Dissociation of changes in apparent myofibrillar Ca2+ sensitivity and twitch relaxation induced by adrenergic and cholinergic stimulation in isolated ferret cardiac muscle.

In isolated, aequorin-injected ferret cardiac muscle we measured the apparent myofilament Ca2+ sensitivity and its relationship to twitch relaxation time in the presence of autonomic perturbations. The Ca2+-tension relation was determined from the peak aequorin luminescence and peak twitch tension measured in muscles across a broad range of bathing [Ca2+] in the presence and absence of acetylcholine (ACh) (1 microM) or isoproterenol (ISN) (1 microM), or both drugs. ACh shifted the relationship of peak tension to (peak) aequorin light leftward, which suggests an increase in myofilament Ca2+ sensitivity, but it did not alter relaxation, which was measured as the time for peak tension to decay by 50% (t 1/2 R). ISN produced its previously documented effects, i.e., a rightward shift of the relationship of peak tension to peak aequorin light and a decrease in t1/2R. ACh abolished the ISN effect on the peak tension-aequorin light relationship but did not reverse the effect of ISN to decrease t1/2R. The effects of ACh and ISN of modulating the apparent myofilament Ca2+ sensitivity in intact muscles, corroborate findings of previous studies in isolated myofibrillar preparations. However, these perturbations of myofilament Ca2+ sensitivity in the intact muscle do not relate to twitch relaxation, measured as t1/2R, since (a) ACh affects the former but not the later and (b) the effect of ISN on the Ca2+-tension relationship is abolished by ACh, while the relaxant effect persists.

Prospective, randomized, multicenter comparison of laser-facilitated balloon angioplasty versus stand-alone balloon angioplasty in patients with obstructive coronary artery disease. The Laser Angioplasty Versus Angioplasty (LAVA) Trial Investigators.

OBJECTIVES: The goal of this study was to examine the relative safety and efficacy of laser-facilitated percutaneous transluminal coronary angioplasty (PTCA) versus "stand-alone" PTCA. BACKGROUND: Plaque debulking with lasing before PTCA may result in improved lumen dimensions and decreased rates of periprocedural ischemic complications, thus improving short- and long-term outcomes after percutaneous intervention. The mid-infrared holmium:yttrium-aluminum-garnet (YAG) laser has been shown to be effective in a variety of plaque subtypes and may be particularly useful in high risk acute ischemic syndromes. METHODS: A total of 215 patients (mean [+/-SD] age 61 +/- 12 years) with 244 lesions were prospectively randomized at 14 clinical centers to laser versus stand-alone PTCA. After laser treatment, all patients underwent PTCA; 148 patients (69%) had unstable angina. RESULTS: The procedural success rate without major catheterization laboratory complications was similar in patients assigned to laser treatment or PTCA alone (96.6% vs. 96.9%, p = 0.88), as was the in-hospital clinical success rate (89.7% vs. 93.9%, p = 0.27). There was no difference in postprocedural diameter stenosis after laser treatment compared with PTCA (18.3% +/- 13.6% vs. 19.5% +/- 15.1%, p = 0.50). However, use of the laser, versus PTCA alone, did result in significantly more major and minor procedural complications (18.0% vs. 3.1%, p = 0.0004), myocardial infarctions (4.3% vs. 0%, p = 0.04) and total in-hospital major adverse events (103% vs. 4.1%, p = 0.08). At a mean follow-up time of 11.2 +/- 7.7 months, there were no differences in late or event-free survival in patients assigned to laser treatment versus PTCA alone. CONCLUSIONS: Compared with stand-alone PTCA, laser-facilitated PTCA results in a more complicated hospital course, without immediate or long-term benefits.

Modifiable risk factors for vascular access site complications in the IMPACT II Trial of angioplasty with versus without eptifibatide. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.

