Cardiovascular Disorders Triggered by Obstructive Sleep Apnea—A Focus on Endothelium and Blood Components

Obstructive sleep apnea (OSA) is known to be an independent cardiovascular risk factor. Among arousal from sleep, increased thoracic pressure and enhanced sympathetic activation, intermittent hypoxia is now considered as one of the most important pathophysiological mechanisms contributing to the development of endothelial dysfunction. Nevertheless, not much is known about blood components, which justifies the current review. This review focuses on molecular mechanisms triggered by sleep apnea. The recurrent periods of hypoxemia followed by reoxygenation promote reactive oxygen species (ROS) overproduction and increase inflammatory response. In this review paper we also intend to summarize the effect of treatment with continuous positive airway pressure (CPAP) on changes in the profile of the endothelial function and its subsequent potential clinical advantage in lowering cardiovascular risk in other comorbidities such as diabetes, atherosclerosis, hypertension, atrial fibrillation. Moreover, this paper is aimed at explaining how the presence of OSA may affect platelet function and exert effects on rheological activity of erythrocytes, which could also be the key to explaining an increased risk of stroke.     

血管紧张素转换酶基因rs4340和rs4343多态性与心房颤动的相关性

目的探讨血管紧张素转换酶(Angiotensin converting enzyme,ACE)基因rs4340和rs4343多态性与心房颤动(简称房颤)的相关性。方法选择重庆地区4家三甲医院就诊的102例房颤患者及同期住院的无房颤病史患者100例,抽取患者静脉血,分别提取基因组DNA,采用单核苷酸多态性-限制性片段长度多态性(Single nucleotide polymorphism,restriction fragmentlength polymorphism,SNP-RFLP)法及基因测序检测ACE基因rs4340和rs4343的基因型。结果房颤组ACE基因rs4340多态性的基因型及等位基因分布与对照组相比,差异无统计学意义(P>0.05),房颤组rs4343的基因型和等位基因分布与对照组间差异有统计学意义(P<0.001或P=0.001)。与对照组相比,房颤组GG+AG基因型频率明显高于AA基因型频率(P<0.001)。II/AA基因型在房颤组中出现的频率明显少于对照组(P=0.001),而II/AG基因型在房颤组中出现的频率明显高于对照组(P=0.002)。房颤组中rs4340和rs4343各基因型左房前后径与右房横径差异均无统计学意义(P>0.05);而将两位点联合分析发现,携带II/AA基因型房颤患者的左房前后径和右房横径均明显小于其他基因型(P<0.001),同时,携带II/AG基因型房颤患者的左房前后径和右房横径均明显大于其他基因型(P<0.001)。结论 ACE基因rs4343多态性与房颤显著相关,II/AA基因型是房颤发生发展的保护因子,而II/AG基因型是预测房颤发生发展的危险因子。     

Heart Failure and Atrial Fibrillation: From Basic Science to Clinical Practice

Heart failure (HF) and atrial fibrillation (AF) are two growing epidemics associated with significant morbidity and mortality. They often coexist due to common risk factors and shared pathophysiological mechanisms. Patients presenting with both HF and AF have a worse prognosis and present a particular therapeutic challenge to clinicians. This review aims to appraise the common pathophysiological background, as well as the prognostic and therapeutic implications of coexistent HF and AF.     

Structure‐Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of Kv1.5 Channel Blockers

Atrial fibrillation (AF) is the most prevalent nonfatal cardiac rhythm disorder associated with an increased risk of heart failure and stroke. Considering the ventricular side effects induced by anti‐arrhythmic agents in current use, K_v1.5 channel blockers have attracted a great deal of deliberation owing to their selective actions on atrial electrophysiology. Herein we report new chemotypes of K_v1.5 channel blockers that were identified through a combination of structure‐based virtual screening and in silico druglike property prediction including six scoring functions, as well as electrophysiological evaluation. Among them, five of the 18 compounds exhibited >50 % blockade ratio at 10 μM , and have structural features different from conventional K_v1.5 channel blockers. These novel scaffolds could serve as hits for further optimization and SAR studies for the discovery of selective agents to treat AF.     

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.     

