Early changes in coronary artery wall structure detected by microcomputed tomography in experimental hypercholesterolemia

Changes in the structure of the artery wall commence shortly after exposure to cardiovascular risk factors, such as hypercholesterolemia (HC), but may be difficult to detect. The ability to study vascular wall structure could be helpful in evaluation of the factors that instigate atherosclerosis and its pathomechanisms. The present study tested the hypothesis that early morphological changes in coronary arteries of hypercholesterolemic (HC) pigs can be detected using the novel X-ray contrast agent OsO(4) and three-dimensional micro-computed tomography (CT). Two groups of pigs were studied after they were fed a normal or an HC (2% cholesterol) diet for 12 wk. Hearts were harvested, coronary arteries were injected with 1% OsO(4) solution, and cardiac samples (6-mum-thick) were scanned by micro-CT. Layers of the epicardial coronary artery wall, early lesions, and perivascular OsO(4) accumulation were determined. Leakage of OsO(4) from myocardial microvessels was used to assess vascular permeability, which was correlated with immunoreactivity of vascular endothelial growth factor in corresponding histological cross sections. OsO(4) enhanced the visualization of coronary artery wall layers and facilitated detection of early lesions in HC in longitudinal tomographic sections of vascular segments. Increased density of perivascular OsO(4) in HC was correlated with increased vascular endothelial growth factor expression and suggested increased microvascular permeability. The use of OsO(4) as a contrast agent in micro-CT allows three-dimensional visualization of coronary artery wall structure, early lesion formation, and changes in vascular permeability. Therefore, this technique can be a useful tool in atherosclerosis research.     

The coronary circulation in exercise training

Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. In large animals, EX increases capillary exchange capacity through angiogenesis of new capillaries at a rate matched to EX-induced cardiac hypertrophy so that capillary density remains normal. However, after EX coronary capillary exchange area is greater (i.e., capillary permeability surface area product is greater) at any given blood flow because of altered coronary vascular resistance and matching of exchange surface area and blood flow distribution. The improved coronary capillary blood flow distribution appears to be the result of structural changes in the coronary tree and alterations in vasoreactivity of coronary resistance arteries. EX also alters vasomotor reactivity of conduit coronary arteries in that after EX, α-adrenergic receptor responsiveness is blunted. Of interest, α- and β-adrenergic tone appears to be maintained in the coronary microcirculation in the presence of lower circulating catecholamine levels because of increased receptor responsiveness to adrenergic stimulation. EX also alters other vasomotor control processes of coronary resistance vessels. For example, coronary arterioles exhibit increased myogenic tone after EX, likely because of a calcium-dependent PKC signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, EX augments endothelium-dependent vasodilation throughout the coronary arteriolar network and in the conduit arteries in coronary artery disease (CAD). The enhanced endothelium-dependent dilation appears to result from increased nitric oxide bioavailability because of changes in nitric oxide synthase expression/activity and decreased oxidant stress. EX also decreases extravascular compressive forces in the myocardium at rest and at comparable levels of exercise, mainly because of decreases in heart rate and duration of systole. EX does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. While there is evidence that EX can decrease the progression of atherosclerotic lesions or even induce the regression of atherosclerotic lesions in humans, the evidence of this is not strong due to the fact that most prospective trials conducted to date have included other lifestyle changes and treatment strategies by necessity. The literature from large animal models of CAD also presents a cloudy picture concerning whether EX can induce the regression of or slow the progression of atherosclerotic lesions. Thus, while evidence from research using humans with CAD and animal models of CAD indicates that EX increases endothelium-dependent dilation throughout the coronary vascular tree, evidence that EX reverses or slows the progression of lesion development in CAD is not conclusive at this time. This suggests that the beneficial effects of EX in CAD may not be the result of direct effects on the coronary artery wall. If this suggestion is true, it is important to determine the mechanisms involved in these beneficial effects.     

