Sex-related differences in the associations between plasma free fatty acid levels and clinical features in patients with hypertrophic cardiomyopathy

Yang et al. Biology of Sex Differences (2016) 7:63 DOI 10.1186/s13293-016-0118-2 RESEARCH Open Access Sex-related differences in the associations between plasma free fatty acid levels and clinical features in patients with hypertrophic cardiomyopathy Chengzhi Yang, Changlin Zhang, Jiansong Yuan, Jingang Cui, Shengwen Liu, Fenghuan Hu, Weixian Yang, Xuanye Bi and Shubin Qiao* Abstract Background: Previous studies have indicated that inefficient energy utilization may play a pivotal role in hypertrophic cardiomyopathy (HCM). However, whether plasma free fatty acid (FFA), a main energy substrate of heart, has an effect on HCM remains unclear. Besides, several studies have suggested sex-related differences in HCM features and FFA metabolism. Here, we aimed to explore the association between plasma FFA levels and HCM and potential effects of sex on this relation. Methods: A total of 412 patients (age 47.8 ± 12.7 years, 243 males (59.0%)) with HCM were recruited. Complete medical history was collected. Echocardiography and cardiovascular magnetic resonance imaging (CMRI) were performed. Fasting plasma FFA was determined by clinical laboratory. Left ventricular mass (LVM), maximum wall thickness (MWT), and left atrium diameter (LAD) were assessed with CMRI. Results: The median FFA levels were 0.38 (interquartile range (IQR) 0.27–0.52) mmol/L in men and 0.40 (IQR 0.30–0. 59) mmol/L in women. The FFA levels were significantly lower in men compared with those in women (p = 0.005). Compared with women, men had greater LVM index (LVMI) (96.8 ± 37.6 vs. 78.6 ± 31.5 g/m2, p < 0.001). FFA levels in male patients correlated positively with LVM, LVMI, LAD, cholesterol levels, high-density lipoprotein-cholesterol (HDL-C) levels, heart rate, and systolic blood pressure (SBP). However, none of these variables were significantly associated with sqrt (FFA) in female patients except a borderline correlation of LAD (p = 0.050). Multiple linear regression analysis was performed in male patients and revealed that HDL-C (β = 0.191, p = 0.002), heart rate (β = 0.182, p = 0.004), SBP (β = 0.167, p = 0.007), LVMI (β = 0.132, p = 0.032), and LAD (β = 0.165, p = 0.009) were independently associated with increasing FFA levels. Conclusions: In patients with HCM, LVMI, LAD, HDL-C, SBP, and heart rate were independently associated with increasing plasma FFA levels in males, whereas not in females. These results suggest that sex may affect the pathogenesis of HCM through influencing FFA metabolism. And these sex-related differences should be taken into account in therapeutic approaches to influence myocardial FFA metabolism in HCM. Keywords: Hypertrophic cardiomyopathy, Free fatty acid, Sex, Left ventricular mass index, Left atrium diameter * Correspondence: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. Biology of Sex Differences (2016) 7:63 Background Hypertrophic cardiomyopathy (HCM), a common cause of sudden death in young people, is characterized by primary asymmetric left ventricular hypertrophy without an alternative cause [1, 2]. With a prevalence of 2‰ in the general population, HCM has been established as the most frequent genetic heart disease [3, 4]. More than 1400 mutation sites in at least 11 genes encoding proteins of the cardiac sarcomere are responsible for (or associated with) HCM [3–6]. However, pathways from mutation to clinical phenotype are still poorly understood [2]. Nevertheless, some studies have showed sex differences in clinical features. Male patients had greater left ventricular mass index (LVMI) [7] and disease penetrance [8], while female patients were more likely to have severe symptoms of heart failure [9]. Several studies have suggested that inefficient energy utilization resulted from sarcomeric mutations plays a pivotal role in HCM [2, 3]. Circulating free fatty acids (FFAs) are mainly from lipolysis in the adipose tissue [10]. It is well known that FFAs are important energy substrates of the heart, where FFA oxidation supplies about 70% of energy consumption [10, 11]. However, high concentrations of FFA under pathological conditions have been shown to be proarrhythmic [12] and exacerbate heart failure [13, 14], which are common clinical features of HCM. Besides, many studies indicate that pathologic hypertrophy [11, 15] and heart failure [13, 16] are associated with a reduction in FFA oxidation. In addition, previous data suggest that reduced myocardial long-chain FFA uptake contributes to some types of HCM [17]. Moreover, septal hypertrophy is a feature of the developing mammalian heart [18], where FFA utilization is limited [19]. Early infants (less than 6 months of age) in whom if the shift of myocardial substrate utilization from glucose to FFA is prevented sometimes exhibit typical features of HCM [20]. Therefore, FFA may play an important role in HCM. Furthermore, recent literature has suggested that female patients with heart failure had higher myocardial FFA uptake [21]. And there were sex-related differences in serum FFA levels [22] and FFA metabolism [23]. However, to date, few studies have been performed to evaluate the associations of FFA with cardiac structural and functional parameters. Hence, here we sought to explore the relation between FFA levels and HCM with a large cohort of HCM patients. Considering aforementioned sex-related differences in HCM features and FFA metabolism, we determined potential effects of sex on the relation between FFA and HCM. Owing to its threedimensional tomographic imaging with high spatial resolution, cardiac magnetic resonance imaging (CMRI) was employed in the diagnosis and morphological characterization of HCM in the present study [24]. Page 2 of 10 Methods Study population The protocol of this study was approved by Fuwai Hospital (Beijing, China) ethics committee and complied with the Declaration of Helsinki. The informed consents were obtained from all participants. Consecutive patients with HCM, evaluated at Fuwai Hospital (Beijing, China) from December 2012 to December 2015, were enrolled. The diagnosis of HCM was based on a maximum left ventricular wall thickness ≥15 mm (or ≥13 mm with an unequivocal family history of HCM), as measured by ech (...truncated)