Impaired formation of beta-adrenergic receptor-nucleotide regulatory protein complexes in pseudohypoparathyroidism.

Decreased activity of the guanine nucleotide regulatory protein (N) of the adenylate cyclase system is present in cell membranes of some patients with pseudohypoparathyrodism (PHP-Ia) whereas others have normal activity of N (PHP-Ib). Low N activity in PHP-Ia results in a decrease in hormone (H)-stimulatable adenylate cyclase in various tissues, which might be due to decreased ability to form an agonist-specific high affinity complex composed of H, receptor (R), and N. To test this hypothesis, we compared beta-adrenergic agonist-specific binding properties in erythrocyte membranes from five patients with PHP-Ia (N = 45% of control), five patients with PHP-Ib (N = 97%), and five control subjects. Competition curves that were generated by increasing concentrations of the beta-agonist isoproterenol competing with [125I]pindolol were shallow (slope factors less than 1) and were computer fit to a two-state model with corresponding high and low affinity for the agonist. The agonist competition curves from the PHP-Ia patients were shifted significantly (P less than 0.02) to the right as a result of a significant (P less than 0.01) decrease in the percent of beta-adrenergic receptors in the high affinity state from 64 +/- 22% in PHP-Ib and 56 +/- 5% in controls to 10 +/- 8% in PHP-Ia. The agonist competition curves were computer fit to a "ternary complex" model for the two-step reaction: H + R + N in equilibrium HR + N in equilibrium HRN. The modeling was consistent with a 60% decrease in the functional concentration of N, and was in good agreement with the biochemically determined decrease in erythrocyte N protein activity. These in vitro findings in erythrocytes taken together with the recent observations that in vivo isoproterenol-stimulated adenylate cyclase activity is decreased in patients with PHP (Carlson, H. E., and A. S. Brickman, 1983, J. Clin. Endocrinol. Metab. 56:1323-1326) are consistent with the notion that N is a bifunctional protein interacting with both R and the adenylate cyclase. It may be that in patients with PHP-Ia a single molecular and genetic defect accounts for both decreased HRN formation and decreased adenylate cyclase activity, whereas in PHP-Ib the biochemical lesion(s) appear not to affect HRN complex formation.

Quantification of aortic regurgitation utilizing continuous wave Doppler ultrasound.

Aortic regurgitation and mitral stenosis are hemodynamically similar, insofar as both result in passive ventricular filling across a narrow orifice driven by a declining pressure gradient. Because mitral stenosis is successfully characterized by Doppler ultrasound determination of the velocity half-time, or time constant, aortic regurgitation might be quantified in an analogous fashion. Eighty-six patients with diverse causes of aortic regurgitation underwent continuous wave Doppler examination before cardiac catheterization or urgent aortic valve replacement. The Doppler velocity half-time was defined as the time required for the diastolic aortic regurgitation velocity profile to decay by 29%, whereas catheterization pressure half-time was calculated as the time required for transvalvular pressure to decay by 50%. Doppler velocity and catheterization pressure half-times were linearly related (r = 0.91). Doppler velocity half-times were inversely related to regurgitant fraction (r = -0.88). Angiographic severity (1+ = mild to 4+ = severe) was also inversely related to pressure and velocity half-time; a Doppler half-time threshold of 400 ms separated mild (1+, 2+) from significant (3+, 4+) aortic regurgitation with high specificity (0.92) and predictive value (0.90). The Doppler velocity half-time was independent of pulse pressure, mean arterial pressure, ejection fraction and left ventricular end-diastolic pressure. Estimation of transvalvular aortic pressure half-time utilizing continuous wave Doppler ultrasound is a reliable and accurate method for the noninvasive evaluation of the severity of aortic regurgitation.

Reassessment of the association between gastrointestinal arteriovenous malformations and aortic stenosis.

PURPOSE AND PATIENTS AND METHODS: The purported association between aortic stenosis and gastrointestinal arteriovenous malformations (AVMs) has not been rigorously evaluated. The diagnosis of aortic stenosis in most the prior studies has been based on clinical examination. We therefore utilized two-dimensional and Doppler echocardiography to document the presence or absence of aortic stenosis in 29 men with gastrointestinal AVMs documented by endoscopy. RESULTS: Of the 29 patients studied, 22 (76 percent) had ejection systolic murmurs and 18 (62 percent) had echocardiographic evidence of aortic sclerosis. However, none of the patients had any evidence of aortic stenosis as assessed by Doppler echocardiography. CONCLUSION: Although previous case reports and retrospective studies have suggested an association between gastrointestinal AVMs and aortic stenosis, our study does not support this association and suggests the need for a prospective trial.

