Association Between Visceral Fat, Blood Pressure and Arterial Stiffness in Patients with HFpEF: A Mediation Analysis

Min Sun,1,2 Lei Gao,1 Hongmei Bai,1 Weiwei Hu,1 Xiaofang Zhang,1 Jin Xiao,1 Xiangliang Deng,1 Hongmei Tao,1 Ping Ge,2 Yuhong Qin,1,* Dongying Zhang1,*

1Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Health Management Center, The First Branch of the Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

Purpose: To investigate the association of visceral fat with arterial stiffness of heart failure patients with preserved ejection fraction (HFpEF) and to evaluate the extent to which this association is mediated by blood pressure (BP).
Patients and Methods: This cross-sectional descriptive study (clinicaltrials.gov identifier: NCT04535726) recruited 94 patients with HFpEF totally from October to December 2020. The obesity-related measurements included visceral fat area (VFA), body mass index (BMI), waist circumference (WC), hip circumference (HC), waist–hip ratio (WC/HC), abdominal circumference (AC), body fat mass and fat percentage. Brachial-ankle pulse wave velocity (baPWV) was used to estimate the degree of arterial stiffness. Mediation analysis was performed to reveal whether the effect of visceral fat area on arterial stiffness can be mediated by BP in patients with HFpEF and the extent to which this association was mediated by BP.
Results: About 93.6% of HFpEF patients were accompanied with abdominal obesity. Patients in baPWV ≥ 1800cm/s group were older, with a higher incidence of type 2 diabetes mellitus (T2DM), hypertension and abdominal obesity. VFA, systolic BP (SBP), diastolic BP (DBP) and pulse pressure (PP) were correlated with baPWV in total group. Adjusted for age ≥ 75 years old, gender, smoking, T2DM, calcium channel blocker and statins, the mediation effect of systolic SBP and PP on the VFA-baPWV association were 53.3% (indirect effect was 2.28, 95% CI 0.62– 4.73) and 48.4% (indirect effect was 2.07, 95% CI 0.51– 4.38), respectively. DBP failed to mediate the association between VFA and baPWV (indirect effect was 0.50, 95% CI − 0.41– 2.14).
Conclusion: The association of visceral fat with baPWV in HFpEF patients may be partly accounted for SBP or PP. Elevated SBP and PP might be important potential targets for preventing arterial stiffness in HFpEF patients.

Keywords: mediation analysis, blood pressure, visceral fat area, brachial-ankle pulse wave velocity, HFpEF

Introduction

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease with typical diastolic dysfunction of the left ventricle (LV).1,2 Studies had proven that arterial stiffness, which means the decrement of arterial compliance, was an important harmful factor for LV diastolic function and HFpEF.3,4 Brachial-ankle pulse wave velocity (baPWV) is a widely used measure for arterial stiffness, and numerous studies had found baPWV to be associated with visceral fat, waist circumference (WC), and body mass index (BMI),5–7 while the underlying mechanism of these observations is not fully understood. Blood pressure (BP) as a leading promoter of arterial stiffness might mediate the association of BMI with baPWV.8–10 Compared with systemic obesity evaluated by BMI, abdominal obesity was the main form of Chinese HFpEF patients11–13 and may cause more serious adverse consequences in obese HFpEF patients.14 Thus, a key unsolved mystery for HFpEF-patient health is the extent to which the effect of abdominal obesity on baPWV might be mediated by BP. To address this concern, we applied a mediation analysis to investigate the extent of blood pressure mediated the association of visceral fat area (VFA, a method to measure abdominal obesity)15 with baPWV within HFpEF.

Materials and Methods Participants and Study Design

A total of 131 patients with HFpEF were recruited to the study from October to December 2020. The eligible subjects at screening required an age over 50 years, signs and symptoms of heart failure, an ejection fraction of 50% or higher, elevated level of natriuretic peptides or B-type natriuretic peptide (with different cutoffs depending on whether the rhythm was sinus or atrial fibrillation and/or flutter: sinus rhythm at least higher than 125 pg/mL, fibrillation and/or flutter rhythm at least higher than 365 pg/mL), changes in the structure and/or function of the heart and the HFA-PEFF score ≥5 points (details see the consensus recommendation from the Heart Failure Association of the European Society of Cardiology).16 Patients with malignant tumor, severe valvular disease, severe liver or kidney insufficiency (severe liver insufficiency defined as the level of aspartate transaminase or alanine transaminase higher than 3 × ULN or the level of total bilirubin higher than 2 × ULN at admission. Severe kidney insufficiency was defined as the level of estimated glomerular filtration rate lower than 30 mL/min/1.73 m2), and missing brachial-ankle pulse wave velocity (baPWV) or VFA data were excluded. Finally, 94 HFpEF patients were included (Figure 1), and all patients agreed to participate with a written informed consent. The study was a cross-sectional study with clinicaltrials.gov identifier of NCT04535726. All procedures were complied with the Declaration of Helsinki and followed the instructions of local ethic committee of the First Affiliated Hospital of Chongqing Medical University (approval NO. 2020-606).

