Hypertension and Arrhythmias: A Clinical Overview of the Pathophysiology-Driven Management of Cardiac Arrhythmias in Hypertensive Patients 高血压和心律失常：对高血压患者心律失常病理生理驱动管理的临床概述
Jacopo Marazzato 1[(), Federico Blasi , Michele Golino 1[(), Paolo Verdecchia , Fabio Angeli 1,4and Roberto De Ponti (1) 和 Roberto De Ponti (1)1 Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; 意大利瓦雷泽 21100 英苏布里亚大学医学和外科系;j.marazzato88@gmail.com (J.M.); federico.blasi.md@gmail.com (F.B.); micheleg1390@gmail.com (M.G.);angeli.internet@gmail.com (F.A.)2 Fondazione Umbra Cuore e Ipertensione-ONLUS, 06100 Perugia, Italy; verdecchiapaolo@gmail.com 意大利佩鲁贾 06100 年乌姆布拉心脏和高血压基金会; verdecchiapaolo@gmail.com3 Division of Cardiology, Hospital S. Maria della Misericordia, 06100 Perugia, Italy 意大利佩鲁贾 06100 年圣玛利亚慈悲医院心脏病学部4 Department of Medicine and Cardiopulmonary Rehabilitation, Maugeri Care and Research Institute, 意大利玛乔里护理和研究所内科和心肺康复科IRCCS Tradate, 21049 Tradate, Italy 意大利 Tradate 的 IRCCS Tradate, 21049* Correspondence: roberto.deponti@uninsubria.it; Tel.: +39-0332278934 * 通讯地址：roberto.deponti@uninsubria.it；电话：+39-0332278934
Citation: Marazzato, J.; Blasi, F.; Golino, M.; Verdecchia, P.; Angeli, F.; De Ponti, R. Hypertension and Arrhythmias: A Clinical Overview of the Pathophysiology-Driven Management of Cardiac Arrhythmias in Hypertensive Patients. . Cardiovasc. Dev. Dis. 2022, 9, 110. https://doi.org/10.3390/ jcdd9040110 引用：Marazzato, J.; Blasi, F.; Golino, M.; Verdecchia, P.; Angeli, F.; De Ponti, R. 高血压和心律失常：高血压患者心律失常病理生理管理的临床概述。 。心血管发育与疾病。2022, 9, 110. https://doi.org/10.3390/jcdd9040110
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Abstract 摘要
Because of demographic aging, the prevalence of arterial hypertension (HTN) and cardiac arrhythmias, namely atrial fibrillation (AF), is progressively increasing. Not only are these clinical entities strongly connected, but, acting with a synergistic effect, their association may cause a worse clinical outcome in patients already at risk of ischemic and/or haemorrhagic stroke and, consequently, disability and death. Despite the well-known association between HTN and AF, several pathogenetic mechanisms underlying the higher risk of in hypertensive patients are still incompletely known. Although several trials reported the overall clinical benefit of renin-angiotensinaldosterone inhibitors in reducing incident AF in HTN, the role of this class of drugs is greatly reduced when diagnosis is already established, thus hinting at the urgent need for primary prevention measures to reduce AF occurrence in these patients. Through a thorough review of the available literature in the field, we investigated the basic mechanisms through which HTN is believed to promote , summarising the evidence supporting a pathophysiology-driven approach to prevent this arrhythmia in hypertensive patients, including those suffering from primary aldosteronism, a non-negligible and under-recognised cause of secondary HTN. Finally, in the hazy scenario of AF screening in hypertensive patients, we reviewed which patients should be screened, by which modality, and who should be offered oral anticoagulation for stroke prevention. 由于人口老龄化，动脉高血压（HTN）和心律失常，即房颤（AF）的患病率逐渐增加。这些临床实体不仅密切相关，而且具有协同作用，它们的关联可能导致患者在已经处于缺血和/或出血性中风风险的情况下出现更糟糕的临床结果，进而导致残疾和死亡。尽管已知 HTN 和 AF 之间存在密切关联，但导致高血压患者发生 风险增加的几种病因机制仍不完全清楚。尽管有几项试验报告了肾素-血管紧张素-醛固酮抑制剂在减少 HTN 患者发生 AF 方面的整体临床益处，但当 诊断已经确立时，这类药物的作用大大减弱，因此迫切需要采取初级预防措施来减少这些患者发生 AF 的情况。 通过对该领域现有文献的彻底审查，我们调查了高血压被认为促进 的基本机制，总结了支持以病理生理学为基础的方法来预防高血压患者这种心律失常的证据，包括那些患原发性醛固酮增多症的患者，这是继发性高血压的一个不可忽视且未被认识的原因。最后，在高血压患者的房颤筛查模糊情景中，我们审查了应该对哪些患者进行筛查，采用哪种方式进行筛查，以及谁应该接受口服抗凝治疗以预防中风。
The overall prevalence of hypertension (HTN) in adults is roughly [1] and becomes even more common with advancing age [2]. HTN is also a well-known risk factor for atrial fibrillation (AF) [3-5], which may even occur when borderline values of blood pressure (BP) are recorded [6-10]. Moreover, AF exerts an important prognostic role in hypertensive patients, thus potentially leading to ischaemic and haemorrhagic stroke, hospitalisations for heart failure, and, in the worst circumstances, death [10-12]. Therefore, it stands to reason that primary prevention measures devoted to reducing incident are required to avoid potentially troublesome cardiac and cerebrovascular events which may occur in this clinical scenario. Moreover, increasing age and the associated burden of other comorbidities such as diabetes mellitus, heart failure, coronary artery disease, chronic kidney disease, obesity, and obstructive sleep apnea would synergistically act with HTN as major contributors to AF development and progression [10]. 成年人高血压（HTN）的总体患病率大约为 [1]，随着年龄增长变得更为普遍 [2]。HTN 也是房颤（AF）的众所周知的危险因素 [3-5]，即使在记录到血压边缘值时也可能发生 [6-10]。此外，AF 在高血压患者中发挥着重要的预后作用，可能导致缺血性和出血性中风、心力衰竭住院治疗，甚至在最糟糕的情况下导致死亡 [10-12]。因此，可以理解的是，需要采取主要预防措施来减少发生 ，以避免可能在这种临床情况下发生的令人困扰的心脏和脑血管事件。此外，随着年龄增长以及其他合并症的负担，如糖尿病、心力衰竭、冠心病、慢性肾脏疾病、肥胖和阻塞性睡眠呼吸暂停，将与高血压共同作用，成为 AF 发展和进展的主要因素 [10]。
Through a review of the available literature, we investigated the pathophysiological mechanisms responsible for incident AF in hypertensive patients. The aim of this review was therefore to summarise a pathophysiology-driven, patient-tailored approach to prevent the onset of cardiac arrhythmias, namely atrial fibrillation, in the general population affected by HTN. To underscore the importance of a pathophysiological approach to HTN, a dedicated focus has also been reported on which hypertensive patients would greatly benefit from specific treatment options in the setting of primary hyperaldosteronism, a non-negligible cause of secondary HTN. 通过对现有文献的审查，我们调查了高血压患者发生房颤的病理生理机制。因此，本综述的目的是总结一种以病理生理为驱动、针对患者的方法，以预防一般受高血压影响的人群中心房颤等心律失常的发生。为了强调高血压病理生理方法的重要性，还专门关注了哪些高血压患者在原发性醛固酮增多症的情况下将极大受益于特定治疗选择，这是继发性高血压的一个不可忽视的原因。
