Dog Coronary Arteries Research Articles

ST segment elevation: the lost measure of early ischemic preconditioning in the landmark study of Murry et al. 1986

BackgroundIn their landmark study Murry et al. (Circulation 74:1124, 1986) showed dramatic ST segment elevation of the ECG during the first occlusion of a dog coronary artery. They made the insightful observation that “… in subsequent occlusions, these changes were slower to develop and frequently did not reach the magnitude seen during the first occlusion.” This electrophysiological preconditioning has been almost completely dismissed as irrelevant to ischemic preconditioning in animal models. We found in the Ossabaw miniature swine model of metabolic syndrome that brief coronary occlusion often led to ST elevation that quickly progressed to ventricular tachycardia and fibrillation.HypothesisAn AMPKγ3 mutation in Ossabaw swine will explain the extreme ST elevation and provide evidence for the relevance of ST segment ischemic preconditioning.Methods and ResultsLean mutants had impaired glucose tolerance compared to wild type Ossabaw swine. Myocardial ischemia induced by balloon occlusion of the circumflex artery elicited profound electrocardiographic ST elevation in lean mutant compared to wild type swine. Infusion of an AMPK agonist, AICAR (0.5 mM), prior to occlusion significantly reduced ST elevation in lean mutants, while completely preventing ST segment elevation in wild type. Ischemic preconditioning of the ST segment changes occurred in wild type pigs during the course of 5 occlusions, but only occurred in mutant pigs with AICAR infusion. Infusion of compound C (30 μM), an AMPK antagonist, prior to occlusion blocked the AICAR‐induced attenuation of ST elevation in lean mutants. The KATP channel agonist pinacidil increased ST elevation and the antagonist glibenclamide attenuated ST elevation during occlusion. While the degree of diet‐induced MetS (obesity, further impaired glucose tolerance, insulin resistance, and hypertension) was not different between mutant and wild type swine, except for greater plasma lipids in mutants, there was no difference in ST elevation during myocardial occlusion.ConclusionsLean Ossabaw swine with the V199l AMPK mutation have impaired glucose tolerance and exacerbated KATP channel‐mediated ST elevation during myocardial ischemia. Excess calorie diet induces MetS and abolishes cardioprotection in wild type AMPK swine. ST segment changes are an excellent measure of ischemic preconditioning in this model, thus showing the relevance of Murry’s landmark discovery.

PANDORA`S BOX OR «NO-REFLOW» PHENOMENON (CLINICAL CASE)

It has been established that successful repefusion of ocluded infarct-dependent coronary artery (IDCA) during percutaneous coronary intervention does not mean restoration of myocardial perfusion. This «no-reflow» phenomenon is known from the studies of R. Kloner, C. Ganote, R. Jennings (1974). They were among the first to note only a partial restoration of coronary blood flow after the reperfusion of mechanically occluded for 90-180 minutes coronary artery in dogs. The authors considered damage to the capillary endothelium, edema of the damaged wall and extravasal tissues, and protrusion into the capillary cavity to be the cause of this phenomenon.
 The frequency of the phenomenon of «no-reflow» after the successful restoration of coronary blood flow in the IDCA varies between 5 - 40% of all cases. The development of this phenomenon was an unfavorable prognostic factor, primarily in terms of mortality and deterioration of the functional state of the left ventricle.
 The pathophysiology of the «no-reflow» phenomenon remains poorly understood. Obviously, it has a multifactorial nature and cannot be described by any one mechanism.
 Analyzing the phenomenon of «no-reflow», it is noted that in spite of the reperfusion of IDCA, there are pronounced pathophysiological changes in the microcirculatory tract, the essence of which is to block myocardial perfusion in the area of myocardial infarction.
 During the COVID-19 pandemic, the number of patients with myocardial infarction increased, including an increase in the number of diagnosed «no-reflow» and «slow-flow» phenomena, which is associated with the impact of SARS СOVID-19 virus on the myocardium, namely the development of microvascular damage.
 There is currently no specific therapy for the prevention and treatment of «no-reflow» phenomen that would be recommended for patients with STEMI.
 This article presents a clinical case of the phenomenon of «no-reflow» in patient B., 56 years old, who complained of severe chest pain, irradiation in the left shoulder and lower jaw, shortness of breath, general weakness. History of hypertension, coronavirus PCR +. Troponin I - 5.4 ng/ml. According to the electrocardiogram: elevation of the ST segment in II. III, aVF leads. At the time of contrast infusion during stenting of infarct-dependent right coronary artery, its slow filling was recorded - the phenomenon of «no-reflow» TIMI 0, MBG-0. The patient was discharged from the hospital in satisfactory condition under the supervision of a family doctor.
 Conclusions:
 
