leptin and Aortic-Valve-Stenosis

Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR).. In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents.. Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92-1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08-1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82-1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64-0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI).. The adipokine leptin may promote the development of AS.

Topics: Adipokines; Adiponectin; Adult; Aged; Aortic Valve Stenosis; Biomarkers; Case-Control Studies; Female; Heart Valve Prosthesis Implantation; Humans; Leptin; Male; Middle Aged; Risk Assessment

Leptin replacement therapy (LRT) has drastically improved the prognosis of patients with lipodystrophy, but pro-inflammatory properties of leptin could become evident in the long term. Here, we report a 30-year-old Japanese woman with generalized lipodystrophy-associated progeroid syndrome due to a heterozygous LMNA variant (c.29C > T; p.T10I), who was diagnosed with severe aortic stenosis (AS) after more than a decade of LRT, which required transcatheter aortic valve implantation. Given her marked hypoadiponectinemia and the LMNA variant, our patient might have been susceptible to progeria-associated disorders, including aortic stenosis, which could have been exaggerated by the prolonged 'imbalanced adipokines' caused by LRT between pro-inflammatory leptin and anti-inflammatory adiponectin. Thus, long-term LRT could be associated with AS in patients with the LMNA variant to cause generalized lipodystrophy-associated progeroid syndrome and hypoadiponectinemia.

Topics: Adiponectin; Adult; Aortic Valve Stenosis; Female; Humans; Lamin Type A; Leptin; Lipodystrophy; Lipodystrophy, Congenital Generalized; Metabolism, Inborn Errors

The role of the adipokines in the pathogenesis of aortic stenosis (AS) is not well established. The aim was to evaluate the relationship between adipokines and clinical characteristics as well as echocardiographic indices and noninvasive markers of vascular remodeling in patients with severe AS with preserved ejection fraction (EF).. Sixty-five patients (F/M: 38/27; age: 68.3 ± 9.0 years; body mass index [BMI]: 29.6 ± 4.3 kg/m2) with severe AS with preserved EF: 33 patients with paradoxical low-flow low-gradient AS (PLFLG AS) and 32 patients with normal flow high-gradient AS (NFHG AS) were prospectively enrolled into the study. Twenty-four subjects (F/M: 14/10; age: 65.4 ± 8.7 years; BMI: 29.6 ± 4.3 kg/m2) who matched as to age, sex, BMI and coronary artery disease (CAD) constituted the control group (CG). Clinical data and markers of vascular remodeling were related to the serum adipokines.. There were no differences in the adipokines concentrations in the AS/CG. Patients with AS and coexisting CAD were characterized by decreased serum adiponectin (9.9 ± 5.5 vs. 12.7 ± 5.8 μg/mL, p = 0.040) and leptin (8.3 ± 7.8 vs. 21.6 ± 17.1 ng/mL, p < 0.001) levels compared to subjects without CAD. There were no differences in the serum adipokines concentrations between patients with PLFLG AS and NFHG AS. Systemic hypertension, diabetes, hyperlipidemia or markers of vascular remodeling did not discriminate adipokines concentrations. Multivariate regression analysis indicated that age (F = 3.02; p = 0.015) and E/E' index (F = 0.87, p = 0.032) were independent predictors of the adiponectin level in the AS group.. The presence of AS with preserved EF did not change the adipokine serum profile. Adipokines levels were modified by coexisting atherosclerosis but not the typical cardiovascular risk factors or the hemodynamic type of AS.

Topics: Adipokines; Adiponectin; Aged; Aortic Valve Stenosis; Biomarkers; Case-Control Studies; Coronary Artery Disease; Cytokines; Female; Humans; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Prospective Studies; Resistin; Severity of Illness Index; Stroke Volume; Vascular Remodeling; Ventricular Function, Left

Calcific aortic valve disease (CAVD) affects 2-6% of the population over 65 years, and age, gender, smoking, overweight, dyslipidemia, diabetes contribute to the development of this disease. CAVD results, in part, from the osteoblast differentiation of human valvular interstitial cells (VICs). This study aims to elucidate the effects of leptin on osteoblast phenotype of VICs and the signalling pathways involved.. Patients who underwent aortic valve replacement for CAVD (n = 43) were included in this study. Patients with coronary artery disease (CAD) without CAVD (n = 129) were used as controls.. Patients with CAVD had higher serum leptin concentrations than CAD patients (p = 0.002). Leptin was found in calcific aortic valves, with higher concentrations in calcified versus non-calcified zones (p = 0.01). Chronic leptin stimulation of human VICs enhanced alkaline phosphatase (ALP) activity and ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. Moreover, inhibiting Akt or ERK during leptin stimulation lowered the expression of osteoblast markers in VIC.. Taken together, these findings indicate that leptin plays a critical role in CAVD development by promoting osteoblast differentiation of human aortic VICs in an Akt- and ERK-dependent manner. This study highlights the role of leptin in CAVD development, and further studies are needed to determine whether reducing circulating leptin levels or blocking leptin actions on VICs is efficient to slow CAVD progression.

