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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Left ventricular hypertrophy is a major risk factor associated with the appearance of adverse cardiovascular events. A distortion in myocardial structure, mediated by an abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighbouring interstitial spaces, alters the electrical and mechanical behaviour of the myocardium. The mechanisms responsible for the regulation of cardiac myocyte growth and collagen accumulation are therefore of considerable interest. Herein we review results of in vivo studies conducted in the authors' laboratory that addressed these issues in various experimental models. The findings indicate that in arterial hypertension myocardial hypertrophy is related to ventricular systolic pressure work. Myocardial fibrosis, on the other hand, is not related to haemodynamic workload, but rather the presence of mineralocorticoid excess relative to sodium intake and excretion. Accordingly, fibrosis can appear in both the hypertensive left and non-hypertensive right ventricles. Pharmacological probes, administered in variable doses, were used to further test and support this hypothesis. In both primary and secondary hyperaldosteronism, it was possible to prevent the pathological structural remodelling of the myocardium with an aldosterone receptor antagonist, while in unilateral renal ischaemia ACE inhibition was similarly cardioprotective. Other studies demonstrated that it was feasible to regress the fibrous tissue response and normalise diastolic stiffness. This concept of cardioreparation suggests that heart failure due to this type of structural remodelling may be reversible.
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PMID:Regulatory mechanisms of myocardial hypertrophy and fibrosis: results of in vivo studies. 130 Dec 54

The major risk factor associated with the appearance of adverse cardiovascular events and outcome attributable to cardiovascular disease is left ventricular hypertrophy (LVH). Why this should be so resides not in the increase in myocardial mass per se, but in the disruption of myocardial structure. An abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighboring interstitial spaces represents such a distortion in structure. Furthermore, this fibrosis disrupts the electrical and mechanical behavior of the hypertrophied myocardium. Mechanisms responsible for fibrillar collagen accumulation have been examined in intact animals and cultured cardiac fibroblasts. In vivo studies indicate that myocardial fibrosis is associated with the presence of chronic mineralocorticoid excess, relative to sodium intake and excretion, not hemodynamic workload. Accordingly, fibrosis can appear in both the hypertensive, hypertrophied and nonhypertensive, nonhypertrophied ventricles. In both primary and secondary hyperaldosteronism it was possible to prevent myocardial fibrosis with an aldosterone receptor antagonist, while in unilateral renal ischemia angiotensin converting enzyme (ACE) inhibition was similarly cardioprotective. A regression in fibrous tissue and normalization of diastolic stiffness has also been possible using ACE inhibition, bringing forward the concept of cardioreparation and the notion that heart failure due to fibrosis may be reversible. In vitro studies indicate that effector hormones of the renin-angiotensin-aldosterone system stimulate fibroblast collagen synthesis. Aldosterone, in pathophysiologic concentrations, and angiotensin II, in much larger concentrations, each enhance collagen synthesis without altering the mitogenic potential of these cells. Thus, elevations in circulating aldosterone and angiotensin II, relative to sodium intake, have the potential to not only alter sodium homeostasis and vascular tonicity, but also the structure of cardiovascular tissue. Thus, myocardial fibrosis represents a structural basis for pathologic hypertrophy and ultimately accounts for the appearance of adverse cardiovascular events and outcomes.
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PMID:Pathologic hypertrophy with fibrosis: the structural basis for myocardial failure. 136 63

The cardiac interstitium is composed of non-myocyte cells and a structural fibrillar protein network which plays a dominant role in governing the structure, architecture, and mechanical behaviour of the myocardium. Herein we review the fibrillar collagen network, its various components, and the functions they serve in the normal and structurally remodelled myocardium in arterial hypertension. The heterogeneity in myocardial structure, created by the altered behaviour of non-myocyte cells, particularly cardiac fibroblasts, which are responsible for collagen synthesis or degradation and thereby fibrous tissue accumulation, is a major determinant for the appearance of diastolic dysfunction and ultimately systolic myocardial failure. Regulatory mechanisms related to this fibrous tissue response are reviewed to draw attention to the hitherto neglected role of cardiac fibroblasts in mediating adverse structural remodelling of the myocardium and showing how this can be prevented through the use of pharmacological agents that interfere with the regulation of the myocardial collagen matrix. Several lines of evidence suggest that circulating and tissue renin-angiotensin-aldosterone systems (RAAS) are involved in the structural remodelling of the non-myocyte compartment. These include the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition and aldosterone receptor antagonism that were found to prevent myocardial fibrosis in the rat with renovascular hypertension. In the rat with genetic hypertension, established left ventricular hypertrophy and abnormal myocardial diastolic stiffness due to interstitial fibrosis, RAAS inhibition resulted in restoration of myocardial structure and function to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial collagen matrix remodelling in arterial hypertension. 139 56

