Echocardiographic examination of women previously treated with fenfluramine: long-term follow-up of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fenfluramine hydrochloride was withdrawn from the market in September 1997 after reports of heart valve abnormalities in patients who used it. The prevalence of echocardiographic abnormalities and the clinical cardiovascular status of patients who received fenfluramine monotherapy remains uncertain. METHODS: A long-term, follow-up evaluation was undertaken in subjects who were randomly assigned to receive either fenfluramine hydrochloride (60 mg daily) or placebo as part of a double-blind smoking cessation therapy study. Cardiovascular status was evaluated by echocardiography, medical history, and physical examination. RESULTS: From the group of 720 smokers who had originally participated in the smoking cessation therapy trial, 619 women were enrolled; data from 530 (276 in the fenfluramine group and 254 in the placebo group) were evaluable. No statistically significant differences were identified in the prevalence of aortic or mitral regurgitation by Food and Drug Administration criteria or by grade, aortic or mitral valve leaflet mobility restriction or thickening, elevated pulmonary artery systolic pressure, or abnormal left ventricular ejection fraction. No significant differences were demonstrated in cardiovascular status by physical examination, and no serious cardiac events were noted among fenfluramine-treated subjects. CONCLUSION: There was no evidence of drug-related heart disease up to 4.9 years after anorexigen therapy in subjects who were randomly assigned to receive fenfluramine at the recommended dose for up to 3 months.

Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation.

BACKGROUND: The conventional treatment strategy for patients with atrial fibrillation who are to undergo electrical cardioversion is to prescribe warfarin for anticoagulation for three weeks before cardioversion. It has been proposed that if transesophageal echocardiography reveals no atrial thrombus, cardioversion may be performed safely after only a short period of anticoagulant therapy. METHODS: In a multicenter, randomized, prospective clinical trial, we enrolled 1222 patients with atrial fibrillation of more than two days' duration and assigned them to either treatment guided by the findings on transesophageal echocardiography or conventional treatment. The composite primary end point was cerebrovascular accident, transient ischemic attack, and peripheral embolism within eight weeks. Secondary end points were functional status, successful restoration and maintenance of sinus rhythm, hemorrhage, and death. RESULTS: There was no significant difference between the two treatment groups in the rate of embolic events (five embolic events among 619 patients in the transesophageal-echocardiography group [0.8 percent]) vs. three among 603 patients in the conventional-treatment group [0.5 percent], P=0.50). However, the rate of hemorrhagic events was significantly lower in the transesophageal-echocardiography group (18 events [2.9 percent] vs. 33 events [5.5 percent], P=0.03). Patients in the transesophageal-echocardiography group also had a shorter time to cardioversion (mean [+/-SD], 3.0+/-5.6 vs. 30.6+/-10.6 days, P<0.001) and a greater rate of successful restoration of sinus rhythm (440 patients [71.1 percent] vs. 393 patients [65.2 percent], P=0.03). At eight weeks, there were no significant differences between the two groups in the rates of death or maintenance of sinus rhythm or in functional status. CONCLUSIONS: The use of transesophageal echocardiography to guide the management of atrial fibrillation may be considered a clinically effective alternative strategy to conventional therapy for patients in whom elective cardioversion is planned.

Subarachnoid hemorrhage or migraine?

The differential diagnosis of "the worst headache of my life" is illustrated by the following history.

Pentobarbital-activated Cl(-) channels in cultured adult and embryonic human DRG neurons.

Developmental differences in pentobarbital-activated Cl(-) currents were studied in adult and embryonic human dorsal root ganglia (DRG) neurons using whole-cell patch-clamp recordings. Pentobarbital-induced Cl(-) conductance was significantly greater in adult DRGs (28.4 pS) than in embryonic cells (19.1 pS). Fluctuation analysis of the spectral density plots of Cl(-) channel activation by pentobarbital showed age differences in the length and number of open time constants (adult cells, tau(1), tau(2), tau(3) were 224, 8. 4, 1.5 ms, respectively; embryonic cells tau(1) and tau (2) were 165 and 26.3 ms, respectively). The different kinetic properties of human adult and embryonic DRG Cl(-) channels opened by pentobarbital may reflect the presence of different subunits in the two populations of neurons.

