Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of outcomes than left ventricular ejection fraction or end-systolic volume index: prospective cohort study.

OBJECTIVES: Ejection fraction (EF) and end-systolic volume index (ESVI) are established predictors of outcomes following ST-segment elevation myocardial infarction (STEMI). We sought to assess the relative impact of infarct size, EF and ESVI on clinical outcomes and left ventricular (LV) remodelling. DESIGN: Prospective cohort study. SETTING: Academic hospital in Chicago, USA. PATIENTS: 122 patients with STEMI following acute percutaneous reperfusion. MAIN OUTCOME MEASURES: Death, recurrent myocardial infarction (MI) and heart failure. METHODS: Cardiac magnetic resonance imaging was obtained within 1 week following STEMI in 122 subjects. ESVI, EF and infarct size were tested for the association with outcomes over 2 years in 113 subjects, and a repeat study was obtained 4 months later to assess LV remodelling in 91 subjects. RESULTS: Acute infarct size correlated linearly with the initial ESVI (r = 0.69, p<0.001), end-diastolic volume index (EDVI) (r = 0.42, p<0.001) and EF (r = -0.75, p<0.001). All were independently associated with outcomes (one death, one recurrent MI and 16 heart failure admissions). However, infarct size was the only significant predictor of adverse outcomes (p<0.05) by multivariate analysis. The smallest infarct size tertile had an increased EF (49% (SD 8%) to 53% (6%); p = 0.002) and unchanged EDVI (p = 0.7). In contrast, subjects with the largest infarct tertile also had improved EF (32% (9%) to 36% (11%); p = 0.002) at the expense of a dramatic increase in EDVI (86 (19) to 95 (21) ml/m(2); p = 0.005). CONCLUSIONS: Infarct size, EF and ESVI can predict the development of future cardiac events. Acute infarct size, which is independent of LV stunning and loading, directly relates to LV remodelling and is a stronger predictor of future events than measures of LV systolic performance.

A novel point mutation in cluster 3 of the thyroid hormone receptor beta gene (P247L) causing mild resistance to thyroid hormone.

Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) beta gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31-year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequencing the TRbeta gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRbeta had a Ka for triiodothyronine (T3) 30% that of the wild-type TRbeta, approximately a threefold reduction in T3-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to < 0.01 microU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT3: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRbeta but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRbeta mutation is associated with a realtively mild RTH. Results of responses to LT3 underscore the variable phenotype of RTH.

Counter-regulatory hormone responses to insulin-induced acute hypoglycemia in hypopituitary patients.

Patients with hypopituitarism are predisposed to fasting hypoglycemia and are considered unusually sensitive to insulin-induced acute hypoglycemia. However, whether impaired response of counter-regulatory hormones, such as glucagon, epinephrine (E), and nor-epinephrine (NE) contribute to the susceptibility to acute hypoglycemia in hypopituitary patients has not been systematically evaluated. Therefore, we compared counter-regulatory hormone responses to insulin-induced acute hypoglycemia in 9 patients with hypopituitarism who were off hormone replacement therapy and 13 normal healthy subjects. All subjects received aa prime-continuous intravenous infusion of insulin (0.1 Unit/kg body weight.h) till plasma glucose declined to less than 2.5 mmol/l or occurrence of hypoglycemic symptoms. All normal subjects and 7 out of 9 hypopituitary patients recovered spontaneously from hypoglycemia. Two hypopituitary patients with hypothalamic pathology however needed intravenous glucose, glucagon and hydrocortisone to assist recovery from hypoglycemia. Overall, patients with hypopituitarism showed a slower rate of recovery of plasma glucose after hypoglycemia than normal subjects (0.78 +/- 0.33 mmol/l.h vs. 1.72 +/- 0.15 mmol/l.h, respectively; p = 0.02). The responses of key counter-regulatory hormones, glucagon, E and NE, to hypoglycemia however were essentially similar in both the groups. We conclude that the lack of cortisol (secondary to ACTH deficiency) and GH in hypopituitary patients may be primarily responsible for the slow recovery of plasma glucose after acute hypoglycemia; and plasma glucagon, E, and NE responses are not impaired.

Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway.

We have recently shown that glucose and glucosamine regulate the transcription of transforming growth factor-alpha (TGF alpha) in rat aortic smooth muscle (RASM) cells. Based on the increased potency of glucosamine compared to glucose, we hypothesized that stimulation of TGF alpha transcription by glucose is mediated through the hexosamine biosynthesis pathway. The yeast cDNA for the rate-limiting enzyme of this pathway, glutamine:fructose-6-phosphate amidotransferase (GFA), was therefore expressed in RASM cells. GFA-transfected cells showed an increase in GFA activity, exhibiting a 2.2-fold increase in the synthesis of glucosamine-6-phosphate, the first product of the hexosamine biosynthetic pathway. To test the effect of GFA overexpression on TGF alpha transcriptional activity, cells were transiently cotransfected with GFA along with a reporter plasmid containing the firefly luciferase gene under control of the TGF alpha promoter. GFA-transfected cells exhibited a glucose-dependent 2-fold increase in TGF alpha activity compared to control cells. Maximal stimulation of TGF alpha-luciferase activity by glucosamine, however, was equivalent in GFA-and control-transfected cells, confirming that the stimulation observed by both agents operated through the same pathway. This increase in TGF alpha activity was inhibited (85% at 0.5 mM glucose and 69% at 30 mM glucose) by the glutamine analog and inhibitor of GFA, 6-diazo-5-oxonorleucine (10 microM). Control studies confirmed that the increased TGF alpha-luciferase activity in the GFA-expressing cells was not an artifact of altered growth, survival, or transfection efficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of thiazide therapy on glucose, insulin and cholesterol metabolism and of glucose on potassium: results of a cross-sectional study in patients from the Hypertension Detection and Follow-up Program.

Fasting and one hour post-glucose load blood samples were obtained from 497 participants in the Hypertension Detection and Follow-up Program (HDFP), 79.8% of whom were on antihypertensive therapy at the time of their five-year examination. Major findings include a positive correlation between glucose/insulin ratio and serum potassium (P = 0.0014) and a weaker negative correlation between fasting insulin and serum potassium (P = 0.004). These data are compatible with a primary effect of hypokalaemia producing insulin 'resistance'. In addition, the glucose load was followed by a mean reduction in serum potassium of 0.135 +/- 0.525 meq/l (P less than 0.001). Twenty percent of participants experienced a drop of more than 0.5 meq/l. Cholesterol was associated with the fasting glucose/insulin ratio (P less than 0.032). The results are compatible with the hypothesis that prevention of hypokalaemia may prevent certain metabolic effects attributed to thiazide.

Lingual thyroid. Diagnosis and treatment.

We describe four patients who presented with a lingual thyroid condition (three females and one male, aged between 7 and 22 years). Only the male patient was symptomatic with mild dysphagia and hemoptysis. The diagnosis was suspected in three patients, and was confirmed by iodine 123 or 131 scanning in all patients and by a computed tomographic scan in the one patient studied. The patient with dysphagia received a 10-mCl therapeutic dose of iodine 131 before thyroxine replacement was started. The diagnosis and management of lingual thyroid is discussed. All patients need lifelong thyroxine suppression. Unenhanced computed tomographic scans have a diagnostic appearance due to the iodine content of the ectopic thyroid tissue.

Glucose-dependent insulinotropic polypeptide augmentation of insulin. Physiology or pharmacology?

