Roger M. Mills

Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure : A randomized, double-blind, placebo-controlled clinical trial

OBJECTIVESnThe goal of this study was to further define the role of nesiritide (human b-type natriuretic peptide) in the therapy of decompensated heart failure (HF) by assessing the hemodynamic effects of three doses (0.015, 0.03 and 0.06 microg/kg/min) administered by continuous intravenous (IV) infusion over 24 h as compared with placebo.nnnBACKGROUNDnPrevious studies have shown beneficial hemodynamic, neurohormonal and renal effects of bolus dose and 6-h infusion administration of nesiritide in HF patients. Longer term safety and efficacy have not been studied.nnnMETHODSnThis randomized, double-blind, placebo-controlled multicenter trial enrolled subjects with symptomatic HF and systolic dysfunction (left ventricular ejection fraction < or =35%). Central hemodynamics were assessed at baseline, during a 24-h IV infusion and for 4 h postinfusion.nnnRESULTSnOne hundred three subjects with New York Heart Association class II (6%), III (61%) or IV (33%) HF were enrolled. Nesiritide produced significant reductions in pulmonary wedge pressure (27% to 39% decrease by 6 h), mean right atrial pressure and systemic vascular resistance, along with significant increases in cardiac index and stroke volume index, with no significant effect on heart rate. Beneficial effects were evident at 1 h and were sustained throughout the 24-h infusion.nnnCONCLUSIONSnThe rapid and sustained beneficial hemodynamic effects of nesiritide observed in this study support its use as a first-line IV therapy for patients with symptomatic decompensated HF.

Plasma B-Type Natriuretic Peptide Levels Predict Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery

Background—Postoperative (postop) atrial fibrillation (AF) occurs in up to 60% of patients after cardiac surgery, leading to longer hospital stays and increased healthcare costs. Recently, B-type natriuretic peptide (BNP) has been reported to predict occurrence of nonpostoperative AF. This study evaluates whether elevated preoperative (preop) plasma BNP levels predict the occurrence of postop AF. Methods and Results—One hundred eighty-seven patients with no history of atrial arrhythmia who had a preoperative BNP level and had undergone cardiac surgery were identified. Their records were reviewed, and postoperative ECG and telemetry strips were analyzed for AF until the time of discharge. Postop AF was documented in 80 patients (42.8%). AF patients were older (68±11 versus 64±14 years, P =0.04), but there was no difference in sex distribution, hypertension, left ventricular (LV) function, LV hypertrophy (LVH), left atrial size, history of coronary artery disease (CAD), or β-blocker use. Preop plasma BNP levels were higher in the postop AF patients (615 versus 444 pg/mL, P =0.005). After adjustment for age, sex, type of surgery, hypertension, LV function, LVH, left atrial size, CAD, and β-blocker use, the odds ratios of postop AF according to increasing quartiles, compared with patients with lowest quartile, were 1.8, 2.5, and 3.7 (Ptrend=0.03). Conclusions—An elevated preop plasma BNP level is a strong and independent predictor of postop AF. This finding has important implications for identifying patients at higher risk of postop AF who could be considered for prophylactic antiarrhythmic or β-blocker therapy.

Resistance exercise prevents glucocorticoid-induced myopathy in heart transplant recipients.

PURPOSEnTo determine the effect of resistance exercise training (ET) on glucocorticoid-induced myopathy in heart transplant recipients (HTR), 14 male HTR were randomly assigned to a ET group that trained for 6 months (54 +/- 3 yr old; mean +/- SD) or a control group (51 +/- 8 yr old; mean +/- SD).nnnMETHODSnFat mass, fat-free mass, and total body mass were measured by dual-energy x-ray absorptiometry before and 2 months after transplantation (Tx), and after 3 and 6 months of ET or control period. The exercise regimen consisted of lumbar extension (MedX) performed 1 d.wk-1 and variable resistance exercises (Nautilus) performed 2 d.wk-1. PreTx body composition did not differ between groups.nnnRESULTSnAt 2 months after Tx, fat-free mass was significantly decreased below baseline in both control (-3.4 +/- 2.1%) and ET groups (-4.3 +/- 2.4%). Fat mass was significantly increased at 2 months after Tx in both the control (+8.3 +/- 2.8%) and ET groups (+7.3 +/- 4.0%). Six months of ET restored fat-free mass to levels 3.9 +/- 2.1% greater (P < or = 0.05) than before Tx. Fat-free mass of the control group decreased progressively to levels that were 7 +/- 4.4% lower than preTx values (P < or = 0.05). Both groups increased knee extension, chest press, and lumbar extensor strength, but improvements in the ET group were four- to six-fold greater (P < or = 0.05).nnnCONCLUSIONnOur results demonstrate that glucocorticoid-induced changes in body composition in HTR occur early after Tx. However, 6 months of specific ET restores fat-free mass to levels greater than before Tx and dramatically increases skeletal muscle strength. Resistance exercise, as part of a strategy to prevent steroid-induced myopathy, appears to be safe and should be initiated early after heart Tx.

