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1.  Effect of Hypoglycemic Agents on Ischemic Preconditioning in Patients With Type 2 Diabetes and Symptomatic Coronary Artery Disease 
Diabetes Care  2013;36(6):1654-1659.
To assess the effect of two hypoglycemic drugs on ischemic preconditioning (IPC) patients with type 2 diabetes and coronary artery disease (CAD).
We performed a prospective study of 96 consecutive patients allocated into two groups: 42 to group repaglinide (R) and 54 to group vildagliptin (V). All patients underwent two consecutive exercise tests (ET1 and ET2) in phase 1 without drugs. In phase 2, 1 day after ET1 and -2, 2 mg repaglinide three times daily or 50 mg vildagliptin twice daily was given orally to patients in the respective group for 6 days. On the seventh day, 60 min after 6 mg repaglinide or 100 mg vildagliptin, all patients underwent two consecutive exercise tests (ET3 and ET4).
In phase 1, IPC was demonstrated by improvement in the time to 1.0 mm ST-segment depression and rate pressure product (RPP). All patients developed ischemia in ET3; however, 83.3% of patients in group R experienced ischemia earlier in ET4, without significant improvement in RPP, indicating the cessation of IPC (P < 0.0001). In group V, only 28% of patients demonstrated IPC cessation, with 72% still having the protective effect (P < 0.0069).
Repaglinide eliminated myocardial IPC, probably by its effect on the KATP channel. Vildagliptin did not damage this protective mechanism in a relevant way in patients with type 2 diabetes and CAD, suggesting a good alternative treatment in this population.
PMCID: PMC3661846  PMID: 23250803
2.  Hypotheses, rationale, design, and methods for evaluation of ischemic preconditioning assessed by sequential exercise tests in diabetic and non-diabetic patients with stable coronary artery disease – a prospective study 
Ischemic preconditioning is a powerful mechanism of myocardial protection and in humans it can be evaluated by sequential exercise tests. Coronary Artery Disease in the presence of diabetes mellitus may be associated with worse outcomes. In addition, some studies have shown that diabetes interferes negatively with the development of ischemic preconditioning. However, it is still unknown whether diabetes may influence the expression of ischemic preconditioning in patients with stable multivessel coronary artery disease.
This study will include 140 diabetic and non-diabetic patients with chronic, stable coronary artery disease and preserved left ventricular systolic function. The patients will be submitted to two sequential exercise tests with 30-minutes interval between them. Ischemic parameters will be compared between diabetic and non-diabetic patients. Ischemic preconditioning will be considered present when time to 1.0 mm ST-segment deviation is greater in the second of two sequential exercise tests. Exercise tests will be analyzed by two independent cardiologists.
Ischemic preconditioning was first demonstrated by Murry et al. in dog’s hearts. Its work was reproduced by other authors, clearly demonstrating that brief periods of myocardial ischemia followed by reperfusion triggers cardioprotective mechanisms against subsequent and severe ischemia. On the other hand, the demonstration of ischemic preconditioning in humans requires the presence of clinical symptoms or physiological changes difficult to be measured. One methodology largely accepted are the sequential exercise tests, in which, the improvement in the time to 1.0 mm ST depression in the second of two sequential tests is considered manifestation of ischemic preconditioning.
Diabetes is an important and independent determinant of clinical prognosis. It's a major risk factor for coronary artery disease. Furthermore, the association of diabetes with stable coronary artery disease imposes worse prognosis, irrespective of treatment strategy. It’s still not clearly known the mechanisms responsible by these worse outcomes. Impairment in the mechanisms of ischemic preconditioning may be one major cause of this worse prognosis, but, in the clinical setting, this is not known.
The present study aims to evaluate how diabetes mellitus interferes with ischemic preconditioning in patients with stable, multivessel coronary artery disease and preserved systolic ventricular function.
PMCID: PMC4029531  PMID: 24330253
Ischemic preconditioning; Exercise test; Coronary heart disease; Angina; Myocardial ischemia
3.  Hypotheses, rationale, design, and methods for prognostic evaluation of cardiac biomarker elevation after percutaneous and surgical revascularization in the absence of manifest myocardial infarction. A comparative analysis of biomarkers and cardiac magnetic resonance. The MASS-V Trial 
Although the release of cardiac biomarkers after percutaneous (PCI) or surgical revascularization (CABG) is common, its prognostic significance is not known. Questions remain about the mechanisms and degree of correlation between the release, the volume of myocardial tissue loss, and the long-term significance. Delayed-enhancement of cardiac magnetic resonance (CMR) consistently quantifies areas of irreversible myocardial injury. To investigate the quantitative relationship between irreversible injury and cardiac biomarkers, we will evaluate the extent of irreversible injury in patients undergoing PCI and CABG and relate it to postprocedural modifications in cardiac biomarkers and long-term prognosis.