Shear stress-induced vasodilation in porcine coronary conduit arteries is independent of nitric oxide release

The present study was performed to determine the importance of nitric oxide in eliciting epicardial coronary artery dilation during sustained increases in shear stress in the absence of pulsatile flow. Isolated first-order porcine epicardial coronary conduit arteries (approximately 500 microm) were preconstricted (U-46619) and subjected to steady-state changes in flow in vitro. Nonpulsatile flow (shear stress range from 0 to approximately 100 dyn/cm2) produced a graded dilation of epicardial arteries. Inhibiting nitric oxide synthase with 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME) blocked bradykinin-induced vasodilation but did not affect the flow-diameter relation or the maximum change in diameter from static conditions (67 +/- 10 microm in control vs. 71 +/- 8 microm after L-NAME, P = not significant). The addition of indomethacin (10(-5) M) had no effect on flow-mediated vasodilation. Depolarizing vascular smooth muscle with KCl (60 mM) or removing the endothelium blocked bradykinin vasodilation and completely abolished flow-mediated responses. The K+ channel blocker tetraethylammonium chloride (TEA; 10(-4)M) attenuated flow-mediated vasodilation (maximum diameter change was 110 +/- 18 microm under control conditions vs. 58 +/- 10 microm after TEA, P < 0.001). These data indicate that epicardial coronary arteries dilate to steady-state changes in nonpulsatile flow via a mechanism that is independent of nitric oxide production. The ability to completely block this with KCl and attenuate it with TEA supports the hypothesis that epicardial coronary arteries dilate to steady levels of shear stress through hyperpolarization of vascular smooth muscle. This may be secondary to the release of an endothelium-dependent hyperpolarizing factor.     

Prostanoids and hemodynamics in man before and during cardiopulmonary bypass

The plasma concentration of 6-keto-PGF1 alpha, the stable degradation product of prostacyclin, was similar in the radial and pulmonary arteries and in the coronary sinus before and after the induction of the anesthesia in patients undergoing coronary artery bypass surgery. After the beginning of the mechanical ventilation and anesthesia the pulmonary vascular resistance decreased although no changes were detected in the plasma levels of 6-keto-PGF1 alpha or TXB2. During the prebypass period after the sternotomy and cannulation of the large vessels the plasma level of 6-keto-PGF1 alpha was increased similarly in the radial and pulmonary arteries and even more in the coronary sinus. During the cardiopulmonary bypass the concentration of 6-keto-PGF1 alpha remained at the increased level as compared to the values before the anesthesia. This indicates that pulmonary circulation is perhaps not the main source of prostacyclin in man. The plasma level of TXB2 was increased during the prebypass period significantly only in the coronary sinus, but during the bypass also in the radial artery. The concentration ratio of 6-keto-PGF1 alpha/TXB2 was increased significantly during the prebypass period in the radial and pulmonary arteries. At the same time the pulmonary vascular resistance was, however, returned to the preanesthesia level and was thus not decreased. The vascular resistance in the systemic circulation was increased during the prebypass period. The plasma level of 6-keto-PGF1 alpha or TXB2 in the radial and pulmonary arteries did not correlate significantly with the total vascular resistance in the systemic and pulmonary circulation, respectively. The vascular resistance in the coronary circulation did not correlate significantly with TXB2 level in the radial artery or coronary sinus. There was, however, a slight positive correlation between the blood flow and the concentration of TXB2 in the coronary sinus (r = 0.76, P less than 0.01). Coronary sinus flow did, however, not correlate with the plasma level of 6-keto-PGF1 alpha in the radial artery or coronary sinus. These results indicate that the detected plasma concentrations of prostacyclin and thromboxane A2 have no significant effects on the total vascular resistance in vivo.     

Exercise training-induced coronary vascular adaptation.

Aerobic exercise training induces an increase in coronary vascular transport capacity. This increased transport capacity is the result of increases in both blood flow capacity and capillary exchange capacity. These functional changes are the result of two major types of adaptive responses, structural vascular adaptation and altered control of vascular resistance. Structural vascular adaptation occurs in response to exercise training in at least two forms, increases in the cross-sectional area of the proximal coronary arteries and angiogenesis. Angiogenesis has been demonstrated in that training causes moderate cardiac hypertrophy while maintaining or increasing capillary density and increasing arteriolar density. Training-induced changes in coronary vascular control have been shown to include altered coronary responses to vasoactive substances, changes in endothelium-mediated vasoregulation, and alterations in the cellular-molecular control of intracellular free Ca2+ in both endothelial and vascular smooth muscle cells isolated from coronary arteries of exercise-trained animals. The signal or signals for these adaptive responses remain unknown. The hypothesis that the adaptive strategy entails maintenance of normal shear stress in coronary arterial vessels is discussed. We propose that as a result of training-induced structural vascular adaptations and alterations in the control of vascular resistance, shear stress throughout the coronary vasculature is returned to the level present in sedentary animals. The signal for adaptation may be peak shear stress during exercise and/or average shear stress over a 24-h period of time.     

