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Adiponectin and Left Ventricular Structure and Function in Healthy Adults

Department of Internal Medicine (M.K., E.M., C.M., C.P., E.F.), University of Pisa, 56126 Pisa, Italy; and The Medical Research Laboratories (A.F., J.F.), Clinical Institute and Medical Department M (Diabetes and Endocrinology), Aarhus University Hospital, DK-8000 C Aarhus, Denmark

Address all correspondence and requests for reprints to: Michaela Kozakova, M.D., Ph.D., Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy. E-mail: m.kozakova{at}int.med.unipi.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Adiponectin inhibits protein synthesis in cardiac myocytes, thereby opposing the effect of cardiac workload and trophic factors (in particular, insulin) on left ventricular (LV) mass and wall thickness (WT).

Objective: We tested whether adiponectin and its isoforms are related to LV mass, WT, and function independently of metabolic factors.

Design: This was a cross-sectional study.

Subjects: The study included 77 healthy volunteers (42 men) aged 30–59 yr with normal LV structure and function.

Main Outcome Measures: Insulin response and insulin sensitivity were assessed by oral glucose tolerance test and euglycemic hyperinsulinemic clamp. LV mass, WT, stroke work, chamber function, and myocardial longitudinal function were evaluated by standard Doppler echocardiography and tissue Doppler imaging. Total and molecular isoforms of adiponectin were measured in plasma.

Results: By multivariate analysis, independent factors affecting LV mass were sex, body mass index, stroke work, and current smoking (R² = 0.66). Independent correlates of LV WT were age, stroke work, and plasma adiponectin (standardized r = 0.28, 0.41, and –0.26, P at least < 0.005, R² = 0.48). LV longitudinal late diastolic velocity was independently related to age, body mass index, and adiponectin (standardized r = 0.20, 0.26, –0.33, P at least < 0.05, R² = 0.30). High-molecular-weight adiponectin (47% of total), but not lower molecular-weight isoforms, insulin sensitivity, or other metabolic factors, was inversely and independently related to WT (standardized r = –0.27, P < 0.01) and myocardial longitudinal late diastolic velocity (standardized r = –0.28, P < 0.05).

Conclusion: In healthy subjects, circulating total and high-molecular-weight adiponectin are related to LV WT and diastolic function, independently of age and metabolic factors.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adiponectin is a collagen-like protein synthesized in white adipose tissue and circulating in relatively high concentrations in serum. Adiponectin receptors are expressed in cultured cardiac myocytes and heart tissue (1, 2), and experimental evidence implies that adiponectin inhibits hypertrophic signaling in the myocardium (3) and may thus influence cardiac remodeling (4, 5). A recent epidemiologic study of 2839 Japanese men demonstrated that serum adiponectin is inversely and independently associated with electrocardiographically diagnosed left ventricular (LV) hypertrophy (LVH) (6). In addition, adiponectin has been suggested to influence LV diastolic function, independently of LV mass, possibly through its effect on growth factors and the matrix metalloproteinase-2 (7, 8). Adiponectin plays also an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues, and several studies demonstrated a link between adiponectin and insulin resistance (9). Low levels of circulating adiponectin have been described in conditions associated with insulin resistance, such as obesity, hypertension, and diabetes (10, 11), which are also associated with LVH, cardiac remodeling and impairment of LV function. Although hypertension is a leading cause of LVH, an increase in LV mass may occur independently of blood pressure (BP) (12). Large population-based studies have shown that only about 50% of LV mass variation can be explained by demographic and hemodynamic factors (12, 13, 14). Thus, nonhemodynamic mechanisms are likely to contribute to increase in LV mass and wall thickness (WT); in particular, a role for insulin resistance and compensatory hyperinsulinemia in the pathogenesis of LVH (15, 16, 17) and concentric LV remodeling (18) has been suggested.

