David L. Hess

Reduction of Plasma Homocyst(e)ine Levels by Breakfast Cereal Fortified with Folic Acid in Patients with Coronary Heart Disease

BACKGROUNDnThe Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels.nnnMETHODSnTo test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease.nnnRESULTSnPlasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 microg of folic acid daily, approximating the increased daily intake that may result from the FDAs enrichment policy, increased plasma folic acid by 31 percent (P=0.045) but decreased plasma homocyst(e)ine by only 3.7 percent (P= 0.24). However, cereals providing 499 and 665 microg of folic acid daily increased plasma folic acid by 64.8 percent (P<0.001) and 105.7 percent (P=0.001), respectively, and decreased plasma homocyst(e)ine by 11.0 percent (P<0.001) and 14.0 percent (P=0.001), respectively.nnnCONCLUSIONSnCereal fortified with folic acid has the potential to increase plasma folic acid levels and reduce plasma homocyst(e)ine levels. Further clinical trials are required to determine whether folic acid fortification may prevent vascular disease. Until then, our results suggest that folic acid fortification at levels higher than that recommended by the FDA may be warranted.

Long-term follow-up of patients with recurrent unexplained syncope evaluated by electrophysiologic testing.

Electrophysiologic testing was performed in 53 patients with recurrent syncope that remained unexplained despite a thorough neurologic and noninvasive cardiac evaluation. Fifteen patients had no structural heart disease, 9 had mitral valve prolapse and 29 had structural heart disease other than mitral valve prolapse. Nonsustained ventricular tachycardia was induced in 15 patients (28%), sustained ventricular tachycardia was induced in 9 (17%), ventricular fibrillation was induced in 4 (8%) and sinus node function was abnormal in 2 (4%). Female sex and lack of structural heart disease were independently associated with a negative electrophysiologic study (p less than 0.001). Patients with inducible ventricular tachycardia or ventricular fibrillation were treated with drugs selected on the basis of the results of electropharmacologic testing. The recurrence rate of syncope was 43% over a 31 +/- 10 month period (mean +/- standard deviation) of follow-up in patients with a negative electrophysiologic study, 40% over a 22 +/- 6 month period in patients with inducible nonsustained ventricular tachycardia, 0% over a 30 +/- 12 month period in patients with inducible sustained ventricular tachycardia and 25% over a 21 +/- 10 month period in patients with inducible ventricular fibrillation. In patients with recurrent unexplained syncope undergoing electrophysiologic testing, a potential cause of syncope is least likely to be found in women without structural heart disease. The results of programmed ventricular stimulation must be interpreted with regard to the method of induction of ventricular tachycardia and the type of ventricular tachycardia induced. The excellent response rate in patients with inducible sustained ventricular tachycardia whose therapy is guided by the results of electropharmacologic testing suggests that sustained ventricular tachycardia is a clinically significant response.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism

OBJECTIVEnData on fetal blood homocyst(e)ine concentrations are not available. We tested the hypothesis that homocyst(e)ine crosses the maternal/placental/fetal interphases and is sequestered by the fetus.nnnSTUDY DESIGNnThe concentration of homocyst(e)ine was determined at parturition in peripheral venous plasma from 35 nulliparous healthy pregnant women and umbilical arterial and venous plasma from their conceptus.nnnRESULTSnFindings demonstrated a descending concentration gradient of plasma homocyst(e)ine from maternal vein to umbilical vein and to umbilical artery; the decrease at each interphase approximated 1 micromol/L. The neonate weight and gestational age were inversely related to maternal homocyst(e)ine concentrations.nnnCONCLUSIONnThe umbilical vein to umbilical artery homocyst(e)ine decrement suggests that uptake of homocyst(e)ine occurs in the fetus. The likely incorporation of homocyst(e)ine into the fetal metabolic cycle may implicate maternal homocyst(e)ine as having a potential nutritional role in the fetus. Further studies are required to explain the role of homocyst(e)ine in fetal metabolism and development.