We have previously demonstrated that baroreceptor discharge sensitivity is depressed in dogs with experimental heart failure and that this depressed sensitivity can be reversed by the Na+,K(+)-ATPase inhibitor ouabain. This suggests that enhanced Na+,K(+)-ATPase activity in baroreceptors is responsible for the blunted baroreceptor discharge sensitivity seen in heart failure state. Because aldosterone, a known stimulator of Na+,K(+)-ATPase, is elevated in heart failure the present study was undertaken to determine the effects on baroreceptor discharge of perfusion of the carotid sinus with aldosterone in normotensive dogs. Single unit baroreceptor activity was recorded as well as carotid sinus pressure and the diameter of the carotid sinus. Perfusion of the carotid sinus with aldosterone (in Krebs-Henseleit solution) significantly elevated threshold pressure (108.5 +/- 3.1 mm Hg versus 92.7 +/- 4.6 mm Hg, p less than 0.05) and reduced peak discharge rate (40.3 +/- 3.9 spikes/sec, p less than 0.05). These effects appeared 15 minutes after aldosterone perfusion and remained constant for the next 60 minutes. There was no change in the carotid sinus pressure-diameter curve during perfusion with aldosterone. Perfusion of the carotid sinus with ouabain (0.1 microgram/ml) during aldosterone perfusion did not reverse the blunted baroreceptor discharge. The blunted baroreceptor activity induced by perfusion of the carotid sinus with aldosterone was prevented by removal of the endothelial cells in the carotid sinus area with a balloon-tipped catheter or by perfusion with saponin. Finally, perfusion of the carotid sinus with spironolactone (10 ng/ml), a mineralocorticoid receptor antagonist, prevented the inhibitory effect of aldosterone. These data suggest that aldosterone reduces maximum baroreceptor discharge.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aldosterone reduces baroreceptor discharge in the dog. 154 52

The cardiac interstitium is composed of nonmyocyte cells and a structural protein network which plays a dominant role in governing the structure, architecture, and mechanical behavior of the myocardium. The heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for myocardial collagen metabolism and fibrous tissue accumulation, may largely explain the appearance of diastolic and/or systolic myocardial failure. Regulatory mechanisms that are related to the fibrous tissue response in various cardiovascular diseases, e.g., hypertensive heart disease, dilated cardiomyopathy or post myocardial infarction, are of primary clinical interest. A better understanding of the hitherto neglected role of cardiac fibroblasts in mediating an adverse structural remodeling of the myocardium will lead to specific pharmacologic agents that interfere with the fibrous tissue response. Several lines of evidence based on in vivo and in vitro studies suggest that circulating and tissue renin-angiotensin-aldosterone systems (RAAS) are involved in the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition or aldosterone receptor antagonism that was found to prevent myocardial fibrosis in the rat with renovascular or genetic hypertension. In cultured adult cardiac fibroblasts, an angiotensin (Ang)II- or aldosterone-mediated dose-dependent increase in collagen synthesis could be completely abolished by the use of AngII type 1 or mineralocorticoid receptor antagonists, respectively. Likewise, the AngII-mediated decrease in the activity of matrix metalloproteinase 1, the key enzyme for interstitial collagen degradation, could be antagonized by AngII receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological modulation of cardiac fibroblast function. 777 64