Moreover, when AF nonetheless develops as an unavoidable consequence of atrial myopathy, it should be recognised in a timely manner to avoid potentially harmful consequences. Although several issues do exist about the possibility of AF screening in hypertensive patients, in this hazy scenario, we investigated the available modalities to detect silent/subclinical AF episodes in hypertensive patients and which patients should be offered oral anticoagulation for stroke prevention. 此外，即使房颤作为心房肌病的不可避免后果而发展，也应及时识别，以避免潜在的有害后果。尽管在高血压患者中进行房颤筛查的可能性存在一些问题，在这种模糊的情况下，我们调查了可用的方法来检测高血压患者中的潜在/亚临床房颤发作，以及哪些患者应该接受口服抗凝治疗以预防中风。
2. Materials and Methods 2. 材料和方法
We performed a bibliographic research on Medline considering manuscripts published up to 2021, according to the following Boolean research strings: "Arterial hypertension AND arrhythmias", "Arterial hypertension AND atrial fibrillation", "Arterial hypertension AND supraventricular arrhythmias". The literature research was independently conducted by two authors (FB and JM) and then revised by JM, FB, and MG, who reached a shared decision by consensus in case of discordance. 我们在 Medline 上进行了文献检索，考虑了截至 2021 年发表的手稿，根据以下布尔检索字符串进行检索："动脉高血压 AND 心律失常"，"动脉高血压 AND 心房颤动"，"动脉高血压 AND 心室上性心律失常"。文献检索由两位作者（FB 和 JM）独立进行，然后由 JM、FB 和 MG 进行修订，对于不一致的情况，他们通过共识达成共同决定。
3. Common Pathophysiological Aspects Explaining the Link between Hypertension and Cardiac Arrhythmias 3. 解释高血压与心脏心律失常之间联系的共同病理生理学方面
As observed in animal models, HTN per se is associated with ion channel imbalance and the progressive development of myocardial fibrosis in hypertensive hearts [13-15]. The ensuing molecular and structural alterations would therefore represent a fertile substrate for arrhythmogenesis. On the one hand, HTN-related shear stress would lead to both a long outward potassium current (Kv1.5) [13] and the altered release of intracellular calcium from the sarcoplasmic reticulum [14], thus leading to a shorter action potential duration and delayed afterdepolarizations (DAD) in myocardial cells, respectively. In fact, a shorter action potential duration would predispose to enhanced automatism and re-entrant mechanisms [16]. In addition to ion channel abnormalities, HTN is also associated with maladaptive gap junction remodelling due to the abnormal expression of gap junction proteins such as connexin 43 and which would determine the abnormal conduction properties and fibrotic evolution of myocardial tissue, thus prompting nonuniform anisotropy, slow conduction, and, therefore, arrhythmogenesis in hypertensive hearts. In addition to this, cardiovascular risk factors, HTN included, are accompanied by low-grade inflammation and oxidative stress, which further promote ion channels and connexin downregulation/dysfunction, abnormal handling, and, finally, the activation of profibrotic signaling, which would all promote arrhythmogenesis [18]. 正如动物模型所观察到的，高血压本身与离子通道失衡和高血压心脏中心肌纤维化的逐渐发展相关[13-15]。随之而来的分子和结构改变因此将成为心律失常的肥沃基质。一方面，高血压相关的剪应力会导致长时间向外的钾离子电流（Kv1.5）[13]和来自肌浆网的细胞内钙释放的改变[14]，从而分别导致心肌细胞动作电位持续时间缩短和延迟后去极化（DAD）。事实上，较短的动作电位持续时间会使自律性增强和再进入机制易发生[16]。除了离子通道异常外，高血压还与适应不良的缝隙连接重塑相关，这是由于缝隙连接蛋白如连接蛋白 43 和[2]的异常表达，这将决定心肌组织的异常传导特性和纤维化演变，从而促使高血压心脏中的非均匀各向异性、缓慢传导，因此导致心律失常。 除此之外，心血管风险因素，包括高血压，在低级炎症和氧化应激的伴随下，进一步促进离子通道和连接蛋白的下调/功能障碍，异常 处理，最终激活促纤维化信号，这些都会促进心律失常的发生[18]。
Furthermore, as displayed on Figure 1, the HTN-related activation of the reninangiotensin-aldosterone (RAA) cascade and sympathetic nervous system (SNS), in addition to myocardial ischemia in hypertrophic hearts, would also play a major role in the pathogenesis of cardiac arrhythmias in HTN [19,20]. All these mechanisms are discussed in the next sections of this article. 此外，如图 1 所示，高血压相关的肾素-血管紧张素-醛固酮（RAA）级联和交感神经系统（SNS）的激活，加上肥厚心脏中的心肌缺血，也将在高血压心脏心律失常的发病机制中发挥重要作用[19,20]。所有这些机制将在本文的后续部分中讨论。
Figure 1. Electro-pathological and clinical changes occurring in hypertensive hearts. ARP, atrial refractory period; SNS, sympathetic nervous system; CV, conduction velocity; CX43, connexin 43; DADs, delayed afterdepolarizations; EADs, early afterdepolarizations; ECM, extracellular matrix; LA, left atrial; LA Vol, left atrial volume; LV, left ventricular; RAAS, renin-angiotensin-aldosterone system. See text for further details. 图 1. 高血压心脏中发生的电-病理学和临床变化。ARP，心房不应期；SNS，交感神经系统；CV，传导速度；CX43，连接蛋白 43；DADs，延迟后去极化；EADs，早期后去极化；ECM，细胞外基质；LA，左心房；LA Vol，左心房容积；LV，左心室；RAAS，肾素-血管紧张素-醛固酮系统。有关更多细节，请参阅正文。
3.1. Myocardial Electro-Pathological Remodelling in Arterial Hypertension: The Key Role of Renin-Angiotensin-Aldosterone and Sympathetic Nervous Systems 动脉高血压中的心肌电-病理重塑：肾素-血管紧张素-醛固酮和交感神经系统的关键作用
Different hormone systems are involved in this complex scenario. On the one hand, angiotensin II, a mediator of RAAS, does modulate specific ion currents in cardiac myocytes, including L- and T-type inward and currents [23]. Moreover, in a murine model, aldosterone seems to increase the molecular expression of L-type channels while reducing the activity of both delayed rectifier ( ) and transient outward currents (Ito1) [24]. Aldosterone has also been shown to induce overload due to the opening of ryanodine receptors in the sarcoplasmic reticulum [25], which may increase delayed afterdepolarizations (DAD), thereby raising the chance of cardiac arrhythmias mediated by triggered activity [26]. In this regard, Pluteanu et al. [27] demonstrated the existence of subcellular alterations in handling in spontaneous hypertensive rats, which were associated with an increased propensity of atrial myocytes to develop frequency-dependent and arrhythmogenic alternans, a mechanism potentially triggering cardiac arrhythmias. 此复杂情景涉及不同的激素系统。一方面，RAAS 的介质血管紧张素 II 确实调节心脏肌细胞中特定的离子电流，包括 L-和 T-型内向 和 电流[23]。此外，在小鼠模型中，醛固酮似乎增加了 L-型 通道的分子表达，同时降低了延迟整流器( )和瞬时外向 电流（Ito1）的活性[24]。醛固酮还被证明能通过肌浆网中瑞诺狄海因受体的开放引起 超载，这可能增加延迟后除极（DAD）的发生，从而增加由诱发活动介导的心律失常的机会[26]。在这方面，Pluteanu 等人[27]证明了自发性高血压大鼠细胞内处理的亚细胞变化存在，与心房肌细胞发生频率相关和心律失常的 交替性增加趋势有关，这可能是触发心律失常的机制。
