Douglas Greig

Pleiotropic effects of atorvastatin in heart failure: role in oxidative stress, inflammation, endothelial function, and exercise capacity.

BACKGROUND Increased oxidative stress, a common feature in chronic heart failure, has been associated with inflammation, endothelial dysfunction, and extracellular matrix degradation. Statins have known anti-inflammatory and anti-oxidant effects; however, their role in chronic heart failure is still controversial. METHODS This was a prospective study of 38 patients with stable systolic chronic heart failure. Patients received a 4-week placebo course, followed by atorvastatin 20 mg/day for 8 weeks. Oxidative stress, inflammation and remodeling markers, brachial artery flow-mediated vasodilation, and 6-minute walk test were evaluated at baseline, 4, and 8 weeks. RESULTS Mean age was 58 +/- 12. Mean left ventricular ejection fraction was 27% +/- 12%. No significant differences were observed between measurements at baseline and after placebo. Atorvastatin induced a significant decrease of matrix metalloproteinase-9 activity, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, interleukin-6, and malondialdehyde, and a significant increase of endothelial superoxide dismutase activity when compared with placebo. No differences in tissue inhibitor of matrix metalloproteinase and matrix metalloproteinase-2 activities were observed. Atorvastatin use was associated with an improved flow-dependent brachial vasodilation and exercise capacity in the 6-minute walk test. CONCLUSIONS In chronic heart failure patients, atorvastatin therapy is associated with a decrease of inflammation and extracellular matrix remodeling, improving both endothelial function and exercise capacity.

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.

Oxidative stress after reperfusion with primary coronary angioplasty: lack of effect of glucose-insulin-potassium infusion.

Objective To evaluate the oxidative stress status and the modification with glucose-insulin-potassium (GIK) therapy in patients with acute myocardial infarction undergoing primary percutaneous transluminal coronary angioplasty. Design Prospective, randomized, double-blinded, placebo-controlled study. Setting Cardiac intensive care unit at the university hospital. Patients Twenty patients were randomized to GIK solution (30% glucose in water with insulin 50 IU/L, and KCl 40 mM) vs. placebo (normal saline) at 1.5 mL/kg/hr for 24 hrs. The control group was 15 healthy volunteers with no heart disease. Interventions Eligible patients were randomized by a blinded pharmacist, patients with acute myocardial infarction were treated by primary percutaneous transluminal coronary angioplasty and randomized to GIK or placebo (saline solution). Primary angioplasty was successful in nine of ten patients (90%) and ten of ten patients (100%) in the GIK and placebo groups, respectively. Nine (100%) and six (60%) patients from GIK and placebo groups, respectively, underwent stent implantation. Measurements and Main Results We determined plasma levels of lipid peroxidation estimated by the malondialdehyde assay, superoxide dismutase, glutathione peroxidase, and catalase erythrocyte activities at admission and 0.5 and 24 hrs after angioplasty. Baseline determinations were compared with a control group (n = 15). Baseline clinical characteristics and time to treatment (4.5 ± 3.5 hrs) were similar between groups. Angioplasty success rate (Thrombolysis in Myocardial Infarction [TIMI] 3 flow with residual stenosis ≤30%) was 90% and 100% in GIK and placebo groups, respectively. Patients with acute myocardial infarction had an increase of malondialdehyde at baseline (2.9 ± 1.7 vs. 1.1 ± 0.3 &mgr;M, p < .01) and lower enzymatic activities of superoxide dismutase (0.5 ± 0.5 vs. 1.3 ± 0.4 U/mg hemoglobin, p < .01) and catalase (147 ± 73 vs. 198 ± 31 U/g hemoglobin, p < .01). These measurements did not change significantly after angioplasty and no differences were observed between GIK and placebo groups. Conclusion Patients with acute myocardial infarction had increased levels of oxidative stress associated with a reduction in enzymatic antioxidant reserve. Administration of GIK solution did not improve these abnormalities among patients undergoing primary angioplasty.

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.

Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure.

Increased serum uric acid has been identified as an independent risk factor for cardiovascular disease. However, because of its antioxidant capacity, uric acid may play a beneficial role in endothelial function. This paradoxical relationship between uric acid and endothelial function in chronic heart failure patients remains poorly understood. Thirty‐eight chronic heart failure patients (New York Heart Association functional class II–III, mean age 58±10 years and mean left ventricular ejection fraction 25±8%) and twelve age‐and‐sex‐matched healthy controls were studied. Chronic heart failure patients showed higher uric acid levels (7.3±2.3 mg/dL vs. 6.1±0.2 mg/dL, p<0.05) and lower extracellular superoxide dismutase activity (136±36 U ml−1 min−1 vs. 203±61 U ml−1 min−1, p<0.01) and endothelium‐dependent vasodilatation (4.0±1.6% v. 9.1±3.0%, p<0.01) when compared with control subjects. In chronic heart failure patients, correlations between both uric acid levels and extracellular superoxide dismutase activity (r=0.45; p<0.01), and uric acid and endothelium‐dependent vasodilatation (r=0.35; p=0.03) were detected. These correlations were not observed in healthy individuals, suggesting a positive effect of uric acid on endothelial function partially mediated by modulation of extracellular superoxide dismutase activity in chronic heart failure.

