Faculty Bibliography

BACKGROUND: The clinical use of positive inotropic therapy at home in patients awaiting cardiac transplantation has not been reported since United Network for Organ Sharing (UNOS) regulations were changed to allow home infusions in Status 1B patients. METHODS: We observed 21 consecutive patients with UNOS 1B status during positive inotropic therapy at home. We used hemodynamic monitoring at the initiation of therapy to optimize dosing. We selected for home therapy patients with stable clinical status and improved functional capacity during inotropic treatment. Implantable cardioverter defibrillators were placed in all but 1 patient before discharge. RESULTS: Initial positive inotropic therapy included dobutamine in 12 patients (mean dose, 4.5 mcg/kg/min; range, 2.5-7.5 mcg/kg/min), milrinone in 8 patients (mean dose, 0.44 mcg/kg/min; range, 0.375-0.55 mcg/kg/min), and dopamine at a dose of 3 mcg/kg/min in 1 patient. Patients had improved functional capacity (New York Heart Association Class 3.7 +/- 0.1 to 2.4 +/- 0.2, p < 0.01), improved renal function (serum creatinine, 1.5 +/- 0.1 to 1.3 +/- 0.1, p < 0.01), improved resting hemodynamics, and decreased number of hospitalizations during positive inotropic infusion therapy when compared with pre-treatment baseline. Implantable cardioverter defibrillator discharges were infrequent (0.19 per 100 patient days of follow-up). Actuarial survival to transplantation at 6 and 12 months was 84%. CONCLUSIONS: Continuous positive inotropic therapy at home was safe and was associated with decreased health care costs in selected patients awaiting cardiac transplantation

Clinically unrecognized intravascular volume overload may contribute to worsening symptoms and disease progression in patients with chronic heart failure (CHF). The present study was undertaken to prospectively compare measured blood volume status (determined by radiolabeled albumin technique) with clinical and hemodynamic characteristics and patient outcomes in 43 nonedematous ambulatory patients with CHF. Blood volume analysis demonstrated that 2 subjects (5%) were hypovolemic (mean deviation from normal values -20 +/- 6%), 13 subjects (30%) were normovolemic (mean deviation from normal values -1 +/- 1%), and 28 subjects (65%) were hypervolemic (mean deviation from normal values +30 +/- 3%). Physical findings of congestion were infrequent and not associated with blood volume status. Increased blood volume was associated with increased pulmonary capillary wedge pressure (p = 0.01) and greatly increased risk of death or urgent cardiac transplantation during a median follow-up of 719 days (1-year event rate 39% vs 0%, p <0.01 by log-rank test). Systolic blood pressure was significantly lower in hypervolemic patients than in those with normovolemia or hypovolemia (107 +/- 2 vs 119 +/- 2 mm Hg, p = 0.008), and hypotension was independently associated with increased risk of hypervolemia in multivariate analysis (odds ratio 2.64 for a 10-mm Hg decrease in systolic blood pressure, 95% confidence interval 1.13 to 6.19, p = 0.025). These findings demonstrate that clinically unrecognized hypervolemia is frequently present in nonedematous patients with CHF and is associated with increased cardiac filling pressures and worse patient outcomes

Anemia is highly prevalent in patients with chronic heart failure (HF) and is associated with poor clinical outcomes. Multiple mechanisms contribute to anemia in chronic HF, and subnormal compensatory rise in endogenous erythropoietin levels in response to anemia is one contributory factor. Randomized trials with recombinant human erythropoietin therapy in anemic patients with chronic kidney disease and concomitant heart disease have demonstrated a reduction in left ventricular hypertrophy but variable effects on clinical outcome. Preliminary clinical trials in anemic patients with chronic HF demonstrate that erythropoietin therapy is well tolerated and associated with short-term clinical improvement. The optimum target hemoglobin, erythropoietic agent, and dosing regimen, and the role of iron supplementation in patients with chronic HF, are not known. Additional studies are needed to determine the safety and efficacy of long-term erythropoietic therapy in chronic HF patients

BACKGROUND: Outpatient positive inotropic support combined with implantation of an automatic implantable cardioverter defibrillator (AICD) may be used as a successful bridge to cardiac transplantation in patients with end-stage heart failure. A detailed comparative cost analysis of this outpatient strategy versus in-hospital care has not been previously reported. METHODS AND RESULTS: Twenty-one United Network for Organ Sharing 1B patients awaiting cardiac transplantation received continuous outpatient inotropic therapy for a total of 3070 patient-days. Daily costs for outpatient and in-hospital treatment were calculated. Nonparametric decision analysis was used to determine the strategy with greatest cost savings (immediate hospital discharge after AICD implantation versus in-hospital care). A threshold analysis was performed to test the robustness of the decision analysis model. The outpatient strategy realized an average savings of $71,300 to $120,500 per patient. Decision analysis showed that no fixed period of in-hospital monitoring was more cost-saving than immediate hospital discharge after AICD implantation. Threshold analysis revealed that AICD costs would need to exceed $82,000 (currently $62,000) or that the difference between the outpatient and the in-hospital costs would need to be < or = $475 per day for any other intermediate strategy to be considered cost-saving. CONCLUSION: Outpatient inotropic therapy combined with AICD implantation in selected patients awaiting cardiac transplantation is an effective cost-minimizing strategy