Glucose-dependent insulinotropic polypeptide (GIP) is said to be a major physiologic factor in the augmentation of the insulin response to oral glucose. Whether GIP promotes insulin release at physiologic concentrations of glucose or GIP, however, is questionable. To investigate this further, volunteers were infused with 10, 20, or 40 g intravenous (i.v.) glucose, with or without simultaneous GIP infusion, to produce plasma levels of GIP or glucose similar to those seen after oral glucose. The effect of 40 g i.v. glucose with three times the original dose of GIP was also investigated. No significant enhancement of glucose-stimulated insulin secretion was seen when GIP was infused with 10 or 20 g i.v. glucose; however, with 40 g a doubling of the insulin response occurred. The higher dose of GIP caused a further increase in insulin response (30-min increment, 972 +/- 191 pmol/L; compared with glucose alone, 356 +/- 100 pmol/L, P less than 0.01; and compared with low GIP, 602 +/- 247 pmol/L, P less than 0.02). The glucose increment after the 40-g i.v. dose was +9.2 mmol/L. The concentration of GIP and glucose required to produce significant potentiation of the insulin response appears to be in the pharmacologic, rather than physiologic, range.

Mixed meal tolerance test and reactive hypoglycemia.

Twenty-six patients with symptoms suggestive of postprandial hypoglycemia were investigated by oral glucose tolerance test (OGTT). During the OGTT, symptomatic hypoglycemia occurred in 10 (38.5%). Nine of these 10 sugjects were given mixed meal tolerance tests (MMTT) and symptomatic hypoglycemia failed to occur in any case. During the OGTT the nadir glucose was significantly lower than that during MMTT (44.1 +/- 1.5 vs. 77.3 +/- 4.8 mg/dl +/- SEM, respectively; p less than 0.0005). Serum insulin during MMTT peaked significantly earlier than during OGTT (46.7 +/- 7.3 vs. 86.7 +/- 11.7 minutes (SEM, respectively; p less than 0.0125). The early secretion of insulin during MMTT may explain the lack of symptomatic hypoglycemia in these patients. We conclude that reactive hypoglycemia, when tested by a more natural stimulus (such as mixed meal) rather than by OGTT, is uncommon.

Hemoglobin A1 in the diagnosis of chemical diabetes mellitus.

HbA1 was determined in 16 subjects with normal oral glucose tolerance test (OGTT), in 8 subjects with normal fasting plasma glucose (FPG) but with abnormal OGTT (chemical diabetes mellitus) and in 25 subjects with overt diabetes mellitus. The HbA1 values were 7.53 +/- 0.1%, 8.37 +/- 0.17% and 11.92 +/- 0.42% (+/- SEM), respectively. The HbA1 values of subjects with chemical diabetes mellitus were significantly higher (p less than 0.0025) than those of subjects with normal OGTT. Thus, the determination of HbA1 may prove to be useful to substantiate a significantly abnormal glucose tolerance (chemical diabetes mellitus).

A membrane abnormality in lymphocytes from diabetic subjects.

The fluorescence properties of the hydrophobic probe 1,6-diphenyl1-1,3,5-hexatriene incorporated in the lymphocytes of 30 diabetic patients and 21 normal control subjects were studied. The mean value of the probe polarization was 0.314 for the control group and 0.294 for the patient group. The difference was significant at p < 0.001. The decreased polarization was correlated with the level of plasma glucose in the patients (p < 0.01). Nanosecond fluorescence results obtained from the lymphocytes of 7 patients and 5 controls indicated that there was no significant difference in the probe lifetimes between the two groups of subjects and suggest that the decreased polarization of the probe in the patient group resulted from a more fluid lipid environment of cell membranes.

Determination of insulin antibodies.

Insulin antibodies were determined as percentage binding of 125I-insulin in the sera of normal persons and of diabetic subjects treated and untreated with insulin. The effect of the dilution of the serum, circulating insulin and extraction of free and total insulin was evaluated. The determination of insulin antibodies in samples at a final dilution of 1:10 clearly discriminated between insulin-treated and untreated subjects. In insulin-treated subjects, the determination of insulin antibodies in samples at a final dilution of 1:100 gave false-negative results in 28 per cent. However, the determination of insulin antibodies at a final dilution of 1:100 discriminated between insulin-resistant and non-resistant diabetic subjects. Extraction of total insulin at pH 3.0 using 0.1 N HCl increased the percentage of 125I-insulin binding significantly. Extraction of free insulin by charcoal from the samples did not increase the binding of 125I-insulin. The injection of crystalline insulin 4 hours prior to withdrawing the samples did not decrease binding of 125I-insulin.

