Phosphorylation of GATA4 at serine 105 is required for left ventricular remodelling process in angiotensin II‐induced hypertension in rats

In this study, we investigated whether local intramyocardial GATA4 overexpression affects the left ventricular (LV) remodelling process and the importance of phosphorylation at serine 105 (S105) for the actions of GATA4 in an angiotensin II (AngII)‐induced hypertension rat model. Adenoviral constructs overexpressing wild‐type GATA4 or GATA4 mutated at S105 were delivered into the anterior LV free wall. AngII (33.3 µg/kg/h) was administered via subcutaneously implanted minipumps. Cardiac function and structure were examined by echocardiography, followed by histological immunostainings of LV sections and gene expression measurements by RT‐qPCR. The effects of GATA4 on cultured neonatal rat ventricular fibroblasts were evaluated. In AngII‐induced hypertension, GATA4 overexpression repressed fibrotic gene expression, reversed the hypertrophic adult‐to‐foetal isoform switch of myofibrillar genes and prevented apoptosis, whereas histological fibrosis was not affected. Overexpression of GATA4 mutated at S105 resulted in LV chamber dilatation, cardiac dysfunction and had minor effects on expression of myocardial remodelling genes. Fibrotic gene expression in cardiac fibroblasts was differently affected by overexpression of wild‐type or mutated GATA4. Our results indicate that GATA4 reduces AngII‐induced responses by interfering with pro‐fibrotic and hypertrophic gene expressions. GATA4 actions on LV remodelling and fibroblasts are dependent on phosphorylation site S105.     

Inhibition of left ventricular remodelling in spontaneously hypertensive rats by G alpha q-protein carboxyl terminus imitation polypeptide GCIP-27 is not entirely dependent on blood pressure

The G(q)-protein is located at the convergent point in the signal transduction pathway that leads to ventricular remodelling. In G-protein signalling pathways, the carboxyl terminus of the G(alpha)-subunit plays a vital role in G-protein-receptor interaction. The aim of the present study was to explore the effects of a synthetic G(alphaq) carboxyl terminus imitation peptide, namely GCIP-27, on left ventricular (LV) remodelling and blood pressure in spontaneous hypertensive rats (SHR). In the present study, 10, 30 or 90 microg/kg, i.p., GCIP-27 was administered for 8 weeks to SHR. In addition, another two groups of SHR were treated with either 6 mg/kg losartan or vehicle (saline). Wistar-Kyoto rats were used as controls. Systolic blood pressure (SBP) was measured using the standard tail-cuff method once every 2 weeks. At the end of the experiment, the LV mass index (LVMI) was evaluated. In addition, LV structure and function, collagen content, microstructure and ultrastructure were examined using echocardiography, the hydroxyproline assay, routine light microscopy and transmission electron microscopy, respectively. In the losartan- and GCIP-27 (10, 30 and 90 microg/kg)-treated groups, SBP was decreased significantly compared with that of the vehicle (saline) group. However, even at the highest concentration used, the hypotensive effect of GCIP-27 was weaker than that of losartan. For example, after 8 weeks treatment, SBP had decreased by 30.4% in the losartan-treated group compared with decreases of 10.5, 13.1 and 18.5% in the 10, 30 and 90 microg/kg GCIP-27-treated groups, respectively. Both GCIP-27 (10, 30 and 90 microg/kg) and losartan (6 mg/kg) significantly reduced LV posterior wall thickness, the thickness of the interventricular septum, collagen content and LVMI, with the effects of GCIP-27 at all three concentrations tested being greater than those of losartan. In conclusion, GCIP-27 effectively attenuates LV remodelling in SHR and the antiremodelling effect may not be dependent entirely on decreases in blood pressure.     

Enhanced external counterpulsation reduces indices of central blood pressure and myocardial oxygen demand in patients with left ventricular dysfunction