Influence of underlying coronary artery disease on the natural history and prognosis of exercise-induced left bundle branch block.

The long-term prognosis of exercise-induced left bundle branch block (BBB) in patients with and without underlying coronary artery disease (CAD) was examined by following 15 patients (7 with normal coronary arteries and 8 with CAD) for an average of 6.6 years (range 2.2 to 11.2). Over the follow-up interval, permanent left BBB developed in 8 of the 15 patients. Seven of these 8 had underlying CAD, compared to 0 of 6 patients with normal coronary arteries and normal left ventricular function (p less than 0.002). In 1 patient with normal coronary arteries and a left ventricular ejection fraction of 0.34, permanent left BBB developed. During follow-up, 4 patients died; 3 had significant CAD and 1 had depressed left ventricular function. In no patient did high-grade atrioventricular block develop and no patient required pacing. Thus, development of permanent left BBB in patients with exercise-induced left BBB is related to presence or absence of underlying CAD or myocardial disease. When left BBB is found in the absence of underlying heart disease, there does not tend to be progression of the conduction disturbance and the prognosis is excellent.

A randomized factorial trial of reperfusion strategies and aspirin dosing in acute myocardial infarction. The DUCCS-II Investigators.

The focus of new research efforts to improve the morbidity and mortality associated with acute myocardial infarction (AMI) has turned to adjuvant agents that show promise of improving outcomes following coronary thrombolysis. We enrolled 162 patients with AMI in a randomized trial comparing front-loaded tissue-plasminogen activator (t-PA) plus weight-adjusted heparin with anisoylated plasminogen streptokinase activator complex (APSAC) without heparin as well as standard-dose (325 mg) and low-dose (81 mg) aspirin. The primary end point was an in-hospital morbidity profile; secondary end points were clinical and angiographic potency and hemorrhagic events. Selected sites performed an electrocardiographic substudy to determine the time to 50% ST-segment recovery and the time to steady state. Although the trial was terminated when the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I trial showed that t-PA had a significant mortality advantage over streptokinase, important trends were evident. Patients given t-PA and heparin were better anticoagulated (p = 0.001), yet AP-SAC-treated patients had more bleeding complications. The primary end point favored t-PA (25.4% vs 31.3%), and the secondary end points were similar in both groups. In the electrocardiographic substudy, the t-PA group achieved both 50% ST-segment recovery and steady-state recovery sooner than the APSAC group. Patients taking low-dose aspirin had lower in-hospital mortality and less recurrent ischemia but more strokes than the standard-dose aspirin group. Thus, this trial demonstrated trends favoring front-loaded t-PA with weight-adjusted heparin over APSAC without heparin in the treatment of AMI. The use of low-dose aspirin did not appear to impose a loss of protection from adverse events, nor did standard-dose aspirin increase serious bleeding.

The impact of aging on adrenergic receptor function: clinical and biochemical aspects.

From this discussion, several conclusions can be drawn. First, with advancing age there is a decrease in cardiovascular responsiveness and, more specifically, there is a decrease in catecholamine-stimulated chronotropic and inotropic responses. This decreased function has its biochemical correlate in the observation that cyclic AMP levels are decreased in response to isoproterenol infusion in cells or tissues derived from aged organisms. Second, although most work on human circulating cells suggests that beta-adrenergic receptor densities are unchanged, measurements of beta-adrenergic receptor concentrations in various cells from various animals (predominantly rats) have yielded conflicting results. Some of this disparity could be due to the observation that local concentrations of norepinephrine, such as those found intramyocardially, may be very different from those in circulating plasma. Indeed, whereas circulating norepinephrine levels tend to rise with age, the intramyocardial norepinephrine levels tend to fall with senescence. Thus, circulating lymphocytes may or may not be an appropriate model to reflect the catecholamine milieu to which other tissues may be exposed. Accordingly, a note of caution must be entered in terms of extrapolating findings regarding the levels of human lymphocyte beta-adrenergic receptors and cyclic AMP activity to those found, for example, in the human heart. Furthermore, it is likely that age-related changes in adrenergic function may be the result of changes in coupling of receptors to the adenylate cyclase system, as suggested by Feldman and co-workers, and/or changes in steps distal to cyclase activation, as suggested by Guarnieri and colleagues.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural network analysis of serial cardiac enzyme data. A clinical application of artificial machine intelligence.

