Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes.

The objective of this study was to determine the metabolic effects of estrogen replacement therapy in postmenopausal women with type 2 diabetes. Twenty-five postmenopausal, type 2 diabetic women completed a randomized, blinded, cross-over trial of conjugated equine estrogen, 0.625 mg/day, vs. placebo for 8 weeks, separated by a 4-week washout period. When compared with 8 weeks of placebo, estrogen reduced fasting serum glucose (7.2 +/- 0.3 vs. 8.4 +/- 0.4 mmol/L, P = 0.0003), glycated hemoglobin (8.7 +/- 0.4% vs. 9.3 +/- 0.4%, P = 0.04), total cholesterol (5.27 +/- 0.20 vs. 5.50 +/- 0.21 mmol/L, P = 0.04), low-density lipoprotein cholesterol (2.47 +/- 0.13 vs. 2.69 +/- 0.14 mmol/L, P = 0.02), serum apolipoprotein B (114 +/- 6 vs. 121 +/- 5 mg/dL, P = 0.03), and postprandial glucose area under the curve (by 12%, P = 0.015). Estrogen replacement therapy also increased high-density lipoprotein (HDL) cholesterol (1.27 +/- 0.08 vs. 1.1 +/- 0.07 mmol/L, P = 0.0002), high-density lipoprotein(2) cholesterol (0.41 +/- 0.04 vs. 0.30 +/- 0.03 mmol/L, P = 0.0001), and fasting triglyceride (2.17 +/- 0.21 vs. 1.94 +/- 0.16 mg/dL, P = 0.02) concentrations but not postprandial triglyceride area under the curve (P = not significant). We conclude that estrogen replacement therapy improves glycemic control, blood lipoproteins, and apolipoprotein B concentrations while modestly increasing triglyceride levels in postmenopausal, type 2 diabetic women.

The human leukocyte antigen HLA DRB3*020/DQA1*0501 haplotype is associated with Graves' disease in African Americans.

Information on genetic susceptibility to Graves' disease in African Americans is limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4 polymorphisms in 49 African American patients with adult onset Graves' disease and 47 racially-matched controls using PCR-based sequence-specific priming methods. There were no significant differences in DRB1 or DQB1 allelic frequencies or CTLA-4 polymorphisms between patients and controls. However, we found that the frequency of DRB3 was significantly increased in the patients (75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype (53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in concordance with our previous observations in Caucasian patients with adult-onset Graves' disease. In addition, whereas the frequency of DQA1*0501 was increased (P = 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 = 7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202, particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s) for Graves' disease in adult African Americans. Considering these data with those in Caucasian patients, our results would suggest that the primary Graves susceptible locus is likely DRB3 and not DRB1.

Improvements in diabetic care as measured by HbA1c after a physician education project.

OBJECTIVE: To measure the quality of diabetic care as indicated by HbA1c testing frequency and HbA1c values and to demonstrate improvement in care after an appropriate quality improvement intervention. RESEARCH DESIGN AND METHODS: The quality improvement project used computerized claims and laboratory data relating to HbA1c testing among the private practices of nine physicians caring for diabetic Medicare patients. Nine indicators evaluated three main areas: HbA1c testing frequency, HbA1c values, and frequency of office visits. A quality improvement intervention consisting of a physician component and a patient component was implemented. RESULTS: There were 835 patients and 4,367 visits studied. After the intervention, statistically significant improvements in HbA1c testing frequency and values were noted. Rates of seized opportunities for testing HbA1c improved from 17.7 to 33.9% (P < 0.0001). The percentage of patients with a current HbA1c value improved from 31.3 to 47.6% (P < 0.0001). The median HbA1c values fell from 8.5 to 7.8% (P < 0.006). Patients achieving good or fair control (HbA1c < or = 8%) improved from 43.8 to 56.9% (P = 0.007). The median time between physician visits fell from 70 days to 60 days (P < 0.0001). CONCLUSIONS: The study revealed that HbA1c testing was underused but that after a quality improvement initiative, a significant increase in testing use could be achieved. The quality improvement initiative also resulted in significant improvements in glycemic control. The techniques and interventions used in this study could be used to intervene in larger populations and practice settings to improve medical care for diabetic patients.

