Measurement of Galectin-3 with the ARCHITECT assay: Clinical validity and cost-effectiveness in patients with heart failure.

OBJECTIVES: Galectin-3 (Gal-3) testing is emerging as a valuable tool for the prognosis of heart failure (HF). Our objectives were to determine the clinical validity and cost-effectiveness of the recently developed ARCHITECT Gal-3 automated immunoassay. DESIGN AND METHODS: Gal-3 levels were measured in HF patients with reduced left ventricular ejection fraction with the ARCHITECT i2000SR Gal-3 assay as well as with the reference Gal-3 ELISA assay. The relationship between Gal-3 levels determined with the automated assay and HF severity as well as its predictive value for long-term cardiovascular death were evaluated. The impact of Gal-3 testing on the diagnostic related group (DRG) based reimbursement was also estimated. RESULTS: Gal-3 levels measured with the ARCHITECT assay were related to the severity of HF based on New York Heart Association functional classes (p<0.001) and were also significantly and positively correlated to BNP concentrations (r=0.35, p<0.001). Gal-3 values higher than 19.2 ng/mL were predictive of long-term cardiovascular death in patients with systolic HF and also provided incremental prognostic information to BNP testing. In addition, Gal-3 testing was estimated to save DRG in comparison to standard of care. CONCLUSIONS: Our results demonstrated the clinical validity of the ARCHITECT Gal-3 automated immunoassay for the risk stratification of HF patients. The automation of Gal-3 testing was also cost-effective and might help to preserve hospital budget.

Galectin-3 testing: validity of a novel automated assay in heart failure patients with reduced ejection fraction.

Circulating levels of galectin-3 (Gal-3), a marker of cardiac fibrosis and remodeling, contribute to the risk stratification of patients with heart failure (HF). The aim of our study was to determine the analytical validity and clinical validity of a novel automated Gal-3 assay in HF patients with reduced ejection fraction. We showed an excellent agreement between the VIDAS® Gal-3 automated assay and the ELISA reference method (r=0.90, p<0.001) and a mean difference of -1.3 ng/mL was observed on the Bland and Altman plot. Gal-3 levels measured with the VIDAS® assay were significantly related to NYHA functional classes (p<0.001) and mean Gal-3 levels were 13.8 ng/mL in NYHA II patients, 17.7 ng/mL in NYHA III and 19.6 ng/mL in NYHA IV. Furthermore, our results showed that Gal-3 levels measured with the VIDAS® assay were not only predictive of long-term cardiovascular death in patients with systolic HF but have also provided added value to natriuretic peptide testing in multimarker strategies. Therefore, our data are also supporting the clinical validity of the Gal-3 automated assay.

What is the phenotype of patients with gastrointestinal intolerance to metformin?

BACKGROUND: A substantial minority of type 2 diabetes mellitus (T2DM) patients treated with metformin develop severe gastrointestinal (GI) symptoms leading to drug discontinuation, depriving them of the potentially cardioprotective pleiotropic effects of this first-line oral agent. At present, it is unclear whether treating diabetes without being able to ever use metformin alters cardiovascular outcomes. PATIENTS AND METHODS: From a population of 773 consecutive T2DM outpatients, the cardiometabolic phenotypes of 83 patients who discontinued metformin due to GI intolerance (Met-Intol cases) were compared with those of 332 age- and gender-matched metformin-tolerant (Met-Tol) controls, amounting to a case: control ratio of 1:4. RESULTS: Mean age (SD) was 70 (13) (male:female: 46:54). Metformin intolerance was associated with a reduced prevalence of macroangiopathy (P=0.0486), mainly due to a lower prevalence of CAD (-34%; P=0.0374). Met-Intol cases more often belonged to blood group A and subgroup A Rh+, with 50% and 66% relative increases (P=0.0039 and P=0.0005), respectively. There were twice as many non-right-handers among the Met-Intol (18% vs. 9%; P=0.0262), and this group also had significantly higher serum ferritin and LDL cholesterol levels. Statins/fibrates were used by 66%/19% of Met-Tol vs. 48%/18% of Met-Intol (P=0.0051 for statins). On the other hand, there were no differences between groups as regards smoking, diabetes duration, HbA1c, BMI, blood pressure, waist size, fat mass, visceral fat, liver steatosis, the metabolic syndrome, eGFR, albuminuria, erectile dysfunction and microangiopathy. CONCLUSION: Intolerance to metformin represents an unforeseen phenotype in T2DM patients characterized by a low rate of ischaemic heart disease, left-handedness, ABO group imbalance and an iron load.

