Rami Kahwash， Ohio State University， USA
Cardiac resynchronization therapy (CRT) improves quality of life， functional status， morbidity， and mortality in patients with NYHA Class II-IV heart failure， reduced left ventricular ejection fractions (LVEF)， and prolonged QRS durations. Like other life-prolonging therapies in heart failure (e.g. b-blockers)， CRT improves cardiac structure and function， a process referred to as reverse remodeling. While the average improvement in LVEF observed in CRT trials is about 3% to 5% in absolute terms， some patients experience substantially more improvement or even normalization of LVEF as well as LV volumes.
The first report of such a phenomenon was presented in 2005 by Blanc et al. who described normalization of LV function in a group of patients with left bundle branch block (LBBB) treated with CRT. Following that， Castellant et al. reported a group of hyper-responders comprising 20% of an implantation cohort in CRT recipients. The term super-responders appears to have been first used by Antonio et al. who described a CRT super-response rate of 12% among 87 CRT recipients who were in NYHA Class III or IV at an the time of the implant. In this report， super-response was defined as an improvement in functional class and doubling of the pre-implant LVEF to > 45 % at 6 months after CRT.
Following these reports， a subset of the PROSPECT trial， which included 286 subjects of the original study population who were in NYHA Class III or IV， had QRS >130 ms， and LVEF≤35 %， was evaluated for super-response. Super-response was defined as a decrease in left ventricular end systolic volume (LVESV) by more than 30%. In this study， female gender， QRS duration， non-ischemic etiology， NYHA Class， and worse mechanical dysynchrony at baseline were predictors of super-response， which reached a rate of 37.8% at 6-month follow-up. Another series of 233 patients with NYHA Class II-IV， LVEF≤ 35 %， and QRS≥ 120 ms found， by univariate analysis， that female gender， LBBB， smaller LV volumes， lower BNP， and red cell distribution width (RDW) were associated with super-response， defined as an absolute LVEF increase≥20%. However， LBBB remained the only predictor when multivariate analysis was used. Additionally， super-responders were noted to have lower mortality (9.4 % vs 43.2 %， P=0.006) at mean follow up of 5.5 years. A smaller series of 76 patients in functional Class III or IV found that pre-implant ventricular volume < 68 mm was a predictor of super-response. A similar series linked nonischemic etiology， baseline QRS (144~188 ms)， and QRS narrowing by 40 ms post-CRT to super-response.
Recently， in the Journal of the American College of Cardiology， Hsu et al. reported 6 predictors of CRT super-response， which was defined as the highest quartile of LVEF change (≥ 14.5%) on a 12-month follow-up echocardiogram in a subset of the MADIT-CRT trial (n=752). Female sex， no prior myocardial infarction， QRS ≥ 150 ms， LBBB， BMI < 30 kg/m2， and smaller left atrial volume index were predictors of CRT super-response. Importantly， this analysis demonstrated strikingly lower mortality at a 2-year follow-up in these super-responders， compared to those with lesser remodeling responses with CRT. This analysis confirms those previously cited， extends those observations to mildly symptomatic (NYHA Class I-II) heart failure patients， represents the largest study of predictors of CRT super-response to date， and is a major contribution to our understanding of CRT super-response. Other than the limitations noted by the authors – particularly， short follow up duration， which left the authors unable to determine the timing of response and the outcomes associated with that timing – we believe that the study duration (1 year) may have underestimated the true rate of super-responders. Data from a CARE-HF trial sub-study taught us that reverse remodeling may continue until at least 18 months post-CRT implant. Additionally， the study would have provided more valuable data if it incorporated additional important variables known to influence response to CRT， such as percent pacing， anatomical site of stimulation， and scar burden.
While these findings are novel and important， they may not be unique to CRT， as recovery of LV systolic function with medical therapy in the era before CRT was well reported. Remarkably， the reported predictors of super-response to drug therapies were not that different from the aforementioned predictors of CRT super-response. For example， Binkley et al. identified clinical variables associated with restoration of LVEF to normal (> 50%) from a baseline average of ~ 20% with medical therapy alone. Using a logistic model， female gender， nonischemic etiology， prolonged QRS duration， absence of diabetes mellitus， and higher systolic BP were significant predictors of LV function recovery.
In clinical practice， integration of these study findings may guide clinicians to better select CRT candidates， especially in those patients that may have borderline CRT indications and higher-than-average procedural risks， or at least to set reasonable patient expectations for improvement. However， focusing on super-responders should not distract us from the fact that patients classified as hypo- or non-responders by LVEF or LV volume changes may still derive clinical benefits from CRT. In fact， 40% of patients in the PROSPECT sub-study achieved clinical improvement， despite the absence of echocardiographic mechanical improvement. This observation suggests that CRT may attenuate disease progression when not reversing it. Thus， while focusing attention on CRT super-responders， we should not forget CRT non-progressors. Perhaps， we are not super-selectors yet.
在NYHA分级II-IV级、左室射血分数（LVEF）降低、QRS间期延长的心力衰竭患者，心脏再同步治疗（CRT）能够改善生活质量、功能状态、病残率和死亡率。CRT通过改善心脏结构和功能，达到逆向重构。CRT临床试验中，LVEF平均升高3%~5%，但部分患者LVEF升高非常显著，甚至恢复正常，同时左心室容积也有明显缩小。Blanc等在2005年第一次报告CRT使左束支传导阻滞（LBBB）患者的左心室功能恢复正常。随后，Castellant等报道在一个CRT队列中，约20%为高应答者。Antonio等第一次使用“超应答”这个词组，指NYHA功能分级改善、LVEF在CRT后6个月时升高一倍或以上或> 45%。PROSPECT试验亚组分析中，超应答的预测因素为女性、QRS间期、非缺血性病因、NYHA分级、机械不同步恶化。另一项研究中，超应答者在平均随访5.5年时，死亡率较低，
近期的JACC上，Hsu等报道MADIT-CRT试验亚组分析结果。超应答被定义为12个月随访时超声心动图上LVEF变化的最高四分位数。超应答的6项预测因素是：女性、既往无心肌梗死、QRS ≥ 150 ms、LBBB、体重指数< 30 kg/m2和较小的左心房容积指数。重要的是，这项分析显示，超应答者2年死亡率非常低。这项分析证实上述引用研究观察到的现象，并将此现象扩展到轻度心力衰竭患者（NYHA分级I-II级）。这项分析是迄今为止最大的CRT超应答预测因素研究，对理解CRT超应答有重大贡献。然而，我们相信1年随访时间可能低估超应答的真实频率。CARE-HF试验亚组数据表明，逆向重构可持续至CRT植入后18个月。此外，如果加入其他已知影响CRT应答的重要参数，如起搏比例、起搏刺激的解剖位置和瘢痕负荷，这项研究将提供更有价值的数据。
尽管上述结果有新意，也很重要，但这种现象并非CRT独有。在CRT时代之前，药物治疗使左心室功能恢复已有报道。药物治疗超应答的预测因素与CRT超应答的预测因素很相似，比如女性、非缺血性病因、延长的QRS间期等。
临床实践中，可应用上述研究结果指导医生更好选择CRT候选患者，特别是对那些处于临界CRT适应证和手术风险较高的患者，至少能够对患者设置合理的疗效预期。然而，在注意超应答的同时，也不能忽视低或无应答者仍然可能从CRT获益。事实上，PROSPECT试验亚组分析中，40%的患者尽管缺乏超声心动图提示的改进，却获得临床改善，这提示当CRT不能逆转疾病时，仍可能延缓疾病进展。