The relative role of adiponectin and insulin resistance in LV remodeling has not been investigated in man. Furthermore, evidence in animal as well as human studies has shown that most metabolic actions of adiponectin can be attributed to high-molecular-weight (HMW) complexes of the adipokine (19). Accordingly, HMW adiponectin is a stronger correlate of insulin resistance and is selectively down-regulated in patients with type 2 diabetes (20). Whether the effects of adiponectin on cardiac structure and function are related to insulin sensitivity and whether they are mediated through the HMW isoform of the adipokine is not known. In the present work, we tested these hypotheses in healthy normotensive subjects with normal LV structure and function.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

The study population consisted of 77 healthy volunteers between 30 and 60 yr of age, free of hypertension, diabetes, carotid plaque, and overt cardiovascular disease. At echocardiography, all subjects had normal LV geometry, regional and global function, and no significant valvular regurgitation. Hypertension was defined as a systolic BP 140 mm Hg or greater and/or a diastolic BP 90 mm Hg or greater or current antihypertensive treatment. Diabetes was defined as a fasting plasma glucose 7.0 mmol/liter or greater or a 2-h postload glucose value 11.1 mmol/liter or greater or current therapy with hypoglycemic agents. An atherosclerotic plaque in extracranial carotid arteries was defined as an intima-media thickness 2.0 mm or greater in any carotid segment. Clinical cardiovascular disease was excluded on the basis of medical history and resting electrocardiogram. Normal LV geometry at echocardiography was defined as LV mass index 131 g/m² or less in men and 100 g/m² or less in women and relative wall thickness less than 0.45 (21). Normal LV global function was defined as ejection fraction 55% or greater. In addition, serum cholesterol and triglycerides levels were within limits established before recruitment (<7.8 and < 4.6 mmol/liter, respectively) in the absence of lipid-lowering therapy (Table 1). The local ethics committee approved the study, and written consent was obtained from all participants.

All participants underwent a standardized examination that included interviews, anthropometry, BP measurements, resting electrocardiogram, a fasting blood draw, an oral glucose tolerance test (OGTT), a euglycemic hyperinsulinemic clamp, high-resolution ultrasound of extracranial carotid arteries, conventional Doppler echocardiography, and pulsed-wave (PW) tissue Doppler imaging (TDI). Information regarding medical history, drug use, and alcohol and cigarette consumption was collected during a face-to-face interview using a standardized questionnaire. Height was measured on a clinic stadiometer. Body weight and fat-free mass (FFM) were measured by electrical bioimpedance using a body composition analyzer model TB-300 (Tanita, Tokyo, Japan). Body mass index (BMI) was calculated. A BMI greater than 30 kg/m was considered as a cutoff for obesity. Waist circumference was measured by plastic tape as the narrowest circumference between the lower rib margin and anterior superior iliac crest. Brachial BP was measured three times during three different visits, with a digital electronic tensiometer (model 705cp, regular or large adult cuffs were used according to arm circumference; Omron, Kyoto, Japan) and with the subject seated for at least 10 min. The mean value was used in statistical analysis.

OGTT

After at least 3 d of a 250-g carbohydrate diet and after an overnight (12–14 h) fast, glucose tolerance was assessed by a 2-h, 75-g OGTT. At baseline and at 30-min intervals thereafter, blood samples were obtained for glucose and insulin determination. Areas under OGTT time-concentration curves were calculated by the trapezoidal rule.

Insulin sensitivity

On a separate day (within 1 wk of the OGTT), a euglycemic hyperinsulinemic clamp was performed in all subjects (who were asked to refrain from smoking on the day before the study). Exogenous insulin was administered as a primed-continuous infusion at a rate of 240 pmol/min/m² simultaneously with a variable 20% dextrose infusion adjusted every 5–10 min to maintain plasma glucose level within 0.8 mmol/liter (± 15%) of the target glucose level (4.5–5.5 mmol/liter). Additional blood samples were obtained at 20-min intervals for insulin determination. With this protocol, achieving steady-state plasma insulin levels 568 ± 162 pmol/liter, suppression of endogenous glucose release was virtually complete (22, 23). Insulin sensitivity was expressed as the ratio of the M value (23), averaged over the last 40 min of the 2-h clamp and normalized by the FFM (Tanita bioimpedance) to the mean plasma insulin concentration measured during the same interval (M/I, in units of micromoles per minute^–1 per kilogram_FFM^–1 per nanomole^–1) (24).

Analytical procedures

Plasma glucose was measured by the glucose oxidase technique (glucose analyzer; Beckman, Fullerton, CA). Serum concentrations of insulin were measured by RIA using a kit specific for human insulin (less than 0.2% cross-reactivity with proinsulin; Linco Research, St. Louis, MO). Serum total and high-density lipoprotein cholesterol and triglycerides were assayed by standard methods.