In addition to ion channel modifications, the RAAS plays a key role in the progression of atrial and ventricular fibrosis through the proliferation of fibroblasts in the extracellular matrix . In fact, myocardial fibrosis, associated with connexin dysregulation, generally leads to slow and heterogeneous conduction velocity, nonhomogenous impulse propagation, and re-entrant atrial and ventricular arrhythmias [11,28]. HTN, as well as the ensuing LV hypertrophy, may also cause an abnormal expression of junctional complexes, which have been associated with greater myocardium vulnerability [15,29]. Moreover, the imbalance between oxygen demand and supply occurring in this setting would further activate myofibroblasts and induce hypertrophic modifications in vascular smooth muscle cells [29,30], thus leading to a vicious cycle made up of collagen deposition [31], progressive myocyte hypertrophy, and diastolic dysfunction [32], which is regarded as the first compensatory pathophysiological response in hypertensive hearts [33]. In addition to these mechanisms, SNS would also lead to enhanced RAAS activity and HTN-induced LV afterload, with a remarkable synergistic effect on arrhythmia onset in hypertrophic hearts [20]. 除了离子通道的修改外，RAAS 通过在细胞外基质中成纤维细胞的增殖，在心房和心室纤维化的进展中发挥关键作用。实际上，与连接蛋白失调相关的心肌纤维化通常导致缓慢和不均匀的传导速度、非均匀的冲动传播以及房室折返性心律失常。高血压以及随之而来的左心室肥厚也可能导致连接复合物的异常表达，这与更大的心肌易感性有关。此外，在这种情况下氧需求和供应之间的不平衡会进一步激活肌成纤维细胞并诱导血管平滑肌细胞的肥大修饰，从而导致由胶原沉积、逐渐的肌细胞肥大和舒张功能障碍组成的恶性循环，这被认为是高血压心脏中的第一种代偿性病理生理反应。 除了这些机制外，SNS 还会导致 RAAS 活性增强和 HTN 诱导的 LV 后负荷增加，在肥厚心脏中对心律失常发作具有显著的协同作用[20]。
From a pathophysiological perspective, diastolic dysfunction generally causes a reduction in LA passive emptying, thus increasing LA pressures during atrial diastole and eventually causing LA enlargement [34]. Over time, the progressive distension and stretching of the LA and pulmonary veins may induce an electrical remodelling of these anatomical chambers, thus leading to shorter atrial effective refractory periods [35], the greater dispersion of atrial repolarisation and, therefore, vulnerability to . LA stretching would also prompt electrical dissociation among muscle bundles, which would further facilitate the initiation and maintenance of multiple small re-entrant wavelets to sustain this cardiac arrhythmia [20]. 从病理生理学的角度来看，舒张功能障碍通常会导致 LA 被动排空减少，从而增加心房舒张期间的 LA 压力，最终导致 LA 扩大[34]。随着时间的推移，LA 和肺静脉的逐渐扩张和拉伸可能会诱发这些解剖腔室的电重塑，从而导致房颤发作的房性有效不应期缩短[35]，房室复极化的分散增加，因此易受 的影响。LA 的拉伸还会促使肌束之间的电解离，进一步促进多个小的再入波波维持这种心律失常的发生和持续[20]。
As to the clinical implication of these pathophysiological mechanisms, AF episodes in hypertensive patients are greatly associated with the severity of LV myocardial stiffness or, in other words, the extent of diastolic dysfunction [38]. In this regard, as assessed on a vast patient cohort undergoing echocardiographic evaluation [38], Tsang et al. showed how the greater the degree of diastolic dysfunction, the higher the probability of AF episodes occurring [38]. Therefore, as shown on Figure 1, the increased LV mass, LV myocardial stiffness, and ensuing diastolic dysfunction and LA enlargement would all play a great role in the genesis of cardiac arrhythmias, namely AF, in hypertensive patients . 关于这些病理生理机制的临床意义，高血压患者的房颤发作与左心室心肌僵硬的严重程度密切相关，换句话说，与舒张功能障碍的程度有关[38]。在这方面，通过对大量接受超声心动图评估的患者队列进行评估[38]，Tsang 等人展示了舒张功能障碍程度越大，房颤发作的概率越高[38]。因此，如图 1 所示，左心室质量增加、左心室心肌僵硬增加、随之而来的舒张功能障碍和左房扩大都将在高血压患者中起到重要作用，即心律失常的发生，即房颤 。
3.2. The Role of Myocardial Ischemia 3.2. 心肌缺血的作用
Myocardial ischemia may lead to arrhythmogenesis in HTN due to mechanisms inherently connected to LVH or atherosclerotic disease involving the major epicardial coronary arteries. On the one hand, changes in arteriolar wall thickening and relative capillary density may lead to reduced microvascular flow in hypertrophic hearts [41-43]. However, HTN-mediated ischemia is not limited to small vessels only, and the global involvement of the coronary artery tree in hypertensive hearts well explains the overall risk of myocardial ischemia and scar formation in these patients [29]. In this regard, a strong connection between the obstruction of atrial coronary branches and AF occurrence in the setting of acute myocardial infarction has been described [44,45]. As observed in studies conducted on animal models [46], atrial ischemia and the ensuing LA stretching synergistically interact in leading to a reduced myocardial conduction velocity and an increased conduction heterogeneity, which would elicit myocardial vulnerability and AF. Of note, not only could atrial ischemia be the result of atherosclerotic heart disease, but pulmonary hypertension and the ensuing combination of hypoxia with increased atrial pressure may prompt AF by means of ischemic mechanisms [47]. 心肌缺血可能导致高血压患者出现心律失常，这是由于与左心室肥厚或累及主要心外膜冠状动脉的动脉粥样硬化等机制内在相关。一方面，动脉小壁增厚和相对毛细血管密度的变化可能导致心肌肥厚心脏微血管流量减少。然而，高血压介导的缺血不仅仅限于小血管，心脏大动脉组全面涉及说明了高血压患者心肌缺血和瘢痕形成的整体风险。在这方面，已经描述了房间隔冠状动脉阻塞与急性心肌梗死并发持久性心房颤动之间的强关联。正如动物模型研究所观察到的，房间隔缺血和随之发生的左心房伸展相互作用导致心肌传导速度减慢和传导不均匀性增加，这将引发心肌易感性增加和心房颤动。 值得注意的是，房颤可能不仅是动脉粥样硬化性心脏病的结果，而且肺动脉高压和随之而来的低氧与增加的心房压力的结合可能通过缺血机制促使房颤发生 [47]。
Moreover, Kolvekar et al. described an association between atrial ischemia and the sclerosis of sinus node and atrioventricular node branches [48], and, as pointed out in a retrospective study conducted by Ciulla et al. [49], the prevalence of AF seems higher in patients with a diseased sinus node artery vs. . Hence, the ischemic damage caused by flow abnormality in the sinus node artery may undermine the structural integrity of the sinus node itself, thus determining a widespread structural and electrical atrial remodelling, which represents the underlying substrate to AF development in this clinical setting. 此外，Kolvekar 等人描述了房颤与窦房结和房室结支的硬化之间的关联 [48]，正如 Ciulla 等人在一项回顾性研究中指出的那样 [49]，房颤的患病率在窦房结动脉疾病患者中似乎更高 vs. 。因此，窦房结动脉流动异常引起的缺血损伤可能破坏窦房结本身的结构完整性，从而确定广泛的结构和电气性心房重塑，这代表了此临床情况下房颤发展的潜在基质。
