Effect Of The Heart Rate Reduction Induced By β-blockers On Rat With Chronic Heart Failure

Chronic heart failure (Abbreviation: Heart failure) is generally regardedas the end-stage of a variety of cardiovascular diseases, with complex clinicalsymptom clusters. Heart rate was increased in heart failure patients, results inexcessive sympathetic nervous system activation. The rise of heart rate, whichplayed a compensatory role, improved the cardiac output in heart failurepatients. However, when heart rate increases to a certain limit, it may increasethe myocardial oxygen consumption, impaire ventricular filling and aggravatemyocardial ischemia, leading to further deteriorations of heart failure. Inrecent years, clinical studies have shown that, patients with heart failure andHR>70bpm have a significantly greater cardiovascular mortality and risk ofhospital admission than those with HR <70bpm. Every5bpm increase inheart rate in patients with heart failure results in an8%increase incardiovascular deaths and a16%increase in heart failure hospitalizations. It isimportant to control the heart rate. By blocking β1-adrenergic (β1-AR) receptor,β-blockers inhibit the overactive of the sympathetic nervous system, reduceheart rate, and improve the cardiac function. We studied cardiac function andβ1-adrenergic receptor mRNA levels in heart failure rat at differentmagnitudes of heart rate reduction, to explore the relationship between heartrate reduction induced by β-blockers and cardiac function.Objective：To investigate the relationship among heart rate reductioninduced by β-blocker and Cardiac function and β1-AR mRNA levels in heartfailure rats.Methods: Heart failure models were induced by surgical ligation of theleft coronary artery. Sham operation group had thoracotomy but no ligature ofthe artery. Echocardiographic evaluation was performed at4weeks aftersurgery in all of the rats. Ejection fraction less than40%was considered as the successful standard of heart failure models.39heart failure rats entered thestudy and were randomly assigned to control group (G0) or one of the threeβ-blocker treatment groups.Heart rate of The treatment groups rats werereduced to different magnitudes by β-blocker, including40±5bpm (G1),80±5bpm (G2) and120±5bpm (G3).β-blocker was given by intragastricadministration, while the rats of sham group and G0group receives vehicle inthe same way. All of the rats received6weeks of treatment. At the end of thestudy, echocardiography and cardiac catheterization laboratory wereconducted to evaluate the cardiac function. The β1-AR mRNA expressionlevels of myocardium were assessed by reverse reaction PCR (RT-PCR).Results:1EchocardiographyFour weeks after the operation, compared with the sham group,interventricular septum thickness at end-diastolic(IVSd),fractionalshortening(FS) and ejection fraction(EF) decreased in rats of the G0group.The differences were statistically significant (P<0.01). Left ventricularend-diastolic dimension (LVEDD) and left ventricular end-systolicdimension(LVESD) of the G0group were higher than the sham group, thedifferences were statistically significant (P<0.01). There was no significantdifference between the sham group and the G0group in left ventricularposterior wall thickness at end-diastolic (LVPWd)(P>0.05). No significantdifferences were found among the rats of G1, G2, G3and G0groups in allof these echocardiographic indexes (P>0.05).After6weeks of treatment, both FS and EF of G1and G2groups werehigher than G0group. The differences were statistically significant(P<0.05).Compare G3groups with G0group, there was no statisticaldifference, including FS and EF (P>0.05). There were no statisticaldifferences among the rats of G1, G2, G3and G0groups, including IVSd,LVPWd, LVEDD and LVESD (P>0.05).2Heart rate and blood pressure Compare with the sham group, the Heart rate (HR) of the rats in G0group increased, while systolic blood pressure(SBP) and diastolic bloodpressure(DBP) decreased, the differences were statisticallysignificant(P<0.05). Prior to drug treatment, there were no statisticaldifferences among the rats of G1, G2, G3and G0groups, including HR, SBPand DBP (P>0.05).After6weeks of β-blocker treatment, HR reductions of the rats in G1, G2and G3groups were38.75±8.88bpm,75.33±7.23bpm,102.33±11.33bpmrespectively, the differences were statistically significant(P<0.01). There wereno statistical differences among the rats of G1, G2, G3and G0groups,including SBP and DBP (P>0.05).3Hemodynamic indexesCompared with the sham group, left ventricular systolic pressure(LVSP)，maximum rising rate of left ventricular pressure (+dp/dtmax)and leftventricular pressure maximum falling rate (-dp/dtmax) significantly declinedin heart failure rats(P<0.05), while left ventricular diastolic pressure(LVDP)was elevated significantly(P<0.05). LVSP，+dp/dtmax and-dp/dtmax of theG1and G2groups were higher than G0group. The differences werestatistically significant(P <0.05).Compared with the sham group, LVSP and+dp/dtmax of the G1and G2groups decreased (P <0.05). But LVDP and-dp/dtmax were similar to the sham group (P>0.05). LVDP of the G3groupwas significantly lower than the G0group (P <0.05). Compared the G3groupwith the G0group, there was no statistical difference, including LVSP,+dp/dtmax and-dp/dtmax. When compared with the sham group, LVDP of theG3group was higher, while+dp/dtmax and-dp/dtmax was lower, thedifferences were statistically significant (P <0.05).4Myocardium β1-AR mRNA expression levelsMyocardium β1-AR mRNA expression levels of the rats in G0groupwere significantly lower than the sham group (P<0.01). In G1, G2and G3groups, myocardium β1-AR mRNA expression levels were higher than the G0group (P<0.01), but the expression levels were still lower when compare with the sham group(P <0.05). Myocardium β1-AR mRNA expression levels of theG3group were higher than G1and G2groups (P <0.05).There was nostatistical difference between G1and G2groups (P <0.05).Linear correlation analysis was performed to assess the relationshipbetween heart rate reduction and β1-AR mRNA expression levels. The scatterplot suggested a linear trend of the two indexes. The correlation coefficient ofthe linear correlation was0.904(P<0.01).Conclusions:Heart rate reduction was positively correlated with β1-AR mRNAexpression levels. When heart rate reduced40±5bpm and80±5bpm, thefunction of left ventricular was improved. However, when the heart ratedecreased120±5bpm, cardiac function was not further improved.