Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congestive heart failure is a syndrome common in the United States, especially in elderly patients. The most common etiology is coronary artery disease. A number of general factors contribute to the heart failure syndrome, including loss of muscle, decreased myocardial contractility, pressure or volume overload, or restricted filling. All of these factors may play a role in a given patient as, for example, with coronary artery disease. Although systolic dysfunction with a reduced ejection fraction is the most common heart failure syndrome, up to 40% of patients may have a relatively preserved ejection fraction with diastolic dysfunction. As the heart begins to fail, a number of compensatory mechanisms are activated. These include increased heart rate, the Frank-Starling mechanism, increased catecholamines, activation of the renin-angiotensin system, and release of atrial natriuretic peptides. Although these mechanisms are initially helpful to the cardiovascular system, they frequently overshoot, initiating a vicious cycle. For example, with a decrease in cardiac output, there is a reflex increase in systemic vascular resistance in order to maintain perfusion pressure. This increase in resistance, however, acts as a load on the left ventricle and further reduces cardiac output. The best evidence for the existence of this vicious cycle is the beneficial change in hemodynamics produced by vasodilator drugs and the ACE inhibitors. Thus, an understanding of pathophysiology allows for the selection of rational therapy. An unresolved problem in heart failure patients is how best to reduce the high incidence of sudden death, which is one of the major challenges for the future.
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PMID:Pathophysiology of congestive heart failure. 139 15

The heart is one of the major target organs that becomes secondarily involved with the unrelenting and progressive vascular disease of essential hypertension. As a result of this increasing afterload that is imposed upon the left ventricle, the ventricular chamber adapts structurally and functionally. Structural changes involve an increase in muscle mass that is achieved through left ventricular hypertrophy (in a manner similar to the arteriolar changes demonstrated by increased thickening). Unless antihypertensive therapy is interdicted in this disease process, left ventricular failure will ensue as the major cardiac hemodynamic consequence. Left ventricular hypertrophy is also associated with a risk that is independent of the pressure overload and hemodynamic risk. Although antihypertensive therapy will reduce from the hemodynamic alterations, only recently have epidemiological findings suggested that the independent risk of LVH may be reduced with pharmacological therapy. There are no data available to indicate just which agents may reduce the risk from LVH; but relatively recent studies seem to indicate that while all agents may reduce LVH with prolonged therapy only certain classes of agents will do so independent of their hemodynamic factors. Some of these agents, however, may impair cardiac function if arterial pressure is increased abruptly following therapeutic reduction of cardiac mass. Other agents may preserve normal function--or even may improve function. Among those classes of antihypertensive agents that reduce cardiac mass at least in part due to nonhemodynamic factors, are the angiotensin converting enzyme inhibitors, the calcium antagonists, and most adrenergic inhibitors. Evidence will be presented demonstrating the hemodynamic/structural dissociation of those pharmacological agents that reduce cardiac mass with short-term treatment in spontaneously hypertensive rats with left ventricular hypertrophy. Although centrally active adrenolytic, angiotensin converting enzyme (ACE) inhibitors, and calcium antagonists all reduce cardiac mass, their structural and cardiac functional effects differ greatly. Even within the ACE inhibitor group their effects vary--improving, impairing, or not changing the Frank-Starling relationships following reduction in left ventricular mass. We postulate great variability of cardiac intramyocytic penetrance of the pharmacological agents and their local intracellular effects on mitogenesis of the ventricular myocyte. The implications on cardiac function and therapy have vast potential. Therefore, current investigative areas involving new concepts of molecular biology of the cardiac myocyte may provide great promise to the quest of unraveling some of the newly postulated questions: What is the role of ionized intracellular calcium? Do the local renin-angiotensin systems in the cardiac and vascular myocyte participate in the development and regression of hypertrophy?(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Left ventricular hypertrophy: dissociation of structural and functional effects by therapy. 183 47

1. Although heart failure is commonly associated with depressed systolic function, there is increasing evidence that impaired diastolic performance is also universally present and might be a key determinant of symptoms, physical capacity and even survival in some subsets of patients. 2. Reduced diastolic distensibility increases cardiac filling pressure not only at rest, but even more during exercise when diastolic filling time is reduced. The increases in filling pressure and diastolic wall stress lead to pulmonary congestion and subendocardial ischaemia, it also triggers myocardial hypertrophy and a detrimental remodelling of the ventricular cavity. Perhaps even more importantly, impaired ventricular distensibility limits the use of the Frank-Starling mechanism, impairing systolic pump function and cardiac output adaptation during exercise. Therapies able to improve the distensibility of the ventricle are, therefore, desirable in heart failure. 3. Nitrates, angiotensin converting enzyme (ACE) inhibitors and diuretics may indirectly increase left ventricular chamber compliance by their effects on the right side of the heart. Cardiac glycosides do not improve myocardial relaxation and may even cause diastolic contracture at toxic doses. The new beta 1-adrenoceptor partial agonist, xamoterol, on the other hand, consistently lowers left ventricular filling pressure at rest and during exercise, and produces an increase in left ventricular dynamic compliance through the direct lusitropic effect of beta 1-adrenoceptor stimulation. These beneficial effects are maintained during prolonged therapy and also appear sufficient to slow the remodelling of the ventricular cavity. The improvement in symptoms and in exercise tolerance observed during xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) therapy might, therefore, be related to the improvement in left ventricular diastolic distensibility induced by this drug.
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PMID:Focus on diastolic dysfunction: a new approach to heart failure therapy. 257 54