Total adiponectin was measured in plasma using a validated in-house time-resolved immunofluorimetric assay, as previously described (25). In a subset of 57 randomly selected subjects, adiponectin isomers [low-molecular-weight (LMW), medium-molecular-weight (MMW), and HMW complexes] were separated and quantified using a validated in-house method (26).

Carotid ultrasound

To exclude the presence of carotid plaques, high-resolution B-mode ultrasound (SSD 5500 SV, Aloka, Tokyo, Japan) of extracranial carotid arteries was performed bilaterally, according to a previously described scanning and reading protocol (27).

Echocardiographic examination

Cardiac images were obtained with a standard ultrasound machine (SSD 5500 SV; Aloka) with a 2.5- to 3.5-Mhz, phased-array probe. Conventional B-mode, M-mode, and Doppler echocardiography was used for assessment of LV structure, chamber function, and diastolic filling pattern. PW TDI of mitral annular motion was used to assess LV longitudinal myocardial function (28).

Two-dimensionally targeted M-mode echocardiograms of the LV were obtained just below the tips of the mitral valve leaflets, with the M-mode cursor perpendicular to the LV long axis. In digitized images, septal and posterior WT and LV chamber dimensions were measured at end diastole, and the Penn convention was used to calculate LV mass by an anatomically validated formula (29). LV mass was normalized for body surface area (LV mass index, grams per meter^–2). Mean WT was calculated as an average of interventricular septal and posterior wall thickness at end-diastole. A relative WT was calculated as a sum of interventricular and posterior WT at end-diastole, divided by end-diastolic LV inner diameter. Ejection fraction was estimated by Simpson’s method. Stroke volume was determined as the product of aortic cross-sectional area and velocity-time integral (12, 30). Doppler transaortic flow was obtained in the apical projection in which peak flow velocity was maximal by tracing (12). Aortic valve opening was measured in the long-axis view and aortic area was calculated by circular geometry. Stroke work was determined as the product of stroke volume and systolic BP and was converted into gram-meters (g-m) by multiplying by 0.0144 (30). Transmitral flow velocities were examined by pulsed-Doppler from the four-chamber apical view, and peak early inflow velocity and peak atrial inflow velocity were measured. All measurements were performed by a single reader and taken as the mean of five consecutive beats. Brachial BP was measured at the end of echocardiographic examination (Omron, model 705cp). The intraindividual variability of LV mass measurements (assessed in 40 subjects) was 4.6 ± 3.0%. To test the reproducibility of echocardiography for LV mass assessment, in 25 subjects the ultrasound study was repeated 2–4 wk later. The difference between the two studies averaged 7.6 ± 4.6%.

To record mitral annular motion velocities, which reflect LV longitudinal function, color-guided PW tissue Doppler was used. In the apical four-chamber view, the sample volume was placed over the mitral annulus in two different areas: septal and lateral. The cursor was aligned so that the angle of incidence between the Doppler beam and the longitudinal motion of the mitral annulus was as close as possible to 0° (28). From spectral traces peak systolic velocity (PSV_TDI), peak velocities during early diastolic filling (PEV_TDI) and during atrial contraction (PAV_TDI) were measured in three consecutive beats by a single reader. The values used for the statistical analysis represent an average of septal and lateral sites (28). The intraindividual variability of the measurements (assessed in 40 subjects) was 5.8 ± 4.3, 6.3 ± 4.8, and 5.4 ± 3.9% for PSV_TDI, PEV_TDI, and PAV_TDI, respectively.

Statistical analysis

Data are expressed as mean ± SD. Variables with a skewed distribution (plasma fasting triglycerides and insulin, glucose, and insulin areas under OGTT curves) are given as median and (interquartile range) and were log transformed for use in statistical analyses. ANOVA was used to compare continuous variables and a ² test for categorical variables. Relationships between the outcome variables (LV mass, mean WT, and LV longitudinal velocities) and continuous variables were evaluated by univariate Pearson correlation coefficients. Multiple regression analysis was then used to test the independence of the associations. Statistical analysis was performed by JMP software, version 3.1 (SAS Institute Inc., Cary, NC).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical and metabolic characteristics of study population are given in Table 1 and echocardiographic parameters are shown in Table 2.