The study will include 150 patients with multivessel coronary artery disease (CAD) with left ventricle ejection fraction (LVEF) and a formal indication for CABG; 50 patients will undergo CABG with cardiopulmonary bypass (CPB); 50 patients with the same arterial and ventricular condition indicated for myocardial revascularization will undergo CABG without CPB; and another 50 patients with CAD and preserved ventricular function will undergo PCI using stents. All patients will undergo CMR before and after surgery or PCI. We will also evaluate the release of cardiac markers of necrosis immediately before and after each procedure. Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and systolic left ventricle dysfunction assessed by CMR.
The MASS-V Trial aims to establish reliable values for parameters of enzyme markers of myocardial necrosis in the absence of manifest myocardial infarction after mechanical interventions. The establishments of these indices have diagnostic value and clinical prognosis and therefore require relevant and different therapeutic measures. In daily practice, the inappropriate use of these necrosis markers has led to misdiagnosis and therefore wrong treatment. The appearance of a more sensitive tool such as CMR provides an unprecedented diagnostic accuracy of myocardial damage when correlated with necrosis enzyme markers. We aim to correlate laboratory data with imaging, thereby establishing more refined data on the presence or absence of irreversible myocardial injury after the procedure, either percutaneous or surgical, and this, with or without the use of cardiopulmonary bypass.
PMCID: PMC3468382  PMID: 22898311
Cardiopulmonary bypass; Necrosis markers; Myocardial infarction; PCI; CABG
4.  Comparison of Non-Invasive Methods for the Detection of Coronary Atherosclerosis 
Clinics (Sao Paulo, Brazil)  2009;64(7):675-682.
Non-invasive detection of atherosclerosis is critical for its prevention.
To correlate non-invasively detectable indicators of coronary atherosclerosis, or Coronary Artery Disease (i.e., classical risk factors, hs-CRP test results, carotid intima-media thickness, endothelial function, ankle-brachial index and calcium score by computed tomography) with the extent of coronary disease assessed by the Friesinger index from conventional coronary angiography.
We conducted a prospective study of 100 consecutive patients, mean age 55.1 ± 10.7 years, 55% men and 45% women. Patients with acute coronary syndrome, renal dialytic insufficiency, collagen disease and cancer were not included. All patients were subjected to clinical evaluation and laboratory tests. Endothelial function of the brachial artery and carotid artery were evaluated by high-resolution ultrasound; ankle-brachial index and computed tomography for coronary determination of calcium score were also performed, and non-HDL cholesterol and TG/HDL-c ratio were calculated. All patients were subjected to coronary angiography at the request of the assistant physician. We considered patients without an obstructive lesion (< 29% stenosis) demonstrated by coronary angiography to be normal.
Univariate analysis showed that calcium score, HDL-c, TG/HDL ratio and IMT were significantly correlated with the Friesinger index. However, multivariate analysis indicated that only calcium score and low HDL-c levels correlated significantly with the extension of CAD. On the other hand, hs-CRP, LDL-c, flow-mediated dilation, and Framingham score did not correlate with the Friesinger index. ROC analysis showed that calcium score, HDL-c and TG-HDL ratio accurately predicted extensive CAD in a statistically significant manner.
It is possible to approximately determine the presence and extent of CAD by non-invasive methods, especially by calcium score, HDL-c and TG/HDL-c ratio assays.
PMCID: PMC2710442  PMID: 19606245
Risk factors; Lipids; C-reactive protein; Tomography; Atherosclerosis
5.  Vascular and Metabolic Response to Statin in the Mildly Hypertensive Hypercholesterolemic Elderly 
Clinics (Sao Paulo, Brazil)  2008;63(5):589-594.
Much evidence indicates the importance of the endothelium and hypercholesterolemia in atherosclerosis, as well as the decline in endothelial function with aging. However, it is unclear if treating dyslipidemia in elderly patients improves endothelial function and reduces C-reactive protein levels.
To evaluate vasomotor function, lipids and C-reactive protein in mildly hypertensive and hypercholesterolemic elderly patients treated with atorvastatin.
