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Background Geographic differences and background therapy have not been explored in the global VICTORIA trial, which enrolled high-risk patients with recent worsening heart failure with reduced ejection fraction (HFrEF). Methods and results Among 5050 patients enrolled in 5 pre-specified geographic regions, 34% were from Eastern Europe, 18% Western Europe, 23% Asia Pacific, 14% Latin and South America, and 11% North America (Table 1). Patients from Western Europe were older, had more atrial fibrillation, and lower glomerular filtration rates. Patients from Eastern Europe had more coronary artery disease and exhibited more advanced symptoms (∼50% New York Heart Association [NYHA] class III), whereas those from Latin and South America were less symptomatic (∼70% NYHA class II). North American patients had the largest body mass index as well as more diabetes and hypertension. Levels of NT-proBNP at randomization and MAGGIC risk scores were highest in Western European patients. Evidence-based triple medication therapy was used most frequently in Latin and South America and less frequently in North America; conversely, cardiac resynchronization therapy and implantable cardioverter defibrillators were most frequently used in North America and least frequently in Latin and South America. The overall primary composite event rate (cardiovascular death or HF hospitalization) in the placebo arm was 36.6/100 person-years over a median of 10.8 months and after adjusting for the MAGGIC score. When examined by region, these event rates were nominally highest in North America and lowest in Western Europe. Conclusion Substantial regional differences exist in characteristics and treatments among patients in this global trial of patients with HFrEF and a recent worsening event. These findings demonstrate the continuing unmet needs and opportunities for enhancing care in HFrEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): VICTORIA was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Bayer AG, Wuppertal, Germany.

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome that may emerge from overlapping systemic processes associated with several medical co-morbidities, often within an inflammatory milieu. Identification of unique proteins associated with distinct phenotypes may yield insight into novel therapeutics. Purpose Determine if unique clusters of circulating proteins are associated with specific clinical characteristics in patients with HFpEF. Methods A targeted discovery proteomics approach with 358 unique proteins associated with cardiovascular disease and inflammation (Olink) was used at baseline in VITALITY-HFpEF among 789 participants with documented left ventricular EF ≥45% and recent decompensation ( Results Four unique clusters were identified containing 24, 66, 197, and 81 proteins, respectively. Figure 1 shows the adjusted association of the 4 protein clusters, shown with their hub proteins, with the clinical characteristics. The color (red: positive, green: negative relationship) and intensity indicate the magnitude of the standardized difference (relative to the variation [i.e., T-value]); p-value shown in boxes. Cluster 3, with tumor necrosis factor receptor 1 as a hub protein that mediates apoptosis and inflammation, was associated with greater frailty and physical limitation along with shorter 6MWD. In contrast, cluster 4, with protein C as a hub protein that regulates anticoagulation and exerts a protective function on endothelial cells, is associated with less frailty and younger age, and more frequently male sex. Cluster 2 was associated with only younger age and cluster 1 with no clinical characteristics. Conclusions Proteomics appear to identify specific clinical phenotypes associated with HFpEF. Further exploration of this approach may provide insight into the diverse pathophysiology characterizing this disorder and a more targeted approach to therapy. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): VITALITY-HFpEF was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Bayer AG, Wuppertal, Germany.

Acipenserids (sturgeons) live in large rivers and lakes in North America and Eurasia, where many species and populations are considered imperiled. One of the most pervasive threats across the global range of sturgeon is water resource development (e.g., hydropower dams, water intakes for irrigation, industrial use, or human consumption). We report on the outcome of a literature review focused on interactions between sturgeon and water resource development. We focused on the persistent issue of dam passage (both upstream and downstream), impingement, and entrainment, which are all relevant issues for both existing and planned facilities. We discuss aspects of sturgeon sensory physiology, and how knowledge of sensory physiology can be used for behavioural guidance. We also consider how the swimming ability and style of sturgeon is relevant for passage. Most of the literature emanated from research on just a few species (especially lake sturgeon, white sturgeon, green sturgeon, and shortnose sturgeon). Although there are several examples of apparent “success stories” (e.g., successful upstream fish passage, efforts to reduce impingement and entrainment), there are also many failures, and such examples are likely under-reported. Without significant investments in solutions-oriented research related to sturgeon-water resource development interactions, we submit that fish passage, entrainment and impingement problems for acipenserids will remain. There is a need for research that spans life-stages, compares different species, and considers how passage, entrainment, and impingement influence demography. Further, there is a need for investment into evidence-based implementation of mitigation infrastructure and management strategies to ensure conservation needs of sturgeons are adequately considered.