Global revascularization: the role of the cardiologist

There are compelling reasons for cardiologists to undertake a more global approach to patients with peripheral vascular diseases: atherosclerosis is a 'systemic' disease frequently causing both coronary and peripheral vascular problems in the same patient; coronary artery disease is the most common cause of morbidity and mortality in patients with peripheral vascular disease; and peripheral vascular disease negatively impacts the management of angina pectoris and congestive heart failure. There are four major areas of special interest to the cardiologist: (1) iliac arteries (vascular access), (2) renal arteries (hypertension and volume overload), (3) subclavian arteries (coronary steal with a left internal mammary artery [LIMA] graft), and (4) carotid arteries (stroke). Technical skills necessary to perform coronary angioplasty are transferable to the peripheral vasculature. However, an understanding of the natural history of peripheral disease, patient and lesion selection criteria, and knowledge of other treatment alternatives are essential to performing these procedures safely and effectively. Appropriate preparation and training, and a team approach, including an experienced vascular surgeon, are both desirable and necessary before interventional cardiologists who are inexperienced in the treatment of peripheral vascular disease attempt percutaneous peripheral angioplasty. There are inherent advantages for patients when the cardiologist performing the procedure is also a clinician. Judgments regarding the indications, timing, and risk/benefit ratio of procedures are enhanced by a long-term relationship between physician and patient. Finally, in view of the increased incidence of coronary artery disease in patients with atherosclerotic peripheral vascular disease, the participation of a cardiologist in their care seems appropriate.     

Coronary endothelial dysfunction after cardiomyocyte-specific mineralocorticoid receptor overexpression

The deleterious effects of aldosterone excess demonstrated in cardiovascular diseases might be linked in part to coronary vascular dysfunction. However, whether such vascular dysfunction is a cause or a consequence of the changes occurring in the cardiomyocytes is unclear. Moreover, the possible link between mineralocorticoid receptor (MR)-mediated effects on the cardiomyocyte and the coronary arteries is unknown. Thus we used a mouse model with conditional, cardiomyocyte-specific overexpression of human MR (hMR) and observed the effects on endothelial function in isolated coronary segments. hMR overexpression decreased the nitric oxide (NO)-mediated relaxing responses to acetylcholine in coronary arteries (but not in peripheral arteries), and this was prevented by a 1-mo treatment either with an MR antagonist, vitamin E/vitamin C, or a NADPH oxidase inhibitor. hMR overexpression did not affect coronary endothelial NO synthase content nor its level of phosphorylation on serine 1177, but increased cardiac levels of reactive oxygen species, cardiac NADPH oxidase (NOX) activity, and expression of the NOX subunit gp91phox, which was limited to endothelial cells. Thus an increase in hMR activation, restricted to cardiomyocytes, is sufficient to induce a severe coronary endothelial dysfunction. We suggest a new paracrine mechanism by which cardiomyocytes trigger a NOX-dependent, reactive oxygen species-mediated coronary endothelial dysfunction.     

Bifurcation asymmetry of the porcine coronary vasculature and its implications on coronary flow heterogeneity