Black-white differences in postprandial triglyceride response and postheparin lipoprotein lipase and hepatic triglyceride lipase among young men.

Black-white differences in serum triglycerides and high-density lipoprotein (HDL) cholesterol concentrations are known. However, the metabolic basis for these differences is not clear. This study determined the magnitude of postprandial triglyceride concentrations, lipoprotein lipase and hepatic triglyceride lipase activities in postheparin plasma, and serum lipid and lipoprotein cholesterol concentrations in healthy young adult black men (n = 22) and white men (n = 28). Postprandial triglyceride concentrations were measured at 2, 3, 4, 5, 6, and 8 hours after a standardized test meal. Serum lipid and lipoprotein cholesterol concentrations were similar between the races in this study sample. However, incremental (above basal) increases in triglycerides were significantly greater in white men versus black men at 2 hours (P = .01) and tended to be greater at 3 hours (P = .12) and 4 hours (P = .06) after the fat load. In a multivariate analysis that included age, race, apolipoprotein E (apoE) genotype, fasting triglycerides, obesity measures, alcohol intake, and cigarette use, fasting triglycerides (P = .04) and, to a lesser extent, race (P = .07) were associated independently with the 2-hour incremental increase in triglycerides. The incremental triglyceride response correlated inversely with HDL cholesterol in both whites (r = -.38, P = .04) and blacks (r = -.59, P = .004). Lipoprotein lipase activity was higher (P = .049) and hepatic triglyceride lipase activity lower (P = .0001) in black men compared with white men; racial differences persisted after adjusting for the covariates. While lipoprotein lipase activity tended to associate inversely with the postprandial triglyceride concentration in both races, hepatic triglyceride lipase activity tended to correlate positively in whites and inversely in blacks. These results suggest that compared with whites, blacks may have an efficient lipid-clearing mechanism that could explain the black-white differences in lipoproteins found in the population at large.

Dopamine-beta-hydroxylase inhibition: a novel sympatho-modulatory approach for the treatment of congestive heart failure.

Pre-clinical and clinical studies suggest that chronic sympathetic activation in congestive heart failure (CHF) is a maladaptive response which accelerates the progressive worsening of the disease. Consequently, therapeutic interventions which inhibit sympathetic nerve function are likely to favorably alter the natural course of the disease. Indeed, recent clinical studies have shown that treatment with carvedilol, a beta-blocker, reduces mortality and the risk of death and hospitalization. The therapeutic value of beta-blockers, however, may be limited by their propensity to cause acute hemodynamic deterioration which results from abrupt withdrawal of sympathetic support. Thus, although the introduction of beta-blockers represents an important advance in the treatment of CHF, a better tolerated means of modulating the sympathetic nervous system would be highly desirable. An alternative strategy for directly modulating sympathetic nerve function is to inhibit the biosynthesis of norepinephrine (NE) via inhibition of dopamine-beta-hydroxylase (DBH), the enzyme which catalyzes the conversion of dopamine (DA) to NE in sympathetic nerves. This approach may have the following three merits over beta-blockade. First, this class of drugs would be expected to produce gradual modulation, as opposed to abrupt blockade, of sympathetic nerve function and, consequently, would not be associated with acute hemodynamic worsening thereby obviating the need for dose-titration. Second, from a theoretical standpoint, DBH inhibitors, at low doses, would preferentially inhibit NE release in the heart since the storage pool of NE in this organ is selectively depleted in CHF. Lastly, inhibition of DBH would augment the levels of DA which, via agonism of dopamine receptors, could have beneficial effects on renal function. Nepicastat is a novel, selective and potent (IC50 = 9 nM) inhibitor of DBH. Preclinical studies have shown that nepicastal produces gradual modulation of catecholamine levels (reduction in NE and elevation of DA and DA/NE ratio) in cardiovascular tissues and plasma, attenuates sympathetically-mediated cardiovascular responses and also has salutary effects on renal function. In a canine heart failure model, normalization of transmyocardial norepinephrine balance with nepicastat retards the process of ventricular dilation and prevents progressive worsening of cardiac function. Early short-term clinical studies in CHF patients have shown that nepicastat is well tolerated and produces significant and dose-dependent increases in plasma DA/NE concentrations.