Comparison between intact and bioactive parathyroid hormone assays in patients with severe heart failure.

OBJECTIVES: Parathyroid hormone (PTH) is a major systemic calcium-regulating hormone. Recent evidence has suggested that measurement of PTH might provide complementary information for the diagnosis and risk stratification of patients with heart failure (HF). The aim of our study was to compare intact and bioactive PTH assays in patients with severe heart failure. DESIGN AND METHODS: The following measurements were carried out in blood samples from 73 patients with severe heart failure: bioactive PTH (1-84) assay, intact PTH assay, non-PTH (1-84), 25-hydroxyvitamin D, B-type natriuretic peptide (BNP), N-terminal proBNP (Nt-proBNP), Galectin-3 and high sensitive troponin T (hsTnT). RESULTS: The correlation between intact and bioactive PTH assays was very high in HF patients. However, the bioactive PTH concentrations were lower than those measured with the intact assay. Intact and bioactive PTH as well as non-PTH (1-84) was significantly and positively correlated to BNP, Nt-proBNP, and galectin-3 but not to hsTnT. The strongest relationships with these cardiac biomarkers and with cardiovascular death were observed with the bioactive PTH assay. CONCLUSIONS: The PTH concentrations obtained with intact and bioactive assays are not comparable in patients with severe HF. The specificity of PTH assays might therefore impact on the potential diagnosis and prognosis values of PTH testing in patients with heart failure.

Increased circulating concentrations of bioactive PTH 1-84 in patients with heart failure.

BACKGROUND: PTH is related to left ventricular hypertrophy and its circulating levels are associated with worse prognosis in patients with heart failure (HF). The objectives of our study were to measure the circulating levels of bioactive PTH 1-84 through third-generation assay in HF patients, to determine their association with the disease severity as well as their relation with recognized biomarkers of HF worsening and prognosis. METHODS: PTH 1-84 concentrations were determined in 76 HF patients and in 49 healthy volunteers. Circulating levels of amino-terminal proatrial natriuretic peptide (Nt-proANP), B-type natriuretic peptide (BNP), Nt-proBNP, proBNP, and big endothelin-1 (Big ET-1) were also measured. RESULTS: HF patients had in- creased PTH 1-84 levels in comparison to controls. A significant increase of the PTH 1-84 circulating concentrations was observed according to the New York Heart Association functional classes. PTH 1-84 circulating concentrations were also significantly correlated with Nt-proANP, BNP, Nt-proBNP, proBNP, and Big ET-1. CONCLUSIONS: PTH 1-84 circulating levels are significantly increased in HF patients in comparison to healthy individuals. Our study has also demonstrated that circulating concentrations of bioactive PTH are related to HF severity and well-established biomarkers of the worsening of the disease.

Statin therapy and cataract in type 2 diabetes.

BACKGROUND: It was recently reported that the prolonged use of statins may predispose to incident cataract in the general population. Cataract is a frequent comorbidity of diabetes, and statins are widely prescribed in patients with type 2 diabetes (T2D) both for primary and secondary cardiovascular prevention. For this reason, this study aimed to assess whether or not the use of statins was associated with an increased prevalence of cataract in such a high-risk population and, conversely, whether or not there was greater usage of statins, or any other lipid-lowering drugs, in T2D patients with cataract. PATIENTS AND METHODS: This was a cross-sectional analysis of 780 T2D outpatients, with a mean age (± 1 SD) of 64 ± 12 years and diabetes duration of 13 ± 9 years. Diabetic retinopathy (DR) was found in 23%, and cataract was diagnosed in 16.8% (n=131). Age and diabetes duration of the patients with cataract were significantly higher than those of patients without cataract (n = 649): 75 ± 9 vs 62 ± 11 years, and 20 ± 11 vs 12 ± 8 years, respectively (both P < 0.0001). HbA(1c) was non-significantly higher in the cataract group: 7.75 ± 1.55% vs 7.57 ± 1.49% (NS). RESULTS: Statins, fibrates and/or ezetimibe use did not differ between patients with and without cataract, nor was cataract prevalence higher in statin users (n=435) vs non-users (n = 345). Statin use in patients with cataract was not higher than in cataract-free subgroups with mean age (n=218) or with both mean age and diabetes duration (n = 161) similar to those of patients with cataract. CONCLUSION: In this cross-sectional analysis of a large diabetic population at very high risk of both DR and cataract, chronic therapy with statins was not cataractogenic, and the presence of cataract was not associated with more statin or other lipid-lowering drug use. This suggests that the benefits of statin therapy in T2D may far outweigh any potential ocular drawbacks as a side effect which, in any case, were not supported by our findings.