As expected, LV mass and mean WT were higher in men than women (187 ± 39 vs. 134 ± 32 g and 0.86 ± 0.09 vs. 0.77 ± 0.09 cm, respectively, P < 0.0001 for both) and increased with age, office BP, anthropometric parameters, and stroke work (Table 3). Furthermore, both measures increased with fasting plasma glucose and insulin and decreased with M/I value. Relative WT increased with age (r = 0.36, P = 0.001) and office systolic BP (r = 0.28, P = 0.01). No relationships were observed between LV structure and postload plasma glucose or insulin concentrations (at any time point during the OGTT or as areas under the respective OGTT curves) or alcohol consumption. Total adiponectin levels were higher in women than men (8.8 ± 2.6 vs. 7.0 ± 2.0 mg/liter, P = 0.001) and were inversely related to LV mass and mean WT (Table 3 and Fig. 1).

View larger version (27K): [in this window] [in a new window]   FIG. 1. Relationships between LV mass, WT, longitudinal LV diastolic function, and total and HMW adiponectin. Scatterplot and linear correlations between LV mass and total and HMW adiponectin (A); LV mean WT and total and HMW adiponectin (B); peak velocity of mitral annular motion (C) during atrial contraction (PAVTDI) and total and HMW adiponectin. Full symbols indicate men and empty symbols indicate women.

To assess whether any of the variables that showed a significant association with indices of LV mass and WT in univariate analysis (Table 3) contributed independently to the variability of these measures, multiple regression analyses were performed, entering standardized LV mass and WT as dependent variables and all their significant correlates as independent variables. All analyses were adjusted also for smoking habit. Independent factors affecting LV mass were sex, BMI, stroke work, and current smoking, together explaining 66% of LV mass variance (Table 4). Neither fasting plasma insulin nor insulin sensitivity and adiponectin were independently related to LV mass. Independent correlates of mean WT were age, stroke work, and plasma adiponectin (explaining 48% of its variability) (Table 4). Neither smoking nor any anthropometric and metabolic parameter replaced or canceled adiponectin in a multivariate model. When the multivariate models were run in the nonobese subjects alone (n = 59, 30 males, aged 43 ± 8 yr, BMI 24.6 ± 3.1 kg/m², plasma adiponectin 8.0 ± 2.6 mg/liter, LV mass 152 ± 40 g, mean WT 0.81 ± 0.10 cm), adiponectin and stroke work were independently related to both LV mass and WT (Table 4).

LV systolic and diastolic function

LV ejection fraction was not related to age, BP, or anthropometric and metabolic parameters, whereas stroke volume increased with BMI (r = 0.31, P < 0.01). LV longitudinal PSV_TDI decreased with age and mean BP (Table 3) and was not related to any anthropometric or metabolic parameter. Transmitral peak early inflow velocity decreased with age and LV mass (r = –0.40 and –0.30, P at least < 0.01); peak atrial inflow velocity increased with BMI and fasting plasma insulin (r = 0.40 and 0.36, P at least = 0.001) and decreased with total adiponectin (r = –0.22, P = 0.05). Only BMI remained independently related to transmitral peak atrial velocity (R² = 0.16) in multivariate model. Table 3 and Fig. 1 show the univariate correlations between LV longitudinal diastolic velocities (PEV_TDI and PAV_TDI) and age, BP, LV structure, and metabolic parameters. By multivariate model, independent correlates of PEV_TDI were age and mean BP [β ± SE = –0.41 ± 0.10 (P < 0.00012) and –0.24 ± 0.10 (P < 0.05), R² = 0.33]. Independent correlates of PAV_TDI were age, BMI, and plasma adiponectin (Table 4). Neither LV mass nor WT was independently related to PEV_TDI and PAV_TDI.

Adiponectin isomers

In the 57 subjects (28 males, aged 42 ± 8 yr, BMI 26.3 ± 4.5 kg/m², plasma adiponectin 8.0 ± 2.3 mg/liter, LV mass 154 ± 41 g, mean WT 0.80 ± 0.09 cm) in whose sera adiponectin isoforms were measured, the HMW, MMW, and LMW isoforms accounted for 47, 34, and 19% of total circulating adiponectin, respectively. The univariate associations between adiponectin isoforms and LV mass, LV WT, PAV_TDI, and M/I were generally similar to those of total plasma adiponectin but weaker for MMW and LMW (r values for MMW and LMW ranged from 0.24 to 0.35) than HMW (Table 3 and Fig. 1). In multivariate models, only HMW adiponectin remained independently related to mean WT and PAV_TDI (Table 4).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The major novel finding of this study is that, in normotensive subjects with normal LV geometry, circulating total and HMW adiponectin are inversely and independently related to LV WT. Moreover, adiponectin levels are related to LV longitudinal diastolic function, independently of LV mass and wall thickness.