Enhanced external counterpulsation (EECP) therapy decreases angina episodes and improves quality of life in patients with left ventricular (LV) dysfunction. However, the underlying mechanisms relative to the benefits of EECP therapy in patients with LV dysfunction have not been fully elucidated. The purpose of this study was to investigate the effects of EECP on indices of central haemodynamics, aortic pressure wave reflection characteristics, and estimates of LV load and myocardial oxygen demand in patients with LV dysfunction. Patients with chronic stable angina and LV ejection fraction < 40% but > 30%, were randomized to either an EECP group (LV ejection fraction = 35.1 ± 4.6%; n = 10) or sham‐EECP group (LV ejection fraction = 34.3 ± 4.2%; n = 7). Pulse wave analysis of the central aortic pressure waveform and LV function were evaluated by applanation tonometry before and after 35 1‐h sessions of EECP or sham‐EECP. Enhanced external counterpulsation therapy was effective in reducing indices of LV wasted energy and myocardial oxygen demand by 25% and 19%, respectively. In addition, indices of coronary perfusion pressure and subendocardial perfusion were increased by 9% and 30%, respectively, after EECP. Our data indicate that EECP may be useful as adjuvant therapy for improving functional classification in heart failure patients through reductions in central blood pressure, aortic pulse pressure, wasted LV energy, and myocardial oxygen demand, which also suggests improvements in ventricular–vascular interactions.     

Direct effects of esmolol and landiolol on cardiac function, coronary vasoactivity, and ventricular electrophysiology in guinea-pig hearts

The ultra-short acting, selective β(1)-adrenergic antagonists landiolol and esmolol are widely used perioperatively; however, little is known about their acute direct actions on the heart. The current study utilized the Langendorff perfused heart system to measure changes in cardiac function and hemodynamics in response to each drug. Furthermore, electrophysiological analysis was performed on isolated ventricular myocytes. Direct application of esmolol significantly decreased systolic left ventricular pressure and heart rate at concentrations > 10 μM, while it dose-dependently increased coronary perfusion pressure. Esmolol also shortened the action potential duration (APD) in a concentration-dependent manner, an action maintained even when the delayed rectifier K(+) current or ATP sensitive K(+) current was blocked. Moreover, esmolol inhibited both the inward rectifier K(+) current (I(K1)) and the L-type Ca(2+) current (I(CaL)) and increased the outward current dose-dependently. In contrast, landiolol had minimal cardiac effects. In the Kyoto Model computer simulation, inhibition of either I(K1) or I(CaL) alone failed to shorten the APD; however, an additional increase in the time-independent outward current caused shortening of the APD, equal to that induced by esmolol. In conclusion, esmolol directly inhibits cardiac performance significantly more so than landiolol, an effect revealed to be at least in part mediated by esmolol-induced APD shortening.     

贝那普利对高血压病和冠心病左室舒张功能不全的影响

目的 :了解贝那普利对高血压病和冠心病左室舒张功能的影响。方法 :81例左室舒张功能不全病人 (高血压 4 5例 ,冠心病 36例 ;男性 56例 ,女性 2 5例 )应用贝那普利 10～ 2 0mg(冠心病在口服硝酸酯类药基础上加服贝那普利 5mg) ,po ,qd× 5mo ;用药前后用彩色多普勒超声心动图测定舒张早期最大峰值速度 (E峰 )、舒张晚期最大峰值速度 (A峰 )、E/A峰值速度比值及最快充盈率 (PFR)。结果 :治疗后比治疗前E峰、E/A比值、PFR均升高 ,而A峰降低 ,差别均有非常显著意义 (P <0 .0 1)。结论 :高血压病和冠心病病人服用贝那普利 5mo左右 ,对左室舒张功能不全有明显改善作用。     

中性粒细胞与淋巴细胞比值同非ST段抬高型急性冠状动脉综合征病人左室收缩功能不全的关系探讨

目的 探讨中性粒细胞与淋巴细胞比值(NLR)同非ST段抬高型急性冠状动脉综合征(NSTE-ACS)病人左室收缩功能不全(LVSD)的关系.方法 200例NSTE-ACS病人纳入该项研究,根据入院时的NLR值分为低水平、中水平、高水平三组,分析NLR水平与NSTE-ACS病人LVSD的关系.结果 高水平NLR组病人年龄较大(P=0.003)、糖尿病及非ST段抬高型心肌梗死(NSTEMI)病人较多(P=0.015,P=0.011)、左室射血分数(LVEF)较低(P<0.001),白细胞数、中性粒细胞数及NLR偏高(P=0.005,P<0.001,P<0.001),淋巴细胞数偏低(P<0.001),差异有统计学意义.在Pearson线性相关分析中,NLR与NSTE-ACS病人LVEF呈负相关.受试者工作特征曲线(ROC曲线)结果显示NLR对NSTE-ACS病人LVSD有诊断价值.在单因素及多因素Logistic回归分析中,NLR≥2.73是校正其他危险因素后NSTE-ACS病人LVSD的独立预测因子.结论 NLR是NSTE-ACS病人左室收缩功能不全的独立预测因子.     

