Vessels of the heart and lung in some experimental defects]

Under study were changes of intraorganic blood vessels of the heart and lungs in some experimental defects (open arterial defect, coarctation of the aorta, simultaneous existence of these two defects, stenosis of the pulmonary trunk, defect of the interatrial septum, triad of Fallot, syndrom of Lutembachet). Morphological data correlated with blood pressure in the pulmonary circulation and cardiac chambers. The complex of compensatory-adaptational mechanisms consisting of comparatively active and passive zones is formed in the heart and lungs. In most cases the changes develop in the vessels already existing. In hypertrophy of the myocardium when there is hypertension and hypervolemia in coronary vessels, sinusoids perform the function of blood reservoir, to a certain degree balancing the blood pressure, and luminar ducts relieve the muscle from excessive blood. The changes in the vascular system of the lung are directly dependent upon the pressure in the pulmonary circulation and the duration of observation. The closing arteries are the most active link in the chain of compensatory-adaptational mechanisms.     

Adaptive structures of the arteries of the heart participating in the regulation of coronary circulation

By means of a complex of anatomical, histological and histochemical methods cardiac vessels have been studied in 20 control dogs and in 84 dogs with experimentally produced circulatory disturbances peculiar for congenital heart diseases presented as an open arterial duct, coarctation of the aorta and the pulmonary trunk stenosis. The experimental animals have been observed for 6-12 months. In the animals with experimentally produced disturbances of the general and coronary hemodynamics hyperplasy in the coronary branches of the arteries appears, it is more pronounced in functionally loaded cardiac parts, as well as thickening of their walls at the expense of new formations and hyperthrophy of smooth muscle cells. In both control and experimental dogs in the coronary vessels at various branching levels certain formations are revealed; they are of compensatory-adaptive value: intimal and adventitial musculature, polypoid pulvinars, muscular-elastic constrictors, muscular cuffs and precapillary sphincters. They differ in structure, sources of their origin and in their functional value. Degree of their manifestation increases significantly after reproduction of the hemodynamic disturbances in the heart vascular system. The active role of these formations in regulation of the coronary circulation is demonstrated owing to a high content of ribonucleinic acid and glycogene in their smooth muscle cells and also an elevated succinate dehydrogenase, cytochromoxydase, acid and alcaline phosphatase activities.     

Structural changes in cardiac vessels in experimental patent ductus arteriosus

In 43 puppies an experimental arterial duct was produced. The animals were observed for 1--2 months and then killed. Their hearts were separately weighed, and their vessels were studied by means of a complex histomicrometry method. In the puppies with the artificially produced arterial duct, hypertrophy of both cardiac ventricles was gradually developing, combined with thickening medial tunica of the coronary arteries at all levels of their branching. Simultaneously, the oblique-longitudinal musculature of the vascular walls grew stronger. In the distributing arteries it occurred at the expense of the muscular fasciculi situated in adventitia, in the resistance arteries--at the expense of the fasciculi situated in intima. The hypertrophic-hyperplastic changes noted in the vessels of the coronary system were connected with cardiac hypertrophy and with disorders of coronary hemodynamics.     

The arterial circulation of the heart

Blood flows into the aorta and its branches during left ventricular systole. Most of the arterial walls in the body stretch during systole in accordance with their elastic properties (Roston, 1962a, b). During diastole, the rebound of the distended walls supplies an additional propulsive force pushing the blood forward. Since the metabolic exchange between most of the tissues in the body and their blood vessels is ordinarily the same throughout the cardiac cycle, it makes little difference whether or not the blood flow occurs during systole or diastole. The circulation in the coronary arteries behaves in a quite different way. Because the muscle fibers of the heart contract during systole and relax during diastole, different conditions for blood flow and metabolic exchange exist during the phases of the cardiac cycle. As a result, specification of whether blood flows in the coronary arteries during systole or diastole may be important. Such specification complicates the study of the coronary artery circulation. For example, because of the arterial elasticity, some of the blood which enters the coronary arteries during diastole comes in contact with the muscle fibers during systole. The present work contains a theoretical study of the coronary artery circulation.     

