Navx-guided Cryoablation of Atrial Tachycardia Inside the Left Atrial Appendage

Radiofrequency ablation procedures inside the left atrial appendage (LAA) are likely to involve dangerous complications because of a high thrombogenic effect. Cryoablation procedures are supposed to be safer. We describe two cases of successful cryoablation procedures. Two NavX-guided cryoablations of permanent focal atrial arrhythmias arising from the LAA were performed. Left atrial reconstruction and mapping allowed the zone of the earliest atrial potential to be recorded; the entire course of the ablation catheter was monitored. The arrhythmias were successfully ablated; no thrombotic complications were observed.     

The WATCHMAN Left Atrial Appendage Closure Device for Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 6 million people in the United States ¹. Since AF affects primarily elderly people, its prevalence increases parallel with age. As such, it is expected that 15.9 million Americans will be affected by the year 2050 ². Ischemic stroke occurs in 5% of non-anticoagulated AF patients each year. Current treatments for AF include rate control, rhythm control and prevention of stroke ³.The American College of Cardiology, American Heart Association, and European Society of Cardiology currently recommended rate control as the first course of therapy for AF ³. Rate control is achieved by administration of pharmacological agents, such as β-blockers, that lower the heart rate until it reaches a less symptomatic state ³. Rhythm control aims to return the heart to its normal sinus rhythm and is typically achieved through administration of antiarrhythmic drugs such as amiodarone, electrical cardioversion or ablation therapy. Rhythm control methods, however, have not been demonstrated to be superior to rate-control methods ^4-6. In fact, certain antiarrhythmic drugs have been shown to be associated with higher hospitalization rates, serious adverse effects ³, or even increases in mortality in patients with structural heart defects ⁷. Thus, treatment with antiarrhythmics is more often used when rate-control drugs are ineffective or contraindicated. Rate-control and antiarrhythmic agents relieve the symptoms of AF, including palpitations, shortness of breath, and fatigue ⁸, but don''t reliably prevent thromboembolic events ⁶.Treatment with the anticoagulant drug warfarin significantly reduces the rate of stroke or embolism ^9,10. However, because of problems associated with its use, fewer than 50% of patients are treated with it. The therapeutic dose is affected by drug, dietary, and metabolic interactions, and thus requires detailed monitoring. In addition, warfarin has the potential to cause severe, sometimes lethal, bleeding ². As an alternative, aspirin is commonly prescribed. While aspirin is typically well tolerated, it is far less effective at preventing stroke ¹⁰. Other alternatives to warfarin, such as dabigatran ¹¹ or rivaroxaban ¹² demonstrate non-inferiority to warfarin with respect to thromboembolic events (in fact, dabigatran given as a high dose of 150 mg twice a day has shown superiority). While these drugs have the advantage of eliminating dietary concerns and eliminating the need for regular blood monitoring, major bleeding and associated complications, while somewhat less so than with warfarin, remain an issue ^13-15.Since 90% of AF-associated strokes result from emboli that arise from the left atrial appendage (LAA) ², one alternative approach to warfarin therapy has been to exclude the LAA using an implanted device to trap blood clots before they exit. Here, we demonstrate a procedure for implanting the WATCHMAN Left Atrial Appendage Closure Device. A transseptal cannula is inserted through the femoral vein, and under fluoroscopic guidance, inter-atrial septum is crossed. Once access to the left atrium has been achieved, a guidewire is placed in the upper pulmonary vein and the WATCHMAN Access Sheath and dilator are advanced over the wire into the left atrium. The guidewire is removed, and the access sheath is carefully advanced into the distal portion of the LAA over a pigtail catheter. The WATCHMAN Delivery System is prepped, inserted into the access sheath, and slowly advanced. The WATCHMAN device is then deployed into the LAA. The device release criteria are confirmed via fluoroscopy and transesophageal echocardiography (TEE) and the device is released.     