Kinetic evidence for both a fast and a slow secretory pathway for apolipoprotein A-I in humans.

The kinetics of apolipoproteins A-I and A-II were examined in human subjects using leucine tracers administered intravenously. High density lipoproteins were separated and apoA-I and A-II were isolated. The specific activity or enrichment data for these apolipoprotein were analyzed by mathematical compartmental modeling. In 11 of 14 subjects studied with a bolus-injected [3H]leucine tracer, in 3 subjects studied similarly with [3H]leucine, and in one subject studied by primed dose, constant infusion of [3H]leucine, a rapidly turning-over apoA-I fraction was resolved. A similar component was observed in 7 of 10 studies of apoA-II. The apoA-I data were analyzed using a compartmental model (Zech, L.A. et al. 1983. J. Lipid Res. 24: 60-71) modified to incorporate plasma leucine as a precursor for apoprotein synthesis. The data permitted resolution of two apoA-I pools, one, C(2), turned-over with a residence time of less than 1 day, the other, C(1), a slowly turning-over pool, appeared in plasma after a delay of less than half a day. C(1) comprised the predominant mass of apoA-I and was also the primary determinant of the residence time of apoA-I. Although the mass of the fast pool, C(2), was considerably less than that of C(1), because of its rapid turnover, the quantities of apoA-I transported through this fast pathway were 2- to 4-fold greater. These kinetic studies indicate that apoA-I is secreted into both fast and slowly turning-over plasma pools. The latter is predominantly measured with radioiodinated apoA-I tracers. The data can be analyzed by postulating either separate input pathways to each of the pools or by assuming the fast pool is the precursor to the slow pool. Thus, apoA-I could be initially secreted as a family of particles that are rapidly cleared from plasma, and a portion of this apoprotein then reappears in a slowly turning-over pool that constitutes the major mass of apoA-I. The physiologic identity of these kinetically distinct apoA-I species is unknown; however, the fast pool of apoA-I demonstrated in these studies is strikingly similar to that seen in subjects with Tangier disease who lack the slow pool.

Evaluation of the efficacy and safety of oral nicardipine in treatment of urgent hypertension: a multicenter, randomized, double-blind, parallel, placebo-controlled clinical trial.

This study was a prospective, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of oral nicardipine for the treatment of urgent hypertension in the emergency department. Of 57 patients with urgent hypertension 53 patients were enrolled: 36 men and 17 women, 43 black and 10 white, age range 48 +/- 11 years, and diastolic blood pressure 128 +/- 7 mm Hg. Patients were randomly assigned to receive 30 mg nicardipine or placebo in blind fashion followed by 30 mg open-label nicardipine in nonresponders. Responders to one or two doses of nicardipine received 30 or 40 mg nicardipine three times a day for 1 week after discharge from the emergency department. Adequate blood pressure reduction, defined as a reduction of diastolic blood pressure to less than 100 mm Hg or by at least 20 mm Hg, was achieved in 65% and 22% of patients who received 30 mg nicardipine or placebo (p = 0.002). Adequate blood pressure reduction after administration of open-label nicardipine occurred in 76% of the nonresponders to placebo. Blood pressure reductions were maintained at 1 week after discharge. The drug was well tolerated, and no significant adverse events occurred. We conclude that oral nicardipine is a safe and effective drug for the initial treatment of urgent hypertension.

Treatment of cholesterol-fed rabbits with dietary vitamins E and C inhibits lipoprotein oxidation but not development of atherosclerosis.

