Sluggish sitosterol turnover and hepatic failure to excrete sitosterol into bile cause expansion of body pool of sitosterol in patients with sitosterolemia and xanthomatosis.

Sitosterolemia and xanthomatosis are characterized by the development of tendon and tuberous xanthomas at an early age and premature atherosclerosis despite normal plasma cholesterol concentrations. The reason(s) for the xanthoma formation and premature atherosclerosis are not clearly understood. The accumulation of sitosterol in the tissues of these patients could be due to increased uptake of low density lipoprotein (LDL) via LDL receptors because of an expanded sitosterol pool caused by sluggish turnover and decreased excretion of sitosterol into bile and feces coupled with the hyperabsorption of sitosterol. We have studied sitosterol and cholesterol turnovers, the biliary and fecal excretion of neutral and acidic steroids, and the response of plasma sterol (sitosterol and cholesterol) levels to either a sterol-free formula or low plant sterol diet in three patients. The average half-life of the first exponential (tA1/2) for sitosterol was 9.2 +/- 3.3 (mean +/- SD) days, which was more than twice that in normal humans. The second exponential (tB1/2) was 156 +/- 108 days, which was nearly 10 times longer than that for normal humans. The average cholesterol production rate in pool A was 0.87 g/day, which is about 40% of that in normal humans. Cholesterol synthesis measured by the sterol balance technique was also found to be about 70% lower than that for normal humans. In two patients fed a sterol-free formula diet, by 25 days their plasma sitosterol and cholesterol levels had decreased by 42% and 36%, respectively. However, in one patient plasma sitosterol and cholesterol concentrations remained unchanged while on the low plant sterol-mixed food diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Lutembacher syndrome or mitral stenosis and acquired atrial septal defect after transseptal mitral valvuloplasty.

Critical mitral stenosis in selected patients may be treated successfully with percutaneous mitral valvuloplasty. Complications of this procedure, particularly an atrial septal defect following transseptal approach, are generally of minor clinical significance. We describe a woman who initially underwent a successful percutaneous double-balloon mitral valvuloplasty via the transseptal approach. Three months later she presented with right-sided heart failure. Color Doppler echocardiography and cardiac catheterization demonstrated an atrial septal defect (ASD) as well as restenosis of the mitral valve. We conclude that significant ASDs may occur following transseptal mitral valvuloplasty with appearance of right ventricular failure and that color Doppler imaging aids in the diagnosis of this new variant of the classical Lutembacher syndrome.

Homologues of the human C and A apolipoproteins in the Macaca fascicularis (cynomolgus) monkey.

We used antisera to human A and C apolipoproteins to identify homologues of these proteins among the high-density lipoprotein apoproteins of Macaca fascicularis (cynomolgus) monkeys, and NH2-terminal analysis was used to verify the homology. The NH2-terminal sequence of the M. fascicularis apoA-I is identical with that of another Old World species, Erythrocebus patas, and differs from human apoA-I at only 4 of the first 24 residues. M. fascicularis apoA-II contains a serine for cysteine replacement at position 6 and is therefore monomeric like the apoA-II from all species below apes. Human and monkey apoA-II are not otherwise different through their first 25 residues. About 20% of M. fascicularis apoC-I aligns with human apoC-I through residue 22, and 80% lacks an NH2-terminal dipeptide. Otherwise, the monkey apoC-I differs from the human protein at only 2 of 25 positions. Two forms of M. fascicularis apoC-II were identified. ApoC-II1 is highly homologous with human apoC-II, whereas an NH2-terminal hexapeptide is absent from apoC-II2. ApoC-II2 was the predominant species, and apoC-II1 appears to represent a propeptide from which a hexapeptide prosegment is cleaved at a Gln-Asp bond. Both forms of monkey apoC-II are potent activators of lipoprotein lipase. There are two polymorphic forms of M. fascicularis apoC-III, and their electrophoretic mobilities become identical after treatment with neuraminidase. Except for a glycine for serine substitution at position 10, the first 15 NH2-terminal residues of M. fascicularis and human apoC-III are the same.

No increase in serum digoxin concentration with high-dose diltiazem.