Figure 1 Population screening flow diagram.

Abbreviation: baPWV, brachial-ankle pulse wave velocity.

Baseline Data

Clinical features and medical history were collected by the investigator. Laboratory results and echocardiogram data were defined using the first-time examination after admission. All the laboratory data were tested in the same laboratory with the same standard. All the echocardiographic data were collected by the same echocardiologist using the same ultrasound machine (Vivid E95, AU11403, GE Vingmed Ultrasound AS).

Body Measurements

Body weight and height were recorded without shoes using a Detecto balance beam scale and a wall-mounted stadiometer to the nearest 0.1 kg and 0.1 cm, respectively. BMI, WC, hip circumference (HC) and AC were measured by a standard procedure described before.17 Systemic obesity is defined as BMI ≥ 28.0kg/m2.18 Abdominal obesity was defined as WC ≥ 90.0 cm (male) or 85.0 cm (female), or WC/HC ≥1.0, or VFA ≥80 cm2.19 Bioelectrical impedance analysis, emerged as an assessment tool of body composition,20 was used to identify and measure VFA, body fat mass and fat percentage in the present study as reported.21

BP and Arterial Stiffness Measurement

BP and arterial stiffness evaluated by baPWV were detected twice by a BP-203 RPE III networked arteriosclerosis detection device (Omron Health Medical [China], Co, Ltd) at the same time as possible in a comfortable environment. All participants were asked to rest peacefully at least 30 minutes on sitting before the test without smoking, drinking or moving. Observer was asked to do not talk with participant during the test. The cuffs were evenly and tightly wrapped around the bilateral upper arms and the lower edges of cuffs were 2.5cm from the elbows. The center of the cuff was located above the brachial arteries. Systolic BP (SBP) and diastolic BP (DBP) were the average values of upper limbs. Pulse pressure (PP) was calculated by SBP minus DBP.

Statistical Analysis

Categorical parameters were displayed by number (%), and continuous parameters were expressed as mean ± standard deviation (SD) or median (quartiles). Χ²-test or Fisher’s exact test was used to check the difference between groups for categorical variables. t-test or Mann–Whitney U-test was performed for continuous variables. Linear regression analysis was carried out to show the associations of body measurements with baPWV, with baPWV used as the dependent variable, body measurements (VFA, BMI, WC, HC, WC/HC, AC, body fat mass, fat percent, SBP, DBP, PP, age, fasting plasma glucose (FBG) and glycosylated hemoglobin (HbA1c)) used as independent variables. SPSS software (Version 25.0, IBM) was used for statistical analyses. A P-value <0.05 was considered to be statistically significant in two-tailed.

The PROCESS macro developed by Hayes22 was used to calculate the total effect, indirect effect (the effect of VFA on baPWV through BP) and direct effect (BP-independent effect of VFA on baPWV) of VFA on baPWV mediated by BP. The proportion of the mediation is the outcome of indirect effect divided by total effect. In mediation analysis models, predictor variable (X) was VFA; mediator variables (M) were SBP, DBP or PP; the outcome variable (Y) was baPWV. In multiple mediation analysis, age ≥75 years old, gender, smoking, type 2 diabetes mellitus (T2DM), calcium channel blocker (CCB) and statins were considered to be covariates. The differences were considered to be statistically significant if the 95% bootstrap confidence interval (CI) did not cross 0.

Results Baseline Characteristics

All patients were divided into two groups, baPWV <1800 cm/s group (n = 40) and ≥1800 cm/s group (n = 54). Patients in baPWV ≥1800cm/s group were older, with a higher incidence of T2DM, hypertension and abdominal obesity, a lower possibility to take CCB and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II type 1 receptor blocker (ARB), a higher level of SBP, PP, WC, AC, VFA, high-density lipoprotein cholesterol (HDL-C), FBG and mean E/e’, and a thicker posterior wall of left ventricle (LVPW), compared with the patients in baPWV <1800 cm/s group. There were no significant differences in other characteristics between two groups (Table 1).

Table 1 Characteristic Distribution of Participants in This Study

Linear Regression Analysis Between Body Measurements and baPWV

VFA, SBP, DBP, PP, age and FBG were significantly correlated with baPWV (Table 2); the values were β=5.898 for VFA (95% CI 2.226–9.569, P=0.002), β=10.049 for SBP (95% CI 5.935–14.706, P<0.001), β=10.753 for DBP (95% CI 2.657–18.849, P=0.010), β=13.645 for PP (95% CI 7.347–20.114, P<0.001), β=19.730 for age (95% CI 11.258–28.203, P<0.001), β=55.437 for FBG (95% CI 3.294–107.580, P=0.037).