Do high ferritin levels confer lower cardiovascular risk in men with Type 2 diabetes?

AIMS: High ferritin levels are associated with insulin resistance and liver steatosis, both thought of as emerging cardiovascular risk factors. The association between ferritin and cardiovascular disease is poorly documented in cardiometabolic states with higher cardiovascular risk, such as diabetes and metabolic syndrome. We therefore characterized a cohort of males with Type 2 diabetes mellitus (T2DM) according to ferritin levels and prevalent macroangiopathy. METHODS: The presence of overall macroangiopathy, peripheral and/or coronary artery disease was documented in 424 consecutive T2DM males, who were divided according to ferritin quartiles (Q) as follows: QI-III, normal ferritin (NF; n=318), mean+/-1 sd ferritin 133+/-72 ng/ml; and QIV patients, high ferritin (HF; n=106), ferritin 480+/-228 ng/ml. RESULTS: Age, age at diabetes diagnosis, smoking, ethanol intake, body mass index, waist circumference, blood pressure and presence of metabolic syndrome did not differ between groups. However, the prevalence of macroangiopathy was unexpectedly much lower in patients with high ferritin, as follows: 25% vs. 43% for overall macroangiopathy; 7% vs. 16% for peripheral artery disease; and 16% vs. 31% for coronary artery disease (P=0.0009, P=0.0140 and P=0.0035, respectively, vs. NF patients). Insulin resistance index and prevalence of liver steatosis were higher in HF compared with NF patients as follows: 2.17% vs. 1.89% and 78% vs. 64% (P=0.0345 and P=0.0059, respectively). Liver enzymes (aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase) were significantly higher in HF, by 33%, 42% and 72%, respectively (all P<0.0002), suggesting a higher prevalence of steatohepatitis. Glycated haemoglobin, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides, urate, high-sensitivity C-reactive protein and albuminuria were not different between groups. CONCLUSIONS: Our results demonstrate that T2DM males with high ferritin levels exhibit a markedly decreased prevalence of macroangiopathy, despite more severe insulin resistance and higher markers of steatohepatitis. High ferritin levels and/or steatosis may thus paradoxically confer a lowered cardiovascular risk in diabetic males.

Circulating levels of stress associated peptide Urocortin in heart failure patients.

The available data suggest that Urocortin (UCN), a cardioprotective and vasoactive peptide known from fish neuroendocrinology, is involved in cardiac regulation. The aim of this study was to determine UCN plasma concentrations in patients with heart failure (HF). Plasma concentrations of UCN, measured in 42 fully treated HF patients. UCN, were determined using a specific ELISA assay after acidic extraction with Sep-Pak C18 columns. Circulating levels of other neurohormones Nt-proBNP, Nt-proANP and Big ET-1 were also determined. Reference values were obtained from 20 healthy age- and sex-matched subjects. In comparison with controls, UCN plasma concentrations (geometric mean [95% CI]) were significantly increased in HF patients (88 pmol/L [75-105] vs 46 [39-54], p<0.001). As expected, the other neurohormones were also significantly increased in HF patients (Nt-proBNP: 3501 pg/ml [2356-5202] vs 35 [24-51], Nt-proANP: 5498 pg/ml [4336-6971] vs 324 [255-411] and Big ET-1: 15.8 pg/ml [13.6-18.4] vs 5.9 [5.2-6.8]; p<0.01 for all vs controls). No significant correlation was observed between UCN and the other HF biomarkers. Our results demonstrate that plasma concentrations of UCN are significantly increased in patients with HF and that UCN may participate in the neurohumoral response of HF.

Handedness, insulin sensitivity and pancreatic B-cell function in Type 2 diabetes.

