Advances in pharmacological studies of silymarin

Silymarin is the flavonoids extracted from the seeds of Silybum marianum (L) Gearth as a mixture of three structural isomers: silybin, silydianin and silychristin, the former being the most active component. Silymarin protects liver cell membrane against hepatotoxic agents and improves liver function in experimental animals and humans. It is generally accepted that silymarin exerts a membrane-stabilizing action preventing or inhibiting membrane peroxidation. The experiments with soybean lipoxygenase showed that the three components of silymarin brought about a concentration-dependent non-competitive inhibition of the lipoxygenase. The experiments also showed an analogous interaction with animal lipoxygenase, thus showing that an inhibition of the peroxidation of the fatty acid in vivo was self-evident. Silybin almost completely suppressed the formation of PG at the highest concentration (0.3 mM) and proved to be an inhibitor of PG synthesis in vitro. In our experiments, silybin at lower dose (65 mg/Kg) decreased liver lipoperoxide content and microsomal lipoperoxidation to 84.5% and 68.55% of those of the scalded control rats respectively, and prevented the decrease of liver microsomal cytochrome p-450 content and p-nitroanisole-0-demethylase activity 24 h post-scalding. Effects of silymarin on cardiovascular systen have been studied in this university since 1980. O. O silymarin 800 mg/Kg/d or silybin 600 mg/Kg/d reduced plasma total cholesterol, LDL-C and VLDL-C. They however, enhanced HDL-C in hyperlipenic rats. Further studies showed that silymarin enhanced HDL-C in hyperlipemic rats. Further studies showed that silymarin enhanced HDL-C but didn't affect HDL-C, a property of this component which is beneficial to treatment of atherosclerosis. The results showed silymarin 80 mg or silybin 60 mg decreased in vitro platelet aggregation (porcentagem) in rats. The maximal platelet aggregation induced by ADP declined significantly, and time to reach maximal platelet aggregation and five-minute disaggregation didn't change. In our experiments, iv silybin 22,4 mg/kg lowered the amplitude and duration of diastolic blood pressure (DBP) more than those of systolic (SBP), but the descending aortic blood flow, cardiac contractility and ECG did not change significantly in anesthetized open-chest cats. The results indicated a reduction of peripheral resistance and dilatatory action on the resistant blood vessels. These effects are beneficial to coronary heart disease. We also observed the effects of silybin on morphological change, the release of glutamic oxaloacetate aminotrasferase (GOT) and lactate dehydrogenase (LDH) as well as the radioactivity of 3H-TdR incorporated into DNA in normal cardiac cells and cells infected by coxsackie B5, virus os newborn rats. The results showed that silynin did not affect the morphology of normal cell, and that the pathological change of cells infected by virus was delayed and reduced as compared to control. We have investigated the effect of silybin on synthesis and release of LTs in the cultured porcine cerebral basilar arteries (PCBA). Silybin 100 and 500 µmol/L declined the amounts of LTs released from the PCBA incubsated in the presence of A 23187, AA and indomenthacin. The result suggests that silybin can inhibit the activity of 5-lipoxygenase of cerebral blood vessel and may protect the brain from ischemia.

Hyperhomocystinemia in patients with coronary artery disease

Hyperhomocystinemia has been related to an increased risk of cardiovascular disease in several studies. The C677T polymorphism for the gene that encodes the methylenetetrahydrofolate reductase enzyme (MTHFR) and low plasma folate levels are common causes of hyperhomocystinemia. Due to differences in nutritional patterns and genetic background among different countries, we evaluated the role of hyperhomocystinemia as a coronary artery disease (CAD) risk factor in a Brazilian population. The relation between homocysteine (Hcy) and the extent of CAD, measured by an angiographic score, was determined. A total of 236 patients referred for coronary angiography for clinical reasons were included. CAD was found in 148 (62.7%) patients and 88 subjects had normal or near normal arteries. Patients with CAD had higher Hcy levels [mean (SD)] than those without disease (14 (6.8) vs 12.5 (4.0) µM; P = 0.04). Hyperhomocystinemia (Hcy >17.8 µM) prevalence was higher in the CAD group: 31.1 vs 12.2% (P = 0.01). After adjustment for major risk factors, we found an independent association between hyperhomocystinemia and CAD (OR = 2.48; 95% CI = 1.02-6.14). Patients with a more advanced coronary score had a higher frequency of hyperhomocystinemia and tended to have higher mean Hcy levels. An inverse relation between plasma folate and Hcy levels was found (r = -0.14; P = 0.04). Individuals with the MTHFR C677T polymorphism had a higher prevalence of hyperhomocystinemia than those without the mutated allele. We conclude that hyperhomocystinemia is independently associated with CAD, with a positive association between Hcy level and disease severity.

