Background
Diastolic dysfunction (DD) is a condition characterized by abnormal cardiac relaxation, stiffness or filling. Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome with symptoms and signs of HF, but with normal or only mildly reduced ejection fraction, and is closely associated with DD [
1]. In developed countries, the prevalence of HF is about 1–2% of the adult population, and ≥ 10% among persons > 70 years of age [
1]. About half of HF patients have HFpEF [
2]. The EURObservational Research Program: the Heart Failure Pilot Survey (ESC_HF Pilot) conducted a prospective 1-year survey among 136 cardiology centers in 12 countries with over 5.000 HF patients enrolled [
3]. The all-cause mortality rate after 1 year was 13.4% in acute HFpEF and 5.9% in chronic, stable HFpEF. DD in itself, not accompanied by HF, is associated with increased all-cause mortality, and it is often asymptomatic [
4]. Despite HFpEF being a major and growing health problem in the USA and Europe, the understanding of this condition is still scarce and there is no medical treatment of proven benefit for HFpEF [
5]. In particular, HFpEF is associated with female sex‚ increasing age and obesity [
1]. The reasons for the female preponderance for HFpEF remain unsolved [
6]. It is therefore of interest to examine features associated with DD, among them metabolic risk factors, for better understanding of possible sex-specific mechanisms leading to HFpEF.
Adipose tissue is an endocrine organ that produces a range of biologically active substances, such as the adipokines. They constitute a group of protein hormones with functions in the regulation of energy metabolism, insulin sensitivity, inflammation, atherosclerosis and cell proliferation [
7]. Biologically important members include, among others, tumor necrosis factor-α, interleukin-6, interleukin-10, omentin, leptin and adiponectin [
8]. The latter is abundantly produced and secreted by adipose tissue, and during the previous decade adiponectin has been shown to have antidiabetic, anti-inflammatory, anti-atherogenic and cardioprotective effects [
7]. Low levels of adiponectin are in longitudinal studies associated with the development of insulin resistance [
9] and hypertension [
10], and adiponectin is negatively associated with body mass index (BMI) and body-fat [
11]. Reduced plasma adiponectin is associated with the metabolic syndrome [
12] and higher risk of myocardial infarction [
13], although, paradoxically, in chronic HF adiponectin levels tend to be high, and increasing with disease severity [
14]. It has been postulated that uric acid can affect adipocytes by inducing downregulation of adiponectin [
15]. Thus, there may be a biologically relevant interplay between uric acid and adiponectin.
The relationship between adiponectin and DD has not been thoroughly investigated. Since there is a female preponderance for HFpEF, it is of relevance to assess whether these associations may differ by sex. Therefore, we wanted to do cross-sectional analyses and examine the associations between adiponectin and echocardiographic indices of DD in a large cohort of men and women from the general, non-diabetic population.
Discussion
To our knowledge, this is the first study to demonstrate sex differences in the association between adiponectin and DD in a general, non-diabetic population. In this study of 1165 women and 896 men, we have shown that a lower adiponectin was associated with higher odds of indices of DD in women, including e’ < 9, E/e’ ratio ≥ 8, concentric LV hypertrophy, and moderately enlarged LA. In addition, lower adiponectin was associated with higher LV mass in women. These associations were not found in men. Rather, low adiponectin was associated with decreased odds of concentric LV hypertrophy and eccentric LV hypertrophy in men. Except for a severely enlarged atrium, we found no marker of DD that was associated with a high adiponectin in women, and conversely, we found no marker of DD at all that was associated with a low adiponectin in men.
Traditionally, high adiponectin levels have been regarded as favorable in terms of cardiac health, but research has challenged this view, and the role and action of adiponectin in heart disease is not clear. In general, low adiponectin has been associated with the development of coronary heart disease in healthy subjects [
24], but high adiponectin was a risk factor for severity of HF and mortality in patients with chronic HF [
25]. A current theory to this equivocal relationship of adiponectin and heart disease is that high levels are beneficent in healthy subjects, but that adiponectin levels can be upgraded as a compensatory mechanism in the face of chronic HF [
14]. This may explain, in our study, why in women low adiponectin was associated with moderately enlarged LA, but higher adiponectin was associated with severely enlarged LA. Adiponectin could also increase simply due to reduced kidney function, which commonly coexists with HF [
26].