BACKGROUND: Laterality is associated with various health conditions. No study has addressed the influence of handedness on Type 2 diabetes mellitus (T2DM) phenotype, including glucose homeostasis, glucose-lowering therapies and metabolic control. METHODS: Five hundred and seventy-six consecutive adult T2DM outpatients underwent homeostasis model assessment (HOMA) of pancreatic B-cell function (B), insulin sensitivity (S), hyperbolic product (B x S) and age-standardized B x S deficit. Right-handed patients (87.5%; RH; n = 504) had similar age, gender, diabetes duration and education than non-right-handed patients (12.5%; non-RH; n = 72). RESULTS: Non-RH were more insulin-sensitive: 66% (39%) vs. 52% (36%) [mean (1 sd); P = 0.0024] and had significantly higher B x S and lower age-adjusted B x S deficit: 35% (20%) vs. 26% (17%) and 1.08% (0.40%) vs. 1.32% (0.55%)/year (non-RH; P = 0.0005 and P < 0.0001, respectively). CONCLUSIONS: Non-right-handed T2DM patients are more insulin-sensitive, have higher hyperbolic product and less age-standardized B x S deficit. These may modulate glucose-lowering therapy requirements and glycaemic control.

Circulating urotensin II levels in moderate to severe congestive heart failure: its relations with myocardial function and well established neurohormonal markers.

Urotensin II (UII) is a potent vasoactive cyclic peptide thought to play a role in myocardial hypertrophy and remodelling. We therefore determined UII plasma levels in congestive heart failure (CHF) patients and its relationship with the severity of the disease and well-established markers of left ventricular function. UII was significantly higher in CHF patients (n = 57) than in controls (n = 48) [geometric mean (pg/ml), 95% PI: 1.32 (0.67-2.59) versus 0.84 (0.31-1.61), p < 0.0001], was related to the functional class of the disease and correlated negatively with left ventricular ejection fraction (r = -0.316, P = 0.016). Furthermore, UII correlated significantly with Big-ET1 (r = 0.32, p = 0.03), BNP (r = 0.42, p = 0.005) but poorly with Nt-proANP (r = 0.28, p = 0.07). Our results suggest that UII could play a role in worsening the course of congestive heart failure and is associated with established markers of cardiovascular dysfunction.

Cardiac and hemodynamic effects of intravenous dofetilide in patients with heart failure.

This study assesses the effects of dofetilide, a new selective Ikr blocker with class III properties, on left ventricular function and hemodynamics of heart failure and compares these effects with those of placebo and amiodarone. Because available antiarrhythmic drugs may depress myocardial performance, an invasive hemodynamic study was performed to assess the safety of this agent. Hemodynamic and angiographic data were obtained at baseline and after 30 minutes of double-blind infusion of dofetilide (8 microg/kg; n = 12), placebo (n = 12), or amiodarone (5 mg/kg; n = 6) in heart failure patients (New York Heart Association class II or III, ejection fraction <35%). Intravenous dofetilide preserved the inotropic indexes and the end-systolic volume index despite a slight but significant decrease in heart rate, whereas intravenous amiodarone increased end-diastolic and end-systolic volume indexes. Amiodarone induced a negative inotropic effect illustrated by a rightward shift of the pressure-volume loop and a reduction in pressure-derived indexes of contractility. Intravenous dofetilide acutely prolonged QT interval more than intravenous amiodarone; however, dofetilide did not slow the overall relaxation rate and reduced QT dispersion. In an acute setting, compared with intravenous amiodarone, intravenous dofetilide preserves cardiac function offering a hemodynamic advantage to treat arrhythmias in patients with impaired left ventricular function.

Direct comparison between endothelin-1, N-terminal proatrial natriuretic factor, and brain natriuretic peptide as prognostic markers of survival in congestive heart failure.

BACKGROUND: Endothelin-1 (ET-1) and cardiac natriuretic peptide plasma concentrations have prognostic significance in congestive heart failure (CHF). However, their respective prognostic values in this setting have never been directly compared. METHODS AND RESULTS: We studied the prognostic performances of ET-1, N-terminal proatrial natriuretic factor (N-proANF), and brain natriuretic peptide (BNP) to predict the long-term cardiac mortality in fully treated patients with CHF. Peripheral plasma concentrations of the 3 peptides were measured in 109 patients (left ventricular ejection fraction [LVEF] < 35%) in New York Heart Association (NYHA) functional classes II (n = 65) or III to IV (n = 44). The outcome of the patients was evaluated 3 years after the beginning of the study, and a Cox regression model was used to identify predictors of death. Plasma concentrations of the 3 peptides increased with the severity of heart failure. By univariate analysis, 6 parameters were significantly associated with death during follow-up: ET-1 level, NYHA classes III to IV, N-proANF level, BNP level, LVEF, and age (all P < .01). By multivariate analysis, only ET-1 level and, to a lesser extent, N-proANF level contributed significantly and independently to risk stratification (chi2 = 53.4 and 12.8; P < .0001 and P < .001, respectively). CONCLUSION: In a group of patients in whom the vast majority were administered angiotensin-converting enzyme inhibitor therapy, plasma ET-1 and N-proANF concentrations identify better than several clinical markers a very high-risk group, fairly amenable to heart transplantation or new therapies.

Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary artery disease on cardiac hormonal activation.

BACKGROUND: Cardiac natriuretic peptides are activated in heart failure. However, their diagnostic and prognostic values have not been compared under the routine conditions of an outpatient practice. METHODS: We studied the diagnostic and prognostic value of plasma N- and C-terminal peptides of the atrial natriuretic factor prohormone (N-proANF and ANF respectively) and brain natriuretic peptide (BNP) to evaluate the severity of congestive heart failure (CHF) as reflected by the New York Heart Association (NYHA) classification and to predict its 2-year mortality. Peripheral plasma concentrations of the three natriuretic peptides were measured in 27 normal subjects (CTR), in 32 patients with coronary artery disease (CAD) and normal left ventricular ejection fraction and in 101 patients with chronic CHF in functional classes I and II (n = 61) or III and IV (n = 40). RESULTS: Plasma concentrations of the three peptides increased in the presence of CHF in relation to its severity (P < 0.01). BNP was unable to distinguish CTR from CAD, just as ANF could not differentiate CAD from CHF I-II; only N-proANF displayed a significant and continuous increase from CTR to CAD, CHF I-II and III-IV. Receiver-operating characteristic curves showed better evaluation of the degree of CHF by BNP than by ANF or ejection fraction (P < 0.05). Assessment of the 2-year prognosis revealed that N-proANF and BNP were the best independent predictors of outcome after the NYHA classification. These peptides identify a very high-mortality group. CONCLUSION: Plasma N-proANF and BNP concentrations are good indicators of the severity and prognosis of CHF in an outpatient practice. CAD does not stimulate BNP as long as ventricular dysfunction is not present, although increased N-proANF levels in this setting suggest an early humoral activation.

Dose-related hemodynamic and electrocardiographic effects of the calcium promoter BAY y 5959 in the presence or absence of congestive heart failure.

OBJECTIVES: The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure. BACKGROUND: There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes. METHODS: Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 microg/kg body weight per min. RESULTS: In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 microg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 microg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 microg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 microg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses. CONCLUSIONS: BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response--combining bradycardia, reduced preload and improved cardiac output--appeared to be achieved at a dose of approximately 2.0 microg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.

Hemodynamic and cardiac effects of the selective T-type and L-type calcium channel blocking agent mibefradil in patients with varying degrees of left ventricular systolic dysfunction.

OBJECTIVES: This study sought to assess the hemodynamic and cardiac effects of two dose levels of mibefradil in patients with varying degrees of ischemic left ventricular dysfunction. BACKGROUND: Mibefradil is a new, selective T-type and L-type calcium channel blocking agent. Because L-type channel blockade may depress myocardial performance, an invasive hemodynamic study was performed to assess the safety of this agent. METHODS: We performed an open label study, examining the effects of two intravenous doses of mibefradil, selected to produce plasma levels comparable to those measured after oral administration of 50 mg (dose 1: 400 ng/ml) or 100 mg (dose 2: 800 ng/ml) of the drug. Variables studied included the indexes of left ventricular function and neurohormone levels. Patients were stratified according to ejection fraction (EF) (> or = 40%, n = 26; < 40%, n = 24) and the presence (n = 15) or absence (n = 35) of heart failure. RESULTS: In patients with preserved systolic function, dose 1 had no clinically significant hemodynamic effects, but dose 2 decreased mean aortic pressure and systemic vascular resistance (-8.5 mm Hg, -12%, both p < 0.01) and also reduced end-systolic stress and volume, thus improving EF (52% to 58%, p < 0.01). Heart rate tended to decrease. In patients with depressed EF, heart rate decreased significantly with both doses. The effects of dose 1 mimicked those observed after dose 2 in patients with preserved EF. Dose 2 (plasma levels 1,052 +/- 284 ng/ml) still decreased left ventricular systolic wall stress and improved EF (24.0% to 28.5%, p < 0.05) but also significantly depressed the maximal first derivative of left ventricular pressure. Examination of individual pressure-volume loops in two patients with heart failure showed a clear rightward shift of the loop despite a decrease in systolic pressure, suggesting negative inotropy. Neurohormone levels were unchanged at both dose levels and in all subgroups. CONCLUSIONS: Intravenous mibefradil was well tolerated and produced an overall favorable cardiovascular response. However, high plasma concentrations might produce myocardial depression in patients with heart failure, and caution should be exerted in this setting.

