The Effects Of Combination Therapy With Low Dose Of Perindopril And Irbesartan On Dilated Cardiomyopathy And The Related Mechanism

Chapter 1The effects of combination therapy with low dose of perindopril andirbesartan on cardiac function and prognosis in a rat modelof dilated cardiomyopathyBackground The main hazard of dilated cardiomyopathy (DCM)is chronic heart failure (CHF). It has been reported that combinationtherapy with ACEIs and ARBs would produce better therapeutic effectsto patients with CHF. It is not well known if half of the conventionaldosage of ACEIs for heart failure combined with half of the conventionaldosage of ARBs for heart failure would also bring better short-term andlong-term therapeutic effects to CHF induced by DCM. This studyconfirmed this hypothesis by combination therapy with perindopril andirbesartan in a rat model of DCM.Objective To evaluate the effects of combination therapy with lowdose of perindopril and irbesartan on cardiac function and prognosis in arat model of DCM.Methods For inducing DCM, adriamycin was administeredintraperitoneally in Sprague-Dawley rats. Then the rats were divided into4 groups. Normal group (n=14), which was administered distilled water.Rats with DCM were randomly divided into DCM-control group (n=26),perindopril group (n=24) and combination therapy (combination therapywith perindopril and irbesartan ) group (n=24). The DCM-control groupwas administered distilled water. The perindopril group was administeredperindopril 2mg.kg^-1.d^-1. The combination therapy group wasadministered perindopril 1mg.kg^-1.d^-1 and irbesartan 25mg.kg^-1.d^-1. All thedrugs were given orally by gastric gavage once a day. Plasma potassiumand creatinine were measured by automatic biochemistry analyzer; brainnatriuretic peptide (BNP) was assessed by ELISA; LVEF weredetermined by ultrasonic cardiogram. Each rat's survival time duringintervention was recorded. Results (1) Each group plasma concentrations of potassium andcreatinine showed no significant differences between pre-intervention andpost-intervention (P＞0.05). (2) Before intervention, plasmaconcentrations of BNP of each DCM group were higher than those of thenormal group (P＜0.05). In both perindopril group and combinationtherapy group, plasma concentrations of BNP were much lower afterintervention compared with those before intervention (P＜0.01).However, plasma concentrations of BNP decreased more in thecombination therapy group than in the perindopril group (P＜0.01). (3)Before intervention, LVEF of each DCM group was lower than that of thenormal group (P＜0.05). LVEF in both perindopril group andcombination therapy group was much higher after intervention comparedwith that before intervention (P＜0.01). However, LVEF increased morein the combination therapy group than in the perindopril group (P＜0.05). (4) Log rank test showed that the life span of perindopril groupwas longer than that of the DCM-control group (P＜0.05), but wasshorter than that of the combination therapy group (P＜0.05). Coxregression analysis showed that combination therapy or onlyadministering perindopril could prolong the survival time, butcombination therapy's contribution was bigger.Conclusions (1) Rats with DCM have elevated plasmaconcentrations of BNP and decreased LVEF. (2) Both monotherapy withperindopril and combination therapy with half of the conventional dosagefor CHF of perindopril and half of the conventional dosage for CHF ofirbesartan in a rat model of DCM can reduce the plasma concentrations ofBNP, increase LVEF and prolong survival time. (3) Combinationtherapy can more effectively improve left ventricular function andprognosis in rats with DCM than monotherapy with perindopril. Chapter 2The effects of combination therapy with perindopril and irbesartanon the expression of AT₁ receptor and lamin A and NF-κB in themyocardium of a rat model of dilated cardiomyopathyBackground Many clinical trials about combination therapy withACEIs and ARBs in CHF have been reported, but the related mechanismshave not been fully illuminated. The renin-angiotensin system (RAS) isactivated in patients with CHF; the mutation or deficiency of theexpression of lamin A/C may induce DCM; and the NF-kappa B(NF-κB)is over activated in the myocardium of patients with CHF. All thesefindings imply that the changes of expression of angiotensinâ…¡type 1receptors (AT₁Rs) and lamin A/C and NF-κB might participate in thepathogenesis of DCM. It is worth investigating if combination therapywith ACEIs and ARBs might more obviously affect these factors toachieve better therapeutic effects on CHF of DCM.Objective To evaluate the effects of combination therapy withperindopril and irbesartan on the mRNA expression of AT₁Rs and laminA and on the protein expression of NF-κB in the myocardium of the ratswith DCM.Methods The methods of inducing an animal model of DCM,grouping for drug treatment, and measuring LVEF and BNP have beenmentioned in the chapter one. The mRNA expression of AT₁Rs and laminA in the myocardium was detected by reverse transcription-polymerasechain reaction (RT-PCR); the pathological lesions of cardiac muscletissues after HE staining were evaluated by light microscope; and theprotein