Table 2 Linear Regression Analysis Between Independent Variables and baPWV

SBP or PP Mediated the Association Between VFA and baPWV in the Mediation Analysis

To better understand the relationships among VFA, baPWV and BP, mediation analysis was performed to examine the direct and indirect (BP-mediated) effects of VFA on baPWV. As shown in Figure 2, VFA demonstrated a significant total effect on baPWV (total effect = 5.90; 95% CI 2.23–9.57) in the whole cohort. The indirect effect (through SBP or PP) of VFA on baPWV was prominent (indirect effect through SBP = 2.08; percent mediation through SBP = 35.3%; indirect effect through PP = 2.07; percent mediation through PP = 35.1%). After adjusted for age ≥75 years old, gender, smoking, T2DM, CCB and statins, the mediation effect of SBP and PP on the VFA-baPWV association were 53.3% (indirect effect was 2.28, 95% CI 0.62–4.73) and 48.4% (indirect effect was 2.07, 95% CI 0.51–4.38), respectively. We failed to discover DBP mediated the association between VFA and baPWV in the mediation analysis (indirect effect was 0.50, 95% CI −0.41–2.14) (Supplemental Figure 1).

Figure 2 Mediation effect of blood pressure in the association between visceral fat area and brachial-ankle pulse wave velocity. (A) Mediation Analysis Model of SBP on the association between VFA and baPWV. (B) Mediation Analysis Model of PP on the association between VFA and baPWV. Model 1 and 3: Unadjust. Model 2 and 4: Adjust for age ≥75 years old, gender, smoking, type 2 diabetes mellitus, calcium channel blocker and statins.

Abbreviations: VFA visceral fat area; baPWV, brachial-ankle pulse wave velocity; SBP, systolic blood pressure; PP, pulse pressure.

Discussion

Our findings suggest that in the patients of HFpEF, VFA was associated with baPWV, and this association might be partly mediated via SBP or PP. The results intensified the value of developing effective complex interventions that target SBP and PP as means to delay or improve arterial stiffness in abdominal-obese HFpEF patients.

The purpose of the present study was to better understand the risk factors of arterial stiffness in patients with HFpEF. As one of the risk factors of HFpEF,23 visceral fat leads to the increase in adipocyte size, production of biologically active molecules (eg, proinflammatory cytokines and adipokines), promotion of oxidative stress and the increasing tone of sympathetic nervous system and level of BP,24 which may contribute to the decrement of arterial compliance. Previous studies had demonstrated obesity parameters, including VFA, BMI, WC, HC, WC/HC, AC, body fat mass and fat percentage, were correlated with arterial stiffness.25,26 However, abdominal obesity had been shown to be the most prevalent form of Chinese HFpEF patients compared with systemic obesity,11–13 and visceral fat area may correlate better with arterial stiffness in Chinese and American population in all measures of obesity,25,26 which was consistent with our results. These findings may account for the emergence of VFA as a better facilitator for baPWV within HFpEF. However, the previous studies had focused exclusively on the primary effect of visceral fat on baPWV and ignored possible complex mechanisms and processes, such as BP between them.

In this study, we found SBP and PP were associated with both visceral fat and arterial stiffness, which was consistent with previous studies.27,28 Both the Dallas Heart Study and another study enrolled 1189 Singaporean women who identified a positive association between BP and visceral fat.27,29 Elevated BP had been confirmed as an essential risk factor for arterial stiffness.28,30 However, those studies only provided a hypothesis that BP could bridge the gap between visceral fat and arterial stiffness, and the extent to which BP mediates this effect remains unclear. Gender, ageing, T2DM and smoking had been documented to contribute to the increase in arterial stiffness through several pathological pathways.31–33 Meanwhile, pharmacological interventions have been of great value in reducing the stiffness of artery, such as antihypertensives, statins, antidiabetics and anti-inflammatory drugs.31 By lowering central blood pressure, CCB might be beneficial in reducing PWV.34 Through increasing the bioavailability of nitric oxide, CCB could improve the function of endothelia.35 Probably due to the profibrotic action of the renin–angiotensin system, ACEI and ARB drugs were superior to other antihypertensive agents in reducing arterial stiffness.34 Studies had also proved that statins may have additional benefits in lowering PWV through their anti-inflammatory and antioxidant effects on arterial wall.34 Whether these factors would impact the effect of BP on baPWV is unclear.

To the best knowledge of us, this is the first study to demonstrate that the VFA-baPWV association might be partly mediated through SBP or PP. Although this conclusion was based on the statistic of this cross-sectional study, it may remind us that targeting SBP and PP might be a mean to delay or ameliorate arterial stiffness in abdominal-obese HFpEF patients.