Several recent findings have suggested that adiponectin is able to influence cardiac remodeling in pathologic states. However, the effect of adiponectin seems to differ in different conditions and study populations. In a large group of Japanese men, adiponectin was inversely and independently associated with electrocardiographic evidence of LVH (6). An inverse relationship between plasma adiponectin and LV mass index was described in patients with type 2 diabetes (31) and essential hypertension (32). Yet another study in untreated hypertensive patients did not observe any association between circulating adiponectin and LV mass (33), whereas in hemodialysis patients the presence of LVH was associated with increased plasma adiponectin levels (34). To better assess the role of adiponectin in cardiac remodeling, we studied the association of LV mass and WT with adiponectin (while controlling for confounding factors like gender, age, BMI, insulin sensitivity, plasma insulin level, and smoking habit) in a population of normotensive subjects with normal LV geometry.

In such a population, adiponectin was independently and inversely related to LV WT. An increase in LV WT is produced largely by an increase in the size of terminally differentiated cardiomyocytes. A necessary mediator of myocyte hypertrophy is protein synthesis, which under physiological conditions is stimulated primarily by an increase in cardiac workload (35). In our study group, stroke work, which represents a robust estimate of cardiac workload (30), was the strongest independent predictor of LV WT. Our clinical data are supported by experimental evidence showing that adiponectin may directly attenuate hypertrophic signaling in the myocardium by activating AMP-activated protein kinase (3, 4). AMP-activated protein kinase activation and increased cardiac workload have opposite effects on the phosphorylation of eukaryotic elongation factor-2, which mediates the translocation step of peptide-chain elongation in the process of protein synthesis (3, 35).

In a subgroup of subjects with adiponectin isoforms, LV WT was independently associated only with HMW adiponectin, in keeping with the hypothesis that the biological activity of adiponectin is mainly due to its HMW isoform (19, 20). Nevertheless, at least in our data, total circulating adiponectin seems to reflect well the biological effect of HMW adiponectin on the heart.

Two additional results should be noted. First, current smoking was directly and independently related to LV mass, a finding that is in agreement with a recent study (14) showing an association between greater LV mass and current smoking in a large population (n = 4869) free of cardiovascular disease. Second, when divided according to gender, adiponectin remained inversely and independently related to LV WT only in women, who had higher total (8.8 ± 2.6 vs. 7.0 ± 2.0 mg/liter, +25%) and HMW adiponectin (4.4 ± 1.9 vs. 3.3 ± 1.4 mg/liter, +33%). Therefore, gender-related differences in plasma adiponectin, which are probably linked to androgen status (36), could partly account for gender-related differences in LV structure (37). In accord with prior data from our laboratory (38), neither insulin sensitivity nor plasma levels of fasting or postload insulin were independent predictors of LV mass or WT in the population of normotensive nondiabetic subjects. More importantly, in multivariate models of WT, total and HMW adiponectin was not replaced or canceled by inclusion of any anthropometric or metabolic parameter. Such a finding can be interpreted as evidence that adiponectin concentrations do not simply stand for a cluster of metabolic parameters (BMI, waist, plasma insulin, serum lipids, etc.) as a composite marker (39) but imply a direct biological action. In particular, adiponectin is considered a readout of insulin sensitivity (19), but in this study M/I value did not have an independent relation to cardiac parameters.

In our normotensive subjects, circulating adiponectin was not related to LV systolic function (either chamber or longitudinal myocardial function), whereas both total and HMW adiponectin were inversely related to late diastolic longitudinal velocity of myocardium, independently of age, LV mass, or WT. This observation is in agreement with a recently published study showing that in hypertensive patients pioglitazone improves LV diastolic function without LV mass regression and that this improvement is paralleled by an increase in the plasma adiponectin and matrix metalloproteinase-2 levels (7).