Coronary artery plaque burden and calcium scores in healthy men adhering to long-term wine drinking or alcohol abstinence

Observational studies suggest there are clinical benefits to moderate red wine (RW) consumption. However, the effects on coronary vasculature and overall lifestyle are unclear. We investigated whether a lifestyle of regular long-term RW consumption is associated with changes in coronary plaque burden, calcium score, carotid intima/media thickness, endothelial function, and metabolic variables, compared with alcohol abstinence. Healthy volunteers were evaluated by coronary computed tomography angiography (CTA) as well as carotid and brachial artery ultrasound. Nutritional status, psychological status, and metabolic variables were assessed. The study included 101 drinkers [aged 58.9±7.3 years (means±SD)], from wine brotherhoods, and 104 abstainers, from Anglican, Evangelical and Catholic churches both in the city of São Paulo, Brazil. No significant differences in demographics were noted. Lesion prevalence per patient assessed by coronary CTA and classified as absent (0), 1-25, 26-49, and ≥50% stenosis was similar between groups. When analyzed by individual arteries, i.e., left anterior descending, circumflex, and right coronary, prevalence was also not different. On the other hand, calcium scores were higher among drinkers than abstainers (144.4±362.2 vs 122.0±370.3; P<0.01). However, drinkers reported less history of diabetes and exercised more. RW drinkers consumed 2127.9±387.7 kcal/day while abstainers consumed 1836.0±305.0 (P<0.0001). HDL cholesterol was significantly higher among drinkers compared to abstainers (46.9±10.9 vs 39.5±9.0 mg/dL; P<0.001), while fasting plasma glucose was lower (97.6±18.2 vs 118.4±29.6 mg/dL; P<0.02). Liver enzymes were normal in both groups. In conclusion, long-term wine drinkers displayed a similar plaque burden but greater calcium score than abstainers, despite a more atherogenic diet, and the mechanisms for the increased calcium scores in the former remain speculative.

Use of medicines recommended for secondary prevention of acute coronary syndrome

ABSTRACT OBJECTIVE : To analyze if the demographic and socioeconomic variables, as well as percutaneous coronary intervention are associated with the use of medicines for secondary prevention of acute coronary syndrome. METHODS : In this cohort study, we included 138 patients with acute coronary syndrome, aged 30 years or more and of both sexes. The data were collected at the time of hospital discharge, and after six and twelve months. The outcome of the study was the simultaneous use of medicines recommended for secondary prevention of acute coronary syndrome: platelet antiaggregant, beta-blockers, statins and angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker. The independent variables were: sex, age, education in years of attending, monthly income in tertiles and percutaneous coronary intervention. We described the prevalence of use of each group of medicines with their 95% confidence intervals, as well as the simultaneous use of the four medicines, in all analyzed periods. In the crude analysis, we verified the outcome with the independent variables for each period through the Chi-square test. The adjusted analysis was carried out using Poisson Regression. RESULTS : More than a third of patients (36.2%; 95%CI 28.2;44.3) had the four medicines prescribed at the same time, at the moment of discharge. We did not observe any differences in the prevalence of use in comparison with the two follow-up periods. The most prescribed class of medicines during discharge was platelet antiaggregant (91.3%). In the crude analysis, the demographic and socioeconomic variables were not associated to the outcome in any of the three periods. CONCLUSIONS : The prevalence of simultaneous use of medicines at discharge and in the follow-ups pointed to the under-utilization of this therapy in clinical practice. Intervention strategies are needed to improve the quality of care given to patients that extend beyond the hospital discharge, a critical point of transition in care.

Infectious agents in coronary atheromas: a possible role in the pathogenesis of plaque rupture and acute myocardial infarction

