Prognostic Impact and Arrhythmic Potential of Peri-infarct Zone by Cardiac MRI

描述（由申请人提供）：心肌梗死（MI）后心源性猝死（SCD）的发生率保持不变，并且在MI后第一年最为显著。据报道，在梗塞周围区观察到的显著细胞各向异性是室性心律失常的潜在原因。心脏磁共振成像（CMR）可以表征MI后心肌组织的变化和心室功能。最近，我们的研究小组证明了使用对比增强CMR（PIZCMR）量化梗死周围区域范围的临床可行性，并报告了其与MI后全因死亡率的强预后相关性。(3)在一项144例MI患者的研究中，我们使用了一种新的自动化技术，根据信号强度阈值（分别高于远端正常心肌> 3SD和2 - 3SD）将晚期增强区域量化为核心和梗死周围（PIZCMR）区域。PIZCMR以绝对质量（MDE外围）和总增强区域的百分比（%MDE外围）定量。我们发现，% MDEperipheral是全因死亡率的一个强有力的预测因子，随着患者年龄和左心室射血分数（LVEF）的增加而增加。随着数字信号处理的最新进展，微伏T波电交替（MTWA）在检测不稳定的电生理底物，暴露后MI患者SCD。在治疗方面，在大规模随机临床试验中，冠状动脉疾病患者的SCD显著降低证实了omega-3多不饱和脂肪酸（ω-3 FA）对恶性心律失常具有膜稳定作用的强有力实验证据。这些已发表的研究结果为阐明PIZCMR与MI后死亡率之间的预后相关性的致病基础提供了动力。该建议的中心假设是PIZCMR包含产生折返性室性心动过速所必需的结构和电基质，并且其愈合可以通过-3 FA促进，转化为降低SCD和/或需要除颤的显著室性心动过速事件的风险。因此，我们计划将414例急性心肌梗死患者随机分为两组，（4gm/天，持续9个月）或安慰剂被设计用于检验以下假设：1）PIZCMR的直接心肌定量提供了超过LVEF和MTWA的与MACE的增量预后关联; 2）口服补充1）-3FA可以有益地改变PIZCMR与MACE的预后关联; 3）与安慰剂对照组相比，患有急性MI并具有大的PIZCMR的患者通过MTWA表现出伴随的电异质性;和4）对患有急性MI的患者口服β-FA补充剂，减少PIZCMR的心肌范围并使MTWA正常化。 项目叙述：心源性猝死（SCD）是心脏病发作患者最常见的死亡原因。虽然SCD可以通过植入自动内部心脏复律-除颤（AICD）装置有效地中止，但是仅使用心脏功能评估来选择接受AICD装置的患者的当前标准是不准确的，并且可能导致巨大的医疗保健成本和装置故障的可能严重并发症。因此，需要一种更好的非侵入性方法来识别AICD治疗最适合的高危患者。已知心脏病发作疤痕周围的区域（梗死周围区）在产生危及生命的心律失常方面至关重要，心律失常可导致心脏病发作后的SCD。磁共振成像是一种不需要使用有害辐射的成像技术，它可以比传统技术更好地显示组织特征的差异。我们的研究小组最近设计了一种新的方法，通过使用心脏磁共振成像（CMR）来测量144名心脏病发作患者的心脏梗死周围区。此外，我们发现，当我们在CMR研究后对这些患者的临床病程进行长达4年的随访时，梗死周围区的大小预测了患者在心脏病发作后的死亡。因此，目前提出的研究旨在评估CMR是否可以提供心肌的重要信息，这些信息可以改善SCD或其他严重结局的预测，超出目前使用心脏功能的非特异性标准。此外，我们还计划确定从CMR中获得的信息是否与心脏节律问题有关，如一种称为微伏T波交替的技术所证明的那样。大量证据表明，摄入omega-3多不饱和脂肪酸（鱼油）是安全的，耐受性良好，可以稳定心脏的电信号，降低SCD的风险。我们还建议调查在最近心脏病发作的患者中，omega-3脂肪酸是否可以促进梗死周围区的愈合。此外，这项研究的结果将提供洞察力，如果非侵入性MRI可以提高识别的高风险的SCD患者谁是最好的管理与AICD治疗。

DESCRIPTION (provided by applicant): The incidence of sudden cardiac death (SCD) after myocardial infarction (MI) has remained unchanged and is most significant in the first year after MI. The marked cellular anisotropy observed in the peri-infarct zone has reported to be a potential cause of ventricular arrhythmias. Cardiac magnetic resonance imaging (CMR) can characterize myocardial tissue changes and ventricular function after MI. Recently, our group demonstrated the clinical feasibility of quantifying the extent of the peri-infarct zone using contrast-enhanced CMR (PIZCMR) and also reported its strong prognostic association with post-MI all-cause mortality.(3) In a study of 144 patients with MI, we used a novel automated technique to quantify the late-enhancing region into the core and peri-infarct (PIZCMR) regions based on signal-intensity threshold (>3SDs and 2 to 3 SDs above remote normal myocardium, respectively). PIZCMR was quantified in absolute mass (MDEperiphery) and as a percentage of the total enhancing region (%MDEperiphery). We found that %MDEperiphery was a powerful predictor of all-cause mortality incremental to patient age and left ventricular ejection fraction (LVEF). With recent advances in digital signal processing, microvolt T-wave alternans (MTWA) in detecting unstable electrophysiological substrate that exposes post-MI patients to SCD. On the therapeutic side, strong experimental evidence of membrane stabilization effects of omega-3 polyunsaturated fatty acids ()-3 FA) against malignant arrhythmias has been substantiated by a remarkable reduction of SCD in patients with coronary artery disease in large-scale randomized clinical trials. These published findings provide the impetus for the present proposal to elucidate the pathogenic basis underlying the observed