However, not only AF could be the result of ischemic mechanisms involving atrial branches of epicardial coronary arteries (i.e., primary atrial ischemia), but ventricular ischemia could also be responsible for this cardiac arrhythmia (i.e., ventricular-induced or secondary atrial ischemia). On the one hand, atrial stretching occurring in the setting of myocardial infarction would increase the LA surface area, thus prolonging electrical conduction and facilitating AF initiation and maintenance [50]. However, the greater the ischemic involvement of the LV, the higher the incidence of AF. In a subanalysis of the CULPRIT-SHOCK (Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock) trial, compared with patients with LV myocardial infarction and no cardiogenic shock (CS), the authors observed a significant incidence of AF in patients with CS: global ischemia induced by extensive LV involvement in CS, the ensuing extensive myocardial injury, and the increased LA size and pressure would all explain the remarkable prevalence 然而，房颤不仅可能是涉及心外膜冠状动脉的心房支的缺血机制的结果（即原发性心房缺血），而且室壁缺血也可能是导致这种心律失常的原因（即室壁诱发或继发性心房缺血）。一方面，在心肌梗死的情况下发生的心房拉伸会增加左心房表面积，从而延长电传导时间，促进房颤的发生和维持。然而，左心室的缺血程度越大，房颤的发生率就越高。在 CULPRIT-SHOCK（心源性休克中的罪犯病变单独 PCI 与多支血管 PCI）试验的亚分析中，与左心室心肌梗死且无心源性休克（CS）的患者相比，作者观察到 CS 患者中房颤的显著发生率：由 CS 中广泛左心室受累引起的全局缺血、随之而来的广泛心肌损伤以及增大的左心房尺寸和压力都可以解释这一显著的普遍性。
of AF observed in this high-risk population [51]. Moreover, myocardial ischemia may also lead to the transmural dispersion of ventricular repolarization, which may favour early after depolarizations (EAD) and polymorphic ventricular tachycardias in the affected patients . 在这个高危人群中观察到的 AF 的来源[51]。此外，心肌缺血也可能导致心室复极化的传壁分散，这可能有利于患者早期后去极化(EAD)和多形性心室扑动。
4. Arterial Hypertension and Atrial Fibrillation: Pathophysiology-Based Strategies to Prevent a Hazardous Association 4. 动脉高血压和房颤：基于病理生理学的策略以预防危险的关联
Given the remarkable prevalence of in hypertensive patients, the clinical impact of blood pressure in relation to the occurrence of AF deserves special analysis. A pathophysiology-based approach to HTN in AF patients and a proposed algorithm for the early detection of AF in HTN are provided in the next sections of this article. 鉴于高血压患者中 的显著患病率，血压与房颤发生的临床影响值得特别分析。本文的下一部分提供了基于病理生理学的 HTN 在 AF 患者中的方法和 HTN 早期检测 AF 的建议算法。
4.1. Clinical Implications of High Blood Pressure in Patients with Atrial Fibrillation 房颤患者高血压的临床意义
The presence of uncontrolled HTN in AF patients promotes the already described electro-anatomical atrial remodelling, which is responsible for AF evolution from paroxysmal to more persistent clinical forms of arrhythmia with an overall dismal prognosis in this patient population [54-61]. Indeed, in a large Swedish registry of AF patients on oral anticoagulants, Friberg et al. found that HTN was not only an independent predictor for thromboembolic complications but also of intracranial [HR 1.32, 95% CI (1.15-1.52)] and major bleedings [HR 1.25, 95% CI (1.16-1.33)] [62]. These results are indeed reflected by the integration of HTN in both CHA2DS2-VASc and HAS-BLED scores to estimate the thromboembolic and haemorrhagic hazard, as recommended by current guidelines on AF management . However, it is still debated which, between a long-standing history of increased blood pressure and high systolic blood pressure values per se, portends a greater risk of ischemic and haemorrhagic events in hypertensive patients. In a vast community-based prospective registry, Ishii et al. showed that, in AF patients, only systolic blood pressure values beyond were significantly associated with a higher risk of ischemic [HR 1.74, 95% CI (1.08-2.72)] and bleeding events [HR 2.01, 95% CI (1.21-3.23)] as compared with adequately matched normotensive cases [65]. Similar results were provided by a subanalysis of the Japanese J-RHYTHM AF registry, including more than 7046 patients with nonvalvular AF [66], suggesting that every clinician should aim at an adequate blood pressure control to improve outcome in AF patients. 房颤患者中未控制的高血压促进了已描述的电生理解剖性心房重塑，这导致房颤从阵发性演变为更持续的心律失常临床形式，总体预后在这一患者群体中令人沮丧[54-61]。事实上，在瑞典一个大型房颤患者口服抗凝剂登记处，Friberg 等人发现高血压不仅是血栓栓塞并发症的独立预测因子，还是颅内出血[HR 1.32，95% CI（1.15-1.52）]和主要出血[HR 1.25，95% CI（1.16-1.33）]的预测因子[62]。这些结果确实反映了高血压在 CHA2DS2-VASc 和 HAS-BLED 评分中的整合，用于估计根据目前房颤管理指南推荐的血栓栓塞和出血危险 。然而，长期增高的血压史和高收缩压值本身之间哪个更能预示高血压患者缺血和出血事件的风险仍存在争议。在一个庞大的社区前瞻性登记处，Ishii 等人。 研究显示，在房颤患者中，只有收缩压值超过 与较好匹配的正常血压病例相比，明显与缺血风险[HR 1.74，95% CI（1.08-2.72）]和出血事件[HR 2.01，95% CI（1.21-3.23）]更高相关。日本 J-RHYTHM 房颤登记簿的亚分析也提供了类似的结果，包括超过 7046 名非瓣膜性房颤患者，暗示每位临床医生都应该致力于控制血压，以改善房颤患者的预后。
Moreover, HTN seems responsible for cardioembolic stroke through mechanisms which would act independently from AF. Although the SPRINT (Systolic Blood Pressure Intervention Trial) reported an exceedingly high risk of thromboembolic events in patients with pre-existent and new-onset , despite adequate blood pressure control [67], on the other hand, a body of evidence suggests that HTN per se could also directly promote left atrial thrombosis. In this regard, Zabalgoitia et al. [68] demonstrated a lower flow velocity and a higher risk of thrombosis in the left atrial appendix in hypertensive patients regardless of AF, with results confirmed by a subanalysis of the SPAF-III (Stroke Prevention in Atrial Fibrillation III) trial [69]. In hypertensive patients, endocardial thrombogenesis seems promoted by oxidative stress [70-73], which is increased by RAAS activation and by the subsequent inflammation occurring in diseased atria and in the left atrial appendage [74-76]. 此外，高血压似乎通过机制导致心房栓塞性卒中，这些机制将独立于房颤。尽管 SPRINT（收缩压干预试验）报告称，尽管患有既往和新发高血压的患者在血压控制充分的情况下存在极高的血栓栓塞事件风险，另一方面，大量证据表明高血压本身也可能直接促进左心房血栓形成。在这方面，Zabalgoitia 等人证明了高血压患者左心房附属器内的血流速度较低，血栓风险较高，而这与房颤无关，这一结果得到了 SPAF-III（房颤中的卒中预防 III）试验的子分析证实。在高血压患者中，内膜血栓形成似乎受氧化应激的促进，而氧化应激受 RAAS 激活以及随后在患病心房和左心房附属器中发生的炎症的影响而增加。