 The phenomenon of «no-reflow» is a topical and unresolved issue of myocardial revascularization in real clinical practice.
 The most common prerequisite for the development of the phenomenon of «no-reflow» after myocardial revascularization is late hospitalization, and aggravating circumstances - comorbid pathology (COVID-19, hypertension, diabetes).
 This clinical case is interesting because the patient with lesions of the lower left ventricular wall PCI was complicated by the phenomenon of «no-reflow», as evidenced by the slowing of ST segment resolution, lack of myocardial perfusion, parietal thrombosis throughout the RCA.
 Further search for ways to prevent and treat irreversible blood flow syndrome after successful reperfusion of infarct-dependent coronary artery is needed.

Evaluation of non-ECG and ECG-gated computed tomographic angiography for three-dimensional printing of anomalous coronary arteries in dogs with pulmonic stenosis

Introduction/objectivesCoronary artery abnormalities are described sporadically in dogs, most commonly with pulmonic stenosis. Computed tomographic angiography (CTA) allows non-invasive assessment of coronary anatomy. Three-dimensional (3D) models improve the understanding and visualization of spatially complex anatomy. The study objective was to evaluate coronary artery anomalies using CTA imaging and using rapid prototyping technology to create life-sized coronary artery models of these studies. Animals, material and methodsCombined retrospective case and prospective pilot study. Inclusion criteria were dogs with reported coronary artery anomalies. The CTA data sets were imported into a medical imaging framework for the analysis of the coronary arteries and into a 3D-planning and printing software for creating printable 3D models. The 3D models were printed using fusion deposition modeling technology. ResultsSix male dogs with an R2A coronary artery anomaly and pulmonic stenosis diagnosed by CTA were included. Electrocardiogram (ECG)-gated CTA allowed better identification of anomalous coronary arteries than non-gated CTA. In all dogs, the right coronary artery had a smaller diameter than the left and the left coronary artery or its branch had a prepulmonic course. All ECG-gated studies were 3D printed while non-gated studies were not printable due to CTA artifacts. ConclusionIn dogs, CTA is effective for diagnosis of coronary artery anomalies. Printed 3D models of ECG-gated CTA studies were of excellent quality and allowed direct visualization of abnormal coronary artery anatomy. The usefulness of these models to improve the understanding of anomalous coronary artery anatomy could be evaluated in future studies.

Histological and ultrastructural studies on the coronary artery of adult domestic dog (Canis familiaris).

The objective of this work was to study the histological structure of the dog's coronary artery by light and transmission electron microscope (TEM). The coronary artery consisted of three tunics: tunica intima, tunica media and tunica adventitia. The tunica intima consisted of endothelium rested directly on internal elastic lamina without the subendothelial connective tissue layer. The tunica media were composed of smooth muscle fibres interspersed with few elastic and collagen fibres. The tunica adventitia consisted of collagen and elastic fibres intermingled with fibroblast cells; it had vasa vasorum and nervi vasorum. Some histomorphometric measurements were performed and compared statistically. The ultrastructural study showed that the endothelial cells were communicated through complex junctions and characterised by filiform cytoplasmic processes passed through the opening of the underlying internal elastic membrane. The smooth muscle fibres of tunica media communicated with each other through cytoplasmic processes. The tunica adventitia showed minute non-myelinated nerve. This work revealed that the dog's coronary arteries are typical muscular arteries, which show little structural variations from that of other mammals.