The branching pattern of the coronary arteries and veins is asymmetric, i.e., many small vessels branch off of a large trunk such that the two daughter vessels at a bifurcation are of unequal diameters and lengths. One important implication of the geometric vascular asymmetry is the dispersion of blood flow at a bifurcation, which leads to large spatial heterogeneity of myocardial blood flow. To document the asymmetric branching pattern of the coronary vessels, we computed an asymmetry ratio for the diameters and lengths of all vessels, defined as the ratio of the daughter diameters and lengths, respectively. Previous data from silicone elastomer cast of the entire coronary vasculature including arteries, arterioles, venules, and veins were analyzed. Data on smaller vessels were obtained from histological specimens by optical sectioning, whereas data on larger vessels were obtained from vascular casts. Asymmetry ratios for vascular areas, volumes, resistances, and flows of the various daughter vessels were computed from the asymmetry ratios of diameters and lengths for every order of mother vessel. The results show that the largest orders of arterial and venous vessels are most asymmetric and the degree of asymmetry decreases toward the smaller vessels. Furthermore, the diameter asymmetry at a bifurcation is significantly larger for the coronary veins (1.7-6.8 for sinus veins) than the corresponding arteries (1.5-5.8 for left anterior descending coronary artery) for orders 2-10, respectively. The reported diameter asymmetry at a bifurcation leads to significant heterogeneity of blood flow at a bifurcation. Hence, the present data quantify the dispersion of blood flow at a bifurcation and are essential for understanding flow heterogeneity in the coronary circulation.     

Effects of diabetes on the vascular response to nitric oxide and constrictor prostanoids: gender and regional differences

To analyze the effects of diabetes mellitus on the vascular responsiveness to nitric oxide and thromboxane receptor stimulation, 2 mm long segments of basilar, coronary, renal and tail arteries from male and female, control (normoglycemic) and streptozotocin-induced diabetic rats, were prepared for isometric tension recording. In the segments at basal resting tension, the thromboxane analog U46619 (10(-9)-10(-5) M) produced concentration-dependent contraction, which was similar in arteries from male and female rats, and was reduced by diabetes in coronary arteries from male and in tail arteries from female rats. In the vascular segments precontracted with endothelin-1 (10(-9) M), acetylcholine (10(-9)-3 x 10(-5) M) produced concentration-dependent relaxation which was similar in all arteries from normoglycemic male and female rats, and was increased by diabetes in tail arteries from female, but not in those from male rats. In precontracted segments the nitric oxide donor sodium nitroprusside (10(-10)-10(-5) M) also produced concentration-dependent relaxation, which was higher in basilar arteries from normoglycemic females compared with males, and was increased by diabetes in tail arteries from female but not from male rats. These results suggest that diabetes may increase the relaxation to nitric oxide in tail arteries, and may reduce the contraction to thromboxane receptor activation in coronary and tail arteries in a gender-dependent way. These changes in vascular reactivity may be adaptative to the vascular alterations produced by diabetes.     

Muscular ETB receptors develop postnatally and are differentially distributed in specific segments of the rat vasculature.

The endothelin/endothelin-receptor system is a key player in the regulation of vascular tone in mammals. We raised and characterized an antiserum against rat ETB receptor and investigated the distribution of ETB receptors in different vascular beds during postnatal development (day 0 through day 28) and in the adult rat. We report the tissue-specific and age-dependent presence of vasoconstrictor ETB receptors. At the time of birth, vascular smooth muscle cells from all tissues examined did not exhibit ETB receptor immunoreactivity. The occurrence of ETB receptor immunoreactivity in the postnatal development was time dependent and started in small coronary and meningeal arteries at day 5, followed by small mesenteric arteries as well as brachial artery and vein at day 14. At day 21, ETB receptors were present in the media of muscular segments of pulmonary artery, large coronary arteries, and intracerebral arterioles. At day 28, ETB receptor immunoreactivity was evident in interlobular renal arteries, vas afferens, and efferens. Large renal arteries, mesenteric artery, and elastic segments of pulmonary arteries, as well as coronary and mesenteric veins, did not exhibit ETB receptor immunoreactivity. These data demonstrate the age-dependent and tissue-specific presence of ETB receptors, mainly on arterial smooth muscle cells in the vascular system of the rat.     

