The debate surrounding which combination of immunosuppressive agents is most advantageous to cardiac transplant recipients has continued, in part due to a lack of definitive clinical trial data from a comparison of agents currently used. The primary purpose of this study is to compare the incidence of ISHLT rejection≥ grade 3A or HDC, requiring treatment. Between 11/01& 6/03, 343 de novo cardiac transplant recipients at 28 US sites were randomized to 3 treatment groups: Group 1: TAC target level (TL)=10–20 ng/mL first 3 months; then 5–15 ng/mL, SRL 6 mg loading dose,TL= 4–12 ng/mL,ssteroids. Group 2: TAC (as above),MMF dose=3 gm/day, TL=3–5 ng/mL,ssteroids.Group 3:CYA TL=200–400 ng/mL months1–3, then 100–300 ng/mL,MMF (as above),ssteroids.

OBJECTIVE:The objective of this study was to assess the quality of outpatient care received by patients with congestive heart failure (CHF) and whether differences in care and outcomes exist by race/ethnicity.BACKGROUND:Appropriate outpatient CHF management can improve patient well-being and reduce the need for costly inpatient care. Yet, little is known regarding outpatient CHF management or whether differences in this care exist by race/ethnicity.METHODS:Using automated data sources, we identified a cohort of insured patients seen in an outpatient setting for CHF between September 1992 and August 1993. Medical record abstraction was used to confirm diagnosis of CHF. Patients (N = 566) were followed until September 1998. Race/ethnicity differences in outpatient management and medical care utilization were assessed using generalized estimating equations. Differences in mortality and hospitalization for CHF, controlling for patient characteristics and outpatient management, were assessed using Cox and Andersen-Gill models, respectively.RESULTS:With the exception of beta blocker use and primary care visit frequency, few differences by race/ethnicity in patient characteristics and CHF management were found. However, older black patients had more hospital use both at baseline and during follow up. These differences persisted after adjusting for patient characteristics and clinical management. No race/ethnicity differences were found in mortality.CONCLUSIONS:In an insured population, older black patients with CHF have substantially more hospital use than older white patients. This increased use was not explained by differences in CHF outpatient management. Further research is needed to understand why race/ethnicity differences in hospital use are observed among older patients with CHF.

PREVIEW Abnormal diastolic function is a common cause of clinical heart failure, particularly among elderly patients. Through early diagnosis and careful management of diastolic dysfunction, these patients can expect improved functional capacity and, in some cases, a favorable long-term outcome. In this article, Drs Torosoff and Philbin discuss how to confirm the diagnosis of diastolic heart failure through objective testing. Current approaches to the treatment of symptoms, including reduction of intravascular volume, heart rate control, and elimination of precipitating factors, are also presented.

Background and Purpose: Prior studies have shown conflicting results with respect to the mortality risk attendant to obesity among patients with heart failure (HF). We sought to address this question among participants in the Digitalis Investigators Group (DIG) trial. Methods: Using the public-access version of the DIG trial database, we examined clinical characteristics and long-term survival among trial patients segregated by body mass index (BMI). First, patients were separated into 4 equal groups based on quartiles of BMI. Then, patients were separated into 4 physiologically relevant groups based on actual BMI: "Obese" (BMI > 30, N = 1960), "Overweight" (BMI 26-30, N = 3084), "Normal" (BMI 20-25, N = 2334) and "Underweight" (BMI<20, N = 409). Chi square tables, ANOVA, the Kaplan-Meier method and proportional hazards models were used to examine differences among the groups. Results: Among 7787 DIG patients, mean (±SD) BMI was 27.3±5.4. In the quartile analyses, higher BMI was associated with younger age, diabetes, hypertension, non-ischemic cause of HF, higher ejection fraction, and lower creatinine. Women and non-whites were disproportionately represented among the lowest and highest quartiles of BMI. Patients in the highest quartile of BMI were least likely to have rales, elevated JVP or a third heart sound but most likely to have edema or be treated with diuretics. They least often received open-label digitalis prior to study enrollment. Crude survival by BMI quartile is shown in Figure 1 . Overall mortality was 28% in the highest quartile of BMI and 40% in the lowest. In proportional hazards models, BMI quartile remained predictive of survival. Each 5 unit increase in BMI was associated with an 8% reduction in the risk of death (odds ratio, OR, 0.92; 95% confidence interval, CI, 0.88-0.96). Results for the physiological analyses were nearly identical to the quartile analyses, except that diuretic use and non-ischemic cause of HF were not higher among Obese patients. Crude survival by BMI group is shown in Figure 2 View Large Image Figure ViewerDownload (PPT). Overall mortality was 28% in the Obese group and 44% in the Underweight group. In proportional hazards models, BMI group remained predictive of survival. Relative to Obese patients, Normal patients (OR = 1.19, CI = 1.06-1.33) and Underweight patients (OR = 1.56, CI = 1.31-1.86) were at significantly higher risk of death. Conclusion: Higher BMI was associated with better survival in the DIG trial while lower BMI was associated with worse. This relationship persisted even after accounting for substantive differences among the groups.