Assessment of Left Atrial Work During Acute Coronary Occlusion

Left atrial (LA) work can be measured through speckle tracking echocardiography by calculating LA pressure–strain loop area, which includes two distinct phases of active contraction/relaxation (A-work) and passive dilation/emptying (V-work). Echocardiographic and hemodynamic data were acquired at baseline and during occlusions of left anterior descending (LAD: n = 7) and left circumflex (LCx: n = 9) coronary arteries in dogs. Left ventricular (LV) circumferential strain was decreased and mean LA pressure was increased in both occlusions. Doppler-derived stroke volume was maintained during LAD occlusion, but it decreased during LCx occlusion. A-work increased during LAD occlusion, but it did not change during LCx occlusion. V-work decreased during LCx occlusion more than during LAD occlusion. The compensatory mechanism of LA function was limited during LCx occlusion, but this occurred during LAD occlusion. This study provided insight into a role of LA function in variable hemodynamic consequences in acute myocardial infarction.

Entrando no Ano do Jubileu da ANAMT

Entrando no Ano do Jubileu da ANAMT

Hydrogen sulphide induces vasoconstriction of rat coronary artery via activation of Ca(2+) influx.

Hydrogen sulphide (H2S) exhibits a dual modulation of isolated artery tension. This study investigated the vasoconstrictive effect of sulphur sodium hydride (NaHS), a donor of gaseous H2S, on rat coronary artery. The contractile response of isolated arteries was recorded using a wire myograph. Fluo-3/AM was used to load vascular smooth muscle, and intracellular calcium was determined using confocal laser microscopy. The protein expression of Rho kinase was examined using Western blot. NaHS induced concentration-dependent contractions of rat coronary artery, and the contraction reached approx. 65% of 60 mm KCl-induced contraction. The NaHS-induced contraction was elevated following the removal of endothelium or the use of the nitric oxide synthase inhibitor L-NAME. The cyclooxygenase inhibitor indomethacin reduced NaHS-induced contraction. The Rho kinase inhibitor Y-27632 significantly attenuated NaHS-induced vasoconstriction. Furthermore, NaHS elevated the protein expression of Rho kinase. NaHS-induced contraction was completely abolished in a Ca(2+)-free solution and suppressed by the Ca(2+) influx blocker nifedipine (100 nm). NaHS also significantly increased the change rate of Ca(2+) fluorescence intensity. However, treatment with a Cl(-)/HCO(3-) exchanger blocker, K(+) channel blockers, the mitogen-activated protein kinase inhibitor U-0126 or cyclic adenosine monophosphate did not affect contraction. Species-dependent differences in NaHS-induced vasoconstriction were observed because these effects were only modest in dog coronary artery and absent in rabbit coronary artery. NaHS induces the contraction of rat coronary artery, which is dependent on the activation of Ca(2+) influx. Rho kinase likely participates in the vasoconstriction.

Comparative on acute myocardial infarction models in Beagle dogs and mongrel dogs

To compare the acute myocardial infarction models in Beagle dogs and mongrel dogs, and study whether the Beagle dog model is sensitive to drug intervention. The acute myocardial infarction model of dog was set up through ligation of anterior descending branch of coronary artery in dogs, in order to observe morphological changes of the heart and determine artery length and heart coefficient of exposed anterior descending branch of coronary artery. The epicardium electrocardiogram (sigmaST, N-ST) was used to measure the degree of myocardial ischemia. The quantitative histological assay (nitroblue tetrazolium, N-BT stain) was adopted to determine the area of myocardial infarction. There was no significant difference between Beagle dogs and mongrel dogs in terms of sigmaST, N-ST and ischemia area. The diltiazem group of Beagle dogs showed obvious reduction in the ischemia area (P < 0.05 and P < 0.01), with notable decline in sigmaST and N-ST, however, it had no statistical difference compared with the Beagle dog model group. Beagle dogs had clear coronary branches, longer exposed arteries and less difference in organ coefficient, which were suitable for the preparation of the myocardial infarction model, whereas mongrel dogs had irregular coronary branches and exposed arteries, with greater individual difference. Beagle dogs are superior to mongrel dogs in the preparation of the acute myocardial infarction model, which is sensitive to for drug intervention.

