Osvaldo Pérez

Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure

Our previous studies suggest that the increase in heart rate from rest to peak exercise is reduced in patients with chronic heart failure (CHF) and this is associated with increased oxidative stress, as determined by malondialdehyde (MDA) plasma levels.

Relation between oxidative stress, catecholamines, and impaired chronotropic response to exercise in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

O stress has been implicated in the pathogenesis of chronic heart failure (HF). Different studies have shown that reactive oxygen species are produced in the failing myocardium, causing injury in cardiac myocytes.1–3 Different factors classically associated with cardiomyocyte dysfunction and death in chronic HF, such as increased plasma catecholamine levels, are well-known stimuli for the generation of reactive oxygen species.4 In patients with advanced chronic HF at rest, the circulating norepinephrine concentrations are much higher, generally 2 to 3 times the level found in normal subjects.5,6 During comparable levels of exercise, much greater elevations in circulating norepinephrine occur in patients with chronic HF than in normal subjects. However, despite the increase in norepinephrine with exercise, patients with chronic HF had an attenuated heart rate response to exercise; this finding has been attributed to postsynaptic desensitization of the -adrenergic receptor pathway.7 A relation between cardiac exercise capacity and oxidative stress determined by malondialdehyde (MDA) plasma levels, a marker of lipid peroxidation, has been proposed.8 Experimental data also suggest that hydrogen peroxide may attenuate the -adrenoceptor– linked signal transduction in the heart by changing the functions of Gs proteins and the catalytic subunit of the adenylyl cyclase.9 In the present study we investigated the association between MDA plasma levels, catecholamines at peak exercise, and impaired heart rate response to exercise in patients with chronic HF. • • • We enrolled 27 patients with chronic HF secondary to coronary heart disease (n 15) or idiopathic dilated cardiomyopathy (n 12). They fulfilled the following criteria: (1) chronic stable HF in New York Heart Association functional classes II to IV; (2) ability to complete a symptom-limited treadmill exercise test; (3) evidence of left ventricular (LV) dilation and LV ejection fraction 40% as determined by radionuclide-gated pool scan; and (4) treatment with diuretics, digitalis, and vasodilators. We excluded patients with (1) coronary artery bypass surgery, angioplasty, or myocardial infarction in the last 6 months; (2) chronic angina; (3) uncontrolled hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 90 mm Hg); (4) hypertensive myocardiopathy; (5) change in maintenance therapy or use of blockers in the last 2 months; (6) implanted pacemaker; (7) significant valvular disease; and (8) presence of other conditions that affect determination of oxidative stress status, such as renal insufficiency (plasma creatinine 2 mg/dl), autoimmune diseases, neoplasia, advanced liver or pulmonary disease, and acute or chronic inflammation. All patients signed an informed consent approved by our institutional review board and ethics committee. For clinical assessment we used New York Heart Association functional class and the Mahler et al10 clinical score (range 0 to 12 points), which evaluates the severity of dyspnea. The score depends on ratings for 3 different categories: functional impairment, magnitude of task, and magnitude of effort. Dyspnea is rated in 5 degrees from 0 (severe) to 4 (unimpaired) for each category. The ratings for each of the 3 categories are added to form the score. LV end-diastolic and LV end-systolic diameters were determined by Doppler 2-dimensional echocardiography, and LV ejection fraction was determined by radionuclide ventriculography. Each patient performed a 6-minute corridor walk test and a maximal exercise test with gas exchange. Plasma norepinephrine and epinephrine specimens were collected from an indwelling venous line after patients had been in the supine position in a quiet room for 30 minutes. Measurements were repeated at maximal exercise. Determination of catecholamines was performed by high-performance liquid chromatography using a commercial kit (Chromsystems Instruments & Chemicals GmbH, Munchen, Germany). The interand intra-assay coefficients were 6% and 5%, respectively. The ratio of the increment in heart rate divided by the increment in norepinephrine from From the Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile; and the Departments of Biochemistry and Molecular Biology and Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Faculty of Medicine and the FONDAP Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile. Dr. Castro was supported in part by Grant FONDECYT 1010992, Santiago; and Dr. Lavandero was supported in part by Grant FONDAP 15010006, Santiago, Chile. Dr. Castro’s address is: Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile, Marcoleta 367, Santiago, Chile. E-mail: pcastro@med.puc.cl. Manuscript received January 23, 2003; revised manuscript received and accepted April 7, 2003.

