Abstract
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.