The effect of incremental diltiazem dosing during concomitant digoxin administration over a four-week period in eight healthy adult volunteers (mean age, 28 +/- 4 years) was studied. The study group received 0.25 mg of digoxin twice daily for two days, after which they received 0.25 mg daily for the duration of the study. Following baseline electrocardiographic evaluation and measurement of trough digoxin levels, all subjects received 120 mg of diltiazem daily for one week, then 240 mg daily for one week, followed by 360 mg daily for one week. Resting electrocardiographic parameters (heart rate, P-R interval), renal function, electrolyte values, and digoxin and diltiazem concentrations were measured weekly. Daily administration of 360 mg of diltiazem plus 0.25 mg of digoxin resulted in a significant decrease in heart rate (from 68 +/- 9 beats per minute to 61 +/- 10 beats per minute; p less than 0.05), a marginal increase in P-R interval (from 169 +/- 22 msec to 179 +/- 21 msec; p = 0.08), and no significant change in trough serum digoxin concentration (from 0.85 +/- 0.08 ng/ml to 0.90 +/- 0.08 ng/ml; p = NS). The administration of up to 360 mg of diltiazem per day with 0.25 mg of digoxin per day was not associated with significant increases in serum digoxin concentrations in healthy subjects.

Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study.

The effects of orally administered diltiazem combined with maximally tolerated doses of beta-blockers and nitrates were assessed in 12 patients, who during stress testing exhibited persistent effort angina and continued objective evidence for inducible myocardial ischemia. Patients performed multistage semisupine exercise on a bicycle ergometer during equilibrium-gated radionuclide angiography after consecutive 2 week treatment periods of placebo or diltiazem 90 mg qid (mean dose 340 mg/day) combined with maximally tolerated propranolol (mean dose 178 mg/day) and isosorbide dinitrate (mean dose 137 mg/day). All medications (including diltiazem or placebo) were administered four times daily for the duration of the study. Diltiazem or placebo was administered according to a double-blind design, with randomized cross-over at the end of each 2 week treatment period. The average number of angina attacks decreased during the double-blind cross-over phase of the trial (7 +/- 7 episodes/week at baseline vs 4 +/- 3 on placebo vs 2 +/- 2 on diltiazem; p = .08). Angina pectoris was abolished during peak exercise in eight of 12 patients on diltiazem (p less than .05 vs placebo). Diltiazem increased total exercise duration from 276 +/- 92 to 310 +/- 78 sec (p less than .005 vs baseline). Diltiazem likewise increased the time to onset of angina from 231 +/- 84 sec at baseline to 305 +/- 77 sec (p less than .005), as well as the time to the onset of 1 mm ischemic ST segment depression (p = .01). Diltiazem decreased heart rate at rest, during submaximal workload, and at peak exercise (p less than .05), and decreased systolic blood pressure at peak exercise only (p less than .05). A significant decline in rate-pressure product at submaximal and peak exercise was noted (p less than .05). At any given workload there was significantly less ST segment depression during submaximal (p = .05) and peak exercise (p less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)

Inferoseptal myocardial infarction: another cause of precordial ST-segment depression in transmural inferior wall myocardial infarction?

Electrocardiographic ST-segment depression in the anterior precordial leads is a frequent observation during the initial hospital phase of acute transmural inferior myocardial infarction (MI), but is of uncertain significance. No available clinical studies have examined the prevalence of inferoseptal necrosis complicating inferior MI. Therefore, the clinical course, electrocardiographic features, radionuclide angiograms and cardiac enzyme changes in 57 patients with transmural inferior MI who did not have prior anterior or concomitant "true posterior" MI, associated anterior or posterolateral asynergy by radionuclide ventriculography, or left or right bundle branch block were reviewed retrospectively. Patients were categorized according to the presence (group A) or absence (group B) of precordial ST-segment depression and according to the presence (group I) or absence (group II) of radionuclide septal wall motion abnormalities. There were no significant differences in global left ventricular ejection fraction (group A, 49 +/- 8, group B, 52 +/- 41; group I, 51 +/- 7, group II, 51 +/- 6), right ventricular ejection fraction (group A, 45 +/- 9, group B, 42 +/- 7; group I, 43 +/- 8, group II, 41 +/- 8), or clinical outcome in the hospital. However, chi-square analysis revealed a significant (p less than 0.05) association between the presence or absence of septal asynergy and the presence or absence of precordial ST depression. In addition, average peak creatine kinase elevation (group I, 761 +/- 164 IU; group II, 698 +/- 178 IU) attained marginal significance by paired t test (p = 0.06). Precordial ST-segment depression during transmural inferior MI is frequently associated with septal asynergy by gated radionuclide angiography (15 of 26 patients, 58%).(ABSTRACT TRUNCATED AT 250 WORDS)

Unstable angina with episodic ST segment elevation and minimal creatine kinase release culminating in extensive, recurrent infarction.

