Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes

Heuvel, Mieke van den; Sorop, Oana; Koopmans, S.J.; Dekker, R.A.; Vries, René de; Beusekom, Heleen M.M. van; Eringa, Etto C.; Duncker, Dirk J.; Danser, A.H. Jan; Giessen, Willem J. van der

doi:10.1152/ajpheart.00311.2011

Cited by 51 publications

(58 citation statements)

References 63 publications

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“…However, in two subsequent studies in Yorkshire × Landrace and Yorkshire pigs, respectively, diabetes was accompanied by augmented hypercholesterolaemia. In the first of these studies, van den Heuvel et al reported increased atherosclerosis in abdominal aortas [26], but in the other, Hamamdzic et al observed no effect on intimal area, intima/media ratio or the degree of stenosis of the coronary arteries, although the lesions were reported to be more complex in diabetic compared with control animals [25]. In the latter study, an approximately 50% reduction in body weight was also reported for the diabetic pigs compared with the controls.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, diabetes has been reported to augment cholesterol levels in Yucatan and Sinclair minipigs [22,23]. In the widely used Yorkshire pig model of diabetes, inconsistent results have been obtained regarding the effect of diabetes on atherosclerosis and cholesterol level [24][25][26]. Impairment of kidney function and severe weight faltering in animal models of diabetes may further obscure the link between hyperglycaemia and atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

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Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs

et al. 2015

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Aims/hypothesis Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease, but whether there is a direct and independent role for impaired glucose control in atherogenesis remains uncertain. We investigated whether diabetes with poor glycaemic control would accelerate atherogenesis in a novel pig model of atherosclerosis, the D374Y-PCSK9 + transgenic minipig. Methods Nineteen minipigs were fed a cholesterol-enriched, high-fat diet; ten of these pigs were injected with streptozotocin to generate a model of diabetes. Restricted feeding was implemented to control the pigs' weight gain and cholesterol intake. After 49 weeks of high-fat feeding, the major arteries were harvested for a detailed analysis of the plaque burden and histological plaque type.Results Stable hyperglycaemia was achieved in the diabetic minipigs, while the plasma total and LDL-cholesterol and creatinine levels were unaffected. Diabetes failed to increase atherosclerosis in any of the vessels examined. The plaque burden in the aorta and right coronary artery was comparable between the groups, and was even reduced in the left anterior descending (LAD) coronary and iliofemoral arteries in the diabetic pigs compared with the controls. The distribution of plaque types and the collagen and macrophage contents were similar between the groups, except for a reduced infiltration of macrophages in the LAD arteries of the diabetic pigs. Conclusions/interpretation Poorly controlled diabetes with no alterations in plasma cholesterol or creatinine concentrations did not augment the plaque burden or promote the development of more advanced lesions in this large-animal model of humanlike atherosclerosis. This is consistent with clinical studies in patients with type 1 diabetes, indicating that hyperglycaemia per se is not an independent promoter of atherosclerotic disease, but that other diabetes-associated risk factors are important.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs

et al. 2015

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“…This is especially true in light of increasing evidence that coronary microvascular dysfunction is present in a variety of coronary vascular disease states (19), with evidence of reduced NO/cGMP signaling (40) and increased ET signaling (36). Those observations have fueled the concept that microvascular dysfunction is an important component of, and contributor to, myocardial ischemia in patients with coronary artery disease (28).…”