Aortic regurgitation: quantitative methods by echocardiography.

Quantification of aortic regurgitation (AR) is a common and difficult clinical problem. The severity of regurgitation has traditionally been estimated with the use of contrast aortography, which is impractical as a screening tool or for serial examinations. In the past two decades, Doppler echocardiography has emerged as an important tool in the quantification of AR. Pulsed Doppler mapping of the depth of the regurgitant jet into the left ventricle was one of the initial echocardiographic methods used for this purpose. The slope and pressure (or velocity) half-time of continuous-wave Doppler profiles of regurgitant jets are also useful. These Doppler techniques may be used to determine the regurgitant volume or regurgitant fraction in patients with AR. The use of color Doppler to measure the height (or cross-sectional area) of the regurgitant jet relative to the height (cross-sectional area) of the left ventricular outflow tract is both sensitive and specific in the quantification of AR. More recently, the continuity principle has been used to determine the effective aortic regurgitant orifice area, which increases as AR becomes more severe. Although this is a promising tool, calculation of this value is not yet common practice in most echocardiography laboratories. Although no single echocardiographic technique is without limitations, all have some validity, and it is reasonable to use a combination of them to obtain a composite estimate of the severity of AR.

Comparison of cardiovascular adaptations to long-term arm and leg exercise in wheelchair athletes versus long-distance runners.

The effect of long-term arm exercise on cardiac morphology and function is unknown. To study these effects, highly trained wheelchair athletes were compared with long-distance runners and controls. In addition, the wheelchair athletes were compared with the long-distance runners to determine if long-term leg exercise confers a training effect during the performance of dynamic arm exercise. The study included 31 male subjects (mean age of 33+/-5 years), who comprised 3 groups matched for age and weight: wheelchair athletes (n = 9), long-distance runners (n = 12), and healthy controls (n = 10). All underwent echocardiography at rest and arm ergometry exercise testing with expiratory gas analysis. The peak work rate during arm exercise was highest among the wheelchair athletes, and was significantly higher in both groups of trained athletes compared with the control group (p<0.001). Runners demonstrated a significantly lower submaximal heart rate response to arm exercise compared with wheelchair and control subjects. Wheelchair athletes had increased left ventricular (LV) volume and mass by echocardiography compared with controls, but not to the same degree as that of runners. Although chamber dimensions and wall thickness did not differ among the groups, the LV volume index tended to be largest in the runners. Doppler indexes of diastolic LV filling were similar between the trained and untrained subjects. These data demonstrate that both long-term arm and leg exercise yield increases in LV volume and mass compared with untrained control subjects, although to a lesser degree in arm-trained athletes. Runners demonstrated a transfer of training effect in the performance of dynamic arm exercise, as demonstrated by their ability to achieve a higher peak work rate than controls, and showed a lower heart rate response to submaximal exercise than the wheelchair athletes and control subjects.

Moderate-high intensity exercise training after myocardial infarction: effect on left ventricular remodeling.

