This study comprehensively assesses myocardial ischemia in patients with cardiac amyloidosis (CA) using cardiovascular magnetic resonance (CMR) and histopathological analysis. The study included 93 CA patients, 42 with cardiac AL amyloidosis and 51 with cardiac ATTR amyloidosis, along with 73 patients without CA and 24 healthy volunteers. CMR was performed to evaluate myocardial perfusion, including stress and rest myocardial blood flow (MBF) and myocardial perfusion reserve (MPR). Endomyocardial biopsies and explanted hearts were also analyzed histopathologically. Key findings include: - CA patients showed severe reduction in stress MBF and MPR compared to healthy volunteers and patients with three-vessel disease (3VD) or unobstructed coronary arteries. - Stress MBF and MPR were significantly reduced in CA patients, with no significant difference between AL and ATTR amyloidosis. - Histological analysis revealed extensive small vessel amyloid deposition, myocyte atrophy, and cytoplasmic vacuolization, as well as capillary disruption and rarefaction. - VEGF expression was significantly increased in cardiomyocytes, indicating activation of hypoxia pathways. - The reduction in myocardial perfusion was correlated with the severity of cardiac amyloid infiltration and functional and structural myocardial changes. The study highlights the multifactorial origin of myocardial ischemia in CA, including direct amyloid infiltration, disruption of myocardial mechanics, and coronary microvascular dysfunction. These findings have implications for understanding the pathophysiology of CA and may aid in the development of new treatments.This study comprehensively assesses myocardial ischemia in patients with cardiac amyloidosis (CA) using cardiovascular magnetic resonance (CMR) and histopathological analysis. The study included 93 CA patients, 42 with cardiac AL amyloidosis and 51 with cardiac ATTR amyloidosis, along with 73 patients without CA and 24 healthy volunteers. CMR was performed to evaluate myocardial perfusion, including stress and rest myocardial blood flow (MBF) and myocardial perfusion reserve (MPR). Endomyocardial biopsies and explanted hearts were also analyzed histopathologically. Key findings include: - CA patients showed severe reduction in stress MBF and MPR compared to healthy volunteers and patients with three-vessel disease (3VD) or unobstructed coronary arteries. - Stress MBF and MPR were significantly reduced in CA patients, with no significant difference between AL and ATTR amyloidosis. - Histological analysis revealed extensive small vessel amyloid deposition, myocyte atrophy, and cytoplasmic vacuolization, as well as capillary disruption and rarefaction. - VEGF expression was significantly increased in cardiomyocytes, indicating activation of hypoxia pathways. - The reduction in myocardial perfusion was correlated with the severity of cardiac amyloid infiltration and functional and structural myocardial changes. The study highlights the multifactorial origin of myocardial ischemia in CA, including direct amyloid infiltration, disruption of myocardial mechanics, and coronary microvascular dysfunction. These findings have implications for understanding the pathophysiology of CA and may aid in the development of new treatments.