| Congestive heart failure(CHF) is the common clinical syndrome accompanied with a higher morbidity and mortality rate. Its pathophysiologic changes mainly develop in neuroendocrine-cytokine system activation and myocardium remodeling. Excessus activated neuroendocrine system and renin-angiotensin-aldosterone system(RAAS) further lead to myocardium remodeling and CHF aggravation. For patients with CHF the activation of neuroendocrine system is very important. Changes of adrenergic nerve tension influence the CHF proceeding by adrenoceptor mediated biological effect. Recently, the studies of CHF make the CHF therapy change from previous hemodynamics mode to evidence-based medicine mode aimed at improving myocardium biological behaviour and raising patient long term survival rate and quality of life. Accordingly, blocking vicious cycle of neurohormone activation and myocardium remodeling become the key point of CHF treatment. Now, researches on CHF pathogenesis and treatment have evolved deeply. CHF medication can achieve anticipated curative effect at the early stage, however, which is difficult to have the intended effect for decompensate CHF(DCHF). Patients with DCHF often emerge oliguria, internal environment disorders and renal failure and died at the end stages. For a few years, we cured a lot of patients with DCHF. Glucocorticoid adding to usual treatment in patients with DCHF often turn round the refractory situation, making the patients urine volume increase obviously, the general states and heart-renal function improved obviously. Henceβ-blocker and ACEI can be added and improve CHF states and decease end-point events. Adrenergic system plays an important role in regulating cardiovascular system. Endogenic catecholamines(adrenalin and noradrenaline) regulate their biological action by activating nine adrenoceptor(AR) subtypes. Recently, studies on CHF have indicate thatβ1-AR begins down-regulate when CHF is in its light degree.β1-AR is so down-regulate that it can't react to adrenalin when CHF is in its very severe degree.β2-AR is not down-regulate in the exhausted heart. It was discovered thatβ3-AR existed in myocardium lately.β3-AR up-regulate 2 to 3 folds in the exhausted heart than the normal heart. Up-regulation ofβ3-AR at certain phase can delay myocardial cell impairment further, butβ3-AR continuous augment leads to myocardium inhibition aggravation and heart function deterioration. Myocardiumα1-AR stimulation may induce cardiac musculotone moderate enhancement(effect obviously less thanβ1-AR). In pathologic environment,α1-AR sustains myocardial contractility in compensatory form under circumstances ofβ-AR system down-regulation and uncoupling of G-protein and effectors. In spite of the 4 kinds AR existing up-regulation or down-regulation in the exhausted heart, it is not clear how the 4 kinds AR change before and after the treatmentof CHF, especially treated with glucocorticoid.Although there is a few reports on CHF be treated with glucocorticoid at home,it's very rare abroad,and it isn't clear if glucocorticoid influence myocardium AR and hemodynamics.Objectives: 1. we establish rat models of CHF after acute myocardial infarction; We treat them with dexamethasone, and observe if and how dexamethasone influence on hemodynamic of rats with CHF; 2. To measure rats myocardialα1,β1,β2,β3-AR density, and to observe if and how dexamethasone influence on myocardial AR of rats with CHF; 3 to enroll the patients with DCHF whom conventional therapy is ineffective, to observe if prednisone added to conventional therapy can significantly relieve hyperemia symptom and improve clinical state.Methods: Part 1: Waster rats (n=40) were anesthetized with chloral hydrate in abdominal cavity, small animal breathing machine assisted respiration, to make acute myocardial infarction model by ligating ramus descendens anterior arteriae coronariae sinistrae of rats. Rats model with CHF formed 12 weeks later when rats showed foodintake and activity amount reduced obviously, mental status dispirited,weight increased obviously, mouth, nose and limbs far-end cyanosis. Rats with CHF were divided randomly into two groups, one group was injected dexamethasone(1mg /kg) intramuscularly at the first and forth day respectively,the other group was injected equi-volume saline likewise, and observing the changes of symptoms of rats with CHF; measuring rats hemodynamics index including blood pressure(BP), heart rate(HR) and left ventricular end-diastolic pressure (LVEDP) 4 days later. Part 2: To measure every group rats myocardialα1,β1,β2,β3-AR density by immunohistochemical method ,and to understand the AR density changes .Taking the first part rats'myocardium tissues for testing myocardialα1,β1,β2,β3-AR density and 5 normal rats for normo-contrast group and taking gray scale of slice as AR density. Part 3: The study enrolled 35 patients with DCHF. Patients were included if they had orthopnea and refractory edema due to acute DCHF that was severe and had taken more 1 week hospitalization and intravenous therapy in addition to diuretics. The exclusion criteria were the following: Patients with an sign of infection or any conditions that would contraindicate glucocorticoids; systolic blood pressure lower than 80 mm Hg or higher than 140 mm Hg; cardiogenic shock; volume depletion; mechanical