Continuous ambulatory monitoring of absolute right ventricular pressure and mixed venous oxygen saturation in patients with heart failure using an implantable haemodynamic monitor: results of a 1 year multicentre feasibility study.

BACKGROUND: Implantable sensors that monitor haemodynamics over time may be useful in patients with heart failure. This multicentre study assessed the feasibility of a system that has one sensor measuring absolute pressure and another measuring mixed venous oxygen saturation (SvO(2)). Both sensors were mounted on leads that were implanted in the right ventricle. METHODS: Twenty-one patients with heart failure (NYHA II-III) were included. Comparisons were made to right heart catheterizations at implant and at 2, 6 and 12 months thereafter. Patients underwent several haemodynamic provocations during the catheterizations. RESULTS: Overall, among functioning sensors, the IHM-1 values were highly correlated with reference values for all time points during all provocations, demonstrating high reproducibility and stability (r(2)=0.91, 0.79 and 0.78 for systolic, right ventricular diastolic and SvO(2), respectively). Although IHM-1 underestimated reference pressure values by 4.5 mmHg and SvO(2)by 1.6%, this difference was consistent across provocation and stable over 12 months of follow-up. Twelve of the 21 oxygen sensors failed to function and two pressure sensors had component failures. Preliminary analysis of long-term data revealed haemodynamic patterns that may be key indicators for therapeutic interventions. CONCLUSION: This multicentre feasibility study demonstrated the accuracy and stability of sensors implanted in the right ventricle. The IHM-1, using right ventricular pressures and SvO(2), with improved performance, might be useful in the study of pathophysiological mechanisms and treatment interventions in heart failure.

Sympathetic reinnervation of the sinus node and exercise hemodynamics after cardiac transplantation.

BACKGROUND: Sympathetic cardiac reinnervation occurs variably after cardiac transplantation (CT) in humans. We hypothesized that sinus node reinnervation would partially restore normal chronotropic response to exercise. METHODS AND RESULTS: Thirteen recent CT recipients, 28 late CT recipients (> or =1 year after CT), and 20 control subjects were studied. Sinus node sympathetic reinnervation was determined by heart rate (HR) change after tyramine injection into the artery that perfused the sinus node. HR changes of <5 and > or =15 bpm were defined, respectively, as denervation and marked reinnervation. During treadmill exercise, HR, blood pressure, and expired O(2) and CO(2) were measured. All early transplant recipients exhibited features typical of denervation (basal HR, 88+/-2 bpm; peak HR, 132+/-4 bpm, peaking 1.8+/-0.3 minutes after exercise cessation and slowly declining after exercise). A similar pattern was found in the 12 late transplant recipients with persistent sinus node denervation. However, in patients with marked reinnervation, exercise HR rose more (peak HR, 142+/-4 and 141+/-2 bpm), peaked earlier after cessation of exercise (0.7+/-0.4 and 0. 3+/-0.1 minute), and fell more rapidly. Exercise duration and maximal oxygen consumption were not related significantly to reinnervation status, but a trend existed for longer exercise time in markedly reinnervated patients. CONCLUSIONS: The present studies suggest that sympathetic reinnervation of the sinus node is accompanied by partial restoration of normal HR response to exercise. Both maximal oxygen consumption and exercise duration were markedly shorter in CT patients than in control subjects, and most of the difference was not related to innervation status.

Endothelial dysfunction in patients with heart failure: relationship to disease severity.

BACKGROUND: Heart failure is associated with abnormal endothelium-dependent vasodilation. However, the relationship of this abnormality to heart failure severity has not been well defined. METHODS AND RESULTS: We used strain-gauge plethysmography to assess forearm blood flow (FBF) responses to endothelium-dependent, endothelium-independent, and reactive hyperemic stimuli in normal subjects (n = 29) and in patients with mild (n = 26) and severe (n = 41) heart failure. FBF responses to intra-arterial methacholine (0.3, 1.5, 3.0 microg/min) were significantly (P < .005) and similarly reduced in patients with mild (2.8 +/- 0.4, 5.9 +/- 0.7, and 7.7 +/- 1.1 mL/min/dL) and severe (2.7 +/- 0.4, 5.4 +/- 0.7, and 6.9 +/- 0.9) heart failure compared with normal subjects (4.5 +/- 0.4, 9.4 +/- 1.0, and 12.0 +/- 1.1). FBF responses to nitroprusside (1, 5, 10 microg/min) were significantly reduced in mild (2.4 +/- 0.3, 6.7 +/- 1.1, and 11.9 +/- 2.0, P < .05) and severe (1.9 +/- 0.2, 5.1 +/- 0.5, and 7.3 +/- 0.9, P < .001) heart failure groups compared with normal subjects (3.8 +/- 0.5, 10.8 +/- 1.2, and 14.9 +/- 1.2). However, FBF responses were reduced to a greater extent (P < .001) in mild heart failure compared with severe heart failure. Peak reactive hyperemia was significantly impaired only in severe heart failure. There was no correlation between methacholine responses and ejection fraction, maximum oxygen consumption, wedge pressure, or serum norepinephrine. CONCLUSION: Impaired endothelium-dependent vasodilation is present and near maximum in mild heart failure. Endothelial dysfunction may be an early finding in human heart failure.

Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human heart: observations made after implantation of left ventricular assist device.

BACKGROUND: Heart failure is characterized by progressive left ventricular remodeling, a complex process that results from cell growth and cell death. The quantitative contribution of apoptotic cells toward left ventricular remodeling has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has been responsive to angiotensin-converting enzyme inhibition in experimental heart failure, but the dynamics and responsiveness to chronic left ventricular unloading have not been studied. METHODS AND RESULTS: We studied 8 patients with severe heart failure before and after chronic left ventricular unloading with a left ventricular assist device (LVAD). Tissue from the left ventricular apex removed at the time of LVAD implantation was examined for apoptosis using the technique of terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) in 10 patients. These same hearts explanted at the time of cardiac transplantation were then examined for apoptosis after patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients with equally severe heart failure who underwent heart transplantation without the use of an LVAD served as controls. Eight hearts obtained at autopsy approximately 6 hours after death from patients who died of non-cardiovascular disease causes served as non-heart failure controls. Additionally, 6 hearts were examined by immunohistochemistry for the antiapoptotic protein, Bcl-2, and for the repair and/or proliferation marker, proliferating cell nuclear antigen (PCNA), before and after LVAD. Apoptosis was not detected in the tissue sections from the hearts of 8 patients at the time of LVAD implantation. Only 1 of these patients had limited apoptosis (< 1 apoptotic cell/1,000 myocytes) after LVAD insertion. Three of 10 patients with severe heart failure who did not receive an LVAD but underwent transplantation showed limited apoptosis (< 1 apoptotic cell/1,000 myocytes). Likewise, none of the control hearts from patients who died of noncardiovascular disease manifested apoptosis. Six of 6 patients overexpressed Bcl-2 at the time of LVAD insertion. In all these patients, Bcl-2 returned to negligible levels after chronic unloading of the heart. Likewise, PCNA was abundantly expressed in 5 of 6 failing hearts at the time of LVAD implantation and was reduced in 4 of 5 hearts after chronic unloading by LVAD. CONCLUSION: Apoptosis is a rare or inconsistent finding in the failing human heart. Overexpression of such indicators of cellular stress and DNA replication and/or repair as Bcl-2 and PNCA in heart failure may be altered by optimizing left ventricular loading conditions by such mechanical devices as the LVAD.

Memory improvement following cardiac transplantation.

Seventeen patients with severe cardiomyopathy underwent neuropsychological evaluation prior to and at least 1 year after successful heart transplantation. Study candidates were screened, and individuals with a history of stroke, cardiac arrest, or medical and neurological conditions which might affect brain function were excluded. Pre-transplant testing revealed normal intelligence and normal attentional, language, and executive abilities but impaired recent memory. Following heart transplant, memory functioning improved significantly, reaching normal levels. Other cognitive abilities remained unchanged. Results suggest that cardiomyopathy is associated with mesial temporal dysfunction, possibly attributable to inadequate or reduced cerebral blood flow and related hypometabolism. This cerebral dysfunction is potentially reversible following successful transplantation, which restores cardiac output and cerebrovascular perfusion.

Effects of pimobendan on exercise tolerance and quality of life in patients with heart failure.

There has been an intensive search for safe and clinically effective inotropic agents for use as adjunctive therapy in patients with advanced heart failure. Pimobendan is a benzimidazole-pyridazinone derivative with calcium-sensitizing properties that increases myocardial contractile force without increasing intracellular calcium. This review summarizes the data from five controlled, randomized prospective trials of pimobendan that demonstrate significant improvements in exercise capacity and quality of life in patients with heart failure. The clinical benefits of pimobendan found in these trials contrast with the adverse experience noted previously with milrinone and enoximone. This may be related to the different mechanism of action of pimobendan or to a study design that permitted examination of a lower dosage. These cumulative data suggest that pimobendan may have a useful adjunctive role in heart failure and that further assessment of its effects on overall mortality is needed.