To our knowledge, only a few studies have examined sex differences in the association between adiponectin and DD. In one paper, a cohort consisting of 193 patients undergoing cardiac catheterization for coronary artery disease was divided by sex. The authors found a negative relationship between adiponectin and DD (evaluated by correlation with LV end-diastolic pressure, and Tau, the time constant of the decrease in LV pressure), but they could not report a significant sex difference in this association [
27]. A recent population based study of 556 individuals did not find any association between DD and adiponectin for either sex [
28]. The study categorized patients into DD grades: grade I (mild DD) if lateral e’ < 10 cm/s, E/A ratio < 0.8, EDT > 200 ms, and E/e’ ratio ≤ 8; grade II (moderate DD) if lateral e’ < 10 cm/s, E/A ratio 0.8–1.5, EDT 160–200 ms, and E/e’ ratio 9–12; and grade III (severe DD), if lateral e’ < 10 cm/s, E/A ratio ≥ 2, EDT < 160 ms, and E/e’ ratio ≥ 13. The fact that our population was much larger and used somewhat different DD indices, may account for the divergent results.
Experimental studies may shed some light on the effects of adiponectin on the development of DD and the sex differences in the overall action of adiponectin. In adiponectin deficient mice, pressure overload resulted in concentric cardiac hypertrophy and mortality to a greater degree than in pressure overloaded wild type [
29]. Another study in adiponectin deficient mice, in which the animals were subjected to aldosterone-induced hypertension in addition to uninephrectomy, showed that hypoadiponectinaemia exacerbated hypertension-induced DD with increased LV mass, increased E/A ratio, reduced e’ wave and increased E/e’ ratio in the adiponectin deficient mice compared to the wild type [
30]. Transgenic mice that overexpressed adiponectin were protected from DD after pressure overload compared to wild type [
31]. Induced activity of the enzyme heme oxygenase-1 (HO-1) has been associated with reduced oxidative stress, increased insulin sensitivity and increased adiponectin levels [
32,
33]. One study pharmacologically induced HO-1 in both lean and obese female and male mice, and discovered that although female obese mice had higher levels of several inflammatory cytokines than male obese mice, HO-1 induction and a subsequent increase in adiponectin, reduced inflammatory cytokines to similar levels in females and males [
34]. Similar results were found in another study on obese female and male mice that administered a peptide that increased HO-1 and adiponectin levels [
35], and the effects were independent of body weight in the female animals only. In both these studies, adiponectin levels were similar in obese male and female mice, but treatment raised adiponectin levels significantly higher in females than males. These animal studies are suggestive of sex differences in concentration/production and activity of adiponectin, especially in the obese subjects. Indeed, adiponectin levels are generally higher in women than in men, perhaps in part because of a negative correlation with testosterone [
36], and post-menopausal women have lower levels of adiponectin [
37]. Also in humans, the relative sex difference in adiponectin is less pronounced in obese than non-obese [
38]. Additionally, one study found DD to be more strongly correlated with abdominal adiposity in women than in men [
24]. Although several studies have confirmed a positive correlation between insulin sensitivity and adiponectin in both sexes [
38], one study found a lower number of adiponectin receptors in female skeletal muscle and speculates that this may result in a reduced insulin sensitizing effect of adiponectin in women compared with men [
39]. Adiponectin can be separated into three complexes: low molecular weight form, middle molecular weight form, and high molecular weight form (HMW), and some suggest that the ratio of HWM to total adiponectin levels is more closely associated with insulin sensitivity than total levels alone [
40]. HMW adiponectin was lower in men, but not in women, with diabetes and coronary artery disease [
41]. The dissimilarity in adiponectin levels between men and women may be due solely to a higher level of HWM in women than men [
40]. Unfortunately, only total adiponectin was available in our survey, so it was not possible for us to examine the HMW fraction in relation to DD and sex. In sum, it is possible that discrepancies between men and women in adipose tissue activity, distribution of adiponectin receptors and HMW adiponectin content have contributed to the sex differences in the association between adiponectin and DD reported in our study. With the above in mind, the facts that our cohort had a mean BMI > 25 kg/m
2, i.e. within the overweight range, and a mean age in the mid-sixties may have influenced our results. The relationship between adiponectin, obesity, sex, and organ damage is a complex one and further studies are clearly needed.
The main strengths of this study were the large cohort size, the high attendance rate and the ability to correct for several covariates, including eGFR and use of antihypertensive medication, and the use of the newest guideline based definitions of DD. The most important limitation was its cross-sectional design. Other relevant limitations include the lack of fasting blood samples, and the single measurement of total adiponectin available. A quantification of HMW adiponectin could have provided more data in our models. Moreover, our estimation of LA was based on the diameter; LA volume measurements may have yielded additional information. Data on tricuspid regurgitation velocity would also have strengthened the study. Our exclusion of subjects with diabetes may be a further limitation. The fact that our cohort largely consisted of middle-aged, healthy Northern Europeans limits the study’s generalizability to other ethnic groups.