Otávio Rizzi Coelho

Effect of Spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy

Epidemiologic studies have shown an important increase in the high mortality of patients with congestive heart failure (CHF) despite optimal medical management. Ventricular arrhythmia was recognized as the most common cause of death in this population. Electrolyte imbalance, myocardial fibrosis, left ventricular dysfunction, and inappropriate neurohumoral activation are presumed responsible for sudden cardiac death. In this study, we focused on the deleterious effects of the overproduction of aldosterone that occurs in patients with CHF. Secondary hyperaldersteronism can be part of several factors thought to be responsible for sudden cardiac death. We randomized 35 patients (32 men, aged 48 +/- 9 years) with systolic dysfunction (ejection fraction 33 +/- 5%) and New York Heart Association class III CHF secondary to dilated or ischemic cardiomyopathy into 2 groups. The treatment group received spironolactone, an aldosterone receptor antagonist, along with standard medical management using furosemide, angiotensin-converting enzyme inhibitors, and digoxin. The control group received only the standard medical treatment. Holter monitoring was used to assess the severity of ventricular arrhythmia. After 20 weeks, patients who received spironolactone had a reduced hourly frequency of ventricular premature complexes (VPCs) (65 +/- 18 VPCs/hour at week 0 and 17 +/- 9 VPCs/hour at week 16) and episodes of nonsustained ventricular tachycardia (VT) (3.0 +/- 0.8 episodes of VT/24-hour period at week 0, and 0.6 +/- 0.3 VT/24-hour period at week 16). During monitored treadmill exercise, a significant improvement in ventricular arrhythmia was found in the group receiving spironolactone (39 +/- 10 VPCs at week 0, and 6 +/- 2 VPCs at week 16). These findings suggest that aldosterone may contribute to the incidence of ventricular arrhythmia in patients with CHF, and spironolactone helps reduce this complication.

Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal.

OBJECTIVE The present study aimed to verify the existence of a rebound inflammatory effect after statin withdrawal in the acute phase of myocardial infarction (MI). METHODS In a prospective observational cohort, changes in C-reactive protein (CRP) between the first and the fifth day after MI were evaluated in 249 consecutive patients who were using statins prior to and during MI (SS), statins prior to but not during MI (SN), no statin prior to but during MI (NS), and no statin prior to nor during MI (NN). Data are presented as median (interquartile range). RESULTS At baseline, statin users presented a trend to lower CRP values as compared with those without this treatment before the MI (NN: 1.0(0.4-1.5)mg/dL vs. NS: 1.0(0.3-2.8)mg/dL vs. SS: 0.5(0.3-1.0)mg/dL vs. SN: 0.6(0.4-1.0)mg/dL; p=0.08). By the fifth day, median CRP was significantly higher in the SN (18.1(16.1-23.2)mg/dL) group as compared with other groups (NN: 10.5(9.3-13.2)mg/dL vs. NS: 2.9(1.5-4.5)mg/dL vs. SS: 1.1(0.8-2.4)mg/dL; p<0.0001). At the fifth day, the median CRP in the NN group was lower than in the SN group (p<0.0001), but higher than the NS and SS groups (p<0.0001). There was no significant correlation between CRP change and the change of LDL-cholesterol, HDL-cholesterol or triglycerides. CONCLUSION The present study has, for the first time, provided evidence for the existence of a rebound inflammatory effect after statin cessation. This rebound reaction may contribute for the adverse outcome of patients who stop statin treatment during MI.