There has been a recent resurgence of interest in the study and application of computerized neural networks within the broad field of artificial intelligence. These "intelligent machines" are modeled after biological nervous systems and are fundamentally different from the many computerized expert systems that previously have been introduced as clinical decision-making aids. The authors describe a neural network designed and trained to predict the probability of acute myocardial infarction (AMI) based on the analysis of paired sets of cardiac enzymes. The neural network predicted 24 of 24 (100%) AMIs and 27 of 29 (93%) No-AMIs when compared with a pathologist's interpretation of the patient's laboratory data (P less than 0.000001). The authors attempted to validate the network's diagnoses by two independent methods. When compared with echocardiogram and EKG for diagnosis of AMI, the neural network agreed with the cardiologist's interpretation in 12 of 14 (86%) AMIs and 1 of 3 (33%) No-AMIs, but the correlation was not statistically significant. Using autopsy outcome for validation, the neural network agreed with the anatomic evidence in 24 of 26 (92%) AMIs and 4 of 6 (67%) No-AMIs (P = 0.001). The authors conclude that neural networks can be successfully applied to the analysis of cardiac enzyme data and suggest that broader applications exist within the domain of clinical decision support.

Rate-related left bundle branch block with chest pain and normal coronary arteriograms treated by exercise training.

A clinical observation of chest pain associated with the onset of rate-related left bundle branch block has been described in patients with normal coronary arteriograms. The authors used standard cardiac rehabilitation techniques for exercise training in a 47-year-old woman with these manifestations. Serial treadmill tests revealed that during the course of 3 months of exercise training, the heart rate at onset of LBBB gradually rose from 133 to 175 beats per minute, and she no longer developed symptoms during her routine daily activities or exercises. Exercise training was a successful nonpharmacologic strategy that delayed the onset of rate-related LBBB and chest pain in this patient and avoided the need for beta blocker therapy.

The beta-adrenergic receptor in heart failure.

Although the role of the autonomic nervous system in the pathophysiology of heart failure has been studied for decades, only within the past few years have adrenergic receptors and their alterations occupied center stage. There is now considerable evidence linking such receptors to many of the phenomena of heart failure; recent work appears to have significant therapeutic implications.

Supine cross-table lateral chest roentgenogram for the detection of pericardial effusion.

We performed a prospective, blinded, controlled study to test the hypothesis that supine cross-table lateral chest roentgenograms might have an advantage over conventional lateral chest roentgenograms for the detection of pericardial effusion using the epicardial fat stripe sign. In comparison with echocardiography as the gold standard, we found that supine cross-table lateral chest roentgenograms had greater sensitivity (51%) for pericardial effusions than conventional lateral chest roentgenograms (sensitivity, 31%). Specificity was essentially the same for both techniques. A large pericardial effusion was more readily detected by supine cross-table lateral chest roentgenograms (86%) than by the conventional lateral chest roentgenograms (36%). We conclude that a supine cross-table lateral chest roentgenogram should be included in the evaluation of patients with suspected pericardial effusion or in patients in whom a large cardiac silhouette is detected on a standard chest roentgenogram.

Intravenous nitroglycerin in the treatment of spontaneous angina pectoris: a prospective, randomized trial.

