Analysis of influencing factors of heart rate deceleration capacity in patients with dilated cardiomyopathy / 中华心血管病杂志

Objective@#To investigate the determinants affecting the heart rate deceleration capacity (DC) in patients with dilated cardiomyopathy (DCM).@*Methods@#One hundred patients with DCM (DCM group) and 202 healthy subjects (control group) were respectively enrolled. Echocardiography and 24 hours electrocardiogram were performed in all subjects. DC value was compared between the two groups. Multiple regression analysis was made to evaluate the related determinants of DC ((age, sex, echocardiographic parameters including the left atrial diameter (LAD) and left ventricular ejection fraction (LVEF)).@*Results@#(1) DC value was significantly lower in DCM group than in control group( (4.40±2.03) ms vs. (7.30±1.81) ms, P<0.01), prevalence of DC value≤4.5 ms was significantly higher in DCM group than in control group (62% vs. 6%, P<0.01). (2) DC value in the DCM group decreased in proportion to increasing LAD dimension, DC value was (5.60±2.04) ms, (4.50±2.07) ms and (3.60±1.62) ms (P<0.05) in DCM patients with LAD≤40 mm, 40 mm<LAD≤50 mm and LAD>50 mm, respectively. (3) DC value in the DCM group was negatively related to the LAD (r=-0.366, P<0.01), positively related to the LVEF (r= 0.241, P<0.01), but not related with age and sex. Multiple factors regression analysis showed that increased LAD was related to the reduced DC values independtly.@*Conclusion@#DC value of the patients in the DCM group is decreased, which indicate the decrease of the vagus nerve tension, and increased LAD is related to the reduced DC value independtly in DCM patients.

Effect of metoprolol on sarcoplasmic reticulum Ca2+ leak in a rabbit model of heart failure / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Studies have shown that β-blockers can improve cardiac performance in heart failure (HF) by reversing protein kinase A (PKA)-mediated sarcoplasmic reticulum (SR) Ca2+ leak. However, it is being strongly questioned as to whether the PKA-mediated ryanodine receptor (RyR2) hyper-phosphorylation is a critical regulator of SR Ca2+ leak. In this study, we used a rabbit HF model to investigate whether β-blockers affect SR Ca2+ leak by other potential mechanisms.</p><p><b>METHODS</b>New Zealand white rabbits were randomly divided in three groups (n=7 in each group): normal group, metoprolol-untreated group and metoprolol-treated group. Cardiac function was determined by echocardiography and hemodynamic assays. The SR Ca2+ leak was measured by a calcium-imaging device, and the expression and activities of related proteins were evaluated by Western blotting and auto-phosphorylation.</p><p><b>RESULTS</b>In the metoprolol-untreated group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca2+ leak, reduced associated amount of FK506 binding protein 12.6 (FKBP12.6), increased expression and activity of PKA and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and increased phosphorylated RyR2 phosphorylation sites (with unchanged RyR2-P2030). In the treated group, there was partly increased ventricular cavity size with preserved systolic function, but no prominent Ca2+ leak, with unchanged expression and activity of PKA, CaMKII and their RyR2 phosphorylation sites.</p><p><b>CONCLUSION</b>Chronic administration of metoprolol prevented the SR Ca2+ leak by restoring not only PKA-dependent but also CaMKII-dependent hyper-phosphorylation of RyR2, which may be one of the potential mechanisms by which β-blockers improve cardiac function and reduce the incidence of fatal arrhythmia in HF.</p>

Effects of different cumulative percent of right ventricular apical pacing on cardiac function / 中国综合临床