Catheter Ablation in Combination With Left Atrial Appendage Closure for Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting millions of individuals worldwide ^1-3. The rapid, irregular, and disordered electrical activity in the atria gives rise to palpitations, fatigue, dyspnea, chest pain and dizziness with or without syncope ^{4, 5}. Patients with AF have a five-fold higher risk of stroke ⁶.Oral anticoagulation (OAC) with warfarin is commonly used for stroke prevention in patients with AF and has been shown to reduce the risk of stroke by 64% ⁷. Warfarin therapy has several major disadvantages, however, including bleeding, non-tolerance, interactions with other medications and foods, non-compliance and a narrow therapeutic range ^8-11. These issues, together with poor appreciation of the risk-benefit ratio, unawareness of guidelines, or absence of an OAC monitoring outpatient clinic may explain why only 30-60% of patients with AF are prescribed this drug ⁸.The problems associated with warfarin, combined with the limited efficacy and/or serious side effects associated with other medications used for AF ^12,13, highlight the need for effective non-pharmacological approaches to treatment. One such approach is catheter ablation (CA), a procedure in which a radiofrequency electrical current is applied to regions of the heart to create small ablation lesions that electrically isolate potential AF triggers ⁴. CA is a well-established treatment for AF symptoms ^{14, 15}, that may also decrease the risk of stroke. Recent data showed a significant decrease in the relative risk of stroke and transient ischemic attack events among patients who underwent ablation compared with those undergoing antiarrhythmic drug therapy ¹⁶.Since the left atrial appendage (LAA) is the source of thrombi in more than 90% of patients with non-valvular atrial fibrillation ¹⁷, another approach to stroke prevention is to physically block clots from exiting the LAA. One method for occluding the LAA is via percutaneous placement of the WATCHMAN LAA closure device. The WATCHMAN device resembles a small parachute. It consists of a nitinol frame covered by fabric polyethyl terephthalate that prevents emboli, but not blood, from exiting during the healing process. Fixation anchors around the perimeter secure the device in the LAA (Figure 1). To date, the WATCHMAN is the only implanted percutaneous device for which a randomized clinical trial has been reported. In this study, implantation of the WATCHMAN was found to be at least as effective as warfarin in preventing stroke (all-causes) and death (all-causes) ¹⁸. This device received the Conformité Européenne (CE) mark for use in the European Union for warfarin eligible patients and in those who have a contraindication to anticoagulation therapy ¹⁹.Given the proven effectiveness of CA to alleviate AF symptoms and the promising data with regard to reduction of thromboembolic events with both CA and WATCHMAN implantation, combining the two procedures is hoped to further reduce the incidence of stroke in high-risk patients while simultaneously relieving symptoms. The combined procedure may eventually enable patients to undergo implantation of the WATCHMAN device without subsequent warfarin treatment, since the CA procedure itself reduces thromboembolic events. This would present an avenue of treatment previously unavailable to patients ineligible for warfarin treatment because of recurrent bleeding ²⁰ or other warfarin-associated problems.The combined procedure is performed under general anesthesia with biplane fluoroscopy and TEE guidance. Catheter ablation is followed by implantation of the WATCHMAN LAA closure device. Data from a non-randomized trial with 10 patients demonstrates that this procedure can be safely performed in patients with a CHADS₂ score of greater than 1 ²¹. Further studies to examine the effectiveness of the combined procedure in reducing symptoms from AF and associated stroke are therefore warranted.     

术前使用左心耳3D模型及左心耳封堵体外模拟治疗心房颤动患者的疗效

摘要 目的：探讨术前使用左心耳3D模型及左心耳封堵体外模拟治疗心房颤动患者的疗效。方法：回顾性选择2021年1月至2022年10月来我院诊治的心房颤动患者,对照组行经食管超声心动图检查、心脏CT造影检查及左心耳封堵术。观察组行经食管超声心动图检查、心脏CT造影检查、基于心脏CT造影数据打印左心耳3D模型、应用3D打印模型进行左心耳封堵体外模拟演练及左心耳封堵术,对比两组相关指标。结果：两组经食管超声心动图检查左心耳各径线对比无差异（P>0.05）。两组经CT检查左心耳各径线对比无差异（P>0.05）。两组封堵器固定大小对比有差异（P<0.05）。术后经食管超声心动图检查发现,观察组术后3个月及12个月血流通过封堵器几率高于对照组,但组间对比无差异（P>0.05）。术后3个月及12个月时,两组的左心房内径降低,且同时间点观察组较对照组（P<0.05）;两组术后3个月及12个月时左心室内径对比无差异（P>0.05）。观察组的封堵器型号匹配率较对照组高,手术操作时间、X线曝光量、造影剂使用量、封堵器术中释放次数较对照组低（P<0.05）,观察组的残余分流及手术并发症较对照组低,但组间对比无差异（P>0.05）。观察组术后3个月封堵器位置、有无残腔及不良心血管事件与对照组相比无差异（P>0.05）,术后12个月,封堵器位置良好率较对照组低（P<0.05）,其余两组间对比无差异（P>0.05）。结论：术前使用左心耳3D模型及左心耳封堵体外模拟可提高心房颤动患者的疗效。     