Heart transplantation for patients over age 60.

As the proportion of people over age 60 in our society continues to rise, so does the number of potential heart transplant candidates. Advanced recipient age, however, has long been used as an exclusion criterion for transplantation, though the upper age limit remains poorly defined. The purpose of our study was to analyze the outcomes of 31 heart transplant recipients over age 60 at our institution. They were followed with regard to early and late morbidity and mortality. Mean follow-up time was 50 months. The 1- and 5-yr survival rates were 90% and 85%. These rates were not significantly different compared with younger (age 18 to 59) recipients transplanted in the same time period. The older recipients more frequently developed osteoporotic changes as well as cutaneous and visceral malignancies, but had infrequent rejection episodes. Overall, heart transplantation is safe and effective for patients over age 60 with end-stage congestive heart failure. Both 1- and 5-yr survival rates are well within the acceptable range and do not differ significantly from younger recipients. Individualized immunosuppression might help reduce the incidence of malignancy in older recipients, but further studies are needed. Matching donor and recipient age would make the best use of available organs.

Contribution of collagen, elastin, and smooth muscle to in vivo human brachial artery wall stress and elastic modulus.

BACKGROUND: The contributions of collagen, elastin, and smooth muscle to arterial mechanical properties in the in vivo human artery are not known. METHODS AND RESULTS: We used a recently developed intravascular ultrasound technique to measure total brachial artery wall stress and incremental elastic modulus (Einc) in seven normal human subjects at baseline and after intra-arterial norepinephrine (1.2 micrograms) and nitroglycerin (100 micrograms). Then we applied a modified Maxwell model to estimate the elastic modulus of elastin (EE); the recruitment of collagen fibers supporting wall stress; and the differential contributions of collagen, elastin, and smooth muscle to wall stress and Einc over a wide range of pressure and smooth muscle tone. With this model, EE was 3 x 10(6) dynes/cm2. Collagen fibers were recruited increasingly as transmural arterial pressure increased and reached a value of approximately 5% to 6% at 100 mm Hg under each of the conditions studied. Isobaric smooth muscle contraction resulted in a small decrease in total wall stress and no significant change in total Einc while shifting the predominant element contributing to these mechanical parameters from collagen in parallel with the smooth muscle to collagen in series with the smooth muscle. In contrast, isometric smooth muscle contraction produced large increases in total wall stress (from 0.11 x 10(6) dynes/cm2 after nitroglycerin administration to 1.35 x 10(6) dynes/cm2 after norepinephrine administration) and Einc (from 3.84 x 10(6) dynes/cm2 after nitroglycerin administration to 57.8 x 10(6) dynes/cm2 after norepinephrine administration) entirely as a result of the additional contribution of the smooth muscle and its associated series collagen. CONCLUSIONS: This study describes a technique for determining arterial elastic properties and a model that can be used to estimate a number of mechanical parameters of the human brachial artery in vivo. This technique may be useful in studies of the arterial elastic properties of arteries in patients with vascular pathology.

Abnormal desmopressin-induced forearm vasodilatation in patients with heart failure: dependence on nitric oxide synthase activity.

BACKGROUND: Peripheral vasodilatation in response to muscarinic agonists has been shown to be subnormal during heart failure. However, a more recent study suggested that the abnormal muscarinic-induced vasodilatation was not due to abnormal nitric oxide synthase activity. This study was designed to show that nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation and to determine whether vasodilatation mediated by nitric oxide synthase is abnormal during heart failure. METHODS: Desmopressin (10, 50, and 100 ng/min) was infused into the brachial artery of 10 healthy subjects and eight patients with heart failure, and forearm blood flow was measured by venous occlusion plethsymography. Desmopressin responses were then recorded during inhibition of nitric oxide synthase with L-monomethylarginine or after aspirin. RESULTS: In healthy subjects, desmopressin caused a significant (p < 0.001) dose-dependent increase in forearm blood flow of 0.9 +/- 0.6, 4.0 +/- 2.6, and 7.9 +/- 2.6 ml/min/dl, respectively. Desmopressin responses in heart failure of 0.8 +/- 0.6, 1.7 +/- 1.4, and 3.1 +/- 1.0 ml/min/dl were significantly less (p < 0.001) than normal. L-Monomethylarginine reduced desmopressin responses in normal subjects (p < 0.01), and this inhibitory effect was significantly (p < 0.01) greater than in patients with heart failure. Aspirin did not affect desmopressin-induced vasodilatation. CONCLUSION: Nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation. In response to desmopressin, patients with heart failure have subnormal vasodilatation mediated through nitric oxide synthase.

Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators.

BACKGROUND: We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a "third-generation" beta -blocking agent with vasodilator properties, in chronic heart failure. METHODS AND RESULTS: Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P < .001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P < .001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (P < .001). Carvedilol also lowered the hospitalization rate (by 58% to 64%, P = .01) and was generally well tolerated. CONCLUSIONS: In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

Endothelial nitric oxide pathway function in the peripheral vasculature of patients with heart failure.

Many studies have investigated the pathophysiologic contributions of abnormalities in the endothelial nitric oxide pathway to the heightened vasoconstrictor tone that is characteristic of the clinical syndrome of heart failure. The most consistent abnormality is a reduced vasodilator response to muscarinic stimulation with either acetylcholine or methacholine, a finding which has been identified in several animal models of heart failure as well as in forearm and leg resistance vessels in patients with heart failure. More recent studies with desmopressin, a vasopressin 2 receptor agonist that stimulates nitric oxide production independent of the muscarinic receptor, have demonstrated that the abnormality in endothelium-dependent vasodilation was not limited to the muscarinic pathway. At present, the mechanisms of the defect in the endothelial nitric oxide pathway are unknown. But, they appear not to be directly related to sympathetic stimulation. Finally, studies using transplant recipients have demonstrated that this defect is reversible. In addition, a pilot study has demonstrated that supplemental oral L-arginine, the precursor for nitric oxide, has beneficial effects on forearm blood flow responses to exercise, arterial compliance nad functional status as assessed by increased distances during a 6-minute walk test and lower scores on the Living with Heart Failure Questionnaire. These studies suggest that the endothelial nitric oxide pathway may be a target for therapeutic interventions in heart failure.

Treatment of hyperlipidemia after heart transplantation and rationale for the Heart Transplant Lipid Registry.

Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant Lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation.

Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure.

BACKGROUND: Patients with heart failure have reduced peripheral blood flow at rest, during exercise, and in response to endothelium-dependent vasodilators. Nitric oxide formed from L-arginine metabolism in endothelial cells contributes to regulation of blood flow under these conditions. A randomized, double-blind crossover study design was used to determine whether supplemental oral L-arginine can augment peripheral blood flow and improve functional status in patients with moderate to severe heart failure. METHODS AND RESULTS: Fifteen subjects were given 6 weeks of oral L-arginine hydrochloride (5.6 to 12.6 g/d) and 6 weeks of matched placebo capsules in random sequence. Compared with placebo, supplemental oral L-arginine significantly increased forearm blood flow during forearm exercise, on average from 5.1 +/- 2.8 to 6.6 +/- 3.4 mL. min-1. dL-1 (P < .05). Furthermore, functional status was significantly better on L-arginine compared with placebo, as indicated by increased distances during a 6-minute walk test (390 +/- 91 versus 422 +/- 86 m, P < .05) and lower scores on the Living With Heart Failure questionnaire (55 +/- 28 versus 42 +/- 26, P < .05). Oral L-arginine also improved arterial compliance from 1.99 +/- 0.38 to 2.36 +/- 0.30 mL/mm Hg (P < .001) and reduced circulating levels of endothelin from 1.9 +/- 1.1 to 1.5 +/- 1.1 pmol/L (P < .05). CONCLUSIONS: Supplemental oral L-arginine had beneficial effects in patients with heart failure. Further studies are needed to confirm the therapeutic potential of supplemental oral L-arginine and to identify mechanisms of action in patients with heart failure.

Measurement of pulmonary artery diastolic pressure from a right ventricular pressure transducer in patients with heart failure.