Objective To evaluate the effect of permanent right ventricular apical (RVA) pacing in different cumulative percent of right ventricular pacing( CUM% VP) on the heart function and cardiac ventricle structure in subjects with normal basic heart function. Methods Patients who had implanted pacemaker when heart function was still normal were recruited in the study while they revisited for replacement or examinations of implanted pacemaker at outpatient. According to different CUM% VP, patients were divided into group A ( CUM% VP≥85% ,n =78) and group B( CUM% VP≤40% ,n =63) . The primary composite endpoint was defined as new-onset heart failure, death, left ventricular ( LV ) dysfunction and remodeling. The occurrence of endpoints were compared between the two groups. The left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF) and interventricular septum(IVS) were measured through baseline and follow-up, their absolute alterations ( △ LVEF, △ LVEDD and △ IVS ) were observed. Results The mean duration of two assessment was 7.4 years in group A and 7.7 years in group B, respectively. Before pacemaker implantation,there were no differences in age, sex, basic diseases, cardiac function and constituent ratio of pacemakers between the two groups. By comparing the outcomes of group A with those of group B at the end of follow up, we found that: △ LVEDD in group A was significantly larger than that in group B ( [3. 8 ± 0. 5] mm vs [1.4 ± 0. 4] mm,t = 4. 540,P ＜ 0. 01 ), △ LVEF was ( - 6.5 ± 1.2) % and ( - 3.3 ± 1.0) % in group A and B, respectively,with significant difference between the two groups(t = 2. 578 ,P ＜0. 01 ). There were no significant difference in AIVS between the two groups. No death occurred in both group at the end of follow up. The incidence of LV dysfunction and remodeling was 25.6% (20/78) in group A,which was significantly higher than that of 6.3% (4/63) in group B( x2 =9. 183 ,P =0. 002). and the incidence of new-onset heart failure was 10. 3% (8/78)in group A,which was significantly higher than that of 1.6% (1/63) in group B (x2 =4.383,P =0.036).Conclusion Among patients with normal basic LV function who underwent permanent RVA pacing,there are potential risk in developing LV remodel, function damage and heart failure. The risk increases with the pacing time getting longer and CUM% VP getting higher.

Simvastatin prevents hypertrophy and keeps cardiac function in myocardium of rabbit with overlord by promoting PPAR gamma and inhibiting NF-kappa B / 中国药理学通报

Aim To observe the effects of simvastatin on PPARγ and p65 subunit of NF-κB and to invest the mechanism of simvastatin preventing hypertrophy and keeping cardiac function.Methods 24 rabbits were divided into 4 groups.Rabbits received sham operation as health control in group I. In other groups, aortic regurgitation and coarctation of ascending aorta were operated in rabbits.Rabbits received no drugs in Group Ⅱ. In group Ⅲ, rabbits were given simvastatin 5 mg·kg~(-1)·d~(-1) after the operation for 8 weeks. In group Ⅳ, rabbits were given simvastatin 5 mg·kg~(-1)·d~(-1) after 4 weeks of operation for 4 weeks. At the beginning and the end of the experiment, left ventricular end diastolic pressure (LVEDP) was measured with catheter. At the end of the experiment, heart weight (HW), left ventricular weight (LVW), body weight (BW), heart weight/body weight radio (HW/BW radio), left ventricular weight/body weight radio (LVW/BW radio) were measured.The PPARγ mRNA expression was analyzed by RT-PCR. PPARγ and p65 protein expression in cardiomyocyte nuclear were analyzed through Western blot. The activity of p65 was analyzed with EMSA.Results The HW, LVW, HW/BW were significantly decreased in the early and late treatment group than in CHF group(P<0.05,P<0.01). The LVW/BW was significantly decreased inearly treatment group than in CHF group, too (P<0.01). The LVEDP was significantly decreased in the early and late treatment group than in CHF group (P<0.01). The mRNA and protein of PPARγ significantly fell in CHF heart (P<0.01). The activity and protein expression of p65 were significantly increased in CHF heart (P<0.01). Simvastatin increased the mRNA and protein expression of PPARγ and decreased the activity and protein expression of p65 (P<0.01).Conclusions Simvastatin inhibits the cardiac hypertrophy and improves cardiac function. The mechanism of simvastatin on cardiac remodeling and function relates to the increase of PPARγ expression and preventing the NF-κB activation.