OBJECTIVES: This study was designed to identify potential predictors of vascular access site (VAS) complications in the large-scale Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II trial, which studied angioplasty with versus without a new glycoprotein (GP) IIb/IIIa receptor inhibitor (eptifibatide). BACKGROUND: GP IIb/IIIa receptor inhibition during coronary interventions has been associated with excess VAS complications. If other predictors of VAS complications could be identified, they might be manipulated to reduce complications. METHODS: A total of 4,010 patients undergoing percutaneous transluminal coronary revascularization (PTCR) were randomized into one of three bolus/20- to 24-h infusion arms: placebo bolus/placebo infusion; 135-microg/kg body weight eptifibatide bolus/0.5-microg/kg per min eptifibatide infusion; or 135-microg/kg eptifibatide bolus/0.75-microg/kg per min eptifibatide infusion. Heparin during the procedure was weight adjusted and stopped 4 h before sheaths were removed. Logistic regression modeling was used to identify independent predictors of VAS complications. RESULTS: VAS complications were more common in patients treated with eptifibatide (9.9% vs. 5.9% placebo-treated patients, p < 0.001). Multivariate analysis identified eptifibatide therapy (p < 0.0001), advanced age (p = 0.0001), longer time to sheath removal (p = 0.0002), stent placement (with intense post-stent anticoagulation) (p = 0.0004), female gender (p = 0.0006), PTCR within 24 h of thrombolytic therapy (p = 0.002), larger heparin doses during PTCR (p = 0.009), major coronary dissection (p = 0.03) and placement of a venous sheath (p = 0.04) as independent predictors of VAS complications. CONCLUSIONS: VAS complications may be reduced by early sheath removal, by avoiding placement of venous sheaths and by limiting heparin dosing to avoid excessive activated clotting times. Early sheath removal during inhibition of platelet aggregation by eptifibatide is feasible.

Flattening postprandial blood glucose responses with guar gum: acute effects.

It has been proposed that high-carbohydrate, high-fiber (HCF) diets might serve as useful therapeutic modality in non-insulin-dependent diabetes mellitus (NIDDM). One problem in evaluating clinical trials of this therapy is that, by their very nature, the trials cannot be double blinded. We have developed HCF and placebo granola-type bars using complex absorbable carbohydrate and guar gum fiber to circumvent this methodologic problem. The HCF bars, when consumed with an ad lib. diet, assure an HCF intake without imposing other dietary restrictions. To test the short-term efficacy of the bars, 9 normal adult volunteers, 2 women with impaired glucose tolerance, and 20 patients with NIDDM consumed the bars alone or with meals. Blood glucose responses when HCF bars were consumed alone were blunted when compared with the placebo response (P less than 0.0005 to P less than 0.002), with the most marked suppression occurring in the early postprandial period. In contrast, when the bars were consumed along with breakfast, HCF and placebo responses were virtually identical in the early postprandial period, but showed a progressively greater difference from 90 to 240 min (P less than 0.02 to P less than 0.0005). When consumed with lunch as well as breakfast, the HCF bars caused flattening of blood glucose responses during the late postprandial period after breakfast and maintained flattened responses during the early and late postprandial periods after lunch (P less than 0.05 to P less than 0.005). It is concluded that these HCF bars can be used to blunt postprandial blood glucose responses, in subjects with either normal or abnormal carbohydrate metabolism.

Effect of guar gum on mineral balances in NIDDM adults.

The self-selected diet of 16 subjects with non-insulin-dependent diabetes mellitus (NIDDM) was supplemented for 6 mo with either a granolalike bar containing 35.5 g carbohydrate and 6.6 g guar gum/bar or a placebo bar containing carbohydrate but no guar gum. Subjects consumed a mean of 4.8 bars/day. Average guar gum consumption at the end of the study was 31.7 g/day. One week before and at the end of the study, subjects were admitted to a metabolic ward and fed a controlled diet similar to their self-selected diet. Food, feces, and urine were composited for analysis of iron, zinc, copper, calcium, magnesium, and manganese. Eight subjects consuming the guar gum supplement and 6 subjects consuming the placebo bar completed collections for mineral balance. Neither consumption of guar gum nor placebo bar significantly changed apparent mineral balance for iron, copper, zinc, calcium, manganese, or magnesium from prestudy levels to 6-mo levels, and no significant differences were observed between the two groups. With the exception of copper, men consumed significantly more minerals than women. We conclude that consumption of guar gum by patients with NIDDM does not adversely affect apparent mineral balance.

