Sympathetic Overactivity, Endothelial Dysfunction, Inflammation, and Metabolic Abnormalities Cluster in Grade III (World Health
Organization) Obesity
Reversal through sustained weight loss obtained with laparoscopic adjustable gastric banding
- Antonio E. Pontiroli, MD1,
- Pierluigi Pizzocri, MD1,
- Rita Paroni, PHD1 and
- Franco Folli, MD2
- 1Università degli Studi di Milano, Ospedale San Paolo, Milan, Italy
- 2Diabetes Division, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
- Address correspondence and reprint requests to Antonio E. Pontiroli, Università degli Studi di Milano, Ospedale San Paolo,
Via Antonio di Rudinìı 8, 20142 Milan, Italy. E-mail: antonio.pontiroli{at}unimi.it
Obesity (often complicated by type 2 diabetes), arterial hypertension, and hyperlipidemia show insulin resistance (1), metabolic abnormalities (triglycerides, insulin and blood glucose levels, and HDL cholesterol levels [2]), subclinical inflammation (3,4), functional and metabolic indexes of endothelial dysfunction (5–7), and sympathetic overactivity (8–12). Inflammation (C-reactive protein, white cells, and interleukins) is linked to metabolic abnormalities, sympathetic overactivity,
and endothelial dysfunction (3,13,14).
Enlarged adipose tissue, infiltrated by macrophages, releases substances (adipokines) (15) that can explain most features of obesity (type 2 diabetes, arterial hypertension, and accelerated atherosclerosis) (16–18) including leptin, which is considered a risk factor for cardiovascular disease (19,20) and acts directly on the myocardium, stimulating cardiac hypertrophy (21,22).
Weight loss decreases the metabolic impact of obesity, reduces prevalence of type 2 diabetes and arterial hypertension (23), prevents their incidence (24,25), improves insulin resistance (26) and endothelial dysfunction (4,7), and reduces sympathetic overactivity (27), adipokines, and adhesion molecules (4,7), as well as white cells (28).
In this study, we analyzed interrelationships of metabolic abnormalities, sympathetic overactivity, inflammation, and endothelial
dysfunction in obesity, including their changes induced by weight loss (laparoscopic adjustable gastric banding [LAGB]).
RESEARCH DESIGN AND METHODS—
LAGB is regularly performed at Ospedale San Raffaele and Ospedale San Paolo, Milano, Italy, in morbidly obese patients (World
Health Organization criteria) (25,26). For this study, we considered 69 patients (15 men and 54 women, aged 42.3 ± 1.07 years, BMI 45.1 ± 0.78 kg/m2) undergoing LAGB during the period of 2002–2004. Inclusion/exclusion criteria, schedule for assessments, and diet after LAGB
have already been published (25,26). Waist circumference was measured, and ultrasound scan (29) of visceral and subcutaneous adipose tissue was performed; all evaluations were repeated after 1 year.
QT intervals on electrocardiogram were measured according to Bazett’s formula, together with heart rate (corrected QT [QTc]
= QT/√ RR) (30). Specimens for endothelin-1 (ET-1), E-selectin, and intracellular adhesion molecule (ICAM)-1 were collected in prechilled
tubes (EDTA tubes with 200 μl aprotinin for ET-1), centrifuged at 4°C, and stored at −70°C. Blood glucose, insulin, leptin,
triglyceride, HDL cholesterol levels, and adhesion molecules (ICAM-1, E-selectin, and ET-1) were measured as published before
(7,22,25–28). The homeostasis model assessment (HOMA) index was calculated as insulin (in microunits per milliliter) × blood glucose
(in micromoles per liter) × 22.5−1 (31).
Calculations and statistical analysis
Because normality had not been verified on all variables, data were log transformed. Changes of variables were then analyzed.
Pairwise correlations between changes of variables were calculated. A stepwise regression analysis was carried out to estimate
the independent contribution of variables (significant at linear regression plus age and sex) on heart rate and QTc. A P value <0.05 was considered statistically significant.
