Plasma Leptin Level Is Associated With Myocardial Wall Thickness in Hypertensive Insulin-Resistant Men

Paolisso, Giuseppe; Tagliamonte, Maria; Galderisi, Maurizio; Zito, Guido Antonio; Petrocelli, Antonio; Carella, Carlo; Divitiis, Oreste de; Varricchio, M

doi:10.1161/01.hyp.34.5.1047

Cited by 143 publications

(97 citation statements)

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“…Similar to our observations, several population‐based studies, including MESA (Multi‐Ethnic Study of Atherosclerosis)10 and a previous study of elderly participants in the original cohort of FHS,29 have reported an inverse association between circulating leptin concentrations and LVM but no association with measures of LV systolic function 29. In contrast, other observational studies of men with hypertension,22 of severely obese patients23 and of patients with myocardial infarction24 have reported a positive association between leptin and cardiac hypertrophy. Furthermore, in patients with CAD16 and acute myocardial infarction,24 a positive association has been reported between circulating leptin levels and markers of LV diastolic dysfunction.…”

Section: Discussionsupporting

confidence: 88%

“…Accordingly, investigators have related circulating concentrations of adipokines to imaging indices of cardiac remodeling. These prior studies have typically been conducted in small samples, or samples with an overrepresentation of obese individuals or elderly people, and usually focused on a single adipokine 10, 11, 13, 21, 22, 23, 24, 25, 26…”

Section: Discussionmentioning

confidence: 99%

“…Prior investigations relating adipokines to cardiac structure and function have focused on single adipokines10, 11, 15, 16, 17, 18, 19, 20, 21 and related them to traditional measures of cardiac remodeling (such as LV mass [LVM]). These studies often focused on obese individuals with comorbidities16, 22, 23, 24, 25, 26, 27, 28 or the elderly20, 21, 29 and were limited by modest sample sizes. To our knowledge, no prior investigation has related a panel of adipokines of contemporary interest to a range of cardiac remodeling indices in a younger sample relatively free of comorbidities.…”

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confidence: 99%

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Association of Circulating Adipokines With Echocardiographic Measures of Cardiac Structure and Function in a Community‐Based Cohort

Jeinsen

Short

Xanthakis

et al. 2018

JAHA

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BackgroundAdipokines mediate cardiometabolic risk associated with obesity but their role in the pathogenesis of obesity‐associated heart failure remains uncertain. We investigated the associations between circulating adipokine concentrations and echocardiographic measures in a community‐based sample.Methods and ResultsWe evaluated 3514 Framingham Heart Study participants (mean age 40 years, 53.8% women) who underwent routine echocardiography and had select circulating adipokines measured, ie, leptin, soluble leptin receptor, fatty acid–binding protein 4, retinol‐binding protein 4, fetuin‐A, and adiponectin. We used multivariable linear regression, adjusting for known correlates (including weight), to relate adipokine concentrations (independent variables) to the following echocardiographic measures (dependent variables): left ventricular mass index, left atrial diameter in end systole, fractional shortening, and E/e′. In multivariable‐adjusted analysis, left ventricular mass index was inversely related to circulating leptin and fatty acid–binding protein 4 concentrations but positively related to retinol‐binding protein 4 and leptin receptor levels (P≤0.002 for all). Left atrial end‐systolic dimension was inversely related to leptin but positively related to retinol‐binding protein 4 concentrations (P≤0.0001). E/e′ was inversely related to leptin receptor levels (P=0.0002). We observed effect modification by body weight for select associations (leptin receptor and fatty acid–binding protein 4 with left ventricular mass index, and leptin with left atrial diameter in end systole; P<0.05 for interactions). Fractional shortening was not associated with any of the adipokines. No echocardiographic trait was associated with fetuin‐A or adiponectin concentrations.ConclusionsIn our cross‐sectional study of a large, young to middle‐aged, relatively healthy community‐based sample, key indices of subclinical cardiac remodeling were associated with higher or lower circulating concentrations of prohypertrophic and antihypertrophic adipokines in a context‐specific manner. These observations may offer insights into the pathogenesis of the cardiomyopathy of obesity.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Association of Circulating Adipokines With Echocardiographic Measures of Cardiac Structure and Function in a Community‐Based Cohort