Nutritional risk of high-carbohydrate, guar gum dietary supplementation in non-insulin-dependent diabetes mellitus.

Dietary supplementation with high-carbohydrate, guar gum fiber (HCF) is effective in acutely blunting postprandial blood glucose levels. We report the effect of such supplementation on the diet and nutritional status of a group of 16 subjects with non-insulin-dependent diabetes mellitus (NIDDM) who incorporated either HCF bars (35.7 g carbohydrate and 6.6 g guar gum/bar) or placebo bars (identical except for the absence of guar gum) into the diet for 6 mo as part of a double-blind, randomized clinical trial. The HCF subjects achieved mean daily intake of 4.8 +/- 0.4 bars, constituting 51.2 +/- 3.1% of total calories and providing 29.7 +/- 2.6 g guar gum daily. Energy intakes and body weight did not change significantly in either group. Food consumption patterns and nutrient intakes did change, although not enough to impair the nutritional integrity of the diet because the bars themselves served as a source of nutrients. The bars were rich in thiamin, B6, folacin, phosphorus, iron, zinc, and copper, adequately replacing any decrease in nutrient intake as a result of foods being dropped from the diet. In fact, daily intakes of B6, folacin, and copper actually increased due to contributions from the bars. Nutrients in which the bars were poor (vitamins A, C and B12) resulted in suboptimal intakes (less than 66% RDA). Although no significant change in nutritional status of the HCF group occurred as determined by arm muscle area, arm fat area, hemoglobin, hematocrit, or serum albumin, transferrin, iron, ferritin, calcium, phosphate, B12, and magnesium levels, these indicators of nutritional status are rather insensitive.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term ingestion of guar gum is not toxic in patients with noninsulin-dependent diabetes mellitus.

The use of diets rich in unabsorbable carbohydrate ("fiber") has been advocated for the treatment of noninsulin-dependent diabetes mellitus (NIDDM). The soluble viscous fibers such as guar gum are most effective in normalizing carbohydrate intolerance in such patients; particulate fibers such as cellulose have little or no effect. While the latter are known to affect many aspects of nutrition when consumed in great quantity, little is known of the toxicity of guar gum. Eight adults with NIDDM are reported here who consumed at least 30 grams of guar gum for at least 16 weeks without any change in hematologic, hepatic, or renal function. Serologic screening revealed no change in lipid, protein or mineral metabolism, and no change in electrolyte balance. It is concluded that consumption of 30 grams of guar gum per day for prolonged periods is without serious consequences.

Long-term effects of guar gum on blood lipids.

While guar gum has been shown to lower total cholesterol and low density lipoprotein cholesterol (LDL-C) in diabetic patients over the short-term, the long-term effects are less well studied and may be unpredictable. Granola bars with and without 6.6 g guar gum were developed and fed to 16 adult volunteers with Type II diabetes mellitus who had been randomized in a double-blind fashion into guar and placebo groups of equal size. Four to six bars were consumed daily with an ad lib diet over a 6-month period. Total cholesterol, total high density lipoprotein cholesterol (HDL-C), subfractions HDL2-C and HDL3-C, LDL-C, and beta-apoprotein were measured at 0 and 6 months. Although LDL-C was lower and triglycerides higher at 6 months than at baseline, these changes were of equal magnitude and direction in both guar and placebo groups. Using each subject as his own control, only the change in triglycerides was statistically significant (P less than 0.025). When male subjects alone were analyzed, the guar group showed a statistically significant decrease in LDL, while the placebo group did not. Other lipid parameters were not significantly changed during the study, despite a positive effect on carbohydrate metabolism from the guar bars. The data suggest either that the hypolipemic effects of guar gum in patients with Type II diabetes mellitus are not sustained for 6 months, or the effects occur only in men.