RESULTS—
Weight loss (BMI at 1 year 37.0 ± 0.94 kg/m2) caused significant decreases (P < 0.01 to P < 0.001 vs. baseline) in visceral fat (88.5 ± 3.21 to 53.0 ± 3.08 mm), waist circumference (125.5 ± 1.74 to 109.5 ± 1.62
cm), metabolic variables (HOMA index 5.6 ± 0.48 to 2.3 ± 20.18), triglycerides (1.6 ± 0.14 to 1.2 ± 0.11 mmol/l), HDL cholesterol
(1.21 ± 0.04 to 1.33 ± 0.04 mmol/l), sympathetic tone (systolic blood pressure [133.2 ± 1.85 to 126.5 ± 1.55 mmHg], diastolic
blood pressure [84.1 ± 1.51 to 80.0 ± 1.61 mmHg], heart rate [73.9 ± 1.40 to 65.3 ± 1.39], QTc [418.5 ± 3.86 to 400.7 ± 3.49
ms], and leptin [39.0 ± 1.98 to 20.6 ± 1.34 ng/ml]), and inflammation/endothelial dysfunction (white cells [7,867 ± 336 to
7,012 ± 314 fl], ICAM-1 [325.8 ± 10.68 to 281.1 ± 6.79 ng/ml], E-selectin [66.7 ± 6.39 to 43.4 ± 2.99 ng/ml], and ET-1 [1.3
± 0.07 to 1.1 ± 0.05 pg/ml]).
Changes of almost all metabolic variables, sympathetic tone, inflammation/endothelial dysfunction, and insulin resistance
correlated with changes of BMI and visceral fat (data not shown). Changes of ICAM-1 significantly correlated with ET-1 (r = 0.328), E-selectin (r = 0.673), HOMA (r = 0.239), and leptin (r = 0.251); E-selectin correlated with ET-1 (r = 0.294), HOMA (r = 0.342), and leptin (r = 0.337) (P < 0.05 to P < 0.001).
Changes of sympathetic activation (heart rate and QTc) correlated with BMI and at least one measure of visceral fat, leptin,
insulin, and insulin resistance. At stepwise regression analysis, an ultrasound scan of visceral adipose tissue and leptin
were the only significant predictors of heart rate, while leptin and heart rate were the only significant predictors of QTc.
Figure 1 shows the correlations for heart rate and QTc.
CONCLUSIONS—
We confirmed that weight loss is accompanied by improvement of metabolic variables and indexes of inflammation/endothelial
dysfunction and of sympathetic overactivity, thus pointing to a pivotal role of BMI (4,7,26–28); changes of sympathetic overactivity and adhesion molecules correlated with changes of BMI and visceral fat. Finally, changes
of heart rate and QTc correlated with leptin and visceral fat, thus raising the hypothesis that heart rate and QTc are crucial
aspects of this cluster.
The correlation between changes of BMI and visceral fat, and adhesion molecules, agrees with previous studies considering
these molecules (3,4,7,32,33), tumor necrosis factor-α, P-selectin, and interleukin-6 (4). The correlations between adhesion molecules, and some metabolic variables not previously described, indicate a correlation
between several aspects of the cluster and agree with previous findings of an association between C-reactive protein and metabolic
variables (3,32,33).
Heart rate and QTc correlated with BMI, visceral fat, and insulin resistance (HOMA). These correlations have been reported
in a few studies, supporting a causal role of BMI and visceral fat on these, as well as on other, indexes of sympathetic activity
(11,12,33–39,40).
Leptin correlated with heart rate and QTc. Chronic leptin administration leads to hypertension and tachicardia in rats, and
this effect is prevented by adrenergic β-blockade (41). Leptin increases sympathetic activity in the central nervous system (42) and has a direct action in the heart, as leptin has specific receptors in heart tissues (21,22).
Adhesion molecules did not correlate with heart rate and QTc; the possible correlation between sympathetic drive and immune
function, in particular between adrenergic agonists/antagonists and adhesion molecules, has recently received a great deal
of attention (43). For instance, β-adrenergic agonists and antagonists have different effects on white cells and ICAM-1 (43–48). Psychological stress, physical stress, hypertension, painful anestesia, adrenaline, and norepinephrine administration have
specific effects on ICAM-1 levels, white cells, NK cells, E-selectin, P-selectin, L-selectin, and heart rate (49–56). An indirect association between adhesion molecules and sympathetic overactivity might be mediated by insulin resistance,
leptin, or body weight. In our study, leptin correlated with ICAM-1 and E-selectin, and this agrees with experiments showing
that leptin upregulates proinflammatory immune responses (57). At stepwise regression analysis, visceral fat and leptin were the only significant predictors of heart rate and QTc.
In conclusion, these data indicate a cluster of metabolic, immune, and sympathetic abnormalities. This cluster, favored by,
if not essentially linked to obesity, is a more complex entity than originally supposed. Sympathetic activity and subinflammation
coexist and are probably essential features of the cluster and can be corrected through stable weight loss by LAGB.