Characterization of CD4+CD28null T cells in patients with coronary artery disease and individuals with risk factors for atherosclerosis

Risk factors for atherosclerosis may contribute to chronic low-grade inflammation. A highly cytotoxic and inflammatory CD4(+) cell subset (CD4(+)CD28(null) cells) has been associated with inflammatory diseases, including acute coronary syndromes (ACS). The aim of this study was to quantify and characterize CD4(+)CD28(null) cells in individuals with risk factors for atherosclerosis and patients with coronary artery disease (CAD). In order to achieve this goal, peripheral blood mononuclear cells (PBMCs) from individuals with risk factors for atherosclerosis and patients with CAD were analyzed using flow cytometry to detect cytotoxic molecules and evaluate the expression of homing receptors and inflammatory cytokines in CD4(+) cell subsets. The cells were evaluated ex vivo and after stimulation in culture. We found no differences in the proportions of CD4(+)CD28(null) cells among the groups. Compared with the CD4(+)CD28(+) population, the ex vivo CD4(+)CD28(null) subset from all groups expressed higher levels of granzymes A and B, perforin, granulysin and interferon-γ (IFN-γ). Individuals with risk factors and patients with ACS showed the highest levels of cytotoxic molecules. After stimulation, tumor necrosis factor-α (TNF-α) expression in the CD4(+)CD28(null) subset from these groups increased more than in the other groups. Stimulation with LPS decreased the expression of cytotoxic molecules by CD4(+)CD28(null) cells in all groups. In conclusion, our results show that risk factors for atherosclerosis may alter the CD4(+)CD28(null) cells phenotype, increasing their cytotoxic potential. Our findings also suggest that CD4(+)CD28(null) cells may participate in the early phases of atherosclerosis.

Amlodipine Reduces Cardiac Iron Overload in Patients with Thalassemia Major: A Pilot Trial

BACKGROUND Iron chelation therapy in patients with thalassemia major may not prevent iron overload in all organs, especially those in which iron enters cells through specific calcium channels. We designed a controlled pilot study to assess the potential of the calcium channel blocker amlodipine in strengthening the efficacy of iron chelation. METHODS Fifteen patients with thalassemia major undergoing chelation therapy were randomized to receive amlodipine added to standard treatment in a 1:2 allocation for 12 months. T2* values for assessment of iron overload in the liver and heart using magnetic resonance imaging were obtained at baseline and at 6 and 12 months. RESULTS In the amlodipine-treated group, heart T2* increased significantly in comparison to baseline at 6 and 12 months (21.7 ± 7.2 ms to 28.2 ± 7.9 ms and 28.3 ± 8.0 ms, with P = .007 and .03, respectively), while no differences were observed in the control group (25.1 ± 8.8 ms to 24.7 ± 7.8 ms and 26.2 ± 11.4 ms; P = .99 and 0.95, respectively); significant differences between groups were observed at 6 months (28.2 ± 7.9 ms vs 24.7 ± 7.8 ms in the control group, P = .03). A significant reduction in ferritin levels also was observed in the treated group at 12 months. CONCLUSIONS The use of amlodipine in conjunction with standard chelation therapy may suggest a new strategy in preventing and treating iron overload in patients with thalassemia major, especially in organs where iron absorption depends on active uptake by calcium channels like the heart.

Níveis séricos de interleucina-6 (IL-6), interleucina-18 (IL-18) e proteína C reativa (PCR) na síndrome coronariana aguda sem supradesnivelamento do ST em pacientes com diabete tipo 2

BACKGROUND Atherosclerosis is an inflammatory disease, and serum levels of inflammatory markers such as interleukin 6 (IL-6), interleukin 18 (IL-18) and C-reactive protein (CRP) are used to evaluate patients with coronary artery disease. In patients with type-2 diabetes, atherosclerosis is related to a larger number of events such as myocardial infarction and death, when compared with patients without diabetes. OBJECTIVE To evaluate the inflammatory response in patients with diabetes and acute events of coronary instability. METHODS Two groups of patients were primarily selected. The first group was comprised of diabetic outpatients with stable angina (D-CCS) and presence of coronary artery disease on coronary angiography (n=36). The second group was comprised of diabetic patients seen in the emergency room with acute coronary syndrome (D-ACS) without ST-segment elevation (n=38). Non-diabetic patients with ACS (n=22) and CCS (n=16) comprised the control group. Serum levels of CRP, IL-6 and IL-18 were determined using nephelometry (CRP) and ELISA (IL-6 and IL-18) techniques. RESULTS Higher serum IL-6 levels were found in diabetic or non-diabetic patients with ACS than in the group with CCS. On the other hand, diabetic patients with ACS had higher CRP levels in comparison with the other groups. Serum IL-18 levels were not significantly different among the patients studied. CONCLUSION our findings suggest a more intense inflammatory activity in patients with coronary instability. This inflammatory activity, as measured by CRP, seems to be even more intense in diabetic patients.