In this review we report our recent findings of histopathological features of plaque instability and the association with Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP) infection, studying thrombosed coronary artery segments (CAS) of patients who died due to acute myocardial infarction. Vulnerable plaques are known to be associated with fat atheromas and inflammation of the plaque. Here we demonstrated that vulnerability is also related with focal positive vessel remodeling that maintains relatively well preserved lumen even in the presence of large atheromatous plaques. This phenomena may explain why the cinecoronariography may not detect large and dangerous vulnerable plaques. Greater amount of these bacteria in vulnerable plaques is associated with adventitial inflammation and positive vessel remodeling: the mean numbers of lymphocytes were significantly higher in adventitia than in the plaque, good direct correlation was obtained between numbers of CD20 B cells and numbers of CP infected cells in adventitia, and between % area of MP-DNA in the plaque and cross sectional area of the vessel, suggesting a cause-effect relationship. Mycoplasma is a bacterium that needs cholesterol for proliferation and may increase virulence of other infectious agents. In conclusion, co-infection by Mycoplasma pneumoniae and Chlamydia pneumoniae may represent an important co-factor for plaque instability, leading to coronary plaque thrombosis and acute myocardial infarction, since larger amount of these bacteria strongly correlated with histological signs of more vulnerability of the plaque. The search of CMV and Helicobacter pilori in these tissues resulted negative.

Pathogenesis of chronic Chagas cardiomyopathy: the role of coronary microvascular derangements

There is ample experimental and clinical evidence of functional and structural microvascular abnormalities occurring in patients with Chagas cardiomyopathy, possibly due to the inflammatory process and/or autonomic disturbances caused by Trypanosoma cruzi infection. Those microvascular derangements are likely to constitute at least an ancillary factor that potentiates and amplifies the chronic inflammation in myocardial tissue. It is possible to devise appropriate therapeutic interventions aimed at reverting or slowing the progression of the microvascular abnormalities to positively affect the natural history of Chagas cardiomyopathy.

Prenatal tracheal ligation or intra-amniotic administration of surfactant or dexamethasone prevents some structural changes in the pulmonary arteries of surgically created diaphragmatic hernia in rabbits

PURPOSE: Characterization of the structural changes occurring in the pulmonary arteries resulting from surgically produced congenital diaphragmatic hernia in rabbits, with particular emphasis on the preventive effects of prenatal tracheal ligation or administration of intra-amniotic dexamethasone or surfactant. METHODS: Twenty rabbit fetuses underwent surgical creation of a left-sided congenital diaphragmatic hernia on the 24th or 25th gestational day. They were divided according to the following procedures: congenital diaphragmatic hernia (n = 5), congenital diaphragmatic hernia plus tracheal ligation (n = 5), congenital diaphragmatic hernia plus intra-amniotic administration of dexamethasone 0.4 mg (n = 5) or surfactant (Curosurf 40 mg, n = 5). On gestational day 30, all the fetuses were delivered by caesarean section and killed. A control group consisted of five nonoperated fetuses. Histomorphometric analysis of medial thickness, cell nuclei density, and elastic fiber density of pulmonary arterial walls was performed. RESULTS: Arteries with an external diameter > 100 mum have a decreased medial thickness, lower cell nuclei density, and greater elastic fiber density when compared with arteries with external diameter <= 100 mum. Congenital diaphragmatic hernia promoted a significant decrease in medial thickness and an increase in cell nuclei density in artery walls with external diameter > 100 mum. Prenatal treatments with tracheal ligation or intra-amniotic administration of dexamethasone or surfactant prevented these changes. In arteries with external diameter <= 100 mum, congenital diaphragmatic hernia promoted a significant increase in medial thickness and in cell nuclei density and a decrease in elastic fiber density. The prenatal treatments with tracheal ligation or intra-amniotic administration of dexamethasone or surfactant prevented these changes, although no effect was observed in elastic fiber density in the congenital diaphragmatic hernia plus dexamethasone group. CONCLUSIONS: Congenital diaphragmatic hernia promoted different structural changes for large or small arteries. The prenatal intra-amniotic administration of dexamethasone or surfactant had positive effects on the lung structural changes promoted by congenital diaphragmatic hernia, and these effects were comparable to the changes induced by tracheal ligation.

Low coronary perfusion pressure is associated with endocardial fibrosis in a rat model of volume overload cardiac hypertrophy

