Features of Cardiac Remodeling, Associated With Blood Pressure and Fibrosis Biomarkers, Are Frequent in Subjects With Abdominal Obesity

Abstract

White subjects with AO (waist circumference >94 cm for men and >80 cm for women) 2 aged 40 to 65 years and age-and sex-matched healthyAbstract-Incidence and prevalence of abdominal obesity (AO) are growing exponentially. Subjects with AO are at higher risk of developing heart failure. The purpose of the study was to investigate early changes in cardiac and arterial structure and function and extracellular matrix biomarkers in normotensive healthy subjects with AO. Subjects with AO and age-and sex-matched controls underwent echocardiography, MRI (cardiac remodeling index), carotid intima-media thickness, pulse wave velocity, and blood fibrosis biomarkers measurements. We enrolled 87 subjects with AO and 53 controls. Although normotensive, subjects with AO had higher systolic blood pressure (BP; 122±11 versus 116±11 mm Hg; P=0.003), left ventricular mass (94±24 versus 84±21 g; P=0.034), and cardiac remodeling index (0.67±0.16 versus 0.60±0.10 g/mL; P=0.026) but unchanged carotid intima-media thickness and pulse wave velocity. Diastolic dysfunction (E′ <10 cm/s) could be detected in 38% of subjects with AO (4% in controls). Left ventricular remodeling, as assessed by cardiac remodeling index, was positively and independently associated with higher BP (systolic BP and mean arterial pressure but not diastolic BP) and AO. Higher BP, AO, and procollagen-III-N-terminal peptide (≥2.4 ng/mL) concentrations (odds ratio, 4.15 [1.42-12.2]; P=0.01) were positively associated with diastolic dysfunction. Early cardiac structural remodeling, fibrosis, and diastolic dysfunction were detectable in healthy subjects with AO. Higher BP, procollagen-III-N-terminal peptide, and AO were independently associated with early cardiac structural and functional changes. It is to be investigated whether in subjects with AO, an early BP reduction, even if normotensive, combined with weight loss may avoid adverse cardiac remodeling and protect against progression to heart failure. From the INSERM, Center d'Investigation Clinique CIC-P 9501, Nancy, France (R.E., P.R., A.K.S., C.A., K.K., R.F., F.Z.); CHU-Nancy, Department of Cardiology, Nancy, France (F.Z.); Université de Lorraine, Nancy, France (P.R., D.M., P.Y.M., F.Z.); INSERM, U1116, Nancy, France (P.R., P.Y.M., F.Z.); Clermont Université, Université d'Auvergne, UMR6284, Clermont-Ferrand, France (R.E.); CHU Clermont-Ferrand, Department of Cardiology, ClermontFerrand, France (R.E.); CHU-Nancy, Department of Radiology, Nancy, France (D.M.); CHU-Nancy, Department of Nuclear Medicine, Nancy, France (P.Y.M.); and INSERM, U947, Nancy, France (D.M. Metabolic PhenotypingBlood was sampled between 8 and 10 am after maintaining a supine position for 30 minutes and the following were assessed: fasting glucose, oral glucose tolerance test (to exclude patients with diabetes mellitus), glycohemoglobin, serum creatinine (estimated glomerular filtration rate by the MDRD [Modification of the Diet in Renal Disease] formula), 9 ultrasensitive C-reactive protein, alanine aminotransferase, lipid profile, leptin, ...

Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids

“…Interestingly, loss of Lcn2 also blunts the increase in plasma PINP, a marker of procollagen type I processing in mice challenged by mineralocorticoids. This preclinical observation extends to humans: within a cross-sectional study of asymptomatic normotensive obese participants at risk to develop cardiovascular disease but without left ventricular hypertrophy (ie, HF stage A), 17 we observed that plasma NGAL/ MMP-9 was significantly associated with fibrosis biomarkers previously associated with mineralocorticoid effects in HF. 18 This suggests that NGAL/MMP-9 is already altered at the early stage of cardiac remodeling that precedes clinical HF, and may, therefore, be a key factor in the aldosterone signaling pathway leading to tissue remodeling.…”

“…17 Subjects presenting overweight (body mass index >25 kg/m 2 ) and AO (>94 cm for male and >80 cm for female) were compared with age-sex matched healthy volunteers (body mass index <25 kg/m 2 , without AO). This cohort was chosen because of its previous extensive cardiovascular phenotyping, indicating that the obese subjects display early cardiovascular abnormalities, in the absence of the confounding effects related to advanced CVDs.…”

“…In a cohort of normotensive asymptomatic obese subjects and age-sex matched healthy volunteers, 17 plasma-free NGAL and Gal-3 concentrations did not significantly differ between the 2 populations, whereas subjects with AO displayed a 3.8-fold higher NGAL/MMP-9 concentration (P<0.0001), 1.4-fold in plasma aldosterone levels (P<0.0001), 1.9-fold higher in PINP (P<0.0001), 4.1-fold higher in cardiotrophin-1 (CT-1) (P<0.0001), and 20% lower in type I collagen telopeptide concentration (P<0.0001) versus controls (Table 1). No significant correlation was observed between free NGAL and plasma aldosterone, or with ECM biomarkers (data not shown).…”

Vascular Mineralocorticoid Receptors

“…9 Although in heart failure with reduced ejection fraction, primary damage mostly occurs in cardiac myocytes, in HFpEF vascular cells are seen as the predominant cell type that translates the chronic inflammatory state into cardiac injury. 9 In line with this, patients with HFpEF are older and more often obese when compared with patients with reduced ejection fraction, 10 and cardiac remodeling in HFpEF is independently associated with higher blood pressure 11,12 and vascular stiffness. 13 There is an increasing body of evidence that aldosterone and mineralocorticoid receptor (MR) signaling in vascular cells facilitates the transition from cardiovascular risk into hypertension and heart disease.…”

Valve, Ventricle, and Vessel

“…However, CMR may surely be a useful adjunct to echocardiography in this setting because of a lower interobserver variability for assessing left ventricular mass and volume 18 and also for its ability to detect cardiac fibrosis. 5,19 Moreover, the specific ability of the 4D-flow sequences to analyze the blood velocities in all 4 spatiotemporal dimensions is another advantage of CMR. The latter opens up the potential for imaging of aortic flow patterns and the possibility of associating, for example, vorticity and eccentricity with aortic valve and ventricular characteristics, as proposed by von Knobelsdorff-Brenkenhoff and et al 1 It must, however, be recognized that the acquisition times of a 4D-flow CMR sequence (10-20 minutes) may be too long for the tolerance of some patients, especially the elderly, and that irregular heart rate or breathing patterns leading to suboptimal data are not uncommon.…”