Effects of biological sex on the pathophysiology of the heart

Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches.     

Role of insulin-like growth factor 1 and phosphoinositide 3-kinase in a setting of heart disease

1. The insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3-K) pathway is a critical regulator of cell and organ growth. 2. In the heart, the IGF1-PI3-K pathway induces physiological heart growth with preserved or enhanced cardiac function. 3. The present review specifically discusses the role of the IGF1-PI3-K pathway in the setting of heart disease. 4. Genetic mouse models have highlighted the beneficial effects of the IGF1-PI3-K pathway in the heart in a setting of disease. These include maintenance of contractile function, antifibrotic and anti-apoptotic actions, inhibition of signalling transducers activated in disease settings and regeneration.     

Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure

1. In general, cardiac hypertrophy (an increase in heart mass) is a poor prognostic sign. Cardiac enlargement is a characteristic of most forms of heart failure. Cardiac hypertrophy that occurs in athletes (physiological hypertrophy) is a notable exception. 2. Physiological cardiac hypertrophy in response to exercise training differs in its structural and molecular profile to pathological hypertrophy associated with pressure or volume overload in disease. Physiological hypertrophy is characterized by normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is commonly associated with upregulation of fetal genes, fibrosis, cardiac dysfunction and increased mortality. 3. It is now clear that several signalling molecules play unique roles in the regulation of pathological and physiological cardiac hypertrophy. 4. The present review discusses the possibility of targeting cardioprotective signalling pathways and genes activated in the athlete's heart to treat or prevent heart failure.     

Functional characterization of the cAMP-binding proteins Epac in cardiac myocytes

The cyclic AMP (cAMP)-binding proteins, Epac, are guanine nucleotide exchange factors for the Ras-like small GTPases. Since their discovery in 1998 and with the development of specific Epac agonists, many data in the literature have illustrated their critical role in multiple cellular events mediated by the second messenger cAMP. Given the importance of cAMP in cardiovascular physiology and physiopathology, there is a growing interest to delineate the role of these multi-domain Epac in the cardiovascular system. This review will focus on recent pharmacological and biochemical studies aiming at understanding the role of Epac in cardiomyocyte signaling and hypertrophy     

Myocardial energetics in cardiac hypertrophy

1. This review is presented with the intent of illustrating the representative studies of functional and myocardial energetic consequences of hearts with postinfarction left ventricular (LV) remodelling or with concentric hypertrophy and diastolic LV dysfunction in porcine models. 2. Both eccentric and concentric cardiac hypertrophy are associated with the abnormal myocardial energetics that are most severe in hearts with congestive heart failure (CHF). Presently, these abnormalities cannot be satisfactorily explained to be the cause(s) of the dysfunction of failing hearts or cause the progress from compensated cardiac hypertrophy to CHF. 3. Mechanisms governing abnormal myocardial high-energy phosphate (HEP) metabolism in hearts with cardiac hypertrophy and CHF are unclear. Myocardial energy metabolism studies use both kinetic and thermodynamic models. The thermodynamic studies examine the myocardial steady state levels of high- and low-energy phosphate, which indicate myocardial energy state or phosphorylation potential that is defined by the ratio of [ATP]/([ADP][Pi]). The kinetics studies examine the reaction velocity that is regulated by: (i) quantity and activity of the key enzymes; (ii) the concentrations of all the substrates and products; and (iii) the Michaelis-Menten constants of each substrate of the reaction. 4. Significant alterations in myocardial concentrations of phosphocreatine (PCr), ATP and ADP, myocardial oxidative phosphorylation (OXPHOS) protein expression and substrate preference are found in hearts with postinfarction LV remodelling and CHF. However, to define a causal relationship is a different matter. 5. Future studies of animal models of LV hypertrophy or heart failure using gene manipulation may provide additional insights to answer the persisting question of whether limitations of ATP synthetic or transport capacities contribute to the pathogenesis of LV remodelling or failure.     

