Intramyocardial Arteries Research Articles

Cardiac Adaptation to Severe Congenital Diaphragmatic Hernia

ABSTRACTObjective Prenatal heart adaptations to congenital diaphragmatic hernia (CDH) could help define postnatal outcome. Methods We retrospectively analyzed post-mortem tissues from fetuses with severe CDH (n = 7). Histology and immunohistochemical distribution of desmin, muscle actin [HHF35], endothelin-1 [ET-1] and TGF-β were evaluated. Results In the atrium, desmin, HHF35, ET-1, TGF-β were found expressed only in preterm CDH. Dishomogeneous ventricular distribution of cardiac growth factors were detected in term CDH. The cardiomyocyte nucleus/cytoplasmatic ratio in CDH was higher compared with controls (p = 0.01). Small intramyocardial artery density and vascular wall thickness was increased in CDH compared with controls (p = 0.03 and p < 0.01). In comparison with the ventricles, the interventricular septum showed a greater vessel density (p = 0.01) and a greater vascular wall thickness, particularly compared with the CDH right ventricle (p = 0.02). Conclusion Left ventricle immaturity seems to be a cardiac adaptive response of severe CDH in utero.

Myocarditis in patients with subarachnoid hemorrhage: A histopathologic study

Cardiac abnormalities after subarachnoid hemorrhage (SAH) such as electrocardiographic changes, echocardiographic wall motion abnormalities, and elevated troponin levels are independently associated with a poor prognosis. They are caused by catecholaminergic stress coinciding with influx of inflammatory cells into the heart. These abnormalities could be a sign of a myocarditis, potentially giving insight in pathophysiology and treatment options. These inflammatory cells are insufficiently characterized, and it is unknown whether myocarditis is associated with SAH. Myocardium of 25 patients who died of SAH and 18 controls was stained with antibodies identifying macrophages (CD68), lymphocytes (CD45), and neutrophil granulocytes (myeloperoxidase). Myocytolysis was visualized using complement staining (C3d). CD31 was used to identify putative thrombi. We used Mann-Whitney U testing for analysis.In the myocardium of SAH patients, the amount of myeloperoxidase-positive (P < .005), CD45-positive (P < .0005), and CD68-positive (P < .0005) cells was significantly higher compared to controls. Thrombi in intramyocardial arteries were found in 22 SAH patients and 1 control. Myocytolysis was found in 6 SAH patients but not in controls.Myocarditis, consisting of an influx of neutrophil granulocytes, lymphocytes, and macrophages, coinciding with myocytolysis and thrombi in intramyocardial arteries, occurs in patients with SAH but not in controls. These findings might explain the cardiac abnormalities after SAH and may have implications for treatment.

Young Investigator Award session – Basic Science3433D printed models for surgical planning in complex congenital heart disease344Ultrafast doppler imaging of intramyocardial coronary arteries345Quantification of mitral regurgitation with multiple jets: in vitro comparison of two-dimensional PISA techniques346Non-invasive ultrasonic chordal cutting

Young Investigator Award session – Basic Science3433D printed models for surgical planning in complex congenital heart disease344Ultrafast doppler imaging of intramyocardial coronary arteries345Quantification of mitral regurgitation with multiple jets: in vitro comparison of two-dimensional PISA techniques346Non-invasive ultrasonic chordal cutting

Abstract 18108: Extreme Physical Activity Reverses Beneficial Vascular Effects of Moderate Physical Activity. Study in an Animal Model