伊贝沙坦对老年原发性高血压患者降血压、逆转左心室重构的随机、对照临床观察

目的探讨伊贝沙坦对老年原发性高血压患者逆转左心室重构的保护作用。方法将52例经过洗脱期的老年原发性高血压患者随机分为伊贝沙坦组和安慰剂组,治疗8周。用药前、治疗中、用药后分别行偶测血压、动态血压、超声心动图测定,观察并比较治疗前后、两组偶测血压、动态血压、左房内径(LA)、左室舒张末期内径(LVDd)、舒张期室间隔厚度(IVSd)、左室后壁厚度(LVPW d)、E/A比值和左室重指数(LVM I)水平的变化。结果(1)偶测血压:治疗组SBP由(152±13)mmHg下降至(130±10)mmHg(P<0.05),DBP由(96±8)mmHg下降至(78±6)mmHg(P<0.01);对照组SBP由(148±13)mmHg下降至(145±10)mmHg(P>0.05),DBP由(97±8)mmHg上升至(98±6)mmHg。两组降压幅度相比较,P<0.01;(2)治疗组动态血压检测:患者24 h平均收缩压和24 h平均舒张压均降低(P<0.05),不仅白昼dSBP、dDBP,而且夜间nSBP、nDBP也明显降低(P<0.05);(3)超声心动图检测:治疗组IVSd、LVPW d、LVM I显著下降(P<0.05),E/A比值显著提高(P<0.05);对照组患者各项指标无统计学差异(P>0.05),两组相比较,IVSd、LVPW d、LVM I差异有显著性(P<0.05),LA差异有极显著性(P<0.01)。结论伊贝沙坦对老年原发性高血压患者在有效降压的同时,可逆转左心室重构,且不良作用小。     

Drug-induced changes in blood flow in the acutely ischaemic canine myocardium; relationship to subendocardial driving pressure

SUMMARY 1. The effects of various drugs have been studied on blood flow and oxygen handling (availability, extraction and consumption) in both normal and acutely ischaemic regions of the canine myocardium. Ischaemia was produced by the acute ligation of the anterior descending branch of the left coronary artery.
2. Lidoflazine, like other coronary vasodilator drugs, increases blood flow in the normal myocardium, but does not increase flow through the ischaemic region. Drugs of this type may, in addition, open up 'shunt' vessels within the ischaemic region.
3. Of three cardiac stimulants studied, only oxyfedrine consistently increases blood flow through the ischaemic region; isoprenaline and glucagon do not.
4. Noradrenaline causes marked increases in flow through the ischaemic region: its effect is associated with an increase in coronary pressure in the artery distal to the ligature.
5. Evidence is put forward that the critical factor determining flow through ischaemic regions of the myocardium is the transventricular driving pressure. When the effects of various drugs on flow and driving pressure are analysed and compared, the only drugs that increase flow in an ischaemic region are those that increase the pressure gradient across the wall of the left ventricle.     

生脉散注射液与黄芪注射液对冠心病伴左心功能不全的疗效比较

目的：观察生脉散注射液与黄芪注射液对冠心病伴左心功能不全（ＬＶＤ）的疗效比较。方法：冠心病伴ＬＶＤ５１例。生脉散组３２例，给生脉散注射液８支（１０ｍＬ／支）加入１０％葡萄糖注射液５００ｍＬ静脉滴注（静滴），ｑｄ；黄芪对照组１９例，应用黄芪注射液６支（２ｍＬ／支）加入１０％葡萄糖注射液５００ｍＬ静滴，ｑｄ，２组均用药１４ｄ。结果：生脉散不仅能改善左室收缩功能（ＳＶ，ＣＯ，ＣＩ，ＦＳ，ＥＦ）（Ｐ＜０．０１），对舒张功能也有显著的疗效（ＰＥ，ＥＳ，ＰＥ／ＰＡ）（Ｐ＜０．０１）。临床无明显不良反应。而黄芪注射液仅对左心收缩功能（ＣＯ，ＣＩ，ＦＳ，ＥＦ）有改善（Ｐ＜０．０１或Ｐ＜０．０５）。结论：生脉散注射液治疗冠心病伴ＬＶＤ疗效优于黄芪注射液。     

Hypocarnitinaemia induced by sodium pivalate in the rat is associated with left ventricular dysfunction and impaired energy metabolism