Left ventricular hypertrophy following volume overload is regarded as an example of cardiac remodeling without increased fibrosis accumulation. However, infarction is associated with increased fibrosis within the noninfarcted, hypertrophied myocardium, particularly in the subendocardial regions. It is conceivable to suppose that, as also occurs postinfarction, low coronary driving pressure may also interfere with accumulation of myocardial fibrosis following aortocaval fistula. PURPOSE: To investigate the role of acute hemodynamic changes in subsequent deposition of cardiac fibrosis in response to aortocaval fistula. METHOD: Aortocaval fistula were created in 4 groups of Wistar rats that were followed over 4 and 8 weeks: aortocaval fistula 4 and aortocaval fistula 8 (10 rats each) and their respective controls (sham-operated controls - Sh), Sh4 and Sh8 (8 rats each). Hemodynamic measurements were performed 1 week after surgery. Hypertrophy and fibrosis were quantified by myocyte diameter and collagen volume fraction at the end of follow up. RESULT: Compared with Sh4 and Sh8, pulse pressure, left ventricular end-diastolic pressure, and +dP/dt were higher in aortocaval fistula 4 and aortocaval fistula 8, but -dP/dt was similar. Coronary driving pressure (mm Hg), used as an estimate of perfusion pressure, was lower in aortocaval fistula 8 (52.6 ± 4.1) than in Sh8 (100.8 ± 1.3), but comparable between aortocaval fistula 4 (50.0 ± 8.9) and Sh4 (84.8 ± 2.3). Myocyte diameter was greater in aortocaval fistula 8, whereas interstitial and subendocardial fibrosis were greater in aortocaval fistula 4 and aortocaval fistula 8. Coronary driving pressure correlated inversely and independently with subendocardial fibrosis (r² = .86, P <.001), whereas left ventricular systolic pressure (r² = 0.73, P = .004) and end-diastolic pressure (r² = 0.55, P = 012) correlated positively and independently with interstitial fibrosis. CONCLUSION: Coronary driving pressure falls and ventricular pressures increase early after aortocaval fistula and are associated with subsequent myocardial fibrosis deposition.

Natural history of stenosis in the iliac arteries in patients with intermittent claudication undergoing clinical treatment

PURPOSE: Inspite of the long experience with the treatment of intermittent claudication, little is known about the natural history of stenotic lesions in the iliac segment. With the advent of endovascular treatment, this knowledge has become important. METHODS: Fifty-two stenosis, diagnosed using arteriography, in 38 claudicant patients were analyzed. After a minimum time interval of 6 months, a magnetic resonance angiography was performed to determine whether there was arterial occlusion. The primary factors that could influence the progression of a stenosis were analyzed, such as risk factors (smoking, hypertension, diabetes, sex, and age), compliance with clinical treatment, initial degree of stenosis, site of the stenosis, and length of follow-up. RESULTS: The average length of follow-up was 39 months. From the 52 lesions analyzed, 13 (25%) evolved to occlusion. When occlusion occurred, there was clinical deterioration in 63.2% of cases. This association was statistically significant (P = .002). There was no statistically significant association of the progression of the lesion with the degree or site of stenosis, compliance with treatment, or length of follow-up. Patients who evolved to occlusion were younger (P = .02). The logistic regression model showed that the determinant factors for clinical deterioration were arterial occlusion and noncompliance with clinical treatment. CONCLUSIONS: The progression of a stenosis to occlusion, which occurred in 25% of the cases, caused clinical deterioration. Clinical treatment was important, but it did not forestall the arterial occlusion. Prevention of occlusion could be achieved by early endovascular intervention or with the development of drugs that might stabilize the atherosclerotic plaque.

Coronary arterial disease after electroconvulsive therapy: a case report

Objectives Unipolar depression (UPD) is a leading cause of global burden of diseases, particularly among the elderly, whose treatment may be challenging. In such cases, ECT is often recommended due to its safety and efficacy. This report presents a case of a 67-year-old male inpatient that developed a rare cardiac complication during ECT. Methods Clinical case report with patient’s consent and bibliographic review. Results A 67-year-old male inpatient with recurrent severe psychotic depression was hospitalized and ECT was indicated after failure of the pharmacological treatment. A comprehensive clinical pre-evaluation revealed only nonspecific ST-segment changes in electrocardiogram. During the 7th ECT session, it was observed transitory ST-segment depression followed by a discrete increase of plasma troponin I. Severe tri-vessel coronary artery stenosis was found and a percutaneous coronary angioplasty was performed, with satisfactory psychiatric and cardiac outcomes. Conclusions Unipolar depression (UPD) and cardiovascular disease are often coexistent conditions, especially among the elderly. In the current case, myocardial ischemia was detected lately during ECT therapy and its treatment allowed the UPD treatment to be completed adequately.