Understanding of chronic heart failure (HF) has progressed from the concept of a purely hemodynamic disorder to that of a syndrome that results from dysfunction in interconnected molecular pathways. As a result, the focus of research investigations and clinical care has shifted to measurement and modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers provide a window into the pathophysiology of chronic HF and therefore have important therapeutic implications. However, the use of biomarkers in the treatment of HF remains in its infancy. This is partly a result of shortcomings in research studies and a dearth of biomarker-guided clinical trials. In this review, we summarize the potential therapeutic implications of promising biomarkers that uniquely capture the molecular dysfunction that occurs in chronic HF. We discuss the need for strict statistical standards in biomarker studies, provide an overview of biomarker-guided clinical trial design, and discuss the therapeutic potential of a multimarker-based strategy.

This study explores how muscle and liver energy stores are linked with social status and the social environment in Neolamprologus pulcher, a cooperatively breeding fish that lives in colonies comprised of up to 200 distinct social groups. Subordinate muscle energy stores were positively correlated with the number of neighbouring social groups in the colony, but this pattern was not observed in dominant N. pulcher. Furthermore, liver energy stores were smaller in dominants living at the edge of the colony compared with those living in the colony centre, with no differences among subordinates in liver energy stores. Subordinate N. pulcher may build up large energy stores in the muscles to fuel rapid growth after dispersal, which could occur more frequently in high-density environments. Dominant N. pulcher may use the more easily mobilized energy stores in the liver to fuel daily activities, which could be more energetically demanding on the edge of the colony as a result of the increased predation defence needed on the edge. Overall, this study demonstrates that both subordinate and dominant physiology in N. pulcher varies with characteristics of the social environment. Furthermore, dominant and subordinate energy storage strategies appear to differ due to status-dependent variation in daily activities and variation in the need to prepare for future reproductive or dispersal opportunities.

BACKGROUND In selecting patients with acute myocardial infarction for thrombolytic therapy, it is important to identify patients who are at high risk for intracranial hemorrhage, for whom thrombolytic therapy is ill advised. We hypothesized that presenting pulse blood pressure, representing the "hammer" effect on cerebral vessels and the effects of age on arterial compliance, might predict thrombolysis-related intracranial hemorrhage better than systolic, diastolic, or mean arterial blood pressures. METHODS AND RESULTS Of 3483 Thrombolytic Predictive Instrument (TPI) Project subjects receiving thrombolytic therapy for acute infarction, we identified and obtained detailed clinical data on the 19 with treatment-related intracranial hemorrhages confirmed by computed tomography and on 175 matched controls. Systolic, diastolic, mean arterial, and pulse blood pressures were each significantly related to the occurrence of intracranial hemorrhage, with pulse pressure most highly related. The mean pulse pressure in patients who developed intracranial hemorrhage was 63 mm Hg, 34% higher than the 47 mm Hg mean value for those not developing hemorrhage (P = .0001). Excess pulse pressure, defined as the extent to which a patient's pulse pressure exceeded 40 mm Hg for systolic blood pressures of at least 120 mm Hg, was even more strongly related: its mean value of 23 mm Hg for patients was 130% higher than its mean value of 10 mm Hg for controls (P < .0001). With logistic regression models to estimate the relative risks (odds ratios) for intracranial hemorrhage conferred by each form of blood pressure, the relative risk for hemorrhage was greatest for excess pulse pressure: for each 10-point pulse pressure excess, the relative risk for intracranial hemorrhage was increased by 1.85 (P = .0002; 95% confidence interval [CI], 1.34 to 2.55) by itself and 1.76 (P = .001; 95% CI, 1.26 to 2.46) when adjusted for age. In this sample, excess pulse pressure by itself predicted hemorrhage as well as systolic pressure and age together. When excess pulse pressure was combined with age to make a logistic regression model predicting intracranial hemorrhage, age contributed less to the prediction than when combined with the other blood pressure forms, even though this model predicted better than any other combination of age and pressure (receiver-operating characteristic curve area, 0.82 versus 0.77 with systolic pressure and age, 0.75 with mean arterial pressure, 0.71 with diastolic pressure, and 0.81 with both systolic and diastolic pressures). CONCLUSIONS We found that excess pulse blood pressure predicted thrombolysis-related intracranial hemorrhage better than other forms of pretreatment blood pressure, perhaps better describing the pathophysiology of intracranial hemorrhage, including the effect of age. These findings will need confirmation in larger studies with comparable clinical detail.