Nausea and vomiting during acute myocardial infarction and its relation to infarct size and location.

Nausea and vomiting occurring during myocardial ischemia is believed to be associated with inferior wall infarction. However, data supporting such an association are limited, and an alternative hypothesis that cardiac vomiting is related to infarct size has also been advanced. The 2 hypotheses were tested in a cross-sectional study of 265 patients consecutively admitted to the coronary care unit. Nausea or vomiting was a good predictor of myocardial infarction (p less than 0.0001). The odds of having an infarction was 3.14 times greater for patients with nausea or vomiting than for those without these symptoms. Nausea was not a good predictor for inferior wall infarction (p = 0.14): 51% of patients with inferior infarcts had nausea or vomiting and 66% with anterior infarcts had these symptoms. Using peak serum creatine kinase level as an index of infarct size, nausea or vomiting was a good predictor of larger infarction. While 55% of all patients with infarction had nausea or vomiting, for patients with infarctions that produced a peak creatine kinase level of more 1,000 IU/liters, 78% had nausea or vomiting. Sex was a marginally important variable. After adjusting for sex, the presence of nausea or vomiting still predicted infarct size (p less than 0.001). Thus, cardiogenic nausea and vomiting are associated with larger myocardial infarctions but do not suggest infarcts in a particular location.

Acute fluoride toxicity. Pathophysiology and management.

Acute intoxication with inorganic fluoride disrupts numerous physiological systems. As a potent acid it acts corrosively on the skin and mucous membranes, producing severe burns. As the most electronegative element it tightly binds many cations essential to homeostasis, producing, for example, profound hypocalcaemia and resultant inhibition of normal blood coagulation. As a metabolic poison it stimulates some enzymes, such as adenylate cyclase, and severely inhibits others, such as Na(+)-K(+)-ATPase and the enzymes of carbohydrate metabolism. Death can result from these processes and also from a delayed, explosive hyperkalaemia. Therapy of acute poisoning is aimed first, at preventing the absorption of fluoride by incorporating it into insoluble fluoride compounds; secondly, at enhancing fluoride tolerance by maintaining normal blood pH and electrolytes, and aggressive general support of the toxic patient; and thirdly, at manipulating renal excretion or removing fluoride with dialysis and haemoperfusion. If the poisoned patient can be supported for 24 hours, the prognosis improves markedly, although delayed toxicity can occur.

The manipulation of potassium efflux during fluoride intoxication: implications for therapy.

Based on findings in 2 fluoride-toxic patients, it was suspected that hyperkalemia played a clinically important role in the etiology of sudden death from fluoride poisoning. Using fluoridated human erythrocytes as an in vitro model, it was confirmed that fluoride produced a marked potassium efflux from intact cells. Further, neither glucose and insulin in pharmacologic doses, nor various buffers could halt the efflux by shifting the potassium intracellularly. If these results can be extrapolated to the clinical situation, removal of potassium and fluoride via exchange resins or dialysis remains the only reasonable approach to this life threatening problem. Aside from sudden hyperkalemia and hypocalcemia, no serologic marker for fluoride toxicity has been identified. A high degree of clinical suspicion is therefore essential to the diagnosis.

Sodium fluoride produces a K+ efflux by increasing intracellular Ca2+ through Na+-Ca2+ exchange.