Therefore, blood pressure control is paramount to minimize the risk of myocardial ischemia, stroke, and oral-anticoagulant-related bleedings in AF cases. Until more data are available, blood pressure values in AF patients on oral anticoagulants should be at least and for systolic and diastolic blood pressure values, respectively , and oral anticoagulants should be used with caution in patients with persistent uncontrolled hypertension [10]. Moreover, in case of any clinical suspicion of myocardial ischemia, the prompt assessment of the atherosclerotic involvement of epicardial coronary arteries is mandatory in these patients. 因此，控制血压对于减少房颤患者发生心肌缺血、中风和口服抗凝药相关出血的风险至关重要。在有更多数据可用之前，房颤患者口服抗凝药时的血压值应至少为 和 ，分别为收缩压和舒张压值 ，在持续未控制的高血压患者中应谨慎使用口服抗凝药[10]。此外，在出现任何心肌缺血的临床怀疑时，必须及时评估这些患者心外膜冠状动脉的动脉粥样硬化受累情况。
Therefore, it stands to reason that primary prevention measures to prevent AF occurrence and the early detection of this arrhythmia [68] are paramount in patients diagnosed with HTN to avoid the described life-threatening major cerebral and cardiovascular events. 因此，可以说，在诊断为高血压的患者中，首要预防措施是预防房颤发生和早期检测这种心律失常[68]，以避免描述的危及生命的主要脑血管事件和心血管事件的发生。
4.2. Primary Prevention of Atrial Fibrillation: A Pathophysiology-Based Approach in Patients with Essential Hypertension 4.2. 基本高血压患者房颤的初级预防：一种基于病理生理学的方法
Given the predominant role of RAAS in the pathogenesis of AF, ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) seem a reasonable first-line treatment option in hypertensive patients. Moreover, LVH has been shown to be partially reversible after treatment with RAAS blockers, with studies demonstrating improved electrical and structural parameters and reduced AF burden following treatment with these agents [78-80]. 考虑到 RAAS 在 AF 发病机制中的主导作用，ACE 抑制剂（ACEi）和血管紧张素受体拮抗剂（ARB）似乎是高血压患者合理的首选治疗选项。此外，RAAS 阻滞剂治疗后 LVH 已显示出部分可逆性，研究表明这些药物治疗后改善了电生理和结构参数，并减轻了 AF 负荷 [78-80]。
In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9193 hypertensive patients were randomized to once-daily losartan- or atenolol-based antihypertensive therapy to detect outcome differences regarding the long-term occurrence of new-onset AF. Compared with Atenolol, Losartan was associated with significantly fewer AF episodes and a better overall outcome [RR 0.67, 95% CI 0.55-0.83] [81]. 在 Losartan 干预降低高血压终点指标 (LIFE) 研究中，9193 名高血压患者被随机分配到每日一次的 Losartan- 或 Atenolol-基础的抗高血压治疗组，以检测新发 AF 的长期发生差异。与 Atenolol 相比，Losartan 与显著较少的 AF 发作和较好的总体结果相关 [RR 0.67, 95% CI 0.55-0.83] [81]。
ACEi or ARB could have an even greater role in avoiding AF occurrence in patients with LVH and systolic heart failure [82-84]. Although this effect has been attributed to the antifibrotic and antiapoptotic effect of these drugs, this superiority over betablockers is nonetheless quite surprising. Therefore, despite the intrinsic antiarrhythmic effect of betablockers, both cardiac fibrosis and negative remodelling play a central role in AF onset in hypertensive patients. Even when tested versus calcium antagonists, RAAS blockers showed a lower risk of AF development in a similar patient population [85]. ACEi 或 ARB 在具有 LVH 和收缩性心力衰竭的患者中避免 AF 发生可能会发挥更大的作用[82-84]。尽管这种效果被归因于这些药物的抗纤维化和抗凋亡作用，但与贝塔受体阻滞剂相比，这种优势仍然令人惊讶。因此，尽管贝塔受体阻滞剂具有固有的抗心律失常作用，在高血压患者中，心脏纤维化和负性重塑在 AF 发生中起着核心作用。即使与钙拮抗剂相比，RAAS 阻滞剂在类似的患者群中显示出较低的 AF 发展风险[85]。
Although RAAS blockers showed a net superiority over beta-blockers for AF prevention in HTN patients, their combined use seems beneficial in hypertensive patients suffering from heart failure. In a meta-analysis including 11,952 patients, Nasr et al. reported that betablockers significantly reduced the incidence of AF onset in heart failure, provided that a background treatment with ACEi was warranted, and similar outcomes were observed for MRA in similar patients [86]. Another clear benefit of betablockers is the well-known protection against sudden cardiac death . 尽管 RAAS 阻滞剂在高血压患者中预防 AF 方面优于贝塔受体阻滞剂，但它们的联合使用在患有心力衰竭的高血压患者中似乎是有益的。在一项包括 11,952 名患者的荟萃分析中，Nasr 等人报告称，贝塔受体阻滞剂显著降低了心力衰竭患者 AF 发生的发病率，前提是需要与 ACEi 背景治疗，并且类似的结果也观察到了 MRA 在类似患者中的表现[86]。贝塔受体阻滞剂的另一个明显好处是其对突发心脏死亡的众所周知的保护 。
In light of this evidence, betablockers seem to further support the action of RAAS blockers in AF prevention in hypertensive patients; however, they should not be regarded as a first-line therapy for HTN unless there is a specific indication for their use, such as heart failure, angina symptoms, or established AF [1]. 根据这些证据，贝塔受体阻滞剂似乎进一步支持 RAAS 阻滞剂在高血压患者中预防 AF 的作用；然而，除非存在特定适应症，如心力衰竭、心绞痛症状或已确诊的 AF，否则不应将其视为高血压的一线治疗方案 [1]。
In conclusion, although RAAS inhibitors do not seem to prevent AF recurrence in patients with an already established diagnosis of this cardiac arrhythmia [88-90], ACEi and ARB should be first offered to patients with essential hypertension to prevent incident AF. Although betablockers and MRA should be generally used in addition to ACEi and ARB in specific settings, MRA are to be first considered in specific subsets, such as patients suffering from primary aldosteronism (PA), a non-negligible cause of secondary hypertension. 总之，尽管 RAAS 抑制剂似乎不能预防已确诊为这种心脏心律失常的患者 AF 复发 [88-90]，但 ACEi 和 ARB 应首先提供给患有原发性高血压的患者，以预防发生 AF。尽管贝塔受体阻滞剂和 MRA 应通常与 ACEi 和 ARB 一起在特定情况下使用，但 MRA 首先应考虑在特定亚组中使用，如患有原发性醛固酮分泌增多症（PA）的患者，这是继发性高血压的一个不可忽视的原因。
Finally, there is strong evidence from preclinical research and clinical studies that targeting inflammation and oxidative stress may provide a path to ameliorate cardiac arrhythmia burden. Indeed, cardioprotective SGLT2 inhibitors, statins, and omega-3 fatty acids exhibit potent antioxidative and anti-inflammatory properties. These agents most likely affect the proarrhythmia primary mechanisms, such as triggered activity as well as profibrotic signalling. However, the causal relationship is missing, and further studies are required to assess the real impact of these drugs on arrhythmogenesis in hypertensive patients [18]. 最终，有来自临床前研究和临床研究的强有力证据表明，针对炎症和氧化应激可能为减轻心律失常负担提供途径。事实上，心脏保护性 SGLT2 抑制剂、他汀类药物和ω-3 脂肪酸具有强大的抗氧化和抗炎特性。这些药物很可能影响促心律失常的主要机制，如触发活性和纤维化信号传导。然而，缺乏因果关系，需要进一步研究评估这些药物对高血压患者心律失常发生的真实影响[18]。