BACKGROUND: Regular exercise increases exercise capacity and physical fitness, but questions remain about the effects of exercise on left ventricle (LV) remodeling after myocardial infarction. This study investigated the effects of moderate to high intensity exercise training on LV remodeling after a first myocardial infarction. METHODS: An exercise group of 68 patients in cardiac rehabilitation after a first myocardial infarction had an initial echocardiogram and exercise stress test. Thirty patients completed the 12 weeks of training and had echocardiograms suitable for quantitative analysis. Follow-up echocardiograms and exercise tests were performed. A carefully matched control group of 30 patients with echocardiograms at fixed intervals after myocardial infarction and no formal exercise training were also studied. LV size was expressed as the endocardial surface area-to-body surface area (ESAi), whereas infarct size was characterized by the percent abnormal wall motion (%AWM) by echocardiography using an endocardial surface area mapping technique. Indices of LV shape (sphericity) were also assessed. RESULTS: In the exercise group, no significant changes were seen in ESAi (57.95 +/- 13.1 vs 57.80 +/- 12.04 cm2/m2) or in %AWM (19.33 +/- 15.27 vs 20.11 +/- 15.95) from the initial to the final echo. The indices of sphericity were also unchanged. None of these parameters changed in the control group. Within each group was found heterogeneity in LV remodeling. Multivariate regression analysis revealed initial ESAi and initial %AWM to predict change in ESAi over time. CONCLUSIONS: In this study of patients with predominately small infarcts, exercise training did not adversely affect LV remodeling after myocardial infarction. Remodeling is heterogeneous and appears related to infarct and LV size.

Papillary fibroelastoma: increasing recognition of a surgical disease.

Papillary fibroelastomas are uncommon benign tumors usually involving the heart valves, which historically have been diagnosed at autopsy. With the advent of echocardiography, however, the number of patients diagnosed in life has increased. Papillary fibroelastomas represent a surgically treatable cause of cerebrovascular and cardiovascular ischemia and infarction making their identification clinically important. We report three unusual cases of papillary fibroelastoma; two patients presenting with symptoms of cerebrovascular ischemia and one presenting with myocardial infarction. We also present a comprehensive review of the literature and provide a compilation of all case reports to date.

Immediate effect of aortic valve replacement for aortic stenosis on left ventricular diastolic chamber stiffness.

Diastolic dysfunction is common after coronary artery bypass surgery, and we hypothesized that left ventricular (LV) hypertrophy associated with aortic stenosis may lead to worsening LV diastolic function after aortic valve replacement for aortic stenosis. Transesophageal echocardiographic LV images and simultaneous pulmonary arterial wedge pressures were used to define the LV diastolic pressure cross-sectional area relation before and immediately after aortic valve replacement for aortic stenosis in 14 patients. In all patients, LV diastolic chamber stiffness increased, as evidenced by a leftward shift in the LV diastolic pressure cross-sectional area relation. At comparable LV filling (pulmonary arterial wedge) pressures the mean LV end-diastolic cross-sectional area preoperatively was 17.9 +/- 1.7 cm2, but decreased by 32% after aortic valve replacement to 12.1 +/- 1.2 cm2 (p = 0.0001). In conclusion, after aortic valve replacement, diastolic chamber stiffness increased in all patients.

Cost-effectiveness of stress-echocardiography.

Because of constraints on the costs of providing medical care, cardiologists in the future will find themselves challenged to provide care for their patients in the most cost-effective manner possible. Although stress-echocardiography has been shown to compare favorably with other tests in diagnostic accuracy, data on cost-effectiveness are scarce. In this article, general concepts of cost-effectiveness as they relate to stress-echocardiography are reviewed and the available literature is summarized. Although definitive data are lacking, there is evidence to suggest that stress-echocardiography may prove to be cost-effective in several clinical situations.

Ventricular remodeling in active myocarditis. Myocarditis Treatment Trial.

BACKGROUND: Remodeling of the left ventricle with the development of a spherical cavity occurs in dilated cardiomyopathy and is associated with a poor long-term prognosis. The early effects of myocarditis on left ventricular geometry have not been previously described or correlated with clinical outcome. METHODS: The baseline echocardiograms of 35 patients with biopsy-confirmed myocarditis were compared with 20 normal controls. Left ventricular end-diastolic volume, long axis length, and mid-cavity diameter were measured. The degree of sphericity was expressed as the ratio of the mid-cavity diameter to the long axis length. Left ventricular ejection fraction was assessed by radionuclide angiography. RESULTS: In patients with myocarditis, mean left ventricular volume of 81 +/- 29 mL/m(2) was significantly greater than 50 +/- 8 mL/m(2) in controls (P =.001). Chamber dilatation occurred primarily along the mid-cavity diameter, which measured 5.3 +/- 0.8 cm in patients with myocarditis versus 4.2 +/- 0.4 cm in controls (P =.001). The degree of left ventricular sphericity in patients with myocarditis, 0.64 +/- 0.08, was significantly greater than that of controls, 0.54 +/- 0.04 (P =.001). When patients were stratified according to left ventricular volume, patients with increased left ventricular volume (>75 mL/m(2)) were associated with a more spherical chamber and lower left ventricular ejection fraction than patients with a more normal left ventricular volume (

