclization by Engineered Squalene-Hopene Cyclases.

Squalene-hopene cyclases (SHCs) have great potential for the industrial synthesis of enantiopure cyclic terpenoids. A limitation of SHC catalysis has been the enzymes' strict (S)-enantioselectivity at the stereocenter formed after the first cyclization step. To gain enantio-complementary access to valuable monocyclic terpenoids, an SHC-wild-type library including 18 novel homologs was set up. A previously not described SHC (AciSHC) was found to synthesize small amounts of monocyclic (R)-γ-dihydroionone from (E/Z)-geranylacetone. Using enzyme and process optimization, the conversion to the desired product was increased to 79 %. Notably, analyzed AciSHC variants could finely differentiate between the geometric geranylacetone isomers: While the (Z)-isomer yielded the desired monocyclic (R)-γ-dihydroionone (>99 % ee), the (E)-isomer was converted to the (S,S)-bicyclic ether (>95 % ee). Applying the knowledge gained from the observed stereodivergent and enantioselective transformations to an additional SHC-substrate pair, access to the complementary (S)-γ-dihydroionone (>99.9 % ee) could be obtained.

Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices.

BACKGROUND: Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. METHODS AND RESULTS: In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (P=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. CONCLUSIONS: In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442129.

Laccase versus laccase-like multi-copper oxidase: a comparative study of similar enzymes with diverse substrate spectra.

Laccases (EC 1.10.3.2) are multi-copper oxidases that catalyse the one-electron oxidation of a broad range of compounds including substituted phenols, arylamines and aromatic thiols to the corresponding radicals. Owing to their broad substrate range, copper-containing laccases are versatile biocatalysts, capable of oxidizing numerous natural and non-natural industry-relevant compounds, with water as the sole by-product. In the present study, 10 of the 11 multi-copper oxidases, hitherto considered to be laccases, from fungi, plant and bacterial origin were compared. A substrate screen of 91 natural and non-natural compounds was recorded and revealed a fairly broad but distinctive substrate spectrum amongst the enzymes. Even though the enzymes share conserved active site residues we found that the substrate ranges of the individual enzymes varied considerably. The EC classification is based on the type of chemical reaction performed and the actual name of the enzyme often refers to the physiological substrate. However, for the enzymes studied in this work such classification is not feasible, even more so as their prime substrates or natural functions are mainly unknown. The classification of multi-copper oxidases assigned as laccases remains a challenge. For the sake of simplicity we propose to introduce the term "laccase-like multi-copper oxidase" (LMCO) in addition to the term laccase that we use exclusively for the enzyme originally identified from the sap of the lacquer tree Rhus vernicifera.

Clinically irrelevant circulating human leukocyte antigen antibodies in the presence of ventricular assist devices.

INTRODUCTION: Identification of anti-human leukocyte antigen (HLA) antibodies by single-antigen beads (SAB) allows for prediction of donor-specific crossmatches (virtual crossmatches), thus facilitating the allocation of organs from deceased donors. However, the clinical relevance of HLA antibodies identified by SAB has been less than clear. This study demonstrates that sera from cardiac transplant candidates with a ventricular assist device (VAD) or infection may contain clinically irrelevant antibodies that bind to the beads but not to lymphocytes. METHODS: Investigated were 5 cardiac transplant candidates (3 with VAD, all with infections, and 1 retransplant) with positive HLA antibodies detected by SAB, but negative by cytotoxicity. To determine clinical relevance of the antibodies, flow cytometric crossmatches (FCXM) were performed. Untreated beads and elution buffer-treated beads to dissociate the ß-2 microglobulin and the peptide from the heavy chain were used. RESULTS: The virtual crossmatch data were compared with data from actual FCXMs. Of 40 T-cell and B-cell FCXM, SAB-identified HLA antibodies were predictive for only 1 T-cell and 9 B-cell FCXM outcomes. Patients' sera contained a mixture of antibodies directed against cryptic epitopes on the heavy chain and exposed epitopes. The mean fluorescence intensity of antibodies varied from 1,040 to 11,000. CONCLUSIONS: Sera from cardiac transplant candidates with or without VAD may contain natural antibodies that do not bind to intact antigens on the cell surface. Therefore, great care must be exercised before denying a life-saving transplant to these patients simply on the basis of SAB results.

Coronary artery disease, coronary revascularization, and outcomes in chronic advanced systolic heart failure.