4.3. Focus on Primary Aldosteronism: An Under-Recognized Cause of Secondary Hypertension Prompting a Targeted Medical and Surgical Treatment 4.3. 焦点在原发性醛固酮增多症：一种被低估的继发性高血压原因，促使进行有针对性的药物和手术治疗
PA, also known as primary hyperaldosteronism or Conn's syndrome, refers to the excess production of aldosterone essentially caused by hyperplasia or tumors involving adrenal glands and resulting in high blood pressure in the affected patients [91]. It is the most common endocrine cause of secondary hypertension, with a prevalence spanning from in hypertensive patients to in those with resistant HTN [92]. Moreover, a body of evidence suggests that PA confers a greater risk of stroke, AF, and cardiovascular disease than similar patient cohorts with essential hypertension [93]. PA，也被称为原发性醛固酮增多症或康氏综合征，指的是由于肾上腺的增生或肿瘤过度产生醛固酮，导致患者血压升高 [91]。它是继高血压患者的最常见内分泌原因之后的二级高血压，其患病率从 到抗高血压治疗无效的患者中的 [92]。此外，大量证据表明，与原发性高血压相比，PA 患者更容易患中风、房颤和心血管疾病 [93]。
As to associated cardiac arrhythmias, is by far the most observed rhythm disorder (7.2% prevalence on average), with other cardiac arrhythmias occurring in up to of cases . 至于相关的心律失常， 是最常见的节律失常（平均患病率 7.2%），其他心律失常在 的病例中也有发生 。
PA could promote arrhythmogenesis through different mechanisms [96]. On the one hand, aldosterone hypersecretion induces inflammation by producing reactive oxygen species which activate proinflammatory transcription factors in macrophages [74-76], causing cardiac interstitial macrophage infiltration with subsequent fibrosis [97]. On the other hand, through resting membrane hyperpolarization, ATPase inhibition, and the suppression of channel conductance, aldosterone-mediated hypokalemia further explains the mechanisms of arrhythmogenesis occurring in PA patients [98-100]. Accordingly, a study from the German Conn's Registry confirmed that AF was more commonly found in patients with the hypokalemic variant of PA than in those with normal values of serum potassium levels [95]. PA 可能通过不同的机制促进心律失常的发生[96]。一方面，醛固酮过度分泌通过产生活性氧自由基在巨噬细胞中激活促炎转录因子，引发炎症反应 [74-76]，导致心脏间质巨噬细胞浸润并随之纤维化 [97]。另一方面，通过静息膜极化、 酶抑制和 通道传导抑制，醛固酮介导的低钾血症进一步解释了 PA 患者心律失常发生的机制 [98-100]。在德国 Conn's 注册研究中的一项研究证实，低钾型 PA 患者中常见的是房颤，而正常血钾水平的患者中较少见 [95]。
Therefore, PA has targeted medical treatment and potentially curative surgical solutions, which may ameliorate the associated cardiovascular risks as well as the rate of incident . 因此，PA 有针对性的药物治疗和潜在的治愈性手术解决方案，这些解决方案可能改善相关心血管风险以及发病率 。
Figure 2 shows a flowchart helping the clinician to diagnose and manage PA when clinically suspected [101]. Broadly speaking, patients who demonstrate a suppressed renin, markedly elevated aldosterone (i.e., when plasma aldosterone concentration is greater than or ), and spontaneous hypokalemia can also be diagnosed with PA without confirmatory testing [102]. When PA diagnosis is confirmed, dietary sodium restriction and medical treatment with MRA should be immediately offered, not only to reduce blood pressure but also to lower the overall risk of AF occurrence [103]. However, surgical adrenalectomy seems associated with even better long-term cardiovascular outcomes [101], a further reduction in AF occurrence, and other major cardiovascular comorbidities in these patients [104]. Therefore, in the case of PA diagnosis, cross-sectional imaging is required to localise the adrenal mass, thus prompting further surgical evaluation in selected PA cases (Figure 3). 图 2 显示了一个流程图，帮助临床医生在临床上怀疑时诊断和管理原发性醛固酮增多症[101]。广义上讲，表现出肾素抑制、醛固酮显著升高（即血浆醛固酮浓度大于 或 ）和自发性低钾血症的患者也可以在没有确诊测试的情况下被诊断为原发性醛固酮增多症[102]。当原发性醛固酮增多症确诊时，应立即提供饮食限钠和 MRA 药物治疗，不仅可降低血压，还可降低房颤发生的整体风险[103]。然而，手术切除肾上腺似乎与更好的长期心血管结果相关[101]，进一步降低这些患者的房颤发生率和其他主要心血管并发症[104]。因此，在原发性醛固酮增多症确诊的情况下，需要进行横断面成像以定位肾上腺肿块，从而在选定的原发性醛固酮增多症病例中促使进一步的手术评估（图 3）。
Figure 2. Screening and diagnostic approach for primary aldosteronism. A positive screen for primary aldosteronism should suggest high aldosterone levels and a suppressed renin activity. Confirmatory testing can be used in this setting. Solid arrows indicate recommended decision pathways; dashed arrows indicate other possible diagnostic alternatives in appropriate clinical contexts. * Confirmatory testing suggesting aldosterone hypersecretion: (1) oral sodium suppression (positive if urinary aldosterone excretion rate is greater than 12-14 mg/die); (2) supine intravenous saline suppression (positive if aldosterone levels are greater than after of saline infusion); (3) fludrocortisone suppression (positive if seated aldosterone greater than with plasma renin activity lower than ); and, finally, (4) captopril challenge (positive if less than suppression of aldosterone from baseline while plasma renin activity remains suppressed post of oral captopril). , atrial fibrillation; BP, blood pressure; HTN, hypertension; MRA, mineralcorticoid-receptor antagonists; OSAS, obstructive sleep apnea syndrome; PA, primary aldosteronism. (Modified and adapted from document of The Endocrine Society [101]). 图 2. 原发性醛固酮增多症的筛查和诊断方法。对原发性醛固酮增多症的阳性筛查应提示高醛固酮水平和抑制的肾素活性。在这种情况下可以使用确诊性检测。实线箭头表示推荐的决策路径；虚线箭头表示适当临床背景下的其他可能诊断选择。* 确诊性检测提示醛固酮分泌亢进：（1）口服钠抑制（如果 尿醛固酮排泄率大于 12-14 mg/die 则为阳性）；（2）卧位静脉盐水抑制（如果盐水输注 后醛固酮水平大于 则为阳性）；（3）氟氢可的松抑制（如果静坐时醛固酮大于 且血浆肾素活性低于 则为阳性）；最后，（4）卡普托普利挑战（如果口服卡普托普利 后，醛固酮从基线抑制少于 而血浆肾素活性仍然被抑制则为阳性）。 ，房颤；BP，血压；HTN，高血压；MRA，矿物皮质激素受体拮抗剂；OSAS，阻塞性睡眠呼吸暂停综合征；PA，原发性醛固酮增多症。 (修改并改编自《内分泌学会文献[101]》中的文档)。