GABA-Induced Cl- current in cultured embryonic human dorsal root ganglion neurons.

gamma-Aminobutyric acid (GABA)-activated channels in embryonic (5-8 wk old) human dorsal root ganglion (DRG) neurons in dissociated culture were characterized by whole cell and single-channel techniques. All DRG neurons when held at negative holding membrane potentials displayed inward current to micromolar concentrations of GABA applied by pressure pulses from closely positioned micropipettes. The current was directly proportional to the concentration of GABA (EC50, 111 microM; Hill coefficient, 1.7). DRG neurons also responded to micromolar concentrations of pentobarbital and alphaxalone but not to cis-4-aminocrotonic acid (CACA), glycine, or taurine. Baclofen (100 microM) affected neither the holding currents nor K+ conductance (when patch pipettes were filled with 130 mM KCl) caused by depolarizing pulses. Whole cell GABA-currents were blocked by bicuculline, picrotoxin, and t-butylbicyclophosphorothionate (TBPS; all at 100 microM). The reversal potential of whole cell GABA-currents was close to the theoretical Cl- equilibrium potential, shifting with changes in intracellular Cl- concentration in a manner expected for Cl--selective channels. The whole cell I-V curve for GABA-induced currents demonstrated slight outward rectification with nearly symmetrical outside and inside Cl- concentrations. Spectral analysis of GABA-induced membrane current fluctuations showed that the kinetic components were best fitted by a triple Lorentzian function. The apparent elementary conductance for GABA-activated Cl- channels determined from the power spectra was 22.6 pS. Single-channel recordings from cell-attached patches with pipettes containing 10 microM GABA indicated that GABA-activated channels have a main and a subconductance level with values of 30 and 19 pS, respectively. Mean open and closed times of the channel were characterized by two or three exponential decay functions, suggesting two or three open channel states and two closed states. Single channels showed a lack of rectification. The actions of GABA on cultured human embryonic DRG neurons are mediated through the activation of GABAA receptors with properties corresponding to those found in the CNS of human and other mammalian species but differing from those of cultured human adult DRG neurons.

Alphaxalone activates a Cl- conductance independent of GABAA receptors in cultured embryonic human dorsal root ganglion neurons.

Whole cell and cell-attached patch-clamp techniques characterized the neurosteroid anesthetic alphaxalone's (5alpha-pregnane-3alpha-ol-11,20-dione) effects on GABAA receptors and on Cl- currents in cultured embryonic (5- to 8-wk old) human dorsal root ganglion neurons. Alphaxalone applied by pressure pulses from closely positioned micropipettes failed to potentiate the inward Cl- currents produced by application of GABA. In the absence of GABA, alphaxalone (0.1-5.0 microM) directly evoked inward currents in all dorsal root ganglion neurons voltage-clamped at negative membrane potentials. The amplitude of the current was directly proportional to the concentration of alphaxalone (Hill coefficient 1.3 +/- 0.15). The alphaxalone-induced whole cell current was carried largely by Cl- ions. Its reversal potential was close to the theoretical Cl- equilibrium potential, changing with a shift in the external Cl- concentration as predicted by the Nernst equation for Cl- ions. And because the alphaxalone-current was not suppressed by the competitive GABAA receptor antagonist bicuculline or by the channel blockers picrotoxin and t-butylbicyclophosphorothionate (TBPS; all at 100 microM), it did not appear to result from activation of GABAA receptors. In contrast to GABA-currents in the same neurons, the whole cell current-voltage curves produced in the presence of alphaxalone demonstrated strong inward rectification with nearly symmetrical bath and pipette Cl- concentrations. Fluctuation analysis of the membrane current variance produced by 1.0 microM alphaxalone showed that the power density spectra were best fitted to double Lorentzian functions. The elementary conductance for alphaxalone-activated Cl- channels determined by the relationship between mean amplitude of whole cell current and variance was 30 pS. Single-channel currents in cell-attached patches when the pipette solution contained 10 microM alphaxalone revealed a single conductance state with a chord conductance of approximately 29 pS. No subconductance states were seen. The current-voltage determinations for the single-channels activated by alphaxalone demonstrated a linear relationship. Mean open and shut times of single alphaxalone-activated channels were described by two exponential decay functions. Taken together, the results indicate that in embryonic human DRG neurons, micromolar concentrations of alphaxalone directly activate Cl- channels whose electrophysiological and pharmacological properties are distinct from those of Cl- channels associated with GABAA receptors.