New Zealand White rabbits were made hypercholesterolemic by feeding a high cholesterol diet (10 g/kg diet) with or without added antioxidants. The antioxidants used were either probucol (10 g/kg) or vitamin E (10 g/kg) plus vitamin C (0.6 g/kg). Serum cholesterol concentrations were monitored as a function of time. At the end of 10 wk, serum and lipoprotein vitamin E concentrations, the extent of oxidation of lipoprotein fractions (thiobarbituric acid reacting substances), the susceptibility of lipoprotein to oxidation in vitro (conjugated diene formation) and the extent of atherosclerosis (aortic area stained by Sudan IV and plaque thickness) were measured. Rabbits fed diets supplemented with vitamins E and C had markedly higher serum vitamin E concentrations, marked vitamin E enrichment in all lipoprotein fractions, less oxidation in VLDL and LDL and enhanced resistance of LDL to further in vitro oxidation, but did not have significantly less aortic atherosclerosis. Rabbits given supplemental probucol likewise exhibited reduced oxidation of lipoproteins. However, aortic atherosclerosis in these animals was significantly lower, as were serum cholesterol concentrations. Inhibition of lipoprotein oxidation itself was not sufficient to reduce atherosclerosis in cholesterol-fed New Zealand White rabbits.

A cell culture system for screening human serum for ability to promote cellular cholesterol efflux. Relations between serum components and efflux, esterification, and transfer.

A cell culture system was employed to test a large number of samples of human serum for the ability to stimulate the efflux of cell cholesterol. The extent of efflux obtained with each specimen was correlated with the serum concentrations of cholesterol, triglycerides, apoprotein (apo) B, apo A-I, apo A-II, and lipoprotein subfractions (ie, high-density lipoprotein2 [HDL2], HDL3, lipoprotein [Lp] A-I, and LpA-I:A-II). In addition, the subsequent esterification of the released cholesterol and the distribution of the synthesized exogenous cholesteryl esters between HDL and low-density lipoprotein/very-low-density lipoprotein provided estimates of the lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities of each serum. The values for these activities were analyzed for correlations with cell efflux and the various serum parameters. Cell cholesterol efflux best correlated with serum total HDL cholesterol values. HDL2 and HDL3 correlated about equally well with efflux, whereas LpA-I demonstrated a much greater association with efflux than did LpA-I:A-II. Analysis of the data by partial correlation analysis indicated that HDL3 and LpA-I were the HDL subfractions most closely associated with efflux. Esterification of the released radiolabeled cholesterol was strongly and positively correlated with serum triglyceride concentrations and negatively related to the serum concentrations of HDL2. There was no relation between esterification values, which reflect LCAT activity, and efflux. The transfer of the labeled cholesteryl esters between HDL and apoB-containing lipoproteins was used as a measure of CETP activity and demonstrated a pattern in which all apoB-related parameters were positively correlated to transfer of esterified cholesterol, and all HDL associated parameters, particularly HDL3, were negatively related to transfer. No relations were observed between efflux, esterification, and transfer.

Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake.

To determine the interactive effects of hormones, exercise, and diet on plasma lipids and lipoproteins, serum estrogen and progesterone levels, nutrient intake, and plasma lipid, lipoprotein, and apolipoprotein concentrations were measured in 24 hypoestrogenic amenorrheic and 44 eumenorrheic female athletes. When compared to eumenorrheic athletes, amenorrheic athletes had higher levels of plasma cholesterol (5.47 +/- 0.17 vs. 4.84 +/- 0.12 mmol/L, P = 0.003), triglyceride (0.75 +/- 0.06 vs. 0.61 +/- 0.03 mmol/L, P = 0.046), low-density lipoprotein (LDL; 3.16 +/- 0.15 vs. 2.81 +/- 0.09 mmol/L, P = 0.037), high-density lipoprotein (HDL; 1.95 +/- 0.07 vs. 1.73 +/- 0.05 mmol/L, P = 0.007), and HDL2 (0.84 +/- 0.06 vs. 0.68 +/- 0.04 mmol/L, P = 0.02) cholesterol. Plasma LDL/HDL cholesterol ratios, very low-density lipoprotein and HDL3 cholesterol, and apolipoprotein A-I and A-II levels were similar in the two groups. Amenorrheic athletes consumed less fat than eumenorrheic subjects (52 +/- 5 vs. 75 +/- 3 g/day, P = 0.02), but similar amounts of calories, cholesterol, protein, carbohydrate, and ethanol. HDL cholesterol levels in amenorrheic subjects correlated positively with the percent of dietary calories from fat (r = 0.42, n = 23, P = 0.045) but negatively with the percent from protein (r = -0.49, n = 23, P = 0.017). Thus, exercise-induced amenorrhea may adversely affect cardiovascular risk by increasing plasma LDL and total cholesterol. However, cardioprotective elevations in plasma HDL and HDL2 cholesterol may neutralize the risk of cardiovascular disease in amenorrheic athletes.