Introduction: Moderate aerobic exercise reduces atherosclerotic burden. However, recent data show increased cardiovascular disease burden and mortality in the most trained individuals. Aim: To assess vascular remodeling after very high intensity training. Methods: Wistar rats underwent very high (INT, 60min 60cm/s, n=20) or moderate intensity (MOD, 45min 35cm/s, n=20) treadmill training for 16 weeks. Sedentary rats (SED n=20) served as controls. Morphologic analyses were performed in descending thoracic aorta and intramyocardial arteries. Aortic wall oxidative stress was quantified with dihydroethidium (DHE). In vivo functional remodeling was assessed in a hemodynamic study. Ex vivo vascular reactivity to acetilcholine (Ach), phenylephrine (Phe) and KCl was studied in intact- and denuded-endothelium conditions. Results: INT promoted increased aorta wall thickness, elastin fiber disorganization and disruptions in tunica media compared to MOD and SED. Lumen of intramyocardial arteries was narrower and tunica media was thicker in INT rats (Fig A). An in vivo hemodynamic study showed a higher pulse pressure in the INT group (Fig B), suggesting a stiffer aorta. MOD exercise improved ex vivo endothelial function by increasing Ach-mediated vasodilatation and reducing Phe vasoconstriction response; INT exercise did not provide further benefits (Fig C). Conversely, Phe response was increased in endothelium deanuded aorta of the INT group (Fig D); increased response to KCl in the INT group confirmed tunica media hypereactivity. DHE staining was increased in the tunica media of the INT group. Conclusions: While moderate exercise improves vascular function, high intensity exercise blunts it by increasing vascular wall thickness and stiffness, and by inducing tunica media hipereactivity. Oxidative stress likely mediates these effects. Our findings provide important insights into increased atherosclerotic burden in very high trained individuals.

Surgical Management of Intramyocardial Left Anterior Descending Artery.

An intramyocardial left anterior descending artery can be found in up to 30% of patients undergoing coronary artery bypass graft procedures. We review the various techniques available to identify an intramyocardial left anterior descending artery.

Extending Flaps Lifts an Infarcted Heart Toward Repair

Normal hearts comprise 2 × 109 myocytes, but this number may be doubled in excessively hypertrophied hearts. After a heart attack caused by blockage of one of the arteries that supply the heart, approximately 20% or more of cardiomyocytes are acutely and irreversibly lost in the ischemic area. However, the damage is not limited to the acute interruption of blood flow. Reperfusion of the ischemic territory can cause additional damage due to a burst of toxic reactive oxygen species. Moreover, additional cardiomyocytes are lost in the peri-infarct area during the subacute phase, leading to extension of the infarcted area. The ensuing remodeling response, which consists of cardiomyocyte hypertrophy and collagen accumulation, is insufficient to compensate for the massive cell loss, thus leading to scar expansion, ventricular chamber dilation, and failure.

Angiotensin Ⅱ Activates MCP-1 and Induces Cardiac Hypertrophy and Dysfunction via Toll-like Receptor 4.

Angiotensin Ⅱ(Ang Ⅱ) produces reactive oxygen species (ROS), thus contributing to the development of cardiac hypertrophy and subsequent heart failure, and stimulates the expression of monocyte chemoattractant protein-1 (MCP-1). In addition, Toll-like receptor 4 (TLR4) is involved in the upregulation of MCP-1. In order to clarify whether TLR4 is involved in the onset of cardiac dysfunction caused by Ang Ⅱ stimulation, we investigated the effects of TLR4 on oxidative stress, the MCP-1 expression and cardiac dysfunction in mice with Ang Ⅱ-induced hypertension. TLR4-deficient (Tlr4(lps-d)) and wild-type (WT) mice were randomized into groups treated with Ang Ⅱ, norepinephrine (NE) or a subdepressor dose of the Ang Ⅱreceptor blocker irbesartan (IRB) and Ang Ⅱ for two weeks. Ang Ⅱ and NE similarly increased systolic blood pressure in all drug-treated groups compared to that observed in the control group among both WT and Tlr4(lps-d) mice (p＜0.05). In the WT mice, Ang Ⅱ induced cardiac hypertrophy as well as vascular remodeling and perivascular fibrosis of the intramyocardial arteries and monocyte/macrophage infiltration in the heart (p＜0.05). Furthermore, Ang Ⅱ treatment decreased the left ventricular diastolic function and resulted in a greater left ventricular end-systolic dimension (p＜0.05) in addition to producing a five-fold increase in the NADPH oxidase activity, ROS content and MCP-1 expression (p＜0.05). In contrast, the Tlr4(lps-d) mice showed little effects of Ang Ⅱ on these indices. In the WT mice, IRB treatment reversed these changes compared to that seen in the mice treated with Ang Ⅱ alone. NE produced little effect on any of the indices in either the WT or Tlr4(lps-d) mice. TLR4 may be involved in the processes underlying the increased oxidative stress, selectively activated MCP-1 expression and cardiac hypertrophy and dysfunction seen in cases of Ang Ⅱ- induced hypertension.