Abnormal diastolic function is a common cause of clinical heart failure, particularly among elderly patients. Through early diagnosis and careful management of diastolic dysfunction, these patients can expect improved functional capacity and, in some cases, a favorable long-term outcome. In this article, Drs Torosoff and Philbin discuss how to confirm the diagnosis of diastolic heart failure through objective testing. Current approaches to the treatment of symptoms, including reduction of intravascular volume, heart rate control, and elimination of precipitating factors, are also presented.

The Digitalis Investigation Group (DIG) trial was the first large simple trial conducted by the National Heart, Lung, and Blood Institute in conjunction with the Department of Veterans Affairs. A large simple trial is a major undertaking. Simplification at the sites requires careful planning and discipline. Lessons learned from the DIG trial were: (1) keep a large simple trial very simple and keep all study procedures very simple; (2) ancillary studies are important and can complement a large simple trial but require careful advanced planning; (3) anticipate special needs when shipping study drugs internationally; (4) regional coordinating centers can be very useful; (5) recruit as many capable sites as possible; (6) provide research-inexperienced sites/investigators with extra help to obtain federalwide assurance statements from the Office for Human Research Protections and institutional review board approvals; (7) adequately reimburse sites for the work completed; (8) maintain investigator enthusiasm; (9) monitor the slow performers and sites with numerous personnel changes; (10) choose an endpoint that is easy to ascertain; (11) keep the trial simple for participants; and (12) plan early for closeout and for activities between the end of the trial and publication of results.

W niniejszym badaniu wykorzystano baze danych z badania DIG w celu stwierdzenia, czy kombinacje ro?nych zmiennych klinicznych mog± s³u?yae do przewidywania LVEF u poszczegolnych pacjentow z niewydolnoci± serca. Na podstawie zastosowanego modelu mo?liwe by³o prawid³owe okrelenie LVEF z dok³adnoci± do 0,05 (± 5 LVEF j.m.) jedynie w 45% przypadkow. Mimo faktu ?e kategoryzuj±ce analizy wykaza³y, i? u niemal wszystkich z 38% pacjentow z najni?sz± przewidywan± LVEF faktyczna LVEF wynosi³a £ 0,45, metoda ta jest zawodna w przypadku pozosta³ych 62% chorych.

Previous analyses have implied diminished efficacy of angiotensin converting enzyme inhibitors (ACEI), and equivalent or enhanced efficacy of beta-blockers (BB), in African Americans (AA) with congestive heart failure (CHF), when compared to placebo. These results may have been influenced by lead-time bias, in that AA may not have been entered into the older ACEI trials until late in their CHF course. Our goal was to use a prospective cohort study of 29,686 CHF patients within a single health system to examine the impact on AA mortality of administering ACEI and BB within the first year of CHF diagnosis. Pharmacy claims from 1995-1998 were available for 3353 newly diagnosed CHF patients (39.2% AA; N=1317) within the health maintenance organization. Rates of ACEI and BB use were 46.4% and 54.0%; 43.4% and 28.9%; and 40.7% and 18.6%, for Whites, AA, and other races, respectively. The relative risk reductions (RRR) for ACEI were 68.7%, P<.0001; 52.1%, P<.0001; and -36.3%, P=.56, for Whites, AA, and other races, respectively. The RRR for BB were 59.0%, P<.0001; 34.6%, P=.009; and 74.3%, P=.17, for Whites, AA, and other races, respectively. Age- and gender-adjusted survival rates for AA were significantly enhanced in those taking ACEI, BB, or a combination of the two: P<.001, P=.001, and P=.003, respectively. Although we could not control for selection bias, these data suggest that AA benefit from both ACEI and BB when treatment is initiated within the first year of CHF diagnosis. Future, similar analyses other databases should control for the duration of illness to avoid lead-time bias in AA with CHF.

