Intermuscular Adiposity is Associated with Coronary Microvascular Dysfunction Independently of Body Mass Index and Modifies its Effect on Adverse Cardiovascular Outcomes

Background: Skeletal muscle (SM) fat infiltration, or intermuscular adipose tissue (IMAT), reflects muscle quality and is associated with inflammation, a key determinant in cardiometabolic disease. Coronary flow reserve (CFR), a marker of coronary microvascular dysfunction (CMD), is independently associated with BMI, inflammation and risk of heart failure, myocardial infarction and death. We sought to investigate the relationship between skeletal muscle quality, CMD and cardiovascular outcomes. Methods: Consecutive patients (N=669) undergoing evaluation for CAD with cardiac stress PET demonstrating normal perfusion and preserved left ventricular ejection fraction were followed over median 6 years for major adverse cardiovascular events (MACE), including death and hospitalization for myocardial infarction or heart failure. CFR was calculated as stress/rest myocardial blood flow and CMD defined as CFR<2. Subcutaneous adipose tissue (SAT), SM and IMAT areas (cm 2 ) were obtained from simultaneous PET attenuation correction CTs using semi-automated segmentation at the twelfth thoracic vertebra (T12) level. Results: Median age was 63 years, 70% were female and 46% nonwhite. Nearly half of patients were obese (46%, BMI 30-61) and BMI correlated highly with SAT and IMAT (r=0.84 and 0.71, respectively, p<0.001) and moderately with SM (r=0.52, p<0.001). Decreased SM and increased IMAT, but not BMI or SAT, remained independently associated with decreased CFR (adjusted p=0.03 and p=0.04, respectively). In adjusted analyses, both lower CFR and higher IMAT were associated with increased MACE [HR 1.78 (1.23-2.58) per -1U CFR and 1.53 (1.30-1.80) per +10 cm 2 IMAT, adjusted p=0.002 and p<0.0001, respectively], while higher SM and SAT were protective [HR 0.89 (0.81-0.97) per +10 cm 2 SM and 0.94 (0.91-0.98) per +10 cm 2 SAT, adjusted p=0.01 and 0.003, respectively]. Every 1% increase in fatty muscle fraction [IMAT/(SM+IMAT)] conferred an independent 2% increased odds of CMD [CFR<2, OR 1.02 (1.01-1.04), adjusted p=0.04] and a 7% increased risk of MACE [HR 1.07 (1.04-1.09), adjusted p<0.001]. There was a significant interaction between CFR and IMAT, not BMI, such that patients with both CMD and fatty muscle demonstrated highest MACE risk (adjusted p=0.02). Conclusion: Increased intermuscular fat is associated with CMD and adverse cardiovascular outcomes independently of BMI and conventional risk factors. The presence of CMD and skeletal muscle fat infiltration identified a novel at-risk cardiometabolic phenotype.