Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

BACKGROUND: The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. METHODS: Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. RESULTS: The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. CONCLUSION: Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Prediction of first coronary events with the Framingham score: a systematic review

BACKGROUND: Uncertainty exists about the performance of the Framingham risk score when applied in different populations. OBJECTIVE: We assessed calibration of the Framingham risk score (ie, relationship between predicted and observed coronary event rates) in US and non-US populations free of cardiovascular disease. METHODS: We reviewed studies that evaluated the performance of the Framingham risk score to predict first coronary events in a validation cohort, as identified by Medline, EMBASE, BIOSIS, and Cochrane library searches (through August 2005). Two reviewers independently assessed 1496 studies for eligibility, extracted data, and performed quality assessment using predefined forms. RESULTS: We included 25 validation cohorts of different population groups (n = 128,000) in our main analysis. Calibration varied over a wide range from under- to overprediction of absolute risk by factors of 0.57 to 2.7. Risk prediction for 7 cohorts (n = 18658) from the United States, Australia, and New Zealand was well calibrated (corresponding figures: 0.87-1.08; for the 5 biggest cohorts). The estimated population risks for first coronary events were strongly associated (goodness of fit: R2 = 0.84) and in good agreement with observed risks (coefficient for predicted risk: beta = 0.84; 95% CI 0.41-1.26). In 18 European cohorts (n = 109499), the corresponding figures indicated close association (R2 = 0.72) but substantial overprediction (beta = 0.58, 95% CI 0.39-0.77). The risk score was well calibrated on the intercept for both population clusters. CONCLUSION: The Framingham score is well calibrated to predict first coronary events in populations from the United States, Australia, and New Zealand. Overestimation of absolute risk in European cohorts requires recalibration procedures.

Eosinophilic disorders

Eosinophilic inflammatory responses occur in association with multiple disorders. Although the initial cause and the affected organs vary among the different eosinophilic disorders, there are only 2 major pathways that mediate eosinophilia: (1) cytokine-mediated increased differentiation and survival of eosinophils (extrinsic eosinophilic disorders), and (2) mutation-mediated clonal expansion of eosinophils (intrinsic eosinophilic disorders). Independent from the original trigger, the most common cause of eosinophilia is the increased generation of IL-5-producing T cells. In some cases, tumor cells are the source of eosinophil hematopoietins. The intrinsic eosinophilic disorders are characterized by mutations in pluripotent or multipotent hematopoietic stem cells leading to chronic myeloid leukemias with eosinophils as part of the clone. Here, we propose a new classification of eosinophilic disorders on the basis of these obvious pathogenic differences between the 2 groups of patients. We then discuss many known eosinophilic disorders, which can be further subdivided by differences in T-cell activation mechanisms, origin of the cytokine-producing tumor cell, or potency of the mutated stem cell. Interestingly, many subgroups of patients originally thought to have the idiopathic hypereosinophilic syndrome can be integrated in this classification.

Intravenous immunoglobulin preparations contain anti-Siglec-8 autoantibodies

BACKGROUND: Human intravenous immunoglobulin (IVIg) preparations are used for the treatment of autoimmune and allergic diseases. Natural autoantibodies are believed to contribute to IVIg-mediated anti-inflammatory effects. OBJECTIVE: To address the question of whether IVIg preparations contain anti-sialic acid-binding Ig-like lectin-8 (anti-Siglec-8) autoantibodies. METHODS: The presence of possible anti-Siglec-8 autoantibodies in IVIg preparations was first examined by functional eosinophil death and apoptosis assays. Specificity of IVIg effects was shown by depleting anti-Siglec-8 autoantibodies from IVIg. Binding of purified anti-Siglec-8 autoantibodies to recombinant Siglec-8 was demonstrated by an immunodot assay. RESULTS: IVIg exerts cytotoxic effects on purified human blood eosinophils. Both potency and efficacy of the IVIg-mediated eosinophil killing effect was enhanced by IL-5, granulocyte/macrophage colony-stimulating factor, IFN-gamma, TNF-alpha, and leptin. Similarly, inflammatory eosinophils obtained from patients suffering from the hypereosinophilic syndrome (HES) demonstrated increased Siglec-8 cytotoxic responses when compared with normal blood eosinophils. Pharmacologic blocking experiments indicated that the IVIg-mediated additional eosinophil death in the presence of cytokines is largely caspase-independent, but it depends on reactive oxygen species. Anti-Siglec-8 autoantibody-depleted IVIg failed to induce caspase-independent eosinophil death. CONCLUSION: IVIg preparations contain natural anti-Siglec-8 autoantibodies. CLINICAL IMPLICATIONS: Anti-Siglec-8 autoantibodies present in IVIg preparations may have therapeutic relevance in autoimmune and allergic diseases, respectively, such as Churg-Strauss syndrome.