Prevention of ischemia-induced cardiac Sudden death by n−3 polyunsaturated fatty acids in dogs

The objective of this study was to obtain functional information associated with the prevention by n−3 polyunsaturated fatty acids (PUFA) of ischemia-induced fatal cardiac ventricular arrhythmias in the intact, conscious, exercising dog. Thirteen dogs suceptible to ischemia-induced ventricular fibrillation were prepared surgically by ligation of their anterior descending left coronary artery and placement of an inflatable cuff around their left circumflex artery. After 4 wk of recovery, exercise-plus-ischemia tests were performed without and then with an intravenous infusion of an emulsion of free n−3 PUFA just prior to occluding the left circumflex artery while the animals were running on a treadmill. One week later the exercise-plus-ischemia test was repeated but with a control infusion replacing the emulsion of n−3 PUFA. The infusion of the free n−3 PUFA in quantities of 1.0 to 10 g prevented ventricular fibrillation in 10 of the 13 dogs tested (P<0.005), apparently without esterification of the PUFA into membrane phospholipids. The antiarrhythmic effect of the n−3 PUFA was associated with slowing of the heart rate, shortening of the QT-interval (electrical action potential duration), reduction of left ventricular systolic pressure, and prolongation of the electrocardiographic atrial-ventricular conduction time (P-R interval). These effects are comparable with those we have reported in studies with cultured neonatal rat cardiac myocytes.     

iPSC-Cardiomyocyte Models of Brugada Syndrome—Achievements,Challenges and Future Perspectives

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias.     

The cardiac antiarrhythmic effects of polyunsaturated fatty acid

Each year in the United States alone some 250,000 persons die within one hour of an acute myocardial infarction. These deaths are largely due to ischemia-induced ventricular arrhythmias, primarily ventricular fibrillation (VF). Thus a safe, simple means of preventing such arrhythmias has considerable public health benefit potential. We have demonstrated that the intravenous infusion of n-3 polyunsaturated fatty acids (PUFA) from fish oils will prevent ischemia-induced VF in prepared, nonanesthetized, exercising dogs, confirming earlier feeding studies in rats. We show that this protective effect is due to an action of the free acidic form of the PUFA to alter the electrophysiology of individual cardiac myocyte so that the cells are electrically more stable. The electrophysiologic effects, in turn, result from direct and specific effects of the PUFA to block the fast voltage-dependent sodium channels. The binding of the free fatty acids is directly to the protein of the sodium channels and results in prolongation of the inactivated state of these channels. Other ion channels are also affected by the PUFA. Two clinical trials with n-3 PUFA are mentioned which inadvertently support the antiarrhythmic potential of PUFA ingestion.     

Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart

In the heart, the delayed rectifier K current, I_K, composed of the rapid (I_Kr) and slow (I_Ks) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel I_K, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered I_K in the heart, using electrophysiology to evaluate changes in I_K in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of I_Kr and I_Ks densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of I_Kr did a proarrhythmic phenotype of I_Ks depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.     

Myocardial membrane fatty acids and the antiarrhythmic actions of dietary fish oil in animal models

Epidemiologic studies, animal studies, and more recently, clinical intervention trials all suggest a role for regular intake of dietary fish oil in reducing cardiovascular morbidity and mortality. Prevention of cardiac arrhythmias and sudden death is demonstrable at fish or fish oil intakes that have little or no effect on blood pressure or plasma lipids. In animals, dietary intake of fish oil [containing both eicosapentaenoic acid (EPA, 20∶5n?3) and docosahexaenoic acid (DHA, 22∶6n?3)] selectively increases myocardial membrane phospholipid content of DHA, whereas low dose consumption of purified fatty acids shows antiarrhythmic effects of DHA but not EPA. Ventricular fibrillation induced under many conditions, including ischemia, reperfusion, and electrical stimulation, and even arrhythmias induced in vitro with no circulating fatty acids are prevented by prior dietary consumption of fish oil. The preferential accumulation of DHA in myocardial cell membranes, its association with arrhythmia prevention, and the selective ability of pure DHA to prevent ventricular fibrillation all point to DHA as the active component of fish oil. The antiarrhythmic effect of dietary fish oil appears to depend on the accumulation of DHA in myocardial cell membranes.     

Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.     

Diabetic Cardiovascular Disease Induced by Oxidative Stress

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.     