expression of NF-κB was assessed by immunohistochemistry.Results (1) Compared with those in the normal group, expressionlevels of AT₁Rs in the DCM-control group were down-regulated (P＜0.05). Compared with those in the DCM-control group, expression levelsof AT₁Rs in both perindopril group and combination therapy group wereup-regulated (P＜0.05). Expression levels of AT₁Rs were more obviously up-regulated in the combination therapy group than in theperindopril group (P＜0.01). (2) Compared with those in the normalgroup, expression levels of lamin A in the DCM-control group weredown-regulated (P＜0.05). Expression levels of lamin A in thecombination therapy group were higher than those in the DCM-controlgroup (P＜0.05). (3) Compared with those in the normal group,cardiac muscle tissues in the DCM-control group were obviouslydamaged. Compared with those in the DCM-control group, pathologicallesions of cardiac muscle tissues in both perindopril group andcombination therapy group were attenuated (P＜0.01). (4) Comparedwith that in the normal group, NF-κB in the DCM-control group wasmore obviously expressed (P＜0.05). Compared with that in theDCM-control group, obviously expressed NF-κB was attenuated in bothperindopril group and combination therapy group (P＜0.05). Obviouslyexpressed NF-κB was attenuated more in the combination therapy groupthan in the perindopril group (P＜0.05).Conclusions (1) Down-regulation of the expression of AT₁Rsand lamin A, and the over-expression of NF-κB might participate in thepathogenesis of DCM. (2) Both monotherapy with perindopril andcombination therapy with perindopril and irbesartan can attenuatepathological lesions of cardiac muscle tissues. (3) Both monotherapywith perindopril and combination therapy can up-regulate the expressionof AT₁Rs and attenuate the expression of NF-κB, and the combinationtherapy's effects are more obvious. Furthermore, combination therapy canup-regulate the expression of lamin A. The effects of combination therapyon the expression of AT₁Rs, lamin A and NF-κB may contribute to thebetter therapeutic effects on heart failure. Chapter 3The therapeutic effects of combination therapy with low dose ofperindopril and irbesartan in patientswith dilated cardiomyopathyBackground The prognosis of DCM is very poor, and in China,the 5-year survival rate is about 65.3ï¼…after the symptom occurs.Nowadays, therapeutic measures, such as heart transplantation, leftventricular reconstruction operation and cardiac resynchronizationtherapy are used in clinic, but these measures are too expensive to bewidely used. Since 1990s, there were clinical trials investigating ifcombination therapy with ACEIs and ARBs could produce better effectson patients with CHF. In 2005, combination therapy with ACEIs andARBs was suggested in the guideline of CHF. But until now, it is notclear what is the appropriate dose of combination therapy with ACEIs andARBs in treating patients with DCM.Objective To evaluate the effects of combination therapy with lowdose of perindopril and irbesartan on patients with DCM and the relatedadverse reactions.Methods 60 hospitalized patients or outpatients with DCM wereenrolled, and the patients were randomly divided into two groups,conventional therapy group (n=30) and combination therapy group (n=30). The age, sex, patient's condition, and course of disease showed nosignificant differences between the conventional therapy group and thecombination therapy group. The conventional therapy group wasadministered perindopril 4mg/d and the combination therapy group wasadministered perindopril 2mg/d and irbesartan 75mg/d. The othertherapeutic measures in these two groups were just the same. Plasmapotassium and creatinine were studied by automatic biochemistryanalyzer; brain natriuretic peptide (BNP) was assessed by ELISA; leftventricular ejection fraction (LVEF) were measured by ultrasoniccardiogram. Results (1) In both groups, cardiac function was improved afterdrug treatment (P＜0.05; P＜0.01); cardiac function was moremarkedly improved in the combination therapy group than in theconventional therapy group (P＜0.05). (2) In both groups, plasmaconcentrations of BNP were much lower after drug treatment (P＜0.01),however, plasma concentrations of BNP in the combination therapygroup was lower than those in the conventional therapy group (P＜0.05).(3) In both groups, LVEF was much higher after drug treatment (P＜0.01), but LVEF in the combination therapy group was higher than thatin the conventional therapy group (P＜0.05). (4) In each group, plasmaconcentrations of potassium and creatinine showed no significantdifferences between pre-intervention and post-intervention (P＞0.05).Conclusions (1) Both monotherapy with pedndopril andcombination therapy with half of the conventional dosage for CHF ofperindopril and half of the conventional dosage for CHF of irbesartan inpatients with DCM can improve cardiac function, reduce the plasmaconcentrations of BNP and increase LVEF. (2) Combination therapywith perindopril and irbesartan in patients with DCM can moreeffectively improve cardiac function, reduce the plasma concentrations ofBNP and increase LVEF than monotherapy with perindopril, withoutincreased adverse reactions.