Anatomical Indicators of Dominance between the Coronary Arteries of Dogs

En los corazones humanos la dominancia coronaria es derecha. Sin embargo, no encontramos referencias en la literatura sobre los indicadores de esta dominancia en perros. Utilizamos 30 corazones de perros de ambos sexos y raza mixta, fijados en formaldeido al 10%. Las ramas de las arterias coronarias fueron disecadas con especial atencion a los niveles considerados como referencias. En 96,7% de los corazones, la rama circunfleja de la arteria coronaria izquierda excedio o llego a la crux cordis. La arteria interventricular subsinuosa, termino antes de llegar al apice en 21 casos, en el apice en 5 casos y despues del apice en 4 casos. La arteria interventricular paraconal, termino antes de llegar al apice en 2 casos, en el apice en 11 casos y despues del apice en 17 casos. La region del apice del corazon estaba irrigada por ramas de la arteria coronaria izquierda a traves de la rama interventricular paraconal o a traves de los dos ramas interventriculares. La longitud media y el numero de ramas ventriculares de la arteria coronaria izquierda son mas grandes que las ramas de la arteria coronaria derecha. La rama interventricular subsinuosa es una rama de la rama circunfleja de la arteria coronaria izquierda. En los corazones de los perros, sin embargo, la dominancia es izquierda. La norma de dominancia en los perros es diferente de la norma de dominancia en humanos encontrada en la literatura.

Myocardial ischemia: Some historical notes

This brief historical review alludes to some early work of clinical and experimental myocardial ischemia, illustrated with facsimiles and passages quoted from the original publications. Briefly, the first experimental ligation of a coronary artery in dog was performed some 300 yr ago by Petri Chirac (1698). The systematic experimental study on the influence of interrupting coronary circulation may be said to have begun with Erichsen (1841), followed by the work of Panum (1862), who embolized the coronary arteries of a young dog with a mixture of tallow, wax, oil and lamp black. Bezold and Boyemann (1862) were the first to produce ventricular fibrillation by clamping a rabbit's left coronary artery (“coronaria magna”). Samuelson (1881) demonstrated the first “successful reperfusion” after a 4-min ligation of a coronary artery. Conheim and von Schulthess-Rechenberg (1881) introduced the first experimental model in order to produce “ischaemia-induced arrhythmias.” Clinically, the termangina pectoris was first used by Rougnon (1801) and again by Heberden (1816). The first description of atherosclerotic changes (“ossifications”) in the coronary arteries was reported by Morgagni (1761). Jenner and Perry (1801) associated angina pectoris, the new disease described by Rougnon, with the atherosclerotic changes described by Morgagni. Jenner had already diagnosed the condition in his friend John Hunter (1794). The first coronary occlusion correctly diagnosed at bedside and confirmed by autopsy was communicated by Hammer in Vienna (1878).

Effects of Lüfukang Capsules ( ) on Coronary Artery Ligation-Induced Arrhythmia in Dogs

To observe the effects of Lüfukang Capsules on arrhythmia induced by ligation of coronary artery in dogs. Thirty dogs were randomly divided into 5 groups, the model group administrated with equal volume of distilled water, the positive control group administrated with Wenxin Granules, and the small, medium and large dosage LFKC groups, 6 dogs in each group. Thirty minutes after medication, electrocardiogram was conducted and the time of arrhythmia occurrence, times of ventricular premature beat (VP), and incidence rates of ventricular tachycardia (VT) and ventricular fibrillation (VF) were recorded in the model dogs with arrhythmia induced by ligation of coronary artery. Compared with the model group, the occurrence time of arrhythmia induced by the coronary artery ligation in the medium and large LFKC groups was significantly delayed (20.45 +/- 9.10 and 19.92 +/- 3.78, respectively, both P < 0.05). The frequency of VP in the medium and large LFKC groups was also significantly decreased (8.17 +/- 6.62 and 3.83 +/- 2.79, respectively, both P < 0.01). LFKC has anti-arrhythmic effects for the experimental arrhythmia induced by the ligation of coronary artery in dogs.

Protective effect of Xinning tablet on acute myocardial ischemia in anesthesia dogs

Abstract This work aimed to observe the protective effect of Xinning tablets on experimental myocardial ischemia. The canine model of acute myocardial infarction was established by ligating the anterior descending coronary artery of dogs. The ultrasound Doppler method was adopted to determine myocardial blood flow. Heart membrane electrical diagram coup and nitro blue tetrazolium (N-BT) staining were used to calculate the extent of myocardial ischemia and myocardial infarct size. Radioimmunoassay was used to determine plasma ET, TXB 2 and 6-Keto-PGF 1α levels. 30-180 min after administration of Xinning tablets at 1.2 and 0.6 g/kg, the dog myocardial ischemia icon measured from the epicardial electrogram was significantly reduced; the infarct area was decreased according to NBT staining. 30-120 min after the administration, cardiac blood flow was significantly increased in the myocardial ischemia area, the levels of plasma ET and TXB 2 were greatly inhibited, and the 6-Keto-PGF1α content to TXB 2 /6-Keto-PGF1α ratio was increased. Taken together, Xinning tablets have significant protective effect on dog acute myocardial ischemia and myocardial infarction, the mechanism of which may be related to ET inhibition, TXA 2 release and increased myocardial blood flow, consequently improving the impaired heart function.