Acute fluoride intoxication increases intracellular calcium (Cai), manifested by increased twitch tension in cardiac muscle, and by potassium efflux (mediated by Ca2+-dependent K+ channels) in fluoridated erythrocytes. Fluoride, like isoproterenol, stimulates adenylate cyclase, and could increase Cai via the effects of cAMP on Ca2+ channels. However, while the inotropic effects of fluoride mimicked isoproterenol in rat atria, their effects on the time course of isometric contraction were quite different. In addition, acetylcholine negated isoproterenol's effect on twitch tension but did not modulate the effects of fluoride. Further, the Ca2+ channel antagonist verapamil had no effect on fluoride-stimulated K+ efflux from erythrocytes. Fluoride also inhibits Na+-K+ ATPase, and increases intracellular Na+, so could increase Cai via Na+-Ca2+ exchange. Lanthanum, which blocks Na+-Ca2+ exchange, blocks fluoride-induced K+ efflux in erythrocytes. We conclude that the effects of fluoride on adenylate cyclase are not important in intact tissue, and that inhibition of Na+-K+ ATPase and subsequent Na2+-Ca2+ exchange may be the mechanism of increased Cai in acute fluoride toxicity.

Efficacy of preconditioning with intracoronary diltiazem in preventing laser-induced spasm.

Laser energy produces a multitude of effects, resulting both in therapeutic tissue ablation and complications such as laser-induced spasm (LIS). LIS can occur during lasing itself or during subsequent adjunctive angioplasty. Intracoronary diltiazem (ICD) can partially reverse LIS after it occurs. To determine whether pre-treatment with ICD might prevent LIS during laser interventions, 3 groups of 50 lesions each were studied. Group 1 served as controls receiving no ICD during the procedure. Group 2 received 2.5 mg ICD before lasing. Group 3 received ICD before lasing and then a second infusion of 2.5 mg ICD after lasing but before adjunctive therapy. There were no differences in clinical characteristics of the 3 groups. Over 75% of lesions in each group were complex (B2 or C) lesions, and average lesion length was 15 mm in all 3 groups. Procedural success was > or = 94% in all groups. There was no significant difference among groups in pre-procedure artery stenosis, post-procedure stenosis, laser power used or number of laser pulses delivered. Pretreatment with ICD produced vasodilation of the minimum lumen diameter from 0.86 +/- 0.1 to 1.0 +/- 0.1 mm (p < 0.01) and was well tolerated. Control patients exhibited a 12% incidence of LIS. Group 2 had an 80% reduction of LIS during lasing (p < 0.01) but had increased LIS during adjunctive therapy with the same 12% incidence of LIS overall. Group 3 had only a 2% incidence of LIS (p < 0.01). We concluded that pretreatment with ICD significantly reduces LIS. Multiple infusions of ICD are necessary to sustain this protective effect.

Delayed fatal hyperkalemia in a patient with acute fluoride intoxication.

A 19-year-old man presented with acute fluoride poisoning. Initially his serum electrolytes were normal, but two hours later he developed ECG evidence of hyperkalemia followed by refractory ventricular fibrillation, suggesting that hyperkalemia may be important in the cardiotoxicity of acute fluoride intoxication. Treatment of fluoride-induced hyperkalemia consists of removal of fluoride from the body by dialysis, binding fluoride with aluminum or calcium, or enhancing fluoride excretion by inducing a metabolic alkalosis. Direct treatment of the hyperkalemia with glucose, insulin, and bicarbonate is ineffective. Quinidine may be an effective therapy for the hyperkalemia and ventricular irritability, but is as yet untested in human beings.

Environmental electromagnetic interference from electronic article surveillance devices: interactions with an ICD.

A patient with an implantable cardioverter defibrillator (ICD) experienced an inappropriate firing while in close proximity to an electronic article surveillance (EAS) device. Testing revealed the ICD was able to detect high frequency "noise" when close to the EAS device. ICD patients may need counseling to avoid close contact with such devices.

Fluoride-induced hyperkalemia: the role of Ca2+-dependent K+ channels.