Computational simulations of hemodynamic changes within thoracic, coronary, and cerebral arteries following early wall remodeling in response to distal aortic coarctation

Mounting evidence suggests that the pulsatile character of blood pressure and flow within large arteries plays a particularly important role as a mechano-biological stimulus for wall growth and remodeling. Nevertheless, understanding better the highly coupled interactions between evolving wall geometry, structure, and properties and the hemodynamics will require significantly more experimental data. Computational fluid–solid-growth models promise to aid in the design and interpretation of such experiments and to identify candidate mechanobiological mechanisms for the observed arterial adaptations. Motivated by recent aortic coarctation models in animals, we used a computational fluid–solid interaction model to study possible local and systemic effects on the hemodynamics within the thoracic aorta and coronary, carotid, and cerebral arteries due to a distal aortic coarctation and subsequent spatial variations in wall adaptation. In particular, we studied an initial stage of acute cardiac compensation (i.e., maintenance of cardiac output) followed by early arterial wall remodeling (i.e., spatially varying wall thickening and stiffening). Results suggested, for example, that while coarctation increased both the mean and pulse pressure in the proximal vessels, the locations nearest to the coarctation experienced the greatest changes in pulse pressure. In addition, after introducing a spatially varying wall adaptation, pressure, left ventricular work, and wave speed all increased. Finally, vessel wall strain similarly experienced spatial variations consistent with the degree of vascular wall adaptation.     

Outflow pathways of venous blood from the myocardium in the dog and structures participating in their regulation

The intramural pathways of the venous blood outflow from the cardiac wall have been studied histologically, histochemically and micrometrically in 20 control and 84 experimental dogs with an artificially produced circulatory disturbances, peculiar for congenital heart disease (open arterial canal, coarctation of the aorta and stenosis of the pulmonary trunk). The experimental animals have been observed for 6-12 months. In the venous line of the coronary basin several morphologically differed parts, anatomically and functionally connected between themselves and ensuring blood outflow from the myocardium, are distinguished: coronary sinus, subepicardial veins, paired sinusoid veins, myocardial sinusoids and endocardial cushions. In each of them there are their own adaptive structures, participating in regulation of the venous blood stream. In the cardial sinus, in the subepicardial and paired sinusoid veins--these are valves of various complexity. In the myocardial sinusoids, the regulatory function, together with the valves, are performed by the intimal and muscle cushions, connective tissue and muscle bridges. In the endocardial cushions they are realized by the valves, muscle sphincters, bundles of obliquely and longitudinally oriented leiomyocytes. All the adaptive structures mentioned are also found in the hearts of the control animals. Under modelling various hemodynamic disturbances, the degree of their development increases sharply. The latter ensures the maintenance of an optimal regimen of blood circulation in the myocardium of a functionally loaded heart and prevents development of decompensation in the organ.     

Evolution of blood vessels of the heart wall

In progressive development of the organisms, the cardio-vascular system perfects, its construction is adequate to the level and character of the animal's metabolism. The hypobranchial arteries, forming in the subbranchial area in fishes, make the immediate source for the branching off the coronary arteries. Comparison of the data concerning the places where the cranial coronary arteries take their origin in amphibia, reptiles, birds and mammalia demonstrates that the evolutional process is directed towards transference of the places of their branching off on the ventral aorta, and then on the nearest distance to the heart. Certain data are obtained on evolution of the blood circulation pathways in the myocardium and, particularly, on presence of blood vessels in the spongy myocardium in Elasmobranchii, Chondrosteoideii, as well as in the alligator. The most important of the myocardial blood vessels at all stages of evolution is their connection with the cardiac chambers. At definite stages of phylogenesis, simultaneously with compactization of the myocardium and formation of veins from the intertrabecular spaces, the subepicardial and intramural veins unite into a single venous system, bringing blood to the cardiac cavity. In birds, mammalia and human being, the coronary vessels have reached a high degree of development, having penetrated by their branches into all layers of the cardiac wall, and thus they exclude the dependence of the myocardial blood supply from the blood that is present in the cardiac cavity.     