Assessment of endothelial function of large, medium, and small vessels: a unified myograph

Endothelial dysfunction precedes the development of morphological atherosclerotic changes and can also contribute to lesion development in cardiovascular diseases. Currently, there is a lack of a single method to determine endothelial function of the entire range of vessel dimensions from aorta to arterioles. Here we assessed endothelial function of a large range of size arteries using a unified isovolumic myograph method. The method maintains a constant volume of fluid in the lumen of the vessel during contraction and relaxation, which are characterized by an increase and a decrease of pressure, respectively. Segments of six aortas, six common femoral arteries, and six mesenteric arteries from rats; six carotid arteries from mice; and six coronary and carotid arteries from pigs were used. The endothelium-dependent dose-response vasorelaxation was determined with endothelium-dependent vasodilators while arterial preconstriction was induced with vasoconstrictors at a submaximal dose. The circumferential midtension during vascular reactivity varied from 43.1 ± 7.9 to 2.59 ± 0.46 mN/mm (from large to small arteries), whereas the circumferential midstress showed a much smaller variation from 217 ± 23.5 to 123 ± 15.3 kPa (in the same range of vessels). We also found that overinflation and axial overelongation compromised endothelium-dependent vasorelaxation to underscore the significance of vessel preload. In conclusion, an isovolumic myograph was used to unify arterial vasoreactivity from large to small arteries and shows the uniformity of wall stress and %tension throughout the range of vessel sizes.     

Adrenergic control of coronary arteries

This review of adrenergic control of coronary arteries is based on studies conducted on isolated vessels. Both alpha- and beta-adrenergic receptors are present in the coronary vasculature but with different distributions. The large coronary arteries have a larger percentage of alpha receptors, which mediate contraction, whereas the small coronary arteries are equipped almost exclusively with beta receptors, which mediate relaxation. The beta receptors are of the subclass beta 1. Both alpha 1 and alpha 2 receptors are present in the large coronaries. The alpha 2 receptors are prejunctional and inhibit neuronal release of norepinephrine (NE), and are also postjunctional and mediate contraction of the vascular smooth muscle. Evidence is reviewed suggesting that coronary alpha and beta receptors may be different conformational states of the same parent macromolecule in which the alpha state predominates at lower temperatures. Contrary to these results we have observed that whereas the response of the large coronary artery to NE at 39 C is predominantly constriction, it is predominantly dilation at 29 C. The characteristic of the adrenergic receptor is clearly temperature dependent.     

Busulphan-cyclophosphamide cause endothelial injury, remodeling of resistance arteries and enhanced expression of endothelial nitric oxide synthase

Stem cell transplantation (SCT) is a curative treatment for malignant and non malignant diseases. However, transplantation-related complications including cardiovascular disease deteriorate the clinical outcome and quality of life. We have investigated the acute effects of conditioning regimen on the pharmacology, physiology and structure of large elastic arteries and small resistance-sized arteries in a SCT mouse model. Mesenteric resistance arteries and aorta were dissected from Balb/c mice conditioned with busulphan (Bu) and cyclophosphamide (Cy). In vitro isometric force development and pharmacology, in combination with RT-PCR, Western blotting and electron microscopy were used to study vascular properties. Compared with controls, mesenteric resistance arteries from the Bu-Cy group had larger internal circumference, showed enhanced endothelium mediated relaxation and increased expression of endothelial nitric oxide synthase (eNOS). Bu-Cy treated animals had lower mean blood pressure and signs of endothelial injury. Aortas of treated animals had a higher reactivity to noradrenaline. We conclude that short-term consequences of Bu-Cy treatment divergently affect large and small arteries of the cardiovascular system. The increased noradrenaline reactivity of large elastic arteries was not associated with increased blood pressure at rest. Instead, Bu-Cy treatment lowered blood pressure via augmented microvascular endothelial dependent relaxation, increased expression of vascular eNOS and remodeling toward a larger lumen. The changes in the properties of resistance arteries can be associated with direct effects of the compounds on vascular wall or possibly indirectly induced via altered translational activity associated with the reduced hematocrit and shear stress. This study contributes to understanding the mechanisms that underlie the early effects of conditioning regimen on resistance arteries and may help in designing further investigations to understand the late effects on vascular system.     

Estrogen replacement increases coronary artery distensibility in ovariectomized rats.