To the Editor: Hospital and public health personnel are currently receiving smallpox vaccination in a national effort to increase preparedness for a possible deliberate release of smallpox (1). Generalized vaccinia (GV) is a typically self-limited adverse event following vaccination (incidence 23.4–238.2 cases per million primary vaccinees and 1.2–10.8 cases per million revaccinees) (2,3). We report the clinical course and laboratory diagnosis of GV in a 37-year-old woman with a history of at least one uncomplicated childhood inoculation that left a vaccination scar. She was revaccinated on March 12, 2003. Before revaccination, the patient reported no contraindications to vaccination and denied any conditions that typically weaken the immune system (including HIV/AIDS, leukemia, lymphoma, other cancers, radiation, chemotherapy, organ transplant, posttransplant therapy, immunosuppressive medications, severe autoimmune disease, and primary immune deficiency). The patient also confirmed that she did not have a skin disease or a history of eczema or atopic dermatitis, nor was she pregnant or allergic to a vaccine component. On March 14, some 44 hours after vaccination, the patient reported headache, chills, pruritus, chest pain (described as chest “heaviness”), recurrent vomiting, and maculopapular lesions. The lesions, characterized by the patient as “mosquito bites,” first appeared on the face, then the legs, and then the trunk and upper extremities. Maximum oral temperature was 37.7°C. Over the next 4 days, approximately 30 pustules developed, several of which began to drain. Nausea persisted, and the patient had a stiff neck and recurring chest tightness, but physical examination, echocardiography, electrocardiography, and chest radiography were within normal limits. By March 25, the patient’s lesions had all scabbed, the scabs had fallen off, and she felt well enough to return to work. Pustular material obtained on March 18 from two unroofed lesions on the shoulder (Figure) and back tested positive at the Wadsworth Center-Axelrod Institute, New York State Department of Health, for vaccinia virus DNA by a TaqMan (Applied Biosystems, Foster City, CA) real-time polymerase chain reaction assay provided by the Laboratory Response Network, Centers for Disease Control and Prevention. The presence of orthopoxvirus was confirmed by electron microscopy of lesion fluid. Figure Pustular lesion on patient’s shoulder, 6 days after revaccination. This case is the first report of a laboratory-confirmed case of GV among recent civilian vaccinees and is notable for the GV occurrence in a revaccinee. GV was not reported among 132,656 military personnel recently revaccinated (4). A single case of GV in a revaccinee among 38,514 recent civilian vaccinations (5) yields a ratio that exceeds the rate in revaccinees observed in earlier reports and the difference would be even greater if civilians who received primary vaccinations were excluded. This laboratory confirmation of GV demonstrates the potential of laboratory testing to determine the cause of a post-vaccination rash. Possible cases of GV in earlier surveillance efforts represented a mixed group of rashes, some of uncertain etiology (6). This patient’s clinical course is notable for the onset of GV 2 days after vaccination, as compared to a mean of 9 days (range 1–20+) after (generally primary) vaccination (2) and suggests that viremia can occur quickly after vaccination.