Endothelin ETA receptor antagonism does not attenuate angiotensin II-induced cardiac hypertrophy in vivo in rats

1. Angiotensin (Ang) II causes cardiac hypertrophy in vitro and in vivo. It also stimulates the release of endothelin (ET)-1. Endothelin-1 induces hypertrophy of cardiomyocytes in vitro. 2. In the present study, we examined whether the cardiac hypertrophic action of AngII in vivo was mediated by ET-1 via ETA receptors. We also determined whether arginine vasopressin (AVP), another ET-1 stimulator, could cause cardiac hypertrophy in vivo through an ET-1-dependent pathway. 3. In Sprague-Dawley rats (n = 8 per group), we determined whether the orally administered ETA receptor antagonist BMS 193884 could attenuate the cardiac hypertrophic effect of: (i) i.v. AngII infusion at either 100 or 200 ng/kg per min, i.v., for 1 week; (ii) AngII infusion at 100 ng/kg per min, i.v., for 2 weeks; and (iii) AVP infusion at either 2 or 10 ng/kg per min, i.v., for 1 week. Mean arterial pressure and heart rate were also measured. 4. Infusion with AngII for both 1 and 2 weeks increased left ventricular weight. Only AngII infusion at 200 ng/kg per min for 1 week increased blood pressure. Endothelin ETA receptor blockade did not attenuate the left ventricular hypertrophy, even though it reduced the hypertensive effect of AngII. Arginine vasopressin increased blood pressure, but did not cause cardiac hypertrophy. 5. We showed that AngII can cause cardiac hypertrophy through a direct, blood pressure-independent effect on the heart. Endothelin-1 did not mediate the cardiac hypertrophic effect of AngII through ETA receptors. This may indicate the involvement of ETB receptors in this model of cardiac hypertrophy. Arginine vasopressin did not cause cardiac hypertrophy in vivo.     

Distinct role of adrenoceptor subtypes in cardiac adaptation to chronic pressure overload

1. With the generation of gene knockout (KO) or transgenic overexpression (TG) mouse models targeting adrenoceptors (AR), recent studies in vivo have investigated the role of AR subtypes in pressure overload-induced left ventricular (LV) hypertrophy and remodelling. 2. Although subjecting alpha(1B)-KO mice to transverse aortic constriction (TAC) did not reveal significant phenotype differences compared with controls, mice deficient in both alpha(1A)- and alpha(1B)-AR responded to TAC with poor survival, increased cardiomyocyte apoptosis, more severe fibrosis and dysfunction, but a similar degree of LV hypertrophy, compared with wild-type littermates. Following TAC, alpha(1B)-TG mice developed more severe hypertrophy, interstitial fibrosis and LV dysfunction. In contrast, overexpression of alpha(1A)-AR preserved cardiac function and reduced death from heart failure without affecting the degree of LV hypertrophy. Thus, alpha(1A)- and alpha(1B)-adrenoceptor signalling impacts differently on myocardial adaptation to pressure overload. 3. The absence of both beta(1)- and beta(2)-AR significantly suppressed pressure overload-evoked hypertrophy, fibrosis and expression of inflammatory or fibrogenic genes. Conversely, studies on beta(2)-TG mice with TAC revealed adverse consequences, including accelerated development of heart failure, poor survival and more severe interstitial fibrosis, but a comparable degree of hypertrophy compared with wild-type littermates. 4. Collectively, these findings suggest that the effect of ARs on pressure overload-induced myocardial adaptation is subtype specific. Whereas activation of alpha(1B)-AR or beta(2)-AR contributes to maladaptation and the onset of heart failure, activation of alpha(1A)-AR or inactivation of beta(2)-AR is beneficial in the setting of chronic pressure overload.     

Engineered cardiac tissues: a novel in vitro model to investigate the pathophysiology of mouse diabetic cardiomyopathy

Rodent diabetic models, used to understand the pathophysiology of diabetic cardiomyopathy (DCM), remain several limitations. Engineered cardiac tissues (ECTs) have emerged as robust 3D in vitro models to investigate structure–function relationships as well as cardiac injury and repair. Advanced glycation end-products (AGEs), produced through glycation of proteins or lipids in response to hyperglycemia, are important pathogenic factor for the development of DCM. In the current study, we developed a murine-based ECT model to investigate cardiac injury produced by AGEs. We treated ECTs composed of neonatal murine cardiac cells with AGEs and observed AGE-related functional, cellular, and molecular alterations: (1) AGEs (150 µg/mL) did not cause acute cytotoxicity, which displayed as necrosis detected by medium LDH release or apoptosis detected by cleaved caspase 3 and TUNEL staining, but negatively impacted ECT function on treatment day 9; (2) AGEs treatment significantly increased the markers of fibrosis (TGF-β, α-SMA, Ctgf, Collagen I-α1, Collagen III-α1, and Fn1) and hypertrophy (Nppa and Myh7); (3) AGEs treatment significantly increased ECT oxidative stress markers (3-NT, 4-HNE, HO-1, CAT, and SOD2) and inflammation response markers (PAI-1, TNF-α, NF-κB, and ICAM-1); and (4) AGE-induced pathogenic responses were all attenuated by pre-application of AGE receptor antagonist FPS-ZM1 (20 µM) or the antioxidant glutathione precursor N-acetylcysteine (5 mM). Therefore, AGEs-treated murine ECTs recapitulate the key features of DCM’s functional, cellular and molecular pathogenesis, and may serve as a robust in vitro model to investigate cellular structure-function relationships, signaling pathways relevant to DCM and pharmaceutical intervention strategies.     