Simvastatin prevents load-induced protein tyrosine nitration in overloaded hearts.

Abstract—Hydroxymethylglutaryl-coenzyme A reductase inhibitors prevent load-induced left ventricular hypertrophy (LVH). Whether this effect is related to antioxidant properties of this class of drugs is poorly understood. The aim of the present report was to evaluate the regulation of nitrotyrosine production during the development of load-induced LVH and the effect of simvastatin treatment in this process. Rats were subjected to aortic constriction up to 15 days. LVH was evaluated by left/right ventricle mass ratio. Myocardial content of nitrotyrosine, nitric oxide synthase (NOS) isoforms, and phagocyte-type NAD(P)H-oxidase subunits (p67-phox and p22-phox) were analyzed by immunoblotting and immunohistochemistry assays. Another group of rats received treatment with either simvastatin or placebo for 15 days after the onset of pressure overload, and their hearts were also studied. Myocardial nitrotyrosine content was increased from 3 to 15 days of pressure overload in regions of cardiac myocytes in close apposition to myocardial stroma during LVH. Neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) isoforms had their expression increased in coronary vessels (nNOS and iNOS) and in myocardial stroma (eNOS) from day 3 to day 7 of aortic constriction. However, p67-phox and p22-phox expression was increased in cells of myocardial stroma in parallel to augmented myocardial nitrotyrosine content. Simvastatin treatment inhibited the increases in myocardial nitrotyrosine content and in p67-phox and p22-phox expression, and significantly reduced LVH. In conclusion, antioxidant properties of simvastatin might play a role in myocardial remodeling induced by pressure overload.

Aldosterone excess or escape: Treating resistant hypertension.

Aldosterone excess or “escape” can occur after treatment with medications that block the renin‐angiotensin‐aldosterone system or in undiagnosed primary aldosteronism. Spironolactone is thought to be an important addition to resistant hypertension (RH) treatment. In this study, resistant (RH) and controlled (CH) hypertensives and normotensive patients were submitted to echocardiography, flow‐mediated vasodilation, carotid intima‐media wall thickness studies, renin plasma activity, and aldosterone plasma levels and plasma and urinary sodium and potassium concentrations at baseline (pre‐spironolactone phase). Subsequently, for only RH and CH groups, 25 mg/d spironolactone was added to preexisting treatments over 6 months. Afterwards, these parameters were reassessed (post‐spironolactone phase). The RH and CH groups achieved reductions in blood pressure (P<.001), decreases in left ventricular hypertrophy (P<.001), improved diastolic function (Kappa index RH: 0.219 and Kappa index CH: 0.392) and increases in aldosterone concentrations (P<.05). The RH group attained improved endothelium‐dependent (P<.001) and independent (P=.007) function. Optimized RH treatment with spironolactone reduces blood pressure and improves endothelial and diastolic function and left ventricular hypertrophy despite the presence of aldosterone excess or escape.