Endothelial dysfunction early after heart transplantation : assessment with intravascular ultrasound and doppler

BackgroundAllograft vasculopathy after heart transplantation is thought to represent a response to endothelial injury in the graft vessels. To assess endothelial function before the onset of anatomic disease, coronary vasomotor responses to adenosine, acetylcholine, and nitroglycerin were evaluated in transplant recipients by intravascular ultrasound imaging and Doppler flow studies Methods and ResultsNine patients were studied 1 year after heart transplantation. Acetylcholine provoked significant vasoconstriction to 82% of maximal coronary diameter but was associated with an increase in mean coronary blood flow from 63.1 to 204 ml/min. Coronary blood flow increased fivefold in response to adenosine, a normal response ConclusionsThe vasomotor response to acetylcholine at 1 year after heart transplantation is consistent with endothelial dysfunction in the epicardial conduit vessels. Microvascular function as judged by coronary flow reserve appears to be normal.

An update on nesiritide for treatment of decompensated heart failure

In the July 1999 issue of this publication, we described the chemical properties, pharmacology and clinical trials involving nesiritide as a therapeutic agent for patients with decompensated heart failure (Exp. Opin. Invest. Drugs) (1999) 8(7):1063-1072). At the time of publication, the US Food and Drug Administration reviewed the clinical experience with the compound and did not approve the drug for clinical use. More data were requested regarding safety issues, comparison with nitroglycerine, onset of effects, need for invasive haemodynamic monitoring and symptomatic improvement. The VMAC Study was designed to address these issues. A dosing regimen, 0.2 μg/kg bolus followed by 0.01 μg/kg/min continuous infusion, was chosen to provide rapid onset of actions and haemodynamic improvement without a high incidence of symptomatic hypotension. Nesiritide was superior to iv. nitroglycerine in its haemodynamic effects, easier to administer without the need for dose titration and better tolerated overall. The drug could be administered safely without the need for invasive haemodynamic monitoring. Symptomatic hypotension occurred in 4% of patients. Beneficial haemodynamic effects correlated with symptomatic improvement in heart failure patients. Nesiritide appears to be an ideal first-line agent for treatment of patients with acutely decompensated heart failure.

Exercise-induced hypoxemia in heart transplant recipient

Objectives. The purpose of this study was to determine whether heart transplantation has an adverse effect on pulmonary diffusion and to investigate the potentially deleterious effects of impaired pulmonary diffusion on arterial blood gas dynamics during exercise in heart transplant reciplents. n nBackground. Abnormal pulmonary diffusing capacity is reported in patients after orthotopic heart transplantation. Abnormal diffusion may be caused by cyclosporlne or by the persistence of preexisting conditions known to adversely affect diffusion, such as congestive heart failure and chronic obstructive pulmonary disease. n nMethods. Eleven patients (mean age 50 ± 14 years) performed pulmonary function tests 3 ± 1 months before and 18 ± 12 (mean ± SD) months after heart transplantation. Transplant patients were assigned to groups with diffusion > 70% (n = 5) or diffusion < 70% of predicted values (n = 5). The control group and both subsets of patients performed 10 min of cycle exercise at 40% and 70% of peak power output. Arterial blood gases were drawn every 30 s during the 1st 5 min and at 6, 8 and 10 min. n nResults. Significant improvements in forced vital capacity (17,4%), forced expiratory volume in 1 s (11.7%) and diffusion capacity (6.6%) occurred in the patients; however, posttransplantation vital capacity, forced expiratory volume and diffusion were lower (p ≤ 0.05) compared with values in 11 control subjects. Changes in blood gases were similar among groups at 40% of peak power output. At 76% of peak power output, arterial blood gases and pH were significantly (p ≤ 0.05) lower in transplant patients with low diffusion (arterial oxygen pressure 15 to 38 mm Hg below baseline) than in patients with normal diffusion and control subjects. Cardiac index did not differ (p ≥0.05) between transplant patients with noramal and low diffusion at rest or during exercise. Posttransplantation mean pulmonary artery pressure was significantly related to exercise-induced hypoxemia (r = 0.71; p = 0.03). n nConclusions. Abnormal pulmonary diffusion observed in patients before heart transplantation persists after transplantation with or without restrictive or obstructive ventilatory defects. Heart transplant recipients exprience exercise-induced hypoxemia when diffusion at rest is < 70% of predicted. Our data also suggest that abnormal pulmonary gas exchange possibly contributes to diminished peak oxygen consumption in some heart transplant recipients; however, direct testing of this hypothesis was beyond the scope of the present study. This possibility needs to be investigated further.