Forty-seven elderly Brazilian subjects (≥ 65 years old) with LDL cholesterol (LDL-c) ≥ 130 mg/dL were randomly assigned, in a double-blinded manner, to receive either placebo (n = 23) or 20 mg/day of atorvastatin (n = 24) for 4 weeks. Exclusion criteria included diabetes, serious hypertension, obesity, steroid use, hormone replacement, and statin use within the previous six months. All patients underwent clinical examinations, laboratory tests (glucose, lipids, liver enzymes, creatine phosphokinase and high sensitivity C-reactive protein) and assessment of vasomotor function by high-resolution ultrasound examination of the brachial artery (flow-mediated dilation and sublingual nitrate), both before and after treatment.
The patients were 65 to 91 years old; there was no significant difference between basal flow-mediated dilation of placebo (7.3 ± 6.1%) and atorvastatin (4.5 ± 5.1%; p = 0.20). The same was observed after treatment (6.6 ± 6.2 vs. 5.0 ± 5.6; p = 0.55). The initial nitrate dilatation (8.1 ± 5.4% vs. 10.8 ± 7.5%; p = 0.24) and that after 4 week treatment (7.1 ± 4.7% vs. 8.6 ± 5.0%; p = 0.37) were similar. Atorvastatin produced a reduction of 20% of the C-reactive protein and 42% in the LDL-c; however, there were no changes in the flow-mediated dilation.
Atorvastatin produced a significant change of lipids and C-reactive protein; however, there were no changes in vasomotor function, suggesting the existence of intrinsic age-related vessel alterations.
PMCID: PMC2664714  PMID: 18925316
Endothelium; ultrasonography, Aged, Hydroximetilglutaril-CoA reductase inhibitors, C-reactive protein, Lipid
6.  High Ratio of Triglycerides to HDL-Cholesterol Predicts Extensive Coronary Disease 
Clinics (Sao Paulo, Brazil)  2008;63(4):427-432.
An abnormal ratio of triglycerides to HDL-cholesterol (TG/HDL-c) indicates an atherogenic lipid profile and a risk for the development of coronary disease.
To investigate the association between lipid levels, specifically TG/HDL-c, and the extent of coronary disease.
High-risk patients (n = 374) submitted for coronary angiography had their lipid variables measured and coronary disease extent scored by the Friesinger index.
The subjects consisted of 220 males and 154 females, age 57.2 ± 11.1 years, with total cholesterol of 210± 50.3 mg/dL, triglycerides of 173.8 ± 169.8 mg/dL, HDL-cholesterol (HDL-c) of 40.1 ± 12.8 mg/dL, LDL-cholesterol (LDL-c) of 137.3 ± 46.2 mg/dL, TG/HDL-c of 5.1 ± 5.3, and a Friesinger index of 6.6 ± 4.7. The relationship between the extent of coronary disease (dichotomized by a Friesenger index of 5 and lipid levels (normal vs. abnormal) was statistically significant for the following: triglycerides, odds ratio of 2.02 (1.31–3.1; p = 0.0018); HDL-c, odds ratio of 2.21 (1.42–3.43; p = 0.0005); and TG/HDL-c, odds ratio of 2.01(1.30–3.09; p = 0.0018). However, the relationship was not significant between extent of coronary disease and total cholesterol [1.25 (0.82–1.91; p = 0.33)] or LDL-c [1.47 (0.96–2.25; p = 0.0842)]. The chi-square for linear trends for Friesinger > 4 and lipid quartiles was statistically significant for triglycerides (p = 0.0017), HDL-c (p = 0.0001), and TG/HDL-c (p = 0.0018), but not for total cholesterol (p = 0.393) or LDL-c (p = 0.0568). The multivariate analysis by logistic regression OR gave 1.3 ± 0.79 (p = .0001) for TG/HDL-c, 0.779 ± 0.074 (p = .0001) for HDL-c, and 1.234 ± 0.097 (p = 0.03) for LDL. Analysis of receiver operating characteristic curves showed that only TG/HDL-c and HDL-c were useful for detecting extensive coronary disease, with the former more strongly associated with disease.
Although some lipid variables were associated with the extent of coronary disease, the ratio of triglycerides to HDL-cholesterol showed the strongest association with extent.
PMCID: PMC2664115  PMID: 18719750
Lipids; Triglycerides; HDL; Cholesterol; Coronary disease

Results 1-6 (6)