الفهرس 
Chronic Heart FailureOnly 14 pages are availabe for public view
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Abstract
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Summary and Conclusion chronic heart failure (CHF) is the major cause of mortality and morbidity in Western countries. Despite significant improvements in the medical therapy of congestive heart failure, the mortality rate is in excess of 50% after 5 years. It is now well accepted that the syndrome of heart failure (HF) is associated with systemic inflammation characterized by increased activation of proinflammatory cytokines, cardiac auto-antibodies, cell adhesion molecules, the complement system activation, endothelial dysfunction, and increase in the biomarkers of myocyte stress as B-type atrial natriuretic peptide in chronic heart failure. In fact, elevated levels of proinflammatory markers including interleukin-6, tumor necrosis factor, C-reactive protein, and B-type atrial natriuretic peptide predict increased cardiovascular morbidity and mortality in patients with HF. HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors (statins) are well-established therapies in the prevention and treatment of atherosclerotic cardiovascular diseases and also, reducing mortality rate of cardiovascular diseases. Thus, statins could be a useful treatment for HF, a pathophysiological state characterized by neurohormonal activation, inflammation, and endothelial dysfunction. Several animal and human studies have been reported that, statins have shown to beneficially alter mechanisms that appear to play a role in the disease progression of HF through non-lipid lowering effects or pleiotropic effects of statins. Statins have been shown to improve endothelial function and to decrease plasma levels of proinflammatory cytokines in patients with CHD and hyperlipidemia via suppressing transcription of nuclear factor kappa-B, which plays an important role in regulating genes encoding for proinflammatory cytokines and adhesion molecules. Statins have some effects on the activated sympathetic nervous system, inflammation and endothelial dysfunction, including plaque stabilization, which are commonly involved in the pathogenesis and progression of heart failure, and many experimental and clinical studies have been reported that statins having promising therapeutic benefits for patients with heart failure. The aim of the present study is to evaluating and demonstration the potential therapeutic benefits of statins on experimental animal model of heart failure, and clinically on patients with chronic heart failure.
Eperimental study was done on forty adult albino rats of local strains, of both sexes, aged three months and weighing; average 163 gms, were used in this study. These rats were kept under good hygienic conditions and allowed free water and fed ad libitum. The animals were divided into four main groups. Experimental animal
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model of heart failure was induced in rats by doxorubicin (doxorubicin hydrochloride). Rats are divided into 4 groups as follow: Group 1: Normal control saline-treated group, (without heart failure), Group 2: Doxorubicin treated group (for induction of heart failure), Group 3: Atorvastatin-doxorubicin treated group, included 10 rats receiving atorvastatin at dose of 10 mg/kg/day given by oral gavage for 4 weeks; 2 week before induction of heart failure by doxorubicin and 2 weeks concurrently with injection of doxorubicin. This dose of atorvastatin was chosen because it has been shown to be very effective in rats. Group 4: Digoxin-doxorubicin treated group, included 10 rats receiving digoxin at dose of 0.02 mg/kg/day; given by oral gavage for 4 weeks ; 2 week before induction of heart failure by doxorubicin and 2 weeks concurrently with injection of doxorubicin ( standard reference group ). At the end of the experiment, the following had been done:- Assessment of mortality rate in different animal groups and gross morphological changes of heart failure in different animal groups (as large abdomen, ascites, body weight assessment). Blood samples for measurment of blood lipid profile assessment, serum Troponin T assessment as a specific and a sensitive biomarker of heart failure induced by doxorubicin, high sensitive C-reactive proteins assessment as an inflammatory marker in heart failure, cardiac tissue malondialdehyde activity assessment as oxidative stress biomarker of heart failure. Measurement of rat tail systolic blood pressure by tail-cuff plethysmograph which indirectly assessing autonomic sympathic activity on the heart in experimental animal model of heart failure was done on different rat groups. Histopathological study of rat heart tissues from different groups was done. Clinical study was done on patients of chronic heart failure; the study was included 20 patients who have been recruited from the Cardiology Departement outpatient clinic at Menufyia university Hospital presenting with chronic stable symptomatic heart failure (New York Heart Association (NYHA)functional class II or III), and a reduced left ventricular ejection fraction (< 45 %) on echocardiography. All patient received standard heart failure treatment (in the form of loop diuretics, β -blockers plus an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker with or without digoxin and spironolactone) in unchanged dosage for at least one month before the study. So, these patients are chosen according to inclusion and exclusion criteria.
