The influence of the human microbiome and probiotics on cardiovascular health

Cardiovascular disease (CVD) is a major cause of death worldwide. Of the many etiological factors, microorganisms constitute one. From the local impact of the gut microbiota on energy metabolism and obesity, to the distal association of periodontal disease with coronary heart disease, microbes have a significant impact on cardiovascular health. In terms of the ability to modulate or influence the microbes, probiotic applications have been considered. These are live microorganisms which when administered in adequate amounts confer a benefit on the host. While a number of reports have established the beneficial abilities of certain probiotic bacterial strains to reduce cholesterol and hypertension, recent research suggests that their use could be more widely applied. This review presents an up-to-date summary of the known associations of the microbiome with CVD, and potential applications of probiotic therapy.     

Ischaemic Preconditioning of Myocardium

Myocardium has the innate potential to adapt to transient sublethal ischaemia so that it becomes more resistant to a subsequent, more severe, ischaemic insult. The response is called ischaemic preconditioning and protection of the myocardium is manifested by a slowing of adenosine triphosphate decline, limitation of ischaemic necrosis and a reduction in dysrhythmia severity. Protection conferred by preconditioning occurs in two distinct temporal phases. An early phase of protection is observed immediately but wanes within two to three hours (classic preconditioning). This is followed many hours later by a second window of protection (delayed preconditioning). The cellular mechanisms underpinning both forms of protection are currently being intensively investigated. There is evidence that human myocardium can be preconditioned ex vivo and also in situ during elective procedures such as angioplasty and coronary artery bypass grafting. Furthermore, evidence points to the possibility that preconditioning occurs naturally in some ischaemic syndromes, particularly warm-up angina and preinfarction angina. Ultimately, investigation of the mechanisms of preconditioning may contribute to the development of rational therapies for protecting the ischaemic myocardium and, perhaps more importantly, enhance our understanding of the molecular basis of ischaemic heart disease.     

二氮嗪对缺血再灌注致大鼠心肌细胞坏死和凋亡的影响

目的研究二氮嗪对大鼠心肌缺血再灌注损伤的保护效果。方法健康SD大鼠随机分为两组，实验组静脉注射二氮嗪12.5mg／kg进行预处理，对照组静脉注射相应量溶媒，10min后每组大鼠均行左侧开胸，结扎左前降支，造成局部心肌缺血2h，恢复再灌注2h后取心脏，测量心肌梗死面积大小及采用TUNEL法原位标记缺血区凋亡心肌细胞。结果与对照组相比，二氮嗪预处理组心肌梗死面积显著减小（P〈0．05），心肌细胞凋亡发生率明显降低（P〈0．05）。结论二氮嗪对大鼠心肌缺血再灌注损伤具有较好的保护作用，能减少心肌细胞坏死和凋亡。     

Cardioprotective effects of desflurane: effect of timing and duration of administration in rat myocardium

Background. We compared the cardioprotective effects of 1 minimumalveolar concentration (MAC) desflurane administered before,during or after ischaemia, or throughout the experiment (before,during and after ischaemia) on myocardial infarct size following30 min occlusion of the left anterior descending coronary arteryand 3 h reperfusion in adult rats. Methods. Fifty male Sprague–Dawley rats were anaesthetizedwith pentobarbital, intubated and mechanically ventilated. Bloodgases, pH and body temperature (37.5–38°C) were controlled.Heart rate and arterial pressure were measured continuously.Animals were randomly assigned to the following groups (n=10in each group): pentobarbital only (‘Pento’); 15min desflurane administration followed by 10 min of washoutbefore 30 min ischaemia and 3 h reperfusion (‘Precond’);30 min desflurane administration during ischaemia period (‘Isch’);desflurane administration during the 15 first min of reperfusion(‘Reperf’) and desflurane administration throughoutthe experiment (before, during and after ischaemia; ‘Long’).Volumes at risk and infarct sizes were assessed by Indian inkand with 2,3,5-triphenyltetrazolium chloride staining, respectively. Results. Physiological parameters and volumes at risk were notsignificantly different between groups. In the Pento group,mean myocardial infarct size was 65 (SD 15)% of the volume atrisk; myocardial infarct size was reduced to a significant andcomparable extent in the desflurane-treated groups (Precond42 (14)%; Isch 34 (11)%; Reperf 41 (15)%; Long 33 (10)%; P<0.0002vs Pento group). Conclusions. In rats, desflurane 1 MAC significantly decreasedmyocardial infarct size whatever the period and duration ofadministration. Br J Anaesth 2004; 92: 552–7     

Anaesthetics and cardiac preconditioning. Part II. Clinical implications

There is compelling evidence that preconditioning occurs inhumans. Experimental studies with potential clinical implicationsas well as clinical studies evaluating ischaemic, pharmacologicaland anaesthetic cardiac preconditioning in the perioperativesetting are reviewed. These studies reveal promising results.However, there are conflicting reports on the efficacy of preconditioningin the diseased and aged myocardium. In addition, many anaestheticsand a significant number of perioperatively administered drugsaffect the activity of cardiac sarcolemmal and mitochondrialK_ATP channels, the end-effectors of cardiac preconditioning,and thereby markedly modulate preconditioning effects in myocardialtissue. Although these modulatory effects on K_ATP channels havebeen investigated almost exclusively in laboratory investigations,they may have potential implications in clinical medicine. Importantquestions regarding the clinical utility and applicability ofperioperative cardiac preconditioning remain unresolved andneed more experimental work and randomized controlled clinicaltrials. Br J Anaesth 2003; 91: 566–76     

