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Relationship Between Obesity, Cardiac Hemodynamics, and Heart Failure in Adults With Coarctation of Aorta
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Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of the Journal of Invasive Cardiology or HMP Global, their employees, and affiliates.
J INVASIVE CARDIOL 2024. doi:10.25270/jic/24.00163. Epub July 30, 2024.
Abstract
Objectives. Patients with coarctation of aorta (COA) have arterial stiffening and left ventricular (LV) diastolic dysfunction similar to patients with heart failure with preserved ejection fraction (HFpEF) and obese subjects. However, the relationship between obesity, cardiac hemodynamics, and HF in adults with COA is unknown. The purpose of this study was to compare cardiac hemodynamics and prevalence of HFpEF between COA patients with vs without obesity, and to assess the relationship between obesity and HFpEF in this population.
Methods. Adults with COA who underwent right heart catheterization were divided into an obese group (body mass index, BMI > 30 kg/m2) or a non-obese group (BMI ≤ 30 kg/m2). We also selected a control group of subjects without structural heart disease and with normal invasive hemodynamics at rest (n = 36). HFpEF was defined as having clinical symptoms of HF (exertional dyspnea or fatigue), LV ejection fraction of at least 50%, and pulmonary artery wedge pressure (PAWP) greater than 15 mm Hg at rest.
Results. Of 99 COA patients, 29 (29%) had obesity. The obese COA group had higher right atrial pressure and PAWP, and worse pulmonary and systemic vascular function compared with the non-obese COA group and the control group. The overall prevalence of HFpEF in adults with COA was 32%, and the prevalence was higher in COA patients with obesity (55%) compared with those without obesity (23%). Obesity was associated with HFpEF after adjustment for demographic indices, comorbidities, and vascular function.
Conclusions. The abnormal hemodynamics and higher prevalence of HFpEF in COA patients with obesity underscores the need for intervention to address obesity in this population.
Introduction
Obesity is a major public health problem because it currently affects about 40% of adults in the United States, and the prevalence is expected to increase to 50% by 2030.1,2 Obesity is intricately linked to heart failure (HF) through its deleterious effects on volume status, cardiovascular remodeling, tissue metabolism, and systemic inflammation.3-5 More than half of patients with HF have preserved ejection fraction (HFpEF), and the coexistence of HFpEF and obesity is associated with greater cardiac hypertrophy, abnormal myocardial energetics, and heightened pericardial restraint.6-9 Coupled with volume expansion, patients with HFpEF and obesity have increased cardiac filling pressures, systemic and pulmonary venous congestion, and worse HF symptoms.8,9
Coarctation of aorta (COA) is characterized by left ventricular (LV) hypertrophy and diastolic dysfunction, as well as left atrial (LA) remodeling and dysfunction, similar to the pattern of cardiac remodeling observed in patients with HFpEF.10-13 However, the effects of obesity on cardiac hemodynamics and the prevalence of HFpEF in adults with COA have not been systematically studied. The purpose of this study was to compare cardiac hemodynamics and prevalence of HFpEF between COA patients with vs without obesity, and to assess the relationship between obesity and HFpEF in this population.
Methods
Study population
The Mayo Clinic Institutional Review Board approved this study. This is a retrospective cohort study of adults (age ≥ 18 years) with repaired COA that underwent right heart catheterization (RHC) at the Mayo Clinic from January 1, 2003, to December 31, 2022. The indication for RHC was for HF evaluation. We excluded patients with concomitant LV inflow disease, defined as having any of the following conditions: supra-valvular, valvular, or sub-valvular mitral stenosis with mean gradient of at least 3 mm Hg, at least moderate mitral regurgitation, or the presence of a mitral valve prosthesis.12 The COA patients were divided into the obese group (body mass index, BMI > 30 kg/m2) and the non-obese group (BMI ≤ 30 kg/m2).
As a reference group, we selected a control group of patients without structural heart disease (normal echocardiogram and normal invasive hemodynamic indices at rest), under the age of 50 years, and with BMI less than or equal to 30 kg/m2 who underwent RHC within the study period. The patients in the control group were derived from the prospective arm of the MACHD Registry (IRB# 23-001939 and 20-007695) and from the Mayo HFpEF database. The Mayo Clinic Institutional Review Board approved the study, and the patients provided informed consent.