Recent studies have demonstrated that pulmonary artery diastolic (PAD) pressure can be measured from a transducer positioned in the right ventricle (RV) based on the finding that PAD and RV pressures are equal at the time of pulmonary valve opening, which is associated with the time of maximum positive rate of pressure development (dP/dtmax) in the ventricle. The objective of this study was to assess the correlation between estimated PAD (ePAD) pressure, obtained through a RV transducer, and actual PAD (aPAD) pressure in patients with heart failure who have abnormal hemodynamics, reduced systolic function, and variable degrees of mitral regurgitation (MR) and tricuspid regurgitation (TR). Simultaneous measurements of pulmonary artery and RV pressures were obtained with a high-fidelity Millar catheter (Millar Instruments, Houston, TX) in 10 patients with New York Heart Association class III-IV heart failure who were being evaluated for cardiac transplantation. The overall correlation between ePAD and aPAD pressures was .92 (R2 = .878). This was not significantly different during the Valsalva maneuver (r = .96, R2 = .943), submaximal bicycle exercise (r = .87, R2 = .756), or infusions of dobutamine and nitroglycerin (r = .82, R2 = .730). The overall average difference between the average ePAD (24.6 +/- 7.0 mmHg) and aPAD (23.6 +/- 7.0 mmHg) pressures was 1.0 +/- 3.4 mmHg. The average difference between the two pressures in patients with mild to severe MR or TR was not different compared to those patients with no or trace MR or TR. The estimation of PAD pressure from an RV transducer is valid in patients with heart failure who have abnormal hemodynamics, reduced systolic function, and variable degrees of MR and TR. This correlation was observed at rest and during several provocative maneuvers. These data will be important for the development of a chronic, implantable hemodynamic monitor for patients with heart failure.

Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators.

In the Studies of Left Ventricular Dysfunction (LVD), enalapril or placebo was administered in a double-blind fashion to 6797 participants with ejection fraction < or = 0.35. During 40 months' average follow-up, 28.1% of participants randomized to enalapril reported side effects compared with 16.0% in the placebo group (p < 0.0001). Enalapril use was associated with a higher rate of symptoms related to hypotension (14.8% vs 7.1%, p < 0.0001), azotemia (3.8% vs 1.6%, p < 0.0001), cough (5.0% vs 2.0%, p < 0.0001), fatigue (5.8% vs 3.5%, p < 0.0001), hyperkalemia (1.2% vs 0.4%, p = 0.0002), and angioedema (0.4% vs 0.1%, p < 0.05). Side effects resulted in discontinuation of blinded therapy in 15.2% of the enalapril group compared with 8.6% in the placebo group (p < 0.0001). Thus enalapril is well tolerated by patients with LVD; however, hypotension, azotemia, cough, fatigue, and other side effects result in discontinuation of therapy in a significant minority of patients.

Direct effects of smooth muscle relaxation and contraction on in vivo human brachial artery elastic properties.

The direct effect of smooth muscle relaxation on arterial elastic properties is controversial. Studies in animals show both a decrease and an increase in elastic modulus. In human subjects, the contribution of smooth muscle to arterial elastic mechanics has been limited by difficulty in separating the direct effects of a vasodilator drug on the arterial wall from the indirect effects due to reduced blood pressure. The purpose of the present study was to assess the direct contribution of vascular smooth muscle to brachial artery elastic mechanics in normal human subjects in vivo. We measured brachial artery compliance and incremental elastic modulus (Einc) in eight normal subjects (age, 22 to 51 years) by using intravascular ultrasound. A 3.5F 30-MHz intravascular ultrasound catheter was placed through a sheath into the brachial artery, and intraarterial pressure, cross-sectional area, and wall thickness were measured simultaneously under baseline conditions and after the administration of intra-arterial nitroglycerin (100 micrograms) and norepinephrine (1.2 micrograms). A pressurized cuff surrounding the brachial artery was inflated to reduce transmural brachial artery pressure. Using this technique, we were able to measure the following arterial characteristics for the first time in human subjects in vivo: (1) the effective unstressed arterial radius and (2) the pressure-area, stress-strain, and pressure-Einc relations over a wide pressure range (0 to 100 mm Hg). Intra-arterial nitroglycerin increased brachial artery area by 22% and intraarterial norepinephrine decreased brachial artery area by 17% at 100 mm Hg transmural pressure (P < .001 versus baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective study of the seroprevalence of Borrelia burgdorferi infection in patients with severe heart failure.

We conclude that Lyme disease is not a common cause of idiopathic heart failure in the Midwestern United States and that false-positive Lyme disease serologic results are not rare among patients with severe heart failure. Patients with significant cardiac disease who are found to be EIA seropositive should have confirmatory Western blots performed before consideration of treatment. Based on our findings, we cannot recommend either the routine serologic screening of patients with idiopathic cardiomyopathy or aggressive (e.g., parenteral) antibiotic treatment of seropositive patients unless the specific clinical history suggests antecedent Lyme disease.