慢性心力衰竭并发心脏骤停89例临床分析

目的总结发生心脏骤停的慢性心力衰竭（心衰）患者特点,探讨影响心脏骤停和复苏成功率的因素。方法对我科2005-2008年共89例发生心脏骤停的慢性心衰患者的临床资料进行回顾性分析。结果发生心脏骤停的这89例心衰患者中,心功能为Ⅱ-Ⅳ级。高血压性心脏病是最常见的病因,其次为冠心病。心功能Ⅱ-Ⅲ级的患者,发生心脏骤停后复苏的成功率明显高于心功能Ⅳ级的患者。BNP显著增高、低钠血症或者合并其他系统疾病时,患者的预后差,复苏成功率低。结论心功能、BNP及血钠是影响心衰患者复苏成功与否的重要因素。     

白藜芦醇通过线粒体调控血吸虫感染小鼠M1/M2极化

目的探讨白藜芦醇对血吸虫病巨噬细胞极化的作用及机制。方法45只血吸虫感染小鼠3周后,随机分3组,A组感染组,B组白藜芦醇治疗组,C组吡喹酮治疗组,另取15只小鼠为健康对照D组。感染第9周,流式细胞术检测肝脏M1、M2,ATP试剂盒检测肝脏巨噬细胞ATP,实时定量PCR检测M1和M2相关因子、mtDNA。采用虫卵可溶性抗原(SEA)刺激RAW264.7,再给予白藜芦醇处理,检测M1、M2比例,细胞上清中M1和M2相关因子,PGC-1α,mtDNA和ATP。结果B组M1比例高于A组(P<0.01),M2比例低于A组(P<0.05),肝脏巨噬细胞M2相关因子、PGC-1α、mtDNA、ATP、基础耗氧率均低于A组(P<0.05),M1相关因子高于A组(P<0.05)。白藜芦醇使RAW264.7往M1分化增多(P<0.01),往M2分化减少(P<0.01),M2相关因子降低(P<0.05),mtDNA、PGC-1α、ATP、基础耗氧率降低(P<0.05),M1相关因子增高(P<0.05)。结论白藜芦醇通过抑制巨噬细胞线粒体数量和功能促进其往M1分化,抑制其往M2分化。     

GJA1-20k attenuates Ang II-induced pathological cardiac hypertrophy by regulating gap junction formation and mitochondrial function

Cardiac hypertrophy(CH)is characterized by an increase in cardiomyocyte size,and is the most common cause of cardiac-related sudden death.A decrease in gap junction(GJ)coupling and mitochondrial dysfunction are important features of CH,but the mechanisms of decreased coupling and energy impairment are poorly understood.It has been reported that GJA1-20k has a strong tropism for mitochondria and is required for the trafficking of connexin 43(Cx43)to cell–cell borders.In this study,we investigated the effects of GJA1-20k on Cx43 GJ coupling and mitochondrial function in the pathogenesis of CH.We performed hematoxylin–eosin(HE)and Masson staining,and observed significant CH in 18-week-old male spontaneously hypertensive rats(SHRs)compared to age-matched normotensive Wistar-Kyoto(WKY)rats.In cardiomyocytes from SHRs,the levels of Cx43 at the intercalated disc(ID)and the expression of GJA1-20k were significantly reduced,whereas JAK-STAT signaling was activated.Furthermore,the SHR rats displayed suppressed mitochondrial GJA1-20k and mitochondrial biogenesis.Administration of valsartan(10 mg·kg^?1.d^?1,i.g.,for 8 weeks)prevented all of these changes.In neonatal rat cardiomyocytes(NRCMs),overexpression of GJA1-20k attenuated Ang II-induced cardiomyocyte hypertrophy and caused elevated levels of GJ coupling at the cell–cell borders.Pretreatment of NRCMs with the Jak2 inhibitor AG490(10μM)blocked Ang II-induced reduction in GJA1-20k expression and Cx43 gap junction formation;knockdown of Jak2 in NRCMs significantly lessened Ang II-induced cardiomyocyte hypertrophy and normalized GJA1-20k expression and Cx43 gap junction formation.Overexpression of GJA1-20k improved mitochondrial membrane potential and respiration and lowered ROS production in Ang II-induced cardiomyocyte hypertrophy.These results demonstrate the importance of GJA1-20k in regulating gap junction formation and mitochondrial function in Ang II-induced cardiomyocyte hypertrophy,thus providing a novel therapeutic strategy for patients with cardiomyocyte hypertrophy.     

