From hemorrhagic stroke to lipid paradox: a double-hit hypothesis underlying low low-density lipoprotein cholesterol related cardiovascular risk—a narrative review

Abstract Despite overwhelming evidence from large randomized clinical trials supporting a clear benefit of low-density lipoprotein cholesterol (LDL-C) lowering therapy on the primary and secondary prevention of atherosclerotic cardiovascular disease, data from epidemiological and clinical observations demonstrated an increased incidence of hemorrhagic stroke in patients with low LDL-C exposure (<70 mg/dL), especially among East Asians. Meanwhile, emerging studies have reported a paradoxical phenomenon in which hypercholesterolemia is associated with better short-term outcomes in acute coronary syndrome patients, the “lipid paradox.” The underlying mechanism for these two closely connected clinical observations is not clear. This review aimed to summarize the evolution and clinical implications of these two low LDL-C related concepts, and proposed a “double-hit” hypothesis that may help explain these phenomena. It is worth noting that in the era of increasing use of high-intensity LDL-C lowering and dual antiplatelet strategies in atherosclerotic cardiovascular disease in patients receiving percutaneous coronary intervention, balancing the risk of thrombosis with bleeding complication should be a priority in clinical practice. Our hypothesis may raise clinicians’ awareness to identify potential high risk patients with low LDL-C (<70 mg/dL), especially among East Asians.