Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis.

PURPOSE: It is unclear whether intramuscular administration of testosterone esters to hypogonadal men is associated with changes in plasma lipids. We therefore analyzed 19 studies published between 1987 and 1999 that focused on male subjects with nonexperimental hypogonadism, treated subjects with an intramuscular testosterone ester and reported pretreatment and post-treatment concentrations of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, or total triglyceride. METHODS: We calculated study-specific, post-treatment minus pretreatment differences in each plasma lipid concentration (mean [95% confidence interval]). After testing of between-study homogeneity, we combined the study-specific differences. We then determined whether heterogeneity of differences could be explained in models of the differences on study and patient characteristics (mean +/- SE) before and after excluding extreme values using a multiple outlier procedure. RESULTS: The studies represented 272 hypogonadal men (age 44 +/- 4 years; 20% with hypergonadotropic hypogonadism; total testosterone 0.5 +/- 0.2 ng/mL) who received, on average, 179 +/- 13 mg intramuscular testosterone ester every 16 +/- 1 days for 6 +/- 1 months. Fixed-effects estimates of post-treatment minus pretreatment differences were -14 [-17 to -11] mg/dL (total cholesterol), -5 [-8 to -1] mg/dL (LDL cholesterol), -4 [-5 to -2] mg/dL (HDL cholesterol), and -1 [-6 to + 4] mg/dL (triglyceride). Decreases in HDL cholesterol were larger at lower dosages of testosterone ester (r = -0.54, P = 0.055), but were not explained by attrition, regression to the mean, dosing frequency or duration, concomitant elevation of plasma total testosterone, aromatization of testosterone to estradiol, or other study and patient characteristics. CONCLUSION: Intramuscular administration of testosterone esters to hypogonadal men is associated with a small, dosage-dependent decrease in HDL cholesterol and concomitant declines in total cholesterol and LDL cholesterol. The aggregate effect of these changes on cardiovascular risk remains unknown but deserves further study.

RR interval variation, the QT interval index and risk of primary cardiac arrest among patients without clinically recognized heart disease.

AIMS: Autonomic tone influences RR interval variation (RRV) and the heart rate-corrected QT interval index (QTI). Together, QTI and RRV may improve characterization of sympathovagal control and estimation of risk of primary cardiac arrest. We therefore examined effects of QTI and short-term RRV from standard, 12-lead electrocardiograms on risk of primary cardiac arrest among persons without clinically recognized heart disease. METHODS AND RESULTS: We analysed data from a case-control study of risk factors for primary cardiac arrest among enrollees in a large health plan. Cases (n=505) were enrollees aged 18 to 79 years without history of heart disease who had primary cardiac arrest between 1980 and 1994. Controls (n=529) were a demographically similar, stratified random sample of enrollees. We determined enrollee characteristics from ambulatory medical records, QTI and RRV from standard, 12-lead electrocardiograms, and medication use from automated pharmacy files. Low and high values of QTI and RRV were designated as the first and fifth quintiles of QTI (96% and 107%) and RRV (35 ms and 120 ms) among controls. In a model adjusting for clinical predictors of primary cardiac arrest, RRV modified the association between QTI and risk of primary cardiac arrest (P=0.05). Compared to high RRV and low QTI, the risk of primary cardiac arrest (odds ratio [95% CI]) was 0.95 [0.73-1.23] at low RRV and QTI, 1.23 [0.97-1.57] at high RRV and QTI, and 1.55 [1.16-2.06] at low RRV and high QTI. Risk remained elevated after adjustment for other electrocardiographic predictors and medication use. CONCLUSION: Autonomic dysfunction, characterized by high QTI and low RRV on the standard, 12-lead electrocardiogram, is associated with an increased risk of primary cardiac arrest among persons without clinically recognized heart disease.

Reassessing the role of QTc in the diagnosis of autonomic failure among patients with diabetes: a meta-analysis.

OBJECTIVE: A 1992 consensus statement on autonomic testing portrayed Bazett's heart rate-corrected QT interval (QT) prolongation as a specific yet insensitive indicator of diabetic autonomic failure. At that time, only a few small studies had evaluated the accuracy of QTc. To date, even fewer studies have evaluated whether its accuracy is influenced by patient characteristics. RESEARCH DESIGN AND METHODS: We critically appraised 17 studies reporting the sensitivity and specificity of QTc for diabetic autonomic failure. The studies represented 4,584 patients with diabetes (mean age 34.9 years, 46% female, 92% with type 1 diabetes, mean duration of diabetes 14.5 years). We summarized the accuracy of QTc prolongation for diabetic autonomic failure as an odds ratio (OR) (95% CI) and determined whether patient and study design characteristics influenced the accuracy of QTc prolongation by comparing summary receiver operating characteristic curves. RESULTS: Autonomic failure, defined as > or =1.2+/-0.4 (mean +/- SD) abnormal of 2.0+/-1.6 administered cardiovascular reflex tests, was found in 26% (25-28) of patients. The pooled sensitivity and specificity of QTc > 441+/-8 ms for autonomic failure were 28% (26-29) and 86% (85-87), respectively. Autonomic failure was 2.26 times (1.90-2.70) more likely to be present in patients with than in patients without QTc prolongation. At 86% specificity, the sensitivity of QTc prolongation was 46 vs. 12% for men versus women (P = 0.0077), respectively, and, after adjustment for sex, 66 vs. 17% among patients aged 25 vs. 55 years (P = 0.1902) and 61 vs. 27% at thresholds of >420 vs. >460 ms, respectively (P = 0.2964). CONCLUSIONS: QTc prolongation is a specific albeit insensitive indicator of autonomic failure. Although QTc prolongation is relatively accurate for men, accuracy may be even greater for young men at low QTc thresholds.

Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC Study. Atherosclerosis Risk in Communities Study.

Cardiac autonomic activity, as assessed by heart rate variability, has been found to be associated with postmyocardial infarction mortality, sudden death, and all-cause mortality. However, the association of heart rate variability and the incidence of coronary heart disease (CHD) is not well described. The authors report on the association of baseline cardiac autonomic activity (1987-1989) with incident CHD after 3 years (1990-1992) of follow-up of the Atherosclerosis Risk in Communities Study cohort selected from four study centers in the United States by using a case-cohort design. The authors examined 137 incident cases of CHD and a stratified random sample of 2,252 examinees free of CHD at baseline. Baseline, supine, resting beat-to-beat heart rate data were collected. High- (0.16-0.35 Hz) and low- (0.025-0.15 Hz) frequency spectral powers and high-/low-frequency power ratio, estimated from spectral analysis, and standard deviation of all normal R-R intervals, calculated from time domain analysis, were used as the conventional indices of cardiac parasympathetic, sympatho-parasympathetic, and their balance, respectively. Incident CHD was defined as hospitalized myocardial infarction, fatal CHD, or cardiac revascularization procedures during 3 years of follow-up. The age, race, gender, and other CHD risk factor-adjusted relative risks (and 95% confidence intervals) of incident CHD comparing the lowest quartile with the upper three quartiles of high-frequency power, low-frequency power, high-/low-frequency power ratio, and standard deviation of R-R intervals were 1.72 (95% confidence interval (CI) 1.17-2.51), 1.09 (95% CI 0.72-1.64), 1.25 (95% CI 0.84-1.86), and 1.39 (95% CI 0.94-2.04), respectively. The findings from this population-based, prospective study suggest that altered cardiac autonomic activity, especially lower parasympathetic activity, is associated with the risk of developing CHD.

Cerebellar vermis and midbrain dysgenesis in oculomotor apraxia: MR findings.

The MR imaging findings in two patients with the clinical diagnosis of oculomotor apraxia are presented. Both cases showed dysgenesis of the cerebellar vermis, and the colliculi were fused in one patient. No supratentorial abnormalities were seen in either patient.

A parametric analysis of the effects of cardiopulmonary vagal electrostimulation on the digastric reflex in cats.

The thoracic trunk and the cardiac branch of the vagus were stimulated electrically in chloralose-anesthetized cats. The experiments were conducted to determine the parameters of vagal afferent stimulation (VAS) capable of producing an inhibition of the digastric reflex (DGR), to assess the duration of this inhibition, and to test whether endogenous opioids mediate the inhibitory effects. In experiments using intermittent trains of pulses, the effects of pulse number (1, 2, 7 or 35 pulses), frequency (13, 66 or 333 Hz), intensity (0.1, 0.5, 1, 2, 3, 4 or 5 mA), and duration (1 or 3 ms) were evaluated. A 7 pulse train (3 mA) was sufficient to produce maximal inhibition (77 +/- 7%) of the tooth-pulp stimulation-evoked DGR regardless of the pulse duration or frequency. These effects were mediated by vagal afferents since stimulation of the central end produced as much inhibition as stimulation of the intact nerve. VAS also significantly reduced the DGR when elicited by tooth-pulp intensities at 1x -5x threshold. In experiments using 90 s of continuous VAS, 16 combinations of frequency and intensity yielded a threshold intensity for DGR inhibition between 0.1 and 0.5 mA and a threshold frequency at 2 Hz. Maximal DGR inhibition was produced at 5 Hz-0.5 mA by VAS. Reflex inhibition occurred within 10 s and outlasted VAS for longer than 60 s. Opiate-receptor blockade did not alter VAS inhibition of the DGR and, thus, opioids are not likely to mediate VAS-induced digastric inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of vagal afferent modulation of the digastric reflex in cats.

In the present study, we have examined the relative ability of cervical, thoracic, cardiac and diaphragmatic vagal stimulation to modulate the digastric reflex produced by tooth-pulp stimulation in anesthetized cats. The right maxillary tooth pulp was stimulated and the digastric reflex was recorded from the right digastric muscle. Cervical vagal stimulation produced a biphasic effect on the digastric reflex. The reflex was facilitated at conditioning test intervals less than 20 ms and inhibited at conditioning test intervals between 100 ms and 500 ms. Cardiac and thoracic vagal stimulation did not significantly facilitate the digastric reflex but inhibited the reflex at conditioning test intervals between 50 ms and 500 ms with maximum inhibition observed at 200 ms. In contrast, diaphragmatic vagal stimulation produced a weaker inhibition of the digastric reflex. The relative ability of different vagal segments to inhibit the digastric reflex was: thoracic = cardiac = cervical greater than diaphragmatic. The inhibitory effects were not related to cardiovascular responses to vagal afferent stimulation. These findings suggest cardiopulmonary vagal afferents represent an important source of vagal afferents which modulate the digastric reflex in the cat.