Study limitations

We measured stroke volume by Doppler echocardiography, which is less precise than invasive measurements. However, previous studies have demonstrated that, when adequately applied, this technique provides reliable estimates of stroke volume (12, 30). In the calculation of stroke work, the cuff systolic BP was used as a surrogate for mean LV systolic pressure. Due to the pressure-amplification phenomenon through the arterial tree, mean LV systolic pressure is lower than systolic BP measured at the arm, and the differences between these two measurements decreases with increasing arterial stiffness and age. Finally, a single measurement of stroke work at rest was obtained; a single measure cannot entirely reflect chronic LV workload.

Conclusion

The present study has demonstrated a potentially important association between adiponectin and LV WT in healthy normotensive subjects with normal LV structure and function. Our findings suggest that circulating adiponectin, especially in its HMW form, modulates the physiological matching between LV muscle and cardiac work. A workload-induced increase in LV mass is considered an adaptive response to mechanical stress, aimed at preserving cardiac function. Under normal circumstances, adiponectin would restrain the resulting hypertrophy. Hypoadiponectinemia or functional adiponectin resistance, perhaps secondary to down-regulation of adiponectin receptors (40), may contribute to an exaggerated hypertrophic response to hemodynamic load and to inappropriate LVH (7). Adiponectin also seems to influence LV diastolic function, independently of its effect on wall thickness.

	Acknowledgments

 
We thank Karen Mathiassen and Hanne Peterson for expert technical assistance.

	Footnotes

 
This work was partially supported by Grant QLG1-CT-2001-01252 from the European Union and grants from the Danish Medical Research Council, the Danish Diabetes Association, the Italian Space Agency-Project on Disorders of Motor and Cardiorespiratory Control, and AstraZeneca.

Disclosure summary: M.K., E.M., C.M., C.P., E.F. have nothing to declare. A.F. consulted for Hoffmann-La Roche and Merck Sante and received lecture fees from Novo Nordisk and GlaxoSmithKline. J.F. consulted for Pfizer and Hoffmann-La Roche and received lecture fees from Novo Nordisk.

First Published Online April 8, 2008

Abbreviations: BMI, Body mass index; BP, blood pressure; FFM, fat-free mass; g-m, gram-meters; HMW, high-molecular-weight; LMW, low-molecular-weight; LV, left ventricular; LVH, LV hypertrophy; M/I, distribution of insulin sensitivity; MMW, medium-molecular-weight; OGTT, oral glucose tolerance test; PAV_TDI, peak velocities during atrial contraction; PEV_TDI, peak velocities during early diastolic filling; PSV_TDI, peak systolic velocity; PW, pulsed wave; TDI, tissue Doppler imaging; WT, wall thickness.

Received November 21, 2007.