The syndrome of episodic angina at rest, recurrent ST segment elevation (mean = 9 mV) and nontransmural infarction characterized by minimal serum creatine kinase (CK) (mean 243 IU; upper normal limit 132 IU) was studied in 15 patients who presented with these findings. All were initially managed with intensive nitrate and beta-receptor blocker therapy. Eleven patients underwent intraaortic balloon counterpulsation for refractory angina and 13 underwent cardiac catheterization. High grade (greater than or equal to 90%) stenosis of the proximal left anterior descending coronary artery was demonstrated in 11 patients, and coronary spasm without significant, fixed occlusive disease was noted in 2 patients. Urgent aortocoronary bypass surgery was performed in seven patients with recurrent pain or electrocardiographic injury, or both, unresponsive to maximal medical therapy. The initial mean ST segment elevation and CK elevation for this group was 10 mV and 232 IU, respectively. No surgical patient developed recurrent infarction; there was one late death after reoperation. Eight patients whose condition stabilized initially on medical therapy did not undergo urgent surgery. However, five subsequently developed large transmural anterior reinfarction despite intensive medical therapy, and three died from pump failure. These patients on medical therapy did not differ from the surgical group in magnitude of ST segment elevation or increase in serum CK. Their initial mean ST segment elevation and CK elevation were 8 mV and 254 IU, respectively (difference not significant). Thus, repetitive episodes of rest angina with marked anterior wall ST segment elevation and mild CK elevations may define a subset of patients who appear to progress rapidly from minimal nontransmural necrosis to massive transmural infarction. Prompt recognition of this syndrome, followed by cardiac catheterization and urgent aortocoronary bypass surgery, may prevent extensive cardiac muscle loss.

Effects of propranolol on blood lipids and lipoproteins in myocardial infarction.

The effects of propranolol on lipids and lipoproteins were investigated in survivors of a recent myocardial infarction who were enrolled in the double-blind Beta-Blocker Heart Attack Trial. Nonfasting serum samples were obtained in more than 2800 patients assigned randomly to either propranolol or placebo. The propranolol-treated group had high-density lipoprotein cholesterol levels 3-4 mg/dl less and triglyceride concentrations 30-40 mg/dl higher than the placebo group. These effects occurred in men and women in all age categories.

Calculation of the left ventricular ejection fraction by gated radionuclide angiography without direct background correction.

The mathematical characteristics of the cardiac background were studied in 50 patients who underwent both gated radionuclide angiography and cardiac catheterization. The background-corrected ejection fraction (BCEF) was calculated in the standard manner using an operator-defined periventricular background region. The "uncorrected" ejection fraction (UEF) was calculated from the uncorrected left ventricular time-activity curve and compared to both the BCEF and the angiographic ejection fraction (AEF), UEF exhibited remarkable linear correlation with both BCEF and AEF. The empirically determined linear regression equation, AEF = 2.18 (UEF) + 0.13, allowed calculation of a radionuclide ejection fraction corresponding to angiographic methods without direct background correction. When measurement of the left ventricular ejection fraction using this linear regression method was tested prospectively in 25 catheterized patients, the radionuclide regression ejection fraction showed excellent linear correlation with AEF (r = 0.85) and minimal inter-observer variability.

NH2-terminal analysis of four of the polymorphic forms of human serum amyloid A proteins.