Thromboxane A2 receptor antagonism in man and rat by a sulphonylcyanoguanidine (BM-144) and a sulphonylurea (BM-500).

Torasemide, a loop diuretic, has been reported to relax dog coronary artery precontracted by thromboxane A2 (TXA2), an endogenous prostanoid involved in cardiovascular and pulmonary diseases. N-cyano-N'-[[4-(3'-methylphenylamino)pyrid-3-yl]sulphonyl] homopiperidinoamidine (BM-144) and N-isopropyl-N'-[5-nitro-2-(3'-methylphenylamino)-benzenesulphon yl]urea (BM-500), chemically related to torasemide, have been examined for their TXA2 antagonism. The affinity (IC50, the concentration resulting in 50% inhibition) of BM-144 and BM-500 for the TXA2 receptor of washed platelets from man was 0.28 and 0.079 microM, respectively. This is better than for sulotroban (IC50 = 0.93 microM) but less than for SQ-29548 (IC50 = 0.021 microM), two TXA2 antagonists used as reference. The aggregation of platelets from man induced by arachidonic acid was prevented by BM-144 (IC50 = 9.0 microM) and by BM-500 (IC50 = 14.2 microM). Similar results were obtained by use of U-46619, a TXA agonist, as aggregating agent (BM-144, IC50 = 12.9 microM and BM-500, IC50 = 9.9 microM). The contracting effect of U-46619 on rat stomach strip was abolished by BM-144 (IC50 = 1.01 microM) and BM-500 (IC50 = 2.54 microM). Both drugs (BM-144: IC50 = 0.12 microM and BM-500: IC50 = 0.19 microM) also relaxed rat aorta precontracted by U-46619; both were more potent than sulotroban (IC50 = 1.62 microM). The two torasemide derivatives (100 microM) did not significantly affect the myo-stimulating effect of some prostaglandins (PGE2, PGI2, PGF2alpha) or aorta contraction elicited by KCl (30 mM). They did not modify rat diuresis after administration of a 30-mg kg(-1) dose. In conclusion, BM-144 and BM-500 can be regarded as novel non-carboxylic TXA2 receptor antagonists and offer a novel template for the design of more potent molecules.

Abstract 1891: Human Vascular Progenitor Cells Form Conductive Coronary Artery in Dogs with Critical Coronary Artery Stenosis

To determine whether the human heart possesses a coronary vascular progenitor cell (VPC) that regulates the growth of endothelial cells (ECs), smooth muscle cells (SMCs), and vasculogenesis, we have identified vascular niches composed of c-kit-positive KDR-positive VPCs within the coronary circulation. VPCs are connected by functional gap junctions to ECs, SMCs and fibroblasts which operate as supporting cells. Isolated VPCs were self-renewing and clonogenic and differentiated into ECs and SMCs. Subsequently, we tested whether human VPCs possess the ability to create conductive coronary arteries in immunosuppressed dogs with critical coronary stenosis. The presence of a critical stenosis was documented by the absence of reactive hyperemia after the release of a 15 sec occlusion of the LAD. VPCs infected with a lentiviral vector carrying EGFP were then injected above, laterally and below the site of constriction. At 10 days, the lack of reactive hyperemia persisted while at 30 days there was a slow return of CBF possibly mediated by the formation of coronary vessels. Thus, myocardial perfusion was determined; gold-labeled microspheres were injected with the LAD open to establish baseline CBF while lutetium-labeled microspheres were administered after LAD occlusion. Multiple sections from the region proximal to the region distal to the occlusion were processed to evaluate CBF distribution. Every other section was collected for histology. CBF at baseline was similar in all sections but after LAD occlusion there was a doubling in CBF in the fully dilated coronary circulation distal to the stenotic vessel. Histologically, new coronary arteries, 0.8–1.5 mm in diameter, were detected in proximity of the stenotic vessel together with resistance arterioles and capillaries, pointing to vessel regeneration as the mechanism of enhanced CBF in the ischemic myocardium. ECs and SMCs within the vessel wall were all EGFP-positive; the human origin of these cells was confirmed by the detection of human DNA sequences with an Alu probe. In conclusion, the human heart possesses a coronary VPC that can be isolated and expanded in vitro for subsequent autologous transplantation in patients with coronary artery disease and the formation of a biological bypass.

