Tocainide therapy for treatment of ventricular arrhythmias: assessment with ambulatory electrocardiographic monitoring and treadmill exercise

Tocainide has shown promise in the acute suppression of ventricular arrhythmias and in the treatment of such arrhythmias considered refractory to other drugs. However, there is little experience with tocainide therapy using currently acceptable statistical end points in patients not receiving conventional antiarrhythmic drugs concurrently. Accordingly, a double-blind, crossover study design was used to compare the effects of 2 week periods of placebo therapy and small dose (400 mg every 8 hours) tocainide therapy in 10 patients with ventricular arrhythmias who were not receiving quinidlne, procainamide or disopyramide. Ventricular arrhythmias were assessed with 24 hour ambulatory electrocardiographic monitoring and treadmill exercise. Individual patients not responding to small dose tocainide with at least an 80 percent decrease in ventricular premature complexes on ambulatory monitoring were given doses of 600 mg and then 800 mg every 8 hours. Small dose tocainide therapy resulted in a decrease in ventricular premature complexes/hour from 364 ± 98 (standard error) to 127 ± 50 (p < 0.05) and 5 of 10 patients had at least an 80 percent decrease. At higher dose levels, two additional patients had at least an 80 percent decrease. The response of ventricular arrhythmias during treadmill exercise was comparable with that during ambulatory monitoring. Side effects were minor or nonexistent in the seven patients who responded to tocainide, and effective mean serum concentrations were 4.4 ± 1.9 μg/ml, a value significantly lower than that previously reported to suppress refractory ventricular arrhythmias. It is concluded that tocainide is an effective agent in patients not receiving concurrent therapy with conventional agents and that patients selected because of refractory ventricular arrhythmias may require higher serum concentrations of the drug than unselected patients.     

Relation between radionuclide angiographic regional ejection fraction and left ventricular regional ischemia in awake dogs

Multigated equilibrium radionuclide angiography was used to quantitate global and regional ejection fraction (EF) in 26 awake dogs 10 minutes after distal and then proximal occlusion of the left anterior descending (LAD) or left circumflex (LC) coronary artery. Changes in global and regional EF were correlated with simultaneous measurements of the extent of acute left ventricular (LV) ischemia measured by radioisotope-labeled microspheres. The extent of ischemia, defined as the percentage of LV mass with greater than 25% reduction in blood flow from normal regional flow, was linearly related to the percent change in global EF after LAD (r = 0.84) and LC (r = 0.77) occlusions. The extent of ischemia also correlated with regional EF (r = 0.47 to 0.88 for LAD and r = 0.41 to 0.69 for LC occlusions). In 24 of 25 LAD occlusions and in all 20 LC occlusions that produced a measurable ischemic zone, the maximal percent change in regional EF exceeded the percent change in global EF. Two LAD occlusions and 2 LC occlusions reduced regional EF but not global EF. Thus, global and regional EF decreased in direct proportion to the extent of acute myocardial ischemia; regional ischemia produced greater changes in regional than in global EF.     

Management Options for Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is associated with diverse pathophysiologic mechanisms. These mechanisms include increased abnormal colonic motility or transit, intestinal or colorectal sensation, increased colonic bile acid concentration, and superficial colonic mucosal inflammation, as well as epithelial barrier dysfunction, neurohormonal up-regulation, and activation of secretory processes in the epithelial layer. Novel approaches to treatment include lifestyle modification, changes in diet, probiotics, and pharmacotherapy directed to the motility, sensation, and intraluminal milieu of patients with IBS. Despite recent advances, there is a need for development of new treatments to relieve pain in IBS without deleterious central or other adverse effects.     

Clinical Implications of Clonal Hematopoiesis

Clonal hematopoiesis (CH)—an expansion of blood cells derived from a single hematopoietic stem cell—is a defining feature of hematologic cancers, but recently CH was also found to be a frequent consequence of aging. When aging-associated CH results from acquisition of a somatic mutation in a driver gene associated with leukemia, and this mutation is present at a variant allele frequency of at least 0.02 (2%) yet the patient does not meet World Health Organization diagnostic criteria for a hematologic neoplasm, this state is termed clonal hematopoiesis of indeterminate potential (CHIP). CHIP is present in approximately 10% to 15% of people older than 70 years and more than 30% by age 85 years and represents a precursor state for neoplasia akin to monoclonal gammopathy of undetermined significance. Recently, CHIP was unexpectedly found to be an important risk factor for cardiovascular events, with accumulating evidence supporting a mechanism of accelerated atherogenesis as a result of vascular inflammation driven by clonally derived monocytes/macrophages. Risk factors for CHIP include aging, male sex, cigarette smoking, and a common germline variant in the telomere-associated gene TERT. Clonal hematopoiesis can also occur after cytotoxic chemotherapy or radiotherapy for a solid tumor, after hematopoietic stem cell transplant, in the context of aplastic anemia, or after induction chemotherapy for acute leukemia; in each setting, CH has distinct clinical implications. This review summarizes recent studies of CH and CHIP and outlines challenges in clinical management of affected patients.     

Reappraisal of the role of insulin in hypertriglyceridemia

We have previously proposed a sequential hypothesis to help explain the genesis of endogenous hypertriglyceridemia in man. This scheme states that insulin resistance → hyperinsulinemia → increased very low density lipoprotein (VLDL)-triglyceride (TG) production rate → increased plasma TG levels. In this study we have measured each of these metabolic variables in 34 nonobese subjects all consuming the same isocaloric diet. We have found highly significant positive correlations between insulin resistance and insulin response (r = 0.74, p < 0.0001), between insulin response and VLDL-TG production rate (r = 0.72, p < 0.0001), and between VLDL-TG production rate and plasma TG level (r = 0.88, p < 0.0001). Furthermore, these relationships were found to be independent of any possible effect of obesity. Thus, highly positive correlations were found for each step of the scheme, and we believe the over-all hypothesis is greatly strengthened. Additionally, the cross correlation between plasma TG levels and insulin response was also highly significant (r = 0.73, p < 0.0001). On the other hand, glucose response did not correlate with any measure of TG metabolism. On the basis of these results we conclude that insulin plays an important role in the genesis of endogenous hypertriglyceridemia through its influence on VLDL-TG production.     

Comparative plasma catecholamine and hemodynamic responses to handgrip, cold pressor and supine bicycle exercise testing in normal subjects

Serial hemodynamic and plasma catecholamine responses were compared among 10 healthy men (27 +/- 3 years) (+/- 1 standard deviation) during symptom-limited handgrip (33% maximal voluntary contraction for 4.4 +/- 1.8 minutes), cold pressor testing (6 minutes) and symptom-limited supine bicycle exercise (22 +/- 5 minutes). Plasma catecholamine concentrations were measured by radioenzymatic assays: ejection fraction and changes in cardiac volumes were assessed by equilibrium radionuclide angiography. During maximal supine exercise, plasma norepinephrine and epinephrine concentrations increased three to six times more than during either symptom-limited handgrip or cold pressor testing. Additionally, increases in heart rate, systolic blood pressure, rate-pressure product, stroke volume, ejection fraction and cardiac output were significantly greater during bicycle exercise than during the other two tests. A decrease in ejection fraction of 0.05 units or more was common in young normal subjects during the first 2 minutes of cold pressor testing (6 of 10 subjects) or at symptom-limited handgrip (3 of 10), but never occurred during maximal supine bicycle exercise. The magnitude of hemodynamic changes with maximal supine bicycle exercise was greater, more consistent and associated with much higher sympathetic nervous system activation, making this a potentially more useful diagnostic stress than either handgrip exercise or cold pressor testing.