Skeletal muscle adiposity, coronary microvascular dysfunction, and adverse cardiovascular outcomes

BACKGROUND AND AIMS: 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 body mass index (BMI), inflammation and risk of heart failure, myocardial infarction, and death. The relationship between SM quality, CMD, and cardiovascular outcomes is not known. METHODS: Consecutive patients (n = 669) undergoing evaluation for coronary artery disease with cardiac stress positron emission tomography demonstrating normal perfusion and preserved left ventricular ejection fraction were followed over a median of 6 years for major adverse cardiovascular events (MACEs), including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve was calculated as stress/rest myocardial blood flow. Subcutaneous adipose tissue (SAT), SM, and IMAT areas (cm2) were obtained from simultaneous positron emission tomography attenuation correction computed tomography using semi-automated segmentation at the 12th thoracic vertebra level. RESULTS: Median age was 63 years, 70% were female, and 46% were nonwhite. Nearly half of patients were obese (46%, BMI 30-61 kg/m2), and BMI correlated highly with SAT and IMAT (r = .84 and r = .71, respectively, P < .001) and moderately with SM (r = .52, P < .001). Decreased SM and increased IMAT, but not BMI or SAT, remained independently associated with decreased CFR (adjusted P = .03 and P = .04, respectively). In adjusted analyses, both lower CFR and higher IMAT were associated with increased MACE [hazard ratio 1.78 (95% confidence interval 1.23-2.58) per -1 U CFR and 1.53 (1.30-1.80) per +10 cm2 IMAT, adjusted P = .002 and P < .0001, respectively], while higher SM and SAT were protective [hazard ratio .89 (.81-.97) per +10 cm2 SM and .94 (.91-.98) per +10 cm2 SAT, adjusted P = .01 and .003, respectively]. Every 1% increase in fatty muscle fraction [IMAT/(SM + IMAT)] conferred an independent 2% increased odds of CMD [CFR <2, odds ratio 1.02 (1.01-1.04), adjusted P = .04] and a 7% increased risk of MACE [hazard ratio 1.07 (1.04-1.09), adjusted P < .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 = .02). CONCLUSIONS: Increased intermuscular fat is associated with CMD and adverse cardiovascular outcomes independently of BMI and conventional risk factors. The presence of CMD and SM fat infiltration identified a novel at-risk cardiometabolic phenotype.