Epicardial Ablation of Focal Atrial Tachycardia Arising From Left Atrial Appendage in Children

Focal left atrial tachycardia (FLAT) although a common cause of supraventricular tachycardia(SVT) among children, the one''s arising from left atrial appendage (LAA) present a unique challenge for successful ablation because of anatomical location. We present two children with FLAT arising from the epicardial LAA, successfully mapped and ablated through percutaneuous epicardial approach.     

Hemostasis of Left Atrial Appendage Bleed With Lariat Device

New devices designed for minimally invasive closure of the left atrial appendage (LAA) may be a viable alternative for patients in whom anticoagulation is considered high risk. The Lariat (Sentreheart, Redwood City, CA), which is currently FDA-approved for percutaneous closure of tissue, requires both trans-septal puncture and epicardial access. However it requires no anticoagulation after the procedure. Here we describe a case of effusion and tamponade during a Lariat procedure with successful completion of the case and resolution of the effusion.     

Left Atrial Appendage Morphology in Patients with Suspected Cardiogenic Stroke without Known Atrial Fibrillation

The left atrial appendage (LAA) is the typical origin for intracardiac thrombus formation. Whether LAA morphology is associated with increased stroke/TIA risk is controversial and, if it does, which morphological type most predisposes to thrombus formation. We assessed LAA morphology in stroke patients with cryptogenic or suspected cardiogenic etiology and in age- and gender-matched healthy controls. LAA morphology and volume were analyzed by cardiac computed tomography in 111 patients (74 males; mean age 60 ± 11 years) with acute ischemic stroke of cryptogenic or suspected cardiogenic etiology other than known atrial fibrillation (AF). A subgroup of 40 patients was compared to an age- and gender-matched control group of 40 healthy individuals (21 males in each; mean age 54 ± 9 years). LAA was classified into four morphology types (Cactus, ChickenWing, WindSock, CauliFlower) modified with a quantitative qualifier. The proportions of LAA morphology types in the main stroke group, matched stroke subgroup, and control group were as follows: Cactus (9.0%, 5.0%, 20.0%), ChickenWing (23.4%, 37.5%, 10.0%), WindSock (47.7%, 35.0%, 67.5%), and CauliFlower (19.8%, 22.5%, 2.5%). The distribution of morphology types differed significantly (P<0.001) between the matched stroke subgroup and control group. The proportion of single-lobed LAA was significantly higher (P<0.001) in the matched stroke subgroup (55%) than the control group (6%). LAA volumes were significantly larger (P<0.001) in both stroke study groups compared to controls patients. To conclude, LAA morphology differed significantly between stroke patients and controls, and single-lobed LAAs were overrepresented and LAA volume was larger in patients with acute ischemic stroke of cryptogenic or suspected cardiogenic etiology.     

经食道超声心动图评估特发性房颤左心房左心耳的价值

目的:研究经食道超声心动图(TEE)评估特发性房颤左心房左心耳的临床价值。方法:选择自2015年1月到2016年8月在医院接受诊治的特发性房颤患者100例纳入本次研究,阵发性房颤92例,记为阵发性房颤组;持续性房颤8例,记为持续性房颤组。另选同期在医院进行健康体检的心功能正常志愿者90例作为对照组。利用TEE对受试者进行检查,对比房颤组与对照组的左心房及左心耳参数,是否含有自发性显影(LASEC)的房颤患者的左心房及左心耳参数,利用TEE分析对房颤患者的预后情况。结果:阵发性房颤组左心房的前后径和左右径,左心耳血流最大的排空速度(Lev)均明显小于对照组,左心耳的面积变化率及最大的充盈速度(Lfv)均明显大于对照组,差异有统计学意义(P0.05)。持续性房颤组左心房的前后径和左右径均明显大于对照组,左心耳的面积变化率、Lev及Lfv均明显小于对照组,差异有统计学意义(P0.05)。阵发性房颤组左心房的前后径和左右径均明显小于持续性房颤组,左心耳的面积变化率、Lev及Lfv均明显大于持续性房颤组,差异有统计学意义(P0.05)。有LASEC者左心房的前后径和左右径均明显大于无LASEC者,左心耳的面积变化率、Lev及Lfv均明显小于无LASEC者,差异有统计学意义(P0.05)。100例房颤患者中发现34例LASEC,占34.00%,其中有18例患者合并有左心耳血栓,占18.00%。总计有66例患者接受导管射频消融疗法,占66.00%,均未在术中及术后7d内出现血栓及栓塞并发症。结论:利用TEE对特发性房颤的患者左心房及左心耳进行评估,有利于更好的辅助患者的临床治疗,值得重视。     