Timing and Dose of Statin Therapy Define Its Impact on Inflammatory and Endothelial Responses During Myocardial Infarction

Objective—Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI. Methods and Results—ST-elevation MI patients (n=125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non–statin users (12.0±4.1 mg/L) and patients treated with 20 (8.5±4.0 mg/L), 40 (3.8±2.5 mg/L), and 80 mg/day (1.4±1.5 mg/L), and the daily differences remained significant until the seventh day (P<0.0001). The higher the statin dose, the lower the elevation of interleukin-2 and tumor necrosis factor-&agr;, the greater the reduction of 8-isoprostane and low-density lipoprotein(−), and the greater the increase in nitrate/nitrite levels during the first 5 days (P<0.001). Later initiation of statin was less effective than its early introduction in relation to attenuation of CRP, interleukin-2, tumor necrosis factor-&agr;, 8-isoprostane, and low-density lipoprotein(−), as well as in increase in nitrate/nitrite levels (P<0.0001). At the 30th day, there was no longer a difference in lipid profile or CRP between groups; the flow-mediated dilation, however, was proportional to the initial statin dose and was higher for those who started the treatment early (P=0.001). Conclusion—This study demonstrates that the timing and potency of statin treatment during MI are key elements for their main mechanisms of benefit. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00906451.

Most of the patients presenting myocardial infarction would not be eligible for intensive lipid-lowering based on clinical algorithms or plasma C-reactive protein

OBJECTIVE The study we assessed how often patients who are manifesting a myocardial infarction (MI) would not be considered candidates for intensive lipid-lowering therapy based on the current guidelines. METHODS In 355 consecutive patients manifesting ST elevation MI (STEMI), admission plasma C-reactive protein (CRP) was measured and Framingham risk score (FRS), PROCAM risk score, Reynolds risk score, ASSIGN risk score, QRISK, and SCORE algorithms were applied. Cardiac computed tomography and carotid ultrasound were performed to assess the coronary artery calcium score (CAC), carotid intima-media thickness (cIMT) and the presence of carotid plaques. RESULTS Less than 50% of STEMI patients would be identified as having high risk before the event by any of these algorithms. With the exception of FRS (9%), all other algorithms would assign low risk to about half of the enrolled patients. Plasma CRP was <1.0mg/L in 70% and >2mg/L in 14% of the patients. The average cIMT was 0.8±0.2mm and only in 24% of patients was ≥1.0mm. Carotid plaques were found in 74% of patients. CAC ≥100 was found in 66% of patients. Adding CAC ≥100 plus the presence of carotid plaque, a high-risk condition would be identified in 100% of the patients using any of the above mentioned algorithms. CONCLUSION More than half of patients manifesting STEMI would not be considered as candidates for intensive preventive therapy by the current clinical algorithms. The addition of anatomical parameters such as CAC and the presence of carotid plaques can substantially reduce the CVD risk underestimation.

Differential expression of cytokines, chemokines and chemokine receptors in patients with coronary artery disease.

Monocytes/macrophages and lymphocytes have a key role in the pathogenesis of atherosclerosis through the production of inflammatory and anti-inflammatory cytokines. We evaluated mRNA expression and protein production of CCL2, CXCL8, CXCL9, CXCL10, IFN-gamma and IL-10 in vitro as well as the expression of the CCR2 and CXCR3 receptors in peripheral blood mononuclear cells (PBMCs) of patients with coronary artery disease (CAD) and healthy controls in the presence or absence of oxidized LDL (oxLDL). Patients with CAD showed higher constitutive expression of CCL2, CXCL8, CXCL9, CXCL10 and IFN-gamma mRNA and, after stimulation with oxLDL, higher expression of CCL2 and CXCL8 mRNA than the control group. We also detected higher levels of CCL2 and CXCL8 in supernatants of oxLDL-stimulated PBMCs from CAD patients than in corresponding supernatants from controls. Patients with CAD had a higher percentage of constitutive CCR2(+) and CXCR3(+) cells after stimulation with oxLDL. Among CAD patients, the main differences between the stable (SA) and unstable angina (UA) groups were lower IL-10 mRNA production in the latter group. Altogether, our data suggest that PBMCs from CAD patients are able to produce higher concentrations of chemokines and cytokines involved in the regulation of monocyte and lymphocyte migration and retention in atherosclerotic lesions.