Evaluation of Vmax as an index of myocardial contractility during afterload and preload elevations

In order to test if the maximal velocity of shortening (V(max)TP) reflects the level of inotropism and is affected by preload and afterload, the behavior of this index was compared in two groups of anesthetized, atropinized dogs when preload and afterload were raised with an angiotensin II infusion. In seven dogs (group I), the arterial pressure elevation was allowed to inhibit reflectively the sympathetic tone and depress contractility. In eleven dogs (group II), the adrenergic activity was abolished by previous administration of reserpine. In group I, there was a significant decrease in V(max)TP during the angiotensin infusion. In group II, there was no significant change in the value of this index when the drug was infused. In six animals of this group, a further increase of arterial pressure was induced, but the values of V(max)TP remained similar to control. These results suggest that this index reflects the inotropic state of the myocardium and does not suffer significantly from the influence of preload and afterload elevations within our experimental limits.

Is coronary sinus blood oxygen tension behavior determined by myocardial oxygen tension variation during cardiac reperfusion?

The relationship between coronary sinus blood oxygen tension (CSPO 2) and myocardial oxygen tension (MPO 2) variations during cardiac ischemia and reperfusion was studied in anesthetized open-chest dogs. Oxygen tension was measured by a polarographic method. Ischemia resulted in a slightly decreased CSPO 2 and a more pronounced reduction of MPO 2. After reperfusion the CSPO 2 rose rapidly and transiently before it returned gradually to the control level. By contrast, during the recovery period, the MPO 2 increased slowly, with recovery occurring long after the peak of CSPO 2. These data suggest that during the reperfusion phase, the CSPO 2 variation is probably due to opening of the myocardial arteriovenous shunts instead of an increase of flow through the myocardial capillary bed.

Efeito do lisinopril sobre parametros cardiacos e mortalidade no infarto experimental em ratos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1.0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n=10). Myocardial histology was analysed in 3 μm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Hepatic bleeding induced by streptokinase and heparin in a patient with acute myocardial infarction

Although rare, major bleeding is the most important side effect of thrombolytic therapy in acute myocardial infarction (AMI) (Levine et al., 1995). Spontaneous hepatic bleeding in normal liver after thrombolytic administration has rarely been reported in literature. To our knowledge, there are only three cases of hepatic bleeding related to thrombolytic therapy in AMI. In these, the used drugs were anisolylated plasminogen streptokinase activator complex (APSAC) (Garcia-Jiménez et al., 1997; Fox et al., 1991) and rt-PA (Garcia-Jiménez et al., 1997). We report a case of hepatic bleeding after streptokinase followed by units over 60 minutes). The next day, the patient developed third-degree atrioventricular block and a temporary pacemaker was inserted. Twenty-seven hours after streptokinase infusion, the patient complained of refractory chest pain that was interpreted as post-myocardial infarction angina; clotting screen was normal and intravenous heparin was started (80 U/kg followed by 18 U/kg/hour). After four hours of heparin administration, the patient presented abdominal pain and distension, and his blood pressure and hematocrit level dropped. Abdominal ultrasonography revealed free fluid in the peritoneal cavity (about 3,000 mL). A laparotomy disclosed blood in the abdominal cavity with bleeding from the right lateral hepatic segment, which was removed. The remaining abdominal viscera were normal and there was no other evidence of hemorrhage. The partial liver resection presented subcapsular hemorrhage with small parenchymal hemorrhage. Histopathological examination also revealed focal areas of ischemic centrilobular necrosis. The patient died of multiple organ system failure 21 days after admission. Copyright © 2002 By PJD Publications Limited.

Immunohistochemical, tomographic and histological study on onlay iliac grafts remodeling

The information concerning the molecular events taking place in onlay bone grafts are still incipient. The objective of the present study is to correlate the effects of perforation of resident bone bed on (1) the timing of onlay autogenous graft revascularization; (2) the maintenance of volume/density of the graft (assessed through tomography); and (3) the occurrence of bone remodeling proteins (using immunohistochemistry technique) delivered in the graft. Thirty-six New Zealand White rabbits were subjected to iliac crest onlay bone grafting on both sides of the mandible. The bone bed was drill-perforated on one side aiming at accelerating revascularization, whereas on the other side it was kept intact. After grafts fixation and flaps suture all animals were submitted to tomography on both mandible sites. Six animals were sacrificed, respectively, at 3, 5, 7, 10, 20 and 60 days after surgery. A second tomography was taken just before sacrifice. Histological slides were prepared from each grafted site for both immunohistochemistry analysis [osteopontin, osteocalcin, type I collagen and vascular endothelial growth factor (VEGF) anti-bodies] and histometric analysis. The values on bone volume measured on tomography showed no statistic significance (P≥0.05) between perforated and intact sites. Grafts placed on perforated beds showed higher bone density values compared with non-perforated ones at 3 days (P≤0.05). This correlation was inverted at 60 days postoperatively. The findings from VEGF labeling revealed a tendency for earlier revascularization in the perforated group. The early revascularization of bone grafts accelerated the bone remodeling process (osteocalcin, type I collagen and osteopontin) that led to an increased bone deposition at 10 days. The extended osteoblast differentiation process at intermediate stages in the perforated group cooperated for a denser bone at 60 days. © 2008 Blackwell Munksgaard.