The effect of estrogen on the passive characteristics of arteries is not known. We hypothesized that estrogen would increase arterial distensibility as part of its protective effect on the vasculature. Female Sprague-Dawley rats were ovariectomized at 11 weeks of age. One group received a placebo (n = 6), while two other groups (n = 5 each) of rats received a 17beta-estradiol pellet (0.15 mg or 0.5 mg with 60-day release). After 4 weeks of estrogen replacement, coronary and mesenteric arteries (<200 microm diameter) were dissected and mounted on a dual-chamber arteriograph. Lumen diameter and wall thickness were measured in pressurized arteries. The relative changes in diameter (distensibility) as well as wall thickness per unit change in pressure were significantly increased (p < 0.05) in the coronary arteries of the 0.5 mg estradiol replaced rats compared with the ovariectomized control animals and the 0.15 mg estradiol replaced rats. Surprisingly, in the mesenteric arteries from the same animals, there was no difference in distensibility or pressure - wall thickness among the groups. This study provides experimental data of a novel hypothesis that estrogen may afford part of its protection through vascular remodeling of the coronary circulation.     

Influence of coronary artery diameter on eNOS protein content

The purpose of this study was to test the hypothesis that the content of endothelial nitric oxide synthase (eNOS) protein (eNOS protein/g total artery protein) increases with decreasing artery diameter in the coronary arterial tree. Content of eNOS protein was determined in porcine coronary arteries with immunoblot analysis. Arteries were isolated in six size categories from each heart: large arteries [301- to 2,500-microm internal diameter (ID)], small arteries (201- to 300-microm ID), resistance arteries (151- to 200-microm ID), large arterioles (101- to 150-microm ID), intermediate arterioles (51- to 100-microm ID), and small arterioles(<50-microm ID). To obtain sufficient protein for analysis from small- and intermediate-sized arterioles, five to seven arterioles 1-2 mm in length were pooled into one sample for each animal. Results establish that the number of smooth muscle cells per endothelial cell decreases from a number of 10 to 15 in large coronary arteries to 1 in the smallest arterioles. Immunohistochemistry revealed that eNOS is located only in endothelial cells in all sizes of coronary artery and in coronary capillaries. Contrary to our hypothesis, eNOS protein content did not increase with decreasing size of coronary artery. Indeed, the smallest coronary arterioles had less eNOS protein per gram of total protein than the large coronary arteries. These results indicate that eNOS protein content is greater in the endothelial cells of conduit arteries, resistance arteries, and large arterioles than in small coronary arterioles.     

Estrogens, progestins, and coronary artery reactivity in atherosclerotic monkeys

It has been known for many years that sex hormones modulate vasodilator responses of arteries supplying the uterus with blood. Recently, it has been shown that sex hormones such as estrogen modulate vasomotor responses of other arteries, including coronary arteries. It is thought that modulation of vasodilator and constrictor responses of coronary arteries may be one mechanism by which estrogen affects the risk of coronary heart disease. Although several studies have examined the effects (and potential mechanisms) of estrogen on vasodilator responses of nonatherosclerotic arteries, few have focused on estrogen's effects on atherosclerotic coronary arteries. In studies of ovariectomized atherosclerotic female cynomolgus monkeys, both long-term (2 years) and short-term (20 min) estradiol treatment augments dilator responses to acetylcholine, but not nitroglycerin. Presumably, this indicates an effect of estradiol on endothelium-mediated dilator responses of coronary arteries. Addition of the progestin medroxyprogesterone acetate diminishes the beneficial effect of conjugated equine estrogens on these dilator responses. This is significant because a progestin is usually added to estrogen replacement to reduce the risk of endometrial and breast cancer associated with unopposed estrogen therapy. However, it would seem that not all progestins act similarly on vascular reactivity. Studies in monkeys indicate that addition of progesterone or the progestin medroxyprogesterone acetate does not diminish the beneficial effects of estrogen on coronary dilator responses. Thus it would appear that different estrogen/progestin combinations may affect vascular reactivity in different manners, There is also an effort being made to examine the potential of different kinds of estrogens on cardiovascular risk. Studies in monkeys indicate that one of the estrogens found in conjugated equine estrogens (17 alpha-dihydroequilenin) has estrogen effects on vascular reactivity without having detrimental effects on uterine pathology. The isoflavones “plant estrogens” found in soy protein also have estrogenic effects on vascular reactivity and inhibition.     

