Objective-Scavenger receptor class B type I (SR-BI)/apolipoprotein E (apoE) double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the influence of B and T lymphocytes, which can contribute to atherosclerosis, ischemia-reperfusion injury, and cardiomyocyte death, on pathology in dKO mice. Method and Results-The lymphocyte-deficient SR-BI/apoE/recombination activating gene 2 (RAG2) triple knockout mice and corresponding dKO controls generated for this study exhibited essentially identical lipid-rich coronary occlusions, myocardial infarctions, cardiac dysfunction, and premature death (average lifespans 41.6Ϯ0.6 and 42.0Ϯ0.5 days, respectively). Conclusions-B and T lymphocytes and associated immunoglobulin-mediated inflammation are not essential for the development and progression of CHD in dKO mice. Strikingly, the dKO mice bred for this study (mixed C57BL/6ϫSV129ϫBALB/c background; strain 2) compared with the previously described dKO mice (75:25 C57BL/6:SV129 background; strain 1) had a shorter mean lifespan and steeper survival curve, characteristics especially attractive for studying the effects of environmental, pharmacological, and genetic manipulations on cardiac pathophysiology. Key Words: atherosclerosis Ⅲ HDL receptor Ⅲ myocardial infarction Ⅲ RAG2 Ⅲ echocardiography M urine models of dyslipidemia, such as the apolipoprotein E (apoE) or low-density lipoprotein (LDL) receptor knockout (KO) mice, have been used extensively to study atherosclerosis. However, even when subjected to high-fat/highcholesterol diets, all but one of these hypercholesterolemia and atherosclerosis systems usually do not result in spontaneous development of occlusive coronary artery disease, myocardial infarction (MI), cardiac dysfunction, or the premature death that are hallmarks of human coronary heart disease (CHD). The exception, mice doubly deficient for the HDL receptor scavenger receptor class B type I (SR-BI) and apoE (double KO [dKO]) not only exhibit extensive aortic sinus and occlusive coronary arterial atherosclerosis (advanced plaques with fibrous caps, fibrin deposition, and cholesterol clefts), but they also experience severe CHD at a very young age (4 to 6 weeks). [1][2][3] The hearts of dKO mice are hypertrophic and exhibit left ventricular (LV) dilation and multiple, large MIs. Severe cardiac dysfunction is demonstrated by multiple ECG abnormalities (ST segment elevation and depression, anesthesia-induced conductance abnormalities [eg, bradyarrhythmias, atrioventricular blocks]), a 70% reduction in ϮdP/dT, and 50% reduced ejection fraction. The mice die between 5 and 8 weeks of age (mean 6 weeks). Thus, the many similarities in CHD of dKO mice and humans raised the possibility that these mice may help in the study of the pathophysiology of CHD and genetic, pharmacological, and environmental approaches for its prevention and treatment.B and T lymphocytes ...