Background and Hypothesis: Technological advances have placed increasing emphasis on biochemical, echocardiographic, and invasive measurements for the purposes of predicting clinical outcomes among patients with heart failure (HF). We sought to re-evaluate the relationship between symptoms and physical findings and risk of death among a contemporary cohort of patients with heart failure treated with angiotensin-converting enzyme (ACE) inhibitors. Material and Methods: We performed retrospective analyses using the public access version of the Digitalis Investigation Group (DIG) trial database. Kaplan-Meier survival analyses with log-rank tests and proportional hazards models were used to study the relationship between symptoms and physical findings and risk of death among DIG trial participants. Results: A total of 7788 patients with HF were followed for a mean of 37 months. Of these, 77% were males, 65% had prior myocardial infarction, 94% were on ACE inhibitors, and 81% on diuretics. Mortality was significantly higher among patients with elevated jugular venous pressure (log-rank p<0.001), rales (p<0.001), edema (p<0.001), a third heart sound (p<0.001), and higher NYHA functional class (p<0.001). Proportional hazards models were constructed with adjustment for age, gender, race, ejection fraction, body mass index, serum creatinine, duration of HF, heart rate, systolic and diastolic blood pressure, diabetes, etiology of HF, and treatment with ACE inhibitors, diuretics, and digoxin. After simultaneous adjustments for all these factors, elevated jugular venous pressure (Hazard Ratio, HR 1.4, 95% CI 1.3–1.6, p<0.0001), rales (HR 1.6, 95% CI 1.4–1.9, p<0.001), edema (HR 1.4, 95% CI 1.2–1.5, p<0.001), third heart sound (HR 1.2, 95% CI 1.1–1.4, p<0.001), and higher NYHA class (HR 2.1, 95% CI 1.7–2.8, p<0.001) remained strong independent predictors of death. Per the DIG trial protocol, the chronicity or persistence of symptoms and physical findings were noted at study enrollment as existing only within the prior month ("present"), only prior to that ("past) or both ("past-present"). This simple designation was highly related to the risk of death. Patients without a history of rales had 74% actuarial survival. Past history of rales was associated with a 7% decline in survival (95% CI 6–9), present rales with a 14% decline (95% CI 10–19), and past-present rales with a 24% decline (95% CI 21–27) (p<0.001). Similar trends were observed for elevated jugular venous pressure, edema, and third heart sound. Patients in NYHA class I at enrollment had a 78% actuarial survival. When compared with class I, class II patients had a 7% decline in survival (95% CI 6–9); class III a 22% decline (95% CI 20–24); and class IV NYHA CHF a staggering 40% decline in survival (95% CI 32–48) (p<0.001). Conclusions: In a large contemporary cohort of patients with HF treated with ACE inhibitors, symptoms and physical findings remain potent and independent predictors of long-term survival. The chronicity or persistence of symptoms is also important as evidence of clinical improvement appears to improve survival. Background and Hypothesis: Technological advances have placed increasing emphasis on biochemical, echocardiographic, and invasive measurements for the purposes of predicting clinical outcomes among patients with heart failure (HF). We sought to re-evaluate the relationship between symptoms and physical findings and risk of death among a contemporary cohort of patients with heart failure treated with angiotensin-converting enzyme (ACE) inhibitors. Material and Methods: We performed retrospective analyses using the public access version of the Digitalis Investigation Group (DIG) trial database. Kaplan-Meier survival analyses with log-rank tests and proportional hazards models were used to study the relationship between symptoms and physical findings and risk of death among DIG trial participants. Results: A total of 7788 patients with HF were followed for a mean of 37 months. Of these, 77% were males, 65% had prior myocardial infarction, 94% were on ACE inhibitors, and 81% on diuretics. Mortality was significantly higher among patients with elevated jugular venous pressure (log-rank p<0.001), rales (p<0.001), edema (p<0.001), a third heart sound (p<0.001), and higher NYHA functional class (p<0.001). Proportional hazards models were constructed with adjustment for age, gender, race, ejection fraction, body mass index, serum creatinine, duration of HF, heart rate, systolic and diastolic blood pressure, diabetes, etiology of HF, and treatment with ACE inhibitors, diuretics, and digoxin. After simultaneous adjustments for all these factors, elevated jugular venous pressure (Hazard Ratio, HR 1.4, 95% CI 1.3–1.6, p<0.0001), rales (HR 1.6, 95% CI 1.4–1.9, p<0.001), edema (HR 1.4, 95% CI 1.2–1.5, p<0.001), third heart sound (HR 1.2, 95% CI 1.1–1.4, p<0.001), and higher NYHA class (HR 2.1, 95% CI 1.7–2.8, p<0.001) remained strong independent predictors of death. Per the DIG trial protocol, the chronicity or persistence of symptoms and physical findings were noted at study enrollment as existing only within the prior month ("present"), only prior to that ("past) or both ("past-present"). This simple designation was highly related to the risk of death. Patients without a history of rales had 74% actuarial survival. Past history of rales was associated with a 7% decline in survival (95% CI 6–9), present rales with a 14% decline (95% CI 10–19), and past-present rales with a 24% decline (95% CI 21–27) (p<0.001). Similar trends were observed for elevated jugular venous pressure, edema, and third heart sound. Patients in NYHA class I at enrollment had a 78% actuarial survival. When compared with class I, class II patients had a 7% decline in survival (95% CI 6–9); class III a 22% decline (95% CI 20–24); and class IV NYHA CHF a staggering 40% decline in survival (95% CI 32–48) (p<0.001). Conclusions: In a large contemporary cohort of patients with HF treated with ACE inhibitors, symptoms and physical findings remain potent and independent predictors of long-term survival. The chronicity or persistence of symptoms is also important as evidence of clinical improvement appears to improve survival.