We recently demonstrated that the serum amyloid A proteins (SAA) occur in six related polymorphic forms of indistinguishable molecular weights and COOH-terminal sequence. We have now obtained very homogeneous preparations of four of these proteins and shown that their amino acid compositions are similar but not identical. Two of these, SAA1 and SAA4, have the same 20 NH2-terminal residues despite striking differences in electrophoretic mobility and solution properties. SAA5 and SAA2, respectively, lack one and three of the NH2-terminal residues common to SAA1 and SAA4. The data are consistent with the postulate that some of the SAA polymorphs are products of different genes.

Clinical utility of salivary lithium concentration.

Saliva, plasma and erythrocyte lithium concentrations were studied in 40 long-term lithium users. Intersubject variation in saliva to plasma lithium ratio was too great for clinical utility, when based on a group linear regression equation. By contrast, intrasubject data from 8 patients studied on three or more occasions indicated a higher linear correlation (r = 0.91 to 1.00 for 7 of 8 patients). For individual patients the ratio remained stable over varying concentration ranges, and was not affected by time from last dose or length of use of lithium. Based on these data, use of saliva concentrations of lithium for routine monitoring appears feasible after several blood and saliva concentrations are obtained to establish a relationship for a particular patient. Saliva monitoring may facilitate accurate analysis and convenience for some patients.

Hemodynamic correlates of right ventricular ejection fraction measured with gated radionuclide angiography.

Right ventricular function was studied in 60 patients with equilibrium gated radionuclide angiography. The mean (+/- standard deviation) right ventricular ejection fraction in 20 normal subjects was 53 +/- 6 percent, a value in agreement with previous data from both radionuclide and contrast angiographic studies. This value was similar (55 +/- 7 percent) in 11 patients with coronary artery disease but normal left ventricular function. Radionuclide measurements of right ventricular ejection fraction were correlated with right heart hemodynamics. There was a significant negative linear correlation between right ventricular ejection fraction and mean pulmonary arterial pressure (r = -0.82) and between right ventricular ejection fraction and right ventricular end-diastolic pressure (4 = -0.67). Furthermore, patients with elevated right ventricular end-diastolic pressure and mean pulmonary arterial pressure had a more severely depressed ejection fraction than did those with an elevated mean pulmonary arterial pressure alone. Thus, an abnormal value for right ventricular ejection fraction by gated radionuclide angiography in the absence of primary right ventricular volume overload suggests abnormal right heart pressures, whereas a normal value excludes severe pulmonary arterial hypertension or an elevated right ventricular end-diastolic pressure.

Measurement of normal left atrial function with gated radionuclide angiography.

A method is described for measuring relative left atrial volume changes with gated radionuclide angiography, using an approximate computer-generated functional image to locate the atrial region of interest. M mode echocardiographic measurements of left atrial and left ventricular distances from the chest wall allowed calculation of a correction factor for the differential attenuation of atrial and ventricular photons. Background-corrected left atrial time-activity curves obtained from normal subjects exhibited excellent temporal resolution and were used to identify and quantitate the reservoir and contractile phases of left atrial volume change. In 20 normal subjects, the mean (+/- standard deviation) value for left atrial fractional emptying was 0.39 +/- 0.07. Expressed as fractions of the left ventricular stroke volume, mean values of the specific phases of atrial volume change were (1) reservoir volume 0.25 +/- 0.09, (2) contractile volume 0.29 +/- 0.10, and (3) conduit volume 0.46 +/- 0.12.

Exercise-induced coronary spasm with S-T segment depression and normal coronary arteriography.

The unique association of both exercise-induced coronary arterial spasm and S-T segment depression with normal findings on selective coronary arteriography is described. The patient had a prior history of typical effort angina that had recently progressed to angina at rest. Despite the change in anginal pattern, the electrocardiogram disclosed S-T segment depression that was consistent with subendocardial ischemia, during both exercise testing and spontaneous chest pain. Exercise thallium-201 scintigraphy demonstrated the presence of large perfusion defects of the anterior and septal walls of the left ventricle. Coronary arteriographic findings, in the absence of symptoms, were entirely normal. Severe localized, reversible coronary spasm of the proximal left anterior descending coronary artery was subsequently demonstrated during spontaneous angina, isometric arm exercise and after the administration of ergonovine maleate. After treatment with isosorbide dinitrate and nifedipine, the patient had no further chest pain or electrocardiographic changes, and a repeated thallium-201 stress test revealed normal findings and greatly improved exercise tolerance.