BAF200 is required for heart morphogenesis and coronary artery development.

ATP-dependent SWI/SNF chromatin remodeling complexes utilize ATP hydrolysis to non-covalently change nucleosome-DNA interactions and are essential in stem cell development, organogenesis, and tumorigenesis. Biochemical studies show that SWI/SNF in mammalian cells can be divided into two subcomplexes BAF and PBAF based on the subunit composition. ARID2 or BAF200 has been defined as an intrinsic subunit of PBAF complex. However, the function of BAF200 in vivo is not clear. To dissect the possible role of BAF200 in regulating embryogenesis and organ development, we generated BAF200 mutant mice and found they were embryonic lethal. BAF200 mutant embryos exhibited multiple cardiac defects including thin myocardium, ventricular septum defect, common atrioventricular valve, and double outlet right ventricle around E14.5. Moreover, we also detected reduced intramyocardial coronary arteries in BAF200 mutants, suggesting that BAF200 is required for proper migration and differentiation of subepicardial venous cells into arterial endothelial cells. Our work revealed that PBAF complex plays a critical role in heart morphogenesis and coronary artery angiogenesis.

Abstract 347: Comparative Study of Cardiovascular Morphology in Hypertensive, Insulin Resistant and Middle-aged Rats

The objective of this study was to compare the effect of insulin resistance, hypertension and aging on cardiac fibrosis and intramyocardial arteries (IMA). Twenty eight male rats were divided into four groups: control (CON), insulin resistance induced by monosodium glutamate (MSG) administered in neonatal period, spontaneously hypertensive rats (SHR), middle-aged rats (MAR). The first three groups were 22 weeks-old and the older group was 30 weeks-old. The heart was fixed and stained with picro Sirius red to evaluate myocardial collagen density. The lumen diameter, media thickness and media cross- sectional area (CSA) of the IMA were measured with the Image Pro Plus image analysis software. The Lee index was slightly increased in MSG group. The systolic blood pressure was significantly elevated in SHR group (CON 113±2, MSG 122±3, SHR 202±3, MAR 115±3 mmHg). The diameter of the IMA was significantly smaller in SHR (29.8±2.4 μm, p&lt;0.01) vs MAR (35.3±2.2 μm), CON (34.0±2.3 μm) and MSG (34.7±2.4 μm). The media-to-lumen ratio was 29.5 ± 1.2% in CON, 39.8 ± 1.3% in MSG, 30.3 ± 0.6% in MAR and 46.5 ± 4.0% in SHR (P&lt;0.001 vs CON/ MAR, P&lt;0.01 vs MSG). The CSA of IMA was significantly increased in SHR and MSG compared to CON showing growing index of 38.5 and 33.0%, respectively. Interstitial subendocardial collagen density of the left ventricle was 2.8±.0.3% in CON, 3.1±.0.7% in SHR, 2.6±0.6 in MAR and 4.0±.0.8% in MSG (P&lt;0.05 vs SRH, P&lt;0.01 vs CON and MAR).The perivascular collagen density was greater in MSG group (48.4±.2.3%, p&lt;0.001 vs other groups) but was also significantly increased in SHR (42.6±.2.3%) and MAR (36.4±1.4 %) groups compared to CON (29.8±.3.0%, p&lt;0.01). In conclusion, hypertrophic vascular remodeling was more associated to hypertension while cardiac fibrosis was more observed when insulin resistance and obesity were present. There were no significant cardiovascular changes in older animals without hypertension and insulin resistance.

Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart.

The origin and developmental mechanisms underlying coronary vessels are not fully elucidated. Here we show that myocardium-derived angiopoietin-1 (Ang1) is essential for coronary vein formation in the developing heart. Cardiomyocyte-specific Ang1 deletion results in defective formation of the subepicardial coronary veins, but had no significant effect on the formation of intramyocardial coronary arteries. The endothelial cells (ECs) of the sinus venosus (SV) are heterogeneous population, composed of APJ-positive and APJ-negative ECs. Among these, the APJ-negative ECs migrate from the SV into the atrial and ventricular myocardium in Ang1-dependent manner. In addition, Ang1 may positively regulate venous differentiation of the subepicardial APJ-negative ECs in the heart. Consistently, in vitro experiments show that Ang1 indeed promotes venous differentiation of the immature ECs. Collectively, our results indicate that myocardial Ang1 positively regulates coronary vein formation presumably by promoting the proliferation, migration and differentiation of immature ECs derived from the SV.