Study objectives
The study objectives were to (1) compare the clinical characteristics and hemodynamics between obese versus non-obese COA patients, and (2) compare the prevalence of HFpEF between obese vs non-obese COA patients and assess the relationship between obesity and HFpEF diagnosis. HFpEF was defined as clinical symptoms of HF (exertional dyspnea or fatigue), LV ejection fraction (LVEF) of at least 50%, and PA wedge pressure (PAWP) greater than 15 mm Hg at rest.14-18
Cardiac catheterization
The procedural details for performing congenital cardiac catheterization in this institution have been previously described.19,20 In brief, all studies were performed on chronic medications in a fasting state using mild sedation. Pressure measurements were recorded as an average of at least 5 cardiac cycles under spontaneous breathing. Venous access was obtained via internal jugular or femoral vein using 7-French (Fr) balloon-tipped catheters. PAWP was measured after confirming proper wedge position using oximetry and pressure waveform. In patients who underwent left heart catheterization, arterial access was obtained via radial or femoral artery, and arterial catheterization was performed using 4- to 6-Fr pigtail or multipurpose catheters. Oxygen saturation was measured using the standard technique, and cardiac output was calculated using the Fick method.
Pulmonary vascular function was assessed using the following indices: (1) pulmonary vascular resistance index ([mean PA pressure – PAWP]/cardiac index), (2) total pulmonary resistance index (mean PA pressure/cardiac index, (3) PA compliance index (PACI) (stroke volume index/PA pulse pressure), and (4) PA elastance index (systolic blood pressure/stroke volume index).8,21 Systemic vascular function was assessed using the following indices: (1) total arterial compliance index (TACI) (stroke volume index/systemic pulse pressure) and (2) effective arterial elastance index (EaI) ([0.9 x systolic blood pressure]/stroke volume index).8,21
Statistical analysis
Data were presented as mean ± standard deviation, median (IQR), and count (%). Between-group comparisons were performed using an unpaired t-test, Wilcoxon rank sum test, and Fisher’s exact test, as appropriate. The correlates of HFpEF were determined using multivariable logistic regression analysis. First, we created multiple univariable logistic regression models using the following covariates: demographic/anatomic indices (age, sex, COA repair, and LV outflow tract disease), comorbidities (hypertension, diabetes, coronary artery disease, atrial fibrillation, and obesity), and invasive hemodynamic indices (pulmonary and systemic vascular function indices). Covariates with a P-value of less than 0.1 on univariable analysis were used to create the multivariable model, and the final variable selection was based on stepwise backwards selection with a P-value of less than 0.1 required for a covariate to remain in the model. All statistical analyses were performed with BlueSky Statistics software (version. 7.10; BlueSky Statistics LLC), and JMP statistical software (version 17.1.0, JMP Statistical Discovery LLC). A P-value of less than 0.05 was considered statistically significant for all analyses.
Results
Baseline characteristics
There were 99 patients with COA who underwent RHC for HF evaluation. Of the 99 patients, 29 (29%) patients had obesity at the time of RHC. The control group was comprised of 36 subjects without structural heart disease. Table 1 shows a comparison of the baseline clinical characteristics across the 3 groups (control group vs non-obese COA group vs obese COA group). All groups had comparable age and sex distribution.
Compared to the control group, the COA groups had higher levels of N-terminal pro b-type natriuretic peptide (NT-proBNP) and plasma volumes, as well as a higher prevalence of hypertension and use of cardiac medications (Table 1). Within the COA population, the obese COA group had lower levels of NT-proBNP (161 pg/mL [IQR 43-344] vs 402 pg/mL [IQR 163-2583], P = .003), higher plasma volume (3456 mL [IQR 3111-4128] vs 2756 mL [IQR 2431-3218], P < .001), and higher prevalence of obstructive sleep apnea (28% vs 4%, P < .001) compared to the non-obese COA group (Table 1).
Invasive hemodynamic indices
Table 2 compares invasive hemodynamic indices across the 3 groups. Compared to the control group, the COA groups had higher mean right atrial (RA) pressure and PA pressures, and worse pulmonary vascular function (higher pulmonary vascular resistance, total pulmonary resistance index, and PA elastance index, as well as lower PACI). Although there were no significant between-group differences in systolic blood pressure in the control group compared with the COA groups, the COA groups had worse systemic vascular function (higher EaI and lower TACI) because of lower LV stroke volume index in the COA groups (Table 2).