Acute fluoride poisoning is associated with sudden cardiac death by an unknown mechanism. Because F- binds to Ca2+ to cause marked hypocalcemia, lowered serum Ca2+ concentrations have been thought to be a major underlying factor in the ventricular irritability of F(-)-toxic patients. However, correction of the hypocalcemia does not prevent sudden death. Paradoxically, while decreasing extracellular Ca2+ levels, in vitro studies have shown F- increases intracellular Ca2+, which is thought to trigger Ca2+-dependent K+ channels and produce a K+ efflux. The K+ efflux may be important clinically, as patients with F- overdose can exhibit hyperkalemia shortly before cardiovascular collapse. In erythrocyte suspensions, we found that propranolol, which increases the sensitivity of the Ca2+-dependent K+ channels, exacerbates the efflux, and quinidine, which blocks the channel, prevents the efflux. In six dogs, 35 mg/kg of sodium fluoride given intravenously produced intractable ventricular fibrillation within 140 minutes. Four dogs given 200 mg of quinidine sulfate with the sodium fluoride developed no ventricular arrhythmias. The data indicate that F--induced hyperkalemia is important in sudden cardiac death following acute fluoride toxicity and that this hyperkalemia is mediated by Ca2+-dependent K+ channels.

Reappraisal of the electroneurographic and electromyographic diagnosis of diabetic peripheral neuropathy.

Twenty, otherwise unselected, subjects with Type II diabetes mellitus were studied using electroneurographic and electromyographic techniques. Latencies, conduction velocities, amplitude and duration of evoked responses and change of amplitude and duration over distance, as well as H reflex and ulnar F wave were determined for motor nerves. Latency to onset and peak of negative deflection and amplitude of the evoked action potential were determined for sensory nerves. Eleven subjects had amplitude and/or latency abnormalities of the sural, superficial peroneal, and median sensory nerves. One additional subject had abnormality of both the sural and superficial peroneal nerves. Five subjects had mononeuropathies and 2 of these also had membrane instability of the abductor hallucis muscle. Ten subjects had clinical or electrophysiologic findings compatible with carpal tunnel syndrome either as an isolated lesion or superimposed on underlying peripheral neuropathy. It was concluded that all subjects with abnormality of 3 sensory nerves (median, sural and superficial peroneal) had findings compatible with diabetic peripheral neuropathy and that additional electrodiagnostic studies (unless otherwise indicated) did not identify additional abnormalities diagnostic of peripheral neuropathy in the remaining subjects.

Treatment of recurrent toxic shock syndrome with oral contraceptive agents.

PIP: The case of a 20-year old woman who was hospitalized for toxic shock syndrome (TSS) for 4 consecutive months despite use of conventional therapy for prevention of recurrence is described. Following discharge after the 4th episode she was started on oral contraceptives (OCs), and her next 8 menstrual cycles were uneventful despite continued use of tampons. She since discontinued use of tampons and remains asymptomatic. TSS recurrences occur in 30-64% of patients and can follow the initial episode by up to 41 months. The experience of this patient demonstrates the limitations of using antistaphyloccal antibiotics at the end of each menstrual cycle but suggests that hormonal manipulation may be an effective alternative therapy for TSS recurrences. Epidemiological studies show TSS patients use OCs less frequently than controls. Whether OCs suppress the vaginal flora, as some evidence suggests, or make conditions less favorable for the development of TSS in some other way is unknown. OC therapy for recurrences of TSS should receive further study.^ieng

Subclavian-coronary steal through a LIMA-to-LAD bypass graft.

Eighteen months after coronary artery bypass grafting with a left internal mammary artery (LIMA) graft, a 58-year-old woman had a change in the character of her angina to include pain in the left arm, especially with upper extremity work, culminating in an episode of prolonged rest pain. Cardiac catheterization revealed retrograde flow through the LIMA graft to the subclavian artery and stenosis of the left subclavian artery at its origin from the aorta. Restoration of antegrade flow through the LIMA graft to the coronary arteries was achieved by a carotid-subclavian bypass resulting in a resolution of symptoms. The evaluation of recurrent angina after LIMA bypass grafting should exclude the possibility of subclavian artery stenosis as well as disease of the native and graft coronary anatomy.