Benign paroxysmal positional vertigo in mountain bikers

We evaluated 4 men who had benign paroxysmal positional vertigo (BPPV) that occured several hours after intensive mountain biking but without head trauma. The positional maneuvers in the planes of the posterior and horizontal canals elicited BPPV, as well as transitory nystagmus. This was attributed to both the posterior and horizontal semicircular canals (SCCs) on the left side in 1 patient, in these 2 SCCs on the right side in another patient, and to the right posterior SCC in the other 2 patients. The symptoms disappeared after physiotherapeutic maneuvers in 2 patients and spontaneously in the other 2 patients. Cross-country or downhill mountain biking generates frequent vibratory impacts, which are only partially filtered through the suspension fork and the upper parts of the body. Biomechanically, during a moderate jump, before landing, the head is subjected to an acceleration close to negative 1 g, and during impact it is subjected to an upward acceleration of more than 2g. Repeated acceleration-deceleration events during intensive off-road biking might generate displacement and/or dislocation of otoconia from the otolithic organs, inducing the typical symptoms of BPPV. This new cause of posttraumatic BPPV should be considered as an injury of minor severity attributed to the practice of mountain biking.

Proteomics in cardiovascular surgery

Proteomics describes, analogous to the term genomics, the study of the complete set of proteins present in a cell, organ, or organism at a given time. The genome tells us what could theoretically happen, whereas the proteome tells us what does happen. Therefore, a genomic-centered view of biologic processes is incomplete and does not describe what happens at the protein level. Proteomics is a relatively new methodology and is rapidly changing because of extensive advances in the underlying techniques. The core technologies of proteomics are 2-dimensional gel electrophoresis, liquid chromatography, and mass spectrometry. Proteomic approaches might help to close the gap between traditional pathophysiologic and more recent genomic studies, assisting our basic understanding of cardiovascular disease. The application of proteomics in cardiovascular medicine holds great promise. The analysis of tissue and plasma/serum specimens has the potential to provide unique information on the patient. Proteomics might therefore influence daily clinical practice, providing tools for diagnosis, defining the disease state, assessing of individual risk profiles, examining and/or screening of healthy relatives of patients, monitoring the course of the disease, determining the outcome, and setting up individual therapeutic strategies. Currently available clinical applications of proteomics are limited and focus mainly on cardiovascular biomarkers of chronic heart failure and myocardial ischemia. Larger clinical studies are required to test whether proteomics may have promising applications for clinical medicine. Cardiovascular surgeons should be aware of this increasingly pertinent and challenging field of science.

Ecological study of the predictors of successful management of dyslipidemia in HIV-infected patients on ART: the Swiss HIV Cohort Study

PURPOSE: Antiretroviral therapy (ART) may induce metabolic changes and increase the risk of coronary heart disease (CHD). Based on a health care system approach, we investigated predictors for normalization of dyslipidemia in HIV-infected individuals receiving ART. METHOD: Individuals included in the study were registered in the Swiss HIV Cohort Study (SHCS), had dyslipidemia but were not on lipid-lowering medication, were on potent ART for >or= 3 months, and had >or= 2 follow-up visits. Dyslipidemia was defined as two consecutive total cholesterol (TC) values above recommended levels. Predictors of achieving treatment goals for TC were assessed using Cox models. RESULTS: Analysis included 958 individuals with median followup of 2.3 years (IQR 1.2-4.0). 454 patients (47.4%) achieved TC treatment goals. In adjusted analyses, variables significantly associated with a lower hazard of reaching TC treatment goals were as follows: older age (compared to 18-37 year olds: hazard ratio [HR] 0.62 for 45-52 year olds, 95% CI 0.47-0.82; HR 0.40 for 53-85, 95% CI 0.29-0.54), diabetes (HR 0.39, 95% CI 0.26-0.59), history of coronary heart disease (HR 0.27, 95% CI 0.10-0.71), higher baseline TC (HR 0.78, 95% CI 0.71-0.85), baseline triple nucleoside regimen (HR 0.12 compared to PI-only regimen, 95% CI 0.07-0.21), longer time on PI-only regimen (HR 0.39, 95% CI 0.33-0.46), longer time on NNRTI only regimen (HR 0.35, 95% CI 0.29-0.43), and longer time on PI/NNRTI regimen (HR 0.34, 95% CI 0.26-0.43). Switching ART regimen when viral load was undetectable was associated with a higher hazard of reaching TC treatment goals (HR 1.48, 95% CI 1.14-1.91). CONCLUSION: In SHCS participants on ART, several ART-related and not ART-related epidemiological factors were associated with insufficient control of dyslipidemia. Control of dyslipidemia in ART recipients must be further improved.