Pairwise comparisons within the COA groups show significant differences between the 2 groups. Compared with the non-obese COA group, the obese COA group had higher mean RA pressure (10 [IQR 7-16] vs 7 [IQR 5-10] mm Hg, P = .008) and mean PA pressure (28 [IQR 20-38] vs 23 [IQR 18-29] mm Hg, P = .03), as well as worse PA vascular function as evidenced by a higher total pulmonary resistance index (10.64 [IQR 6.92-12.96] vs 7.89 [IQR 4.91-10.86] wu*m2, P = .009), and PA elastance index (1.44 [1.02-1.83] vs 9.78 [0.61-0.98] mm Hg*m2/mL, P < .001), as well as lower PACI (1.33 [IQR 1.04-2.15] vs 1.98 [IQR 1.31-3.20] mL/m2/mm Hg, P = .007) (Table 2). The obese COA group also had worse systemic vascular function as evidenced by a higher EaI (3.11 [IQR 2.70-3.54] vs 2.38 [IQR 2.06-2.78] mm Hg*m2/mL, P = .002), and lower TACI (0.78 [IQR 0.64-0.95] vs 1.01 [IQR 0.79-1.12] mL/mm Hg*m2, P < .001) (Table 2).
Obesity and HFpEF
The prevalence of HFpEF was higher in the obese COA group compared with the non-obese COA group (55% [16/29] vs 23% [16/70], P = .002) (Table 3). Table 4 shows univariable and multivariable logistic regression models assessing relationship between obesity and HFpEF. Obesity was associated with HFpEF diagnosis (adjusted odds ratio [OR] 4.15, 95% CI, 1.31-13; P = .02) after adjustments for demographic indices, comorbidities, as well as pulmonary and systemic vascular function indices. Other correlates of HFpEF were TACI (adjusted odds ratio [OR] 0.12, 95% CI, 0.06-0.41 per 1 mL/mm Hg*m2, P < .001), PACI (adjusted OR 0.36, 95% CI, 0.15-0.56 per 1 mL/mm Hg*m2, P < .001), and atrial fibrillation (adjusted OR 3.13, 95% CI, 1.00-10.7, P = .05).
Discussion
In this study, we assessed the relationship between obesity, cardiac hemodynamics, and HFpEF prevalence in adults with repaired COA. The main findings were (1) the prevalence of obesity in adults with COA undergoing RHC was 29%, and obese COA patients had higher filling pressures, as well as worse pulmonary and systemic vascular function than non-obese COA patients; (2) the overall prevalence of HFpEF in adults with COA was 32%, and the prevalence was higher in obese COA group (55%) compared with the non-obese COA group (23%); and (3) obesity was associated with HFpEF after adjustment for demographic indices, comorbidities, and vascular function.
COA is characterized by aortic isthmus stenosis leading to increase in LV afterload.22 LV pressure overload due to aortic isthmus stenosis can be effectively relieved by surgical or transcatheter therapy with good long-term results.23-26 However, COA patients experience ongoing LV pressure overload even in the absence of residual or recurrent aortic isthmus stenosis because of a high prevalence of systemic hypertension in this population.22,24,27 The etiology of hypertension in this population is multifactorial, and includes factors such as endothelial dysfunction, abnormal smooth muscle reactivity, sympathetic dysregulation, and increased wave reflection due to differences in the tissue characteristics at the site of COA repair.28-30 Collectively, these factors lead to chronic LV pressure overload, LV remodeling (hypertrophy, diastolic dysfunction, systolic dysfunction), LA dilation and dysfunction, pulmonary vascular remodeling and pulmonary hypertension, and right heart dysfunction.10,12 This is similar to the pathogenesis of cardiac remodeling and HF observed in patients with HFpEF.14-18
In a 2017 study, Reddy et al compared the invasive hemodynamic indices of obese HFpEF patients vs non-obese HFpEF patients vs a control group of patients without structural heart disease.8 They observed that, compared with the control group, the HFpEF group had higher filling pressures (RA pressure and PAWP) and higher PA pressures.8 Within the HFpEF cohorts, they also observed that the obese HFpEF patients had higher filling pressures (RA pressure and PAWP) compared with non-obese HFpEF patients. These between-group differences in filling pressures were attributed to higher pericardial restraint in the obese patients as evidenced by greater LV eccentricity index and ventricular interaction.8 The RA pressure, which is an approximation of pericardial pressure, correlated with LV eccentricity index (a measure of ventricular interaction).8,31 The PAWP represents a sum of the LV transmural pressure (LV distending pressure) and the pericardial pressure (approximated as the RA) 8,31 Both components of the PAWP were elevated in the setting of HFpEF and obesity.8
