Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Half a century after the elucidation of its molecular structure, aldosterone is generating the greatest interest, not in the fields of endocrinology or renal medicine but in cardiology-where aldosterone over-activation is now perceived as detrimental in heart failure (HF) and ischaemic heart disease. Clinically, excess aldosterone is associated with higher morbidity and mortality after myocardial infarction (MI) and HF. The Randomised Aldactone Evaluation Study (RALES) study in severe chronic heart failure and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) study in post-MI heart failure have shown that use of non-selective and selective aldosterone receptor antagonists, respectively, improves prognosis. The pathophysiological mechanisms underpinning these damaging aldosterone-mediated cardiovascular effects are still being elucidated, but prime candidates include cardiomyocyte necrosis and apoptosis, and myocardial fibrosis resulting in adverse cardiac remodelling, coronary vasculopathy, tachyarrhythmia and positive feedback activation of the renin-angiotensin-aldosterone system. Practical points for consideration when instigating therapy include preferential use of aldosterone receptor antagonists to maintain electrolyte balance whenever loop or thiazide diuretics are used (vulnerable HF patients require higher ranges of potassium and magnesium to minimise propensity for tachyarrthythmia), for renoprotection and for counteracting aldosterone breakthrough despite adequate ACE inhibition; use of the minimum doses of loop diuretics required to lessen activation of the renin-angiotensin-aldosterone system in HF; use of selective aldosterone receptor antagonists to avoid gynaecomastia/mastalgia and impotence; and prophylactic use of aldosterone receptor antagonists to improve prognosis.
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PMID:Fiftieth anniversary of aldosterone: from discovery to cardiovascular therapy. 1531 May 30

Aim of the investigation was the study of influence of spironolactone (25 - 75 mg/day) on clinico-functional status, parameters of left ventricular (LV) remodeling, as well as safety of its long term application in patients with chronic heart failure (CHF) receiving optimal therapy. Forty nine patients were included in the study - 44 men (89,8%) and 5 women (10,2%) in the age from 28 to 75 years with II-IV NYHA functional class (FC) CHF, LV ejection fraction (EF) 35%, plasma levels of creatinine 150 mmol/L and potassium 5 mmol/L. Main causes of development of CHF were dilated cardiomyopathy, ischemic heart disease (large focal postinfarction cardiosclerosis) and decompensated hypertensive heart [25/20/4 (51%/40,8%/8,2%), respectively]. As a result of randomization procedure 2 groups of observation were formed: group 1 - 19 patients receiving spironolactone in a 24 hour dose 25 - 75 mg, group 2 - control group - 30 patients without therapy with spironolactone. Inhibitors of angiotensin converting enzyme (ACE) took 100%, b-adrenoblockers - 63,2% of patients. Control examination was conducted before randomization, in 6 and 12 months of follow up. During period of observation no changes of FC were noted in control group. In the group of treatment with spironolactone after 6 months in 6 patients FC lowered ( =0,028). By the end of follow up the given effect lost its significance, but 5 (38,5%) patients by termination of the study had FC II of CHF, what was accompanied with moderate increase of distance walked during 6-minute walk test from 354 to 378 m. In patients in the group of spironolactone treatment already after 6 months of treatment there occurred decrease of LV volumes, what by the end of period of observation for LV end diastolic volume (EDV) amounted - 76 ( - 118; - 7), and for LV end systolic volume (ESV) - 53 ml ( - 96; - 7) ml ( =0,008) at absolute increment of LVEF by 3 (0; 12)% ( =0,05). In control group in 12 months decrease of LVEDV was less pronounced and LV ESV did not change. Finally after 12 months of observation the groups became to differ by change of LVEF ( =0,035) and LVESV ( =0,02). Changes of LV volumes were followed by lowering of median concentration of atrial natriuretic peptide (ANP) in plasma by - 51,9 ( - 87; - 43,9) mg/ml. At the same time in control group gradual rise of concentration of the given peptide was observed from initial 107,3 to 168,5 mg/ml at the moment of study termination. Changes of BP level, creatinine concentration in patients in the study were not fixed in any of treatment groups. Development of moderate hyperkaliemia amounted 21.0%, gynecomastia or pain in the region of mammary glands were fixed in 26,3% of patients in 12 months of treatment. Addition of spironolactone in a dose of 75 mg/day to optimal therapy, including ACE inhibitor and b-adrenoblocker is accompanied with improvement of clinical state and FC of patients with moderate and severe CHF. Long term therapy with spironolactone blocks processes of desadaptive LV remodeling and improves LV contractile function, what is reflected in lowering of ANP concentration in plasma of patients with CHF. Application of spironolactone in combination with ACE inhibitor and b-adrenoblocker bisoprolol does not lead to lowering of BP level and worsening of renal function, but is accompanied with development of hyperkaliemia in patients with CHF. Gynecomastia appears to be main reason limiting long term use of spironolactone in patients with CHF in a dose of 75 mg/day.
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PMID:[Efficacy and safety of long-term application of spironolactone in patients with moderate and severe chronic heart failure receiving optimal therapy]. 1826 Sep 39

Up to 15% of patients with essential hypertension have inappropriate regulation of aldosterone; although only a minority have distinct adrenal tumors, recent evidence shows that mineralocorticoid receptor activation contributes to the age-related blood pressure rise and illustrates the importance of aldosterone in determining cardiovascular risk. Aldosterone also has a major role in progression and outcome of ischemic heart disease. These data highlight the need to understand better the regulation of aldosterone synthesis and its action. Aldosterone effects are mediated mainly through classical nuclear receptors that alter gene transcription. In classic epithelial target tissues, signaling mechanisms are relatively well defined. However, aldosterone has major effects in nonepithelial tissues that include increased synthesis of proinflammatory molecules and reactive oxygen species; it remains unclear how these effects are controlled and how receptor specificity is maintained. Variation in aldosterone production reflects interaction of genetic and environmental factors. Although the environmental factors are well understood, the genetic control of aldosterone synthesis is still the subject of debate. Aldosterone synthase (encoded by the CYP11B2 gene) controls conversion of deoxycorticosterone to aldosterone. Polymorphic variation in CYP11B2 is associated with increased risk of hypertension, but the molecular mechanism that accounts for this is not known. Altered 11beta-hydroxylase efficiency (conversion of deoxycortisol to cortisol) as a consequence of variation in the neighboring gene (CYP11B1) may be important in contributing to altered control of aldosterone synthesis, so that the risk of hypertension may reflect a digenic effect, a concept that is discussed further. There is evidence that a long-term increase in aldosterone production from early life is determined by an interaction of genetic and environmental factors, leading to the eventual phenotypes of aldosterone-associated hypertension and cardiovascular damage in middle age and beyond. The importance of aldosterone has generated interest in its therapeutic modulation. Disadvantages associated with spironolactone (altered libido, gynecomastia) have led to a search for alternative mineralocorticoid receptor antagonists. Of these, eplerenone has been shown to reduce cardiovascular risk after myocardial infarction. The benefits and disadvantages of this therapeutic approach are discussed.
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PMID:A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function. 1829 66