Noninvasive assessment of the direct action of oral nifedipine and nicardipine on left ventricular contractile state in patients with systemic hypertension: importance of reflex sympathetic responses.

OBJECTIVES: This study was designed to noninvasively assess the direct action of calcium channel blockers on left ventricular contractility in humans and to establish a framework for determining the importance of reflex sympathetic responses to any pharmacologic intervention. BACKGROUND: Assessment of left ventricular contractility in patients taking calcium channel blockers by using traditional indexes of systolic performance is difficult because of the after-load-reducing and reflex sympathetic effects of the drugs. METHODS: Fifteen hypertensive patients (mean blood pressure 127 +/- 15 mm Hg) were studied with Doppler echocardiography and calibrated subclavian pulse tracings while receiving placebo and 1 week after randomization to treatment with oral nifedipine (20 mg three times daily; n = 7) or nicardipine (30 mg three times daily; n = 8). Left ventricular circumferential end-systolic wall stress versus rate-corrected velocity of shortening (Vcfc) relations were generated over a range of loads using nitroprusside. Data were acquired before and during esmolol infusion, thereby allowing assessment of hemodynamic responses with the sympathetic nervous system functionally intact as well as ablated. The adequacy of sympathetic blockade was confirmed with isoproterenol challenges. In each case, left ventricular contractile state was measured relative to placebo and esmolol data as delta Vcfc at a common end-systolic wall stress. Increased and decreased contractility were defined as delta Vcfc > 0 and delta Vcfc < 0, respectively. RESULTS: Nifedipine and nicardipine equally decreased blood pressure and end-systolic wall stress and increased left ventricular percent fractional shortening and stroke volume. Neither drug alone consistently altered ventricular contractility compared with placebo. Ablation of reflex sympathetic tone with esmolol unmasked a negative inotropic effect for nifedipine (p = 0.03 vs. esmolol alone) but not nicardipine (p = 0.68 vs. esmolol alone). The difference between the contractility effects of nifedipine plus esmolol versus those of nicardipine plus esmolol approached statistical significance (p = 0.07). CONCLUSIONS: Totally noninvasive techniques showed a differential effect on left ventricular contractility between nifedipine and nicardipine when alterations in afterload and reflex sympathetic responses were eliminated as confounding variables. This diagnostic approach, based on the use of pharmacologic probes, should have wide applicability for assessing the direct inotropic effect of any agent, even in the presence of complex primary and secondary physiologic modes of action.

Comparison of sustained-release formulations of nicardipine and verapamil for mild to moderate systemic hypertension.

In this double-blind, parallel, multicenter study, sustained-release (SR) preparations of 2 calcium antagonists, nicardipine and verapamil, were compared for the treatment of mild to moderate systemic hypertension. Two hundred eighteen patients with supine diastolic blood pressures (BP) 95 to 114 mm Hg were randomly assigned to receive nicardipine-SR 45 mg twice daily (n = 73), nicardipine-SR 60 mg twice daily (n = 73) or verapamil-SR 240 mg once daily in the morning (n = 72). All 3 regimens significantly reduced supine and sitting systolic and diastolic BPs compared with baseline values (p < 0.005). The efficacy of drugs became apparent after 2 weeks of therapy, and was sustained throughout the 12-week study. Reductions in sitting diastolic BP and supine and sitting systolic BPs were statistically greater with nicardipine-SR 60 mg twice daily compared with verapamil, and nicardipine-SR 45 mg twice daily was equivalent to verapamil. Asthenia and constipation occurred more frequently in patients treated with verapamil (9.7 and 11.1%, respectively, compared with 6.8 and 4.1% in either nicardipine group). Adverse events reported more frequently with nicardipine were headache (17.8% with nicardipine-SR 60 mg and 15.1% with nicardipine-SR 45 mg vs 13.9% with verapamil) and edema (15.1% in the nicardipine-SR 60 mg group, 8.2% with nicardipine-SR 45 mg vs 4.2% with verapamil). Verapamil, but not nicardipine, produced significant reductions in heart rate. SR preparations of calcium antagonists offer options for effective monotherapy of systemic hypertension. Side-effect profiles differ and may affect choice of therapy.