Medium-term effects of beta-blockade on left ventricular mechanics: a double-blind, placebo-controlled comparison of nebivolol and atenolol in patients with ischemic left ventricular dysfunction.

The aim of this study was to compare the effects on left ventricular function and exercise tolerance of a selective beta-antagonist (atenolol) with those of another selective beta 1-antagonist with vasodilator properties (nebivolol) in patients with ischemic left ventricular dysfunction but no overt congestive heart failure. Beta blockers are widely used in ischemic heart disease, but their effects on left ventricular mechanics and exercise tolerance are poorly defined in the subgroup of patients with significant systolic dysfunction but without clinical evidence of ischemia or congestive heart failure. Angiographic and symptom-limited exercise data were obtained at baseline and after an 8-10-week double-blind treatment with placebo (n = 10), 50 mg atenolol daily (n = 10), or 2.5 mg (n = 10) or 5 mg (n = 10) nebivolol daily. When compared to placebo, both atenolol and nebivolol reduced resting heart rate and improved left ventricular ejection fraction (from 33.9 to 39.2% with atenolol and from 36.5 to 40.8% with nebivolol, both P < .05) while lowering mean systolic wall stress. Only nebivolol, however, produced a parallel downward shift of the pressure-volume relationship during early diastolic filling and improved the early peak filling rate when compared to placebo (+ 10%, P < .05). When compared to baseline, maximal exercise duration increased by 7 and 13 seconds with placebo and atenolol, respectively (both NS vs baseline), and increased by 44 seconds with nebivolol (P = .0077 vs baseline). Both atenolol and nebivolol decreased maximal exercise heart rate; the reduction was more pronounced with atenolol. Prolonged beta 1-adrenoceptor blockade leads to a significant increase in left ventricular ejection fraction in patients with ischemic left ventricular dysfunction. The dissociation between the changes in resting left ventricular function and the changes in exercise duration suggests that in this clinical setting, the changes in systolic function may have less impact on functional capacity than an improvement in diastolic distensibility during the rapid filling phase.

Contractile state is the major determinant of functional outcome in patients with left ventricular dysfunction treated with enalapril.

Large-scale drug trials have focused primarily on mortality and morbidity and less on the functional state of the myocardium. A model was developed to assess myocardial contractile state in patients with left ventricular (LV) dysfunction and to address the questions of differences in function between patients with and without overt heart failure, effects of enalapril, and best predictors of functional outcome. Pressure-angiographic data were obtained from 16 patients with overt heart failure and 47 without heart failure. Repeat studies were conducted in 41 patients following 1 year's treatment with enalapril or placebo. Left ventricular silhouettes were divided into 18 segments to estimate regional ejection fraction, wall stress and myocardial damage (% myocardial damage). Contractile state was assessed and ranked by ejection rate-preload-afterload relationships and by a score method based on 10 myocardial and ventricular function parameters. End-diastolic and end-systolic volumes (EDV, ESV) were significantly greater (P < 0.001), ejection fraction (EF) lower (P < 0.009), % myocardial damage greater (P < 0.008) and contractile state more depressed in patients with overt heart failure. Changes in EDV and ESV (delta placebo vs delta enalapril) were significant (delta EDV, P < 0.003; delta ESV, P < 0.014). Directional shifts in the diastolic pressure-volume relationships with enalapril or placebo depended primarily on the basal contractile state and diastolic volume range. The best single predictors of post-treatment EF were the score index (a surrogate parameter for the contractile state) and ESV. Added benefits of enalapril include the prevention of further dilatation in patients with less depressed contractile state and delay in the onset of heart failure. Asymptomatic patients with LV dysfunction should also be considered for angiotensin converting enzyme (ACE) inhibitor therapy.