Effect of patisiran on stroke volume in hereditary transthyretin‐mediated amyloidosis: insights from pressure–volume analysis of the APOLLO study

Aims 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. Methods and results 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. Conclusions 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. The transthyretin protein is synthesized by the liver. Extracellular deposition of amyloid fibrils causes mechanical disruption of normal tissue architecture, leading to impaired relaxation and increased ventricular stiffness. Progression of cardiac chamber dysfunction over time is marked by reduced ventricular capacitance. Collectively, this leads to reduced stroke volume and decreased isovolumetric pressure–volume area overtime. Patisiran is an RNA interference therapeutic that blocks production of both variant and wild‐type transthyretin (TTR) protein in the hepatocyte by inducing degradation of TTR messenger RNA, thereby reducing circulating TTR protein. Non‐invasive pressure–volume analysis in patients with hereditary transthyretin‐mediated (ATTR) amyloidosis with polyneuropathy suggests that treatment with patisiran may modulate cardiac disease progression from 9 months of th