Effects of valsartan on myocardial calcium/calmodulin-dependent protein kinase-II expression and activity in a rabbit model of heart failure / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effects of valsartan on myocardial expression and activity of calcium/calmodulin-dependent protein kinase-II (CaMK II) in a rabbit model of heart failure.</p><p><b>METHODS</b>Rabbits were divided into sham-operated group, heart failure group (volume overload by aortic valve destruction induced aortic insufficiency plus pressure overload induced by abdominal aortic banding) and heart failure plus valsartan (20 mg x kg(-1) x d(-1), n = 9 each). Seven weeks later, echocardiography and hemodynamic examinations were performed and myocardial CaMK II expression and activity were detected by Western blot and CaMK II activity assay kit, respectively.</p><p><b>RESULTS</b>Compared with the sham operated rabbits, left ventricular mass index [LVMI (3.61 +/- 0.09) g/kg vs. (1.32 +/- 0.06) g/kg, P<0.05] and end-diastolic pressure [LVEDP (23.00 +/- 2.37) mm Hg (1 mm Hg = 0.133 kPa) vs. (-1.50 +/- 0.5) mm Hg, P<0.05] were significantly increased while left ventricular shortening fractions [LVFS (17.38 +/- 3.13)% vs. (37.83 +/- 3.58)%, P<0.05] and ejection fraction [LVEF (38.50 +/- 6.07)% vs. (71.92 +/- 4. 56)%, P<0.05] were significantly decreased (all P<0.05) in heart failure rabbits, these changes could be significantly attenuated by valsartan treatment: LVMI [(2.07 +/- 0.14) g/kg vs. (3.61 +/- 0.09) g/kg, P<0.05], LVEDP [(2.17 +/- 0.72) mm Hg vs. (23.00 +/- 2.37) mm Hg, P<0.05], LVFS [(33.83 +/- 2.85)% vs. (17.38 +/- 3.13)%, P<0.05] and LVEF [(64.45 +/- 3.66)% vs. (38.50 +/- 6.07)%, P<0.05]. CaMK II expression (1.45 +/- 0.13 vs 0.89 +/- 0.05, 1.13 +/- 0.12, P<0.05) and activity [(3.54 +/- 0.17) pmol x min(-1) x microg(-1) vs. (2.18 +/- 0.13) pmol x min(-1) x microg(-1), (2.79 +/- 0.14) pmol x min(-1) x microg(-1), P<0.05] in heart failure rabbits were significantly increased than those sham operated rabbits which could be significantly attenuated by valsartan treatment.</p><p><b>CONCLUSION</b>Valsartan improved cardiac function in heart failure rabbits probably via downregulating myocardial CaMK II expression and activity.</p>

Comparison of cardiac function and expression and activity of myocardial calcium regulatory proteins in rabbit systolic and diastolic heart failure models / 生理学报

The aim of the present study is to investigate the differences in cardiac function, and the expression and activity of calcium regulatory proteins between rabbit systolic heart failure (SHF) and diastolic heart failure (DHF) models. New Zealand white rabbits were randomly divided into three groups: sham operation (SO) group, DHF group (receiving abdominal aortic constriction) and SHF group (receiving aortic valve destruction and abdominal aortic constriction). The cardiac function was detected by echocardiographic and hemodynamic assays. The mRNA expression levels of sarcoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a) and phospholamban (PLB) were evaluated by RT-PCR. The protein expression levels of SERCA2a, PLB, phosphoserine 16-PLB (pSer-16-PLB) and protein kinase A (PKA) were evaluated by Western blot, and the phosphorylation status of PLB was determined by the ratio of pSer-16-PLB protein level to that of PLB. The activity of SERCA2a was measured through inorganic phosphate. The activity of PKA was measured by gamma-(32)P ATP-binding assays. Compared with SO group, there were significantly increased ventricular wall thickness, raised left ventricular end diastolic pressure (LVEDP), reduced diastolic function in DHF group (P<0.05 or P<0.01), and significantly increased ventricular cavity size and LVEDP, reduced systolic function in SHF group (P<0.05 or P<0.01). The expression levels of SERCA2a in DHF and SHF groups were lower than that in SO group (P<0.05), while the expression and activity of PKA in DHF and SHF groups were higher than that in SO group (P<0.05 or P<0.01), and there was no significant difference between DHF and SHF groups. The expression levels of PLB and pSer-16-PLB as well as the phosphorylation status of PLB and activity of SERCA2a in SHF group were lower than those in DHF and SO groups respectively. Posing a contrast, the phosphorylation status of PLB and activity of SERCA2a in DHF group were higher than that in SO group (P<0.05). These results indicate that the SHF and DHF models were successfully established, and there are some differences in the expression and activity of calcium regulatory proteins between two models.

