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Emily M Garland

Publications and source records attributed to Emily M Garland.

7 recordsLinked to original sources
PubMed2006

Beta2-adrenoceptor genotype and function affect hemodynamic profile heterogeneity in postural tachycardia syndrome.

Previous studies suggest that the beta2-adrenoceptor functions abnormally in patients with postural tachycardia syndrome (POTS) and may contribute to their altered hemodynamic profile. To test the hypothesis that the beta2-adrenoceptor response is decreased in POTS, we studied: (1) the arterial vasodilation response to the beta agonist, isoproterenol, and (2) the distribution of common polymorphisms (codons 16 and 27) of the gene coding the receptor (beta2-AR) in a large population with POTS. We measured plasma catecholamines and monitored hemodynamics and changes in forearm and leg blood flow to incremental doses of intraarterial isoproterenol in 9 patients with POTS compared with 8 healthy subjects. For polymorphism assessment we collected DNA from 57 patients with POTS and compared with 67 age-sex matched healthy subjects. Circulating catecholamines were significantly higher in POTS subjects compared with controls. Intrabrachial and intrafemoral isoproterenol infusion elicited a dose-dependent increase in blood flow. In healthy subjects, blood flow increased (mean+/-SEM) 400+/-70% in the forearm and 170+/-40% in the leg, but only 280+/-60% in forearms and 120+/-20% in legs of patients with POTS (ANOVA for both P<0.001). The genotype and allele distributions for codons 16 and 27 beta2-AR variants were not different in the 2 groups. However, the blood pressure and plasma norepinephrine levels diverged in patients according to their genotype. Patients with Gly16Gly and patients with Glu27Glu had lower plasma catecholamines and higher supine and upright blood pressure, compared with other genotypes. Therefore, both decreased beta2-adrenoceptor-related vasodilation and beta2-AR polymorphisms may contribute to the hemodynamic diversity of patients with POTS.

Adrenergic beta-Agonists↗
PubMed2005

Endothelial NO synthase polymorphisms and postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by an excessive rise in heart rate and symptoms consistent with cerebral hypoperfusion in the upright position. NO produced by endothelial NO synthase is a significant factor in the regulation of blood flow. Genetic polymorphisms in the promoter region (T-786C) and exon 7 (E298D) of the NO synthase isoform 3 gene affect enzyme activity and have been associated with a number of cardiovascular diseases. Because some findings in POTS suggest aberrant NO-mediated functions, we postulated that the variant genotypes of these polymorphisms may increase the risk of developing POTS and correlate with more severe symptoms. We genotyped 136 patients with POTS (mean age 32.2+/-9.9 years; 46 men and 90 women) from Nashville, Tenn, and Vienna, Austria, and compared them with 191 healthy volunteers (mean age 29.1+/-8.0 years; 127 men and 64 women). Participants also underwent orthostatic testing with blood pressure, heart rate, and plasma norepinephrine measurements while supine and upright. The frequencies of the -786CC and 298DD genotypes were significantly lower in patients with POTS than in control subjects (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.14 to 0.57; P=0.001 for -786CC; and OR, 0.44; 95% CI, 0.21 to 0.91; P=0.033 for 298DD). According to 2-locus genotype analyses, patients with -786CC and 298EE or 298ED experienced the largest changes in heart rate and plasma norepinephrine with standing. These results indicate that NO may influence the development of POTS and the severity of POTS symptoms.

Adolescent↗
PubMed2005

Influence of an insertion variant in the 5'UTR of the endothelin-1 gene on orthostatic intolerance.

BACKGROUND: Orthostatic intolerance is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has shown that orthostatic intolerance is influenced by endothelial nitric oxide synthase gene polymorphisms. Since endothelin-1 (ET-1) is one of the most important vasoconstrictor peptides, a frequent adenine insertion polymorphism within the 5'-untranslated region (5'UTR), which is of functional importance for ET-1 expression, could influence orthostatic intolerance. The aim of this study was therefore to ascertain whether this frequent variant of the endothelin-1 gene influences the risk for orthostatic intolerance. METHODS: We studied 257 white patients (120 cases with orthostatic intolerance and 137 controls) for genotyping of the 5'UTR I variant. From this cohort, 111 patients and 99 control subjects underwent a tilt-table test or an upright posture study, including monitoring of blood pressure, heart rate, and plasma catecholamines, in the supine position and during 30 minutes of standing. Genotyping was performed in all participants. Chi tests of independence were used to test for associations between orthostatic intolerance and genotype. In addition, an association of the insertion polymorphism with hemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way analysis of variance. RESULTS: The 5'UTR I variant was significantly less common in patients with orthostatic intolerance (allele frequency 0.36 and 0.28, in controls and cases, respectively). Additionally, we found a significant decrease in the risk of orthostatic intolerance among people who were homozygous for the 5'UTR variant (I/I) compared with the wild-type variant (D/D) (odds ratio, 0.41; 95% confidence interval, 0.17 to 0.97; P = 0.04). No association between the 5'UTR variant and heart rate or blood pressure regardless of diagnosis was found. CONCLUSIONS: Our current results suggest that the hereditary adenine insertion variant in the 5'-UTR of the endothelin-1 gene is protective for orthostatic intolerance. The increased ET-1 protein expression that has been linked with the I variant might be associated with a more efficient hemodynamic response to standing. This is likely one of several common genetic loci that may represent modifiers of orthostatic intolerance phenotypes.

5' Untranslated Regions↗
PubMed2004

Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles.

BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process. METHODS AND RESULTS: Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human NET (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose.

Adolescent↗
PubMed2002

No increased herniation of the cerebellar tonsils in a group of patients with orthostatic intolerance.

Orthostatic intolerance, seen predominantly in young women, is characterized by symptoms of lightheadedness, fatigue and palpitations in the upright posture. With standing, plasma norepinephrine levels rise dramatically and heart rate often increases by more than 30 beats per minute, although blood pressure does not usually fall. A theory recently popularized in the media suggests that some cases of orthostatic intolerance are related to hindbrain compression, with or without a Chiari I malformation. As a preliminary investigation of this hypothesis, head or cervical spine MRI scans from 23 females with orthostatic intolerance were reviewed. The cerebellar tonsils averaged 0.3 +/- 1.9 mm below the foramen magnum. These results were compared to measurements from a control group averaging 0.4 +/- 2.6 mm above the foramen magnum (P > 0.05). Tonsillar depression of at least 3 mm occurred in 13 % of both the patient group and the control group. Tonsillar herniation was not found to influence supine or upright blood pressure, heart rate or plasma norepinephrine levels in the patients. We conclude that herniation of the cerebellar tonsils is not a common cause of orthostatic intolerance. However, the single measurement of tonsillar depression might underestimate the number of patients with hindbrain compression.

Adult↗
PubMed2002

Genetic basis of clinical catecholamine disorders.

Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.

Catecholamines↗