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European Heart Journal (2006) 27, 2266–2268 Adiponectin and myocardial infarction: a paradox ora paradigm? Hwee Teoh1, Martin H. Strauss2, Paul E. Szmitko3, and Subodh Verma1* 1 Division of Cardiac Surgery, St Michael’s Hospital, Toronto, Ontario, Canada; 2 Division of Cardiology, North York GeneralHospital, Toronto, Ontario, Canada; and 3 Department of General Internal Medicine, Sunnybrook Health Sciences Centre,Toronto, Ontario, Canada Online publish-ahead-of-print 7 September 2006 This editorial refers to ‘Adiponectin is an independent positively associated with an increased incidence and predictor of all-cause mortality, cardiac mortality, and risk of obesity, diabetes mellitus, insulin resistance, low myocardial infarction in patients presenting with chest HDL, high triglycerides, and ultimately the development of pain’† by E. Cavusoglu et al., on page 2300 Cavusoglu et al.6 reported on a 2-year study that included Once considered a disease of the affluent, obesity now pre- 325 high-risk males with cardiac-related chest pain and under- vails in the poorer developing nations as well.1 Although it is went coronary angiography. Elevated circulating adiponectin widely acknowledged that obesity, together with its allied levels at presentation were found to be independent metabolic disorders, is closely associated with the patho- markers of both myocardial infarction (MI) and all-cause mor- genesis of cardiovascular diseases (CVDs),1,2 the precise tality at 2 years, challenging the accumulated cellular, molecular links between obesity and CVD remain speculat- animal, and human epidemiological data that support adipo- ive. It is evident that adipose tissue, traditionally viewed nectin’s role as a protective cardiovascular molecule. Adding as a passive energy reservoir, plays a role in homeostasis to this paradox was the finding that the same inverse relation- and metabolism. Adipose tissue has autocrine, paracrine, ship previously reported with type 2 diabetes mellitus-related and endocrine functions and synthesizes and releases a hypertension, HbA1c levels, insulin, BMI, and triglycerides5,7 wide array of cytokine-like products collectively termed adi- was seen despite adiponectin levels paralleling cardiovascular pokines. Adipokines include pro- and anti-inflammatory mol- morbidity. Only C-reactive protein (CRP),2 a recognized ecules, complement factors, growth factors, and signalling inflammatory factor, and adiponectin persistently and inde- proteins2 that modulate inflammatory, metabolic, and cardio- pendently transpired as risk factors for MI and mortality, regardless of further statistical adjustments.
Adiponectin is an adipocyte-specific protein that circulates A similar correlation of adiponectin levels with cardiovas- in concentrations greater than any other hormone in the cular mortality was also evident in patients with congestive body. In contrast to many of the other adipokines, adiponec- heart failure.8 In this study, patients with adiponectin levels tin appears to offer cardiovascular and metabolic protection in the upper two tertiles had triple the mortality risk when via insulin sensitizing, anti-inflammatory, lipid metabolism, compared with those patients within the lowest tertile. The anti-atherogenesis, and anti-angiogenic effects, which, in mortality rate was also inversely related to BMI, most prob- part, are mediated through adiponectin receptors.3 Adipo- ably reflecting the known association of cardiac ‘wasting’ nectin accumulates in the sub-endothelium of injured with increased mortality, suggesting that the paradoxical human arteries where it inhibits monocyte adhesion to endo- increase of adiponectin levels in those with the highest mor- thelial cells and ultimately inhibits the migration and pro- tality may have been secondary to weight loss, a known liferation of vascular smooth muscle that contribute to the Animal data support adiponectin as a cardiovascular pro- Adiponectin levels are lower in females when compared tective molecule. In a mouse model of acute MI, adiponectin with males, obese subjects vs. lean subjects, and type 2 null mice responded with larger infarct sizes, greater myo- diabetics vs. non-diabetics. There is a strong negative cardial cell apoptosis, and increased tumour necrosis factor a expression when compared with wild-type con- visceral fat, as well as body mass index (BMI) in both trols.9 Rescue attempts with adiponectin delivered by ade- humans and animals. Low levels of adiponectin are novirus, and recombinant adiponectin infusion prior to orduring the ischaemia-reperfusion procedure, amelioratedall the associated damaging effects,9 suggesting that The opinions expressed in this article are not necessarily those of the exogenous adiponectin protects the heart against ischaemic Editors of the European Heart Journal or of the European Society ofCardiology.
insults. Although adiponectin levels may decline acutely inthe setting of an MI,10 this may, in part, reflect sequestering * Corresponding author. Tel: þ1 416 782 0092; fax: þ1 416 782 0096.
of adiponectin at the site of vascular injury, a hypothesis E-mail address: [email protected] & The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected] cardiovascular and metabolic health, including elevation Professionals Follow-up Study (HPFS)7 of 18 225 male of adiponectin levels, are enhanced following removal of health care providers, there are convincing clinical data visceral, but not subcutaneous fat. Recently, the INTER- for a positive correlation between high baseline plasma HEART investigators determined that despite gross vari- adiponectin and diminished MI risk over a 6-year follow-up in subjects with no prior cardiovascular disease. This corre- measurement is a strong indicator for MI risk globally1 and may be more predictive of MI than BMI, but the relationship variables, family history of MI, BMI, alcohol consumption, of adiponectin to waist-to-hip ratio is not known.