Birefringent pulmonary talc granuloma are often found in lung biopsies from intravenous drug abusers (IVDA) but their clinico-pathological significance remains undefined.

The eucaryotic protein carboxyl methyltransferase specifically modifies atypical D-aspartyl and L-isoaspartyl residues which are generated spontaneously as proteins age. The selectivity of the enzyme for altered proteins in intact cells was explored by co-injecting Xenopus laevis oocytes with S-adenosyl-L-[methyl-3H]methionine and structurally altered calmodulins generated during a 14-day preincubation in vitro. Control experiments indicated that the oocyte protein carboxyl methyltransferase was not saturated with endogenous substrates, since protein carboxyl methylation rates could be stimulated up to 8-fold by increasing concentrations of injected calmodulin. The oocyte protein carboxyl methyltransferase showed strong selectivities for bovine brain and bacterially synthesized calmodulins which had been preincubated in the presence of 1 mM EDTA relative to calmodulins which had been preincubated with 1 mM CaCl2. Radioactive methyl groups were incorporated into base-stable linkages with recombinant calmodulin as well as into carboxyl methyl esters following its microinjection into oocytes. This base-stable radioactivity most likely represents the trimethylation of lysine 115, a highly conserved post-translational modification which is present in bovine and Xenopus but not in bacterially synthesized calmodulin. Endogenous oocyte calmodulin incorporates radioactivity into both carboxyl methyl esters and into base-stable linkages following microinjection of oocytes with S-adenosyl-[methyl-3H]methionine alone. The rate of oocyte calmodulin carboxyl methylation in injected oocytes is calculated to be similar to that of lysine 115 trimethylation, suggesting that the rate of calmodulin carboxyl methylation is similar to that of calmodulin synthesis. At steady state, oocyte calmodulin contains approximately 0.0002 esters/mol of protein, which turn over rapidly. The results suggest the quantitative significance of carboxyl methylation in the metabolism of oocyte calmodulin.

Rhesus monkey rhadinovirus (RRV) is one of the closest phylogenetic relatives to the human pathogen Kaposi sarcoma-associated herpesvirus (KSHV)-a gamma-2 herpesvirus and the etiologic agent of three malignancies associated with immunosuppression. In contrast to KSHV, RRV displays robust lytic-phase growth in culture, replicating to high titer, and therefore holds promise as an effective model for studying primate gammaherpesvirus lytic gene transcription as well as virion structure, assembly, and proteomics. More recently, investigators have devised complementary latent systems of RRV infection, thereby also enabling the characterization of the more restricted latent transcriptional program. Another benefit of working with RRV as a primate gammaherpesvirus model is that its efficient lytic growth makes genetic manipulation easier than that in its human counterpart. Exploiting this quality, laboratories have already begun to generate mutant RRV, setting the stage for future work investigating the function of individual viral genes. Finally, rhesus macaques support experimental infection with RRV, providing a natural in vivo model of infection, while similar nonhuman systems have remained resistant to prolonged KSHV infection. Recently, dual infection with RRV and a strain of simian immunodeficiency virus (SIV) has led to a lymphoproliferative disorder (LPD) reminiscent of multicentric Castleman disease (MCD)--a clinical manifestation of KSHV infection in a subset of immunosuppressed patients. RRV, in short, shows a high degree of homology with KSHV yet is more amenable to experimental manipulation both in vitro and in vivo. Taken together, these qualities ensure its current position as one of the most relevant viral models of KSHV biology and infection.

