The novel findings of the present study are that both obesity and statins are independent predictors of enhanced dilation of coronary resistance arteries in patients undergoing heart surgery. The observed enhanced dilator function of coronary arterioles may independently contribute to improved myocardial perfusion during or after heart surgery, and may, in part, offer an explanation to the improved cardiovascular outcomes in these settings - the obesity paradox.
The obesity paradox was first described in 1999 by Fleishmann et al. who found that a one unit increase in BMI is associated with a 4% reduction in the relative risk of death in hemodialysis patients [16
]. Since then, other patient populations have been identified where those with elevated BMI unexpectedly exhibit decreased morbidity and mortality in comparison to patients with normal BMI. These conditions include: acute and chronic heart failure, coronary artery disease, hypertension, percutaneous coronary intervention, stroke, intensive care unit patients, chronic obstructive pulmonary disease and chronic kidney disease [8
The notion that obesity is being protective in patients who require heart surgery prompted us to raise the possibility that myocardial perfusion, hence coronary microcirculation, is less compromised in obese patients than is usually considered to be the case. In this context, earlier studies using positron emission tomography [5
] and magnetic resonance imaging [7
] showed unaltered myocardial perfusion in obese patients without coronary risk factors, while myocardial blood flow was found reduced only after metabolic or pharmacologic challenge [6
]. Although such non-invasive imaging techniques are powerful tools to measure myocardial blood flow, conclusions are limited as these techniques provide only relative comparisons of myocardial perfusion and are unable to assess the microcirculation independently [18
Herein we present the results of a study in which the dilator function of ex vivo
coronary resistance arteries to the agonist, bradykinin was directly assessed. This study builds upon our previous observation that coronary arterioles isolated from obese patients exhibit enhanced dilations to the endothelium-dependent agonist, bradykinin and the NO donor, sodium nitroprusside in the setting of concomitant hypertension [11
]. In the present study we set out to examine whether or not the observed effect of obesity on coronary responsiveness was influenced by the patients’ medications. Our sample size (64 consecutive patients) allowed us to employ robust statistical models to identify independent predictors of coronary arteriole dilation.
Importantly, our study identified obesity as an independent, positive predictor of coronary arteriole dilations, in patients undergoing heart surgery, with a 5.00 fold increase in the probability of dilating 40% or greater in response to the endothelium-dependent vasodilator, bradykinin (Table ). Two-way ANOVA comparing the interactions between obesity and co-morbid conditions, and between obesity and medications, demonstrated no significance (Tables A and B). These data, together with the multivariable regression analysis, indicate that differences in coronary arterial dilations between obese and non-obese patients are due to obesity, rather than medications and other diseases. Given that, it is plausible that obesity is associated with an augmented coronary dilation, which may correlate enhanced myocardial perfusion in patients undergoing heart surgery. In this context, a recent retrospective analysis by van Straten et al. examining post CABG mortality in a large patient population (10,268 patients) showed that only morbid obesity (BMI > 35) was an independent predictor for late (> 30 days), but not early (< 30 days) mortality [19
], whereas no significant effects on mortality rates were detected in overweight and obese patient populations. Intriguingly, in the unadjusted Kaplan-Meier survival curves, stratified by only preoperative BMI, the authors found a lower survival rate among patients who were normal weight when compared to patients who were overweight. Patient who were underweight had significantly lower survival compared with all other BMI groups [19
]. The average BMI of obese patients in our study was 33.4 kg/m2
. Of these patients only 5 were morbidly obese, and only 2 of the non-obese population were underweight. Given these small numbers, stratification of the data to include underweight and morbidly obese populations was not possible for analysis in the present study. Moreover, due to the nature of our study design – using unidentified surplus surgical specimens – the clinical outcome of heart surgery in obese versus non-obese patients was not investigated. Thus, further studies are needed in order to evaluate to what extent the level of adiposity affects coronary microvascular responses, which may also correlate with the short- and/or long-term outcome of patients undergoing heart surgery.
In this study we also found that statin therapy improves dilator function of coronary resistance arteries in patients undergoing heart surgery. This finding may be expected, but this study provides a direct evidence for the beneficial effects of statin therapy on vasodilator function in coronary resistance arterioles. When obese and non-obese patients were stratified depending on the use of statins, interestingly we found a significantly enhanced coronary dilation in obese subgroups, with our without statin, when responses were compared to non-obese patients with no statin treatment. Previous studies by Vaduganathan et al. found pre- and perioperative statin therapy to be associated with reduced mid-term mortality in patients undergoing heart surgery [20
]. Recent randomized studies by Antoniades et al. demonstrated that pre-operative atorvastatin treatment (40 mg/day for three days) improved saphenous vein relaxations, effects that were independent from the lipid-lowering properties of the drug [22
]. Our study offers further support and direct demonstration for the beneficial effect of statin therapy likely contributing to improved myocardial perfusion following heart surgery through enhancing the dilator function of coronary resistance arteries.
ACE inhibitors are also known to exhibit cardiovascular benefits [24
] and have been shown to improve vascular function in animal models of obesity [25
]. Although approximately half of the patients undergoing heart surgery are on ACE inhibitors, a controversy regarding their preferential use prior to CABG surgery exists [27
]. In our present study ACE inhibitors taken prior to heart surgery had no significant effects on the magnitude of bradykinin-induced dilation in obese patents even though significant interactions between obesity and ACE inhibitors were identified. Our finding that non-obese patients who were taking ACE inhibitors had reduced coronary arteriole dilation is likely due to the disproportionate number of patients taking statins - 65% of non-obese patients on ACE inhibitors were taking statins, as compared to 81% of non-obese patients not on ACE inhibitors taking statins. Indeed, after controlling for the effects of statins in the multivariable model, it was observed that ACE inhibitors were not predictive of vessel dilations within our sample cohort. Moreover, it is also possible that ACE inhibitors, via increasing the tissue level of bradykinin may cause reduced receptor sensitivity to bradykinin, a potential mechanism, which may contribute to the observed reduced dilation of coronary arterioles, ex vivo
; and also may explain the apparent controversy.