Figure 3. (A-D). Computed tomography of the abdomen in a patient with suspected primary aldosteronism. A 78-year-old patient referred to medical attention for dysregulated hypertension, irregular heartbeat, and remarkable peripheral oedema. Upon admission, 12-lead ECG showed atrial fibrillation with high ventricular rate. Transthoracic echocardiogram displayed signs of moderate left ventricular hypertrophy only. Laboratory tests showed remarkably low potassium levels together with high levels of serum aldosterone and suppressed renin activity. Therefore, computed tomography scan of the abdomen with iodine contrast administration was then carried out to identify any adrenal mass (A-D). A , bulky adrenal tumor is well evident from cross-sectional imaging acquired during the arterial phase (A). The mass (white arrows) shows hypodense foci and colliquative areas with signs of compression of the neighboring anatomical structures. From a caudal to a more cranial perspective, the inferior vena cava and renal veins are progressively compressed and anteriorly dislodged by the adrenal mass (dashed arrows, B-D), thus explaining the remarkable peripheral oedema clinically observed in this patient. The patient is currently scheduled for abdominal video laparoscopy for adrenal mass excision and the ensuing histopathologic characterization. 图 3. (A-D)。一名疑似原发性醛固酮增多症患者的腹部计算机断层扫描。一名 78 岁的患者因高血压失控、心律不齐和明显的外周水肿而就医。入院时，12 导联心电图显示心房颤动伴高心室率。经胸超显示仅有中度左心室肥厚的迹象。实验室检查显示钾水平明显降低，血清醛固酮水平升高，肾素活性受抑制。因此，随后进行了腹部含碘造影剂的计算机断层扫描以识别任何肾上腺肿块(A-D)。在动脉期获得的横断面成像清晰显示一个 ，肿大的肾上腺肿瘤(A)。该肿块(白色箭头)显示低密度灶和液化区域，伴有对邻近解剖结构的压迫迹象。 从尾端到更头端的视角，下腔静脉和肾静脉逐渐被肾上腺肿块压迫并向前移位（虚线箭头，B-D），从而解释了临床上观察到的患者明显的周围水肿。患者目前计划进行腹部视频腹腔镜手术以切除肾上腺肿块并进行随后的组织病理学特征描述。
5. Early Detection of Atrial Fibrillation in Hypertensive Patients: A Proposed Algorithm 5. 高血压患者房颤的早期检测：提出的算法
Despite all efforts to prevent AF in hypertensive patients, structural heart disease and atrial cardiomyopathy in this setting would nonetheless cause progressive atrial derangement and electrical vulnerability, thus promoting a vicious cycle known as "atrial failure", which is intimately connected with AF development [105]. 尽管尽一切努力预防高血压患者的房颤，但在这种情况下的结构性心脏病和心房肌病仍然会导致心房逐渐失调和电学易感性，从而促进了一个被称为“心房衰竭”的恶性循环，这与房颤的发展密切相关。
It is well known that AF is a potentially life-threatening cause of cerebral thromboembolism, and clinically silent forms might wreak even greater havoc if not recognised in a timely manner. For these reasons, hypertensive patients with an uncertain history of AF and evidence of prior cerebrovascular events should be accurately studied to differentiate strokes of cardioembolic origin from those secondary to atherosclerotic disease or cerebral haemorrhage [106]. In these cases, ECG monitoring can be helpful to identify patients with clinically silent AF , and, in the case of cryptogenic stroke, an implantable cardiac monitor (ICM) should be considered [10]. Over the last decade, cardiac implantable electronic devices (CIEDs) [109], ICM included [110], have proved extremely helpful in the early detection of subclinical AF episodes, but it is still debated which arrhythmic burden should prompt immediate oral anticoagulation in these patients. For the sake of clarity, clinically silent AF is defined for asymptomatic arrhythmia episodes detected on 12-lead ECG or an ECG strip; conversely, subclinical AF is represented by arrhythmia detected by CIEDs [10]. However, differentiating clinical from subclinical AF is not a matter of mere speculation. In fact, subclinical AF seems to portend a lower thromboembolic risk compared with clinical AF [111], and no clear cause-effect relationship between subclinical and ischemic stroke has been clearly proven in this setting [109]. However, the longer the duration of subclinical AF episodes, the greater their association with thromboembolic events [112]. For this reason, a recent European Heart Rhythm Association (EHRA) consensus document suggested oral anticoagulation administration for subclinical AF episodes longer than day only when a significant risk of cerebral thromboembolism is established (i.e, CHA2DS2Vasc scores and 3 in men and women, respectively) [111]. Whether this strategy pays off in terms of better clinical outcome is unclear. In fact, by randomising elderly patients with stroke risk factors and no AF history to the ICM strategy or usual care, the LOOP study did not prove the superiority of ICM over controls in terms of better clinical outcome after early AF detection [110]. Several issues raised by the same investigators might explain the overall negative results of this trial, such as the inadequate estimate of the primary outcome event rate, the relatively short duration of follow-up, and the initiation of oral anticoagulation for subclinical episodes lasting as low as . In keeping with prior observations [112], these results would suggest that not all subclinical AF episodes may benefit from early anticoagulation, and two ongoing randomized controlled trials might provide clearer answers in patients with CIEDs [113,114]. 众所周知，房颤是导致脑血栓栓塞的潜在危及生命的原因之一，临床上无症状的形式如果未能及时识别可能会造成更大的破坏。因此，对于有高血压病史但房颤病史不确定且有先前脑血管事件证据的患者，应进行准确研究以区分心源性卒中和由动脉粥样硬化疾病或脑出血引起的卒中[106]。在这些情况下，心电图监测可以帮助识别有临床无症状房颤的患者，而对于隐源性卒中，应考虑植入式心脏监测器（ICM）[10]。在过去的十年里，心脏植入式电子设备（CIEDs）[109]，包括 ICM[110]，已被证明在早期检测亚临床房颤发作方面极为有帮助，但目前仍在讨论哪种心律失常负荷应促使这些患者立即口服抗凝。为了明确起见，临床无症状房颤被定义为在 12 导联心电图或心电图条上检测到的无症状心律失常发作；相反，亚临床房颤是由 CIEDs 检测到的心律失常[10]。 然而，将临床 AF 与亚临床 AF 区分开来并非仅仅是一种猜测。事实上，与临床 AF 相比，亚临床 AF 似乎预示着较低的血栓栓塞风险[111]，在这种情况下，亚临床 AF 与缺血性中风之间没有明确的因果关系[109]。然而，亚临床 AF 发作持续时间越长，与血栓栓塞事件的关联性就越大[112]。因此，最近一份欧洲心脏节律协会（EHRA）的共识文件建议，只有在确立了明显的脑血栓栓塞风险时（即 CHA2DS2Vasc 评分在男性和女性分别为 和 3 时），才应在亚临床 AF 发作持续时间超过 天时进行口服抗凝治疗[111]。这种策略是否能带来更好的临床结果尚不清楚。事实上，通过将具有中风风险因素但无 AF 病史的老年患者随机分配到 ICM 策略或常规护理，LOOP 研究并未证明 ICM 在早期 AF 检测后在临床结果方面优于对照组[110]。 同一研究人员提出的几个问题可能解释了这项试验的整体负面结果，例如对主要结局事件率的估计不足，随访时间相对较短，以及对持续时间低至 的亚临床发作进行口服抗凝治疗的启动。与先前的观察结果一致[112]，这些结果表明，并非所有亚临床 AF 发作都能从早期抗凝治疗中受益，而两项正在进行的随机对照试验可能会为携带 CIEDs 的患者提供更清晰的答案[113,114]。
