Sudden cardiac death: influence of diabetes.

This article reviews current thinking on the problem of sudden cardiac death (SCD) within community settings, highlighting progress in understanding risks and mechanisms. Information available on the influence of diabetes as a risk factor for SCD and the question of whether this disease enhances susceptibility to ventricular arrhythmias is summarized as are central strategies in risk stratification and mortality prevention.

On the neural connection.

Discoveries concerning cardiac neural-electrical modulation and local neural remodeling provide powerful new approaches for the development of novel antiarrhythmic strategies. This "view" of developments in this emerging field highlights recent advances and suggests that additional neurally targeted investigations have considerable potential for prevention of arrhythmic diseases.

Sudden cardiac death, genes, and arrhythmogenesis : consideration of new population and mechanistic approaches from a national heart, lung, and blood institute workshop, part I.

Malignant ventricular arrhythmias are the leading mechanism of death in patients with acute and chronic cardiac pathologies. The extent to which inherited mutations and polymorphic variation in genes determining arrhythmogenic mechanisms affect these patients remains unknown, but based on recent population studies, this risk appears significant, deserving much greater investigation. This report summarizes a National Heart, Lung, and Blood Institute workshop that considered sources of genetic variation that may contribute to sudden cardiac death in common cardiac diseases. Evidence on arrhythmogenic mechanisms in recent population studies suggests a significant portion of the risk of sudden cardiac death in such broad populations may be unrelated to traditional risk factors for predisposing conditions such as atherosclerosis, hypertension, and diabetes and instead may involve unrecognized genetic and environmental interactions that influence arrhythmic susceptibility more directly. Additional population and genetic studies directed at discovering the sources of inherited molecular risk that are most directly linked to arrhythmia initiation and propagation, in addition to studies on previously well-described risk factors, would appear to have considerable potential for reducing premature cardiovascular mortality.

Opportunities for sudden death prevention: directions for new clinical and basic research.

Sudden cardiac death (SCD) represents an enormous public health problem in all developed countries of the world, yet its magnitude and precise incidence in different populations and disease subgroups remains unclear. There also remain major questions and research challenges in establishing the sensitive and specific markers of SCD risk needed for optimizing therapeutic strategies and allocation of resources, such as implantable defibrillators. In the past, risk factors for coronary artery disease (CAD) have been heavily relied on to identify risk for SCD. However, although a majority of SCD events continue to occur in the context of this disease etiology, risk factors for CAD appear to have relatively limited ability to predict risk in specific individuals and subgroups with enhanced progressive or inherited susceptibility to lethal arrhythmias. This commentary is intended to assess potentials for progress in developing improved approaches to SCD prediction and prevention through new clinical and basic research on the fundamental causes of ventricular arrhythmias, the development of new markers of electrical instability, and better understanding of the role of genetic variability in their origin.

Sudden cardiac death, genes, and arrhythmogenesis: consideration of new population and mechanistic approaches from a National Heart, Lung, and Blood Institute workshop, Part II.

This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.

Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis.

The inherited long QT syndrome (LQTS) is a familial disease characterized by QT interval changes that often are labile, syncope, and sudden death due to arrhythmias, predominantly in young people. Multiple mutations in five genes encoding structural subunits of cardiac ion channels now have been identified in families with LQTS. Correlations are being described between genotype and specific clinical features in LQTS. However, increasing screening of affected families and sporadic cases has identified incomplete penetrance with highly variable clinical manifestations, even among individuals carrying the same mutations. The identification of LQTS disease genes represents a crucial first step in developing an understanding of the molecular basis for normal cardiac repolarization. This information will be important not only for identifying new therapies in LQTS, but also in further understanding arrhythmias, and their potential therapies, in situations such as heart failure, cardiac hypertrophy, myocardial infarction, or sudden infant death syndrome, where abnormal repolarization has been linked to sudden death. LQTS thus presents a new paradigm to cardiac electrophysiology, in which new molecular information is being brought to bear both on clinical management of patients and on development of a new framework to study the fundamental causes of arrhythmias and new approaches to therapy.

Effect of epinephrine and other lipolytic agents on intracellular lipolysis and lipoprotein lipase activity in 3T3-L1 adipocytes.