Hyperinsulinemic hypoglycemia: effect of epinephrine suppression.

The inhibitory effect of epinephrine on basal and tolbutamide-stimulated insulin release was studied in 5 patients with hyperinsulinemic hypoglycemia. Epinephrine inhibited both basal and tolbutamide-induced insulin release in patients with beta-cell adenoma and hyperplasia, but failed to inhibit insulin release in a patient with beta-cell carcinoma. The inhibition of basal insulin with epinephrine was maximum in patients with beta-cell hyperplasia. This differential inhibitory effect of epinephrine on insulin release may prove to be a useful screening test in the preoperative diagnosis of the nature of the lesion producing hyperinsulinemia.

Immunogenicity of "single component" port insulin.

Twelve diabetic subjects who were not previously treated with insulin were divided into two groups of six each. Group I was treated with single component pork insulin and Group II was treated with standard (USP) insulin for 5 to 10 months. Three out of six in Group I, and five in Group II, developed circulating insulin antibodies. Daily insulin requirement in the two groups were almost the same. Insulin antibody titer did not fall in three insulin-treated diabetic subjects when single component pork insulin was substituted for USP beef-pork insulin. This study shows that the single component insulin is antigenic in human subjects.

Free and total insulin levels in a patient with insulin-resistant diabetes mellitus and chronic lymphatic leukemia: effect of prednisone therapy.

An insulin-resistant diabetic patient who also has chronic lymphocytic leukemia and very high plasma levels of free and total insulin along with high levels of insulin antibodies is described. In response to prednisone therapy, his insulin requirement decreased, but the total and free insulin concentrations increased as insulin antibody measured as the maximal insulin-binding capacity of plasma remained unchanged. In insulin resistance, persistent hyperglycemia, in spite of high levels of immunoreactive free insulin, presumably reflects peripheral tissue unresponsiveness to insulin. The beneficial effect of prednisone treatment in this patient is discussed, and it is postulated to be the result of either increased availability of free insulin or an increased responsiveness of the tissues to insulin or both.

Failure of triiodothyronine to prevent propylthiouracil-induced hypothyroidism and goiter in fetal sheep.

Administration of propylthiouracil (PTU) to pregnant, third trimester sheep led to decreasing serum thyroxine and increasing serum thyroid-stimulating hormone in both mothers and fetuses. Hypothyroidism appeared more pronounced in the fetuses than in the ewes, and goiter formation was observed in all fetuses exposed to PTU. Concomitant administration of triiodothyronine failed to protect the fetuses from the effects of PTU.

The effects of hypophysial portal plasma on the content of immunoreactive growth hormone in the anterior pituitary.

1. Blood plasma obtained from the hypophysial portal vessels of rats has been tested in assay animals for effects on the content of growth hormone in the anterior pituitary.2. Growth hormone was estimated by radioimmuno-assay at 15 min, 30 min, 1 hr and 2 hr after intracarotid or intravenous infusion of portal plasma. There was a significant increase in growth hormone content at 15 min after infusion, but not at 30 min, 1 hr and 2 hr.3. Insulin, cold stress, haemorrhage and treatment with growth hormone had no effect on growth hormone content of the pituitary under the conditions of application of these stimuli.4. Growth hormone was measured in plasma obtained from the pituitary of control and insulin-treated animals. In control animals the amount of growth hormone in this plasma was higher than in base line samples and in the insulin-treated animals it was lower than in base line samples. A calculation based on the growth hormone content of blood obtained directly from the pituitary indicates a daily rate of synthesis and release of about 10 mug.5. The hypothesis that portal plasma stimulated the synthesis of immuno-assayable growth hormone by the anterior pituitary is considered.6. Discrepancies between our results using immuno-assay and those of others using bio-assay are discussed.