异叶青兰总黄酮对高血压大鼠心肌肥厚的影响

目的观察异叶青兰总黄酮对肾性高血压大鼠心肌肥厚的影响。方法左肾动脉狭窄(2K1C)法建立高血压大鼠模型,术后第6周随机分为5组:假手术组(Sham);模型组(Model);异叶青兰总黄酮高剂量组(DHBFH)、低剂量组(DHBFL);卡托普利组(Captopril)。灌胃给药6周后进行超声心动图、心肌病理学检测,白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、基质金属蛋白酶-9(MMP-9)和基质金属蛋白酶抑制剂-1(TIMP-1)mRNA的测定。结果给药6周后,模型组大鼠左心室室壁厚度、心肌细胞大小及左心室心肌间质纤维化程度较假手术组明显升高,IL-1β、TNF-α明显升高(P<0.01),MMP-9、TIMP-1 mRNA的相对表达量明显升高(P<0.01),给予DHBFH后,左心室肥厚及心肌纤维化较模型组明显降低,IL-1β、TNF-α明显降低,MMP-9、TIMP-1 mRNA的相对表达量明显降低(P<0.01)。结论异叶青兰总黄酮能改善高血压大鼠心肌肥厚及心肌纤维化程度,可能与其能够降低血压,降低IL-1β、TNF-α水平,调节MMP-9/TIMP-1的表达有关。     

钙调神经磷酸酶在L-精氨酸抗心肌肥厚中的作用

目的研究L-精氨酸抗右心室心肌肥厚作用及其与钙调神经磷酸酶(calcineurin,CaN)信号通路的关系。方法利用野百合碱(monocrotaline,MCT)诱导大鼠右心室心肌肥厚模型和前列腺素F2α(prostaglandin F2α,PGF2α)诱导心肌细胞肥大模型,分别以右心室肥厚指数(right ventricle hypertro-phy index,RVHI,即右心室/左心室+室间隔)、心肌细胞直径、蛋白含量和心房利钠肽(atrial natriuretic peptide,ANP)mRNA表达为心肌肥厚指标。用RT-PCR法检测mRNA的表达;Western blot法检测蛋白表达;荧光法检测细胞内钙[Ca2+]i的变化情况。结果L-精氨酸200mg.kg-1.d-1预防和治疗给药均明显抑制MCT诱导的大鼠心肌肥厚,降低MCT所致心肌CaN mRNA和蛋白及其下游因子NFAT3及GATA4蛋白表达的增加。L-精氨酸1mmol.L-1也明显抑制PGF2α100nmol.L-1诱导的大鼠心肌细胞肥大和[Ca2+]i升高,阻遏其诱导的CaN mRNA及CaN-,NFAT3-,GATA4-蛋白表达升高。在体和离体实验中一氧化氮合成酶抑制剂NG-硝基-L-精氨酸-甲酯均可完全阻断L-精氨酸的作用。结论L-精氨酸可能通过降低[Ca2+]i,从而抑制CaN信号转导通路而产生抗右心室心肌肥厚作用。     

Promoting physiological hypertrophy in the failing heart

1. Heart failure rates have reached epidemic proportions in Western society. 2. New strategies proposed to improve cardiac function of the failing heart include regeneration, stem cell therapy, innovative methods for the revascularization of ischaemic cardiac tissue and the activation of signalling pathways that promote physiological growth (hypertrophy). 3. The insulin-like growth factor 1-phosphoinositide-3-kinase pathway is a well characterized regulator of physiological hypertrophy. 4. In this mini-review we present studies that suggest promoting physiological hypertrophy in the failing heart may be beneficial.     