BACKGROUND: Associations between coronary artery disease (CAD) and outcomes in systolic heart failure (HF) and that between coronary artery bypass graft (CABG) surgery and outcomes in patients with HF and CAD have not been examined using propensity-matched designs. METHODS: Of the 2707 patients with advanced chronic systolic HF in the Beta-Blocker Evaluation of Survival Trial (BEST), 1593 had a history of CAD, of whom 782 had prior CABG. Using propensity scores for CAD we assembled a cohort of 458 pairs of CAD and no-CAD patients. Propensity scores for prior CABG in those with CAD were used to assemble 500 pairs of patients with and without CABG. Matched patients were balanced on 68 baseline characteristics. RESULTS: All-cause mortality occurred in 33% and 24% of matched patients with and without CAD respectively, during 26 months of median follow-up (hazard ratio {HR} when CAD was compared with no-CAD, 1.41; 95% confidence interval {CI}, 1.11-1.81; P=0.006). HR's (95% CIs) for CAD-associated cardiovascular mortality, HF mortality, and sudden cardiac death (SCD) were 1.53 (1.17-2.00; P=0.002), 1.44 (0.92-2.25; P=0.114) and 1.76 (1.21-2.57; P=0.003) respectively. CAD had no association with hospitalization. Among matched patients with HF and CAD, all-cause mortality occurred in 32% and 39% of those with and without prior CABG respectively (HR for CABG, 0.77; 95% CI, 0.62-0.95; P=0.015). CONCLUSIONS: In patients with advanced chronic systolic HF, CAD is associated with increased mortality, and in those with CAD, prior CABG seems to be associated with reduced all-cause mortality but not SCD.

Effects of peripheral arterial disease on outcomes in advanced chronic systolic heart failure: a propensity-matched study.

BACKGROUND: The effect of peripheral arterial disease (PAD) on outcomes in patients with chronic heart failure (HF) has not been examined in propensity-matched studies. METHODS AND RESULTS: Of the 2689 patients with advanced chronic systolic HF in the Beta-Blocker Evaluation of Survival Trial, 441 had a history of PAD. Propensity scores for a history of PAD, calculated for each patient using a multivariable logistic regression model, were used to assemble a matched cohort of 299 and 1015 patients, respectively, with and without PAD who were well balanced on 65 measured baseline characteristics. Cox regression models were used to estimate hazard ratios and 95% CIs for associations between PAD and outcomes during 4.1 years of follow-up. Patients had a mean age of 63+/-11 years, 19% were women, and 19% were black. All-cause mortality occurred in 43% and 33% of patients with and without a history of PAD, respectively (hazard ratio when PAD was compared with no history of PAD, 1.40; 95% CI, 1.14 to 1.72; P=0.001). All-cause hospitalization occurred in 75% and 63% of patients with and without PAD, respectively (hazard ratio when PAD was compared with no history of PAD, 1.36; 95% CI, 1.16 to 1.58; P<0.0001). PAD-associated hazard ratios for cardiovascular mortality, HF mortality, and HF hospitalization were 1.31 (95% CI, 1.04 to 1.63; P=0.019), 1.40 (95% CI, 0.97 to 2.02; P=0.076), and 1.05 (95% CI, 0.86 to 1.29; P=0.635), respectively. CONCLUSIONS: In a well-balanced propensity-matched population of chronic systolic HF patients, a history of PAD was independently associated with increased mortality and hospitalization.

Role of a percutaneous ventricular assist device in decision making for a cardiac transplant program.

BACKGROUND: The role of a percutaneous ventricular assist device (VAD) for left heart support in the management of patients in cardiogenic shock is not well defined. METHODS: All patients who received LV support using the percutaneous TandemHeart (percTH) ventricular support device (Cardiac Assist, Pittsburgh, PA) were retrospectively reviewed. Indications for insertion included bridge to decision (BTD) or "salvage" and bridge to transplant (BTT). RESULTS: Between April 2005 and December 2008, 22 percTH devices were successfully implanted in patients (13 men) with isolated left heart failure. Mean duration of support was 6.8 +/- 9.4 days (median, 4; maximum, 45 days). Of patients requiring percTH support for at least 3 days, mean pump flows were 3.77 +/- 1.10, 4.22 +/- 0.69, and 4.04 +/- 0.41 L/min on at days 1, 2, and 3. Mean serum aspartate aminotransferase levels were 455 +/- 994 mg/dL before percTH, 551 +/- 1046 mg/dL at day 1, and 231 +/- 225 mg/dL at day 3 after percTH. No mechanical device failure, device-related infections, or cerebrovascular accidents occurred. Ten of 11 BTT patients were successfully bridged. Support was withdrawn in 7 of 11 BTD patients. The percTHs were successfully explanted in 4 BTD patients: 1 as recovery, 1 direct to transplant, and 2 to VAD. CONCLUSIONS: The percTH was reliable, with no mechanical device failures and minimal associated adverse events. We support the use of the percTH in the BTD mode, allowing time for a more complete evaluation of neurologic and end-organ status without the added expense and morbidity of a long-term VAD.

Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials.

AIMS: Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit-risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy. METHODS AND RESULTS: The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III-IV HF symptoms, left ventricular ejection fraction < or = 30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80-1.17; and HR 0.98; 95% CI 0.86-1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial. CONCLUSION: Although low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.

Current clinical outcomes of percutaneous coronary intervention and coronary artery bypass grafting.

BACKGROUND: Randomized trials have compared coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). However, results of these trials in select patients may not accurately reflect current clinical practice using drug-eluting stents (DES) and off-pump CABG. We undertook a prospective registry of coronary revascularization by CABG on-pump and off-pump, and PCI with or without DES, to determine clinical outcomes. METHODS: All patients undergoing isolated coronary revascularization in 8 community-based hospitals were enrolled. Preprocedural, intraprocedural, and postprocedural data were captured, with outcomes obtained at 18 months by patient and physician contact, and the Social Security Death Index. RESULTS: The study enrolled 4336 patients, 71.2% PCI and 28.8% CABG. DESs were used in 2249 PCIs (73.1%), and 596 CABG procedures (47.8%) were off-pump. Incidence of major adverse cardiac events at 18 months was 14.7% for CABG vs 23.3% for PCI (p < 0.001). Cardiac death and myocardial infarction had similar rates. The need for repeat revascularization was significantly less with CABG (6.2% vs 13.6%, p < 0.001). Hazard ratio of CABG to PCI was 0.76 (95% confidence interval, 0.571 to 0.872). CABG outcome was similar on-pump and off-pump, as was repeat revascularization with DES (12.1%) vs BMS (14.9%; p = 0.096). Overall event-free survival was 85.3% in CABG and 76.8% in PCI (p < 0.001). CONCLUSIONS: Rates of repeat revascularization were significantly higher for PCI than for CABG, but mortality and myocardial infarction were the same. There were no significant differences in outcomes between DES and BMS or between on-pump and off-pump CABG.

Low-dose oral enoximone enhances the ability to wean patients with ultra-advanced heart failure from intravenous inotropic support: results of the oral enoximone in intravenous inotrope-dependent subjects trial.

BACKGROUND: We determined whether low-dose oral enoximone could wean patients with ultra-advanced heart failure (UA-HF) from intravenous (i.v.) inotropic support. Chronic parenteral inotropic therapy in UA-HF is costly and requires an indwelling catheter. An effective and safe oral inotrope would have value. METHODS: In this placebo-controlled study, 201 subjects with UA-HF requiring i.v. inotropic therapy were randomized to enoximone or placebo. Subjects receiving intermittent i.v. inotropes were administered study medication of 25 or 50 mg 3 times a day (tid). Subjects receiving continuous i.v. inotropes were administered 50 or 75 mg tid for 1 week, which was reduced to 25 or 50 mg tid. The ability of subjects to remain alive and free of inotropic therapy was assessed for up to 182 days. RESULTS: Thirty days after weaning, 51 (51%) subjects on placebo and 62 (61.4%) subjects in the enoximone group were alive and free of i.v. inotropic therapy (unadjusted primary end point P = 0.14, adjusted for etiology P = .17). At 60 days, the wean rate was 30% in the placebo group and 46.5% in the enoximone group (unadjusted P = .016) Kaplan-Meier curves demonstrated a trend toward a decrease in the time to death or reinitiation of i.v. inotropic therapy over the 182-day study period (hazard ratio 0.76 [95% CI 0.55-1.04]) and a reduction at 60 days (0.62 [95% CI 0.43-0.89], P = .009) and 90 days (0.69 [95% CI 0.49-0.97], P = .031) after weaning in the enoximone group. CONCLUSIONS: Although there was no benefit over placebo in weaning patients from i.v. inotropes from 0 to 30 days, the EMOTE data suggest that low-dose oral enoximone can be used to wean a modest percentage of subjects from i.v. inotropic support for up to 90 days after initiation of therapy.

Rationale and design of the enoximone clinical trials program.

BACKGROUND: Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. METHODS AND RESULTS: The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment. CONCLUSION: These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice.

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.

Prognostic benefit of beta-blockers in patients not receiving ACE-Inhibitors.