Intramyocardial Left Anterior Descending Artery as Cause of Myocardial Ischemia

Intramyocardial Left Anterior Descending Artery as Cause of Myocardial Ischemia

Tmem time: Memory T-Cells in Cardiac Allograft Vasculopathy

Heart transplantation has been extremely successful as a field, but continues to be plagued by a small number of severe complications. Among these, one of the most frustrating may be cardiac allograft vasculopathy (CAV), a concentric non-atherosclerotic intimal thickening leading to narrowing of the cardiac arterial vasculature and progressive ischemia in allografts [1]. A similar phenomenon is seen in all transplanted organs, and seems to be an immunologically mediated event, despite limited to no response to current immunosuppressive therapies. This CAV phenomenon is one of the most limiting factors in the survival of an individual with a cardiac allograft, and is a common cause of ischemic disease leading to graft failure and retransplantation or death. CAV can involve epicardial coronary arteries, thus clinically mimicking atherosclerotic disease, as well as intramyocardial arteries of any size. Coronary angiography performed on transplant patients is effective at monitoring the epicardial disease, and biopsy features may suggest ischemic damage, but there are no good tools yet for formally monitoring the small vessel narrowing (although surrogate measures of perfusion do exist) [2,3]. Likewise, while stents and bypass are available on a selected basis for the epicardial vessels, no such therapies exist for the small vessel pathology [4–6].

Coronary microvasculopathy in heart transplantation: Consequences and therapeutic implications.

Despite the progress made in the prevention and treatment of rejection of the transplanted heart, cardiac allograft vasculopathy (CAV) remains the main cause of death in late survival transplanted patients. CAV consists of a progressive diffuse intimal hyperplasia and the proliferation of vascular smooth muscle cells, ending in wall thickening of epicardial vessels, intramyocardial arteries (50-20 μm), arterioles (20-10 μm), and capillaries (< 10 μm). The etiology of CAV remains unclear; both immunologic and non-immunologic mechanisms contribute to endothelial damage with a sustained inflammatory response. The immunological factors involved are Human Leukocyte Antigen compatibility between donor and recipient, alloreactive T cells and the humoral immune system. The non-immunological factors are older donor age, ischemia-reperfusion time, hyperlipidemia and CMV infections. Diagnostic techniques that are able to assess microvascular function are lacking. Intravascular ultrasound and fractional flow reserve, when performed during coronary angiography, are able to detect epicardial coronary artery disease but are not sensitive enough to assess microvascular changes. Some authors have proposed an index of microcirculatory resistance during maximal hyperemia, which is calculated by dividing pressure by flow (distal pressure multiplied by the hyperemic mean transit time). Non-invasive methods to assess coronary physiology are stress echocardiography, coronary flow reserve by transthoracic Doppler echocardiography, single photon emission computed tomography, and perfusion cardiac magnetic resonance. In this review, we intend to analyze the mechanisms, consequences and therapeutic implications of microvascular dysfunction, including an extended citation of relevant literature data.

Confined ischemia may improve remote myocardial outcome after rat cardiac arrest

Background. Confined ongoing ischemia after ischemia-reperfusion injury (IRI) may alter myocardial recovery. We evaluated in a rat cardiac transplantation model whether distal persistent myocardial ischemia (dMI) and remote preconditioning (RPreC) have a remote myocardial impact after IRI. Material and methods. Syngeneic heterotopic cardiac transplantation was performed on 29 Fischer344 rats to induce IRI, including nine rats which underwent distal ligation of the left anterior coronary artery (LAD) to yield distal MI (IRI+ dMI). RPreC was applied by occluding the left renal artery 5 min prior to reperfusion in six rats with IRI (IRI+ RPreC) as well as in seven with distal MI (IRI+ dMI+ RPreC). Microdialysis, histology and qRT-PCR for inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) were performed after graft harvesting. Results. In contrast to IRI + dMI + RPreC (39 ± 7 μmol), glutamate decreased in IRI + RPreC and IRI + dMI as compared with IRI (26 ± 3 and 31 ± 8 vs 91 ± 20, μmol respectively, p < 0.007). The relative number of vacuolated intramyocardial artery nuclei decreased in IRI + dMI as compared with IRI (0.02 ± 0.01, range 0–12 vs. 0.42 ± 0.31, range 0–3.25 PSU respectively, p < 0.04). iNOS expression decreased in IRI + RPreC as compared with IRI (p < 0.04), and eNOS expression decreased in IRI + dMI + RPreC as compared with IRI + dMI (p < 0.006) along with increased glycerol release. Conclusions. dMI after IRI has a potentially beneficial myocardial impact after cardiac arrest, which is hampered by RPreC.