Mechanisms involved in the metabotropic glutamate receptor-enhancement of NMDA-mediated motoneurone responses in frog spinal cord.

1. The metabotropic glutamate receptor (mGluR) agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) (10-100 microM) depolarized isolated frog spinal cord motoneurones, a process sensitive to kynurenate (1.0 mM) and tetrodotoxin (TTX) (0.783 microM). 2. In the presence of NMDA open channel blockers [Mg2+; (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801); 3,5-dimethyl-1-adamantanamine hydrochloride (memantine)] and TTX, trans-ACPD significantly potentiated NMDA-induced motoneurone depolarizations, but not alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA)- or kainate-induced depolarizations. 3. NMDA potentiation was blocked by (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) (240 microM), but not by alpha-methyl-(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (MCCG) (290 microM) or by alpha-methyl-(S)-2-amino-4-phosphonobutyrate (L-MAP4) (250 microM), and was mimicked by 3,5-dihydroxyphenylglycine (DHPG) (30 microM), but not by L(+)-2-amino-4-phosphonobutyrate (L-AP4) (100 microM). Therefore, trans-ACPD's facilitatory effects appear to involve group I mGluRs. 4. Potentiation was prevented by the G-protein decoupling agent pertussis toxin (3-6 ng ml(-1), 36 h preincubation). The protein kinase C inhibitors staurosporine (2.0 microM) and N-(2-aminoethyl)-5-isoquinolinesulphonamide HCI (H9) (77 microM) did not significantly reduce enhanced NMDA responses. Protein kinase C activation with phorbol-12-myristate 13-acetate (5.0 microM) had no effect. 5. Intracellular Ca2+ depletion with thapsigargin (0.1 microM) (which inhibits Ca2+/ATPase), 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetracetic acid acetyl methyl ester (BAPTA-AM) (50 microM) (which buffers elevations of [Ca2+]i), and bathing spinal cords in nominally Ca2+-free medium all reduced trans-ACPD's effects. 6. The calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W7) (100 microM) and chlorpromazine (100 microM) diminished the potentiation. 7. In summary, group I mGluRs selectively facilitate NMDA-depolarization of frog motoneurones via a G-protein, a rise in [Ca2+]i from the presumed generation of phosphoinositides, binding of Ca2+ to calmodulin, and lessening of the Mg2+-produced channel block of the NMDA receptor.

Trigger points and myofascial pain: toward understanding how they affect headaches.

Myofascial pain, referred from hyperalgesic trigger points located in skeletal muscle and its associated fascia, is a common cause of persistent regional pain. Clinical and experimental literature on manifestations, pathophysiology, and management of pain from myofascial trigger points is reviewed with priority given to how pain referred from trigger points generates, triggers, and maintains headaches--especially chronic and recurrent ones. Because treating myofascial problems may be the only way to offer complete relief from certain types of headache, clinicians must learn to diagnose and manage trigger points in neck, shoulder, and head muscles.