Effects of glucose-insulin-potassium solution on myocardial salvage and left ventricular function after primary angioplasty.

ObjectiveTo evaluate the effects of glucose-insulin-potassium (GIK) therapy on infarct size and left ventricular function when used as an adjuvant therapy to primary angioplasty. DesignProspective, randomized, double-blind, placebo-controlled study. SettingCardiac intensive care unit at a university hospital. PatientsThirty-seven patients with acute myocardial infarction for whom primary angioplasty was indicated. InterventionsEligible patients were randomized by a blinded pharmacist to GIK solution (30% glucose in water with insulin 50 U/L, and KCl 40 mM/L) vs. placebo at 1.5 mL/kg/hr for 24 hrs. Measurements and Main ResultsTc 99m sestamibi myocardial scintigraphy was performed at admission and at 3 months. Primary end points were the changes in left ventricular ejection fraction (LVEF) and the size of salvaged myocardium. Baseline clinical characteristics were similar in both groups. At the 3-month follow-up, a significant overall decrease in infarct size (37 ± 16% vs. 12 ± 10%, p < .005) and an increase in LVEF (34 ± 13% vs. 49 ± 9%, p = .005) were observed. Patients randomized to GIK solution experienced a significant increase in their LVEF at 3 months (39 ± 12 to 51 ± 13, p = .002). Patients who received placebo had no significant differences between baseline and 3-month measurements (44 ± 13 vs. 49 ± 14, p = NS). There was a trend toward an increase in myocardial salvage in the GIK group, which did not reach statistical significance. When patients from both groups were compared directly, differences in LVEF improvement were no longer significant. ConclusionsGIK solution did not improve LVEF or decrease the infarct size among patients undergoing primary angioplasty.

Effects of early decrease in oxidative stress after medical therapy in patients with class IV congestive heart failure

I t has been reported that patients with congestive heart failure (CHF) have increased breath pentane content, conjugated diene levels, and plasma malondialdehyde (MDA) levels, an indirect marker of lipid peroxidation. Ghatak et al found that patients with chronic CHF had increased MDA and superoxide levels, which correlated with the severity of the CHF. Low glutathione levels and superoxide dismutase (SOD) activity have also been reported. There have been no studies in human refractory CHF to evaluate the impact of acute intensive medical therapy on oxidative stress status and antioxidant enzyme activity. We determined the plasma levels of MDA, SOD, catalase (CAT), and glutathione peroxidase (GSH-Px) activities before and after therapeutic intervention in patients with chronic advanced CHF and refractory symptoms (New York Heart Association functional class IV). • • • We enrolled 15 patients admitted to our Coronary Care Unit with the diagnosis of refractory CHF. All patients signed an informed consent approved by our Institutional Review Board and Ethical Committee. Inclusion criteria were: (1) persistence of pulmonary congestion, edema, or worsening of renal function despite optimal treatment with diuretics, digitalis, and vasodilators; (2) evidence of left ventricular dilation and systolic dysfunction as determined by echocardiography, with a left ventricular ejection fraction From the Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile; and the Departments of Chemical Pharmacology and Toxicology; and Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile. Dr. Castro was supported by grants 1990491 and 1010992 from the Fondo Nacional de Ciencia y Tecnologia, FONDECYT, Santiago, Chile, and Dr. Diaz-Araya was supported by grant PT2000-01 from the Faculty of Chemical and Pharmaceutical Science, University of Chile, Santiago, Chile. Dr. Castro’s address is: Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile, Marcoleta 367, Santiago, Chile. E-mail: pcastro@med.puc.cl.

Matrix metalloproteinase-9 activity is associated to oxidative stress in patients with acute coronary syndrome

Abstract In the present work we evaluate the relationship between oxidative stress and matrix metalloproteinases-2 and -9 (MMP-2 and -9) activities in 44 patients with non ST-elevation acute coronary syndrome. We found an early increase in malondialdehyde (MDA) levels (oxidative stress marker) and MMP-9, with decrease of both at day five. A positive correlation was found between fractional changes of MDA and MMP-9, suggesting a common role in the pathophysiology of the acute coronary syndrome.