Field stimulation-induced tetrodotoxin-resistant vasorelaxation is mediated by sodium hypochlorite

This study was done to determine the mechanism of field stimulation-induced tetrodotoxin (TTX)- and NG- nitro-l-arginine (LNA)-resistant vasorelaxation. Field stimulation with platinum and carbon, but not with silver, electrodes (30 V, 30 HZ, 2-5 ms pulse width) as well as electrically stimulated salt (0.9% NaCl) solution (ESSS) or Krebs solution caused 100% relaxation of phenylephrine-contracted rat aortic strips, which was TTX and LNA resistant and endothelium independent. ESSS also relaxed other vascular preparations (rabbit aorta and renal artery, dog coronary artery, pig ductus arteriosus, and rat portal vein). The electric current generated hypochlorite (OCl-) and H2O2 from the salt solution; however, vasorelaxation was caused by NaOCl and not by H2O2. ESSS and NaOCl caused contraction failure of spontaneously beating right atria of rats and did not affect uterine contractions, vascular cAMP, cGMP, or the pH of the tissue bath. Field stimulation, ESSS, and NaOCl did not relax aortic preparations contracted by 32 mmol/L potassium and their vasorelaxant effects on phenylephrine-contracted rat aortic strips and rings were completely reversed by tetraethylammonium and partially by glibenclamide and iberiotoxin. We conclude that electric pulses generate the oxidant OCl- from the salt solution, which causes vasorelaxation by increasing K+ conductance.

Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs

We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI). Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs). We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) group], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent ligation of the coronary artery in dogs. Control animals received saline immediately after the ligation. The infarct size 6 h after MI was significantly smaller in the EPO(0) group than in the control group (61.5 +/- 6.0% vs. 22.9 +/- 2.2%). One week after MI, the circulating CD34-positive mononuclear cell numbers in both the EPO(0) and the EPO(6h) groups were significantly higher than in the control group. In the ischemic region, the capillary density and myocardial blood flow 4 weeks after MI was significantly higher in both the EPO(0) and the EPO(6h) groups than in the control group. Four weeks after MI, left ventricular (LV) ejection fraction in the EPO(6h) (48.6 +/- 1.9%) group was significantly higher than that in either the control (41.9 +/- 0.9%) or the EPO(1wk) (42.6 +/- 1.2%) group but significantly lower than that in the EPO(0) group (56.1 +/- 2.3%). The LV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) groups was significantly lower than either the control or the EPO(1wk) group. Hematologic parameters did not differ among the groups. In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations.

Effect of Levosimendan and Milrinone on Regional Myocardial Ischemia/Reperfusion-Induced Arrhythmias in Dogs

Phosphodiesterase inhibitors as inodilators in heart failure are associated with promotion of arrhythmias. Calcium sensitizers have been proposed for the treatment of severe decompensated heart failure. The effect of levosimendan, a calcium sensitizer, and milrinone, a phosphodiesterase inhibitor, on ventricular arrhythmias was compared in a model of acute regional myocardial ischemia and reperfusion. The left anterior descending coronary artery in dogs was occluded for 25 minutes, followed by reperfusion. The 2 drugs were administered in a hemodynamically equieffective dose (0.1 micromol/kg) 10 minutes before coronary occlusion. Levosimendan, but not milrinone, significantly attenuated the pronounced increase in the number of ventricular premature beats (-63%), tachycardia (-50%), fibrillation (-70%), and inhomogeneity of ventricular electrical activation. Levosimendan significantly improved the overall survival rate. Levosimendan has a more beneficial profile than milrinone regarding the development of ventricular arrhythmias during and after regional myocardial ischemia.