Electrophysiologic mechanism of exercise-induced sustained ventricular tachycardia*

To elucidate electrophysiologic mechanism of exercise-induced ventricular tachycardia (VT), electrophysiologic studies were performed in 12 patients in whom sustained VT had developed during treadmill exercise testing. Six patients had arteriosclerotic coronary heart disease, 3 had cardiomyopathy, and 3 had no clinical evidence of organic heart disease. All patients had had documented episodes of sustained VT related to exertion and had experienced dizziness, syncope, or both. In addition, 3 patients had had nonfatal cardiac arrest. Electrophysiologic studies provoked paroxysms of sustained VT identical to those observed during treadmill exercise testing in 10 patients and provoked ventricular flutter/fibrillation in 1. Seven patients had VT suggestive of a reentrant mechanism, as the VT could be readily initiated with programmed ventricular extrastimulation or terminated by ventricular overdrive pacing, or both. Three patients had VT suggestive of catecholamine-sensitive automaticity. The VT could not be initiated with programmed electrical stimulation, but it could be provoked by intravenous isoproterenol infusion; furthermore, the VT could not be terminated with ventricular overdrive pacing, but it could be abolished by discontinuing isoproterenol infusion. Reproduction of VT in these 10 patients allowed serial pharmacologic testing in selecting an effective antiarrhythmic regimen. Thus (1) exercise-induced VT can be caused by either reentry or catecholamine-sensitive automaticity, and (2) electrophysiologic studies are of use in defining the underlying mechanism of exercise-induced sustained VT.

Electrophysiologic drug testing in patients with malignant ventricular arrhythmias: Importance of stimulation at more than one ventricular site

Sixty-four patients with symptomatic ventricular tachycardia or ventricular fibrillation underwent right ventricular apical programmed stimulation and had no inducible ventricular tachycardia during drug testing. Thirty patients (Group I) did not undergo left ventricular stimulation. Left ventricular stimulation in 38 drug trials induced no ventricular tachycardia in 50% (Group IIA), nonsustained ventricular tachycardia in 24% (Group IIC). Patients in Groups I, IIA, and IIB received chronic antiarrhythmic drug therapy based on the results of electrophysiologic drug testing. Patients in Group IIC underwent further drug testing until sustained ventricular tachycardia was no longer inducible and were then entered into Group IIA or IIB; 4 patients in whom the induction of sustained ventricular tachycardia could not be suppressed by any drug regimen tested were excluded from long-term follow-up. The duration of follow-up (mean +/- standard deviation) was 15.8 +/- 1.5 months in Group I, 13.6 +/- 3.7 months in Group IIA, and 12.1 +/- 4.9 months in Group IIB. Recurrence rates of symptomatic ventricular tachycardia or sudden death were 27% in Group I, 0% in Group IIA, and 20% in Group IIB (p less than 0.02 for Group IIA versus Group I and p greater than 0.05 versus Group IIB). If only right ventricular apical stimulation is performed during electrophysiologic drug testing in patients with malignant ventricular arrhythmias, approximately 50% of drug trials may be incorrectly judged as suppressing the induction of ventricular tachycardia. Drug therapy that suppresses ventricular tachycardia induction with both right and left ventricular programmed stimulation results in a significantly better clinical response than therapy based on the results of only right ventricular apical stimulation.

Circadian myometrial and endocrine rhythms in the pregnant rhesus macaque: Effects of constant light and timed melatonin infusion

Six chronically catheterized rhesus macaques maintained on a 12-hour-light/dark cycle (lights on from 7 AM to 7 PM) showed a nocturnal uterine activity rhythm with peak contractile events between 9 and 11 PM (p less than 0.05). In blood samples collected at 3-hour intervals over a 24-hour period, we determined that plasma melatonin and progesterone concentrations were elevated at night whereas estradiol, estrone, and cortisol reached peak concentrations in the early morning (p less than 0.05). Lights were then left on for the remainder of the study. After 12 days in constant light, daily rhythms in uterine activity and plasma steroid levels were relatively unchanged, whereas melatonin concentrations were suppressed. Animals then received a timed infusion of melatonin (0.2 mg/kg/hr each day from 7 PM to 6 AM daily until delivery). The nocturnal uterine activity rhythm and the rhythms in plasma steroid concentrations were maintained. We conclude that the 24-hour patterns in maternal uterine activity and plasma steroid hormone levels are circadian rhythms generated by an endogenous biologic clock and do not appear to be driven by the pattern of melatonin in circulation.

