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后的第一年最为显著。据报道，在梗死周围区观察到的明显的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）可以表征心肌梗死后的心肌组织变化和心室功能。最近，我们的研究小组证明了使用对比增强CMR （PIZCMR）量化梗死周围区范围的临床可行性，并报道了它与心肌梗死后全因死亡率的预后密切相关。(3)在一项144例心肌梗死患者的研究中，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（mdeperipheral）和占总增强区域的百分比（% mdeperipheral）进行量化。我们发现，mdeperipheral %是全因死亡率随患者年龄和左心室射血分数（LVEF）增加而增加的有力预测因子。随着数字信号处理的最新进展，微伏t波交流电（MTWA）可用于检测心肌梗死后患者暴露于SCD的不稳定电生理基质。在治疗方面，在大规模随机临床试验中，omega-3多不饱和脂肪酸（）-3 FA)对恶性心律失常的膜稳定作用已被冠状动脉疾病患者SCD的显著降低所证实。这些已发表的研究结果为阐明PIZCMR与心肌梗死后死亡率之间观察到的预后关联的致病基础提供了动力。该建议的中心假设是，PIZCMR含有产生再入性室性心动过速所必需的结构和电底物，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律失常事件的风险。因此，我们计划将414名急性心肌梗死患者随机分组，分别补充-3 FA （4 gm/天，持续9个月）或安慰剂，以验证以下假设：1)PIZCMR的直接心肌定量提供了除了LVEF和MTWA之外与MACE的增量预后关联；2)口服补充)-3 FA可改善PIZCMR与MACE预后的相关性；3)急性心肌梗死且PIZCMR大的患者，MTWA表现出电异质性；4)与安慰剂对照组相比，口服)-3 FA补充急性心肌梗死患者，可降低PIZCMR心肌范围并使MTWA正常化。

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.