Left Atrial Appendage Volume Increased in More Than Half of Patients with Cryptogenic Stroke

Background

Ischemic strokes without a well-defined etiology are labeled as cryptogenic, and account for 30–40% of strokes in stroke registries. The left atrial appendage (LAA) is the most typical origin for intracardiac thrombus formation when associated with atrial fibrillation. Here, we examined whether increased LAA volume detected with cardiac computed tomography (cCT) constitutes a risk factor in cryptogenic stroke patients.

Methods

This study included 82 stroke/TIA patients (57 males; mean age, 58 years) with a diagnosis of cryptogenic stroke after extensive radiological and cardiological investigations. Cases were classified using the TOAST criteria modified by European Association of Echocardiography recommendations for defining cardiac sources of embolism. Forty age- and gender-matched control subjects without cardiovascular diseases were selected for pair-wise comparisons (21 males; mean age, 54 years). LAA volume adjusted for body surface area was measured three dimensionally by tracing the LAA borders on electrocardiogram-gated CT slices.

Results

In control subjects, mean LAA volume was 3.4±1.1 mL/m². Mean+2SD, which was considered the upper limit for normal LAA volume was 5.6 mL/m². In paired Student t-test between the patient group and matched controls, LAA volume was 67% larger in cryptogenic stroke/TIA patients (5.7±2.0 mL/m² vs. 3.4±1.1 mL/m²; P<0.001). Forty-five (55%) patients with cryptogenic stroke/TIA had enlarged LAA.

Conclusion

LAA is significantly enlarged in more than half of patients with cryptogenic stroke/TIA. LAA thrombosis may contribute to the pathogenesis of stroke in patients considered to have cryptogenic stroke after conventional evaluation.     

Morphological and Volumetric Analysis of Left Atrial Appendage and Left Atrium: Cardiac Computed Tomography-Based Reproducibility Assessment

Objectives

Left atrial appendage (LAA) dilatation and morphology may influence an individual''s risk for intracardiac thrombi and ischemic stroke. LAA size and morphology can be evaluated using cardiac computed tomography (cCT). The present study evaluated the reproducibility of LAA volume and morphology assessments.

Methods

A total of 149 patients (47 females; mean age 60.9±10.6 years) with suspected cardioembolic stroke/transient ischemic attack underwent cCT. Image quality was rated based on four categories. Ten patients were selected from each image quality category (N = 40) for volumetric reproducibility analysis by two individual readers. LAA and left atrium (LA) volume were measured in both two-chamber (2CV) and transversal view (TV) orientation. Intertechnique reproducibility was assessed between 2CV and TV (200 measurement pairs). LAA morphology (A = Cactus, B = ChickenWing, C = WindSock, D = CauliFlower), LAA opening height, number of LAA lobes, trabeculation, and orientation of the LAA tip was analysed in all study subjects by three individual readers (447 interobserver measurement pairs). The reproducibility of volume measurements was assessed by intra-class correlation (ICC) and the reproducibility of LAA morphology assessments by Cohen''s kappa.

Results

The intra-observer and interobserver reproducibility of LAA and LA volume measurements was excellent (ICCs>0.9). The LAA (ICC = 0.954) and LA (ICC = 0.945) volume measurements were comparable between 2CV and TV. Morphological classification (ĸ = 0.24) and assessments of LAA opening height (ĸ = 0.1), number of LAA lobes (ĸ = 0.16), trabeculation (ĸ = 0.15), and orientation of the LAA tip (ĸ = 0.37) was only slightly to fairly reproducible.