Peritruncal Coronary Endothelial Cells Contribute to Proximal Coronary Artery Stems and Their Aortic Orifices in the Mouse Heart

Avian embryo experiments proved an ingrowth model for the coronary artery connections with the aorta. However, whether a similar mechanism applies to the mammalian heart still remains unclear. Here we analyzed how the main coronary arteries and their orifices form during murine heart development. Apelin (Apln) is expressed in coronary vascular endothelial cells including peritruncal endothelial cells. By immunostaining, however, we did not find Apln expression in endothelial cells of the aorta during the period of coronary vessel development (E10.5 to E15.5). As a result of this unique expression difference, Apln^CreERT2/+ genetically labels nascent coronary vessels forming on the heart, but not the aorta endothelium when pulse activated by tamoxifen injection at E10.5. This allowed us to define the temporal contribution of these distinct endothelial cell populations to formation of the murine coronary artery orifice. We found that the peritruncal endothelial cells were recruited to form the coronary artery orifices. These cells penetrate the wall of aorta and take up residence in the aortic sinus of valsalva. In conclusion, main coronary arteries and their orifices form through the recruitment and vascular remodeling of peritruncal endothelial cells in mammalian heart.     

Embryonic development of the proepicardium and coronary vessels

In the last few years, an increasing interest in progenitor cells has been noted. These cells are a source of undifferentiated elements from which cellular components of tissues and organs develop. Such progenitor tissue delivering stem cells for cardiac development is the proepicardium. The proepicardium is a transient organ which occurs near the venous pole of the embryonic heart and protrudes to the pericardial cavity. The proepicardium is a source of the epicardial epithelium delivering cellular components of vascular wall and interstitial tissue fibroblasts. It contributes partially to a fibrous tissue skeleton of the heart. Epicardial derived cells play also an inductive role in differentiation of cardiac myocytes into conductive tissue of the heart. Coronary vessel formation proceeds by vasculogenesis and angiogenesis. The first tubules are formed from blood islands which subsequently coalesce forming the primitive vascular plexus. Coronary arteries are formed by directional growth of vascular protrusions towards the aorta and establishing contact with the aortic wall. The coronary vascular wall matures by attaching smooth muscle cell precursors and fibroblast precursors to the endothelial cell wall. The cells of tunica media differentiate subsequently into vascular smooth muscle by acquiring specific contractile and cytoskeletal markers of smooth muscle cells in a proximal - distal direction. The coronary artery wall matures first before cardiac veins. Maturity of the vessel wall is demonstrated by the specific shape of the internal surface of the vascular wall.     

Progression of coronary and mesenteric vascular dysfunction in Zucker obese and Zucker diabetic fatty rats

We investigated the progression of vascular dysfunction associated with the metabolic syndrome with and without hyperglycemia in lean, Zucker obese, and Zucker diabetic fatty (ZDF) rats. Responses of aorta and small coronary and mesenteric arteries were measured to endothelium-dependent and -independent vasodilators. Indices of oxidative stress were increased in serum from ZDF rats throughout the study, whereas values were increased in Zucker obese rats later in the study [thiobarbituric acid reactive substances: 0.45 +/- 0.02, 0.59 +/- 0.03 (P < 0.05), and 0.58 +/- 0.03 (P < 0.05) mug/ml in serum from 28- to 40-wk-old lean, Zucker obese, and ZDF rats, respectively]. Acetylcholine (ACh)-induced relaxation was not altered in vessels from lean animals from 8-40 wk. ACh-induced relaxation was nearly abolished in coronary arteries from 28- to 36-wk-old Zucker obese rats and by 16-36 wk in ZDF rats and was attenuated in aorta and mesenteric vessels from ZDF rats [%relaxation to 10 muM ACh: 72.2 +/- 7.1, 17.9 +/- 5.9 (P < 0.05), and 23.0 +/- 4.5 (P < 0.05) in coronary vessels; and 67.9 +/- 9.2, 50.1 +/- 5.5, and 42.3 +/- 4.7 (P < 0.05) in mesenteric vessels from 28- to 40-wk-old lean, Zucker obese, and ZDF rats, respectively]. The attenuated ACh-induced relaxation was improved when vessels were incubated with tiron, suggesting superoxide as a mechanism of endothelial dysfunction. Sodium nitroprusside-induced relaxation was not altered in aorta or coronary arteries and was potentiated in mesenteric arteries from Zucker obese rats. Our data suggest that diabetes enhances the progression of vascular dysfunction. Increases in indices of oxidative stress precede the development of dysfunction and may serve as a marker of endothelial damage.     

Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca²⁺-sensitive K⁺ current in miniature swine with LV hypertrophy

Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ET(A)) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K(+) currents (I(K(+))) in coronary smooth muscle cells. Raising internal Ca(2+) from 200 to 500 nM increased Ca(2+)-sensitive K(+) current in HF-TR and control, but not HF animals. In conclusion, an ET(A)-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca(2+)-sensitive I(K(+)) was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca(2+)-sensitive I(K(+)), illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.     

Diagnosis of supravalvular stenosis of the aorta

The authors analyzed the potentialities of combined radiodiagnosis of supravalvular stenosis (SS) and concomitant diseases of the heart and major vessels (Williams-Beuren syndrome) in 7 patients aged 7 mos. to 24 yrs. Polypositional chest and heart x-ray procedure, catheterization of the cardiac cavities, pulmonary artery and aorta, left ventriculography (6), right ventriculography (4) and angiopulmonography were used. The diagnostic potentialities of each method were defined. It was proved that SS practically in all patients was accompanied by major vascular changes in the pulmonary, vertebral, coronary, carotid, subclavicular, renal and other arteries, heart failure (atrial septal defect, and mitral incompetence).     

Hypertrophy of the heart; electrocardiographic distinction between physiologic and pathologic enlargement

Electrocardiograms of marathon runners were examined to study hypertrophy of the heart due to prolonged physical exertion and to differentiate this from hypertrophy due to various disease states, especially essential hypertension, aortic valvular disease and coarctation of the aorta. The electrocardiogram of the marathon runners was characterized by a slow cardiac rate, high voltage of the QRS complexes and T waves in the standard and/or precordial leads with normal R/T ratios. There was moderate enlargement of the heart as observed on teleoroentgenogram. These findings are characteristic of physiologic hypertrophy of the heart and should be suspected among patients having a history of athletics calling for endurance. Immediately after running, all waves showed an increased voltage and the heart size decreased. The concept of the secondary T wave in hypertension as a part of the left ventricular strain pattern was challenged by the observation that the increased voltage of the R waves in lead V5 and other leads seen in marathon runners and in certain patients with hypertension, aortic stenosis, aortic insufficiency and coarctation of the aorta were not necessarily associated with typical discordant S-T segments and T waves. There was a higher incidence of dyspnea, angina pectoris and cardiac enlargement among hypertensive patients with discordant T waves than among hypertensive patients without these changes. Thus it is felt that the discordant waves are primary and are not merely secondary to the increased area of the R waves. Primary T waves suggest myocardial disease, possibly anoxia of the subendocardium.     

Combined effects of hypertension and conditioning on coronary vascular reserve in rats

To evaluate the combined effects of cardiac overload imposed by hypertension and chronic swim training on coronary vascularity, female rats were made hypertensive by unilateral renal artery stenoses and were exercised in an 8- to 10-wk swimming program. Maximal coronary flow was assessed in isolated retrograde buffer-perfused hearts under conditions of minimal coronary resistance (15 microM adenosine or anoxia). Sedentary normotensive animals, sedentary hypertensive animals, and normotensive animals exposed to a swimming program were also studied. Swimming was associated with an 18% increase in heart weight and with increases in both absolute (ml/min) and relative (ml X g-1 X min-1) maximal coronary flow. Hypertension was associated with a 32% increase in heart weight but with a decrease in absolute and relative coronary flow compared with controls. The combined stimuli resulted in a 63% myocardial hypertrophy and a 19% increase in absolute flow. Relative coronary flow (g tissue-1) was similar in hearts from hypertensive sedentary animals and hypertensive swimmers. These data indicate that the coronary vascular deficit that accompanies the cardiac hypertrophy of hypertension is not worsened by the superimposition of an exercise load that exaggerates the hypertrophy.     