Moreover, in this already hazy scenario, it is all but crystal-clear which hypertensive patients with neither stroke history nor CIEDs/ICM should be screened for silent AF, and, not least, through which modality. On the one hand, the burden of cardiovascular comorbidities and blood biomarkers might play an important role in identifying people at a sufficient risk to warrant AF screening [115]. The thorough assessment of the wave morphology on surface ECG may also be useful in identifying potential risk markers for AF, such as prolonged wave duration, left atrial enlargement, and advanced interatrial (i.e., Bachmann bundle) block. [116]. Similar observation can be made for LVH, diastolic dysfunction, and left atrial enlargement as assessed on transthoracic echocardiogram [116]. However, what would be the best approach for AF screening in high-risk patients? On one side of the spectrum of the available modalities for AF screening, on account of the low cost and the great sensitivity yield, radial pulse taking should be regarded as the first option to be offered in patients aged years and deemed at high risk of developing AF. Surface ECG analysis in the case of arrhythmic pulse is therefore warranted, and, if clinical AF is confirmed, oral anticoagulation should be promptly administered according to the patient's thromboembolic risk profile [10]. Furthermore, a variety of screening technologies have been developed over the years and with progressively better AF detection accuracy [117], but no comparative trials have been carried out so far with any of these devices. Accordingly, European guidelines on AF diagnosis and management [10] strongly recommend a single-lead ECG tracing of s or 12-lead ECG to confirm a diagnosis of clinical AF when detected by screening tools. Although similar observation can be applied to the use of ICM in the same setting, the positive clinical interaction observed in the LOOP 此外，在这个已经模糊不清的情景中，很难确定哪些高血压患者既没有中风史也没有植入心脏起搏器/植入式心律失常监测器的人应该接受无症状房颤筛查，更不用说通过哪种方式进行筛查了。一方面，心血管合并症的负担和血液生物标志物可能在识别具有足够风险需要进行房颤筛查的人群中发挥重要作用。表面心电图上 波形态的全面评估也可能有助于识别房颤的潜在风险标志，如 波持续时间延长、左心房扩大和高级心房间（即巴赫曼束）传导阻滞。对于通过胸部超声心动图评估的左心室肥厚、舒张功能障碍和左心房扩大，也可以得出类似观察结果。然而，在高危患者中进行房颤筛查的最佳方法是什么？在可用的房颤筛查方式的范围中，由于成本低且敏感性高，应该将搏动脉搏动作为首选方式提供给年龄为 岁且被认为有高风险患房颤的患者。 在心律失常脉搏的情况下，因此有必要进行表面心电图分析，如果确认临床房颤，应根据患者的血栓栓塞风险评估及时给予口服抗凝治疗[10]。此外，多年来已开发了各种筛查技术，并且随着房颤检测准确性的逐渐提高[117]，但迄今为止尚未进行任何这些设备的比较试验。因此，欧洲关于房颤诊断和管理的指南[10]强烈建议在通过筛查工具检测到临床房颤时，进行 秒的单导联心电图追踪或 12 导联心电图以确认诊断。尽管类似的观察结果也适用于在相同情况下使用 ICM，但在 LOOP 试验中观察到的积极临床相互作用
trial between high blood pressure values and better clinical outcome in early anticoagulated patients in the ICM arm may prompt the use of an implantable loop recorder (ILR) as a screening tool in selected patients with HTN. 试验中，在 ICM 组早期抗凝患者中高血压值与更好的临床结果之间的正面临床相互作用可能会促使在 HTN 患者中选择性地使用植入式环记录仪（ILR）作为筛查工具。
In conclusion, AF detection in its early stage is paramount, and an appropriate therapy might eschew severe complications potentially leading to disability and death in the affected patients. However, it should be ascertained which patients portend a greater risk of AF and thereby who should be screened for this arrhythmia and by which modality. While waiting for sounder results from ongoing clinical trials, Figure 4 provides a proposed algorithm for silent/subclinical AF detection and management in hypertensive patients. 总之，早期检测房颤至关重要，适当的治疗可能避免患者出现严重并发症，从而导致残疾和死亡。然而，应该确定哪些患者存在更大的房颤风险，以及谁应该接受这种心律失常的筛查以及通过哪种方式。在等待正在进行的临床试验取得更可靠的结果时，图 4 提供了高血压患者隐匿/亚临床房颤检测和管理的建议算法。
Figure 4. Proposed algorithm for early detection and management of silent and subclinical atrial fibrillation episodes. atrial fibrillation; cardiac implantable electronic devices; ICM = internal cardiac monitor; ILR = internal loop recorder; HTN = hypertension . 图 4. 早期检测和管理隐匿和亚临床房颤发作的建议算法。 房颤; 心脏植入式电子设备; ICM = 内部心脏监测器; ILR = 内部环记录器; HTN = 高血压。
6. Conclusions and Future Directions 6. 结论和未来方向
Through enhanced RAAS and the ensuing pathophysiological mechanisms, HTN represents a well-known substrate for cardiac arrhythmias. Although several trials reported the overall clinical benefit of RAAS inhibitors in reducing AF onset in essential HTN, the role of this class of drugs is greatly reduced when AF diagnosis is already established. Therefore, primary prevention measures are strongly recommended to avoid the potential occurrence of AF in a population already at risk of ischemic and/or haemorrhagic cerebral stroke and, consequently, of disability and death. On the one hand, a patient-tailored, pathophysiologydriven strategy is mandatory in all hypertensive patients, from the administration of RAAS inhibitors in essential HTN to the early detection of secondary HTN causes, namely PA, warranting a specific medical and surgical treatment which has proved to ameliorate the overall outcome in this specific population. 通过增强的 RAAS 和随之而来的病理生理机制，高血压代表心律失常的一个众所周知的基质。尽管几项试验报告了 RAAS 抑制剂在降低原发性高血压患者中房颤发作的总体临床益处，但当房颤诊断已经确立时，这类药物的作用大大减少。因此，强烈建议采取初级预防措施，以避免在已经处于缺血和/或出血性脑卒中风险中的人群中潜在发生房颤，从而导致残疾和死亡。一方面，对所有高血压患者都必须采取以患者为中心、以病理生理为驱动的策略，从在原发性高血压中使用 RAAS 抑制剂到早期发现继发性高血压原因，即肾上腺皮质功能亢进，需要特定的医疗和外科治疗，已被证明可以改善这一特定人群的总体预后。
Finally, although several issues still exist as to the possibility of AF screening in the general population affected by HTN, the early detection of silent/subclinical episodes of AF should be nonetheless carried out while waiting for sounder evidence from ongoing randomised controlled trials in the field. 最后，尽管在受高血压影响的一般人群中进行房颤筛查仍存在一些问题，但在等待该领域正在进行的随机对照试验提供更可靠证据的同时，仍应进行房颤的潜在/亚临床发作的早期检测。
Abstract 摘要
Author Contributions: Conceptualization, J.M. and F.B.; methodology, J.M.; validation, R.D.P., F.A. and P.V.; investigation, F.B. and M.G.; writing—original draft preparation, J.M.; writing—review and editing, F.B. and M.G.; visualization, M.G.; supervision, F.A. and P.V.; project administration, R.D.P. All authors have read and agreed to the published version of the manuscript. All authors contributed to the study conception and design. 作者贡献：概念化，J.M. 和 F.B.；方法论，J.M.；验证，R.D.P.，F.A. 和 P.V.；调查，F.B. 和 M.G.；原始草稿准备，J.M.；审阅和编辑，F.B. 和 M.G.；可视化，M.G.；监督，F.A. 和 P.V.；项目管理，R.D.P. 所有作者已阅读并同意发表的手稿版本。所有作者均对研究构思和设计做出了贡献。
Funding: This research received no external funding. 资金：这项研究未获得外部资助。
Institutional Review Board Statement: Not applicable. 机构审查委员会声明：不适用。
Informed Consent Statement: Not applicable. 知情同意声明：不适用。
Conflicts of Interest: The authors declare no conflict of interest. 利益冲突：作者声明没有利益冲突。
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