3T3-L1 adipocytes were used to test the hypothesis that hormone-sensitive lipolysis and lipoprotein lipase activity might be regulated in a reciprocal manner. Intracellular lipolysis was stimulated by catecholamine, dibutyryl cAMP, and ACTH, but not by glucagon. The effects of epinephrine on lipolysis were blocked by the beta-antagonist propanolol but not by the alpha-antagonist phentolamine. Hormone-stimulated lipolysis was not changed by acute (45 min) or chronic (2 days) treatment of the cells with insulin whereas the latter treatment augmented lipoprotein lipase activity about fivefold. Epinephrine did not affect the lipoprotein lipase activity of insulin-stimulated cells. Withdrawal of glucose from the medium decreased lipoprotein lipase activity and the effect of epinephrine on lipolysis. Effects of lipolytic agents on activity of lipoprotein lipase were variable and concentration-dependent. Lipoprotein lipase activity was decreased only by concentrations of epinephrine greater than those inducing maximal intracellular lipolysis, and the decrease in activity occurred about 30 min after the increase in glycerol release. There seems to be no relationship between the level of activity of lipoprotein lipase and the maximal rate of hormone-stimulated lipolysis in 3T3-L1 cells. Unlike in adipose tissue and adipocytes of rats, hormone-stimulated lipolysis and lipoprotein lipase activity in murine 3T3-L1 adipocytes appear to be regulated independently.

Regulation of mammary and adipose tissue lipoprotein lipase and blood triacylglycerol in rats during late pregnancy. Effect of prostaglandins.

The effects of several prostaglandins on lipoprotein lipase activity of mammary gland and adipose tissue and serum triacylglycerol were studied during late pregnancy in rats. Prostaglandins were injected twice daily for 2 days before and once on the day of analysis. In rats pregnant 20 days, prostaglandin F(2alpha) (PGF(2alpha)) increased the activity of lipoprotein lipase in mammary gland fourfold, reduced the activity in adipose tissue about 60%, and decreased serum concentration of triacylglycerol 50%. PGF(2alpha) also reduced serum concentration of progesterone 90% and increased that of prolactin fivefold, but had no effect on serum concentrations of either immuno-reactive insulin or 17beta-estradiol. Injections of 13,14-dihydro-15-keto PGF(2alpha), a metabolite of PGF(2alpha), had similar effects in rats pregnant 20 days, whereas prostaglandins E(1) and E(2) did not. In rats pregnant 16 days, PGF(2alpha) did not affect lipoprotein lipase activity in the tissues or the concentration of triacylglycerol and prolactin in serum, although it decreased serum progesterone 80%.2-Br-alpha-ergocryptine prevented the increase in serum prolactin in response to PGF(2alpha), but did not alter the effect of PGF(2alpha) on lipoprotein lipase activity or serum triacylglycerol. Progesterone completely blocked the effects of PGF(2alpha) on lipoprotein lipase activity and serum triacylglycerol and prolactin concentrations. These findings indicate that the changes in lipoprotein lipase activity and serum triacylglycerol in PGF(2alpha)-treated rats are probably related to the inhibitory action of PGF(2alpha) on progesterone secretion. They also suggest that endogenous F prostaglandins may play a role in the regulation of lipoprotein lipase activity in mammary gland and adipose tissue near parturition.

Stimulation of Na+ transport across the toad urinary bladder by p-chloromercuribenzene sulfonate.

The sulfhydryl reagent p-chloromercuribenzene sulfonate increased the ISC across substrate-replete toad urinary bladder when applied to the mucosal (apical) surface. This increase was accounted for by an increased mucosal to serosal net flux of Na+. In the absence of substrate, the rise in ISC was accompanied by an irreversible increase in tissue conductance which was not apparent in the replete preparation. These findings suggest that p-chloromercuribenzene sulfonate may be useful in marking mucosal functions associated with the Na+ transport apparatus.

Effects of aldosterone on Na+ transport in the toad bladder. I. Glycolysis and lactate production under aerobic conditions.