Effects of Progesterone on Prolactin, Hypothalamic β-Endorphin, Hypothalamic Substance P, and Midbrain Serotonin in Guinea Pigs

Unlike rats, but similar to primates, guinea pigs exhibit prolonged function of the corpus luteum and elevated progesterone secretion after ovulation. The gonadotropins, estrogen (E) and progesterone (P) have been examined throughout the guinea pig estrous cycle. However, neither prolactin secretion nor its regulation by steroid hormones has been characterized, perhaps due to the lack of a specific radioimmunoassay. beta-Endorphin (BE), substance P (SP), and serotonin (5-HT) increase prolactin secretion in rats and monkeys. BE and SP neurons in guinea pigs and 5-HT neurons in monkeys contain progestin receptors which could mediate neuroendocrine effects of steroid hormones. Therefore, the effects of E and P on prolactin, BE, SP, and 5-HT and its metabolite 5-HIAA were examined in guinea pigs which were ovariectomized, E treated (28 days), and E+P treated (14 days E+14 days E+P). The rat NB2 lymphoma cell line was used as a bioassay for serum prolactin. BE and SP levels were measured by radioimmunoassay in four hypothalamic areas: the preoptic region (POA), the mediobasal hypothalamus (MBH), the dorsomedial hypothalamus (DMH), and the mamillary bodies (MB). 5-HT and 5-HIAA were measured in the midbrain raphe area by high-pressure liquid chromatography. E alone had little effect on serum prolactin levels, but E+P significantly increased prolactin as compared with ovariectomized controls. The BE levels increased with E treatment and remained elevated with E+P treatment in MBH and POA. The BE content was stimulated in DMH and MB by E+P treatment and not with E alone. The SP content in MBH, DMH, and MB increased in E-treated guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Neuropeptide Y on the in vitro Release of Gonadotropin-Releasing Hormone, Luteinizing Hormone, and Beta-Endorphin and Pituitary Responsiveness to Gonadotropin-Releasing Hormone in Female Macaques

The objectives of these studies were to examine the release of gonadotropin-releasing hormone (GnRH) and beta-endorphin-like activity (beta-EP) from macaque hypothalami, and the release of luteinizing hormone (LH) and GnRH-induced LH from macaque anterior pituitaries in response to neuropeptide Y (NPY) treatment. Anterior hypothalamic (AH) and mediobasal hypothalamic (MBH) blocks of tissues and the adenohypophysis were bisected along the midline into two equal-sized fragments. Fragments were superfused with medium for 3 h, followed by 3 h of either NPY (80 nM) or medium alone. In a separate experiment, adenohypophyseal (AP) fragments were superfused in accordance with the same protocol (3 h medium - 3 h NPY or medium) except that exogenous GnRH (352 nM) was added for 30 min at the beginning of hour 3 and again at the beginning of hour 6. Immunoactive GnRH, beta-EP, and LH levels were measured in superfusate samples (400 microliters) collected at 10-min intervals. GnRH levels rose within 20-30 min of initiation of NPY treatment, and elevated GnRH release was sustained for the duration of NPY exposure of both AH and MBH fragments from ovarian intact (INT) rhesus (Macaca mulatta: n = 8; p less than 0.05) or Japanese (Macaca fascicularis; n = 4; p less than 0.01) macaques. NPY treatment had no effect on either AH or MBH fragments isolated from ovariectomized (OVX) rhesus macaques (n = 4 for AH, and n = 5 for MBH). In AP fragments isolated from INT rhesus macaques (n = 8), NPY stimulated LH release within 1 h of treatment (p less than 0.05), whereas NPY had no effect on pituitaries from OVX animals (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of corpus luteum age on the steroidogenic response to exogenous human chorionic gonadotropin in normal cycling women

