Introduction
Heart failure with preserved ejection fraction (HFpEF) contributes to nearly half of all heart failure (HF) cases, and this proportion has been increasing in recent years [
1,
2]. Its significant phenotypic heterogeneity from fundamental pathophysiology, which is extremely complicated and poorly understood, creates the primary obstacle to therapy. Recent reports have proposed that a systemic proinflammatory state driven by multiple comorbidities, which can cause myocardial inflammation, oxidative stress, and fibrosis, may also play a significant role in HFpEF development [
2‐
4]. Additionally, changes in cardiomyocyte signaling pathways accelerate cardiomyocyte remodeling and microvascular dysfunction, eventually leading to diastolic dysfunction [
3].
Abdominal adipose deposition has a close relationship with systemic inflammation [
5] and is also a prominent feature of HFpEF [
6,
7]. Several studies have demonstrated that abdominal obesity may predict adverse consequences and a greater risk of all-cause mortality in patients with HFpEF [
8,
9]. However, existing evaluation indicators such as body mass index (BMI) evaluate systemic obesity but fail to evaluate the fat or muscle tissue proportion in the body [
10]. In addition, genetic and environmental factors may also complicate the relationship between BMI and the body fat rate and distribution among different ethnic groups [
11]. Although waist circumference (WC) can reflect abdominal obesity, this measure may not identify obesity in individuals with shorter height, normal WC and more body fat. As for waist-to-hip ratio, gender and age differences make it unsuitable for accurate reflection of abdominal fat changes.
Waist to height ratio (WHtR) is a concept proposed to improve upon waist-to-hip ratio. When evaluating abdominal obesity, WHtR balances the effect of height on the basis of WC and overcomes the disadvantage of waist-to-hip ratio, which has a different reference value for each sex. A previous study showed that for Asian populations with low BMI, WHtR was more suitable than WC for exploring associations between obesity and cardiovascular (CV) disease [
12]. However, little is known about the association of WHtR with outcomes in Chinese patients with HFpEF.
Discussion
This study of 2041 Chinese patients with HFpEF described the clinical characteristics of patients with low and high WHtR in detail, and comprehensively analyzed the associations between WHtR and all-cause death. The results demonstrated that: (1) abdominal obesity, overweight or obesity were highly prevalent in patients with HFpEF; (2) except HF, HFpEF patients had an average of 2–3 comorbidities, and those with high WHtR had heavier comorbidity burden than those with low WHtR; (3) HFpEF patients with high WHtR presented more significant left ventricular enlargement and hypertrophy as well as more severe diastolic dysfunction; (4) High WHtR was an independent risk factor for all-cause death in HFpEF patients, which was still observed in all subgroups.
Our HFpEF patients had lower prevalence of overweight or obesity [
8,
24] while higher prevalence of abdominal obesity than HFpEF patients from other countries [
8], which reflects different obesity patterns among patients with different races, and abdominal obesity deserves much more attention in Chinese patients with HFpEF. HFpEF is often accompanied by a variety of comorbidities [
25,
26], which not only complicate clinical diagnosis and treatment, but also worsen prognosis and quality of life and increase hospitalization expenses [
27]. In the present study, HFpEF patients had an average 2.38 comorbidities (excluding the 1 point assigned for HF), which was consistent with the results of the Spanish RICA registry study of heart failure [
28]. In addition, patients with high WHtR had more comorbidities and also prescribed more drugs (ACEI/ARB, beta blocker and diuretic) than those with low WHtR, indicating that HFpEF is a multiorgan disease involving not only cardiac dysfunction but also noncardiac comorbidities contributing to clinical HF development [
29], and abdominal obesity represented by WHtR may corelate to higher prevalence of multiple comorbidities in HFpEF patients.
Obesity have been demonstrated to exerted direct and indirect effects on the cardiovascular system, including increased myocardial load due to volume expansion, deterioration of arterial hypertension, left ventricular hypertrophy, and increased aortic stiffness [
30]. In our study, HFpEF patients with high WHtR showed significantly higher levels of echocardiographic parameters, indicating that these patients have more significant left ventricular enlargement and hypertrophy, accompanied with more severe diastolic dysfunction. And this rising trend of echocardiographic parameters along with increasing WHtR was also in accordance with the elevated level of NT-proBNP (released in response to increased pressure or volume overload), which has been proved to predict HF events and mortality in a wide variety of HF cohorts [
31].