Tricuspid valve endocarditis complicated by septic pulmonary embolism in an intravenous drug user

Case reportA 32-year-old woman collapsed suddenly in the early hoursof the morning after visiting the toilet. Her partner made anemergency call immediately and started telephone-assistedcardiopulmonary resuscitation. Subsequent professionalresuscitation efforts were unsuccessful, and the woman waspronounced dead at the scene. She was known to be a long-term intravenous drug (IVD) user. A medicolegal autopsywas requested considering the woman’s young age and herspecific history of IVD abuse.Autopsy revealed the body of a poorly nourished Cau-casian woman, 162 cm in height and 55 kg in weight. Onexternal examination, there were prominent areas ofdepigmentation of the skin in the bilateral groin area, theanterior part of the right thigh, and the left cubital fossa.Fresh subcutaneous hemorrhages were seen on the anteriorpart of the right thigh with fresh puncture marks. Externalexamination also revealed multiple petechial hemorrhageson the right lower leg. Other external findings wereunremarkable.Dissection of the heart (weight, 280 g; dimensions13 9 10 9 4 cm) showed almost complete destruction ofthe anterior and septal cusps of the tricuspid valve (Fig. 1).The edges of the ulcerated cusps contained yellowishgranular vegetations. A smaller shaggy vegetation was alsopresent on the atrial aspect of the posterior cusp of thetricuspid valve, but the degree of destruction of the pos-terior cusp was not as severe as that of the anterior andseptal cusps. The leaflets of the tricuspid valve wereedematous and slightly coarse. A yellowish mass with aslightly granular surface was wedged into both branches ofthe pulmonary artery, causing complete obstruction(Fig. 2). The cardiac muscle was grossly normal. Therewas no septal defect. No pathological change was seen inthe coronary arteries.Further findings included septic changes of the spleen(weight, 460 g), congestion of the internal organs, and lungand brain edema.Histological examination of the lesions on the tricuspidvalve and the mass from the pulmonary artery revealed anorganizing thrombus with numerous colonies of bacteria,focal areas of acute inflammation, and microabscess forma-tion (Fig. 3a). Gram staining displayed gram-positive coc-cobacilli (Staphylococcus aureus). Histological examinationof the heart showed dispersed occlusions of small intramyo-cardial arteries bythrombicontaininglarge numbersofgram-positive bacteria with acute inflammation of adjacent areas ofmyocardium (Fig. 3b). There were no signs of nuclear atypiain the cardiomyocytes. Focal microabscesses containinggram-positive bacteria, karyorrhectic debris, and polymor-phonuclear cells surrounded small vessels in both lungs(Fig. 3c). Histologically proven focal and segmental septicglomerular infarcts were present in both kidneys (Fig. 3d).

Remodeling of small intramyocardial coronary arteries distal to total occlusions after myocardial infarction in pigs