Persistencia del estrés oxidativo postrasplante cardíaco: estudio comparativo entre pacientes con trasplante cardíaco y con insuficiencia cardíaca crónica estable

Introduccion y objetivo Existe estres oxidativo en pacientes con insuficiencia cardiaca cronica (ICC). El trasplante cardiaco, alternativa terapeutica importante en estos pacientes, podria disminuir el estres oxidativo al mejorar la funcion cardiaca. Nuestro objetivo fue evaluar el estres oxidativo postrasplante cardiaco. Pacientes y metodo Fueron estudiados 3 grupos experimentales: a) trasplantados cardiacos, sin evidencia de rechazo (n = 11); b) pacientes con ICC capacidad funcional III de la NYHA (n = 19), y c) sujetos controles sanos (n = 14). El estres oxidativo se evaluo determinando valores plasmaticos de malondialdehido (MDA), y actividades de glutation peroxidasa (GSH-Px), catalasa (CAT) y superoxido dismutasa (SOD). Resultados Las caracteristicas demograficas fueron similares entre los grupos. El tiempo postrasplante fue 20,0 ± 4,8 meses. Los valores de MDA en trasplantados y con ICC fueron significativamente mayores que en sujetos normales (3,35 ± 0,8; 3,27 ± 1,7, y 0,90 ± 0,3 µM, respectivamente). La actividad de GSH-Px aumento en trasplantados respecto al grupo control (0,40 ± 0,07 y 0,33 ± 0,05 U/g Hb, respectivamente). La actividad de SOD fue menor en trasplantados respecto al grupo control ICC (0,44 ± 0,1 frente a 0,87 ± 0,6 U/mg Hb). No hubo diferencias en las actividades de CAT entre trasplantados y pacientes con ICC. Conclusion Los pacientes sometidos a trasplante cardiaco tienen un aumento del estres oxidativo, evidenciado por una elevacion del MDA y por una disminucion de la actividad de SOD, a pesar de una mayor actividad de GSH-Px. Este aumento del estres oxidativo fue similar al encontrado en pacientes con ICC estable CF III de la NYHA, y se observo en ausencia de episodios reconocidos de infeccion o rechazo.

Microvascular Coronary Flow Comparison in Acute Myocardial Infarction Angioplasty treated with a mesh covered stent (MGUARD Stent) versus Bare Metal Stent☆ MICAMI-MGUARD

BACKGROUND Distal embolization of thrombus/platelet aggregates decreases myocardial reperfusion during primary percutaneous coronary intervention (PCI), and is associated with worse immediate and long-term prognosis of patients with ST-elevation myocardial infarction (STEMI). OBJECTIVE Assess the efficacy of a mesh covered stent (MGuard™ stent, MGS) in preventing distal embolization and microvascular reperfusion impairment during primary PCI, compared with a bare metal stent (BMS). METHODS Forty patients with STEMI referred for primary PCI were randomized for stenting the culprit lesion with the MGS (n = 20) or a BMS (n = 20). Blinded experts performed off-line measurements of angiographic epicardial and microvascular reperfusion criteria: TIMI flow grade, myocardial blush, corrected TIMI frame count (cTFC). RESULTS At baseline clinical, angiographic and procedural variables were not different between groups. Post PCI TIMI flow grade was similar in both groups. We observed better myocardial Blush grade in group MGS compared to BMS (median value 3.0 vs 2.5, 2p = 0.006) and cTFC (mean cTFC: MGS 19.65 ± 4.07 vs BMS 27.35 ± 7.15, 2p < 0.001, cTFC mean difference MGS-BMS: 7.7, CI 95%: 3.94 to 11.46). MGS stent group had a higher percentage of successful angioplasty (cTFC ≤ 23: MGS 85% vs BMS 30%, 2p < 0.001). We had two cases of acute stent thrombosis (one for each group) at 30days follow up, but no clinical events at 6 months follow up. CONCLUSIONS In this exploratory study, MGS significantly improved microvascular reperfusion criteria compared with a BMS in primary PCI. However its safety and impact on clinical outcomes should be verified in larger randomized clinical trials.