Acute conversion of paroxysmal supraventricular tachycardia with intravenous diltiazem. IV Diltiazem Study Group.

Diltiazem has electrophysiologic effects similar to those of verapamil. Its efficacy and safety in 4 doses for treatment of induced supraventricular tachycardia (SVT) were examined and compared with those of placebo in 87 patients (25 with atrioventricular [AV] nodal reentry tachycardia, 60 with AV reentry associated with an accessory AV connection, and 2 with atrial tachycardia). Conversion to sinus rhythm occurred in 4 of 14 patients (29%) with 0.05 mg/kg of diltiazem, 16 of 19 (84%) with 0.15 mg/kg, 13 of 13 (100%) with 0.25 mg/kg, and 14 of 17 (82%) with 0.45 mg/kg compared with 6 of 24 (25%) treated with placebo. Conversion rates in groups receiving doses of 0.15 to 0.45 mg/kg of diltiazem were superior to that in the placebo group (p less than 0.001). Time to conversion was 3.0 +/- 2.6 minutes in responding diltiazem patients compared with 5.9 +/- 6.1 minutes in responding control patients. Diltiazem administration resulted in significant lengthening of SVT cycle length, AH interval, and AV nodal effective refractory period and block cycle length. The most frequent adverse response to diltiazem was hypotension (7 of 63 patients); however, only 4 patients had symptoms related to hypotension. Thus, intravenous diltiazem in doses of 0.15, 0.25 and 0.45 mg/kg is an effective and safe treatment for the acute management of SVT.

Effect of glyburide and omega 3 fatty acid dietary supplements on glucose and lipid metabolism in patients with non-insulin-dependent diabetes mellitus.

Using a random crossover design, we examined the effects of glyburide for 4 wk on glucose, insulin, lipid, and lipoprotein metabolism in 10 men with non-insulin-dependent diabetes (NIDDM) receiving dietary fish-oil concentrates containing omega 3 (n-3) fatty acids (8 g/d). Compared with glyburide alone, fasting plasma glucose concentrations increased with fish oil. Although glyburide with fish oil decreased fasting glucose concentrations, they did not return to baseline. Basal insulin concentrations were unaltered by fish oil without or with glyburide; however, postprandial insulin concentrations were decreased by fish oil. Although total cholesterol and triglyceride concentrations were unchanged, very-low-density-lipoprotein cholesterol concentrations decreased and low-density-lipoprotein cholesterol rose and apolipoprotein B concentrations trended higher. Thus, glyburide only partially rectified the impaired fuel homeostasis associated with fish-oil supplements in patients with NIDDM. Therefore, we do not recommend intake of fish oil concentrates containing n-3 fatty acids in patients with NIDDM.

Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction.

BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT), the most common form of supraventricular tachycardia, results from conduction through a reentrant circuit comprising fast and slow atrioventricular nodal pathways. Antiarrhythmic-drug therapy is not consistently successful in controlling this rhythm disturbance. Catheter ablation of the fast pathway with radiofrequency current eliminates AVNRT, but it can produce heart block. We hypothesized that catheter ablation of the site of insertion of the slow pathway into the atrium would eliminate AVNRT while leaving normal (fast-pathway) atrioventricular nodal conduction intact. METHODS AND RESULTS: Eighty patients with symptomatic AVNRT were studied. Retrograde slow-pathway conduction (in which the earliest retrograde atrial potential was recorded at the posterior septum, close to the coronary sinus) was present in 33 patients. The retrograde atrial potential was preceded by a potential consistent with activation of the atrial end of the slow pathway (ASP). In 46 of the 47 patients without retrograde slow-pathway conduction, a potential with the same characteristics as the ASP potential was recorded during sinus rhythm. Radiofrequency current delivered through a catheter to the ASP site (in the posteroseptal right atrium or coronary sinus) abolished or modified slow-pathway conduction in 78 patients, eliminating AVNRT without affecting normal atrioventricular nodal conduction. In the single patient without ASP, the application of radiofrequency current to the proximal coronary sinus ablated the fast pathway and AVNRT: Atrioventricular block occurred in one patient (1.3 percent) with left bundle-branch block, after inadvertent ablation of the right bundle branch. AVNRT has not recurred in any patient during a mean (+/- SD) follow-up of 15.5 +/- 11.3 months. Electrophysiologic study 4.3 +/- 3.3 months after ablation in 32 patients demonstrated normal atrioventricular nodal conduction without AVNRT: CONCLUSIONS: Catheter ablation of the atrial end of the slow pathway using radiofrequency current, guided by ASP potentials, can eliminate AVNRT with very little risk of atrioventricular block.

