Piscine orthoreovirus (PRV) is ubiquitous in farmed Atlantic salmon and sometimes associated with disease - most notably, Heart and Skeletal Muscle Inflammation (HSMI). However, PRV is also widespread in non-diseased fish, particularly in Pacific Canada, where few cases of severe heart inflammation have been documented. To better understand the mechanisms behind PRV-associated disease, this study investigated the infection dynamics of PRV from Pacific Canada and the potential for experimental passage of putatively associated heart inflammation in Pacific-adapted Mowi-McConnell Atlantic salmon. Regardless of the PRV source (fish with or without HSMI-like heart inflammation), infections led to high-load viremia that induced only minor focal heart inflammation without significant transcriptional induction of inflammatory cytokines. Repeated screening of PRV dsRNA/ssRNA along with histopathology and gene expression analysis of host blood and heart tissues identified three distinct phases of infection: (1) early systemic dissemination and replication without host recognition; (2) peak replication, erythrocyte inclusion body formation and load-dependent host recognition; (3) long-term, high-load viral persistence with limited replication or host recognition sometimes accompanied by minor heart inflammation. These findings contrast previous challenge trials with PRV from Norway that induced severe heart inflammation and indicate that strain and/or host specific factors are necessary to initiate PRV-associated disease.