J. Herbert Patterson

HFSA Guidelines for Management of Patients With Heart Failure Caused by Left Ventricular Systolic Dysfunction—Pharmacological Approaches

A bar code communication system and method uses a bar code reader to scan a bar code to develop an audible signal that is acoustically coupled to a telephone line. The signal on the telephone line is received by a called station, decoded and the content of the bar code reported back to the calling party, using voice synthesis, for confirmation. The received signal may then be used to control a VCR or other external apparatus.

Vasopressin: a new target for the treatment of heart failure.

BACKGROUND Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. METHODS Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. RESULTS Through activation of V(1a) and V(2) receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V(2) and dual V(1a)/V(2) receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V(1a) receptor antagonism requires further investigation. CONCLUSIONS Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.

Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy.

OBJECTIVE Large variability exists in the improvement in left ventricular (LV) function from beta-blocker treatment. We hypothesized that polymorphisms at codon 389 (Arg389Gly) and 49 (Ser49Gly) in the beta1-adrenergic receptor (AR) gene were associated with LV reverse remodeling changes in response to beta-blocker therapy among heart failure patients. METHODS We prospectively enrolled 61 beta-blocker naive patients with systolic heart failure. Patients underwent baseline echocardiography followed by metoprolol CR/XL. The dose was doubled on a biweekly basis up to 200 mg/day or attainment of maximum tolerated dose. Echocardiography was repeated after the patient received the target or highest tolerated dose for 3 months. RESULTS Among patients with the Arg389Arg genotype, ejection fraction (EF) increased from 23+/-5 to 29+/-10 (P=0.008). Gly389 carriers did not demonstrate any significant change in EF (22+/-9 to 23+/-11; P=0.45). There was a significant between-group difference in EF by genotype (P=0.04). The Arg389Arg genotype was also associated with significantly greater reductions in LV end-diastolic and end-systolic diameters compared to Gly389 carriers. Patients with the Gly49 variant also had a significantly greater reduction in LV end-diastolic diameter compared to Ser49 homozygotes. Multiple regression analysis modeling revealed that the codon 389 polymorphism was a significant predictor of an improvement in EF and both codon 49 and 389 polymorphisms were significant predictors of final LV end-diastolic diameter. CONCLUSIONS Heart failure patients with the Arg389Arg genotype and Gly49 carriers had greater improvements in LV remodeling from beta-blocker treatment.

Clinical benefits of low serum digoxin concentrations in heart failure

OBJECTIVES We sought to determine whether there was a relationship between serum digoxin concentration (SDC), including SDCs typically regarded as low, and clinical efficacy related to digoxin in patients with symptomatic left ventricular dysfunction. BACKGROUND Digitalis glycosides have been used for 200 years in the treatment of heart failure (HF), but the SDC required for optimal clinical efficacy and acceptable toxicity remains controversial. METHODS This relationship was investigated by utilizing data from two randomized, double-blinded, placebo-controlled, digoxin-withdrawal trials: the Prospective Randomized study Of Ventricular failure and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin on Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Major end points were worsening HF, change in left ventricular ejection fraction and treadmill time after randomization. The primary analysis investigated the relationship between SDC at randomization and these end points. A secondary categorical analysis compared these end points in patients who discontinued digoxin versus patients who continued digoxin and had low (0.5 to 0.9 ng/ml), moderate (0.9 to 1.2 ng/ml) or high (>1.2 ng/ml) SDCs at randomization. RESULTS Multiple regression analysis failed to find a relationship between randomization SDC, considered as a continuous variable, and any study end point (all p > 0.236). Multivariable Cox analysis found that the risk of worsening HF was significantly less (all p < 0.02) for patients in any category of SDC who continued digoxin, as compared with patients withdrawn from digoxin. Specifically, patients in the low SDC category were significantly less likely than placebo patients to experience worsening HF during follow-up (p = 0.018). CONCLUSIONS The beneficial effects of digoxin on common clinical end points in patients with HF were similar, regardless of SDC.

β‐adrenergic Receptor Polymorphisms and Responses during Titration of Metoprolol Controlled Release/extended Release in Heart Failure

β‐Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate β‐blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the β1‐adrenergic receptor would be associated with differences in initial tolerability of β‐blocker therapy in patients with heart failure. We also tested whether polymorphisms in the β2‐adrenergic receptor, G‐protein αs subunit (Gsα), and cytochrome P450 (CYP) 2D6 genes or S‐metoprolol plasma concentrations were associated with β‐blocker tolerability.

Synergistic polymorphisms of β1 and α2C-adrenergic receptors and the influence on left ventricular ejection fraction response to β-blocker therapy in heart failure

Objectives The Arg389Gly polymorphism (Arg389Gly) in the &bgr;1-adrenergic receptor gene (ADRB1) has been associated with improvement in left-ventricular remodeling with &bgr;-blocker treatment. One study of risk for heart failure suggested a synergistic effect of ADRB1 Arg389Gly with the insertion/deletion polymorphism in the &agr;2C-adrenergic receptor gene (ADRA2C). We tested whether the ADRA2C insertion/deletion polymorphism was associated with &bgr;-blocker response in heart failure, either alone or in combination with the ADRB1Arg389Gly polymorphism. Methods Fifty-four &bgr;-blocker naive heart failure patients underwent echocardiography before and after 5–6 months of metoprolol CR/XL therapy. Multivariant linear regression modeling was performed to assess the impact of genotypes and other variables on changes in left-ventricular function in response to metoprolol therapy. Results Deletion carriers had a significantly greater negative chronotropic response. Predictors of the end of study ejection fraction were baseline ejection fraction, deletion carrier status and Arg389Arg genotype. Patients with Arg389Arg/Del-carrier status showed the greatest ejection fraction increase with metoprolol CR/XL. Adjusting for baseline ejection fraction, final S-metoprolol plasma concentration and race, final ejection fraction in patients with this genotype combination was significantly higher than all other genotype combination groups. Conclusion ADRB1 and ADRA2C polymorphisms synergistically influence the ejection fraction response to &bgr;-blocker therapy of heart failure patients.

Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers

Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the pharmacokinetics and pharmacologic response of losartan and E3174.

The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady‐state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open‐label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that flvastatin did not significantly change the steady‐state AUC0–24 or half‐life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.

Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/- 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double‐blind, two‐period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12‐hour carvedilol dosing interval, and the concentrations of the R(+) and S(−) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (± SD) R(+) enantiomer AUC0–12 (522 ± 413 vs. 927 ± 506 ng•h/mL, p = 0.01) and a nonsignificant increase in S(−) enantiomer AUC (244 ± 185 vs. 330 ±179 ng•h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 ± 7.2 vs. 4.5 ± 2.2 mL/min/kg; S(−): 22.5 ± 12.3 vs. 12.6 ± 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(−) enantiomer. However, this interaction was of little clinical significance in our sample population.