Carnitine is a naturally occurring compound that is essential in energy metabolism of the mammalian heart. In addition to its essential role in facilitating beta-oxidation, carnitine eliminates excess toxic acyl residues and regulates the mitochondrial acetyl coenzyme A (CoA)/CoA ratio. Thus, it is not surprising that patients with carnitine deficiency syndromes exhibit defects in energy metabolism and in some cases demonstrate left ventricular dysfunction. Pivalic acid is commonly used to create prodrugs, such as pivampicillin and pivmecillinam, to facilitate enteral absorption and increase oral bioavailability. Pivalic acid released from the drug following absorption readily forms an ester with carnitine, which is then excreted as pivaloylcarnitine. Sustained loss of carnitine in the form of this ester induces a state of carnitine deficiency, exemplified by low plasma and tissue carnitine content. This review examines the effects in the rat of short- and long-term sodium pivalate treatment on: (1) cardiac carnitine content; (2) in vitro mechanical function; (3) markers of glycolytic and fatty acid metabolism; and (4) energy substrate metabolism. Treatment with sodium pivalate induces a gradual loss of cardiac carnitine content for up to 12 weeks. Doubling the duration of treatment is not associated with any further decrease in cardiac carnitine content. While heart function following short-term treatment (2 weeks) is normal under aerobic conditions, impaired recovery of function following ischaemia is seen. In contrast, long-term treatment (11-28 weeks) is associated with impaired heart function, which is dependent on workload and substrate availability. Impaired heart function is also associated with reductions in activity of 3-hydroxyacyl CoA dehydrogenase and rates of fatty acid oxidation. However, to maintain adenosine triphosphate production, glucose metabolism, expressed as hexokinase activity and glucose oxidation, is increased in carnitine-deficient hearts. Hearts from sodium pivalate-treated animals demonstrate a cardiomyopathy that is dependent on duration of treatment, workload and substrate supply. This model of hypocarnitinaemia may thus be useful to study the metabolic and cardiac consequences of carnitine-deficiency syndromes.     

卡托普利对实验大鼠左室肥厚的干预作用

目的观察卡托普利逆转压力负荷增加大鼠左室肥厚的作用。方法采用腹主动脉狭窄所致压力负荷增加大鼠左室肥厚模型,将雄性SD大鼠36只随机分为假手术组、模型组、卡托普利组,观察用药4周后左室重量指数（LVMI）、左室心肌病理形态HE染色、左室心肌细胞超微结构等指标的改变。结果模型组LVMI明显高于假手术组（P〈0．01）,卡托普利组（2．32±0．35）明显低于模型组（2．98±0．36）,P〈0．01;左室心肌病理形态HE染色、左室心肌细胞超微结构的改变与LVMI的改变基本一致。结论卡托普利具有逆转心肌肥厚的作用。     

国产曲美他嗪治疗冠心病合并左心功能不全的疗效观察

目的：本研究评价冠心病合并左心功能不全患者在常规治疗情况下加用国产曲美他嗪的临床疗效及安全性。方法：64例冠心病合并左心功能不全（LVEF〈35%）患者,平均年龄（61±9）岁,随即分为治疗组和对照组。治疗组在常规治疗的基础上加用国产曲美他嗪每日60mg,治疗12个月,随诊观察患者临床情况、左心室射血分数（LVEF）、左室舒张末期容积、心胸比率、动态心电图（Holter）记录的心肌缺血次数以及6min步行距离的变化。结果：治疗组患者心功能明显改善,LVEF由（31.6±7.5）%升至（40.7±9.8）%（P〈0.01）;左室舒张末期容积由（58.5±6.8）ml/m2减到（52.1±7.7）ml/m2（P〈0.01）;心胸比率由（57.2±5.6）%降至（53.0±6.9）%（P〈0.01）;Holter记录的心肌缺血次数由（3.6±4.8）次减至（1.2±3.4）次;6min步行距离由（134.8±47.1）m增至（340.9±56.5）m（P〈0.01）。结论：国产曲美他嗪联合其他治疗心功能不全的药物,能够进一步改善冠心病合并左心功能不全患者的心功能,降低左室舒张末期容积,减少心肌缺血次数,增加6min步行距离。     

