Head-up tilt test with clomipramine challenge in vasovagal syndrome--a new tilt testing protocol.

PURPOSE: The aim of the study was to randomly compare clomipramine, used as a challenge-agent during head-up tilt test, with isoproterenol, used in the conventional test, in patients with vasovagal syndrome. SUBJECTS AND METHODS: The serotonergic re-uptake inhibitor clomipramine was infused (5mg in 5min) at the start of head-up tilt test (Clom-HUT) in 126 patients (mean age 41+/-16 years) with positive history of recurrent neurocardiogenic syncope, and in 54 healthy control subjects (mean age 46+/-15 years). All subjects had also been tested with a conventional 60 degrees head-up tilt test (Con-HUT) for 30 min and, if negative, isoproterenol infusion was performed at the end of the test. The two tests were performed in a random order with a 24-h interval between them. RESULTS: Fifty-two of the 126 patients (41%) and two of the 54 controls had a positive response to Con-HUT. In the Clom-HUT the proportion of patients who experienced a positive response increased to 83% (105 subjects), while this happened only to four control subjects. The predictive accuracy of Clom-HUT increased compared to Con-HUT from 58 to 86%, respectively. CONCLUSION: The results indicate an increased responsiveness of central serotonergic neural system in subjects with vasovagal syndrome, the activation of which leads to sympathetic withdrawal. The use of clomipramine infusion during tilt test seems to improve considerably its diagnostic value.

Provocation of neurocardiogenic syncope by clomipramine administration during the head-up tilt test in vasovagal syndrome.

OBJECTIVES: We sought to test the hypothesis that activation of the serotonergic system in patients with vasovagal syndrome during the head-up tilt test provokes syncope. BACKGROUND: Central serotonergic activation participates in the pathogenesis of neurocardiogenic syncope. Drugs increasing serotonin (5-HT) in the central nervous system have not been tested as drug challenges during the head-up tilt test with clomipramine (Clom-HUT). METHODS: The serotonergic re-uptake inhibitor clomipramine was infused (5 mg in 5 min) at the start of Clom-HUT in 55 patients (mean age 40 +/- 17 years) with a positive history of recurrent neurocardiogenic syncope and in 22 healthy control subjects (mean age 46 +/- 15 years). Blood samples were taken at 0, 5, 10 and 20 min for estimation of plasma prolactin and cortisol as neuroendocrine indicators of central serotonergic responsivity. All subjects had been previously tested with a basic 60 degrees head-up tilt test (B-HUT) for 30 min, and if negative, isoproterenol infusion was given at the end of the test. RESULTS: Twenty-nine (53%) of the 55 patients and none of the 22 control subjects had a positive result in the B-HUT. With Clom-HUT, the proportion of patients who experienced a positive response increased to 80% (n = 44), although this happened to only one control subject. Prolactin and cortisol plasma levels increased significantly in the positive Clom-HUT patient group only. CONCLUSIONS: The results indicate an increased responsivity of the central serotonergic neural system in subjects with vasovagal syndrome, the activation of which leads to sympathetic withdrawal. The use of clomipramine infusion with the tilt test seems to considerably improve its diagnostic value.

Association of heart failure in homozygous beta-thalassemia with the major histocompatibility complex.

BACKGROUND: In beta-thalassemia major, heart failure primarily affecting left ventricular systolic function is the most common complication and cause of death. Apart from iron deposition, it has been recently reported that myocarditis might be another contributing factor in the pathogenesis of acute or chronic heart failure, acting possibly through an autoimmune mechanism. In an attempt to assess the role of immunogenetic factors in the development of heart failure associated with beta-thalassemia major, we studied the frequency of major histocompatibility antigens/alleles A, B, DR, and DQ in homozygous beta-thalassemic patients with and without heart failure primarily affecting the left ventricle. METHODS AND RESULTS: Forty-five consecutive unrelated Greek patients with homozygous beta-thalassemia and left-sided chronic heart failure were studied. Fifty-eight unrelated Greek patients with homozygous beta-thalassemia without heart failure and 130 unrelated Greek healthy controls were also studied. In all subjects, class I HLA-A and -B typing was performed by the complement-mediated lymphocytotoxicity assay, whereas class II HLA-DR and -DQ typing was performed by polymerase chain reaction. HLA-DRB1*1401 allele frequency was significantly increased in patients with beta-thalassemia major without left-sided heart failure compared with those with heart failure (corrected P [P(c)]=0. 02, odds ratio 0.1) and healthy controls (P(c)=0.001). HLA-DQA1*0501 allele frequency was increased in patients with heart failure compared with patients without heart failure (P(c)=0.04, odds ratio 14) and healthy controls (P(c)=0.004). CONCLUSIONS: Differences exist in the immunogenetic profile between homozygous beta-thalassemic patients with and without left-sided heart failure, raising the possibility that genetically defined immune mechanisms may play an important role in the pathogenesis of heart failure in beta-thalassemia.