Purpose The possible benefit that hospital teaching status may confer in the care of patients with cardiovascular disease is unknown. Our purpose was to determine the effect of hospital teaching status on in-hospital mortality, use of invasive procedures, length of stay, and charges in patients with myocardial infarction, heart failure, or stroke. Subjects and methods We analyzed a New York State hospital administrative database containing information on 388 964 consecutive patients who had been admitted with heart failure (n = 173 799), myocardial infarction (n = 121 209), or stroke (n = 93 956) from 1993 to 1995. We classified the 248 participating acute care hospitals by teaching status (major, minor, nonteaching). The primary outcomes were standardized in-hospital mortality ratios, defined as the ratio of observed to predicted mortality. Results Standardized in-hospital mortality ratios were significantly lower in major teaching hospitals (0.976 for heart failure, 0.945 for myocardial infarction, 0.958 for stroke) than in nonteaching hospitals (1.01 for heart failure, 1.01 for myocardial infarction, 0.995 for stroke). Standardized in-hospital mortality ratios were significantly higher for patients with stroke (1.06) but not heart failure (1.0) or myocardial infarction (1.06) in minor teaching hospitals than in nonteaching hospitals. Compared with nonteaching hospitals, use of invasive cardiac procedures and adjusted hospital charges were significantly greater in major and minor teaching hospitals for all three conditions. The adjusted length of stay was also shorter for myocardial infarction in major teaching hospitals and longer for stroke in minor teaching hospitals. Conclusion Major teaching hospital status was an important determinant of outcomes in patients hospitalized with myocardial infarction, heart failure, or stroke in New York State.

OBJECTIVES:The purpose of our study was to determine if the presence of African American ethnicity modulates improvement in coronary vascular endothelial function after supplementary L-arginine. BACKGROUND:Endothelial dysfunction is an early stage in the development of coronary atherosclerosis and has been implicated in the pathogenesis of hypertension and cardiomyopathy. Amelioration of endothelial dysfunction has been demonstrated in patients with established coronary atherosclerosis or with risk factors in response to infusion of L-arginine, the precursor of nitric oxide. Racial and gender patterns in L-arginine responsiveness have not, heretofore, been studied. METHODS:Invasive testing of coronary artery and microvascular reactivity in response to graded intracoronary infusions of acetylcholine (ACh) +/- L-arginine was carried out in 33 matched pairs of African American and white subjects with no angiographic coronary artery disease. Pairs were matched for age, gender, indexed left ventricular mass, body mass index and low-density lipoprotein cholesterol. RESULTS:In addition to the matching parameters, there were no significant differences in peak coronary blood flow (CBF) response to intracoronary adenosine or in the peak CBF response to ACh before L-arginine infusion. However, absolute percentile improvement in CBF response to ACh infusion after L-arginine, as compared with before, was significantly greater among African Americans as a group (45 +/- 10% vs. 4 +/- 6%, p = 0.0016) and after partitioning by gender. The mechanism of this increase was mediated through further reduction in coronary microvascular resistance. L-arginine infusion also resulted in greater epicardial dilator response after ACh among African Americans. CONCLUSIONS:We conclude that intracoronary infusion of L-arginine provides significantly greater augmentation of endothelium-dependent vascular relaxation in those of African American ethnicity when compared with matched white subjects drawn from a cohort electively referred for coronary angiography. Our findings suggest that there are target populations in which supplementary L-arginine may be of therapeutic benefit in the amelioration of microvascular endothelial dysfunction. In view of the excess prevalence of cardiomyopathy among African Americans, pharmacologic correction of microcirculatory endothelial dysfunction in this group is an important area of further investigation and may ultimately prove to be clinically indicated.

BACKGROUND Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNHL) are prevalent disorders that occur alone or as components of complex multisystem syndromes. Multiple genetic loci have been identified that, when mutated, cause DCM or SNHL. However, the isolated coinheritance of these phenotypes has not been previously recognized. METHODS AND RESULTS Clinical evaluations of 2 kindreds demonstrated autosomal-dominant transmission and age-related penetrance of both SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss was evident by late adolescence, whereas ventricular dysfunction produced progressive congestive heart failure after the fourth decade. DNA samples from the larger kindred (29 individuals) were used to perform a genome-wide linkage study. Polymorphic loci on chromosome 6q23 to 24 were coinherited with the disease (maximum logarithm of odds score, 4.88 at locus D6S2411). The disease locus must lie within a 2.8 cM interval between loci D6S975 and D6S292, a location that overlaps an SNHL disease locus (DFNA10). However, DFNA10 does not cause cardiomyopathy. The epicardin gene, which encodes a transcription factor expressed in the myocardium and cochlea, was assessed as a candidate gene by nucleotide sequence analysis; no mutations were identified. CONCLUSIONS A syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at 6q23 to 24 (locus designated CMD1J). Recognition of this cardioauditory disorder allows for the identification of young adults at risk for serious heart disease, thereby enabling early intervention. Definition of the molecular cause of this syndrome may provide new information about important cell physiology common to both the ear and heart.