prognostic association of PIZCMR and post-MI mortality. The central hypothesis of this proposal is that PIZCMR contains the structural and electrical substrate essential for the generation of reentrant ventricular tachycardia, and that its healing can be promoted by )-3 FA, translating to a reduced risk of SCD and/or significant ventricular arrhythmic events requiring defibrillation. Accordingly, we plan to randomized 414 patients with acute MI to supplementation with either )-3 FA (4 gm/day for 9 months) or placebo is designed to test the hypotheses that 1) Direct myocardial quantitation of PIZCMR provides incremental prognostic association, beyond LVEF and MTWA, with MACE; 2) Oral supplementation with )-3 FA can beneficially modify the prognostic association of the PIZCMR with MACE; 3) Patients who suffered an acute MI and have a large PIZCMR, exhibit concomitant electrical heterogeneity by MTWA; and 4) Oral )-3 FA supplementation to patients who suffered an acute MI, reduces the myocardial extent of PIZCMR and normalizes MTWA, compared to the placebo control group. Project Narrative: Sudden cardiac death (SCD) is the most common cause of death in patients who have suffered a heart attack. While SCD can be effectively aborted by the implantation of an automatic internal cardiovertion-defibrillaton (AICD) device, the current criteria for selecting patients to receive an AICD device using assessment of heart function alone is inaccurate and can result in enormous healthcare costs and possible serious complications from device malfunction. A better noninvasive method is therefore needed to identify high risk patients for whom AICD therapy can be most appropriately utilized. The region surrounding the scar of a heart attack (peri-infarct zone) has been known to be critical in generating life-threatening arrhythmias that can lead to SCD after a heart attack. Magnetic resonance imaging is an imaging technology that does not require the use of harmful radiation and it can demonstrate differences in tissue characteristics better than conventional technology. Our group has recently devised a new way of measuring the peri-infarct zone of the heart in 144 patients who suffered a heart attack by using magnetic resonance imaging of the heart (CMR). Moreover, we showed that the size of this peri-infarct zone predicts patient death after a heart attack when we followed these patients clinical course up to 4 years after the CMR study. The current proposed study therefore aims to assess whether CMR can provide important information of the heart muscle which can improve the prediction of SCD or other serious outcomes, beyond the current non-specific criteria using heart function. In addition, we also plan to determine if the information gained from the CMR is related to heart rhythm problem as demonstrated by a technology called microvolt T-wave alternans. A large body of evidence suggests that intake of omega-3 polyunsaturated fatty acids (fish oils) is safe, well-tolerated, and can serve to stabilize the electrical signals of the heart and reduce the risk to SCD. We also propose to investigate whether healing of the peri-infarct zone can be promoted by omega-3 fatty acids in patients who have suffered a recent heart attack. In addition, the results of this study will provide insight if noninvasive MRI can improve the identification of patients at high risk of SCD who are best managed with AICD therapy.