HFpEF Patients probably have slightly better survival. However, with the increasing prevalence as time passes, its mortality remained unchanged, making HFpEF becoming the most common form of HF [
32]. These trends emphasize the significance of studies to figure out the pathophysiology of HFpEF and establish effective therapeutic strategies against it. Sadly, there seems no effective treatments to improve the prognosis of HFpEF patients. HFpEF is characterized as the combination of multiple comorbidities, such as diabetes, obesity, chronic lung diseases, anemia, etc. Theses proinflammatory comorbidities interact and drive myocardial inflammation and fibrosis, oxidative stress, and the alteration in cardiomyocyte signaling pathways, which induce microvascular dysfunction and cardiomyocyte remodeling, and eventually left ventricular dysfunction [
4,
33,
34]. Obesity, especially abdominal obesity, is a predominant comorbidity of HFpEF. It has played a crucial role in the incidence and development of HFpEF, thus understanding the impact of abdominal adiposity facilitates better exploring the pro-inflammatory pathology. As a positive endocrine organ, adipose tissue is able to produce multiple proinflammatory cytokines (e.g., tumor necrosis factor-alpha, interleukin-1, interleukin-18) that may cause diastolic dysfunction [
35,
36]. Moreover, animal experiments have also indicated close associations between visceral obesity and increased cardiac macrophage infiltration and cytokine gene expression, aggravating myocardial hypertrophy, fibrosis and injury [
37]. However, few literatures have investigated the impact of abdominal obesity on the mortality and HF deterioration in HFpEF patients. What’s more, although WC can reflect abdominal obesity in some extent, it might ignore a certain group of patients with short height and more adipose, and its diagnostic criterion for abdominal obesity varies with human race. Currently, WHtR as an indicator for abdominal obesity has proven to be a more accurate and advantageous screening tool than WC and BMI for identifying cardiovascular metabolic risk in adults [
15,
38], because it avoids the need for age-, sex- and ethnic-specific boundary values in adults. 0.5 has been internationally recognized as the diagnostic threshold for WHtR [
15,
39,
40]. In Chinese population, Zhang et al. conducted a survey of cardiovascular risk factors among approximately 35,000 people and found that the incidence of hypertension, dyslipidemia and hyperglycemia was significantly reduced with WHtR < 0.50 [
41]. In this study, we used 0.5 as the threshold, finding that higher WHtR (≥ 0.5) was associated with higher risks of all-cause death, consistent with several previous studies [
8,
42‐
44], and this association was also observed in propensity score-matched patients and all subgroups. Our findings suggests that abdominal obesity reflected by WHtR is associated with poor cardiovascular outcomes independent of BMI and WC. This association also holds true in non-obese individuals. Thus, both the amount and the distribution of adipose tissue may be important in patients with HFpEF. However, it should be noted that 95.84% of the patients in our study were male, thus our conclusion maybe more suitable for male patients. Besides, the threshold of 0.5 was derived from investigations mainly conducted among healthy populations not among patients with specific diseases, whether 0.5 could be a suitable boundary value for HFpEF patients lacks solid evidence and should be used carefully. For HFpEF patients, high WHtR may imply worsening outcomes, so more medication should be considered with priority for these patients. In addition, reducing abdominal obesity through diet, exercise, or both may be the fundamental and essential treatment for patients with HFpEF [
45]. Because the long-term outcome of weight loss in HFpEF patients remains unclear, randomized controlled trials are needed to evaluate whether interventions to reduce abdominal obesity successfully reduce risk in HFpEF patients.
Additionally, we evaluated the relationship of BMI in different categories with adverse outcomes in HFpEF (Table
3). Patients with BMI < 18.5 kg/m
2 were used as reference group. Although some HRs showed no statistical significance, we still observed the phenomenon of obesity paradox, as patients with BMI of 24–27.9 kg/m
2 has the lowest HRs across each endpoint. That is, in our data, the overweight patients with HFpEF tended to have the lowest while those with BMI < 18.5 kg/m
2 had the highest risks of adverse outcomes. Our results were different from the previous study [
24], which demonstrated that the lowest mortality was seen with BMI of 26.5–35 kg/m
2 and the highest mortality risk was seen with BMI < 23.5 and > 35 kg/m
2. We consider that these differences may be mainly attributed to race differences, as Asians are more likely to have a higher percentage of body fat at lower BMI and WC than westerners [
46].
A study of Wormser et al. [
47] found that whether assessed alone or in combination, BMI, WC, and waist-to-hip ratio did not exhibit significant incremental predictive value for first-onset cardiovascular disease over traditional risk factors, suggesting that anthropometric parameters provide limited predictive information. It is worth mentioning that these analyses were restricted to individuals without a history of cardiovascular disease at the initial examination. While for individuals who have already been involved with one or more cardiovascular diseases, anthropometric parameters such as BMI and WHtR may exert certain prognostic value. In our study, HRs (95% CI) of WHtR regarding to all-cause death increased from 1.40 (0.89–2.21) of Model 1 to 1.91 (1.06–3.45) of Model 2, indicating that the existence of abdominal obesity (i.e., higher WHtR in our study) may accelerate the deterioration of diseases in HFpEF patients. However, whether WHtR can provide incremental prognostic information over traditional cardiovascular risk factors in HFpEF patients requires further investigations.
There are some limitations to this study. First, we had incomplete measurement of diastolic parameters. The data on mitral annular early diastolic velocity and left atrial volume index were absent and thus failed to be further analyzed. While other diastolic parameters, such as TR velocity (indicates functional alteration), LVMI and RWT (both indicate structural alterations) were available. TR velocity > 2.8 m/s, LVMI > 115/95 g/m2 (male/female), or RWT > 0.42 can be used as the evidence of abnormal morphology or diastolic dysfunction to help identify HFpEF. Secondly, it is a single-center study; however, to date there is no multicenter clinical study with a larger sample. Thirdly, HFrEF, HFpEF and HF with midrange ejection fraction have different clinical characteristics, pathophysiology, treatment and prognosis, which should be further verified in future studies.
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