Accepted March 31, 2008.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Lord E, Ledoux S, Murphy BD, Beaudry D, Palin MF 2005 Expression of adiponectin receptors in swine. J Anim Sci 83:565–578[Abstract/Free Full Text]
2. Fujioka D, Kawabata K, Saito Y, Kobayashi T, Nakamura T, Kodama Y, Takano H, Obata J, Kitta Y, Umetani K, Kugiyama K 2006 Role of adiponectin receptors in endothelin-induced hypertrophy in cultured cardiomyocytes and their expression in infarcted heart. Am J Physiol Heart Circ Physiol 290:2409–2416[CrossRef]
3. Chan AYM, Soltys CLM, Young ME, Proud CG, Dyck JRB 2004 Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in cardiac myocytes. J Biol Chem 279:32771–32779[Abstract/Free Full Text]
4. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Satp K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K 2004 Adiponectin-mediated modulation of hypertrophic signals in the heart. Nature 10:1384–1389[CrossRef]
5. Duda MK, O'Shea KM, Lei B, Barrows BR, Azimzadeh AM, McElfresh TE, Hoit BD, Kop BD, Stanley WC 2007 Dietary supplementation with -3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload. Cardiovasc Res 76:303–310[Abstract/Free Full Text]
6. Mitsuhashi H, Yatsuya H, Tamakoshi K, Matsushita K, Otsuka R, Wada K, Sugiura K, Takefuji S, Hotta Y, Kondo T, Murohara T, Toyoshima H 2007 Adiponectin level and left ventricular hypertrophy in Japanese men. Hypertension 49:1448–1454[Abstract/Free Full Text]
7. Horio T, Suzuki M, Suzuki K, Takamisawa I, Hiuge A, Kamide K, Takiuchi S, Iwashima Y, Kihara S, Funahashi T, Yoshimasa Y, Kawano Y 2005 Pioglitazone improved left ventricular diastolic function in patients with essential hypertension. Am J Hypertens 18:949–957[CrossRef][Medline]
8. Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, Fukui K, Maeda N, Nishizawa H, Nagaretani H, Okamoto Y, Kihara S, Miyagawa J, Shinomura Y, Funahashi T, Matsuzawa Y 2003 Enhanced carbon tetrachloride-induced liver fibrosis in the mice lacking adiponectin. Gastroenterology 125:1796–1807[CrossRef][Medline]
9. Pittas AG, Joseph NA, Greenberg AS 2004 Adipocytokines and insulin resistance. J Clin Endocrinol Metab 89:447–452[Free Full Text]
10. Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y 2003 Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 16:72–75[CrossRef][Medline]
11. Hotta K, Funahashi Y, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanufasa T, Matsuzawa Y 2000 Plasma concentration of a novel adipose specific protein adiponectin in type 2 diabetic patients. Atheroscler Thromb Vasc Biol 20:1595–1599[Abstract/Free Full Text]
12. Devereux RB, Roman MJ, de Simone G, O'Grady MJ, Paranicas M, Yeh JL, Fabsitz RR, Howard BV, for the Strong Heart Study Investigators 1997 Relations of left ventricular mass to demographic and hemodynamic variables in American Indians. The Strong Heart Study. Circulation 96:1416–1423[Abstract/Free Full Text]
13. Lauer MS, Anderson KM, Kannel WB, Levy D 1991 The impact of obesity on the left ventricular mass and geometry: the Framingham Heart Study. JAMA 266:231–236[Abstract/Free Full Text]
14. Heckbert SR, Post W, Pearson GDN, Arnett DK, Gomes AS, Jerosch-Herold M, Hundley WG, Lima JA, Bluemke DA 2006 Traditional cardiovascular risk factors in relation to left ventricular mass, volume, and systolic function by cardiac magnetic resonance imaging. The Multiethnic Study of Atherosclerosis. J Am Coll Cardiol 48:2285–2292[Abstract/Free Full Text]
15. Vetta F, Cicconetti P, Ronzoni P, Rizzo V, Palleschi L, Canarile G, Lupattelli MR, Migliori M, Morelli S, Marigliano V 1998 Hyperinsulinemia, regional adipose tissue distribution and left ventricular mass in normotensive, elderly, obese subjects. Eur Heart J 19:326–331[Abstract/Free Full Text]
16. Verdecchia P, Reboldi G, Schillaci G, Borgioni C, Ciucci A, Telera MP, Santeusanio F, Porcellati C, Brumetti P 1999 Circulating insulin and insulin growth factor-1 are independent determinants of left ventricular mass and geometry in essential hypertension. Circulation 100:1802–1807[Abstract/Free Full Text]
17. Wong CY, O'Moore-Sullivan T, Leano R, Byrne N, Beller E, Marwick TH 2004 Alteration of left ventricular myocardial characteristics associated with obesity. Circulation 110:3081–3087[Abstract/Free Full Text]
18. Sundström J, Lind L, Nyström N, Zethelius B, Andrén B, Hales CN, Lithell HO 2000 Left ventricular concentric remodeling rather than left ventricular hypertrophy is related to the insulin resistance syndrome in elderly men. Circulation 101:2595–2600[Abstract/Free Full Text]
19. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE 2004 Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279:12152–12162[Abstract/Free Full Text]
