The failing heart exhibits an attenuated response to adrenergic stimulation as a result of alterations in the function of β-adrenergicsignal transduction pathway. Such changes include down-regulation of theβ1-adrenoceptors, uncoupling of β2-adrenoceptor from adenylylcyclase, and an increase in the functional activity of Gi-proteins. These changes are not homogeneous in all types of heart failure, but there is a good correlation between alterations in one or more components ofβ-adrenergic receptor complex and the severity of heart failure. Accordingly, patients with different types of heart muscle disease have been observed to exhibit some important pathophysiological differences despite common clinical features. By using specific antibodies and cDNA probes and a combination of molecular approaches, it is now possible to detect the protein and mRNA level of different components and various regulators of the β-adrenoceptor-G protein-adenylyl cyclase system. Instead of the traditional hypothesis that the β-adrenoceptordown-regulation in heart is due to abnormal degradation and synthesis of receptor proteins, it has now become evident that alterations in theβ-receptor signal pathway may be due to transcriptional and post transcriptional abnormalities in different components of failing hearts from both humans and animals. In addition, the availability of transgenic animals is facilitating the study of effects of altering a single component of the β-adrenergic system on the function of the heart regardless of the complexity of the system itself; the work in this area may make it possible to develop gene therapy for human heart failure.

Treatment of heart failure has been successfully target biologically, to counteract deleterious effects resulting from neuroendocrine activation, with the use of several agents (e.g., angiotensine-converting enzyme inhibitors, beta-adrenergic receptor blockers, spironolactone), that provide benefical effects, demonstrated in multicentric trials in controlled populations. However, this mid-term benefit, becomes less effective with time, resulting in progression of the disease to terminal stages and death. The purpose of this paper is to review other pathophysiologic pathways and the potential application of preventive measures to be incorporated in the standardized treatment of heart failure.

In view of the common practice of dieting for weight reduction, the influence of severe food restriction (about 25% of ad libitum intake) on adrenergic mechanisms was studied. Cardiac norepinephrine and epinephrine concentrations as well as plasma norepinephrine levels, were increased upon feeding a restricted diet to rats for 14 days in comparison with control rats that ingested about 30 g food/ day. Bradycardia as well as characteristic electrocardiographic abnormalities, including prolongation of the QRS and QT intervals, were observed in food-restricted rats. Diet-restricted rats did not develop ventricular arrhythmias in response to epinephrine injections as readily as control rats. Depression in both + dP/dt and -dP/dt of the heart in situ as well as reductions in the inotropic responses to epinephrine were evident in diet-restricted rats. Beta-adrenergic binding studies revealed a significant decrease in receptor density, but the dissociation constant for binding was also depressed in the food-restricted rat heart. Downregulation of the beta-adrenergic receptors in the heart may explain the lack of an epinephrine-induced increase in contractile force development as well as arrhythmias in food-restricted rats. These data demonstrate that severe food restriction has marked effects on adrenergic mechanisms and heart function, and thus some caution should be exercised at early periods of this therapy for weight reduction.

Diabetes mellitus is one of the leading public health problems in the industrialized world. About 1 million people in Canada and 10 million people in the United States are afflicted with the disease. It is the eighth health-related cause of death and in fact is considered one of the important risk factors for heart disease. Nearly all the morbidity from diabetes is related to cardiovascular dysfunction—coronary artery disease, hypertension, or renal failure secondary to microvascular disease [1]. Diabetes is recognized clinically by the presence of serious abnormalities in carbohydrate metabolism. The manifestation of the disease is characterized by fasting hyperglycemia and/or impaired glucose clearance from the blood after ingestion of a high glucose load. Generally, there exist two major types of diabetes mellitus, which according to the guidelines of the National Diabetes Data Group [2] are classified as insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM).