Protective effect of left ventricular hypertrophy in right coronary artery occlusions

OBJECTIVE: To test the hypothesis that left ventricular hypertrophy (LVH) reduces the electrocardiographic and functional effects of right coronary artery occlusion. METHODS: We analysed 215 patients (166 males and 49 women,age of 58.9±10.6 years), with occlusion of the right coronary artery without other associated lesions. There was no significant difference (p>0.05) in age and gender distribution between the 78 patients with LVH (left ventricular mass >100g/m²) (Group A) when compared with the 137 patients without LVH (left ventricular mass <100g/m²) (Group B). RESULTS: The electrocardiographic finding of transmural necrosis was more often found in group B patients than in group A patients (56.9% and 30.8%, respectively; p<0.05). The left ventricular function parameters of group A were better than those of group B: the ratio end-diastolic pressure/systolic pressure (EDP/SP) (A: 0.108±0.036; B: 0.121±0.050; p<0.05); the end-diastolic volume index (A: 75.9±31.3ml/m²; B: 88.0±31.0ml/m²; p<0.01); the end-systolic volume index (A: 16.0±10.0ml/m²; B: 27.0 ±20.0ml/m²; p<0.001); the ejection fraction (A 78.6±10.8%; B 67.7±17.9%; p<0.001); the anteroinferior shortening (A: 43.9±10.3%; B: 35.1±12.8%; p<0.001). A higher degree of coronary tortuosity was observed in group A than in group B (78.2% and 24.1%; p<0.001) and also a more frequent absent or minimal diaphragmatic hypokinetic area (A: 80.8%; B: 54.0%; p<0.05). CONCLUSION: LVH reduces the effects of myocardial sequela and protects LV function when right coronary occlusion develops.

Anomalous origin of the left coronary artery from the pulmonary trunk. Clinical features and midterm results after surgical treatment

OBJECTIVE: To report the authors' experience with the anomalous origin of the left coronary artery (AOLCA) from the pulmonary trunk, emphasizing preoperative data, surgical aspects and midterm results of the follow-up. METHODS: Retrospective analysis of 11 patients operated upon at the Royal Brompton Hospital from October, 84 to April, 97. RESULTS: Nine infants had heart failure (HF) and two other children presented with dyspnea and chest pain. All had ECG changes. The echocardiogram identified the anomalous origin of the coronary artery in 7 (64%) patients and hemodynamic studies were performed in 7 patients. All infants were operated upon between the 2nd and 10th month of life. Six patients were treated with aortic reimplantation of the left coronary artery, whereas five were operated upon according to the Takeuchi technique. All patients are alive, with clear improvement of the ECG changes and ventricular function, as evaluated by echocardiography. Two patients operated upon according to the Takeuchi technique required additional surgery due to severe supravalvular pulmonary stenosis. CONCLUSION: AOLCA is a rare disease. Most patients show early signs of severe HF associated with ECG findings. Surgical therapy must be instituted early in the disease, preferentially through aortic implantation of the anomalous coronary artery, with a high possibility of success. Shortly after surgery, clinical and ECG improvement, as well as normalization of left ventricular function, should be expected.

Detection of the viable myocardium. A perfusion scintigraphic study, before and after coronary bypass surgery in myocardial infarction patients

OBJECTIVE: To compare single-photon-emission computed tomography (SPECT) imaging scans using 201Tl and 99mTc-MIBI in detection of viable myocardium, in regions compromised by infarction. METHODS: Thirty-two (59.3±9.8 years old and 87% male) myocardial infarction patients were studied. All had Q waves on the ECG and left ventricle ejection fraction of <50%. They underwent coronary and left ventricle angiographies and SPECT before (including 201Tl reinjection) and after coronary artery bypass surgery (CABG). Improvement in perfusion observed after surgery was considered the gold standard for myocardial viability. RESULTS: Among 102 studied regions of the heart, there were 40 (39.2%) areas of transient perfusion defects in the conventional protocol with 201Tl and 52 (51.0%) after reinjection. Therefore, 12/62 (19.4%) more viable regions were identified by reinjection. Using 99mTc-MIBI, only 14 (13.7%) regions with transient defects were identified, all of which were seen also in 201Tl protocols. After surgery, 49 of a total of 93 regions analyzed (52.7%) were viable. Sensitivity, specificity, accuracy, positive and negative prediction values were, respectively, 201Tl SPECT scans - 65.3%, 90.9%, 77.4%, 88.9% and 70.2%, reinjection protocol with 201Tl scans - 81.6%, 81.8%, 81.7%, 83.3% and 80.0%; 99mTc-MIBI SPECT scans - 20.4%, 90.9%, 53.8%, 71.4% and 50.6%. Logistic regression demonstrated that the reinjection protocol with 201Tl was the best predictor of viability (P<0.001). CONCLUSION: Our data suggest the election of 201Tl for viability studies, especially when using the reinjection protocol.