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Abstract：
Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference therapeutic that inhibits hepatic synthesis of transthyretin, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 APOLLO study. We use left ventricular (LV) stroke volume (SV) to quantify LV function overtime and non-invasive pressure-volume techniques to delineate the effects of patisiran on LV mechanics in the pre-specified cardiac subpopulation of the APOLLO study.
Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14 ml. At 9 months, the least-squares mean change in SV was -0.3 ± 1.2 ml for patisiran and -5.4 ± 1.9 ml for placebo (p = 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3 ml for patisiran and - 8.1 ± 2.3 ml for placebo (p = 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran.
Patisiran may delay progression of LV chamber dysfunction starting at 9 months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.
Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14 ml. At 9 months, the least-squares mean change in SV was -0.3 ± 1.2 ml for patisiran and -5.4 ± 1.9 ml for placebo (p = 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3 ml for patisiran and - 8.1 ± 2.3 ml for placebo (p = 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran.
Patisiran may delay progression of LV chamber dysfunction starting at 9 months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.
摘要：
目的：转甲状腺素蛋白介导的（ATTR）淀粉样变性是由心脏中的转甲状腺素蛋白原纤维沉积引起的，神经,和其他器官。Patisiran,RNA干扰（RNAi）治疗，抑制肝合成的甲状腺素运载蛋白，根据III期APOLLO研究，已被批准用于治疗遗传性ATTR淀粉样变性多发性神经病。我们使用左心室（LV）每搏输出量（SV）来量化随时间推移的LV功能，并使用无创压力容量技术来描述APOLLO研究的预设心脏亚群中patisiran对LV力学的影响。
结果：基线时通过经胸超声心动图评估LVSV，以及9个月和18个月的治疗。为了确定LVSV变化的潜在机制，无创压力容积(PV)参数，包括收缩末期压力-容积关系和舒张末期压力-容积关系，是使用单拍技术得出的。在基线,平均SV为51±14mL。9个月时,对于patisiran和安慰剂,SV的LS平均变化为-0.3±1.2mL(p=0.021).18个月时,对于patisiran,SV的LS平均变化为-1.7±1.3mL,安慰剂为-8.1±2.3mL(p=0.016).LVSV的下降是由安慰剂中相对于patisiran的LV电容降低驱动的。
结论：Patisiran可能在治疗9个月时开始延迟左心室室功能障碍的进展。这些数据阐明了甲状腺素运载蛋白减少疗法调节心脏病进展的机制，需要在正在进行的III期试验中得到证实。
结果：基线时通过经胸超声心动图评估LVSV，以及9个月和18个月的治疗。为了确定LVSV变化的潜在机制，无创压力容积(PV)参数，包括收缩末期压力-容积关系和舒张末期压力-容积关系，是使用单拍技术得出的。在基线,平均SV为51±14mL。9个月时,对于patisiran和安慰剂,SV的LS平均变化为-0.3±1.2mL(p=0.021).18个月时,对于patisiran,SV的LS平均变化为-1.7±1.3mL,安慰剂为-8.1±2.3mL(p=0.016).LVSV的下降是由安慰剂中相对于patisiran的LV电容降低驱动的。
结论：Patisiran可能在治疗9个月时开始延迟左心室室功能障碍的进展。这些数据阐明了甲状腺素运载蛋白减少疗法调节心脏病进展的机制，需要在正在进行的III期试验中得到证实。