The present study was designed to investigate whether microvascular remodeling could occur in hibernating myocardium and infarction regions distal to a total occluded coronary artery after acute myocardial infarction. Copper stents were implanted in the left descending coronary arteries of 64 pigs to induce anterior wall myocardial infarction. The pigs were assigned randomly to group A (n=8; killed at 1 week), group B (n=8; killed at 2 weeks), group C (n=16; killed at 4 weeks), group D (n=16; killed at 3 months), and group E (n=16; killed at 6 months). The control group included six pigs that were subjected to the same procedures but without implantation of copper stents. The wall area (WA) and lumen area (LA) of small intramyocardial coronary arteries (SIMCA) distal to occlusions were measured and the ratios of WA/LA and LA/total vessel area (%L) were calculated. The composition of the arterial wall was determined by Masson's trichrome stain, transmission electron microscope. A significant increase in WA/LA and decrease %L in SIMCA were observed in group B (P<0.05), group C (P<0.01), group D (P<0.01), and group E (P<0.01) compared with the control. There was increased area of collagen fiber in the thickened arterial wall in group C (P<0.05), group D (P<0.01), and group E (P<0.01) compared with the control group, group A, and group B. A significantly increased ratio of the synthetic phenotype vascular smooth muscle cells were found in group B (P<0.05), group C (P<0.01), group D (P<0.01), and group E (P<0.01) compared with the control group. Several weeks after occlusion of epicardial coronary, the SIMCAs distal to occlusion developed remodeling, with an increase in wall thickness and a decrease in lumen size. These structural changes may restrict blood flow to ischemic or hibernating myocardium after revascularization.

Subepicardial endothelial cells invade the embryonic ventricle wall to form coronary arteries

Coronary arteries bring blood flow to the heart muscle. Understanding the developmental program of the coronary arteries provides insights into the treatment of coronary artery diseases. Multiple sources have been described as contributing to coronary arteries including the proepicardium, sinus venosus (SV), and endocardium. However, the developmental origins of coronary vessels are still under intense study. We have produced a new genetic tool for studying coronary development, an AplnCreER mouse line, which expresses an inducible Cre recombinase specifically in developing coronary vessels. Quantitative analysis of coronary development and timed induction of AplnCreER fate tracing showed that the progenies of subepicardial endothelial cells (ECs) both invade the compact myocardium to form coronary arteries and remain on the surface to produce veins. We found that these subepicardial ECs are the major sources of intramyocardial coronary vessels in the developing heart. In vitro explant assays indicate that the majority of these subepicardial ECs arise from endocardium of the SV and atrium, but not from ventricular endocardium. Clonal analysis of Apln-positive cells indicates that a single subepicardial EC contributes equally to both coronary arteries and veins. Collectively, these data suggested that subepicardial ECs are the major source of intramyocardial coronary arteries in the ventricle wall, and that coronary arteries and veins have a common origin in the developing heart.

Signaling pathways involved in the H2O2-induced vasoconstriction of rat coronary arteries

Hydrogen peroxide (H2O2) is an endogenous endothelium-derived hyperpolarizing factor released by flow and involved in the regulation of coronary blood flow. Because opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, the aim of this study was to assess whether H2O2 may act as a coronary vasoconstrictor and if so to determine the underlying signaling mechanisms. Intramyocardial arteries from male Wistar rats were mounted on microvascular myographs for simultaneous measurements of intracellular Ca2+ ([Ca2+]i) and tension. On coronary arteries precontracted with the thromboxane A2 (TxA2) analogue U46619, H2O2 (1–300μM) elicited further moderate contractions in the proximal arterial segments and relaxed the more distal coronary branches, the contractions being markedly augmented in arteries depolarized by raising extracellular K+. H2O2-elicited vasoconstriction on K+30-precontracted coronary arteries was blunted by catalase and significantly reduced by endothelial cell removal and by inhibitors of cyclooxygenase (COX) and of the TxA2 receptor (TP). H2O2 (50μM) increased by about 10-fold basal superoxide anion (O2−) production in coronary arteries measured by lucigenin-enhanced chemiluminescence, and H2O2-elicited contractions were reduced by the superoxide dismutase mimetic tempol and by NADPH oxidase inhibition. Furthermore, blockade of the ERK and p38 mitogen-activated protein (MAP) kinases significantly reduced the contractions elicited by high and low concentrations of peroxide, respectively, whereas Rho kinase inhibition nearly abolished these responses. H2O2 (50μM) elicited simultaneous and similar sustained increases in [Ca2+]i and tension that were blunted by blockade of voltage-dependent L-type channels, but resistant to the nonselective Ca2+ channel blocker 2-aminoethoxydiphenyl borate. Moreover, endothelial cell removal reduced the increases in [Ca2+]i and contraction elicited by peroxide. The present data demonstrate that H2O2 is an endothelium-dependent vasoconstrictor in rat coronary arteries that activates smooth muscle Ca2+ entry through L-type and non-L-type channels and various intracellular signaling pathways including the release of a COX-derived TP agonist, stimulation of the MAP and Rho kinase pathways, and production of NADPH oxidase-derived superoxide.