Section: Integrated Control Of Coronary Resistance Vessel Tone In Swimentioning

confidence: 98%

Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production

Zhou

Beer

Bender

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Zhou Z, de Beer VJ, Bender SB, Danser AH, Merkus D, Laughlin MH, Duncker DJ. Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production. Am J Physiol Heart Circ Physiol 306: H918 -H927, 2014. First published January 24, 2014; doi:10.1152/ajpheart.00331.2013.-Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP) and through inhibition of the endothelin-1 (ET) system. We previously demonstrated that phosphodiesterase-5 (PDE5)-mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of coronary resistance vessel tone by these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine both in vivo, at rest and during graded treadmill exercise, and in vitro. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 g·min Ϫ1 ·kg Ϫ1 iv) each produced coronary vasodilation at rest and during exercise as well as in preconstricted isolated coronary small arteries. In contrast, tezosentan failed to produce further coronary vasodilation in the presence of EMD360527, both in vivo and in vitro. Importantly, EMD360527 (3 M) and cGMP analog 8-Br-cGMP (100 M) had no significant effects on ET-induced contractions of isolated porcine coronary small arteries, suggesting unperturbed ET receptor responsiveness. In contrast, PDE5 inhibition and cGMP blunted the contractions produced by the ET precursor Big ET, but only in vessels with intact endothelium, suggesting that PDE5 inhibition limited ET production in the endothelium of small coronary arteries. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is mediated, in part, via an increase in endothelial ET production. PDE5 inhibition; ETA/ETB blockade; ET; Big ET; coronary vasomotor tone CORONARY BLOOD FLOW IS TIGHTLY coupled to myocardial oxygen demand to maintain a consistently high level of myocardial oxygen extraction (10,16,26). This tight coupling has been proposed to depend on a myriad of vasodilators and vasoconstrictors, including nitric oxide (NO) and endothelin-1 (ET). NO causes coronary vasodilation by stimulating guanylyl cyclase in vascular smooth muscle to generate cyclic guanosine monophosphate (cGMP), which activates cGMP-dependent protein kinase G (PKG) (32). Levels of cGMP in vascular smooth muscle are tightly regulated by several cyclic nucleotide phosphodiesterases (PDEs) that hydrolyze cGMP and terminate its vasodilator effect (2). PDE5 is present in vascular smooth muscle cells in the coronary vascular bed and thus has the potential to regulate coronary blood flow by exerting a vasoconstrictor influence. Indeed, PDE5 inhibition resulted in relaxation of coronary conduit arteries in swine in vitro (45) and in vivo (1),...

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“…Significance with Respect to Existing Methods Another method commonly used to assess changes in regulation of vascular tone is the use of isolated coronary and pulmonary small arteries or arterioles in a pressure or wire myograph 6,14,21 . The advantage of myograph studies is that vessels can be studied independent of surrounding tissue and without potentially confounding effect from circulating factors.…”

Section: Interpretation and Limitationsmentioning

confidence: 99%

“…Several swine models of cardiopulmonary disease, such as diabetes 6 , myocardial infarction 22 , pulmonary hypertension 8,9 and pacing induced heart failure 10 are available and could be combined with chronic instrumentation. A potential drawback is that, when commercially available swine breeds such as Yorkshire, Landrace, Large White etc, are used, adult swine are very large and may therefore be difficult to handle.…”

Section: Future Applicationsmentioning

confidence: 99%

Surgical Placement of Catheters for Long-term Cardiovascular Exercise Testing in Swine

Wijs-Meijler

Stam

Duin

et al. 2016

JoVE

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This protocol describes the surgical procedure to chronically instrument swine and the procedure to exercise swine on a motor-driven treadmill. Early cardiopulmonary dysfunction is difficult to diagnose, particularly in animal models, as cardiopulmonary function is often measured invasively, requiring anesthesia. As many anesthetic agents are cardiodepressive, subtle changes in cardiovascular function may be masked. In contrast, chronic instrumentation allows for measurement of cardiopulmonary function in the awake state, so that measurements can be obtained under quiet resting conditions, without the effects of anesthesia and acute surgical trauma. Furthermore, when animals are properly trained, measurements can also be obtained during graded treadmill exercise.Flow probes are placed around the aorta or pulmonary artery for measurement of cardiac output and around the left anterior descending coronary artery for measurement of coronary blood flow. Fluid-filled catheters are implanted in the aorta, pulmonary artery, left atrium, left ventricle and right ventricle for pressure measurement and blood sampling. In addition, a 20 G catheter is positioned in the anterior interventricular vein to allow coronary venous blood sampling.After a week of recovery, swine are placed on a motor-driven treadmill, the catheters are connected to pressure and flow meters, and swine are subjected to a five-stage progressive exercise protocol, with each stage lasting 3 min. Hemodynamic signals are continuously recorded and blood samples are taken during the last 30 sec of each exercise stage.The major advantage of studying chronically instrumented animals is that it allows serial assessment of cardiopulmonary function, not only at rest but also during physical stress such as exercise. Moreover, cardiopulmonary function can be assessed repeatedly during disease development and during chronic treatment, thereby increasing statistical power and hence limiting the number of animals required for a study. Video LinkThe video component of this article can be found at

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Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes

Cited by 51 publications

References 63 publications

Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs

Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs

Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production

Surgical Placement of Catheters for Long-term Cardiovascular Exercise Testing in Swine

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