Patients had been divided into two groups in the study for follow up: Group A patient (Control group): This was including 10 patients with dilated cardiomyopathy. All of them had symptomatic heart failure (New York Heart Association functional
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class II - III). All received standard antifailure treatment in unchanged dose for at least one month before the study and for 6 weeks during the study without any statin therapy. Group B patient (Statin group): This was including 10 patients with dilated cardiomyopathy. All of them had symptomatic heart failure (New York Heart Association functional class II - III). All received standard antifailure treatment in unchanged dose for at least one month before the study and during the study with atorvastatin therapy 40 mg/day orally for 6 weeks. The following parameters had been assessed (at baseline and at end of the study). A) Blood samples were collected in test tubes at baseline and after 6 weeks of treatment, with patients in the supine position for at least 30 minutes. The sera were separated from blood cells by centrifugation and frozen at −70°C until analyzed for: Blood serum lipid profile assessment in patients with heart failure, high sensitive C-reactive proteins assessment as strong predictive inflammatory biomarker in heart failure, serum troponin-T assessment as biomarker of heart failure in patients with CHF. B) Echocardiographic examination: had been done both basal and after 6 weeks in patients with heart failure; The results of the study showed that atorvastatin treatment in experimental part of study, was significantly reduced mortality rate, reduced gross morphological signs of heart failure as weakness, abdominal ascitic fluids, and improved appetite and body weight, significantly improved rat tail systolic blood pressure in atorvastatin-doxorubicin rat group when compard to other rat groups. Also, atorvastatin was significantly reduced serum levels of blood lipid profiles and also, was significantly reduced serum hs-CRP, serum cTnT, and heart tissues MDA in atorvastatin-doxorubicin rat group when compard to other rat groups. Moreover, atorvastatin was significantly improving and protecting heart tissues against doxorubicin-induced cardiotoxicity in atorvastatin-doxorubicin rat group when compard to other rat groups. While, in the present clinical part of study, it was found that atorvastatin was significantly reduced serum blood lipid profiles, and also, reducing serum markers of heart failure as hs-CRP, serum cTnT, and serum MDA in atorvastatin-treated patients of heart failure versus untreated control group of patients with heart failure. Moreover, atorvastatin was significantly improving echocardiographic parameters (as LV EDD, LV ESD, EF %, shorting fraction %, and E/A veloscity ratio) which were disturbed in patients of heart failure and was improved when they were treated with atorvastatin in comparison to untreated control patient group of heart failure.
The results of experimental and clinical parts of the study were in agreement with other experimental and clinical studies that concluded that, atorvastatin protected against development of doxorubicin-induced heart failure and reduced
Summary and Conclusion
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serum markers of heart failure as hs-CRP, cTnT, MDA and could be reduced mortality rate in treated rats versus control untreated rat groups and also, redued morbidity and mortality, and reducing serum markers of heart failure as serum hs-CRP, serum cTnT, serum MDA in patients with heart failure treated with atorvastatin. Thus, these results of experimental and clinical study were in agreement with results of recent and previous studies that showed that, statins as atorvastatin had a preventive and cardioprotective role against the development of heart failure. The results of the present study suggest that atorvastatin was beneficial in ameloriating doxorubicin-induced cardiotoxicity in rats and exerted therapeutic effects on patients with chronic heart failure, and these cardioprotective effects of atorvastatin could be attributed due to its potential cardioprotective pleiotropic actions (as anti-inflammatory effects , antioxidant effects via preservation of antioxidant glutathione, and antioxidant enzymes as well as scavenging of free radicals, endothelium dysfunction improvement, stimulation of new vessels formation); which are independent of its cholesterol-lowering activity. These potential cardioprotective pleiotropic actions atorvastatin is of good therapeutic value in management of heart failure. It can be concluded that, a further studies are needed to elucidate mechanisms of cardioprotective actions of statins in manegment of heart failure and their clinical application in mangment of heart failure of different etiologies; where this should pave the way for additional large-scale clinical trials to evaluate the long-term clinical benefits of statin therapy in patients with chronic heart failure of different etiologies.