Deletion of Trpm4 Alters the Function of the Nav1.5 Channel in Murine Cardiac Myocytes

Transient receptor potential melastatin member 4 (TRPM4) encodes a Ca²⁺-activated, non-selective cation channel that is functionally expressed in several tissues, including the heart. Pathogenic mutants in TRPM4 have been reported in patients with inherited cardiac diseases, including conduction blockage and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes in Trpm4 knockdown mouse models remain incompletely characterized. To study the functional consequences of Trpm4 deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunoblotting studies on isolated atrial and ventricular cardiac myocytes and surfaces, as well as on pseudo- and intracardiac ECGs, either in vivo or in Langendorff-perfused explanted mouse hearts. We observed that TRPM4 is expressed in atrial and ventricular cardiac myocytes and that deletion of Trpm4 unexpectedly reduces the peak Na⁺ currents in myocytes. Hearts from Trpm4^−/− mice presented increased sensitivity towards mexiletine, a Na⁺ channel blocker, and slower intraventricular conduction, consistent with the reduction of the peak Na⁺ current observed in the isolated cardiac myocytes. This study suggests that TRPM4 expression impacts the Na⁺ current in murine cardiac myocytes and points towards a novel function of TRPM4 regulating the Na_v1.5 function in murine cardiac myocytes.     

Lysophosphatidylcholine accumulation in the ischemic canine heart

The production of cardiac arrhythmias and the elevation of lysophosphatidylcholine level in the ischemic myocardium have been well-documented in a number of studies. However, the relationship between the production arrhythmias and the elevation of tissue lysophosphatidylcholine level was not reported. In this study, the lysophosphatidylcholine level and the occurrence of cardiac arrhythmias in the ischemic canine heart were monitored. A temporal relationship between the accumulation of lysophosphatidylcholine and the occurrence of arrhythmias was established after five hr of ischemia. A significant elevation of lysophosphatidylcholine was detected at three hr of ischemia without the occurrence of arrhythmias. The results indicate that cardiac arrhythmias did not cause the elevation of lysophosphatidylcholine and if lysophospholipids are causally related to the arrhythmias that a critical level of the lysophospholipid must accumulate in order to elicit electrophysiological alterations.     

Simvastatin Attenuates the Oxidative Stress,Endothelial Thrombogenicity and the Inducibility of Atrial Fibrillation in a Rat Model of Ischemic Heart Failure

Increased atrial oxidative stress has an important role in inducing and maintaining atrial fibrillation (AF), and the activation of the small GTPase Rac1 contributes to the oxidative stress. We investigated the relationship of Rac1, atrial endothelial thromboprotective markers and AF inducibility and if simvastatin has a potential beneficial effect on a myocardial infarction (MI)-induced heart failure (HF) rat model. Rats were randomized into three groups (shams, MI group and simvastatin treatment group) and underwent echocardiography, AF induction studies and left atrial (LA) fibrosis analysis. Atrial Rac 1, sodium calcium exchanger (I_NCX), sarcoplasmic reticulum calcium ATPase (SERCA), endothelial nitric oxide synthase (eNOS) and induced nitric oxide synthase (iNOS) were measured. AF inducibility, AF duration and LA fibrosis were significantly higher in the MI group (p < 0.001 vs. sham), which were significantly reduced by simvastatin (p < 0.05 vs. MI). The reduced expressions of atrial eNOS, SERCA, thrombomodulin, tissue factor pathway inhibitor and tissue plasminogen activator in the MI group were significantly improved by simvastatin. Furthermore, the increased expression of atrial iNOS, I_NCX and Rac1 activity were significantly decreased by the simvastatin. Oxidative stress, endothelial dysfunction and thrombogenicity are associated with the promotion of AF in a rat model of ischemic HF. These were associated with increased Rac1 activity, and simvastatin treatment prevents these changes.     

The Role of Mitochondrial Dysfunction in Atrial Fibrillation: Translation to Druggable Target and Biomarker Discovery

Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF.     

Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.     

合并心律失常的心力衰竭56例治疗评价

目的探讨心力衰竭并发心律失常的发病规律及治疗方法。方法回顾性分析了93例慢性心力衰竭病人的临床资料,包括临床特点、诊断治疗方法以及预后。结果心律失常发生率为60.2%,以室性早搏发生率最高32.1%,其次是房性早搏26.8%,心房纤颤21.4%,其他19.7%,经治疗有效71例,总有效率76.3%。结论纠正心功能不全是治疗的关键,应根据具体情况选择性地应用抗心律失常药。