The three-dimensional reconstruction of the bovine kidney pyruvate dehydrogenase complex ( M r ≈ 7.8 × 10 6 ) comprising about 22 molecules of pyruvate dehydrogenase (E 1 ) and about 6 molecules of dihydrolipoamide dehydrogenase (E 3 ) with its binding protein associated with the 60-subunit dihydrolipoamide acetyltransferase (E 2 ) core provides considerable insight into the structural and functional organization of the largest multienzyme complex known. The structure shows that potentially 60 centers for acetyl-CoA synthesis are organized in sets of three at each of the 20 vertices of the pentagonal dodecahedral core. These centers consist of three E 1 molecules bound to one E 2 trimer adjacent to an E 3 molecule in each of 12 pentagonal openings. The E 1 components are anchored to the E 1 -binding domain of the E 2 subunits through an ≈50-Å-long linker. Three of these linkers emanate from the outside edges of the triangular base of the E 2 trimer and form a cage around its base that may shelter the lipoyl domains and the E 1 and E 2 active sites. The docking of the atomic structures of E 1 and the E 1 binding and lipoyl domains of E 2 in the electron microscopy map gives a good fit and indicates that the E 1 active site is ≈95 Å above the base of the trimer. We propose that the lipoyl domains and its tether (swinging arm) rotate about the E 1 -binding domain of E 2, which is centrally located 45–50 Å from the E 1 , E 2 , and E 3 active sites, and that the highly flexible breathing core augments the transfer of intermediates between active sites.

The pharmacological management of heart failure has evolved during the last decade from therapies focused on improving haemodynamics to others that modulate neurohormonal systems which are activated in the setting of left ventricular dysfunction. Despite optimal inhibition of these systems with drugs such as ACE inhibitors, beta-blockers, digoxin and, most recently, spironolactone, the mortality rate remains unacceptably high. Calcium antagonists have long been investigated for use in a variety of cardiovascular diseases, including ischaemic heart disease, hypertension, and heart failure. However, concern has arisen with regard to the use of calcium antagonists in the treatment of left ventricular dysfunction--particularly those agents with negative inotropic activity. In addition, first generation dihydropyridines have also generated concern because of their profound vasodilatory effects and the fact that they have been shown to increase noradrenaline (norepinephrine) levels and neurohormonal activity. The third generation dihydropyridine calcium antagonists appear to be more promising therapies for heart failure, given their pharmacological properties of higher vascular selectivity and their minimal effects on neurohormonal activation. Several trials have been conducted with third generation dihydropyridines and additional trials are ongoing. A new class of calcium antagonists, which blocks the T-type calcium channel, was introduced in 1998. The prototype drug, mibefradil, was rigorously tested for use in heart failure in the Mortality Assessment in Congestive Heart Failure (MACH-1) trial. It was expected that calcium antagonists blocking the T-type calcium channel would be of benefit, because of their lack of negative inotropic effects and their ability to induce regression of hypertrophy. The results of the MACH-1 trial were disappointing, and the trial was prematurely discontinued as a result of excess mortality in the mibefradil arm. The purpose of this review is to examine the evidence-based pharmacotherapeutic strategies in the management of heart failure, and to discuss current and potential roles for calcium antagonists in the therapeutic regimen.

The purpose of this study was to address the timing of sudden death in advanced heart failure patients.Sudden death is a catastrophic event in cardiovascular disease. It has a circadian pattern prominent in the early AM, which has been thought to be due to a surge of sympathetic stimulation. We postulated that the distribution of events in advanced heart failure, with chronic sympathetic activation, would be more uniform implicating other potential mechanisms.We analyzed data from Prospective Randomized Amlodipine Survival Trial (PRAISE). Sudden deaths were analyzed by time of death in 4-h and 1-h blocks for uniformity of distribution in the entire cohort, and in the prespecified ischemic and nonischemic stratum. Further analyses were undertaken in the treatment groups of amlodipine and placebo, and among those receiving background therapy of aspirin and warfarin.Sudden deaths in the overall cohort showed a nonuniform distribution with a PM peak but not an AM peak. The ischemic stratum also showed a PM peak, but sudden deaths within the nonischemic stratum were uniformly distributed. Neither amlodipine treatment nor aspirin or warfarin use altered the distribution.Sudden death in advanced heart failure did not show an AM peak, suggesting that circadian sympathetic activation did not strongly influence these events. The PM peak noted is likely complex in origin and was not affected by antiischemic or antithrombotic medications.