The alpha adrenoceptors on endothelial cells

Endothelial cells release a powerful factor (endothelium-derived relaxing factor [EDRF]) that relaxes smooth muscle cells in response to some vasodilating agents such as acetylcholine. Contraction curves to norepinephrine (NE) in greyhound, mongrel dog, and pig coronary artery rings were studied in vitro in the presence of propranolol. Removal of endothelium increased the sensitivity and maximum contraction in response to NE. In other experiments pig coronary rings were precontracted with a thromboxane mimetic U 46619 in the presence of propranolol. NE relaxed these arteries only if endothelium was present. Methoxamine was without effect but the relaxation response to NE was antagonized by phentolamine, idazoxan, and yohimbine, which suggests that there are alpha 2 adrenoceptors on endothelial cells that mediate the release of EDRF. Greyhound and mongrel dog large coronary arteries relaxed to NE only if prazosin was present, which suggests that alpha 1-adrenoceptor stimulation on the vascular smooth muscle can override the relaxation response to EDRF. Comparison of NE responses in carotid, mesenteric, renal, and femoral large arteries of the pig, greyhound, and mongrel dog indicate the nonuniformity of distribution of alpha 2 adrenoceptors on endothelium and alpha 1 and alpha 2 adrenoceptors on vascular smooth muscle. The integrity of the endothelium must now be considered in interpreting the vascular responses to alpha-adrenoceptor agonists.     

The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease

Obesity, insulin resistance and the metabolic syndrome, are characterized by expansion and inflammation of adipose tissue, including the depots surrounding the heart and the blood vessels. Epicardial adipose tissue (EAT) is a visceral thoracic fat depot located along the large coronary arteries and on the surface of the ventricles and the apex of the heart, whereas perivascular adipose tissue (PVAT) surrounds the arteries. Both fat depots are not separated by a fascia from the underlying tissue. Therefore, factors secreted from epicardial and PVAT, like free fatty acids and adipokines, can directly affect the function of the heart and blood vessels. In this review, we describe the alterations found in EAT and PVAT in pathological states like obesity, type 2 diabetes, the metabolic syndrome and coronary artery disease. Furthermore, we discuss how changes in adipokine expression and secretion associated with these pathological states could contribute to the pathogenesis of cardiac contractile and vascular dysfunction.     

Morphologic changes in the coronary arteries in experimental coarctation of the aorta and following its correction

In 33 puppies 2-4 months of age the model of a congenital heart disease was made as coarctation of the aorta. In 6-12 months 18 animals were taken to study, and in 15 animals the coarctation was removed. The latter animals were observed for other 6-12 months. The hearts of both groups were separately weighed, and the vessels of the coronary system were studied by means of a complex of histological and morphometric methods. Simultaneously, the number of smooth muscle cells, as well as the area and volume of their nuclei in media of small coronary arteries were estimated. At the experimental coarctation of the aorta certain hypertrophic-hyperplastic changes in coronary arteries at all branching levels take place. They are of a compensatory-adaptive character and reflect certain reactions of the vascular wall to an increased coronary hemodynamics under conditions of hyperfunction and hypertrophy of the cardiac muscle. Surgical removal of the coarctation is accompanied with a reduce of the hemodynamic loading of the heart, diminished degree of hypertrophy of the organ and a marked decrease of the hypertrophic-hyperplastic changes in its vessels. At the same time, the cardiac vascular system is adapting to the new conditions of circulation: rearrangement of some coronary arteries and arterioles according to the closed type and reduction of circulation in the vascular branches which have lost their importance in feeding the myocardium.     

Ischaemia with no obstructive coronary arteries

Ischaemia with no obstructive coronary arteries (INOCA) is a common ischaemic heart disease with a female preponderance, mostly due to underlying coronary vascular dysfunction comprising coronary microvascular dysfunction and/or epicardial coronary vasospasm. Since standard ischaemia detection tests and coronary angiograms are not suitable to diagnose coronary vascular dysfunction, INOCA is often overlooked in current cardiology practice. Future research, including large outcome trials, is much awaited. Yet, adequate diagnosis is possible and treatment options are available and vital to reduce symptoms and most probably improve cardiovascular prognosis. This review intends to give a brief overview of the clinical presentation, underlying pathophysiology, and the diagnostic and treatment options in patients with suspected INOCA.