Primary prevention in cardiovascular disease: moving out of the shadows of the truth about death.

AIM: This review identifies deficits in current educational efforts for the primary prevention of cardiovascular disease. DATA SYNTHESIS: Essential fatty acids in the foods we eat have a subtle but powerful influence on hundreds of different processes in the life and death of humans, understanding of which has been delayed by two attitudes in the biomedical community. One involves a bias towards expensive curative/treatment interventions that neglect prevention of initial nutritional causes of disease and death, and the other involves careless logic in interpreting evidence of causes of disease and death. Both attitudes interfere with translation of published science of essential fatty acids into effective prevention of cardiovascular deaths, a situation made worse by a widespread wish for simple descriptions of complex interactions in disease. Some clinical signs and risk factors may be only shadows of true causal factors. For example, attention to cholesterol ignored important evidence that nutritional imbalances in expenditure/intake of energy and in omega-3/omega-6 essential fatty acids cause cardiovascular disease. Balancing the few percentage of daily calories in omega-3/omega-6 nutrients is not a question of obesity or blood cholesterol. Effective prevention through education will require targeting the causal risk factors that are known beyond the shadow of a doubt, but seldom discussed by health professionals and the public. CONCLUSIONS: Death from coronary heart disease comes from acute ischemia and arrhythmia, often following long-term chronic inflammatory vascular damage that predisposes to acute fatal thrombosis and arrhythmia. The three processes involve excessive self-healing actions of natural n-6 autacoids (auto = self, akos = healing) produced from tissue essential fatty acids that come only from foods. Readily corrected nutritional imbalances in expenditure/intake of energy and in omega-3/omega-6 essential fatty acids are causal risk factors with plausible mechanisms contributing to fatal events which can be prevented.

Peptide signaling paths related to intoxication, memory and addiction.

Abstract Many peptides bind to G protein-coupled receptors and activate intracellular signaling paths for adaptive cellular responses. The components of these paths can be affected by signals from other neurotransmitters to produce overall integrated results not easily predicted from customary a priori considerations. This intracellular cross-talk among signaling paths provides a "filter" through which long-term tonic signals affect short-term phasic signals as they progress toward the nucleus and induce long-term adaptation of gene expression which provide enduring attributes of acquired memories and addictions. Peptides of the PACAP family provide intracellular signaling that involves kinases, scaffolding interactions, Ca2 + mobilization, and gene expression to facilitate development of tolerance to alcohol and development of associative memories. The peptide-induced enhancement of NMDA receptor responses to extracellular glutamate also may increase behavioral sensitization to the low doses of alcohol that occur at the onset of each bout of drinking. Because many gene products participate in each signaling path, each behavioral response to alcohol is a polygenic process of many steps with no single gene product sufficient to interpret fully the adaptive response to alcohol. Different susceptibility of individuals to alcohol addiction may be a cumulative result of small differences among the many signaling components. Understanding this network of signals may help interpret future "magic bullets" proposed to treat addiction.

Alcohol, slow wave sleep, and the somatotropic axis.

When alcohol is a large proportion of daily nutrient energy, the network of signals for energy homeostasis appears to adapt with abnormal patterns of sleep and growth hormone (GH) release along with gradual acquisition of an addictive physical dependency on alcohol. Early relapse during treatment of alcoholism is associated with a lower GH response to challenge, perhaps reflecting an altered balance of somatostatin (SS) to somatropin releasing hormone (GHRH) that also affects slow wave sleep (SWS) in dependent patients. Normal patterns of sleep have progressively shorter SWS episodes and longer rapid eye movement (REM) episodes during the overall sleep period, but the early sleep cycles of alcoholics have truncated or non-existent SWS episodes, and the longer REM episodes occur in early cycles. During SWS delta wave activity, the hypothalamus releases GHRH, which causes the pituitary to release GH. Alcohol-dependent patients have lower levels of SWS power and GH release than normal subjects, and efforts to understand the molecular basis for this maladaptation and its relation to continued alcohol dependence merit encouragement. More needs to be learned about the possibility of decreasing alcohol dependency by increasing SWS or enhancing GHRH action.

A review of alcohol clearance in humans.

The level of blood or brain alcohol is considered to influence alcohol ingestion by causing subjective perceptions or neural activations that are reinforcing or rewarding. Alcohol-dependent people may try to maintain some desired tissue level, drinking to replace the millimolar levels that were cleared from the blood by metabolism. The biomedical literature describes many approaches to understanding the role of blood alcohol levels in human physiology and behavior, and this review examines some of the published results. They include the general kinetics of intake and removal of beverage alcohol as well as the characteristics of many different catalysts that can interact with alcohol. Because ingested alcohol creates blood levels that are a 1000-fold greater than those normally experienced during abstinence, ethanol may impose itself as an alternate substrate for the many oxidoreductases that act physiologically on other endogenous alcohols. Many enzymes that can act on millimolar ethanol have been isolated, and their structural genes are sequenced. Unfortunately, the genetic sequence does not indicate the physiological material upon which the translated gene product may act. In a sense, the set of enzymes with catalytic sites occupied by millimolar ethanol during alcohol drinking might constructively be regarded as "orphan gene products" whose physiological role remains to be clarified. This review is designed to indicate some of what is known, what is not known, and what needs to be known to improve the interpretations regarding adaptations to beverage alcohol and the ability of millimolar levels of alcohol to diminish dysphoria. The dysphoria may be influenced by ethanol, by ethanol metabolites, or by altered metabolism of currently unspecified endogenous substrates. A major challenge is to evaluate the multiple alternative variables within a context that stimulates curiosity and encourages quantitative tests of the relative contribution of each variable to the overall physiology of an individual.

Alcohol's impact upon glycobiology.

This report reviews and illustrates ways in which some of the problems linked to excessive alcohol intake may develop from alcohol-induced alterations of eukaryotic cell surface molecules. Alcohol is the number one drug of abuse in the US, affecting at least 15 million Americans and causing annual losses of more than $80 billion and 100,000 lives. An estimated 20-40% of all persons admitted to general hospitals have alcohol-related problems and are often undiagnosed alcoholics being treated for the consequences of their drinking. Chronic alcohol-related cirrhosis of the liver is the ninth leading cause of death in the US, with over 28,000 deaths annually. Alcohol has harmful effects on almost every organ system in the body, producing cardiovascular disorders, liver disease, neuropathological illness and fetal injury. The etiologic mechanisms for these effects of alcohol is a research area of considerable importance to the National Institute for Alcohol Abuse and Alcoholism.

Alcohol and energy intake.

One hundred years of research about the metabolism of alcohol have provided many details, but some general aspects of the physiologic value of alcohol remain uncertain or inadequately proven. Results from epidemiologic studies appear to be in conflict with interpretations based on results from indirect calorimetric studies. The apparent inability of body mass index to be maintained in women when alcohol is consumed with food may indicate impaired metabolic processes that need to be better understood. Current evidence on the effects of alcohol are summarized to identify experimental approaches that may provide information needed to resolve the current contradictions.