Sex affects myocardial blood flow and fatty acid substrate metabolism in humans with nonischemic heart failure

Abstract

In animal models of heart failure (HF), myocardial metabolism shifts from the normal preference for high-energy fatty acid (FA) metabolism towards the more efficient fuel, glucose. However, FA (vs. glucose) metabolism generates more ATP/mole; thus FA metabolism may be especially advantageous in HF. Sex modulates myocardial blood flow (MBF) and substrate metabolism in normal humans. Whether sex affects MBF and metabolism in patients with HF is unknown. We studied 19 well-matched men and women with nonischemic HF with similar ejection fractions (all ≤ 35%). MBF and myocardial substrate metabolism were quantified using positron emission tomography. Women had higher MBF (mL/g/min), FA uptake (mL/g/min), utilization (nmol/g/min) (P<0.005, <0.005, <0.05, respectively) and trended towards higher FA oxidation than men (P=0.09). These findings were independent of age, obesity, and insulin resistance. There were no sex-related differences in fasting myocardial glucose uptake or metabolism. In an exploratory analysis of the longitudinal follow-up of these subjects (mean 7 y), we found that 4 men had a major cardiovascular event, while one woman died of non-cardiac causes. Higher MBF related to improved event-free survival (HR=0.31, P=0.02). In sum, in nonischemic HF, women have higher MBF and FA uptake and metabolism than men, and these changes are not due to differences in other variables that can affect myocardial metabolism (e.g., age, obesity, or insulin resistance). Moreover, higher MBF portends a better prognosis. These sex-related differences should be taken into account in the development and targeting of novel agents aimed at modulating in MBF and metabolism in HF.

Is it time to reassess the role of myocardial metabolic modulation for the treatment of heart failure?

“…16 Indeed, this sexual dimorphism persists, at least for myocardial FA metabolism in patients with HFrEF due to non-ischemic origin. 17 Age is also a critical determinant in myocardial substrate utilization with an increasing dependence on MGU with advancing age. 18 Obesity is another patient attribute that needs to be considered when assessing cardiac metabolic activity.…”

Tactics for preclinical validation of receptor-binding radiotracers

“…For instance, a large [ 18 F]-FDG PET study consisting of 493 men and 470 women spanning 5 decades (32 – 87 years) showed lower metabolism in parietal cortex for men compared to women, while lower metabolism was observed in ventrolateral prefrontal cortex for women compared to men [215]. In a multi-institutional study of nonischemic heart failure, three radiotracers, [ 15 O]-H 2 O, [ 11 C]-palmitate and [ 11 C]-glucose, were used to evaluate myocardial blood flow and metabolism [216]. Findings indicated that sex, but not other variables such as age, was associated with the higher blood flow and fatty acid metabolism observed in women, while glucose metabolism did not differ appreciably between the sexes.…”

Sex Differences in Biopsy-confirmed Diabetic Kidney Disease

“…In order to slow down the progression of DKD, recognizing patients with a high risk at an early stage is important. Sex differences have been taken into account in development or progression in several diseases such as diabetes [3] , chronic kidney disease (CKD) [4] , heart failure [5] , and neuropsychiatric disorders [6] . Recently, a study from the Chronic Renal Insufficiency Cohort that included 3939 adults (half of them had diabetes) showed that male had the higher risk of CKD progression and death compared with female patients [4] .…”