多西环素抑制基质金属蛋白酶对心肌梗死大鼠左室重构和心功能的影响

目的观察多西环素对心肌梗死(myocardial infarc-tion,MI)后大鼠心肌MMP-2和MMP-9活性的影响及其对大鼠心肌梗死后心衰和左室重构的保护作用。方法 48只♂SD大鼠,分为假手术组、模型组、多西环素组,各16只。其中模型组和多西环素组通过结扎冠状动脉左前降支建立MI模型,假手术组仅开胸,未结扎冠状动脉。模型组(腹腔内注射生理盐水0.5 ml,Bid×5 d)、多西环素组(腹腔内注射多西环素15 mg.kg-1.d-1,Bid×5 d),假手术组(腹腔注射生理盐水0.5 ml,Bid×5 d)。术后2周心脏彩超评价心功能,取心肌组织用Masson染色分析心肌梗死面积,明胶酶法分析MMP-2和MMP-9的活性。结果 MI 2周后与模型组相比,多西环素治疗组左室前壁厚度明显增加(P<0.05),左室舒张末期内径缩小(P<0.05),左室短轴缩短率明显增加,EF值增高。治疗组梗死面积百分比缩小,明胶酶谱分析证实治疗组心肌组织MMP-2、MMP-9的活性明显低于模型组。结论多西环素能够在一定程度上通过抑制心肌MMP-2、MMP-9的活性、缩小梗死面积、减轻存活心肌的纤维化而改善心肌梗死大鼠的心功能和左室重构。     

卡托普利对冠心病左室舒张功能的影响

17例冠心病患者(男性12例,女性5例,平均56±6a)采用多普勒血流图,在用卡托普利12.5mg, tid, po×4wk,测定治疗前后左室舒张功能参数,并作对比。治疗4wk后,在心绞痛组,E峰增加,A峰下降,DC增快;在心肌梗死组,A峰与DC均无明显变化。提示卡托普利可改善左室舒张功能。此外,该药可降低血压,但心率变化不大。     

老年高血压动态脉压指数对冠心病临床意义

目的探讨动态血压脉压指数(ABP·PPI)在老年高血压患者中冠心病发生的相关关系。方法选择128例老年高血压患者,检测24 h动态血压(APBM),测定动态脉压指数,以脉压指数(PPI)≤0.40、PPI≥0.41分组,两组进行比较分析。结果冠心病发病率与PPI明显相关。差异有统计学意义(P≤0.01)。结论动态脉压指数与老年高血压冠心病的发生密切相关,且随着动态脉压指数的升高,冠心病发生率明显增多。     

Excess weight in children and adolescents is associated with altered subendocardial blood supply among girls but not boys

Subendocardial viability ratio (SEVR) is a reliable index of myocardial supply‐workload balance. This study sought to investigate whether overweight/obese children and adolescents have altered SEVR and to identify which are the associated factors. This cross‐sectional study involved 789 individuals. Central haemodynamic was measured by radial applanation tonometry. Diastolic time was shorter (496 ± 122 vs 537 ± 140 ms, P = .014) and diastolic pressure‐time index was lower (2681 ± 412 vs 2814 ± 423 mm Hg seconds, P = .024) in overweight/obese compared with eutrophic girls. SEVR was lower in girls than in boys (1.34 ± 0.39 vs 1.48 ± 0.41, P = .018) but only among overweight/obese. SEVR may be affected by small variations in the temporal determinants of cardiac cycle.     

Enhanced external counterpulsation improves endothelial function and exercise capacity in patients with ischaemic left ventricular dysfunction

Enhanced external counterpulsation (EECP) therapy decreases angina episodes and improves quality of life in patients with left ventricular (LV) dysfunction (LVD). However, studies have not elucidated the mechanisms of action and overall effects of EECP in patients with LVD. The purpose of the present study was to investigate the effects of EECP on endothelial function in peripheral conduit arteries and exercise capacity (peak Vo ₂) in patients with LVD. Patients with ischaemic LVD (ejection fraction (EF) 34.5 ± 4.2%; n = 9) and patients with symptomatic coronary artery disease (CAD) and preserved LV function (EF 53.5 ± 6.6%; n = 15) were studied before and after 35 sessions (1 h) of EECP. Brachial and femoral artery flow‐mediated dilation (bFMD and fFMD, respectively) were evaluated using high‐resolution ultrasound. Enhanced external counterpulsation elicited similar significant improvements in the following FMD parameters in the CAD and LVD groups (P ≥ 0.05 between groups for all): absolute bFMD (+53% and +70%, respectively), relative bFMD (+50% and +74%, respectively), bFMD normalized for shear rate (+70% and +61%, respectively), absolute fFMD (+33% and +21%, respectively) and relative fFMD (+32% and +17%, respectively). In addition, EECP significantly improved plasma levels of nitrate/nitrite (+55% and +28%) and prostacyclin (+50% and +70%), as well as peak Vo ₂ (+36% and +21%), similarly in both the CAD and LVD groups (P ≥ 0.05 between groups for all). Despite reduced LV function, EECP therapy significantly improves peripheral vascular function and functional capacity in CAD patients with ischaemic LVD to a similar degree to that seen in CAD patients with preserved LV function.     