The Framingham heart study has shown that arterial hypertension is the major aetiological factor for the development of heart failure. In the presence of heart failure, various regulatory systems may be operative. These include the Frank-Starling mechanism, the neurohormonal system, regulation of cardiac growth and peripheral oxygen delivery. Recently, the interrelationship of the neuroendocrine system and cardiac growth has been examined. In the pressure or volume overloaded heart, growth of the myocardium involves the enlargement of cardiac myocytes, an adaptation governed by ventricular loading. Non-myocyte cell growth, including cardiac fibroblasts, may also occur. However, the haemodynamic load does not appear to be its major physiological stimulus. Cardiac fibroblast activation is responsible for the accumulation of type I and III collagens, the major fibrillar proteins of the myocardial collagen matrix, while vascular smooth muscle cell growth accounts for medial thickening of coronary resistance vessels. This structural remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy: it accounts for abnormal myocardial stiffness and impaired coronary reserve, thereby leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure. Several lines of evidence suggest that circulating and tissue renin-angiotensin-aldosterone systems are involved in the structural remodelling of the non-myocyte compartment, including the 'cardioprotective' effects of angiotensin converting enzyme (ACE) inhibition or the beneficial effects of anti-aldosterone treatment that were found to prevent myocardial fibrosis in renovascular hypertension due to unilateral renal ischaemia under experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the structural remodelling of the myocardium: from hypertrophy to heart failure. 771 13

According to the Framingham Study, arterial hypertension and coronary artery disease are the major etiologic factors in the development of heart failure. Regulatory systems that may affect heart failure include the Frank-Starling mechanism, neurohormonal responses, cardiac growth and peripheral oxygen delivery. Recently, the interrelationship between the neuroendocrine system and cardiac growth has aroused much interest. In the pressure- or volume-overloaded heart, hypertrophic growth of the myocardium includes the enlargement of cardiac myocytes, an adaptation governed by ventricular loading. Nonmyocyte cell growth involving cardiac fibroblasts may also occur but is not primarily regulated by the hemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries, while vascular smooth muscle cell growth accounts for the medial thickening of these vessels. This remodeling of the cardiac interstitium is a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness and impaired coronary vasodilator reserve, leading to ventricular diastolic and systolic dysfunction and, ultimately, symptomatic heart failure. Several lines of evidence suggest that the renin-angiotensin-aldosterone system is involved in regulating the structural remodeling of the nonmyocyte compartment; this accounts for the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition, which prevents myocardial fibrosis in rats with renovascular hypertension. In rats with genetic hypertension, established left ventricular hypertrophy, abnormal diastolic stiffness due to interstitial fibrosis and reduced coronary vasodilator reserve associated with medial wall thickening of intramyocardial resistance vessels, the ACE inhibitor lisinopril restored myocardial structure and function towards normal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The cardiac structure-function relationship and the renin-angiotensin-aldosterone system in hypertension and heart failure. 782 69

Heart failure is a complex clinical syndrome in whose manifestations and prognosis compensatory mechanisms have a prominent role as a response of the organism to an elementary disturbance. There are five basic compensatory mechanisms: the Frank-Starling mechanism, structural changes of the heart, activation of neuroendocrine mechanism, adaptation to hypoxia and anaerobic metabolism. The interaction between the two main neurohumoral mechanisms, namely vasodilatation and vasoconstriction, has been drawing much of the attention recently. Vasoconstriction which evolved into maintaining cardiac output in hypovolemic state, leads to a number of deleterious hemodynamic and metabolic disturbances in heart failure. The organism tends to diminish this negative effects by changing beta adrenergic pathway and by activating vasodilative mechanisms. Once heart failure becomes severe, vasoconstriction predominates due to a loss of normal baroreceptor activity. It is considered that too marked activity of neurohumoral mechanisms is a significant cause of disease progression. By use of contemporary drugs (ACE inhibitors, beta blockers, digitalis), excessive vasoconstrictive mechanisms are tried to be diminished and prognosis of the disease improved.
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PMID:[Pathophysiologic mechanisms of cardiac decompensation]. 817