Dihydropyridine calcium antagonist modulates cholesterol metabolism and eicosanoid biosynthesis in vascular cells.

Recent clinical studies have shown that calcium channel blockers can retard and possibly reduce the angiographic progression of coronary artery disease. Calcium channel blockers also inhibit dietary-induced atherosclerosis in animal models of this disease. In this study, we delineate potential cellular and molecular mechanisms by which nicardipine, a dihydropyridine calcium antagonist, may alter lipoprotein and cholesterol trafficking, affect the regulatory signal transduction pathways involved in accelerating cholesteryl ester (CE) catabolism in vascular smooth muscle cells, and modulate cell-cell interactions of vascular and inflammatory cells. We demonstrate in arterial smooth muscle cells that nicardipine increases 1) LDL binding, uptake, and degradation, 2) RNA transcript levels for the LDL receptor, 3) CE catabolic activity, 4) PGI2 release, and 5) RNA transcript levels for cyclooxygenase. Furthermore, nicardipine blocked cytokine-induced monocyte adhesion to endothelial cells and smooth muscle cells. Taken together, these findings support the hypothesis that nicardipine may function as an anti-atherosclerotic agent by promoting CE catabolism and cholesterol clearance and by reducing monocyte adhesion to the activated endothelium.

Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current.

BACKGROUND: Surgical or catheter ablation of accessory pathways by means of high-energy shocks serves as definitive therapy for patients with Wolff-Parkinson-White syndrome but has substantial associated morbidity and mortality. Radiofrequency current, an alternative energy source for ablation, produces smaller lesions without adverse effects remote from the site where current is delivered. We conducted this study to develop catheter techniques for delivering radiofrequency current to reduce morbidity and mortality associated with accessory-pathway ablation. METHODS: Radiofrequency current (mean power, 30.9 +/- 5.3 W) was applied through a catheter electrode positioned against the mitral or tricuspid annulus or a branch of the coronary sinus; when possible, delivery was guided by catheter recordings of accessory-pathway activation. Ablation was attempted in 166 patients with 177 accessory pathways (106 pathways in the left free wall, 13 in the anteroseptal region, 43 in the posteroseptal region, and 15 in the right free wall). RESULTS: Accessory-pathway conduction was eliminated in 164 of 166 patients (99 percent) by a median of three applications of radiofrequency current. During a mean follow-up (+/- SD) of 8.0 +/- 5.4 months, preexcitation or atrioventricular reentrant tachycardia returned in 15 patients (9 percent). All underwent a second, successful ablation. Electrophysiologic study 3.1 +/- 1.9 months after ablation in 75 patients verified the absence of accessory-pathway conduction in all. Complications of radiofrequency-current application occurred in three patients (1.8 percent): atrioventricular block (one patient), pericarditis (one), and cardiac tamponade (one) after radiofrequency current was applied in a small branch of the coronary sinus. CONCLUSIONS: Radiofrequency current is highly effective in ablating accessory pathways, with low morbidity and no mortality.

Ethanol inhibits human bone cell proliferation and function in vitro.