Topics: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Bicuspid Aortic Valve Disease; Biomarkers; Calcinosis; Case-Control Studies; Cell Differentiation; Cell Transdifferentiation; Cells, Cultured; Female; Heart Defects, Congenital; Heart Valve Diseases; Humans; Leptin; Male; MAP Kinase Signaling System; Middle Aged; Oncogene Protein v-akt; Osteoblasts; Phenotype; Signal Transduction

Ascending thoracic aortic aneurysm (ATAA) is driven by angiotensin II (AngII) and contributes to the development of left ventricular (LV) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments AngII-induced abdominal aortic aneurysms in apolipoprotein E-deficient mice. We hypothesized that locally synthesized leptin mediates AngII-induced ATAA.. Following demonstration of leptin synthesis in samples of human ATAA associated with different etiologies, we modeled in situ leptin expression in apolipoprotein E-deficient mice by applying exogenous leptin on the surface of the ascending aorta. This treatment resulted in local aortic stiffening and dilation, LV hypertrophy, and thickening of aortic/mitral valve leaflets. Similar results were obtained in an AngII-infusion ATAA mouse model. To test the dependence of AngII-induced aortic and LV remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in AngII-infused mice. Locally applied single low-dose leptin antagonist moderated AngII-induced ascending aortic dilation and protected mice from ATAA rupture. Furthermore, LV hypertrophy was attenuated and thickening of aortic valve leaflets was moderated. Last, analysis of human aortic valve stenosis leaflets revealed de novo leptin synthesis, whereas exogenous leptin stimulated proliferation and promoted mineralization of human valve interstitial cells in culture.. AngII-induced ATAA is mediated by locally synthesized leptin. Aortoventricular hemodynamic coupling drives LV hypertrophy and promotes early aortic valve lesions, possibly mediated by valvular in situ leptin synthesis. Clinical implementation of local leptin antagonist therapy may attenuate AngII-induced ATAA and moderate related LV hypertrophy and pre-aortic valve stenosis lesions.. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00449306.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II; Animals; Aortic Aneurysm, Thoracic; Aortic Valve; Aortic Valve Stenosis; Cell Proliferation; Cells, Cultured; Female; Humans; Hypertrophy, Left Ventricular; Leptin; Male; Mice; Mice, Knockout, ApoE; Middle Aged; Vascular Stiffness; Vasoconstrictor Agents; Ventricular Remodeling; Young Adult

Early stages of atherosclerosis and aortic stenosis (AS) are similar. Advanced coronary artery disease is characterized by altered profile of circulating adipocytokines. We hypothesized that plasma profile of adipocytokines is associated with the severity of AS.. The aim of the study was to evaluate the relationship between AS and adipocytokines.. In 74 patients with AS without atherosclerosis and left ventricular ejection fraction above 50% (57 men, 17 women, aged 58 ±9.1 years) and 74 controls, resistin, leptin, and adiponectin levels were determined by the Bio-Rad Luminex system. Aortic valve area indexed to body surface area (AVAI) as well as the mean and peak transvalvular pressure gradients (PG) were assessed by echocardiography.. We observed similar adiponectin and leptin levels in patients with AS and controls (20.8 ±7.9 vs. 20.4 ±3.9 μg/ml, P = 0.67 and 17.0 ±6.4 vs. 16.4 ±5.9 ng/ml, P = 0.52, respectively). Twenty-one patients had mild, 21 moderate, and 32 severe AS. After adjusting for age and the body mass index, adiponectin levels were 20.3 ±0.5 μg/ml in controls, 26.7 ±0.9 μg/ml in mild, 20.2 ±0.9 μg/ml in moderate, and 17.5 ±0.7 μg/ml in severe AS (P <0.001). Leptin levels were 16.4 ±0.7 ng/ml in controls, 21.1 ±1.3 ng/ml in mild, 16.9 ±1.3 ng/ml in moderate, and 14.4 ±1.1 ng/ml in severe AS (P = 0.003). Adiponectin and leptin correlated with the AVAI (r = 0.70, P <0.001; r = 0.37, P = 0.001; respectively), mean PG (r = -0.72, P <0.001; r = -0.27, P = 0.009; respectively), and peak PG (r = -0.67, P <0.001; r = -0.23, P = 0.03; respectively). In a multivariable analysis, the mean PG was the only independent echocardiographic predictor of adiponectin levels (P <0.001), while the AVAI was the only independent echocardiographic predictor of leptin levels in AS patients (P = 0.049).. Lower levels of adiponectin and leptin, but not resistin, are associated with severe AS, suggesting that adipocytokines may be involved in the progression of AS, and especially adiponectin, which plays a protective role in this process.

Topics: Adiponectin; Adult; Aged; Aortic Valve Stenosis; Biomarkers; Disease Progression; Female; Humans; Leptin; Male; Middle Aged; Poland; Reference Values; Resistin; Severity of Illness Index

The aim of the present study was to identify risk markers for the development of valvular aortic stenosis (AS). Lipoprotein(a) (Lp(a)) and Chlamydia pneumoniae IgG antibody titres in plasma and in circulating immune complexes as well as leptin and tissue plasminogen activator (t-PA) in plasma were studied.. One hundred and one patients (41 women and 60 men, mean age 71+/-8 years) with significant AS and 101 age- and sex-matched controls were included in this study. All patients underwent aortic valve replacement at the University Hospital in Umeå, Sweden. The controls had no symptoms of cardiovascular disease and they were examined echocardiographically. An Lp(a) level >or=480 mg x l(-1), a C. pneumoniae-specific IgG titre >or=1/128, a high leptin level and a high t-PA mass concentration in plasma were identified as risk markers for AS. A strong synergism between Lp(a) and C. pneumoniae IgG antibodies in circulating immune complexes was found.. Our data indicate that a chronic C. pneumoniae infection and a high plasma Lp(a) level might influence and aggravate aortic heart valve sclerosis via the formation of circulating immune complexes. The present study also strongly suggests an association between high plasma leptin, t-PA mass concentration and AS.

Topics: Aged; Aortic Valve Stenosis; Chlamydophila Infections; Chlamydophila pneumoniae; Female; Humans; Immunoglobulin A; Immunoglobulin G; Leptin; Lipoprotein(a); Male; Regression Analysis; Risk Factors; Tissue Plasminogen Activator