Effect of cardiac transplantation on Cheyne-Stokes respiration occurring during sleep.

Abstract In conclusion, CSR that occurs during sleep in patients with severe CHF is eliminated by HT.

Mitral Regurgitation and death while awaiting cardiac transplantation

Abstract Patients selected as candidates for orthotopic cardiac transplantation have end-stage heart disease with a poor prognosis. Most cardiac transplantation centers require patients to have an estimated annual mortality of 50% as a criterion for selection as a potential recipient. Even in this highly selected population, there is considerable variation in prognosis. Some patients tolerate months of medical therapy while awaiting transplantation, whereas others die, often unpredictably. From 1987 to 1990, the average patient waiting period from selection as a candidate to transplantation at the University of Florida was 2.3 months. Of 137 patients listed with the United Network for Organ Sharing during this period, 19 (14%) died while awaiting transplantation. We performed a retrospective evaluation of these patients to test the hypothesis that echocardiographic evidence of severe mitral regurgitation may be a simple, easily obtained marker for early death while awaiting transplantation.

Therapeutic potential of nesiritide (recombinant b-type natriuretic peptide) in the treatment of heart failure

This review outlines the chemical properties, pharmacology and clinical trials data which support the development of nesiritide (synthetic human B-type natriuretic peptide, or hBNP) as a therapeutic agent for patients with decompensated congestive heart failure. Nesiritide is a 32-amino acid peptide, structurally identical to endogenous hBNP. Clinical trials with single bolus, repeated boluses and sustained infusions of nesiritide have demonstrated prompt, significant and sustained reductions in pulmonary capillary wedge pressure and increases in cardiac output, consistent with a direct vasodilator effect. Nesiritide has a short half-life, approximately 18 min, which is not dependent upon renal function. It not associated with tachyphylaxis through 24 h of therapy. Nesiritide is not an inotrope, and its action is not dependent upon beta adrenergic receptors. The safety profile has been excellent; the major adverse effect is hypotension. The frequency of ventricular arrhythmia is not increased in patients treated with nesiritide. In our opinion, nesiritide has many attributes of an ideal first-line therapeutic agent for decompensated heart failure.

High-dose angiotensin-converting enzyme inhibition restores body fluid homeostasis in heart-transplant recipients.

OBJECTIVESnWe tested the hypothesis that salt and fluid retention in heart-transplant recipients (HTRs) is caused by a failure to reflexively suppress the renin-angiotensin-aldosterone system (RAAS).nnnBACKGROUNDnIt is known that extracellular fluid volume is expanded (12% to 15%) in HTRs who develop hypertension.nnnMETHODSnResponses to volume expansion were measured in eight HTRs (ages 57 +/- 6 years) and six liver-transplant recipients (LTRs) (ages 52 +/- 2 years) both before and after treatment with captopril (225 mg/day). After three days of a standardized diet, 0.154 mol/l saline was infused at 8 ml/kg/h for 4 h. Blood pressure, hormones, and renal function were monitored for 48 h. After four months, the same subjects received captopril (225 mg/day), and the protocol was repeated.nnnRESULTSnBefore captopril, saline infusion suppressed the RAAS in LTRs but not in HTRs, resulting in elimination of 86 +/- 12% versus 50 +/- 11% of the sodium load by 48-h postinfusion. Blood pressure increased only in the HTRs (+16 +/- 5/9 +/- 3 mm Hg) and remained elevated for 48 h (p < or = 0.05). After captopril, sodium elimination was comparable in the liver (87 +/- 13%) and heart groups (86 +/- 12%) and blood pressure did not change in either group. CONCLUSIONS; Heart transplant recipients have blunted diuretic and natriuretic responses to volume expansion that is mediated by their inability to suppress the RAAS. Pharmacologic suppression of the RAAS normalized defects in blood pressure and fluid homeostasis. These findings indicate that hypertension in HTRs is caused, in part, by a failure to reflexively suppress the RAAS when these patients become hypervolemic.