A prospective, randomized study of i.v. nitroglycerin (TNG) in the management of repetitive spontaneous angina pectoris was undertaken in 40 consecutive patients. The clinical effectiveness of i.v. TNG (group A) was compared with that of oral isosorbide dinitrate (ISDN) and topical 2% nitroglycerin ointment (NO) in combination (group B) during a 72-hour treatment period. The doses of both nitrate regimens were adjusted so that the mean arterial pressure in the two groups was reduced by 15 +/- 3% of control values to the same level (77 mm Hg). The i.v. TNG dose of 10-200 micrograms/min yielded arterial plasma TNG levels of 1.2-65.3 ng/ml and estimated plasma (arterial) clearance of 106 +/- 55 ml/min/kg of body weight (mean +/- SD). In group B, the doses were 20-60 mg (oral ISDN) and 1/2-2 inches (NO) every 6 hours. Intravenous TNG reduced the number of spontaneous ischemic episodes from 3.3 +/- 0.8 per 24 hours during the control period to 1.0 +/- 0.3 per 24 hours during the treatment period (p less than 0.01), while the ISDN/NO combination reduced the number of episodes from 3.1 +/- 0.4 to 1.4 +/- 0.3 (p less than 0.01). Overall, the magnitude of the therapeutic effect of i.v. TNG was statistically indistinguishable from that of ISDN/NO, although i.v. TNG did have somewhat greater clinical benefit on day 2 of the 3-day treatment period. Furthermore, the data suggested more consistent control of ischemic episodes with i.v. TNG during the first 24 hours of the trial. Although both regimens markedly reduced the frequency of spontaneous ischemic episodes, only 36% of patients in group A and 17% in group B experienced no ischemic episodes during the study period (NS). Forty-three percent of patients in group A and 61% in group B (NS) required early coronary artery bypass surgery to control recurrent ischemic episodes refractory to medical therapy. We conclude that i.v. TNG and ISDN/NO, when administered in doses adjusted to produce similar effects on systemic arterial pressure, have nearly equivalent clinical effects in the management of patients with frequent episodes of spontaneous angina pectoris. Intravenous TNG offers the advantage of more consistent control of ischemic episodes during the first 24 hours of treatment. Nevertheless, the recurrence rate of spontaneous ischemic episodes during medical therapy is high with both regimens, and early coronary artery bypass surgery may be required for long-term management.

Blood loss in major lipoplasty procedures with the tumescent technique.

BACKGROUND: Intraoperative blood loss and postoperative anemia have been a concern when more than 1500 ml of lipoplasty material is aspirated. Blood loss is minimal when the targeted area is infiltrated with large volumes of dilute lidocaine and epinephrine. However, little quantitative data are available regarding the intraoperative blood loss and postoperative hemoglobin drop. METHODS: In this prospective study 38 consecutive women were investigated with preoperative measurement of hemoglobin, platelet count, prothrombin time, activated partial thromboplastin time, and postoperative measurement of hemoglobin. Hemoglobin and whole blood volume were calculated from the infranatant portion of the lipoplasty aspirate. All procedures were done with the patient under general anesthesia. RESULTS: The mean (+/-SD) volume of lipoplasty aspirate material was 2900+/-14702.8 ml (range 1000 to 5800 ml). The mean (+/-SD) whole blood volume in lipoplasty aspirate per case was 36+/-50.82 ml (range 1.2 to 251 ml). The mean (+/-SD) fall in hemoglobin was 0.93+/-0.92 gm/dl (range 0.2 to 4.3 gm/dl). The volume of whole blood loss was estimated to be 12.4 ml in each 1000 ml of lipoplasty aspirate. No blood transfusions were required. CONCLUSION: Data show that blood loss with the tumescent technique is remarkably low. Use of this technique permits large-volume lipoplasty aspirate and minimizes the need for blood transfusion.

Valvular regurgitation: dynamic MR imaging.

Cine magnetic resonance (MR) imaging is a new technique that combines short repetition times, limited flip angles, gradient refocused echoes, and cardiac gating. This technique has a temporal resolution of up to 32 time frames per cardiac cycle and accentuates signal from flowing blood. Cine MR images of 56 valves in 27 patients were evaluated and compared with either Doppler echocardiograms or cardiac catheterization images. An area of decreased signal that correlated spatially and temporally with regurgitant blood flow was seen in all instances in which valvular incompetence was demonstrated on either Doppler echocardiograms or cardiac catheterization images (20 valves). This abnormality was seen in nine of 36 cases without valvular incompetence. Cine MR imaging may be sensitive to turbulence and thus sensitive to valvular regurgitation.

Cine MR determination of left ventricular ejection fraction.

Cine MR imaging provides tomographic images of the heart with both high spatial and high temporal resolution. As many as 32 images per cardiac cycle can be acquired with up to four separate anatomic slices and a total imaging time of 128 cardiac cycles. End-diastolic and end-systolic volumes were determined in 11 patients, and ejection fractions were calculated. The results correlated linearly with those from cardiac catheterization (correlation coefficient of .88). We conclude that cine MR imaging can be used to obtain quantitative information about the heart and has the potential to become a valuable noninvasive means of cardiac evaluation.