Figure 1—
Correlations between changes of sympathetic overactivity (QTc, left panels and heart rate, right panels) and indexes of obesity (visceral fat), leptin, and heart rate (horizontal axis). Data are a logarithmic scale.
Acknowledgments
This research was supported by Grant FIRST 2002 (Universita‘ degli Studi di Milano), Ministero dell’Universita‘ e della Ricerca
2002 (grant 2002064582_003), and Ministero della Salute (grant 199/02).
Footnotes
-
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
-
- Accepted September 3, 2006.
- Received July 6, 2006.
- DIABETES CARE
References
- ↵
Laakso M, Edelman SV, Brechtel G: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: a novel
mechanism for insulin resistance. J Clin Invest
85:
1844–1852, 1990
- ↵
Grundy SM: Small LDL, atherogenic dyslipidemia, and metabolic syndrome. Circulation
95:
1–4, 1997
- ↵
Festa A, D’Agostino R Jr, Howard G, Mykkänen L, Tracy RP, Haffner SM: Chronic subclinical inflammation as part of the insulin
resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation
102:
42–47, 2000
- ↵
Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’Andrea F, Molinari AM, Giugliano D: Reduction of inflammatory
cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation
105:
804–809, 2002
- ↵
Steinberg HO, Chaker H, Leaming Rl: Obesity/insulin resistance is associated with endothelial dysfunction: implications for
the syndrome of insulin resistance. J Clin Invest
97:
2601–2610, 1996
-
Arcaro G, Zamboni M, Rossi L: Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity.
Int J Obes Relat Metab Disord
23:
936–942, 1999
- ↵
Pontiroli AE, Pizzocri P, Koprivec D, Vedani P, Marchi M, Arcelloni C, Paroni R, Esposito K, Giugliano D: Body weight and
glucose metabolism have a different effect on circulating levels of ICAM-1, E-selectin, and endothelin-1 in humans. Eur J Endocrinol
150:
195–200, 2004
- ↵
Perkiomaki JS, Koistinen MJ, Yli Mayry S: Dispersion of QT interval in patients with and without susceptibility to ventricular
tachyarrhythmias after previous myocardial infarction. J Am Coll Cardiol
26:
174–179, 1995
-
Leonardo F, Fragasso G, Rosano GMC: Effect of atenolol on QT interval and dispersion in patients with syndrome X. Am J Cardiol
80:
789–790, 1997
-
Alvarez GE, Beske SD, Ballard TP, Davy KP: Sympathetic neural activation in visceral obesity. Circulation
106:
2533–2536, 2002
- ↵
Festa A, D’Agostino R, Hales CN, Mykkanen L, Haffner SM: Heart rate in relation to insulin sensitivity and insulin secretion
in nondiabetic subjects. Diabetes Care
23:
624–628, 2000
- ↵
Kaaja RJ, Poyhonen-Alho MK: Insulin resistance and sympathetic overactivity in women. J Hypertens
24:
131–141, 2006
- ↵
Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF: Increased heart rate and reduced heart-rate variability
are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J
25:
363–370, 2004
- ↵
Natali A, Toschi E, Baldeweg S, Ciociaro D, Favilla S, Sacca L, Ferrannini E: Clustering of insulin resistance with vascular
dysfunction and low-grade inflammation in type 2 diabetes. Diabetes
55:
1133–1140, 2006
- ↵
Wellen KE, Hotamisligil GS: Obesity-induced inflammatory changes in adipose tissue. J Clin Invest
112:
1785–1788, 2003
- ↵
Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, Schauer PR: The chronic inflammatory hypothesis for
the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg
14:
589–600, 2004
-
Moreno PR, Fuster V: New aspects in the pathogenesis of diabetic atherothrombosis. J Am Coll Cardiol
44:
2293–2300, 2004
- ↵
McGill HC Jr, McMahan CA, Herderick EE, Zieske AW, Malcom GT, Tracy RE, Strong JP, the Pathobiological Determinants of Atherosclerosis
in Youth (PDAY) Research Group: Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation
105:
2712–2718, 2002
- ↵
Pontiroli AE, Pizzocri P, Folli F: Plasma leptin levels and coronary heart disease (Letter). Circulation
106:
e42, 2002
- ↵
Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N: Plasma leptin and the risk of cardiovascular disease
in the West Of Scotland Coronary Prevention Study (WOSCOPS). Circulation
104:
3052–3056, 2001
- ↵
Tajmir P, Ceddia RB, Li RK, Coe IR, Sweeney G: Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated
kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways. Endocrinology
145:
1550–1555, 2004
- ↵
Perego L, Pizzocri P, Corradi D, Maisano F, Paganelli M, Fiorina P, Barbieri M, Morabito A, Paolisso G, Folli F, Pontiroli
AE: Circulating leptin correlates with left ventricular mass in morbid (grade III) obesity before and after weight loss induced
by bariatric surgery: a potential role for leptin in mediating human left ventricular hypertrophy. J Clin Endocrinol Metab