However, we failed to reveal DBP to be a mediator of the relationship between VFA and baPWV. Liu discovered the association of increased-childhood BMI and its cumulative burden with adult aortic-femoral pulse wave velocity (afPWV) was predominantly mediated through the long-term-increasing trend of both SBP and DBP.10 However, in the HFpEF cohort, participants were aged, suffered from arterial stiffness, with more metabolic disorders and a tendency of isolated systolic hypertension.36,37 All these factors contributed to the result that only SBP mediated the association of VFA and baPWV. A prospective design will be needed to reveal the nature relationships among VFA, BP and baPWV in the future.

The partly mediated efforts of SBP and PP imply a number of underlying mechanisms mediated VFA-baPWV association, which may have several explanations. Firstly, when fat is deposited around visceral organs, adipokines such as leptin and pro-inflammatory factors are secreting simultaneously, ultimately leading to chronic inflammation and activation of oxidative stress and sympathetic nerves.24 Persistent inflammation is a character of HFpEF.38 Secondly, chronic inflammation, activated oxidative stress and sympathetic nerve will increase blood pressure level and decrease arterial elasticity.24,39 Reduced arterial elasticity and increased arterial stiffness require more force to accommodate blood flow and then lead to the increase of SBP and PP.40,41 Thirdly, elevated blood pressure also promotes the remodeling and fibrosis of vascular, which eventually leads to the development of arterial stiffness.40,42 Overall, excessive visceral fat deposition not only accelerates the process of arterial stiffness by directly promoting chronic inflammation and activating neuroendocrine but also increases the level of BP in various ways.

We found that VFA, SBP and PP were risk factors for arterial stiffness, and SBP or PP might mediate the VFA-baPWV association. Therefore, our study provided evidence that clinicians might prevent arterial stiffness and decrease the level of SBP and PP by losing weight or changing lifestyles, especially in HFpEF patients, which may help to impede the development of diastolic dysfunction of LV. When necessary, in HFpEF patients with abdominal obesity, strategies to control SBP and PP and reduce abdominal adiposity may help to prevent the development of arterial stiffness.

Strengths and Limitations

This is the first study using mediated analysis to reveal the mediator effects of SBP and PP on the association of VFA with baPWV, and the availability of targeted measures of VFA, BP and baPWV enhanced the reproducibility of our findings. However, there are some limitations. First, as a cross-sectional study, we could not confirm the causal relationship. A prospective design will be needed to reveal the nature relationships among VFA, BP and baPWV in the future. Second, the small sample study was comprised of HFpEF patients from Chongqing, China, which may limit the generalizability of the results (for example, the relationship between other obesity parameters and baPWV). Third, baPWV rather than carotid-femoral PWV (the gold assessed standard of arterial stiffness) or cardio-ankle vascular index (considered to be less dependent on BP than baPWV) was used to evaluate the degree of arterial stiffness. However, study had revealed baPWV as a simple and noninvasive manner can be used to access the degree of arterial stiffness.43 Fourth, aortic arch PWV was recommended to be a method to measure the arterial stiffness of local vessel recently by Doppler-derived, single-beat technique or cardiovascular magnetic resonance (CMR), which has been found to be particularly helpful in HFpEF.44 However, study has reported that baPWV had a superior correlation with central aortic PWV measured by CMR than carotid-femoral PWV,45 which suggested that baPWV might provide qualitatively similar data in comparison of aortic PWV. Lastly, peripheral artery disease was not excluded in the study, which may affect the baPWV values.

Conclusion

In this study, we have provided evidence that the association of visceral fat with baPWV in HFpEF group may be partly accounted for SBP or PP. This finding suggested that SBP or PP might be an important potential target for preventing arterial stiffness in obese-HFpEF patients.

Data Sharing Statement

With reasonable request, all individual deidentified participant data of the study will be available from Dongying Zhang forever (email: [email protected]), including laboratory and imaging data. Other documents about this study will not be available because of the privacy of participants.

Ethics Approval

All procedures were followed the instructions of local ethic committee (approval NO. 2020-606).

Acknowledgments

Thanks Dong Qian (Chongqing Medical University) for the help of performing echocardiography and analysis.

Author Contributions

All authors made a significant contribution to the study, whether that is in the conception, acquisition of data, analysis, or in all these areas; took part in drafting, revising or reviewing the article; reviewed and agreed all versions of this article; approved published this article on this journal; and agreed to be accountable for all aspects of the work.

Funding

This work was supported by the National Natural Science Foundation of China (number 81970203, 81970203); Chongqing Health Commission (number 2022MSXM028); China Cardiovascular Health Alliance-Access Research Fund (number 2021-CCA-ACCESS-130).

Disclosure

The authors report no conflicts of interest in this work.

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