physical activity, and a history of diabetes and hypertension Adiponectin levels may be altered by drugs, increasing in (RR 0.41, 95% CI 0.24–0.70, P for trend ,0.001).
response to the peroxisome proliferator-activated receptor Furthermore, adjustments for HbA1c and CRP had little g (PPARg) agonists thiazolidinediones (TZDs),3 as well as by impact, although adjustments for HDL and LDL moderately inhibitors of the renin–angiotensin system, perhaps by com- attenuated this relationship. The diabetic sub-group of bating insulin resistance and hypertension, respectively.13 HPFS had a similar relationship of adiponectin levels to car- TZDs stimulate a substantial production of adiponectin, diovascular risk, and this association was in part mediated and considering PPARg is predominantly expressed in by higher levels of HDL.11 The plasma adiponectin levels adipose tissue and adipose tissue appears essential for reported by Cavusoglu et al. were within the boundaries TZDs to improve insulin sensitivity, this suggests a central of the lowest two HPFS quintiles, which were defined as role for adiponectin in the improved insulin sensitivity the sub-populations with the worst MI odds ratio (OR). This seen with TZDs.3 Antagonism of the cannabinoid receptor indicates that the results may represent a statistical aberra- type 1 with rimonabant has been associated with a 57% tion or that there are other factors at play that have not (P , 0.001) increase in adiponectin in obese dyslipidaemic been formally accounted for in the multivariate adjustment.
patients. The increase in adiponectin is, in part, related to Is there a paradigm that unifies a biologically plausible weight loss in addition to a direct effect of rimonabant to hypothesis to account for adiponectin as a surrogate biologi- cal ‘marker’ for a good cardiovascular prognosis in low-risk Although one might conclude from the study of Cavusoglu patients, yet still be compatible with its association with a et al. that adiponectin is a deleterious adipokine given its poorer prognosis in high-risk patients? The answer is affirma- relationship with increased MI and mortality, it could be tive if adiponectin is viewed first and foremost as a vascular argued that if adiponectin isoforms were measured, or protective ‘mediator’. High levels of adiponectin were serial measurements made, or waist-hip ratio was reported, inversely proportional to adverse cardiovascular events in the results may have differed. Regardless, the paradox is HPFS, a low-risk population, supporting a salutory role in perhaps best viewed from the perspective that the prepon- mediating vascular protection. In high-risk populations, derance of accumulated data supports a cardiovascular pro- such as those in the study by Cavusoglu et al., the cardiovas- tective role of adiponectin and that adiponectin levels are cular protective role of adiponectin should hypothetically be suppressed in chronic diseases such as obesity and diabetes no different. The higher levels of adiponectin may be in mellitus, yet still have the ability to be up-regulated in response to the inflammatory milieu that triggers an response to acute cardiovascular injury.
increased expression, synthesis, and release, which is a In the future, congeners of adiponectin, or pharma- physiological attempt to limit further endothelial damage.
ceutical agents that augment endogenous adiponectin Despite all the counter-regulatory mechanisms that are levels, may ultimately play a role in the management of mobilized in the high-risk patients, including up-regulation obesity. However, the most logical and cost-effective of plasma adiponectin levels, it is intuitive that the repara- approach of dealing with this burgeoning problem is tive processes of the body may be overwhelmed, translating through the prevention of obesity in childhood, which is a into higher cardiovascular morbidity.
true epidemic. Children are increasingly sedentary as phys- Circulating adiponectin predominantly exists as three ical activity disappears from both schools and day to day primary oligomeric complexes—trimeric, hexameric, and life, and as well ingest a diet of energy dense foods and bev- high molecular weight (HMW) adiponectin. Although there erages, of questionable nutritional value. According to a is no consensus concerning the biological significance of recent study from the Institute of Medicine, food marketing the various adiponectin isoforms, the ratio of HMW to may contribute to this epidemic, as advertisers ‘intention- total adiponectin may correlate better with clinical ally target children too young to distinguish advertising benefit than total adiponectin alone,, at least with respect from truth and induce them to eat high-caloric, low- to insulin sensitivity.12 Cavusoglu et al. did not examine nutritional (but highly profitable) ‘junk’ foods’.15 If the the individual adiponectin entities, nor did HPFS for that factors leading to childhood obesity are so readily apparent, matter either, leaving it open to speculation that the so are the actions necessary to mitigate them.
patients with the worse OR for MI may have had thelowest percentages of the biologically active HMW adiponec- Conflict of interest: none declared.
tin or, alternatively, a higher ratio of ‘inert’ adiponectincomplexes, despite high levels of total plasma adiponectin.
Future studies may help to better define the levels of the impact on endothelial function that includes the production 1. Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsup S, Wangai P Jr,Razak F, Sharma AM, Anand SS. Obesity and the risk of myocardial infarc- Central obesity is a reflection of visceral obesity and the tion in 27,000 participants from 52 countries: a case-control study.
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3. Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev 2005;6:13–21.
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Medtronic Award Paper presented at CANN Conference, Halifax, N.S., June 2009 Intrathecal baclofen and pregnancy: Implications for clinical care By Margo DeVries-Rizzo, Diny Warren, Gail Delaney, Simon Levin, Craig Campbell and Sandrine DeRibaupierre Abstract Intrathecal baclofen use during pregnancy is rare. There are no Pregnancy in patients with intrathecal baclofen (ITB) pumps contro

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