BACKGROUND: A synergistic interaction between the angiotensin II (Ang II) type 1 receptor and alpha1-adrenergic receptors has been described. We hypothesized that the nonselective beta-antagonist carvedilol, through its alpha1-adrenergic blocking properties, may modulate vascular reactivity to Ang II in patients with chronic heart failure (CHF). Accordingly, we compared the vasopressor response to infused Ang II in patients treated with carvedilol and metoprolol, a selective beta-antagonist. METHODS AND RESULTS: All subjects were treated with carvedilol or metoprolol for at least 3 months. ACE inhibitor therapy was standardized to enalapril 40 mg/d or the maximally tolerated dose. Exogenous Ang II was administered as sequential intravenous bolus injections (2.5 to 30 ng/kg) titrated to a rise in radial artery systolic pressure of > or =20 mm Hg. The dose of Ang II required to elicit a change of 20 mm Hg in radial artery systolic pressure (PD20) defined the vasopressor response to Ang II. Twenty subjects with CHF (mean left ventricular ejection fraction 28+/-9%, New York Heart Association class II [n=13] and III [n=7]) were studied. There was no correlation between plasma Ang II levels and PD20. However, the PD20 was significantly higher in patients treated with carvedilol than in those treated with metoprolol (20 [range 2.5 to 30] versus 5 [range 2.5 to 10] ng/kg, P=0.019). CONCLUSIONS: The vasopressor response to Ang II infusion in patients treated with carvedilol was significantly lower than in patients treated with metoprolol. Whether this is due to the alpha1-adrenergic blocking or other ancillary properties of carvedilol warrants further investigation

BACKGROUND: Anemia frequently occurs in chronic heart failure (CHF) patients and is associated with a poor prognosis. A low hematocrit may result from an increased plasma volume (hemodilution) or from reduced red blood cell volume (true anemia). The prevalence and clinical outcome of CHF patients with hemodilution is unknown. METHODS AND RESULTS: The prevalence of anemia and its effect on outcome was examined in 196 patients with CHF. The prevalence of hemodilution was assessed in a subset of 37 ambulatory anemic patients with I131-tagged albumin to measure red blood cell and plasma volume. Clinical outcome was monitored. Sixty-one percent of the CHF patients were anemic. The prevalence of anemia increased from 33% in patients with New York Heart Association class II heart failure to 68% in class IV CHF patients. Survival was reduced in anemic patients compared with patients with a normal hematocrit (P<0.05). In the subset of 37 anemic patients, 17 patients (46%) had hemodilution and 20 patients (54%) had a true anemia. Nine patients with hemodilution died or underwent urgent transplant compared with 4 patients in the true anemia group (P<0.04). CONCLUSION: Hemodilution is common in CHF patients. Anemia is associated with a poor prognosis in CHF. Patients with hemodilution tend to do worse than patients with true anemia, which suggests that volume overload may be an important mechanism contributing to the poor outcome in anemic CHF patients

BACKGROUND: Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF. METHODS AND RESULTS: Twenty-six anemic patients aged 57+/-11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [VO2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of VO2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P<0.05). There were significant increases in hemoglobin (11.0+/-0.5 to 14.3+/-1.0 g/dL, P<0.05), peak VO2 (11.0+/-1.8 to 12.7+/-2.8 mL. min(-1) x kg(-1), P<0.05) and exercise duration (590+/-107 to 657+/-119 s, P<0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups. CONCLUSION: EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in VO2 is increased oxygen delivery from increased hemoglobin concentration

Endothelial dysfunction is associated with impairment of aerobic capacity in patients with heart failure and may play a role in the progression of disease. Impaired endothelium-dependent vasodilation in patients with heart failure can be attributed to decreased bioavailability of nitric oxide and attenuated responses to nitric oxide in vascular smooth muscle. Impaired vasodilation in response to nitric oxide derived from vascular endothelium or organic nitrates in vascular smooth muscle may be related in part to increased degradation of the second messenger cyclic guanosine monophosphate by type 5 phosphodiesterase. Sildenafil, a specific type 5 phosphodiesterase inhibitor currently approved for the treatment of erectile dysfunction, has been shown to acutely enhance endothelium-dependent vasodilation in patients with heart failure. Further studies are warranted to characterize the safety and efficacy of type 5 phosphodiesterase inhibition in the treatment of chronic heart failure

OBJECTIVE: To characterise the effects of acetylcholinesterase inhibition with pyridostigmine on parasympathetic tone in patients with chronic heart failure (CHF). DESIGN: Prospective randomised, double blind crossover trial. SETTING: University hospital outpatient heart failure clinic. PATIENTS: 20 ambulatory subjects with stable CHF (mean age 55 years, mean ejection fraction 24%). INTERVENTIONS: Oral administration of a single dose of pyridostigmine 30 mg and matching placebo on separate days. MAIN OUTCOME MEASURES: Heart rate recovery at one minute and three minutes after completion of maximal exercise. RESULTS: Heart rate recovery at one minute after exercise was significantly greater after administration of pyridostigmine than after administration of placebo (mean (SEM) 27.4 (3.2) beats/min v 22.4 (2.4) beats/min, p < 0.01). Heart rate recovery at three minutes after exercise did not differ after administration of pyridostigmine and placebo (mean (SEM) 44.4 (3.9) beats/min v 41.8 (3.6) beats/min, NS). Peak heart rate, peak oxygen uptake, peak respiratory exchange ratio, plasma noradrenaline (norepinephrine) concentrations, and plasma brain natriuretic peptide concentrations did not differ after administration of pyridostigmine and placebo. CONCLUSIONS: Acetylcholinesterase inhibition with pyridostigmine increased heart rate recovery at one minute but not at three minutes after exercise. A specific effect of pyridostigmine on heart rate one minute after exercise suggests that pyridostigmine augments parasympathetic tone in patients with CHF