Angiotensin converting enzyme (ACE) inhibitor therapy in conjunction with loop diuretics and, possibly, digoxin, is associated with a relatively high incidence of recurrent heart failure and death. Even high doses of ACE inhibitors may not completely suppress the renin-angiotensin-aldosterone system; aldosterone "escape' may occur through non-angiotensin II dependent mechanisms involving corticotropin, atrial natriuretic peptide, serum potassium, and deficient high-density lipoprotein cholesterol concentrations. Addition of spironolactone (an aldosterone receptor blocker) to an ACE inhibitor regimen causes marked diuresis and symptomatic improvement. The Randomized Aldactone Evaluation Study (RALES) was organized to explore the role of combination therapy with spironolactone in patients with heart failure. Patients with New York Heart Association Functional Class II-IV heart failure and left ventricular ejection fractions < or = 40% who were on regimens comprising an ACE inhibitor, loop diuretic, and, possibly, digoxin were randomized to receive placebo or spironolactone in doses of 12.5, 25, 50, or 75 mg per day. Eve at the lowest dose of spironolactone, a significant decrease in plasma N-terminal pro-atrial natriuretic peptide occurred, with concomitant increase in concentrations of plasma renin and urinary aldosterone. As prophylaxis for heart failure, a daily dose of 25 mg of spironolactone and monitoring of serum potassium concentrations are recommended; symptomatic therapy in refractory or severe heart failure may require doses as high as 100 mg b.i.d. The RALES Mortality Trial will follow up 1400 similar patients for 3 years to determine the effect of the addition of spironolactone on combined mortality and hospitalization for heart failure.
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PMID:ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). 868 55

Symptomatic heart failure is accompanied by diastolic ventricular dysfunction due largely to an extensive reactive and reparative fibrosis. Experimental evidence suggests a clear association between myocardial fibrosis and chronic inappropriate elevations in circulating angiotensin II (Ang II) and/or aldosterone. Although not entirely elucidated, injury follows Ang II-associated release of adrenal medullary catecholamines and aldosterone-induced myocardial potassium depletion. Increasing evidence indicates locally produced cardiac Ang II plays an important role in tissue repair that may underlie myocardial remodelling, the fibrous tissue accumulation both at and remote to the site of myocardial infarction (MI). Angiotensin converting enzyme (ACE) binding density markedly increases at these fibrous tissue sites after experimental MI, indicating an involvement in wound healing regardless of the cause and location of fibrosis; cells expressing Ang II receptors are primarily myofibroblasts. Therapy with ACE inhibitors and aldosterone receptor antagonist have each been shown to attenuate development of fibrosis.
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PMID:Structural remodelling of the heart by fibrous tissue: role of circulating hormones and locally produced peptides. 868 56

Angiotensin converting enzyme (ACE) inhibition undoubtedly has become the cornerstone of heart failure treatment. Useful in each stage, it should possibly be considered first-line treatment in many patients with mild heart failure in whom fluid retention is not clearly present. Careful consideration of the optimal dose for the individual is important. Until further data are available concerning the efficacy and tolerability of high and low doses, the clinician should consider the target doses used in large controlled heart failure trials. Even under optimal dosing conditions, it is likely that ACE inhibition may not suffice in completely modulating the extensive neurohormonal stimulation extant in heart failure. In part this may result from a breakthrough of the ACE inhibitor effect as well as from activation of hormones and peptides that may not be affected by ACE inhibition. Also, a substantial proportion of patients may not tolerate sufficient ACE inhibition. Alternative or additional therapy aimed at modulating neurohormonal activation concerns interference with other parts of the renin angiotensin system, such as angiotensin II receptor and aldosterone receptor antagonism. Sympathetic activity and catecholamine levels may decrease with dopaminergic D2 agonists and, possibly, beta-blockade; in the latter, this may be confined to patients with pre-existing sympathetic over-activation. Increasing circulating levels of atrial natriuretic peptide via neutral endopeptidase inhibition may offer an alternative way to increase diuresis and natriuresis without neuroendocrine stimulation. Novel possibilities that have not yet been tested sufficiently in patients with heart failure include endothelin receptor antagonism, arginine vasopressin antagonism, and renin inhibition. Finally, digitalis glycosides may be considered neurohormonal modulators in addition to being positive inotropes. Heart failure is a complex condition that involves many organs and systems besides the heart. Polypharmacy tailored to the individual is mandatory. It is thus necessary to investigate approaches to the modulation of neurohormonal activation beyond ACE inhibition.
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PMID:Neurohormonal modulation in heart failure: ACE inhibition and beyond. 868 65