Previous studies indicated that aldosterone enhances active Na+ transport, glycolysis, lactate production and respiration of the toad bladder. Evidence was also presented that the changes in glycolysis and lactate production were secondary to the changes in active Na+ transport. Further analysis of the relationships between metabolism and Na+ transport was undertaken with the aid of two inhibitors of pyruvate metabolism, oxythiamine and phenylpyruvate. These inhibitors prevented the aldosterone-induced increase in oxidation of [6-(14)C] glucose but had little effect on the increase in lactate production. In contrast, the effect on Na+ transport (i.e., Isc) was completely inhibited by oxythiamine plus phenylpyruvate with glucose as substrate. The effect on Na+ transport, however, was obtained with the by-pass substrates, oxaloacetate plus beta-hydroxybutyrate, in the presence of these inhibitors. These results implied that steroidal enhancement of lactate production and Na+ transport were independent effects. To evaluate whether an increase in Na+ transport, per se would augment lactate production, the responses were evaluated under conditions of an imposed Na+ gradient (mucosal Na+ = 5mM; serosal Na+ 110 mM). Addition of NaCl to the mucosal media evoked the same increase in Isc as the addition of aldosterone; both additions increased Isc more than two-fold. Aldosterone reduced lactate production under these conditions while the re-addition of NaCl had no effect on lactate formation. These results are consistent with an action of aldosterone on pathways involved in oxidative energy metabolism, and suggest that the activation of glycolysis may be a function of the net balance between energy production and utilization.

Effects of aldosterone on Na+ transport in the toad bladder. II. The anaerobic response.

The action of aldosterone on active Na+ transport was assessed under aerobic and anaerobic conditions in the isolated urinary bladder of the toad, Bufo marinus. Aldosterone augmented the short-circuit current (Isc) under rigorous anaerobiosis. Four lines of evidence indicate that the increase in anaerobic Isc does not represent an equivalent increase in active Na+ transport: 1. Net Na transport, determined by isotopic fluxes, was the same in the aldosterone-treated and control quarter-bladders, and significantly greater than the simultaneously measured Isc-2. Amiloride, an inhibitor of the apical entry of Na+, did not reduce the steroid-dependent increase in the anaerobic Isc-3. Substitution of choline for Na+ in the mucosal medium reduced the magnitude of the anaerobic Isc values but did not eliminate the effect of aldosterone. 4. Addition of ouabain, a potent inhibitor of the Na+ pump, partially inhibited the effect of aldosterone on the anerobic Isc but a significant hormonal increment remained. The source of the anaerobic Isc was not identified; an effort was made, however, to determine the dependence of this current on glycolysis. During anaerobiosis, aldosterone increased the integral Isc by 42% but did not alter lactate production. These results suggest that the steroid-dependent increase in the anaerobic Isc may involve effects on permeability properties of the epithelium rather than on active transport systems.

The regulation of haemoglobin synthesis in cultured chick blastoderms by steroids related to 5beta-androstane.

1. After 24h of incubation, the blastoderm may be dissected from the early developing chick embryo and successfully maintained under conditions of organ culture in vitro. 2. Low concentrations of steroids related to 5beta-androstane stimulate the synthesis of foetal haemoglobins, types E and P, in a highly steroid- and tissue-specific manner.

Further studies on the effect of aldosterone on electrical resistance of toad bladder.

The fall in transepithelial electrical resistance which accompanies aldosterone stimulation of short-circuit current (Isc) in toad urinary bladder has been studied further to evaluate the possible causal role of this response in hormonal stimulation of Na+ transport. A steady-state change in tissue conductance was found to depend upon both the simultaneous stimulation of transport by the steroid and the metabolic state of the tissue. Changes in metabolic state alone did not alter resistance. A sustained increase in Na+ transport, dependent on pretreatment with aldosterone and elicited by addition of glucose, could be obtained without a sustained decrease in resistance. Amiloride, an inhibitor of Na+ uptake, produced changes in Isc that were linearly correlated with its effects on tissue conductance. On the basis of the conductance-Isc relationship with amiloride, the Isc response to aldosterone was about two-fold higher than would be predicted from its effects on conductance alone. Despite the apparent lack of a simple quantitative dependence of the change in Isc on the change in conductance when the response is fully developed, the results suggest that conductance changes may mediate the initial or early stage of the response.