An Operation Designed to Promote the Growth of New Coronary Arteries,Using a Detached Omental Graft: A Preliminary Report

The human greater omentum exhibits a marked affinity for inflamed surfaces, to which it supplies numerous blood vessels. To achieve myocardial revascularization by omental graft the root of the aorta, the epicardium over both ventricles and the serosal layer of the pericardium were removed in 17 animals. A piece of greater omentum was removed from the abdomen, unfolded and wrapped around the entire heart, and fixed by interrupted sutures to the base of the aorta. Myocardial ischemia was created at the time of operation by ameroid constriction of coronary arteries. Vessels, arteriolar or larger, were found to grow from the root of the aorta, the myocardium and the pericardium into the detached free omental graft, which apparently acted as a conveyer for new vessels, including new coronary arteries, to reach the myocardium.     

Urotensin-II and cardiovascular remodeling

Urotensin-II (U-II), a cyclic undecapeptide, and its receptor, UT, have been linked to vascular and cardiac remodeling. In patients with coronary artery disease (CAD), it has been shown that U-II plasma levels are significantly greater than in normal patients and the severity of the disease is increased proportionally to the U-II plasma levels. We showed that U-II protein and mRNA levels were significantly elevated in the arteries of patients with coronary atherosclerosis in comparison to healthy arteries. We observed U-II expression in endothelial cells, foam cells, and myointimal and medial vSMCs of atherosclerotic human coronary arteries. Recent studies have demonstrated that U-II acts in synergy with mildly oxidized LDL inducing vascular smooth muscle cell (vSMC) proliferation. Additionally, U-II has been shown to induce cardiac fibrosis and cardiomyocyte hypertrophy leading to cardiac remodeling. When using a selective U-II antagonist, SB-611812, we demonstrated a decrease in cardiac dysfunction including a reduction in cardiomyocyte hypertrophy and cardiac fibrosis. These findings suggest that U-II is undoubtedly a potential therapeutic target in treating cardiovascular remodeling.     

In vitro hemodynamic investigation of the embryonic aortic arch at late gestation

This study focuses on the dynamic flow through the fetal aortic arch driven by the concurrent action of right and left ventricles. We created a parametric pulsatile computational fluid dynamics (CFD) model of the fetal aortic junction with physiologic vessel geometries. To gain a better biophysical understanding, an in vitro experimental fetal flow loop for flow visualization was constructed for identical CFD conditions. CFD and in vitro experimental results were comparable. Swirling flow during the acceleration phase of the cardiac cycle and unidirectional flow following mid-deceleration phase were observed in pulmonary arteries (PA), head-neck vessels, and descending aorta. Right-to-left (oxygenated) blood flowed through the ductus arteriosus (DA) posterior relative to the antegrade left ventricular outflow tract (LVOT) stream and resembled jet flow. LVOT and right ventricular outflow tract flow mixing had not completed until approximately 3.5 descending aorta diameters downstream of the DA insertion into the aortic arch. Normal arch model flow patterns were then compared to flow patterns of four common congenital heart malformations that include aortic arch anomalies. Weak oscillatory reversing flow through the DA junction was observed only for the Tetralogy of Fallot configuration. PA and hypoplastic left heart syndrome configurations demonstrated complex, abnormal flow patterns in the PAs and head-neck vessels. Aortic coarctation resulted in large-scale recirculating flow in the aortic arch proximal to the DA. Intravascular flow patterns spatially correlated with abnormal vascular structures consistent with the paradigm that abnormal intravascular flow patterns associated with congenital heart disease influence vascular growth and function.     