Use of the Living With Heart Failure questionnaire to ascertain patients' perspectives on improvement in quality of life versus risk of drug-induced death.

Treatments for heart failure, such as flosequinan, may have opposite effects on survival and quality of life. The Living With Heart Failure questionnaire was used to examine patients' willingness to risk drug-induced death for improved quality of life. In addition, patients' opinions concerning worthwhile improvements in the Living With Heart Failure score were described to provide a perspective for interpreting the results of clinical trials. A sample of 101 patients with heart failure were interviewed in cardiology clinics. Median (interquartile range) Living With Heart Failure questionnaire score were 54 (interquartile range, 34-74). Forty-nine percent of the patients would accept a1 in 100 risk of drug-induced death if the corresponding improvements in the Living With Heart Failure score were 20 (interquartile range, 10-25). In contrast, 40% were willing to accept a risk of drug-induced death equal to or greater than 5 in 100 for significantly (P < .001) smaller score improvements of 5 (interquartile range, 5-10). Living With Heart Failure scores that increase with perceived limitations secondary to heart failure tended to be higher, although not significantly (P = .22), in the subgroup that accepted greater risk of drug-induced death: 45 (interquartile range, 34-73) versus 58 (interquartile range, 42-77). A score improvement of 5, which has been commonly observed in clinical trials, would be sufficient reason for 72% of patients to take a medication that did not have side effects or significant costs. A 5-point improvement was less acceptable when costs or risks were associated with therapy: 52% would pay $60 per month and 38% would risk drug-induced death. These data suggest that many patients with heart failure would accept some risk of drug-induced death for improved quality of life. A 5-point improvement in the Living With Heart Failure score may be clinically significant depending on costs and adverse effects. The Living With Heart Failure questionnaire can be used to help patients evaluate the benefits versus risks of medical interventions.

Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction. SOLVD Investigators.

The aim of this study was to compare the long-term effects of treatment with enalapril or placebo on plasma neurohormones in patients with left ventricular (LV) dysfunction. Elevated neurohormonal levels are associated with increased mortality in patients with congestive heart failure. Multiple studies have shown that angiotensin-converting enzyme inhibitors decrease mortality and morbidity in these patients. In Studies of Left Ventricular Dysfunction (SOLVD), enalapril significantly reduced mortality in patients with symptomatic LV dysfunction (treatment trial). In contrast, in patients with asymptomatic LV dysfunction (prevention trial), there was no significant reduction in mortality with enalapril therapy. The effect of enalapril was examined in 333 prevention trial and 129 treatment trial patients. Plasma norepinephrine (NE) and plasma renin activity were measured in these patients at baseline, and at 4 and 12 months of follow-up. In a subset of these patients, atrial natriuretic peptide (ANP) and arginine vasopressin were also measured. Analysis of covariance models were used to determine the effect of enalapril on each neurohormone. Participants in the treatment trial had significantly higher neurohormonal levels when compared with those in the prevention trial or normal control subjects. In the treatment trial, patients taking enalapril had a greater decrease in plasma NE levels than patients taking placebo (p < 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors for late recurrent rejection after heart transplantation: a multiinstitutional, multivariable analysis. Cardiac Transplant Research Database Group.

BACKGROUND: Previous studies of allograft rejection have focused on early episodes and risk factors from pretransplant variables. METHODS: This multiinstitutional study compared early (< 1 year) and late (> 1 year) rejection episodes and risk factors for recurrent rejection from variables both before and after transplantation among 1251 patients who underwent primary heart transplantation and available follow-up of greater than 1 year. RESULTS: There were a total of 1882 rejection episodes over a mean follow-up of 26 +/- 0.3 months. The hazard function (instantaneous risk per patient per month) peaked at 1 month followed by a low constant risk of rejection after 12 months. By multivariable analysis, the most dominant risk factors for recurrent rejection during the first posttransplantation year were a shorter time interval since transplantation and a shorter time since a previous rejection episode. Other factors included young age, female gender, female donor, positive cytomegalovirus serology, prior infections, and OKT3 induction. In contrast, after the first year, the dominant risk factors for rejection were a greater number of rejections during the first year and the presence of prior cytomegalovirus infections. CONCLUSIONS: These data show a striking time dependency for rejection episodes among heart transplant recipients. Factors that increase risk for rejection in the first year differ from risk factors for rejection in subsequent years. These data suggest that it may be possible to tailor rejection surveillance protocols and immunosuppression intensity, according to specific patient and time-related risk factors.