Effect of treatment on cardiac small resistance arteries in hypertension and diabetes

For many years, different groups have studied the structure, mechanical properties and function of resistance arteries in humans with hypertension, obesity and diabetes, by investigating vessels dissected from biopsies of gluteal subcutaneous tissue [1–5], and evaluated the effects of different treatments on structure and function of these vessels [6–13]. The characteristics of these subcutaneous vessels compared with those of resistance vessels in the heart and kidney cortex of rodents demonstrated that the changes that they exhibit in hypertension, and the effects of antihypertensive therapy, were similar [14], providing evidence of the potential pathophysiological significance of findings in gluteal subcutaneous arteries. Some studies were able to demonstrate that structural changes of gluteal subcutaneous arteries predicted cardiovascular events [15]. Indirect studies have also demonstrated the presence of altered cardiac microcirculation [16–18] and indirect evidence that small myocardial artery dysfunction could result in poorer outcomes [19]. However, direct investigation of small myocardial arteries from humans with hypertension or diabetes has not been performed because of its invasive nature. In this issue, Lynch et al.[20] report for the first time on the structure and distensibility of small arteries dissected from atrial appendage biopsies obtained from normotensive and hypertensive nondiabetic and diabetic individuals during coronary artery bypass graft (CABG) surgery. As it often happens in cases when tissues are obtained from individuals in a cross-sectional study while taking advantage that they are being subject to surgery, difficulties arise when it comes to interpreting the results of the study. Lynch et al. found no significant differences in the lumen diameter, wall thickness, wall-to-lumen ratio or cross-sectional area of arteries from all groups. Arteries from hypertensive nondiabetic patients demonstrated decreased distensibility compared with normotensive nondiabetic patients. There was no difference in distensibility between vessels from hypertensive diabetic patients and either diabetic or nondiabetic normotensive patients. The authors concluded that neither diabetes nor hypertension appeared to influence arterial structure which may indicate that successful treatment of hypertension is associated with normal vascular structure in coronary small arteries. So the questions here are as follows: were vessels ever abnormal, and has treatment really corrected the structure of these small arteries back to normal? This is what previous studies of gluteal subcutaneous arteries would suggest [6–13], as well as indirect studies of the coronary microcirculation [16,17]. To confirm this, one would need a longitudinal study; and, starting medication after a first vessel sample was obtained with a second sampling, for example after 6 months or 1 year. This is clearly quite difficult from an ethical point of view, but could rarely occur if a patient undergoes repeat CABG which is unusual. As this ideal situation from a research question point of view would be rather extraordinary, the question is whether it is better to attempt the imperfect solution which is to have one sample when it is available, attempting at the same time to match hypertensive nondiabetic, hypertensive diabetic and normotensive diabetic individuals with normotensive nondiabetic individuals, all requiring CABG, as Lynch et al.[20] have done. I believe that authors have performed the study that is feasible. However, the result is not unambiguous and inevitably disappointing, requiring speculative conclusions. Vessels were similar in normotensive and hypertensive nondiabetic and diabetic individuals, according to authors, because the blood pressure was similar in all individuals, as a result of treatment. However, if patients were treated predominantly with β-blockers vs. angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or calcium channel blockers (CCBs), one might expect the latter to have normal or near-normal structure and distensibility, whereas β-blocker-treated individuals might not have corrected structure or mechanical properties [6–13,21]. More probably, the patients were treated with combinations of agents, including some of the antihypertensive drugs that do correct and β-blockers such as atenolol which does not correct the structure of vessels and their stiffness, which might explain in part the results found. However, in most studies, structure of small arteries from gluteal subcutaneous tissue did not return to normal [6–13], although in one retrospective study no differences could be found between normotensive and controlled hypertensive individuals treated with a CCB for many years [10] which may be comparable to the results of the study by Lynch et al.[20]. Another source of concern is the fact that hypertensive diabetic individuals had significantly higher SBPs than the other groups, and far above guideline-recommended targets for these high-risk patients, which could result in differences that are not in fact found. As well, glycaemic control in diabetic individuals was suboptimal, and renal function was altered in hypertensive nondiabetic and diabetic individuals, which could also have affected vascular structure and stiffness, but does not seem to according to the structural and mechanical findings of Lynch et al. In the hypertensive group, arteries exhibited increased stiffness compared with normal, whereas the other groups did not. The authors suggest the possibility that metformin use in the diabetic patients resulted in enhanced distensibility on the basis of rodent studies in which metformin was found to reduce oxidative stress and formation of end-glycation products, and increase nitric oxide bioavailability in Goto-Kakizaki rats, a model of nonobese type 2 diabetes, which could increase coronary artery distensibility [22], but this remains speculative. In conclusion, the authors of this article should be commended for having been able to ethically obtain samples of resistance arteries from humans, which allowed this investigation to be carried out. However, conclusions are speculative at best for the reasons given above. If a group of patients with badly controlled hypertension had been studied which allowed showing the presence of abnormal cardiac small arteries in these individuals in comparison to well controlled patients, the conclusions of the study could have been considerably strengthened. As presented, conclusions are tentative and require carrying out further studies to be able to support the claims of the authors. ACKNOWLEDGEMENT Conflicts of interest The work of the author is supported by Canadian Institutes of Health Research (CIHR) grants 37917, 82790 and 102606, by a Canada Research Chair (CRC) on Hypertension and Vascular Research from CIHR/Government of Canada CRC Program and by the Canada Fund for Innovation. In past 2 years, the author has served in advisory boards of Daiichi-Sankyo, Janssen, Novartis, Pfizer, Servier and Takeda and has received research grants from the Canadian Institutes of Health Research and Novartis.

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