冠状动脉内成形及支架术对左室舒张功能的影响

目的　用多普勒超声心动图探查冠状动脉内成形 +支架术 (PTCA+Stent)前后左室舒张功能的变化。方法　对 12例行 PTCA+Stent术的心绞痛患者 ,分别于术前 3～ 10 d(8± 3) d和术后 30～ 6 0 d(42±9) d,分别行多普勒超声心动图检查。并获得左室最大早期舒张血流速度 (E) ,晚期最大舒张血流速度 (A) ,得出舒张早期和晚期最大血流速度比 (E/A)和 E峰加速时间 (EAT) ,测出左房内径 (L A)。结果　 E峰、E/A术后较术前明显增大 (P均 <0 .0 0 1) ,A峰、EAT术后较术前明显减少 (P <0 .0 0 1,P<0 .0 5 ) ,L A术前后无差异 (P>0 .5 )。结论　 PTCA可使狭窄的冠状动脉通畅 ,心肌血流灌注正常或明显改善 ,显著改善冠心病患者的心肌缺血 ,使左室舒张功能改善     

高血压患者动态血压变异性与左心室肥厚的关系探讨

目的 探讨高血压患者动态血压变异性与左心室肥厚（LVH）的关系.方法 选择高血压患者160例,分别给予24 h动态血压监测和超声心动图检查,根据心脏超声检查结果有无LVH,分为LVH组（n=70）和非LVH组（n=90）,比较2组动态血压各参数的变化,统计分析各时间段血压均值及血压变异性与LVH的关系.结果 ①LVH组与非LVH组的年龄、性别构成比较差异无统计学意义（P＞0.05）.②LVH组与非LVH组的24 h平均收缩压、24 h收缩压标准差、24 h舒张压标准差、白昼平均收缩压、白昼收缩压标准差、白昼平均舒张压、白昼舒张压标准差、夜间平均收缩压、夜间收缩压标准差、夜间平均舒张压、夜间舒张压标准差比较,差异均有统计学意义[分别为（152±14）mmHg（1 mmHg=0.133 kPa）比（121±9）mmHg、（18±4）mmHg比（82±5）mmHg、（16 ±5）mmHg比（11±4）mmHg、（153±11） mmHg比（123±10） mmHg、（17±5）mmHg比（13±4） mmHg、（100±9）mmHg比（83±6）mmHg、（16±5） mmHg比（10±3）mmHg、（147±14）mmHg比（112±12）mmHg、（15±6）mmHg比（10±4） mmHg、（96±10） mmHg比（77±8）mmHg、（14±6） mmHg比（8±3） mmHg]（均P＜0.01）.结论 高血压患者动态血压参数及血压变异性异常与LVH关系密切;血压变异性大者,LVH发生率增加.     

Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice

Background and Purpose

We have shown that infusions of apolipoprotein A-I (ApoA-I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA-I mimetic therapy in mice with calcific or fibrotic AVS.

Experimental Approach

Apolipoprotein E-deficient (ApoE^−/−) mice and mice with Werner progeria gene deletion (Wrn^Δhel/Δhel) received high-fat diets for 20 weeks. After developing AVS, mice were randomized to receive saline (placebo group) or ApoA-I mimetic peptide infusions (ApoA-I treated groups, 100 mg·kg⁻¹ for ApoE^−/− mice; 50 mg·kg⁻¹ for Wrn mice), three times per week for 4 weeks. We evaluated effects on AVS using serial echocardiograms and valve histology.

Key Results

Aortic valve area (AVA) increased in both ApoE^−/− and Wrn mice treated with the ApoA-I mimetic compared with placebo. Maximal sinus wall thickness was lower in ApoA-I treated ApoE^−/− mice. The type I/III collagen ratio was lower in the sinus wall of ApoA-I treated ApoE^−/− mice compared with placebo. Total collagen content was reduced in aortic valves of ApoA-I treated Wrn mice. Our 3D computer model and numerical simulations confirmed that the reduction in aortic root wall thickness resulted in improved AVA.

Conclusions and Implications

ApoA-I mimetic treatment reduced AVS by decreasing remodelling and fibrosis of the aortic root and valve in mice.