Valsartan prevents the development of rabbit's heart failure by restoring calcium uptake of sarcoplasmic reticulum / 老年心脏病学杂志（英文版）

Objective Clinical evidence has suggested that ATI receptor blocker (ARB) could prevent the development of heart failure. Decreased sareoplasmic reticulum(SR) Ca2+ content, which is due to reduced SR calcium reuptake by SERCA2a, is responsible for defective systolic function in failing heart. To better understand how ARB could improve cardiac systolic dysfunction, we studied the effects of Valsartan on calcium reuptake of SR and its regulatory proteins in heart failure rabbits. Methods Thirty rabbits were divided into three groups: sham rabbits(controls, n= 11), rabbits with heart failure treated with Valsartan (n= 11) and rabbits with heart failure but without Valsartan treatment (n=8).Rabbit heart failure model was established by volume plus pressure overload. Cardiac function was measured by echocardiography. SR calcium uptake was determined by measuring extra vesicular free [Ca2+] changes in a fluores-cence spectrophotometer. SERCA2a, Serl 6-phosphorylated phospholamban (p-PLB), PKA and PP1a protein abundance were deter-mined by use of Western blot analysis. Results Compared to control rabbits, the ejection fractions in the HF rabbits were significantly decreased (P<0.05), these changes could be significantly attenuated by Valsanan treatment (P<0.05).Calcium reuptake of SR, activity of SERCA2a and PKA decreased in heart failing myocytes (P<0.05), with down regulations of p-PLB, SERCA2a and PKA, but up regulation ofPP1αin ventricular samples from the failing rabbits (P<0.05). All of these changes were attenuated by Valsartan treatment (all P<0.05). Conclusion Valsartan improved cardiac function in volume plus pressure overload induced heart failure of rabbits possibly by restoring the SR calcium uptake resulted from attenuating the activities and expressions of SERCA2a and its regulatory proteins.

Comparison of interfitial remodeling in different rabbit models with diastolic heart failure and systolic heart failure / 基础医学与临床

Objective To compare the differences of cardiac function and interstitial remodeling between diastolic heart failure(DHF) and systolic heart failure(SHF) rabbit models. Methods To establish DHF model with abdo-mial aorta constriction and SHF model with abdomial aorta constriction plus aortic insufficiency. The cardiac func-tion was examined by UCG parameters and homodynamic parameters. The collagen content was measured through hydroxyproline colorimetric assay and shown as collagen area(CA), collagen volume fraction(CVF) and area ratio of Ⅰ to Ⅲ type collagen with PSR. Results Compared with control group, there were significantly increased thick-ness and stiffness of myocardium, impaired diastolic function but normal ejection fraction (EF), and significantly increased collagen content, CA, CVF and area ratio of Ⅰ to Ⅲ type collagen in DHF group; heart chamber was sig-nificantly enlarged, systolic function decreased, and collagen content, CA, CVF significantly increased, but ratio of Ⅰ to Ⅲ type collagen decreased in SHF group(P <0.05 or P <0.01). Conclusion DHF and SHF rabbit mod-els were established successfully, which can simulate clinical profiles and provide technical support to future re-search.

