Naomi S. Fineberg

Echocardiographic detection of coronary artery disease during dobutamine infusion.

BackgroundTwo-dimensional echocardiography performed during dobutamine infusion hasbeen proposed as a potentially useful method for detecting coronary artery disease. However, the safety and diagnostic value of dobutamine stress echocardiography has not been established. Methods and ResultsIn this study, echocardiograms were recorded during step-wise infusion of dobutamine to a maximum dose of 30 gg/kg/min in 103 patients who also underwent quantitative coronary angiography. The echocardiograms were digitally stored and displayed in a format that allowed simultaneous analysis of rest and stress images. Development of a new abnormality in regional function was used as an early end point for the dobutamine infusion. No patient had a symptomatic arrhythmia or complications from stress-induced ischemia. Significant coronary artery disease (<50% diameter stenosis) was present in 35 of 55 patients who had normal echocardiograms at rest. The sensitivity and specificity of dobutamine-induced wall motion abnormalities for coronary artery disease was 89% (31 of 35) and 85% (17 of 20), respectively. The sensitivity was 81% (17 of 21) in those with one-vessel disease and 100% (14 of 14) in those with multivessel or left main disease. Forty-one of 48 patients with abnormal echocardiograms at baseline had localized rest wall motion abnormalities. Fifteen had coronary artery disease confined to regions that had abnormal rest wall motion, and 26 had disease remote from these regions. Thirteen of 15 patients (87%) without remote disease did not develop remote stress-induced abnormalities, and 21 of 26 (81%) who had remote disease developed corresponding abnormalities. ConclusionsEchocardiography combined with dobutamine infusion is a safe and accurate method for detecting coronary artery disease and for predicting the extent of disease in those who have localized rest wall motion abnormalities.

Salt Sensitivity, Pulse Pressure, and Death in Normal and Hypertensive Humans

Although factors such as age, blood pressure, and its responsiveness to changes in sodium balance and extracellular fluid volume status (salt sensitivity) are associated with an increased risk of end-organ disease and cardiovascular events in hypertensive subjects, no such relationship with mortality has been demonstrated for salt sensitivity in normotensive subjects. We conducted long-term follow-up of 430 normal and 278 hypertensive subjects in whom assessment of salt sensitivity of blood pressure was performed as long as 27 years ago. We ascertained the status of 596 subjects (85% of the total population), 123 (21%) of whom had died. The following initial measurements were significantly (P <0.002) associated with subjects who had died compared with subjects known to be alive: age at study, pulse pressure, systolic, diastolic, and mean arterial pressures, hypertension, salt sensitivity, baseline renin levels, and body mass index (but not body weight). A stepwise logistic regression found the following independent predictors of death (odds ratio, 95% CI): age at initial study (1.08, 1.06 to 1.10), baseline blood pressure (1.03, 1.01 to 1.04), sodium sensitivity (1.73, 1.02 to 2.94), and male gender (1.91, 1.15 to 3.17). When survival curves were examined, normotensive salt-sensitive subjects aged >25 years when initially studied were found to have a cumulative mortality similar to that of hypertensive subjects, whereas salt-resistant normotensive subjects had increased survival (P <0.001). These observations provide unique evidence of a relationship between salt sensitivity and mortality that is independent of elevated blood pressure.

Sodium and volume sensitivity of blood pressure. Age and pressure change over time.

Salt sensitivity has been implicated in the age-related increase in blood pressure. We studied the reproducibility of a rapid method for assessing sodium sensitivity and resistance of blood pressure as well as the effect of age on this phenomenon. Blood pressure after volume expansion with 2 1 intravenous saline (0.9%) over 4 hours was compared with that after 1 day of 10 mmol sodium chloride intake and 3 and 40 mg oral doses of furosemide. Normal and hypertensive subjects (n=28) were studied twice within a year. Cross-sectional observations of the effect of age were made from studies in 230 hypertensive and 430 normotensive subjects. Longitudinal observations of blood pressure change over time were made 10 or more years after categorization of sodium responsivity in 31 subjects. The blood pressure response was reproducible in 28 subjects studied twice (r=0.56,p<0.002). Four subjects changed salt-responsiveness status and six were indeterminate on restudy. Sodium sensitivity of blood pressure increased significantly with increasing age in the entire population (n=660, r= ‐038,p<0.001). The relation was more striking in hypertensive subjects (n=230, r= -0.31,p<0.001) in whom a progressive increase in salt sensitivity with decades was seen than in the normotensive group (n=430, r=‐0.19, p<0.01) in whom salt sensitivity was not observed until the sixth decade. Salt-sensitive subjects had a significantly greater increase in systolic (p<0.001) and diastoiic (/?<0.01) pressure over time than those who were salt-resistant Salt sensitivity is a reproducible phenomenon that is related to the age-associated increase in blood pressure characteristic of industrialized societies. In addition, salt sensitivity can be shown to be a predictor of subsequent, age-related blood pressure increase.

Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics

Background. Preformed HLA antibodies (Ab), reported as panel-reactive antibody (PRA), prolong patient waiting time for kidney transplantation. We hypothesized that rituximab (RTX) could reduce PRA via B-cell depletion. This initial study reports the safety, pharmacokinetics, and pharmacodynamics of RTX in patients with end-stage renal failure. Methods. The study was an investigator-initiated single-dose, dose-escalation phase I trial of RTX in chronic dialysis patients (PRA >50%). It was approved by the Institutional Review Board and the Food and Drug Administration. Nine subjects were treated with a single dose of RTX (n=3 per group) at 50, 150, or 375 mg/m2. Peripheral lymphocyte cell surface markers and HLA Ab levels (%PRA and titers) were tested using flow cytometry. Results. There were four significant adverse events: a suspected histoplasmosis infection; two Tenchkoff dialysis catheter infections; and fever (38.7°C) during infusion. At 2 days after RTX therapy, there was depletion of CD19+ cells (pre-RTX 181±137 vs. post-RTX 12±5.6, P =0.006). In 2 (22%) of 9 subjects, there was no appreciable change in PRA. Among the other seven patients, one had a decrease in PRA from 87% to 51% with a concurrent decrease in fluorescence intensity; five patients had changes in histogram architecture suggesting loss of antibody specificity; and one patient had a fourfold decrease in PRA titer from 1:64 to 1:16 at 6 months after treatment. In addition, one of the seven patients converted a donor-specific crossmatch to negative and underwent a successful living donor kidney transplantation. Conclusions. RTX can be safely administered and may be an effective agent to reduce high-titer anti-HLA Abs in subjects awaiting kidney transplantation.

The Diabetes Education Study: A Controlled Trial of the Effects of Diabetes Patient Education

The Diabetes Education Study (DIABEDS) was a randomized, controlled trial of the effects of patient and physician education. This article describes a systematic education program for diabetes patients and its effects on patient knowledge, skills, self-care behaviors, and relevant physiologic outcomes. The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center. Patients were predominantly elderly, black women with non-insulin-dependent diabetes mellitus of long duration. Patients randomly assigned to experimental groups (N = 263) were offered up to seven modules of patient education. Each content area module contained didactic instruction (lecture, discussion, audio-visual presentation), skill exercises (demonstration, practice, feedback), and behavioral modification techniques (goal setting, contracting, regular follow-up). Two hundred seventy-five patients remained in the study throughout baseline, intervention, and postintervention periods (August 1978 to July 1982). Despite the requirement that patients demonstrate mastery of educational objectives for each module, postintervention assessment 11–14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge. However, statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous. Experimental group patients experienced significantly greater reductions in fasting blood glucose (−27.5 mg/dl versus −2.8 mg/dl, P < 0.05) and glycosylated hemoglobin (−0.43% versus + 0.35%, P < 0.05) as compared with control subjects. Patient education also had similar effects on body weight, blood pressure, and serum creatinine. Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization.

Effects of volume expansion and contraction in normotensive whites, blacks, and subjects of different ages.

We studied the blood pressure, natriuretic, kaliuretic and humoral responses of 347 normal subjects after volume expansion and volume contraction to examine possible differences among whites, blacks and subjects of different ages. According to outpatient 24-hour urine collections, blacks excreted less sodium and potassium than whites. After similar states of sodium intake were achieved among all subjects, 2 liters normal saline were given i.v. Blacks and subjects 40 years excreted less sodium than whites or subjects > 40 years, over a 24-hour period. In addition, blacks excreted less potassium. The delay in sodium excretion occurred during the first 12 hours after the salt load. Blacks had a greater suppression of plasma renin activity than whites 24 hours after saline. Blacks also had higher blood pressures than whites after saline administration; their pressure remained elevated until furosemide was given. Furosemide, 120 mg over 24 hours, evoked greater natriuresis, but less kaliuresis in blacks than in whites. The greater prevalence of hypertension in both blacks and older subjects may be related to relatively blunted natriuretic responses when these groups engage in the high sodium-low potassium intake characteristic of our society.

Clinical features of amiodarone-induced pulmonary toxicity.

The incidence and clinical predictors of amiodarone pulmonary toxicity were examined in 573 patients treated with amiodarone for recurrent ventricular (456 patients) or supraventricular (117 patients) tachyarrhythmias. Amiodarone pulmonary toxicity was diagnosed in 33 of the 573 patients (5.8%), based on symptoms and new chest radiographic abnormalities (32 of 33 patients) and supported by abnormal pulmonary biopsy (13 of 14 patients), low pulmonary diffusion capacity (DLCO) (nine of 13 patients), and/or abnormal gallium lung scan (11 of 16 patients). Toxicity occurred between 6 days and 60 months of treatment for a cumulative risk of 9.1%, with the highest incidence occurring during the first 12 months (18 of 33 patients). Older patients developed it more frequently (62.7 +/- 1.7 versus 57.4 +/- 0.5 years, p = 0.018), with no cases diagnosed in patients who started therapy at less than 40 years of age. Gender, underlying heart disease, arrhythmia, and pretreatment chest radiographic, spirometric, or lung volume abnormalities did not predict development of amiodarone pulmonary toxicity, whereas pretreatment DLCO was lower in the group developing it (76.0 +/- 5.5% versus 90.4 +/- 1.4%, p = 0.01). There was a higher mean daily amiodarone maintenance dose in the pulmonary toxicity group (517 +/- 25 versus 409 +/- 6 mg, p less than 0.001) but no difference in loading dose. No patient receiving a mean daily maintenance dose less than 305 mg developed pulmonary toxicity. Patients who developed toxicity had higher plasma desethylamiodarone (2.34 +/- 0.18 versus 1.92 +/- 0.04 micrograms/ml, p = 0.009) but not amiodarone concentrations during maintenance therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional Wall Motion Index for Infarct and Noninfarct Regions after Reperfusion in Acute Myocardial Infarction: Comparison With Global Wall Motion Index