Xanthine-oxidase inhibitors and statins in chronic heart failure: effects on vascular and functional parameters.

BACKGROUND Increased oxidative stress in heart failure (HF) leads to inflammation and endothelial dysfunction (ED). Both statins and allopurinol have known anti-oxidant properties, but their utility in HF has not been fully assessed. METHODS This investigation was a prospective, double-blind, double-dummy study, performed between March 2007 and June 2009. Seventy-four HF patients, with New York Heart Association (NYHA) Class II or III status and left ventricular ejection fraction (LVEF) <40%, were included. Patients received placebo during 4 weeks and were then randomized to receive 4 weeks of either atorvastatin 20 mg/day plus placebo (ATV+PLA group) or atorvastatin 20 mg/day orally plus allopurinol 300 mg/day orally (ATV+ALLO group). Malondialdehyde (MDA), extracellular superoxide dismutase (ecSOD) activity and uric acid (UA) levels, among others, were determined at baseline and after 4 weeks of treatment. ED was assessed by flow-dependent endothelial-mediated vasodilation (FDD), and functional capacity by 6-minute walk test (6MWT). RESULTS Thirty-two patients were randomized to ATV+PLA and 38 to ATV+ALLO. Mean age was 59 ± 2 years, 82% were male, and 22% had an ischemic etiology. Hypertension was present in 60% and diabetes in 15% of those studied. No significant differences were observed between baseline measurements and after placebo. After 4 weeks of treatment, both groups showed a significant decrease on MDA (0.9 ± 0.1 to 0.8 ± 0.1 and 1.0 ± 0.5 to 0.9 ± 0.1 μmol/liter, p = 0.88), UA (7.4 ± 0.4 to 6.8 ± 0.3 and 7.2 ± 0.4 to 5.0 ± 0.3 mg/dl, p < 0.01) and FDD (3.9 ± 0.2% to 5.6 ± 0.4% and 4.6 ± 0.3% to 7.1 ± 0.5%, p = 0.07) with increased ecSOD activity (109 ± 11 to 173 ± 13 and 98 ± 10 to 202 ± 16, U/ml/min, p = 0.41) and improved 6MWT (447 ± 18 to 487 ± 19 and 438 ± 17 to 481 ± 21 m, p = 0.83), with all values for ATV+PLA and ATV+ALLO, respectively; p-values are for comparison between groups after treatment. CONCLUSION Short-term ATV treatment in heart failure (HF) patients reduces oxidative stress and improves FDD and functional capacity. These beneficial effects are not strengthened by the addition of allopurinol.

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.

Effect of primary coronary angioplasty on left ventricular function and myocardial perfusion as determined by Tc-99m sestamibi scintigraphy☆

There is little information available regarding the changes in the size of acute myocardial infarction (AMI) and the evolution of left ventricular (LV) function over time after primary angioplasty. 1 The evaluation of these parameters could give additional insight into the mechanisms of myocardial recovery and the possible additional benefits of adjunctive therapy to primary angioplasty. The size of the AMI can be quantified by using single-photon emission computed tomographic imaging (SPECT) scintigraphy with technetium-99m (Tc-99m) sestamibi. 2‐ 4 In this study, we evaluated the changes in LV function and in the size of the AMI with SPECT scintigraphy in patients with AMI treated with primary angioplasty. To accomplish this, SPECT was performed at the time of admission, at 72 hours, and at 3 months after primary angioplasty. ••• We studied 24 consecutive patients with AMI who were admitted to the emergency room at our institution, in whom primary angioplasty was indicated. A signed informed consent was obtained in all cases. Diagnosis of AMI was based on the classic criteria of chest pain and ST-segment elevation

Four-Limb Acute Ischemia Induced by Ergotamine in an AIDS Patient Treated With Protease Inhibitors

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

2 contiguous electrocardiographic leads. We studied patients with a first AMI who came to the emergency room within 6 hours of the onset of chest pain. Patients with prior infarction, cardiogenic shock, and those in whom coronary angiography revealed patency of the infarct-related artery (Thrombolysis In Myocardial Infarction 3 flow) were excluded. Primary angioplasty was considered to be successful when grade 3 Thrombolysis In Myocardial Infarction flow was obtained with a residual stenosis ,30%. All patients were given aspirin, and those who had stent implantation received ticlopidine or clopidogrel. Intravenous heparin in a bolus of 10,000 IU was given before angioplasty, with subsequent dosing as needed to maintain an activated coagulation time of about 300 seconds. Before primary angioplasty and during the chest