缺血预处理限制线粒体钙超载保护再灌注大鼠心肌

目的研究缺血预处理(IP)对缺血大鼠心肌的保护作用。方法将Wistar大鼠随机分为对照组(CON组)、缺血预处理组(IP组)、5-羟葵酸拮抗IP组(5HD+IP组),每组8只。建立Langendorff灌注模型,平衡灌注20min,全心缺血40 min,再灌注30 min,观察比较各组血流动力学变化;再灌注末取心肌并制备线粒体,电镜观察比较形态学改变;分离、测定线粒体游离钙浓度。结果IP组与对照组相比,能明显改善缺血再灌注大鼠心脏收缩功能,左室发展压(LVDP)有显著差异(P<0.01);缺血末、再灌注末线粒体游离钙浓度显著低于对照组(P<0.01);IP组明显改善心肌、线粒体显微结构。5HD+IP组与IP组比较,再灌注各时间点大鼠心脏收缩功能指标LVDP有显著性差异(P<0.01),缺血末、再灌注末线粒体游离钙浓度显著高于IP组(P<0.01);5HD+IP组心肌细胞、线粒体形态的保存明显比IP组差。结论①IP能改善缺血再灌注大鼠心肌的收缩功能,减少线粒体钙超载,保护心肌细胞和线粒体形态和结构的完整,产生心肌保护作用;②选择性线粒体钾通道拮抗剂5-羟葵酸能翻转缺血预处理的心肌保护作用;③缺血预处理的心肌保护机制可能是通过激活线粒体ATP敏感性钾通道,限制心肌线粒体钙超载,维护线粒体整体形态和功能的完整,产生心肌保护作用。     

Role of endothelium in ischaemia‐induced myocardial dysfunction of isolated working hearts: cardioprotection by activation of adenosine A2A receptors

1 This study aimed to determine the role of the vascular endothelium on recovery of contractile function following global low‐flow ischaemia of guinea‐pig isolated working hearts and the effects of adenosine analogues on this recovery. 2 Guinea‐pig isolated spontaneously beating or paced working hearts were set up and coronary flow (CF), aortic output (AO) (as an index of cardiac function), heart rate (HR), left ventricular pressure (LVP) and dP/dt max recorded. The endothelium was either intact or removed by a blast of oxygen. 3 In spontaneously beating hearts, low‐flow ischaemia for 30 min reduced CF and cardiac contractility (LVP, dP/dt max) but not AO. On reperfusion, CF, LVP and dP/dt max recovered, while AO fell precipitously followed by a gradual recovery, indicative of myocardial stunning. The effects of ischaemia did not differ between endothelium‐intact and ‐denuded hearts, indicating no role of the endothelium in the changes observed. 4 The adenosine analogues, N⁶‐cyclopentyladenosine (CPA, A₁ selective), 5'‐N‐ethylcarboxamidoadenosine (NECA, two‐fold A₂ selective over A₁) and 2‐p‐((carboxyethyl)‐phenethylamino)‐5'carboxamidoadenosine (CGS21680, A_2A selective) were infused (3 × 10^?7 M ) from 10 min into the 30‐min low‐flow ischaemia of denuded hearts and during reperfusion. 5 CGS21680 increased CF and improved the postischaemic functional recovery, as measured by the AO. NECA and CPA were not cardioprotective. The A_2A selective antagonist, ZM241385, attenuated the coronary vasodilatation by CGS21680 and abolished the improved recovery of AO on reperfusion. 6 Reperfusion of paced working hearts caused a dramatic fall in AO which failed to recover. Infusion of CGS21680 from 15 min into the ischaemic period produced vasodilatation but failed to restore AO, presumably because the ischaemic damage was irreversible. 7 Thus, the endothelium plays no role in myocardial dysfunction following low‐flow global ischaemia and reperfusion of guinea‐pig working hearts. The A_2A adenosine receptor‐selective agonist but not the non‐selective A₂ receptor agonist, NECA, attenuated ischaemia‐ and reperfusion‐induced stunning. This was attributed to increased CF and was independent of the endothelium.     

心肌缺血预处理和腺苷预处理对兔心肌缺血保护作用的比较

目的 :研究缺血预处理与“腺苷预处理 对兔心收缩功能和心肌梗死范围的影响 ,探讨两种处理方法对再灌注损伤的可能有益作用。方法 :采用兔缺血再灌注模型 ,分别以缺血前短暂心肌缺血预处理 ,缺血前腺苷预处理和缺血前应用腺苷受体阻滞剂后行缺血预处理。采用 RM- 6 2 80多道生理纪录和分析处理系统处理心肌收缩功能指标 ,采用 Evans蓝 - TTC法测量心肌梗死范围。结果 :与对照组和腺苷受体拮抗剂组相比 ,缺血预处理组及腺苷预处理组心肌梗死范围均减少 （P<0 .0 1） ;左室内压峰值 （L VSP）恢复率和± dp/ dtmax恢复率均增高 （P<0 .0 5 ） ;心律失常发生率均降低。结论 :缺血预处理与腺苷预处理对缺血心脏具有相似的保护作用 ,可改善缺血 -再灌心脏收缩功能 ,缩小心肌梗死范围     

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

It has now been demonstrated that the μ, δ₁, δ₂, and κ₁ opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusion‐induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia‐induced arrhythmias.