Unidad de dolor torácico: primera experiencia en Chile

In large series, nearly 60% of admissions forsuspected acute coronary syndrome (ACS) had a non-coronary etiology of the pain. However,short term mortality of non recognized ACS patients, mistakenly discharged from the emergencyroom is at least twice greater than the expected if they would had been admitted. The concept ofa chest pain unit (CPU) is a methodological approach developed to address these issues.

Effects of Carvedilol on Functional Capacity, Left Ventricular Function, Catecholamines, and Oxidative Stress in Patients With Chronic Heart Failure

INTRODUCTION AND OBJECTIVE Carvedilol is an antioxidant and adrenergic antagonist with demonstrated benefits in terms of mortality from heart failure (HF). The aim of the present study was to evaluate clinical parameters, left ventricular function, oxidative stress levels and neurohumoral status at baseline and after 6 months of treatment with carvedilol in patients with chronic HF. PATIENTS AND METHOD Thirty patients with chronic HF that was stable without beta blocker treatment were included. Functional class was II or III, and left ventricular ejection fraction (LVEF) was < 40%. Mahler score, distance walked in 6 min, peak oxygen consumption, LVEF, plasma catecholamine (norepinephrine) concentration and oxidative stress parameters were evaluated at baseline and after 6 months of treatment with carvedilol. RESULTS Mean age was 59 (2) years, and 23 patients were men. After 6 months of treatment there were clinical improvements as measured by the Mahler score (from 6.8 to 11.0 points; P=.001) and the 6-min walk distance (from 499 [18] to 534 [17] m; P =.032), but no changes in peak oxygen consumption. The LVEF increased from 24 (1) to 31 (2)% (P=.003). In patients with chronic HF, plasma malondialdehyde concentration was significantly lower after 6 months (decrease from 2.4 [0.2] to 1.1 [0.2] micromol/l; P<.001). No significant changes were observed in plasma catecholamine levels or antioxidant enzyme activities. CONCLUSIONS In patients with chronic HF, carvedilol treatment for 6 months was associated with clinical improvements, increased left ventricular function and decreased plasma concentrations of malondialdehyde, with no changes in plasma catecholamine levels.

Angiographic and electrocardiographic parameters of myocardial reperfusion in angioplasty of patients with ST elevation acute myocardial infarction loaded with ticagrelor or clopidogrel (MICAMI—TICLO trial)

INTRODUCTION Ticagrelor has been shown to improve outcomes in patients with ACS. However, the effects of this drug on parameters of microvascular flow in patients presenting with ST-segment elevation myocardial infarction (STEMI) have not been completely evaluated. METHODS Ninety-two patients presenting with STEMI where randomized to a loading dose of clopidogrel (600 mg) or ticagrelor (180 mg) before undergoing primary angioplasty. We assessed angiographic and electrocardiographic parameters of myocardial reperfusion. Blinded operators calculated angiographic corrected TIMI Frame count (cTFC) and myocardial blush grade (MBG) before and after stent implantation. ST segment resolution was also measured in all patients. Primary endpoint was cTFC after PCI. Secondary endpoints were cTFC prior to PCI, TIMI flow grade, MBG and the percentage of ST resolution. RESULTS Of the 92 randomized patients, 70 patients were analyzed. Mean age of patients was 58.8±10 years. Patients presented with a mean ischemic time of 4.4±2.6 hours. There were no significant differences in the time between loading dose and stent deployment (35.2±36.4 in ticagrelor and 42.7±29.5 min in clopidogrel, p=0.36). cTFC before angioplasty was significantly lower in ticagrelor than in clopidogrel (81.1±29.4 vs. 95.1±17.5 frames respectively, p=0.01). After angioplasty there were no differences between ticagrelor and clopidogrel in cTFC (24.6±9.3 vs. 27.0±13.4 frames respectively, p=0.62); MBG grade 3 was present in 76.4 vs. 69.4% of patients, respectively (p=0.41). The percentage of ST resolution did not show any differences between groups (84.8±23.4 in ticagrelor vs. 70.8±33.7 in clopidogrel, p=0.36). CONCLUSION Compared with clopidogrel, ticagrelor loading in patients presenting with STEMI is not associated with an improvement of angiographic and electrocardiographic parameters of myocardial reperfusion after angioplasty.