ACE inhibitors have been shown to be effective in reducing the morbidity and mortality of patients with left ventricular systolic dysfunction, but their application to clinical practice in this situation is still limited. In part, the failure to prescribe an ACE inhibitor to a patient with left ventricular systolic dysfunction is due to perceptions regarding their side effects, such as cough and renal dysfunction. Relatively few patients with left ventricular systolic dysfunction and a serum creatinine > or = 2 mg/dl receive an ACE inhibitor in clinical practice. In this situation one should consider an agent such as fosinopril, which is metabolized by the liver as well as secreted by the kidney. In patients with moderate renal dysfunction, fosinopril has been well tolerated without an increase in serum creatinine. In patients who develop cough due to an ACE inhibitor, consideration should be given to an angiotensin II type 1 receptor blocking agent, such as losartan. The relative safety and efficacy of an ACE inhibitor compared with an angiotensin II type 1 receptor blocking agent is being explored in a prospective randomized trial (Evaluation of Losartan In The Elderly [ELITE]), as well as the safety and pharmacological effectiveness of adding an angiotensin II receptor antagonist to an ACE inhibitor (Randomized Angiotensin receptor antagonists-ACE-inhibitor Study [RAAS]). There may also be a role for the combination of an aldosterone receptor antagonists and an ACE inhibitor in patients with left ventricular systolic dysfunction. Once an ACE inhibitor is administered to a patient with left ventricular systolic dysfunction it should be continued indefinitely. ACE inhibitors may be of value not only in preventing the progression of heart failure but also in reversing endothelial dysfunction and preventing the development of atherosclerosis and its consequences, such as myocardial infarction.
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PMID:ACE inhibitors in heart failure: prospects and limitations. 921 Oct 22

In experimental models where chronic inappropriate (relative to sodium intake and intravascular volume) elevations in circulating mineralocorticoids (aldosterone or deoxycorticosterone) are created, a reactive fibrosis with vascular remodeling is observed in systemic organs and the heart. Until recently, it was assumed that aldosterone was derived solely from adrenal glands via the circulation; however, there is now convincing evidence that cells of the heart and vasculature express genes responsible for the formation of both aldosterone and corticosterone and are capable of producing these steroids. Vascular endothelial and smooth muscle cells express CYP11B1 and CYP11B2, genes responsible for 11 beta -hydroxylase and aldosterone synthase, respectively. Furthermore, smooth muscle cells elaborate aldosterone. There is evidence that similar regulatory mechanisms operate in vascular cells as in adrenal cortex, since aldosterone synthase and 11 beta -hydroxylase expression are differentially modulated by low sodium/high potassium, angiotensin II and ACTH. It is likely that such localized corticosteroid production also occurs at sites of tissue repair, where populations of collagen-producing myofibroblasts, nourished by a neovasculature, predominate. Using a subcutaneous pouch model of granulation tissue we have obtained compelling data which would support such a notion. The mineralocorticoid receptor antagonist, spironolactone, severely attenuates pouch formation over a 2-week period and significantly reduces pouch wall hydroxyproline concentration. This effect is apparent even following adrenalectomy, when circulating corticosteroids are undetectable; however, with adrenalectomy alone, pouch formation is barely affected. This we took to be a possible indication of an effect of local, non-adrenal steroids in maintaining pouch tissue. Spironolactone inhibits angiogenesis. A recent clinical study demonstrates the efficacy of low-dose spironolactone in enhancing survival in patients with advanced chronic cardiac failure. Although it is not known how spironolactone brings about such an improvement in survival, we would propose that inhibition of fibrous tissue formation and/or angiogenesis might be important contributory factors. Further studies are required to address the relative contributions of circulating vs local aldosterone in promoting normal vs pathologic connective tissue formation.
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PMID:Extra-adrenal mineralocorticoids and cardiovascular tissue. 1037 93


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