Immunohistochemical, tomographic and histological study on onlay bone graft remodeling. Part II: Calvarial bone

Objectives: Little information is available on the molecular events that occur during graft incorporation over time. The calvarial bone (Cb) grafts have been reported to produce greater responses compared with other donor regions in maxillofacial reconstructions, but the scientific evidences for this are still lacking. The objectives of this study are (1) to study the morphological pattern of Cb onlay bone grafts and compare them with the biological events through immunohistochemical responses and (2) to establish the effects of perforations in maintaining the volume and bone density of the receptor bed. Material and methods: Sixty New Zealand White rabbits were submitted to Cb onlay bone grafts on the mandible. In 30 rabbits, the receptor bed was perforated (perforated group), while for the remaining animals the bed was kept intact (non-perforated group). Six animals from each group were sacrificed at 5, 7, 10, 20 and 60 days after surgery. Histological sections from the grafted area were prepared for immunohistochemical and histological analyses. Immuno-labeling was found for proteins Osteoprotegerin (OPG), receptor activator of nuclear factor-κβ ligand (RANKL), alkaline phosphatase (ALP), osteopontin (OPN), vascular endothelial growth factor (VEGF), tartrate-resistant acid phosphatase (TRAP), Type I collagen (COL I) and osteocalcin (OC). The tomography examination [computerized tomography (CT) scan] was conducted just after surgery and at the sacrifice. Results: The histological findings revealed that the perforations contributed to higher bone deposition during the initial stages at the graft-receptor bed interface, accelerating the graft incorporation process. The results of the CT scan showed lower resorption for the perforated group (P≤0.05), and both groups showed high bone density rates at 60 days. This set of evidences is corroborated by the immunohistochemical outcomes indicating that proteins associated with revascularization and osteogenesis (VEGF, OPN, TRAP and ALP) were found in higher levels in the perforated group. Conclusions: These findings indicate that the bone volume of calvarial grafts is better maintained when the receptor bed is perforated, probably resulting from more effective graft revascularization and greater bone deposition. The process of bone resorption peaked between 20 and 60 days post-operatively in both groups although significantly less in the perforated group. © 2009 John Wiley & Sons A/S.

Cardiovascular remodeling induced by passive smoking

Coronary heart disease (CHD) is the most common cause of death in many developed countries. The major risk factors for CHD are smoking, high blood pressure, diabetes, high cholesterol levels, and lack of physical activity. Importantly, passive smoke also increases the risk for CHD. The mechanisms involved in the effects of passive smoke in CHD are complex and include endothelial dysfunction, lipoprotein modification, increased inflammation and platelet activation. Recently, several studies have shown that exposure to tobacco smoke can result in cardiac remodeling and compromised cardiac function. Potential mechanisms for these alterations are neurohumoral activation, oxidative stress, and MAPK activation. Although the vascular effects of cigarette smoke exposure are well known, the effects of tobacco smoking on the heart have received less attention. Therefore, this review will focus on the recent findings as to the effects of passive smoking in acute and chronic phases of vascular and cardiac remodeling. © 2009 Bentham Science Publishers Ltd.