OBJECTIVEnThe null hypothesis of this study is that the patterns of steroid secretion exhibited by the human corpus luteum in response to exogenous human chorionic gonadotropin stimulation are independent of corpus luteum age at the time of treatment.nnnSTUDY DESIGNnTwenty-five normally cycling women in whom the midcycle urinary luteinizing hormone surge (luteal day 0) was identified and from whom blood samples were obtained daily from cycle day 11 until menses were prospectively randomized to receive no treatment (group I, n = 5) or exogenous human chorionic gonadotropin 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), +4 (group III, n = 5), +8 (group IV, n = 5), or +12 (group V, n = 5). Serum concentrations of estrone, estradiol, progesterone, 17-hydroxyprogesterone, and androstenedione were measured by specific radioimmunoassays in all subjects; serum human chorionic gonadotropin concentrations were determined by immunoradiometric assay in treated subjects.nnnRESULTSnSerum human chorionic gonadotropin levels (mean +/- SEM) were virtually identical among treatment groups (p greater than 0.05). Luteal phase duration (mean +/- SEM) was prolonged (p less than 0.05) only in group V (18.4 +/- 0.5 days) compared with untreated subjects (group I 13.8 +/- 0.7 days). In all groups estrone and 17-hydroxyprogesterone concentrations closely paralleled those of estradiol and progesterone, respectively. Steroid data and progesterone/estradiol ratios (mean +/- SEM) in groups I and II were indistinguishable and were combined (control, n = 10). Group III subjects exhibited patterns of steroid secretion similar to groups I and II, although progesterone was moderately increased after human chorionic gonadotropin treatment. In groups IV and V, progesterone increased (p less than 0.05) 1 day after human chorionic gonadotropin and remained elevated for 5 to 6 days; a 4-day rise (p less than 0.05) in estradiol began 3 days after treatment, and androstenedione rose modestly in parallel. Progesterone/estradiol ratios in groups III through V increased (p less than 0.05) approximately twofold after human chorionic gonadotropin treatment and remained elevated for 4 to 5 days.nnnCONCLUSIONnThe human corpus luteum exhibits distinct age-dependent patterns of steroid secretion in response to exogenous human chorionic gonadotropin stimulation, an observation that may have clinical implications regarding the empirical use of exogenous human chorionic gonadotropin in support of luteal function.

Effects of estrogen on hypothalamic gonadotropin-releasing hormone release in castrated male rhesus macaques

The evidence that hypothalamic gonadotropin-releasing hormone (GnRH) release increases during the estrogen-induced luteinizing hormone (LH) surge in castrated female macaques and that estrogen induces a similar LH surge in the male suggests that either sexual differentiation of GnRH secretion does not exist or that changes in brain GnRH are not critical for ovulation. We tested this hypothesis by using the push-pull perfusion (PPP) technique to monitor GnRH release in the mediobasal hypothalamus continuously from 10 h before to 50 h after estrogen injection in 9 castrated male rhesus macaques. Blood sampling and PPP were performed with monkeys freely moving in their own cage by using a specially designed swivel/tethering system. PPP samples were collected every 10 min and analyzed for GnRH concentration by radioimmunoassay. Blood samples were collected every hour and plasma LH was measured by bioassay. Estradiol benzoate (EB, 42 micrograms/kg, b. wt.) was subcutaneously injected after 10 h of initial PPP. The PPP was continued for 10 h after EB in 4 and 50 h after EB in 5 monkeys. Hypothalamic GnRH patterns were analyzed by the Pulsar algorithms. The results show that during the 10 h after EB, plasma LH declined rapidly, reaching low or non-detectable levels by 7-9 h, while hypothalamic GnRH releasing patterns did not change during this period (n = 9). In contrast, estrogen enhanced GnRH level and pulse amplitude, but not pulse frequency, several hours before mean peripheral plasma LH increased from suppressed values (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)