90:
4087–4093, 2005
- ↵
Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K: Bariatric surgery: a systematic review and
meta-analysis. JAMA
292:
1724–1737, 2004
- ↵
Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD, Sullivan
M, Wedel H, the Swedish Obese Subjects Study Scientific Group: Lifestyle, diabetes, and cardiovascular risk factors 10 years
after bariatric surgery. N Engl J Med
351:
2683–2693, 2004
- ↵
Pontiroli AE, Folli F, Paganelli M, Micheletto G, Pizzocri P, Vedani P, Luisi F, Perego L, Morabito A, Bressani Doldi S: Laparoscopic
gastric banding prevents type 2 diabetes and arterial hypertension and induces their remission in morbid obesity: a 4-year
case-controlled study. Diabetes Care
28:
2703–2709, 2005
- ↵
Pontiroli AE, Pizzocri P, Librenti MC, Vedani P, Marchi M, Cucchi E, Orena C, Paganelli M, Giacomelli M, Ferla G, Folli F:
Laparoscopic adjustable gastric banding for the treatment of morbid (grade 3) obesity and its metabolic complications: a three-year
study. J Clin Endocrinol Metab
87:
3555–3561, 2002
- ↵
Pontiroli AE, Pizzocri P, Saibene A, Girola A, Koprivec D, Fragasso G: Left ventricular hypertrophy and QT interval in obesity
and in hypertension: effects of weight loss and of normalisation of blood pressure. Int J Obes Relat Metab Disord
28:
1118–1123, 2004
- ↵
Veronelli A, Laneri M, Ranieri R, Koprivec D, Vardaro D, Paganelli M, Folli F, Pontiroli AE: White blood cells in obesity
and diabetes: effects of weight loss and normalization of glucose metabolism (Letter). Diabetes Care
27:
2501–2502, 2004
- ↵
Pontiroli AE, Pizzocri P, Giacomelli M, Marchi M, Vedani P, Cucchi E, Orena C, Folli F, Paganelli M, Ferla G: Ultrasound measurement
of visceral and subcutaneous fat in morbidly obese patients before and after laparoscopic adjustable gastric banding: comparison
with computerized tomography and with anthropometric measurements. Obes Surg
12:
648–651, 2002
- ↵
Bazett HC: An analysis of time relations of the electrocardiogram. Heart
7:
353–370, 1920
- ↵
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and
β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia
28:
412–419, 1985
- ↵
Weyer C, Yudkin JS, Stehouwer CDA, Schalkwjik CG, Pratley RE, Tataranni PA: Humoral markers of inflammation and endothelial
dysfunction in relation to adiposity and in vivo insulin action in Pima Indians. Atherosclerosis
161:
233–242, 2002
- ↵
Wilson CA, Bekele G, Nicolson M, Ravussin E, Pratley RE: Relationship of the white cell count to body fat: role of leptin.
Br J Haematol
99:
447–451, 1997
-
Fauchier L, Maison-Blanche P, Forhan A, D’Hour A, Lepinay P, Tichet J, Vol S, Coumel P, Fauchier JP, Balkau B, the DESIR Study
Group: Association between, heart rate corrected QT interval and coronary risk factors in 2,894 healthy subjects (the DESIR
study). Am J Cardiol
86:
557–559, 2000
-
Festa A, D’Agostino R, Rautaharju P, Mykkanen L, Haffner SM: Relation of systemic blood pressure, left ventricular mass, insulin
sensitivity, and coronary heart disease to QT interval duration in nondiabetic and type 2 diabetic subjects. Am J Cardiol
86:
1117–1122, 2000
-
Ljung T, Holm G, Friberg P, Andersson B, Bengtsson BA, Svensson J, Dallman M, McEwen B, Bjorntorp P: The activity of the hypothalamic-pituitary-adrenal
axis and the sympathetic nervous system in relation to waist/hip circumference ratio in men. Obes Res
8:
487–495, 2000
-
Carella MJ, Mantz SL, Rovner DR, Willis PW 3rd, Gossain VV, Bouknight RR, Ferenchick GS: Obesity, adiposity, and lengthening
of the QT interval: improvement after weight loss. Int J Obes Relat Metab Disord
20:
938–942, 1996
-
Mshui ME, Saikawa T, Ito K, Hara M, Sakata T: QT interval and QT dispersion before and after diet therapy in patients with
simple obesity. Proc Soc Exp Biol Med
220:
133–138, 1999
- ↵
Rissanen P, Franssila-Kallunki A, Rissanen A: Cardiac parasympathetic activity is increased by weight loss in healthy obese
women. Obes Res
9:
637–643, 2001
- ↵
Karlsson AK: Insulin resistance and sympathetic function in high spinal cord injury. Spinal Cord
37:
494–500, 1999
- ↵
Carlyle M, Jones OB, Kuo JJ, Hall JE: Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension
39:
496–501, 2002
- ↵
Hall JE, Hildebrandt DA, Kuo J: Obesity hypertension: role of leptin and sympathetic nervous system. Am J Hypertens
14:
103S–115S, 2001
- ↵
Webster JI, Tonelli C, Sternberg EM: Neuroendocrine regulation of immunity. Annu Rev Immunol
20:
125–163, 2002
-
Mills PJ, Karnik RS, Dillon E: L-selectin expression affects T-cell circulation following isoproterenol infusion in humans.