Influence of lisinopril on cardiac remodeling induced by tobacco smoke exposure

Background: To investigate the effect of lisinopril on cardiac remodeling induced by smoking. Material/Methods: Rats were allocated into 3 groups: group CON (n=8): control; group CSE (n=8): cigarette smoke exposure; group CSE-LIS (n=8): exposed to tobacco smoke and treated with lisinopril. Results: After 2 months, the tail systolic pressure was lower in CSE-LIS (CON=116 ±27 mm Hg, CSE=126±16, CSE-LIS=89±12; P<.001). CSE animals showed higher left ventricular systolic diameter (CON=8.25±2.16 mm/kg, CSE=11.5±1.3, CSE-LIS=9.27±2.00; P=.009) and myocyte cross-sectional area (CON=245±8 μm2, CSE=260±17, CSE-LIS=238±12; P=.01) than CON and CSE-LIS. The ejection fraction (CON =0.91±0.02, CSE=0.86±0.02, CSE-LIS=0.92±0.03; P=.002) and fractional shortening (CON=55.7±4.41%, CSE=48.7±3.43, CSE-LI=58.2±7.63; P=.006) were lower in CSE group than CON and CSE-LIS. CSE and CSE-LIS animals showed higher collagen amounts (CON=3.49±0.95%, CSE= 5.01±1.58, CSE-LIS=5.27±0.62; P=.009) than CON. CON group showed a higher connexin 43 amount in the intercalated disc (CON=3.70±0.38, CSE=2.13±0.53; CSE-LIS=2.17±0.73; P=.004) than CSE and CSE-LIS. There were no differences in IFN-g or TNF-a cardiac levels among the groups. Conclusions: Lisinopril attenuated both morphologic and functional abnormalities induced by exposure to tobacco smoke. In addition, this effect was associated with diminished blood pressure, but not alterations in connexin 43 distribution, cytokine production or collagen amount. © Med Sci Monit, 2010.

A comparative study of myocardial function and morphology during fasting/refeeding and food restriction in rats

Background: This study compared the influence of fasting/refeeding cycles and food restriction on rat myocardial performance and morphology. Methods: Sixty-day-old male Wistar rats were submitted to food ad libitum (C), 50% food restriction (R50), and fasting/refeeding cycles (RF) for 12 weeks. Myocardial function was evaluated under baseline conditions and after progressive increase in calcium and isoproterenol. Myocardium ultrastructure was examined in the papillary muscle. Results: Fasting/refeeding cycles maintained rat body weight and left ventricle weight between control and food-restricted rats. Under baseline conditions, the time to peak tension (TPT) was more prolonged in R50 than in RF and C rats. Furthermore, the maximum tension decline rate (-dT/dt) increased less in R50 than in RF with calcium elevation. While the R50 group showed focal changes in many muscle fibers, such as the disorganization or loss of myofilaments, polymorphic mitochondria with disrupted cristae, and irregular appearance or infolding of the plasma membrane, the RF rats displayed few alterations such as loss or disorganization of myofibrils. Conclusion: Food restriction promotes myocardial dysfunction, not observed in RF rats, and higher morphological damage than with fasting/refeeding. The increase in TPT may be attributed possibly to the disorganization and loss of myofibrils; however, the mechanisms responsible for the alteration in -dT/dt in R50 needs to be further clarified. © 2010 Elsevier Inc. All rights reserved.

Relevãncia do padrão de remodelamento ventricular no modelo de infarto do miocárdio em ratos

Background: The relevance of the remodeling pattern in the model of infarcted rats is not known. Objective: To analyze the presence of different patterns of remodeling in this model and its functional implications. Methods: Infarcted rats (n=47) have been divided according to the geometry pattern, analyzed by echocardiogram: normal (normal mass index and normal relative thickness), concentric remodeling (normal mass index and increased relative thickness), concentric hypertrophy (increased mass index and increased relative thickness) and eccentric hypertrophy (increased mass index and normal relative thickness). Data are median and interquartile range. Results: Infarcted rats showed only two of the four geometric patterns: normal pattern (15%) and eccentric hypertrophy - EH (85%). Groups of normal pattern and EH showed no differences in the values of fractional area change (Normal = 32.1-28.8 to 50.7; EH = 31.3-26.5 to 36.7; p = 0.343). Out of the infarcted animals, 34 (74%) had systolic dysfunction, detected by fractional area change. Considering these two geometry patterns, 77% of animals with eccentric hypertrophy and 57% with normal geometry presented systolic dysfunction (p=0.355). The relative wall thickness, the geometric patterns and the body mass index were not predictors of ventricular dysfunction (p>0.05). On the other hand, infarct size was a predictive factor for ventricular dysfunction in univariate analysis (p<0.001) and multivariate analysis (p = 0.004). Conclusion: Rats that underwent coronary occlusion showed two different patterns of remodeling, which do not constitute a predictor of ventricular dysfunction.