The direct effects of ethanol on human bone cell proliferation and function were studied in vitro. Normal human osteoblasts from trabecular bone chips were prepared by collagenase digestion. Exposure of these osteoblasts to ethanol in concentrations of 0.05% to 1% for 22 hours induced a dose-dependent reduction in bone cell DNA synthesis as assessed by incorporation of 3H-thymidine. After 72 hours of ethanol exposure in concentrations of 0.01% to 1%, protein synthesis as measured by 3H-proline incorporation into trichbroacetic acid (TCA)-precipitable material was reduced in a dose-dependent manner. Human bone cell protein concentrations and alkaline phosphatase total activity were significantly reduced after exposure to 1% ethanol for 72 hours, but not with lower concentrations of ethanol. This reduction in osteoblast proliferation and activity may partially explain the development of osteopenia in humans consuming excessive amounts of ethanol.

Catheter ablation of atrioventricular junction using radiofrequency current in 17 patients. Comparison of standard and large-tip catheter electrodes.

BACKGROUND: Two catheter electrode systems were compared for delivering radiofrequency current for ablation of the atrioventricular junction. Seventeen patients with drug-resistant supraventricular tachyarrhythmias were studied. METHODS AND RESULTS: A 6F or 7F catheter with six or eight standard electrodes (1.25 mm wide, 2.5-mm spacing) was used in the first seven patients (group 1). A 7F quadripolar catheter with a large-tip electrode (4 mm long; surface area, 27 mm2) was used in the final 10 patients (group 2). Both ablation catheters were positioned to record a large atrial potential and a small but sharp His bundle potential from the distal bipolar electrode pair. Radiofrequency current was applied between a large skin electrode on the left posterior chest and either 1) each individual electrode on the standard-tip electrode catheter at 40 V (group 1) or 2) the large-tip electrode at 50-60 V (group 2). Radiofrequency current was limited to 40 V in group patients because of the strong potential for an early impedance rise when higher voltage is applied through standard electrodes. Complete atrioventricular block was achieved in six of seven group 1 patients and all 10 group 2 patients. A junctional escape rhythm followed ablation in five or six group 1 patients (mean cycle length, 1,066 +/- 162 msec) and eight of 10 group 2 patients (mean cycle length, 1,281 +/- 231 msec). Atrioventricular block was produced in a mean of 4.7 +/- 4.6 radiofrequency current applications delivered over a period of 42 +/- 45 minutes using the large-tip electrode (group 2) compared with 46 +/- 22 applications using standard electrodes (15.9 +/- 10.2 applications delivered through the standard-tip electrode) over a period of 147 +/- 59 minutes (group 1). For the application producing atrioventricular block, the large-tip electrode used higher voltage (58 +/- 17 versus 38 +/- 5 V, p less than 0.03) and had lower impedance (103 +/- 22 versus 148 +/- 40 omega, p less than 0.01), resulting in greater power (33.0 +/- 13.0 versus 10.2 +/- 0.6 W, p less than 0.003) and shorter time to block (8 +/- 3 versus 22 +/- 3 seconds, p less than 0.001). Current delivery through standard electrodes was limited by an impedance rise occurring 7 +/- 7 seconds after the onset of one or more radiofrequency current applications at 10 +/- 1 W in six of seven patients. Using the large-tip electrode, an impedance rise occurred in five of 10 patients, but at 25 +/- 10 W and after 21 +/- 9 seconds. Atrioventricular block occurred before the impedance rise in three of these five patients. Complete atrioventricular block persisted in 15 of 16 patients at a mean follow-up of 8.7 months. Atrioventricular conduction returned at 1 month in one group 2 patient and was successfully ablated by a second procedure. Three group 1 patients died 0.5-2 months after ablation, and a fourth patient underwent cardiac transplantation after 10 months. Pathological examination of the heart in two of these patients showed necrosis of the atrioventricular node and origin of the His bundle, without injury to the middle or distal His bundle. All 10 group 2 patients are alive and subjectively improved after ablation. CONCLUSIONS: We conclude that catheter-delivered radiofrequency current effectively produces complete atrioventricular block (94%) without requiring general anesthesia or the risk of ventricular dysfunction or cardiac perforation. The large-tip electrode allows a threefold increase in delivered power and markedly decreases the number of pulses and time required to produce atrioventricular block.