The occurrence of excessive catecholamine release is often associated with stress due to the lifestyle of Western societies. Contrary to the general thinking that excess catecholamines produce cardiotoxicity mainly via binding to adrenoceptors, there is increasing evidence that catecholamine-induced deleterious actions may also occur through oxidative mechanisms. In this overview it is shown that a high dose of isoproterenol induces a biphasic change in cardiac Ca2+ transport in the sarcolemma and in sarcoplasmic reticulum. Both sarcolemmal and sarcoplasmic reticular Ca2+-transport activities are initially increased to maintain Ca2+ homeostasis and then are impaired, which may be associated with the occurrence of intracellular Ca2+ overload. On the other hand, mitochondrial Ca2+-transport activities exhibited a delayed increase. Pretreatment with vitamin E partially prevented the deleterious changes in cardiac membranes as well as the depressed energetic status of the heart muscle cell. It is concluded that excess catecholamines affect Ca2+-transport mechanisms primarily via oxidation reactions involving free radical-mediated damage. Thus drug approaches that reduce circulating catecholamines and/or prevent their oxidation should prove beneficial. A combination therapy involving inhibitors of catecholamine release, blockers of adrenoceptors, and antioxidants may be indicated for stress-induced heart disease.

Occlusion of a coronary artery results in myocardial ischemia and subsequent myocardial infarction. Whenever the infarct size is more than 30% of the ventricular wall, the remaining myocardium attempts to compensate for the loss of muscle mass by changing the size and shape of cardiocytes in addition to developing cardiac hypertrophy, cardiac dilatation and congestive heart failure. This remodeling of the heart is associated with changes in the extracellular matrix including collagen proteins and is most probably due to the activation of both sympathetic nervous system and renin-angiotensin system as well as increased formation of various growth factors. Alterations in contractile function of the infarcted heart are associated with remodelling of the sarcoplasmic reticulum with respect to Ca(2+)-pump and Ca(2+)-release channels as well as contractile and regulatory proteins of the myofibrils. Myocardial infarction has also been shown to result in remodelling of the sarcolemmal membrane with respect to Ca(2+)-channels, Ca(2+)-transport systems, cardiac receptors and signal transduction mechanisms. Although information regarding remodelling of mitochondria in the infarcted heart is limited, alterations in energy yielding and Ca(2+)-accumulating systems are suspected. Accordingly, it is suggested that changes in cardiac contractile dysfunction due to myocardial infarction are associated with remodeling of both extracellular matrix and subcellular organelles in the heart.

The cardiac interstitium is populated by nonmyocyte cell types including transcriptionally active cardiac fibroblasts and endothelial cells. Since these cells are the source of many components of the cardiac extracellular matrix, and because changes in cardiac extracellular matrix are suspected of contributing to the genesis of cardiovascular complications in disease states such as diabetes, hypertension, cardiac hypertrophy and congestive heart failure, interest in the mechanisms of activation of fibroblasts and endothelial cells has led to progress in understanding these processes. Recent work provides evidence for the role of the renin-angiotensin-aldosterone system in the pathogenesis of abnormal deposition of extracellular matrix in the cardiac interstitium during the development of inappropriate cardiac hypertrophy and failure. The cardiac extracellular matrix is also known to change in response to altered cardiac performance associated with post-natal aging, and in response to environmental stimuli including intermittent hypoxia and abnormal nutrition. It is becoming clear that the extracellular matrix mainly consists of molecules of collagen types I and III; they form fibrils and provide most of the connective material for tying together myocytes and other structures in the myocardium and thus is involved in the transmission of developed mechanical force. The data available in the literature support the view that the extracellular matrix is a dynamic entity and alterations in this structure result in the development of heart dysfunction.

Clinical CardiologyVolume 16, Issue 6 p. 521-522 Profiles in CardiologyFree Access Harold Nathan Segall (1897–1990) Robert E. Beamish M.D., Corresponding Author Robert E. Beamish M.D. Division of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, CanadaDivision of Cardiovascular Sciences St. Boniface Hospital Research Centre 351 Tache Avenue Winnipeg, Manitoba, Canada R2H 2A6Search for more papers by this author Robert E. Beamish M.D., Corresponding Author Robert E. Beamish M.D. Division of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, CanadaDivision of Cardiovascular Sciences St. Boniface Hospital Research Centre 351 Tache Avenue Winnipeg, Manitoba, Canada R2H 2A6Search for more papers by this author First published: June 1993 https://doi.org/10.1002/clc.4960160614AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume16, Issue6June 1993Pages 521-522 ReferencesRelatedInformation