Cardiac remodeling induced by 13-cis retinoic acid treatment in acne patients

Background: Currently, 13-cis-retinoic acid (13-cis-RA) is the most effective therapy for acne. Isotretinoin, a first-generation synthetic 13-cis-RA compound, is associated with numerous adverse effects. To investigate the cardiac effects of 13-cis-RA, acne patients receiving 13-cis-RA were studied. Methods: Twenty male patients with acne were enrolled in the study. Patients were treated with a dose of 0.5 mg/kg/d of isotretinoin. All participants were assessed prior to treatment and after 10 weeks of therapy with Doppler-echocardiogram. Results: Patients showed reductions in right atrium vertical diameter, left atrium longitudinal diameter, left atrium volume and left ventricular diastolic diameter over the course of treatment. Significant increases in interventricular septum diastolic thickness, posterior wall diastolic thickness, relative wall relative thickness and left ventricle (LV) mass were observed. The LV mass index showed an increase in ventricular mass and a decrease in the cavity size. Examining LV systolic function, a decrease was observed for the cardiac index. Conclusion: In this study, 10 weeks of 13-cis-RA therapy at a dose of 0.5 mg/kg/d was found to promote concentric-type heart remodeling due to the occurrence of two associated events: heart hypertrophy and hypovolemia. © 2011 Elsevier B.V. All rights reserved.

Smoking is associated with remodeling of gap junction in the rat heart: Smoker's paradox explanation?

Background: In a previous study utilizing the rat model, exposure to tobacco smoke for 5 weeks increased survival after AMI, despite similar age and infarct size between the smokers and nonsmokers, and absence of reperfusion. Objective: Thus, this study aimed to analyze the effects of exposure to tobacco smoke on intensity, distribution or phosphorylation of connexin 43 in the rat heart. Methods: Wistar rats weighing 100 g were randomly allocated into 2 groups: 1) Control (n = 25); 2) Exposed to tobacco smoke (ETS), n = 23. After 5 weeks, left ventricular morphometric analysis, immunohisthochemistry and western blotting for connexin 43 (Cx43) were performed. Results: Collagen volume fraction, cross-sectional areas, and ventricular weight were not statistically different between control and ETS. ETS showed lower stain intensity of Cx43 at intercalated disks (Control: 2.32 ± 0.19; ETS: 1.73 ± 0.18; p = 0.04). The distribution of CX43 at intercalated disks did not differ between the groups (Control: 3.73 ± 0.12; ETS: 3.20 ± 0.17; p = 0.18). ETS rats showed higher levels of dephosphorylated form of Cx43 (Control: 0.45 ± 0.11; ETS: 0.90 ± 0.11; p = 0.03). On the other hand, total Cx43 did not differ between control and ETS groups (Control: 0.75 ± 0.19; ETS: 0.93 ± 0.27; p = 0.58). Conclusion: Exposure to tobacco smoke resulted in cardiac gap junction remodeling, characterized by alterations in the quantity and phosphorylation of the Cx43, in rats hearts. This finding could explain the smoker's paradox observed in some studies.

Extensive impact of saturated fatty acids on metabolic and cardiovascular profile in rats with diet-induced obesity: A canonical analysis

Background: Although hypercaloric interventions are associated with nutritional, endocrine, metabolic, and cardiovascular disorders in obesity experiments, a rational distinction between the effects of excess adiposity and the individual roles of dietary macronutrients in relation to these disturbances has not previously been studied. This investigation analyzed the correlation between ingested macronutrients (including sucrose and saturated and unsaturated fatty acids) plus body adiposity and metabolic, hormonal, and cardiovascular effects in rats with diet-induced obesity. Methods: Normotensive Wistar-Kyoto rats were submitted to Control (CD; 3.2 Kcal/g) and Hypercaloric (HD; 4.6 Kcal/g) diets for 20 weeks followed by nutritional evaluation involving body weight and adiposity measurement. Metabolic and hormonal parameters included glycemia, insulin, insulin resistance, and leptin. Cardiovascular analysis included systolic blood pressure profile, echocardiography, morphometric study of myocardial morphology, and myosin heavy chain (MHC) protein expression. Canonical correlation analysis was used to evaluate the relationships between dietary macronutrients plus adiposity and metabolic, hormonal, and cardiovascular parameters. Results: Although final group body weights did not differ, HD presented higher adiposity than CD. Diet induced hyperglycemia while insulin and leptin levels remained unchanged. In a cardiovascular context, systolic blood pressure increased with time only in HD. Additionally, in vivo echocardiography revealed cardiac hypertrophy and improved systolic performance in HD compared to CD; and while cardiomyocyte size was unchanged by diet, nuclear volume and collagen interstitial fraction both increased in HD. Also HD exhibited higher relative β-MHC content and β/α-MHC ratio than their Control counterparts. Importantly, body adiposity was weakly associated with cardiovascular effects, as saturated fatty acid intake was directly associated with most cardiac remodeling measurements while unsaturated lipid consumption was inversely correlated with these effects. Conclusion: Hypercaloric diet was associated with glycemic metabolism and systolic blood pressure disorders and cardiac remodeling. These effects directly and inversely correlated with saturated and unsaturated lipid consumption, respectively. © 2013 Oliveira Junior et al.; licensee BioMed Central Ltd.