Bradycardia Stimulates Vascular Growth During Gradual Coronary Occlusion

In cultured endothelium, stretch induces release of growth factors that contribute to angiogenesis. We tested the hypothesis that bradycardia, which prolongs ventricular diastolic filling time and volume, promotes collateral vessel growth. An ameroid occluder was placed on coronary arteries of dogs with normal heart rates (AM) or bradycardia (55 bpm; AM+BC). A third group had normal heart rates and no ameroid (control [CON]). Four weeks after occluder placement, myocardial blood flow at rest and maximal vasodilation (adenosine) at equivalent heart rates and vascular morphometry of hearts were measured. In AM dogs, conductance (myocardial flow/diastolic pressure) of collateral-dependent myocardium was similar to collateral-independent myocardium during rest but increased to only one third of CON during maximal vasodilation. In contrast, in AM+BC dogs, conductance was similar in collateral-dependent and -independent regions during maximal vasodilation. Arteriolar length density in collateral-dependent myocardium was 80% greater in AM+BC than AM dogs. Capillary length density in collateral-dependent region of AM dogs was lower than CON but normal in AM+BC dogs. The angiopoietin receptor Tie-2 increased in collateral-dependent regions of AM and AM+BC groups, whereas vascular endothelial growth factor increased in collateral-dependent and -independent regions only in AM+BC dogs. Chronic bradycardia during gradual coronary artery occlusion facilitates angiogenesis/arteriogenesis in collateral-dependent myocardium and preserves maximal perfusion.

Echocardiography as a Noninvasive Swan-Ganz Catheter

Diwan and co-investigators report in this issue of Circulation that the interval between onset of mitral E and annular early diastolic velocity (Ea) by tissue Doppler, TE−Ea, can be used to estimate left ventricular (LV) filling pressure in patients with mitral valve disease.1 Garcia and colleagues were the first to report that the onset of Ea occurred 7.5±3.5 ms after peak mitral inflow velocity in 7 patients with restrictive cardiomyopathy, whereas Ea started 22±19 ms earlier than did E in the normal group.2 Subsequently, TE−Ea has been shown to correlate with the time constant of LV relaxation (τ) demonstrated by Hasegawa and associates in their elegant animal experiment.3 With worsening of heart failure by rapid pacing, Ea progressively decreased in velocity and delayed in onset. Mitral E occurred coincidently with the termination of the early diastolic left arterial (LA) and LV pressure gradient at baseline and all stages of heart failure. In contrast, with increasing heart failure, Ea was progressively delayed after LA to LV pressure crossover, and TE−Ea was related to τ. Rivas-Gotz, Nagueh, and their associates also demonstrated that TE−Ea was prolonged after constriction of the circumflex coronary artery in dogs.4 In patients with heart failure, LV myocardial relaxation and compliance are decreased. See p 3281 Although LV filling is initiated and enhanced by augmentable myocardial relaxation in healthy individuals, it is driven by high filling pressure in patients with heart failure because myocardial relaxation remains reduced, not being sensitive to preload. Myocardial relaxation also affects the isovolumic relaxation time (IVRT). As relaxation becomes abnormal, LV pressure falls more slowly and the opening of the mitral valve is delayed, resulting in a longer IVRT. IVRT, however, becomes shorter as LA pressure increases; hence, IVRT∝τ/LA pressure. Because TE−Ea∝τ, …

Current status and future directions for diagnostic markers of drug-induced vascular injury

Recently, there has been an increased incidence of vascular toxicity in pre-clinical toxicology studies. This is of concern because of the uncertain relevance and extrapolation of this finding to humans. In dogs, profound heart rate (HR) and mean arterial pressure (MAP) changes were considered surrogate markers for drug-induced vascular injury until the early 1990s when endothelin receptor antagonists (ETRA) did not significantly alter HR or MAP but induced identical lesions in the coronary arteries of dogs. Thus significant alterations in HR and MAP were found not to be a prerequisite for this lesion. Clinically, the potential for vascular injury coupled with the lack of an unequivocal non-invasive diagnostic marker is an issue of concern to pharmaceutical companies and the regulatory authorities. Therefore, qualification and validation of biomarkers as diagnostic tools for drug-induced vascular injury would add great value to risk management and expedite the drug development process. This review focuses on the status, progress and future trends in vascular biology aimed at identification and development of diagnostic markers that are specific, sensitive and possess potential utility in both a pre-clinical and clinical setting.