Drug-eluting or bare-metal stents for large coronary vessel stenting? The BASKET-PROVE (PROspective Validation Examination) trial: study protocol and design

BACKGROUND: Based on a subgroup analysis of 18-month BAsel Stent Kosten Effektivitäts Trial (BASKET) outcome data, we hypothesized that very late (> 12 months) stent thrombosis occurs predominantly after drug-eluting stent implantation in large native coronary vessel stenting. METHODS: To prove or refute this hypothesis, we set up an 11-center 4-country prospective trial of 2260 consecutive patients treated with > or = 3.0-mm stents only, randomized to receive Cypher (Johnson ; Johnson, Miami Lakes, FL), Vision (Abbott Vascular, Abbott Laboratories, IL), or Xience stents (Abbott Vascular). Only patients with left main or bypass graft disease, in-stent restenosis or stent thrombosis, in need of nonheart surgery, at increased bleeding risk, without compliance/consent are excluded. All patients are treated with dual antiplatelet therapy for 12 months. The primary end point will be cardiac death/nonfatal myocardial infarction after 24 months with further follow-up up to 5 years. RESULTS: By June 12, 229 patients (10% of the planned total) were included with a baseline risk similar to that of the same subgroup of BASKET (n = 588). CONCLUSIONS: This study will answer several important questions of contemporary stent use in patients with large native vessel stenting. The 2-year death/myocardial infarction-as well as target vessel revascularization-and bleeding rates in these patients with a first- versus second-generation drug-eluting stent should demonstrate the benefit or harm of these stents compared to cobalt-chromium bare-metal stents in this relevant, low-risk group of everyday patients. In addition, a comparison with similar BASKET patients will allow to estimate the impact of 12- versus 6-month dual antiplatelet therapy on these outcomes.

Vascular adaptation of the internal thoracic artery graft early and late after bypass surgery

OBJECTIVE: Flow mismatch between the supplying artery and the myocardial perfusion region has been observed in patients with internal thoracic artery grafts. Thus coronary flow changes of arterial (internal thoracic artery grafts) and saphenous (saphenous vein grafts) bypass grafts were studied early and late after coronary artery bypass grafting. METHODS: Thirty patients undergoing elective bypass surgery (internal thoracic artery and saphenous vein grafts) were studied intraoperatively and (17 patients) 3 to 10 months postoperatively. Coronary flow was measured intraoperatively with the transit-time Doppler scanning technique. Postoperatively, flow velocity and coronary flow reserve were determined with the Doppler flow wire technique. Quantitative angiographic analysis was used to determine vessel size for calculation of absolute flow. RESULTS: Intraoperatively, internal thoracic artery graft flow was significantly lower than saphenous vein graft flow (31 +/- 8 vs 58 +/- 29 mL/min, P < .01). Postoperatively, internal thoracic artery graft flow increased significantly to 42 +/- 24 mL/min at 3 months and to 56 +/- 30 mL/min (P < .02 vs intraoperative value) at 10 months, respectively. However, saphenous vein graft flow remained unchanged over time (58 +/- 29 to 50 +/- 27 mL/min at 3 months and 46 +/- 27 mL/min at 10 months). Coronary flow reserve was abnormally low intraoperatively in the internal thoracic artery (1.3 +/- 0.3) and saphenous vein (1.6 +/- 0.5) grafts but increased significantly to normal values in both types of graft at follow-up. CONCLUSIONS: Bypass flow of the internal thoracic artery graft is significantly reduced intraoperatively when compared with that of the saphenous vein graft. However, 3 and 10 months after the operation, flow of the internal thoracic artery graft increases significantly and is similar to saphenous vein graft flow. This finding can be explained by an early flow mismatch of the native internal thoracic artery in the presence of a large perfusion territory. During follow-up, there is vascular remodeling of the internal thoracic artery, probably because of endothelium-mediated mechanisms.