Sildenafil after cardiac arrest and infarction; an experimental rat model

Objectives. Resuscitation after cardiac arrest may lead to ischemia-reperfusion injury and infarction. We evaluated whether Sildenafil, a phosphodiesterase-5 inhibitor, has an impact on recovery after cardiac arrest in a rat cardiac transplantation model. Design. Sixty-one Fischer344 rats underwent syngeneic heterotopic cardiac transplantation after ischemia and ligation of the left anterior coronary artery of the heart to yield myocardial infarction (IRI + MI). Of these, 22 rats received subcutaneously injected Sildenafil (1 mg/kg/day) (IRI +MI + S). Twenty-three additional grafted animals with transplantation only served as controls with ischemia reperfusion injury (IRI). After 2 days, immunohistochemistry for eNOS, and RT-PCR for iNOS and Aquaporin-7 were performed after graft harvesting and histology. Results. Two days after transplantation, remote intramyocardial arteries were more preserved in IRI + MI + S as compared with IRI +MI and IRI (0.74 ± 0.14, 0.56 ± 0.23 and 0.55 ± 0.22, PSU, p < 0.05, respectively). Decreased eNOS staining confirmed the presence of developing infarction in IRI + MI and IRI + MI + S. The expression of iNOS was significantly lower during IRI + MI +S as compared with IRI + MI (0.02 ± 0.01 and 1.02 ± 0.02, FC, p < 0.05). Conclusions. Administered at the onset of reperfusion and developing infarction, Sildenafil has an impact on myocardial recovery after cardiac arrest and ischemia.

Abstract 467: The Role of Obesity and Aging in Cardiovascular Remodeling in Monosodium Glutamate Treated Rats

The monosodium glutamate (MSG)-induced obese rat is a model associated with insulin resistance and dyslipidemia. The aim of this study was to evaluate the interaction of obesity and aging in cardiovascular remodeling. Male Wistar rats received subcutaneous injections of MSG (4.0g/kg) from the second to the sixth day after birth. The first sacrifice was done at week 16, when insulin resistance of the MSG group was established, and at week 30 we did the second sacrifice, obtaining four groups: control 16-week (CON-16); monosodium glutamate 16-week (MSG-16); control 30-week (CON-30); monosodium glutamate 30-week (MSG-30). Systolic blood pressure (BP) was measured weekly by tail-cuff plethysmography. The myocardium tissue was fixed and stained with Sirius red. The lumen diameter, media thickness and media cross-sectional area (CSA) of the intramyocardial arteries were measured. Cardiac collagen density was estimated with optical microscopy using the Image Pro Plus analysis system. The Lee index was significantly higher in MSG groups (30.43±0.34 and 31.2±0.2 vs 29.5±0.22 and 29.7±1.0 g/cm, p&lt;0.001). The systolic BP was significantly increased in the MSG-30 group (135±2 mmHg, p&lt;0.001) comparing to CON-16 (113±2 mmHg), CON-30 (115±1 mmHg) and MSG-16 (108±2 mmHg). The morphological analyses show similar diameter at the intramyocardial arteries but media thickness was significantly greater in MSG-30 rats (16.3±0.2 μm 2 , p &lt; 0.01) when compared to CON-16(12.5±0.5 μm 2 ) and CON-30(13.±0.4 μm 2 ) groups. Vascular remodeling was evident in obese groups observing an adverse effect of aging when measuring media-to-lumen ratio: 30.2±2.0% (CON-16), 39.9±3.7% (MSG-16), 39.3±1.2% (CON-30), 51.2±1.3% (MSG-30) (MSG-30 vs MSG-16 and CON-30 p&lt; 0.05; MSG-30 vs CON-16, p&lt; 0.001). Media CSA was also increased in MSG groups compared to control group resulting in an elevated growth index suggesting a hypertrophic vascular remodeling in these animals. Myocardial collagen density was significantly greater in obese (4.0±0.5 and 5.1±0.5 %) than in control rats (2.1±1.3% and 2.6±0.6%, p&lt;0.01). We concluded that in this experimental model, the presence of obesity promoted the increase of blood pressure and accelerated the adverse cardiovascular remodeling observed in aging.