ventilation; hypertrophic or restrictive cardiomyopathy; constrictive pericarditis, pulmonary arterial hypertension, or active myocarditis. After written confirmed form was obtained, prednisone (1 mg/kg/day with a maximum dose of 60 mg/day was given for at least 9 days) was added. Primary end points were the effects on daily urine volume; patient assessed dyspnea and physician assessed global clinical status on day 1, day 2, day 3, day 4 and day 9; changes in renal function (serum creatinine, blood uric acid). Secondary end point was overall safety profile.Results:1. Operation achievement ratio is 50% during ligating rat coronary artery to make acute myocardial infarction model. Survival rate of model is 40% postoperative 12 hours.6 rats died during experimental session, there are 10 rats in the study end point (each group has 5 rats,respectively) . 2 .Compared with rats treated with saline,rats treated with dexamethasone had better mental status and appetite,urine volume and activity amount increased,mouth, nose and limbs far-end cyanosis lessened. LVEDP cut down(4.4±0.8 mmHg vs 12.1±2.5mmHg, P<0.05), BP and HR unchanged(P>0.05). 3. Myocardialβ1-AR density down- regulation(-5.13±0.097 vs -5.17±0.016, P< 0.01) in rats with CHF compared with normal rats, Buffy particle diminished in myocardium slice, gray scale value greatened, and i.e.β1-AR density grew down. Compared with rats treated with saline,myocardialβ1-AR density up-regulation obviously(-5.17±0.016 vs -5.14±0.013, P<0.01)in rats treated with dexamethasone.4 Myocardialβ2-AR density up-regulation obviously(-5.14±0.017 vs -5.10±0.015, P<0.01)in rats with CHF compared with normal rats, Buffy particle increased in myocardium slice. Myocardialβ2-AR density had down-regulation tendency in rats treated with dexamethasone compared with rats treated with saline, but statistical analysis is no difference(-5.10±0.015 vs -5.12±0.014, P>0.05). 5. Myocardialβ3-AR density up-regulation obviously(-5.18±0.018 vs -5.16±0.004, P<0.05)in rats with CHF compared with normal rats, buffy particle increased in myocardium slice. Myocardialβ3-AR density up-regulation obviously(-5.16±0.004 vs -5.13±0.011, P<0.05)in rats treated with dexamethasone compared with rats treated with saline. 6. Myocardialα1-AR density up-regulation obviously(-5.16±0.017 vs -5.14±0.003, P<0.01)in rats with CHF compared with normal rats, buffy particle increased in myocardium slice. Gray scale value grew down, and i.e.α1-AR density greatened. Compared with rats treated with saline, Myocardialα1-AR density down-regulation obviously(-5.14±0.003 vs -5.17±0.006, P< 0.01)in rats treated with dexamethasone compared with rats treated with saline. 7. For patients with DCHF, adding prednisone to the usual care resulted in significant relief of the congestive symptoms, which was accompanied with a potent diuresis with time and an improvement in renal function. At the end of study, dyspnea patient-assessed was markedly improved in 80% DCHF patients (P< 0.01), while global clinical status was markedly improved in 68.6 % DCHF patients(P<0.001)due to diuresis. Prednisone had no impact on serum sodium, potassium, chloride, BUN. However, it could significantly lower creatinine and uric acid. Changes from baseline in serum creatinine and uric acid was -12.21μmol/L (P<0.05) and -95.22±239.16 mmol/L (P<0.05), respectively. 8. At the end of study, 34 patients achieved weight loss and only 1 patient stayed unchanged. Overall, the weight loss was 3.17±2.10 kg on average(P<0.01). With respect to safety profile, administration of prednisone in relatively short period was safe and there were no severe side effects (exacerbation of angina, infection and poor controlled hypertension etc.) were observed in the study period.Conclusions: 1 Establishing animal models successfully is an important premise of experiment. We can raise animal model survival rate only by training frequently to accumulate experience, so that experiment can be proceed smoothly. 2 Hemodynamics is one of means to appraise animal model heart function. Amelioration of hemodynamics is one of markers appraising heart function improvement. Compared with rats treated with saline,symptom of CHF and hemodynamics improved in rats treated with dexamethasone. Dexamethasone is effective to therapy of CHF. 3 Myocardialβ1-AR density down-regulation andα1,β2,β3-AR up-regulation obviously in rats with CHF compared with normal rats. 4 Compared with rats treated with saline, myocardialβ1,β3-AR density up-regulation obviously,α1-AR down-regulation,β2-AR no change in rats treated with dexamethasone .Seen from clinical effect, haemodynamics and general condition both better in rats treated with dexamethasone than rats treated with saline. We had a presumption on these grounds that the sum of negativity myodynamia generated byβ3-AR up-regulation andα1-AR down-regulation possibly less than positive myodynamia generated byβ1-AR up-regulation. 5 For patients with DCHF, adding prednisone to the usual care resulted in significant relief of the congestive symptoms, which was accompanied with a potent diuresis with time and an improvement in renal function. There were no severe side effects were observed in the study period and administration of prednisone in relatively short period was safe.
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