Blood Supply to the Interventricular Septum of the Heart in Rodents with Intramyocardial Coronary Arteries

The blood supply to the interventricular septum of the heart was studied in a sample of 1634 specimens belonging to four rodent families, Cricetidae, Arvicolidae, Gliridae, and Muridae. Most specimens (n = 1604) were examined using a corrosion-cast technique, while the remaining 30 were studied by histological techniques. In 1417 cases the coronary artery pattern was normal, and the interventricular septum was fundamentally supplied by one or rarely two septal arteries arising from the right and/or left coronary arteries. In 72 specimens the right and left coronary arteries were normal, while the septal artery arose from a separate ostium in the aorta, behaving as a third coronary artery. The remaining 145 animals possessed anomalies in the origin of the coronary arteries, and the septum was also principally irrigated by a septal artery. In 5 of these 145 anomalous cases the septal artery originated from a separate ostium in the aorta. In all specimens examined a less important vascularization of the septum was established through thinner penetrating vessels originating from the right and/or left coronary arteries. Existence of one or rarely two septal arteries is the most constant feature of the coronary artery arrangement in rodents with intramyocardial coronary arteries.     

Vanilloid Receptor-1 (TRPV1) Expression and Function in the Vasculature of the Rat

Transient receptor potential (TRP) cation channels are emerging in vascular biology. In particular, the expression of the capsaicin receptor (TRPV1) was reported in vascular smooth muscle cells. This study characterized the arteriolar TRPV1 function and expression in the rat. TRPV1 mRNA was expressed in various vascular beds. Six commercially available antibodies were tested for TRPV1 specificity. Two of them were specific (immunostaining was abolished by blocking peptides) for neuronal TRPV1 and one recognized vascular TRPV1. TRPV1 was expressed in blood vessels in the skeletal muscle, mesenteric and skin tissues, as well as in the aorta and carotid arteries. TRPV1 expression was found to be regulated at the level of individual blood vessels, where some vessels expressed, while others did not express TRPV1 in the same tissue sections. Capsaicin (a TRPV1 agonist) evoked constrictions in skeletal muscle arteries and in the carotid artery, but had no effect on the femoral and mesenteric arteries or the aorta. In blood vessels, TRPV1 expression was detected in most of the large arteries, but there were striking differences at level of the small arteries. TRPV1 activity was suppressed in some isolated arteries. This tightly regulated expression and function suggests a physiological role for vascular TRPV1.     

HYPERTROPHY OF THE HEART—Electrocardiographic Distinction Between Physiologic and Pathologic Enlargement

Electrocardiograms of marathon runners were examined to study hypertrophy of the heart due to prolonged physical exertion and to differentiate this from hypertrophy due to various disease states, especially essential hypertension, aortic valvular disease and coarctation of the aorta. The electrocardiogram of the marathon runners was characterized by a slow cardiac rate, high voltage of the QRS complexes and T waves in the standard and/or precordial leads with normal R/T ratios. There was moderate enlargement of the heart as observed on teleoroentgenogram. These findings are characteristic of physiologic hypertrophy of the heart and should be suspected among patients having a history of athletics calling for endurance. Immediately after running, all waves showed an increased voltage and the heart size decreased. The concept of the secondary T wave in hypertension as a part of the left ventricular strain pattern was challenged by the observation that the increased voltage of the R waves in lead V5 and other leads seen in marathon runners and in certain patients with hypertension, aortic stenosis, aortic insufficiency and coarctation of the aorta were not necessarily associated with typical discordant S-T segments and T waves. There was a higher incidence of dyspnea, angina pectoris and cardiac enlargement among hypertensive patients with discordant T waves than among hypertensive patients without these changes. Thus it is felt that the discordant waves are primary and are not merely secondary to the increased area of the R waves. Primary T waves suggest myocardial disease, possibly anoxia of the subendocardium.