芪苈强心胶囊治疗慢性心力衰竭的Meta分析

目的评价芪苈强心胶囊治疗慢性心力衰竭的临床疗效和安全性。方法纳入13个随机对照试验,采用RevMan5．2．4软件进行Meta分析。结果共纳入13个研究试验,共计1154例患者,其研究质量偏低。Meta分析显示在心衰患者常规治疗的基础上加入芪苈强心胶囊后能够改善心衰患者的临床症状[RR=1．24,95％CI（1．17,1．31）];增加心室射血分数[WMD=6．04,95％CI（4．57,7．52）];减小左室舒张末期内径[WMD=4．28,95％CI（2．14,6．41）];降低B型脑钠肽fWMD：113．78,95％CI（32．82,194．75）]和脑钠肽前体N末端片段[WMD=90．21,95％CI（60．07,120．35）]的水平;同时能够显著增加患者的6分钟步行距离[WMD=39．39,95％CI（30．61,48．16）];降低明尼苏达生活质量表积分[WMD=4．20,95％CI（0．36,8．05）]并没有得到理想的结果;对于心血管事件发生情况、AngII、左室短轴缩短率、IL-6、二尖瓣舒张早期血流与二尖瓣运动速度比值等指标有统计学意义（P〈0．05）;此外针对个别芪苈强心胶囊所产生的不良反应,患者均能耐受并且与对照组没有统计学差异。结论使用芪苈强心胶囊治疗慢性心力衰竭是安全和可靠的．应该推广其临床使用范围．弘扬中医药的优势。     

心脏再同步治疗在慢性心力衰竭患者的临床应用

目的评价心脏再同步治疗（cardiac resynchronization therapy,CRT）慢性心力衰竭患者临床应用效果。方法将植入三腔起搏器进行cR王的32名慢性心力衰竭患者根据纽约心脏病学会（New Yor kHeart Association,NYHA）心功能分级分为NYHA心功能Ⅲ级组和。科Y}骆心功能Ⅳ级组。其中NYHA心功能Ⅲ级组14例,NYHA心功能Ⅳ级组18例,并对其进行随访观察治疗,以观察两组患者心功能改善情况,以评价心脏再同步治疗的效果。结果两组在性别构成比、年龄、基础心脏病构成比、左心室射血分数（1础ventricular ejection fraction,LVEF）、术前左室舒张末期内径（1eft ventricular end-diastolic diameter,LVEDD）、植入时心律为窦性心律、术前心电图QRS波时限、术后心电图QRS波时限、左室电极植入靶静脉、植入起搏器类型,及合并糖尿病、高血压病、脑血管疾病史等方面未有统计学差异。术后随访发现,NYHA心功能Ⅳ级组治疗效果明显比例显著低于NYHA心功能Ⅲ级组（5仉O％t】s92．9％,P=0．019）。回顾性分析治疗效果明显与治疗效果不明显两组临床资料,发现治疗效果不明显组NYHA心功能Ⅳ级所占比例明显高于治疗效果明显组（90．O％铘40．9％,P=0．019）,且术前LVEDD明显大于治疗效果明显组[（76．7±10．3）mmvs（68．0±7．6）mm,P=0．012）]。结论NYHA心功能Ⅳ级组CRT后效果不如NYHA心功能Ⅲ级组,较大的术前LVEDD是CRT术后疗效不佳的预测因素。但在药物治疗基础上,CRT仍可改善慢性心力衰竭患者的心功能。     

Telmisartan attenuates isoproterenol-induced cardiac remodeling in rats via regulation of cardiac adiponectin expression

Aim:

To investigate whether telmisartan (Telm) pretreatment attenuates isoproterenol (Iso)-induced postinfarction remodeling (PIR) in rats, and whether the effect of Telm is associated with cardiac expression of adiponectin.

Methods:

PIR was induced in male Wistar rats with two consecutive injections of Iso (80 mg/kg, sc) at an interval of 24 h. Primary culture of ventricular myocytes from neonatal rats was prepared. Iso-induced cardiomyocyte injury was assessed based on cell growth and lactate dehydrogenase (LDH) activity. Cardiac adiponectin expression was measured using qRT-PCR and immunoblot analysis.

Results:

In the rats with PIR, Telm (10 mg·kg⁻¹·d⁻¹, po for 65 d) suppressed Iso-induced increases in gravimetric parameters, cardiomyocyte diameter and collagen volume fraction, but had no effect on Iso-induced myocardial hypertrophy and interstitial fibrosis. The protective effect of Telm was associated with enhanced protein expression of cardiac adiponectin. In cultured cardiomyocytes, Telm (5–20 μmol/L) inhibited the cell death and LDH release induced by Iso (10 μmol/L), and reversed Iso-induced reduction in adiponectin protein expression. In cardiomyocytes exposed to Iso (20 μmol/L), GW9662 (30 μmol/L), a selective antagonist of PPAR-γ, blocked the effects of Telm pretreatment on adiponectin protein expression, as well as the protective effects of Telm on Iso-induced cell injury.

Conclusion:

Telm attenuates Iso-induced cardiac remodeling and cell injury, which is associated with induction of cardiac adiponectin expression.