Central serotonergic responsiveness in neurocardiogenic syncope: a clomipramine test challenge.

BACKGROUND: Central serotonergic mechanisms appear to participate in the pathogenesis of recurrent neurally mediated syncope. The aim of the study was to investigate the responsiveness of the central serotonergic system by measuring the prolactin and cortisol responses to intravenous administration of the serotonin reuptake inhibitor clomipramine. METHODS AND RESULTS: Twenty subjects free of any medical treatment were tested. Twelve had a history of recurrent syncopal attacks and positive tilt test (patient group, mean age 47+/-18 years, 8 men); 8 subjects without syncope and a negative tilt test result served as control subjects (mean age 49+/-10 years, 5 men). Twenty-five milligrams of clomipramine was administered intravenously within 15 minutes, and blood samples were taken at 0, 15, 30, 45, and 60 minutes. Two days later, a tilt test was performed at 60 degrees for 30 minutes and blood samples were taken at 0, 10, 20, and 30 minutes. During the clomipramine challenge, plasma prolactin levels increased in both groups. The levels at 30 minutes were higher in the patient group compared with the control group (17.3+/-7.2 vs 9.3+/-7.6 ng/mL, P=0.05). Similar results were observed for cortisol at 30 minutes (172+/-15 vs 118+/-21 ng/mL P=0. 04) and at 45 minutes (189+/-20 vs 116+/-23 ng/mL, P=0.03). The tilt test was positive in 8 (67%) out of 12 of the patient group and negative in all control subjects. In the samples taken during the tilt test, significant increases in prolactin and cortisol were observed only in the subjects with positive tilt test results. CONCLUSIONS: Patients with a history of neurocardiogenic syncope show a higher responsiveness of the central serotonergic system to clomipramine challenge. The results support the view that central serotonergic mechanisms are involved in the pathophysiology of the syndrome.

Apolipoprotein E epsilon4 allele as a genetic risk factor for left ventricular failure in homozygous beta-thalassemia.

In homozygous beta-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) 4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in beta-thalassemia homozygotes. A total of 251 Greek beta-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE 4 allele frequency (7.9%) not different from population controls (6.5%, P > .05), while patients with LVF had a significantly higher frequency of APOE 4 (12.8%) than the controls (P < .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE 4 allele may represent an important genetic risk factor for the development of organ damage in homozygous beta-thalassemia.

CGMP levels following ANP challenge are markers of subsequent successful reversion of lone atrial fibrillation to sinus rhythm.

The aim of the present study was to assess whether cGMP release to ANP stimulation can be a biochemical marker of subsequent successful electrical cardioversion of lone atrial fibrillation to sinus rhythm. For this purpose, we studied 13 patients with chronic, lone atrial fibrillation of less than one year's duration who presented to our laboratory for electrical therapy of their arrhythmia. Prior to electrical cardioversion, peripheral venous cGMP levels were assessed at baseline and following an intravenous challenge of 50 Ug human ANP. Venous blood samples for cGMP assessment were taken a) at baseline, b) 5 and 10 mins after the end of ANP infusion. ANOVA of repeated measures was used for statistical analysis. Eight of the study patients were successfully cardioverted to sinus rhythm, while the remaining 5 were not. Although no difference was noted between the two groups regarding the mean time of arrhythmia duration as well as left atrial and ventricular dimensions, ANP stimulation provoked significantly greater cGMP release in patients whose arrhythmia reverted to sinus rhythm, when compared with that of patients whose arrhythmia persisted (p < 0.001). Therefore, cGMP levels following ANP challenge might discriminate between patients with chronic AF who are going to be successfully cardioverted and those who are not. These findings imply that the underlying atrial disease might be different in extent/nature between patients with lone AF responsive to cardioversion and those with resistant arrhythmia.

Hormonal responses during tilt-table test in neurally mediated syncope.

The hormonal profile during tilt testing was examined in syncopal patients. An increase in the growth hormones cortisol and prolactin was found during syncope, suggesting an implication of central serotonergic activation.

Decreased post-myocardial infarction heart rate variability and cardiac denervation assessed by metaiodobenzylguanidine scintigraphy.

Decreased heart rate variability, assessed 2 weeks after uncomplicated acute myocardial infarction, is related to the extent of 1-123-metaiodobenzylguanidine-derived efferent sympathetic cardiac denervation. This postinfarction cardiac denervation could be the substrate of reduced postinfarction heart rate variability.