Angiotensin II has a plethora of different actions in the heart including, for instance, also slight positive inotropic effects. Thus cardiotonic therapy with angiotensin converting enzyme (ACE) inhibitors should possibly be complemented by positive inotropic drug therapy. With this respect, novel cardiotonic drugs that increase calcium sensitivity of myofilaments such as pimobendan (CAS 118428-36-7) might be particularly useful, as they will increase force with little, if any concomitant increase in myoplasmic free calcium. These drugs mimic mechanistically the Frank-Starling-Mechanism or alpha-adrenergic effects which also involve, at least partly, calcium sensitization of the myofilaments. The latter may therefore be a useful therapeutic principle, in particular in cases where myofibrillar calcium responsiveness is pathologically depressed such as for instance in the stunned myocardium or under hypoxic conditions.
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PMID:[Modulation of calcium sensitivity in the heart muscle--physiology, pathophysiology and pharmacology]. 838 86

The therapeutic efficacy of cardiac glycosides is not widely appreciated either in respect of their positive inotropic value or antiarrhythmic activity. Although cardiac glycosides do not prevent an increase in ventricular rates during exercise they do slow the heart rate at rest in patients with atrial fibrillation. The clinical importance of the potentially beneficial influence of the digitalis glycosides on the negative force-frequency relationship (Bowditch effect), preload-force relationship (Frank-Starling's Law) and baroreceptor dysfunction in heart failure await clarification. In patients with heart failure, the positive inotropic effects of the digitalis glycosides are mild, but show no tolerance during prolonged administration. Digitalis glycosides are the only group of positive inotropic drugs that persistently increase the ejection fraction during long-term administration in patients with heart failure. These haemodynamic benefits are translated into decreased symptoms and increased exercise capacity in patients with congestive heart failure. Although their clinical efficacy in the different stages of heart failure remains undefined, recent evidence indicates that their therapeutic benefit is on a par with diuretics and ACE inhibitors in symptomatic heart failure. Results of studies specifically directed to determining the impact of the cardiac glycosides on prognosis are awaited.
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PMID:Digitalis--friend or foe? 852 79

In chronic heart failure, various regulatory systems including the Frank-Starling mechanism, the neuro-hormonal response, cardiac growth and peripheral oxygen delivery may be operative. Recently, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth has drawn clinical interest. In the pressure-or volume-overloaded heart, the development of myocyte growth is primarily dependent on ventricular loading. Non-myocyte cell growth involving cardiac fibroblasts may also occur but this is not primarily regulated by the haemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the progression of symptomatic heart failure. The effector hormones of the RAAS, angiotensin II (AngII) and aldosterone (Aldo), appear to be primarily involved in promoting the adverse structural remodelling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, AngII and Aldo have been shown to stimulate collagen synthesis while AngII additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for degradation of fibrillar collagen in the cardiac interstitium, leading to excessive collagen accumulation. These findings may serve as rationale as to why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy beyond the effect of simply unloading the heart in patients with congestive heart failure.
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PMID:The renin-angiotensin-aldosterone system and myocardial collagen matrix remodelling in congestive heart failure. 868 74

An accumulating body of experimental data supports the presence of a paracrine pathway for the modulation of myocardial function by cardiac endothelial cells. Cardioactive substances released by endothelial cells include nitric oxide, endothelin-1, prostanoids, adenylpurines, natriuretic peptides, and other agents that have so far only been characterised in bioassay studies. Endothelial cells also possess enzymatic activities, in particular ACE/kininase activity, which can alter local levels of angiotensin II and bradykinin. Many of the "endothelial" mediators can be produced by cardiac myocytes themselves, often under pathological conditions, suggesting a potential parallel autocrine pathway. Complex reciprocal relationships exist between individual mediators, which affect both their release and actions. Most studies to date have focused on the acute influence of these agents on contractile function; the longer-term modulation both of cardiac structure and function could be equally important. A notable feature of the action of several of the endothelial mediators is that they modify myocardial contractile behaviour predominantly through changes in myofilament properties rather than by altering cytosolic Ca2+ transients. This mode of action often results in a disproportionate effect on myocardial relaxation and diastolic tone. The opposing contractile effects and differing time-scales of action of agents such as nitric oxide and endothelin-1 are reminiscent of the interplay between these factors in the regulation of blood vessel tone. The endothelial paracrine pathway is likely to act in concert and to interact with other cardiovascular regulatory pathways, e.g., the Frank-Starling mechanism, neurohumoral influences, the effects of heart rate, coronary perfusion and load. A better understanding of its physiological and pathophysiological roles may lead to novel therapeutic strategies.
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PMID:Paracrine modulation of heart cell function by endothelial cells. 875 39


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