REVIEW ARTICLE: PDF OnlyFrom hemorrhagic stroke to lipid paradox a double-hit hypothesis underlying low low-density lipoprotein cholesterol related cardiovascular riskZhou, Xin; Yang, Qing*Author Information Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China Corresponding author: Qing Yang, Department of Cardiology, Tianjin Medical University General Hospital, 154, Anshan Road, Heping District, Tianjin 300052, China. E-mail: firstname.lastname@example.org. Received December 1, 2019 Accepted April 7, 2020 This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Journal of Bio-X Research: July 28, 2020 - Volume Latest Articles - Issue - doi: 10.1097/JBR.0000000000000067 Open PAP Metrics 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. Copyright © 2020 The Chinese Medical Association. Published by Wolters Kluwer Health, Inc.