AIMS: Beta-blockers (BBs) confer significant prognostic benefit in patients (pts) with systolic chronic heart failure (CHF). However, major trials have thus far studied BBs mainly in addition to ACE-Inhibitors or angiotensin receptor blockers (ARBs) as background therapy. The magnitude of the prognostic benefit of BBs in the absence of ACE-I or ARB has not as yet been determined. METHODS AND RESULTS: We performed a meta-analysis of all placebo-controlled BB studies in patients with CHF (n>200). Trials were identified via Medline literature searches, meeting abstracts, and contact with study organizations. Results for all-cause mortality and death or heart failure hospitalization were pooled using the Mantel-Haenszel (fixed effects) method. The impact of BB therapy on all-cause mortality in CHF, in the absence (4.8%) and presence (95.2%) of ACE-I (or ARB), was determined from six trials of 13 370 patients. The risk ratio (RR) for BBs vs. placebo was 0.73 [95% confidence interval (CI) 0.53-1.02] in the absence of ACE-I or ARB at baseline, compared with a RR of 0.76 (95% CI 0.71-0.83) in the presence of these agents. When ACE-Inhibitors were analysed in the same way (pre-BB), a RR of 0.89 (0.80-0.99) vs. placebo was observed in studies of >90 days. The impact of BB therapy on death or HF hospitalization in systolic CHF, in the absence and presence of ACE-I, was determined from three trials of 8988 patients. The RR for BBs vs. placebo was 0.81 (95% CI 0.61-1.08) in the absence of ACE-I or ARB at baseline, compared with a RR of 0.78 (95% CI 0.74-0.83) in the presence of these agents. When ACE-Is were analysed in the same way (pre-BB), a RR of 0.85 (95% CI 0.78-0.93) vs. placebo was observed in studies of >90 days. CONCLUSION: The magnitude of the prognostic benefit conferred by BBs in the absence of ACE-I appears to be similar to those of ACE-Is in systolic CHF. These data therefore suggest that either ACE-Is or BBs could be used as first-line neurohormonal therapy in patients with systolic CHF. Prospective studies directly comparing these agents are required to definitively address this issue.

Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST).

OBJECTIVES: The aim of this study was to determine echocardiographic predictors of outcome in patients with advanced heart failure (HF) due to severe left ventricular (LV) systolic dysfunction in the Beta-blocker Evaluation of Survival Trial (BEST). BACKGROUND: Previous studies indicate that echocardiographic measurements of LV size and function, mitral deceleration time, and mitral regurgitation (MR) predict adverse outcomes in HF. However, complete quantitative echocardiograms evaluating all of these parameters have not been reported in a prospective randomized clinical trial in the era of modern HF therapy. METHODS: Complete echocardiograms were performed in 336 patients at 26 sites and analyzed by a core laboratory. A Cox proportional-hazards regression model was used to determine which echocardiographic variables predicted the primary end point of death or the secondary end point of death, HF hospitalization, or transplant. Significant variables were then entered into a multivariable model adjusted for clinical and demographic covariates. RESULTS: On multivariable analysis adjusted for clinical covariates, only LV end-diastolic volume index predicted death (events = 75), with a cut point of 120 ml/m(2). Three echocardiographic variables predicted the combined end point of death (events = 75), HF hospitalization (events = 97), and transplant (events = 9): LV end-diastolic volume index, mitral deceleration time, and the vena contracta width of MR. Optimal cut points for these variables were 120 ml/m(2), 150 ms, and 0.4 cm, respectively. CONCLUSIONS: Echocardiographic predictors of outcome in advanced HF include LV end-diastolic volume index, mitral deceleration time, and vena contracta width. These variables indicate that LV remodeling, increased LV stiffness, and MR are independent predictors of outcome in patients with advanced HF.

The use of beta-adrenergic receptor antagonists in the treatment of African Americans with heart failure.

The addition of beta-adrenergic antagonists to the treatment regimen for heart failure has validated the neurohormonal hypothesis and provided much-improved outcomes. This benefit had been in question for African Americans based on past experiences in the field of hypertension and worrisome data reported from the Beta Blocker Evaluation of Survival Trial. However, the totality of data now demonstrate that African Americans respond favorably to beta blockers and are capable of having the same outcomes in response to medical therapy for heart failure. There should be no reluctance, nor is there an appropriate rationale, to withhold beta-blocker therapy for heart failure to any patient with left ventricular dysfunction without an overt contraindication. The first prospective trial in African Americans with heart failure, the African American Heart Failure Trial (A-HeFT), is ongoing and provides additional insight into the best treatment strategies for this patient population.

Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST).

BACKGROUND: beta-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. METHODS AND RESULTS: Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r=-0.72, P<0.0001) and was the most significant multivariate predictor of change in LVEF (P=0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687+/-333 versus 420+/-246 pg/mL, P<0.05) and greater decrease in plasma norepinephrine in response to bucindolol (-249+/-171 versus -35+/-277 pg/mL, P<0.05). CONCLUSIONS: This study suggests a direct relationship between contractile reserve and improvement in LVEF with beta-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.