Jeinsen

Short

Xanthakis

et al. 2018

JAHA

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“…In a study conducted in healthy individuals free from cardiovascular disease, Pladevall et al (28) showed that leptin deficiency was associated with increased left ventricular mass index, thus demonstrating that leptin has an antihypertrophic effect in the presence of an intact signaling pathway. Although some older studies showed a positive correlation between leptin and LVH when adjusting for body mass index (BMI) (29), others have highlighted that this positive correlation is completely abrogated after adjusting for BMI (30). Nonetheless, it is well established that obesity in clinical populations is associated with elevated leptin primarily due to leptin resistance, implying depressed downstream signaling despite increased leptin levels (4,8,9).…”

Section: Discussionmentioning

confidence: 99%

Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity

Raju

Zheng

Schuleri

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Disruption of the leptin signaling pathway within the heart causes left ventricular hypertrophy (LVH). Because human obesity is a syndrome of leptin resistance, which is not amenable to leptin treatment, the identification of parallel signal transduction pathways is of potential therapeutic value. Ciliary neurotrophic factor (CNTF), which acts parallel to leptin in the hypothalamus, is not previously recognized to have cardiac activity. We hypothesized that CNTF receptors are present on cardiomyocytes and their activation reverses LVH in both leptin-deficient ob͞ob and leptinresistant db͞db mice. The localization of CNTF receptors (CNTFR␣) to the sarcolemma in C57BL͞6, ob͞ob and db͞db was confirmed in situ with immunohistochemistry, and immunoblotting (60 and 40 kDa) on isolated myocytes. ob͞ob mice were randomly assigned to receive s.c. recombinant CNTF (CNTF Ax15; 0.1 mg⅐kg ؊1 per day; n ‫؍‬ 11) calorie-restriction (n ‫؍‬ 9), or feeding ad libitum (n ‫؍‬ 11). db͞db mice were allocated to three similar groups (n ‫؍‬ 8, 7, and 8, respectively) plus a leptin group (1 mg⅐kg ؊1 per day; n ‫؍‬ 7). Echocardiography showed that CNTFAx15 reduced cardiac hypertrophy [posterior wall thickness decreased by 29 ؎ 8% (P < 0.01) in ob͞ob and by 21 ؎ 3% in db͞db mice (P < 0.01)], which was consistent with the reduction of myocyte width. Western blotting showed that leptin and CNTF Ax15 activated Stat3 and ERK1͞2 pathway in cultured adult mice cardiomyocytes and cardiac tissue from in ob͞ob and db͞db mice. Together, these findings support the role of a previously undescribed signaling pathway in obesityassociated cardiac hypertrophy and have therapeutic implications for patients with obesity-related cardiovascular disease and other causes of LVH.signal transduction ͉ cardiac remodeling ͉ mouse ͉ heart ͉ Axokine L eft ventricular hypertrophy (LVH) and its subsequent progression to congestive heart failure represents a major cause of morbidity and mortality in the United States (1). Obesity, an important mediator of LVH (2), results from either deficiency of or receptor insensitivity to leptin (3-5), a hormone that regulates appetite and energy metabolism (6). We have previously demonstrated that both leptin deficiency and resistance contribute to LVH in murine models (7). Additionally, we showed regression of LVH with leptin repletion in leptin-deficient ob͞ob mice. However, because the majority of human obesity is associated with hyperleptinemia and leptin resistance (4,8,9) that is unresponsive to leptin treatment, we sought to identify an alternate signaling axis that regulates cardiac architecture. Here we address this issue with ciliary neurotrophic factor (CNTF), which activates a related signaling pathway to leptin and has similar effects on body weight and metabolism (10-12). The CNTF receptor (CNTFR) complex closely resembles the leptin receptor (ObR) structurally and has a similar distribution in the hypothalamic nuclei associated with regulation of feeding and body weight (13, 14). Both receptors are members of the gp...