We observed similar findings in the current study, whereby the COA groups had higher filling pressures, higher PA pressures, and worse PA vascular function compared with the control group. Within the COA group, we also observed a similar pattern of higher filling pressures and PA pressures, as well as worse pulmonary and systemic vascular function in COA patients with obesity compared with those without obesity. As previously shown, patients with COA have increased arterial stiffness (similar to the findings in patients with HFpEF), and the resulting increase in arterial load is the primary driver for LV and LA remodeling, pulmonary vascular remodeling, and right heart dysfunction.29,30,32
The current study provides new insight about the relationship between obesity and vascular function in patients with COA. We postulate that the higher arterial load resulting from systemic vascular dysfunction in the obese COA patients likely contributes to the worse LV diastolic dysfunction and increased filling pressures, and, in turn, worse pulmonary vascular function and higher RA pressures. These changes in cardiovascular structure and function are invariably responsible for the higher prevalence of HFpEF observed in the obese COA group. While the current study does not provide mechanistic data linking adiposity to vascular dysfunction and pericardial restraint, these mechanisms have been described in patients with acquired forms of HF.33,34
Clinical implications and future directions
Adults with COA have limited longevity because of premature cardiovascular mortality related to ventricular dysfunction and vascular complications.12,35,36 The high prevalence of obesity (29% of the cohort), as well as its relationship to abnormal cardiac hemodynamics and HFpEF, is very concerning considering the guarded prognosis in this population. Fortunately, obesity is a reversible condition, and previous studies have shown the cardiovascular benefits of weight loss therapies. Reddy et al and Sorimachi et al demonstrated that weight loss, either from calorie restriction or bariatric surgery, resulted in improvement in central hemodynamics at rest and with exercise, reduced ventricular interaction, and LV reverse remodeling.37,38 More importantly, these hemodynamic benefits were apparently within 9 months of initiating therapy.37,38 Furthermore, the use of medical therapies such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonist was associated with improvement in cardiac hemodynamics and cardiovascular symptoms.39,40 While there are no clinical trials assessing the efficacy of weight loss therapy in adults with congenital heart disease, an observational study from our group showed that clinically significant weight loss (reduction in BMI by > 5%) was associated with reduction in the risk of cardiovascular events.41 Other potential targets for intervention would include treatment of obesity-related comorbidities, such as sleep apnea and atrial fibrillation.
Limitations
We studied the prevalence of obesity and HFpEF in a sample of COA patients referred for RHC for worsening clinical status or concern for HF, and this study design has an inherent selection bias. Hence, the prevalence of HFpEF in our sample was likely overestimated compared with the expected prevalence in other cohorts of adults with COA. Furthermore, we relied on cross-sectional analysis, and hence were unable to infer causality.
Conclusions
Adults with COA and obesity had higher filling pressures, worse pulmonary and systemic vascular function, and higher prevalence of HFpEF than non-obese COA patients. Obesity was associated with HFpEF after adjustment for demographic indices, comorbidities, and vascular function. The abnormal cardiac hemodynamics and high prevalence of HFpEF in COA patients with obesity underscores the need for intervention to address obesity in this population.
Affiliations and Disclosures
Alexander C. Egbe, MD, MPH, MS; William R. Miranda, MD; C. Charles Jain, MD; Heidi M. Connolly, MD
From the Department of Cardiovascular Medicine, Mayo Clinic Rochester, Minnesota, USA.
Disclosures: The authors report no financial relationships or conflicts of interest regarding the content herein.
Funding: Dr. Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grants (R01 HL158517 and R01 HL160761). The MACHD Registry is supported by the Al-Bahar Research grant.
Address for correspondence: Alexander Egbe, MD MPH, FACC, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA. Email: egbe.alexander@mayo.edu
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