Effects of dichloroacetate in patients with congestive heart failure

Background: Conventional approaches to management of congestive heart failure (CHF) rely on drugs that increase myocardial contractility or reduce ventricular afterload. These approaches often improve cardiac symptoms and survival, but may be associated with significant deleterious effects. An alternative approach is to enhance myocardial energy production. Dichloroacetate (DCA) stimulates pyruvate dehydrogenase activity and accelerates aerobic glucose, pyruvate, and lactate metabolism in myocardial cells. These alterations would be expected to improve myocardial function. Hypothesis: The purpose of the investigation was to assess the efficacy of DCA in patients with left ventricular systolic dysfunction and to examine the mechanism by which improvement occurs. Methods: A total of 25 patients (16 men, 9 women; age range 31-72 years, mean 59) with CHF and ejection fraction ≤40% received an intravenous infusion of 50 mg/kg DCA over 15 min. Indices of systolic and diastolic function were obtained by two-dimensional and Doppler echocardiography performed at baseline, 30 min, and 60 min following completion of DCA infusion. Results: Baseline ventricular ejection fraction was 27.3 ± 9.1%; 17 patients (68%) had nonischemic cardiomyopathy. Heart rate increased after DCA infusion from 73.9 ± 14.5 to 79.2 ± 14.9 beats/min at 60 min; p = 0.02. Left ventricular diastolic and systolic volumes increased at 30 min compared with baseline (248.7 ± 98.1 vs. 259.6 ± 99.6; p = 0.04, and 180.1 ± 80.4 vs. 192.2 ± 84.9; p = 0.002, respectively), but stroke volume (49.2 ± 19.1 vs. 48.9 ± 18.1; p = 0.9) and ejection fraction (27.3 ± 9.1 vs. 25.7 ± 9.8; p = 0.2) were un changed. Indices of diastolic function were also unchanged. Conclusion: Dichloroacetate infusion in patients with CHF is not associated with improvement in noninvasively assesse left ventricular function.     

Myelinated and nonmyelinated nerves: comparison of proton MR properties

The magnetic resonance (MR) relaxation rates of protons were compared in the myelinated and nonmyelinated nerves of the garfish. The long, large olfactory nerve of the garfish, as an easily accessible source of nonmyelinated axons, is uniquely suited for such a comparison. The T1 and T2 measurements revealed distinct and consistent differences between nonmyelinated olfactory nerves and myelinated optic and oculomotor nerves. Comparisons between water content, lipid content, and relaxation rates indicated that the differences in MR properties represent complex differences in the distribution and physical environment of the constituent lipid and water protons.     

Intrauterine growth retardation: evaluation by magnetic resonance. Work in progress

Eleven high risk fetuses between 32 and 37 menstrual weeks gestational age were examined by magnetic resonance (MR) imaging. Serial obstetrical sonograms, birth weights, and serial postnatal examinations were obtained in all subjects. Sagittal MR spin echo images obtained using TR = 0.5 sec and TE = 28 msec were useful for assessing subcutaneous fat. Prospective estimates of fetal fat stores correlated with neonatal outcome better than sonographic measurements of fetal growth parameters or actual birth weight. MR appears to be a safe and useful technique that offers information complementary to obstetrical sonography when IUGR is suspected.     

Prolonged hypolactatemia and increased total pyruvate dehydrogenase activity by dichloroacetate

Dichloroacetate (DCA) given gastrically as a single dose to healthy, fed rats caused transient lowering of blood glucose, lactate, and pyruvate. Chronic daily dosing caused lowering of these metabolites and a delay in the return of lactate to basal levels for 48 hr after the final dose. DCA caused activation of the pyruvate dehydrogenase complex (PDHC), with acute multiple dosing or chronic daily dosing. The elevated active PDHC persisted for 12 hr following the final dose. In addition, total PDHC activity was increased with chronic dosing and persisted for 48 hr following the final dose. This increase was not blocked by protein synthesis inhibitors. DCA increased isolated hepatocyte [¹⁴C-1]pyruvate oxidation and activated hepatocyte PDHC. Glyoxylate and oxalate, hepatic metabolites of DCA, were inhibitory at similar concentrations.     

Combination H1 and H2 receptor antagonist therapy in diabetic autonomic neuropathy

Autonomic neuropathy occurs frequently in diabetic patients but is seldom effectively treated. In our patient, a 34-year-old man with poorly controlled type 1 diabetes and autonomic neuropathy manifested by postural hypotension and diarrhea, treatment with diphenhydramine and cimetidine (H1 and H2 histamine antagonists, respectively) markedly improved the hypotension and diarrhea and led to better blood glucose control.     

Femoral artery compression device for outpatient angiography

To avoid late bleeding from the femoral artery puncture site after outpatient femoral angiography, a compression device was designed to exert continuous pressure over the groin, even when the patient is upright. It has been successfully used in more than 2,000 arterial catheter procedures. The device can also help prevent bleeding in patients who are at increased risk because of hypertension or anticoagulant therapy.