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“…26 In vitro studies have demonstrated that leptin promotes angiogenesis 27 and induces oxidative stress in human endothelial cells. 28 Moreover, epidemiological studies have recently shown that leptin is independently associated with myocardial wall thickness in hypertensive insulin-resistant men, 29 is a risk factor for haemorrhagic stroke in a population-based cohort, 30 and is associated with increased risk of myocardial infarction. 31 Lastly, studies in animal models showed that leptin may have a pathophysiological role in obesity-related hypertension.…”

Section: Discussionmentioning

confidence: 99%

Plasma leptin is independently associated with the intima-media thickness of the common carotid artery

et al. 2001

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OBJECTIVE:To investigate whether intima-media thickness (IMT) of the common carotid artery (CCA), an early marker of asymptomatic atherosclerosis, is signi®cantly and independently associated with plasma concentrations of leptin, an adipose tissue hormone that has recently been proposed as a cardiovascular risk factor in obese patients. DESIGN: Cross-sectional sample of normal-weight and obese men and women. SUBJECTS: One-hundred and twenty healthy subjects (52 men and 68 women), aged 18 ± 45 y and with a wide range of BMI, were recruited for the study. MEASUREMENTS: Fasting plasma leptin concentrations and the IMT of the CCA were measured in all subjects. Leptin concentrations were measured by radioimmunoassay and the IMT of the CCA was quanti®ed by high resolution B-mode ultrasound imaging. Central fat (measured by waist circumference), smoking habits, blood pressure, insulin sensitivity (measured by the insulin tolerance test), and fasting plasma glucose, insulin and lipid pattern (cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol) were also measured. RESULTS: IMT of the CCA was positively correlated with log leptin concentrations (P`0.005 in men and P`0.001 in women), body mass index (P`0.001 in men and women), waist circumference (P`0.001 in men and women), age (P`0.001 in men and P`0.05 in women), and negatively associated with insulin sensitivity in both sexes (P`0.05). IMT was also directly correlated with cholesterol (P`0.05), LDL-cholesterol (P`0.01) and systolic blood pressure in men (P`0.05), and with diastolic blood pressure levels in women (P`0.05). When a multiple linear regression model was used without body mass index (BMI), the correlation between leptin and IMT was maintained in both men (P`0.01) and women (P`0.005), independent of age, insulin sensitivity, smoking habits, systolic blood pressure, fasting glucose, triglycerides, cholesterol, LDL-cholesterol and HDL-cholesterol. By contrast, BMI-adjusted leptin concentrations were not signi®cantly associated with IMT (Pc (partial correlation): 0.41 in men and 0.15 in women). Moreover, when BMI was entered into a multiple linear regression model without leptin, the correlation between BMI and IMT was maintained in both men (P`0.005) and women (P`0.01), independent of the same parameters. CONCLUSION: Plasma leptin concentrations are independently associated with the IMT of the CCA, suggesting that the increase of adipose tissue mass (or leptin per se) may have an unfavourable in¯uence on the development of atherosclerosis. However, the association between IMT and leptin seems to be dependent andaor confounded by the relationship between IMT and obesity.

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Plasma Leptin Level Is Associated With Myocardial Wall Thickness in Hypertensive Insulin-Resistant Men

Cited by 143 publications

References 38 publications

Association of Circulating Adipokines With Echocardiographic Measures of Cardiac Structure and Function in a Community‐Based Cohort

Association of Circulating Adipokines With Echocardiographic Measures of Cardiac Structure and Function in a Community‐Based Cohort

Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity

Plasma leptin is independently associated with the intima-media thickness of the common carotid artery

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