A regional wall motion index has been derived from two-dimensional echocardiograms by use of a 16-segment model that was subdivided into anterior (nine segments) and infero-postero-lateral (seven segments) regions. This new method is compared with the use of a previously described global wall motion index for the analysis of serial echocardiograms after reperfusion in 23 patients who had acute myocardial infarction. Mean global index improved from 1.84 +/- 0.46 to 1.56 +/- 0.37 at 24 hours (p less than 0.01) and to 1.50 +/- 0.29 after 3 days to 7 days (p less than 0.02), whereas mean regional index for infarct regions improved from 2.28 +/- 0.73 to 1.82 +/- 0.58 at 24 hours (p less than 0.01) and to 1.70 +/- 0.42 after 3 to 7 days (p less than 0.01), with no significant change in the noninfarct index (1.34 +/- 0.32 initially and 1.28 +/- 0.36 after 3 to 7 days). Although both global and regional indexes effectively demonstrate early recovery of left ventricular function, (within 24 hours in many patients), the regional index for infarct regions is higher than the global index and effectively distinguishes between infarct and noninfarct segments. An overlap index in which an additional apical segment is included in the anterior region (10 segments) for anterior infarctions and in the infero-postero-lateral region (eight segments) for inferior infarctions results in a greater differentiation between infarct and noninfarct regions, with the mean initial noninfarct overlap index (1.17 +/- 0.33) significantly less than the nonoverlap index.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise echocardiographic detection of coronary artery disease in women

The utility of exercise echocardiography for the diagnosis of coronary artery disease has been demonstrated in populations consisting largely of men with a high prevalence of disease. To determine the diagnostic value of exercise echocardiography in women, 57 women who presented with chest pain were studied with coronary cineangiography and echocardiography combined with either treadmill (n = 38) or bicycle exercise (n = 19). Significant coronary artery disease (greater than or equal to 50% reduction in luminal diameter) was present in 28 (49%) of 57 patients, including 16 (84%) of 19 who had typical angina, and 12 (32%) of 38 who had atypical chest pain. The overall sensitivity and specificity of echocardiography were both 86%. Exercise echocardiography correctly determined the presence or absence of coronary artery disease in 32 (84%) of 38 patients who had atypical chest pain and in 17 (89%) of 19 who had typical angina (p = NS). The exercise electrocardiogram (ECG) was nondiagnostic in 17 patients (30%) who had rest ST segment depression or ST depression with exercise that could also be induced by hyperventilation or changes in position. The correct diagnosis was made by echocardiography in 14 (82%) of 17 patients with a nondiagnostic exercise ECG. In conclusion, exercise echocardiography has a clinically useful level of sensitivity and specificity for the detection of coronary artery disease in women. The technique provides diagnostic information in women presenting with atypical chest pain and in those who have a nondiagnostic exercise ECG.

Estimating dietary sodium intake in individuals receiving a randomly fluctuating intake.

Previous investigations examining techniques to estimate sodium intake in free-living persons failed to consider a varying intake or were not conducted under circumstances in which the intake was actually known. To examine the utility of 24-hour and nocturnal urine collections as estimation of sodium intake under such conditions, we studied 43 white and black men and women ingesting a known sodium intake for 10 days that was randomly varied daily, with a mean intake of 150/+ 2SD (range, 50 to 250/). The mean 24-hour sodium excretion (UNaV) per day was 141/while the mean sodium intake was 151/. On a randomly selected day, both nocturnal and 24-hour UNaV estimated that days sodium intake reasonably well (r = 0.55). A stepwise regression showed that including consideration of age and blood pressure improved the correlation (r = 0.70). However, to estimate mean sodium intake accurately for the entire 10 days, the average of several 24-hour collections was required. Nine collections were optimal (r = 0.75). Nocturnal specimens were not helpful; the average of all 10 collections correlated weakly (r = 0.30) with sodium intake. These data sugj.est that to estimate mean sodium intake accurately in free-living persons, only 24-hour collections are useful, although nocturnal collections arc helpful in evaluating compliance with low sodium intake. (Hypertension 4: 805–808, 1982)