Conclusions

LA and LAA volume measurements on cCT provide excellent reproducibility, whereas visual assessment of LAA morphological features is challenging and results in unsatisfactory agreement between readers.     

Left Atrial Appendage Closure Guided by Integrated Echocardiography and Fluoroscopy Imaging Reduces Radiation Exposure

Aims

To investigate whether percutaneous left atrial appendage (LAA) closure guided by automated real-time integration of 2D-/3D-transesophageal echocardiography (TEE) and fluoroscopy imaging results in decreased radiation exposure.

Methods and Results

In this open-label single-center study LAA closure (Amplatzer^TM Cardiac Plug) was performed in 34 consecutive patients (8 women; 73.1±8.5 years) with (n = 17, EN+) or without (n = 17, EN-) integrated echocardiography/fluoroscopy imaging guidance (EchoNavigator^® [EN]; Philips Healthcare). There were no significant differences in baseline characteristics between both groups. Successful LAA closure was documented in all patients. Radiation dose was reduced in the EN+ group about 52% (EN+: 48.5±30.7 vs. EN-: 93.9±64.4 Gy/cm²; p = 0.01). Corresponding to the radiation dose fluoroscopy time was reduced (EN+: 16.7±7 vs. EN-: 24.0±11.4 min; p = 0.035). These advantages were not at the cost of increased procedure time (89.6±28.8 vs. 90.1±30.2 min; p = 0.96) or periprocedural complications. Contrast media amount was comparable between both groups (172.3±92.7 vs. 197.5±127.8 ml; p = 0.53). During short-term follow-up of at least 3 months (mean: 8.1±5.9 months) no device-related events occurred.

Conclusions

Automated real-time integration of echocardiography and fluoroscopy can be incorporated into procedural work-flow of percutaneous left atrial appendage closure without prolonging procedure time. This approach results in a relevant reduction of radiation exposure.

Trial Registration

ClinicalTrials.gov NCT01262508     

Left Atrial Appendages from Adult Hearts Contain a Reservoir of Diverse Cardiac Progenitor Cells

Aims

There is strong evidence supporting the claim that endogenous cardiac progenitor cells (CPCs) are key players in cardiac regeneration, but the anatomic source and phenotype of the master cardiac progenitors remains uncertain. Our aim was to investigate the different cardiac stem cell populations in the left atrial appendage (LAA) and their fates.

Methods and Results

We investigated the CPC content and profile of adult murine LAAs using immunohistochemistry and flow cytometry. We demonstrate that the LAA contains a large number of CPCs relative to other areas of the heart, representing over 20% of the total cell number. We grew two distinct CPC populations from the LAA by varying the degree of proteolysis. These differed by their histological location, surface marker profiles and growth dynamics. Specifically, CD45^pos cells grew with milder proteolysis, while CD45^neg cells grew mainly with more intense proteolysis. Both cell types could be induced to differentiate into cells with cardiomyocyte markers and organelles, albeit by different protocols. Many CD45^pos cells expressed CD45 initially and rapidly lost its expression while differentiating.

Conclusions

Our results demonstrate that the left atrial appendage plays a role as a reservoir of multiple types of progenitor cells in murine adult hearts. Two different types of CPCs were isolated, differing in their epicardial-myocardial localization. Considering studies demonstrating layer-specific origins of different cardiac progenitor cells, our findings may shed light on possible pathways to study and utilize the diversity of endogenous progenitor cells in the adult heart.     

左心耳封堵术后房颤患者生活质量评价及其影响因素研究

摘要 目的：探讨左心耳封堵术（LAAC）术后对房颤（AF）患者的生活质量的影响,并分析其影响因素。方法：回顾性分析兰州大学第二医院2019年3月至2022年3月期间接受LAAC治疗的213例AF患者的临床资料。根据简明健康调查量表（SF-36）将213例LAAC术后AF患者分为低生活质量组（总分≤50分,n=107）和高生活质量组（总分＞50分,n=106）。收集并比较AF患者术前基线资料、实验室资料和影像学资料。采用多因素Logistic回归模型分析LAAC术后AF患者生活质量的影响因素。结果：低生活质量组心房颤动血栓发生危险度（CHA2DS2-VASc）评分高于高生活质量组（P<0.05）。低生活质量组的凝血酶原时间百分比高于高生活质量组（P<0.05）。高生活质量组红细胞水平高于低生活质量组（P<0.05）。高生活质量组的左心室射血分数（LVEF）高于低生活质量组（P<0.05）。多因素Logistic回归分析结果显示：CHA2DS2-VASc评分偏高、LVEF偏低是影响LAAC术后AF患者生活质量的危险因素（P<0.05）。结论：CHA2DS2-VASc评分偏高、LVEF偏低是影响LAAC术后AF患者生活质量的危险因素,可降低LAAC术后AF患者的生活质量。     