Brain Behav Immun
11:
333–342, 1997
-
Mills PJ, Goebel M, Rehman J, Irwin MR, Maisel AS: Leukocyte adhesion molecule expression and T-cell naive memory status following
isoproterenol infusion. J Neuroimmunol
102:
137–144, 2000
-
Mills PJ, Farag NH, Perez C, Dimsdale JE: Peripheral blood mononuclear cell CD62L and CD11a expression and soluble interstitial
cell adhesion molecule-1 levels following infused isoproterenol in hypertension. J Hypertens
20:
311–316, 2002
-
Kuhlwein EC, Irwin MR, Ziegler MG, Woods VL, Kennedy B, Mills PJ: Propranolol affects stress-induced leukocytosis and cellular
adhesion molecule expression. Eur J Appl Physiol
86:
135–141, 2001
- ↵
Oddera S, Silvestri M, Lantero S, Sacco O, Rossi GA: Downregulation of the expression of intercellular adhesion molecule (ICAM)-1
on bronchial epithelial cells by fenoterol, a beta2-adrenoceptor agonist. J Asthma
35:
401–408, 1998
- ↵
Rehman J, Mills PJ, Carter SM, Chou J, Thomas J, Maisel AS: Dynamic exercise leads to an increase in circulating ICAM-1: further
evidence for adrenergic modulation of cell adhesion. Brain Behav Immun
11:
343–351, 1997
-
Goebel MU, Mills PJ: Acute psychological stress and exercise and changes in peripheral leukocyte adhesion molecule expression
and density. Psychosom Med
62:
664–670, 2000
-
Ohara Y, McCarron RM, Hoffman TT, Sugano H, Bembry J, Lenz FA, Spatz M: Adrenergic mediation of TNF alpha-stimulated ICAM-1
expression on human brain microvascular endothelial cells. Acta Neurochir Suppl
76:
117–120, 2000
-
Heine G, Gabriel H, Weindler J, Ruprecht KW, Kindermann W: Painful regional anaesthesia induces an immunological stress reaction:
the model of retrobulbar anaesthesia. Eur J Anaesthesiol
18:
505–510, 2001
-
Schedlowski M, Hosch W, Oberbeck R, Benschop RJ, Jacobs R, Raab HR, Schmidt RE: Catecholamines modulate human NK cell circulation
and function via spleen-independent beta 2-adrenergic mechanisms. J Immunol
156:
93–99, 1996
-
Rainer TH, Lam N, Cocks RA: Adrenaline upregulates monocyte L-selectin in vitro. Resuscitation
43:
47–55, 1999
-
Lotan D, Prince T, Dagan O, Keller N, Ben-Abraham R, Weinbroum A, Gaby A, Augarten A, Smolinski A, Barzilay Z, Paret G: Soluble
P-selectin and the postoperative course following cardiopulmonary bypass in children. Paediatr Anaesth
11:
303–308, 2001
- ↵
Paret G, Prince T, Keller N, Dagan O, Sasson Y, Barzilai A, Guthmann D, Barzilay Z: Plasma-soluble E-selectin after cardiopulmonary
bypass in children: is it a marker of the postoperative course? J Cardiothorac Vasc Anesth
14:
433–437, 2000
- ↵
Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM: Leptin
regulates proinflammatory immune responses. FASEB J
12:
57–65, 1998