20. Basu R, Pajvani UB, Rizza RA, Scherer PE 2007 Selective downregulation of the high molecular weight form of adiponectin in hyperinsulinemia and in type 2 diabetes: differential regulation from nondiabetic subjects. Diabetes 56:2174–2177
21. Yuda S, Khoury V, Marwick TH 2002 Influence of wall stress and left ventricular geometry on the accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 40:1311–1319[Abstract/Free Full Text]
22. Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA 1990 Obesity and insulin resistance in humans: a dose-response study. Metabolism 39:452–459[CrossRef][Medline]
23. Ferrannini E, Mari A 1998 How to measure insulin sensitivity. J Hypertens 16:895–906[CrossRef][Medline]
24. Ferrannini E, Balkau B, Coppack W, Dekker JM, Mari A, Nolan J, Walker M, Natala A, Beck-Nielsen H, and the RISC Investigators 2007 Insulin resistance, insulin response, and obesity as indicator of metabolic risk. J Clin Endocrinol Metab 92:2885–2892[Abstract/Free Full Text]
25. Frystyk J, Tarnow L, Hansen TK, Parving HH, Flyvbjerg A 2005 Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications. Diabetologia 48:1911–1918[CrossRef][Medline]
26. Andersen KK, Frystyk J, Wolthers OD, Heuck C, Flyvbjerg A 2007 Gender differences of oligomers and total adiponectin during puberty: a cross-sectional study of 859 Danish school children. J Clin Endocrinol Metab 92:1857–1862[Abstract/Free Full Text]
27. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK, for the Cardiovascular Health Study Collaborative Research Group 1999 Carotid-artery intima and media thickness as s risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340:14–22[Abstract/Free Full Text]
28. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephen MR, Fraser AG 2001 Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy, systemic hypertension and in athletes. Am J Cardiol 88:53–58[CrossRef][Medline]
29. Devereux RB, Lutas EM, Casale PN, Kliegfield P, Eisenberg RR, Hammond IW, Miller D, Reis G, Alderman MH, Laragh JH 1986 Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57:450–458[CrossRef][Medline]
30. de Simone G, Devereux RB, Kimball TR, Mureddu F, Roman MJ, Cataldo F, Daniels S 1998 Interaction between body size and cardiac workload. Influence of left ventricular mass during body growth and adulthood. Hypertension 31:1077–1082[Abstract/Free Full Text]
31. Top C, Sahan B, Önde ME 2007 The relationship between left ventricular mass index and insulin sensitivity, postprandial glycaemia, and fasting serum triglyceride and adiponectin levels in patients with type 2 diabetes. J Int Med Res 35:909–916[Medline]
32. Hong SJ, Park CG, Seo HS, Oh DJ, Ro YM 2004 Association among plasma adiponectin, hypertension, left ventricular diastolic function and left ventricular mass index. Blood Pressure 13:236–242[CrossRef][Medline]
33. Della Mea P, Lupia M, Bandolin V, Guzzon S, Sonino N, Vettor R, Fallo F 2005 Adiponectin, insulin resistance, and left ventricular structure in dipper and nondipper essential hypertensive patients. Am J Hypertens 18:30–35[CrossRef][Medline]
34. Komaba H, Igaki N, Goto S, Yokota K, Takemoto T, Hirosue Y, Goto T 2007 Adiponectin is associated with brain natriuretic peptide and left ventricular hypertrophy in hemodialysis patients with type 2 diabetes mellitus. Nephron Clin Pract 107:c103–c108
35. Horman S, Beauloye C, Vertommen D, Vanoverschelde JL, Hue L, Rider MH 2003 Myocardial ischemia and increased heart work modulate the phosphorylation state of eukaryotic elongation factor-2. J Biol Chem 278:41970–41976[Abstract/Free Full Text]
36. Böttner A, Kratzsch JM, Büller G, Kapellen TM, Blüher S, Keller E, Blüher M, Kiess W 2004 Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metab 89:4053–4061[Abstract/Free Full Text]
37. Gardin JM, Siscovick D, Anton-Culver H, Lynch JC, Smith VE, Klopfenstein HS, Bommer WJ, Fried L, O'Leary D, Manolio TA 1995 Sex, age, and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly. The Cardiovascular Health Study. Circulation 91:1739–1748[Abstract/Free Full Text]
38. Galvan AQ, Galetta F, Natali A, Muscelli E, Sironi AM, Cini G, Camastra S, Ferrannini E 2000 Insulin resistance and hyperinsulinemia. No independent relation to left ventricular mass in humans. Circulation 102:2233–2238[Abstract/Free Full Text]
39. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT 2006 Adiponectin multimetric complexes and the metabolic syndrome trait cluster. Diabetes 55:249–259[Abstract/Free Full Text]
40. von Haehling S, Doehner W, Anker SD 2007 Nutrition, metabolism and the complex pathophysiology of cachexia in chronic heart failure. Cardiovasc Res 73:298–309[Abstract/Free Full Text]

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