Effects of metoprolol on cardiac function and myocyte calcium regulatory protein expressions in rabbits with experimental heart failure / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effects of metoprolol on cardiac function and myocyte calcium regulatory protein expressions in rabbits with heart failure.</p><p><b>METHODS</b>Rabbit heart failure model was established by aortic insufficiency induced volume overload followed 14 days later by pressure overload induced by abdominal aorta constricting (HF, n = 11), another 8 rabbits with heart failure were treated with metoprolol (ME) for 6 weeks, sham-operated rabbits (n = 11) served as control. Cardiac function was measured by echocardiography at the end of study. Caffeine-induced calcium transients of myocytes loaded by Fluo-3/AM were observed under Laser scanning confocal microscope. Calcium regulatory protein expression was determined by Western blot analysis.</p><p><b>RESULTS</b>Compared to control animals, the ejection fractions [EF, (45.7 +/- 3.0)% vs. (72. 6 +/- 5.0)%, P < 0.01] and the amplitude of caffeine-induced calcium transients [(16.0 +/- 3.5) FI vs. (43.5 +/- 6.2) FI, P < 0.01] were significantly decreased while its time to peak was significantly prolonged [(129.8 +/- 14.5) s vs. (52.2 +/- 7.4) s, P < 0.01] in HF rabbits. The RyR2 (0.106 +/- 0.007 vs. 0.203 +/- 0.021, P < 0.01) and the ratio of SERCA2a and NCX (1.22 +/- 0.23 vs. 1.96 +/- 0.12, P < 0.01) were also significantly reduced in myocytes of HF rabbits. Metoprolol significantly attenuated the decrease of EF [(60.2 +/- 5.1)%], the amplitude of calcium transient [(32.8 +/- 5.4) FI], the RyR2 expression (0.164 +/- 0.016) and the ratio of SERCA2a and NCX (1.68 +/- 0.17, all P < 0.05 vs. HF rabbits) and attenuated the increase of the time to peak of caffeine-induced calcium transients [(91.4 +/- 10.9) s, P < 0.05 vs. HF rabbits].</p><p><b>CONCLUSION</b>Metoprolol could improve the cardiac function possibly by preventing the alterations of calcium regulatory proteins and increasing calcium transients in failing heart.</p>

Abnormal abundances of calcium cycling regulatory proteins in rabbit myocytes with heart failure / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the abnormal abundances of calcium regulatory proteins in rabbit myocytes with failing hearts.</p><p><b>METHODS</b>Sixteen rabbits were divided into two groups: 8 rabbits with heart failure induced by volume plus pressure overload and 8 sham-operated animals. The hemodynamic parameters and cardiac structure and function were detected via catheterization and echocardiography respectively. L-type calcium channel (LTCC), Ryanodine receptor 2 (RyR2), Sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a), and Na(+)-Ca(2+) exchanger (NCX) protein abundances were determined by Western blot analysis.</p><p><b>RESULTS</b>The ratio of left ventricular mass to body weight, heart rate and left ventricular end diastolic pressure in heart failure rabbits were significantly increased compared with sham-operated rabbits (P < 0.01), but their left ventricular shorten fraction [(21.3 +/- 4.00)% vs. (36.5 +/- 1.36)%] and ejection fraction (0.45 +/- 0.07 vs. 0.70 +/- 0.02) were decreased (P < 0.01). In heart failure rabbits, the abundances of LTCC and RyR2 were significantly decreased (R(LTCC/actin): 0.287 +/- 0.029 vs. 0.624 +/- 0.009; R(RyR2/actin): 0.106 +/- 0.001 vs. 0.203 +/- 0.011; P < 0.01), whereas the expressions of SERCA2a and NCX were markedly increased (R(NCX/actin): 0.497 +/- 0.015 vs. 0.221 +/- 0.014; R(SERCA2a/actin): 0.611 +/- 0.036 vs. 0.433 +/- 0.008; P < 0.01).</p><p><b>CONCLUSIONS</b>Reductions of LTCC and RyR2 might contribute to risk factors of systolic dysfunction in failing hearts. In early stage of heart failure, upregulated SERCA2a and NCX protein levels may be helpful for maintaining cardiac performance.</p>