Inter-Subject Variability in Human Atrial Action Potential in Sinus Rhythm versus Chronic Atrial Fibrillation

Aims

Human atrial electrophysiology exhibits high inter-subject variability in both sinus rhythm (SR) and chronic atrial fibrillation (cAF) patients. Variability is however rarely investigated in experimental and theoretical electrophysiological studies, thus hampering the understanding of its underlying causes but also its implications in explaining differences in the response to disease and treatment. In our study, we aim at investigating the ability of populations of human atrial cell models to capture the inter-subject variability in action potential (AP) recorded in 363 patients both under SR and cAF conditions.

Methods and Results

Human AP recordings in atrial trabeculae (n = 469) from SR and cAF patients were used to calibrate populations of computational SR and cAF atrial AP models. Three populations of over 2000 sampled models were generated, based on three different human atrial AP models. Experimental calibration selected populations of AP models yielding AP with morphology and duration in range with experimental recordings. Populations using the three original models can mimic variability in experimental AP in both SR and cAF, with median conductance values in SR for most ionic currents deviating less than 30% from their original peak values. All cAF populations show similar variations in G_K1, G_Kur and G_to, consistent with AF-related remodeling as reported in experiments. In all SR and cAF model populations, inter-subject variability in I_K1 and I_NaK underlies variability in APD₉₀, variability in I_Kur, I_CaL and I_NaK modulates variability in APD₅₀ and combined variability in I_to and I_Kur determines variability in APD₂₀. The large variability in human atrial AP triangulation is mostly determined by I_K1 and either I_NaK or I_NaCa depending on the model.

Conclusion

Experimentally-calibrated human atrial AP models populations mimic AP variability in SR and cAF patient recordings, and identify potential ionic determinants of inter-subject variability in human atrial AP duration and morphology in SR versus cAF.     

Symptomatic Bradycardia Caused By Premature Atrial Contractions Originating From Right Atrial Appendage

Premature atrial contraction is a common form of supraventricular arrhythmias. In rare cases, severe symptoms other than palpitation may occur. In this report, we present a patient with symptomatic bradycardia which developed secondary to blocked premature atrial contractions and was successfully treated with radiofrequency ablation.     

Clock Genes Display Rhythmic Expression in Human Hearts

Thus far, clock genes in the heart have been described only in rodents, and alterations of these genes have been associated with various myocardial malfunctions. In this study, we analyzed the expression of clock genes in human hearts. Left papillary muscles of 16 patients with coronary heart disease, 39 subjects with cardiomyopathy, and 9 healthy donors (52 males and 12 females, mean age 55.7±11.2; 16–70 yrs) were obtained during orthotopic heart transplantation. We assessed the mRNA levels of PER1, PER2, BMAL1, and CRY1 by real time PCR and analyzed their rhythmic expression by sliding means and Cosinor functions. Furthermore, we sought for differences between the three groups (by ANOVAs) for both the total 24 h period and separate time bins. All four clock genes were expressed in human hearts. The acrophases (circadian rhythm peak time) of the PER mRNAs occurred in the morning (PER1: 07:44 h [peak level 187% higher than trough, p?=?.008]; PER2: 09:42 h [peak 254% higher than trough, p?<?.0001], and BMAL1 mRNA in the evening at 21:44 h [peak 438% higher than trough; p?<?.0001]. No differences were found in the rhythmic patterns between the three groups. No circadian rhythm was detected in CRY1 mRNA in any group. PER1, PER2, and BMAL1 mRNAs revealed clear circadian rhythms in the human heart, with their staging being in antiphase to those in rodents. The circadian amplitudes of the mRNA clock gene levels in heart tissue are more distinct than in any other human tissue so far investigated. The acrophase of the myocardial PER mRNAs and the trough of the myocardial BMAL1 coincide to the time of day of most frequent myocardial incidents.