The mammalian testis contains high levels of a protein, L-isoaspartyl (D-aspartyl) O-methyltransferase (PIMT), postulated to play a role in the repair of age-damaged proteins. To examine the regulation of PIMT concentrations during the development of spermatozoa, poly(A)+ RNA was isolated from purified populations of pachytene spermatocytes and round spermatids. Northern blot analysis revealed that a unique 1.1-1.3 kb PIMT transcript is present in preparations of round spermatid and pachytene spermatocyte poly (A)+ RNA. The concentration of this small PIMT transcript is at least four times higher in mRNA isolated from round spermatids than in mRNA isolated from pachytene spermatocytes, indicating that the PIMT gene is actively transcribed during the haploid phase of spermatogenesis. The germ cell-specific PIMT transcripts are distributed between the polysomal fraction and the nonpolysomal fractions of testis RNA, suggesting that translational controls also contribute to the high concentrations of PIMT in mammalian sperm. PIMT function is not essential for spermatogenesis because the testes from transgenic mice lacking PIMT activity have normal levels of protamine transcripts, and because functional sperm can be recovered from the cauda epididymis. The protein repair function of the PIMT may be more important in maintaining the fertilization competence of translationally-inactive mature sperm during the prolonged period of epididymal transit and storage in the male reproductive tract.

Moderate alcohol consumption (MAC) and platelet inhibition have been independently associated with a reduced risk for the development of acute myocardial infarction (AMI). The effects of MAC on the initial platelet status in patients presenting with AMI are not elucidated. Here we sought to define the effects of MAC on platelet characteristics in AMI patients before applying any reperfusion strategies. The study was designed as an analysis within the cohort study in 23 patients with AMI enrolled in the GUSTO-III. Platelets were investigated by different techniques, including aggregometry, flow cytometry, and ELISA. MAC patients exhibited mild, but consistent, inhibition of platelet aggregability, surface receptor expression, and released substances as compared to non-alcohol consuming patients. These differences were significant for 5 microM ADP (p = 0.04), 10 microM ADP-induced aggregation (p = 0.02); P-selectin (p = 0.01), and PECAM-1 (p = 0.02) platelet-bound expression. Our study confirms that moderate alcohol consumption is associated with diminished platelet activation in patients presenting with AMI. The ability of MAC to favorably modulate the pre-reperfusion platelet status in such patients is of clinical importance, and further investigation in large-scale clinical trials seem warranted.

To compare the prognostic significance of reperfusion assessment by Thrombolysis in Myocardial Infarction (TIMI) flow grade in the infarct related artery and ST-segment resolution analysis, by correlating with clinical outcomes in patients with acute myocardial infarction (AMI).Angiographic assessment, based on epicardial coronary anatomy, has been considered the "gold standard" for reperfusion. The electrocardiogram (ECG) monitoring provides a noninvasive, real-time physiologic marker of cellular reperfusion and may better predict clinical outcomes.Two hundred fifty-eight AMI patients from the Thrombolytics and Myocardia Infarction phase 7 and Global Utilization of Streptokinase tPA for Occluded coronary arteries phase 1 trials were stratified based on blinded, simultaneous reperfusion assessment on the acute angiogram (divided into TIMI grades 01, TIMI grade 2 and TIMI grade 3) and ST-segment resolution analysis (divided into:50% ST-segment elevation resolution or reelevation andor =50% ST-segment elevation resolution). In-hospital mortality, congestive heart failure (CHF) and combined mortality or CHF were compared to determine the prognostic significance of reperfusion assessment by each modality using chi-square and Fisher's Exact tests for univariable correlation and logistic regression analysis for univariable and multivariable prediction models.By logistic regression analysis, ST-segment resolution patterns were an independent predictor of the combined outcome of mortality or CHF (p = 0.024), whereas TIMI flow grade was not (p = 0.693). Among the patients determined to have failed reperfusion by TIMI flow grade assessment (TIMI flow grade 01), the ST-segment resolution ofor =50% identified a subgroup with relatively benign outcomes with the incidence of the combined end point of mortality or CHF 17.2% versus 37.2% in those without ST-segment resolution (p = 0.06).Continuous 12-lead ECG monitoring can be an inexpensive and reliable modality for monitoring nutritive reperfusion status and to obtain prognostic information in patients with AMI.

Significant differences are known to exist between the United States and Canada with respect to coronary catheterization and intervention. In a post hoc analysis, it was hypothesized that these differences may have the greatest impact on outcome in patients at risk for recurrent events such as those following myocardial infarction (MI).The hypothesis was tested in a nonrandomized comparison of the catheterization and revascularization patterns for patients following acute MI in 7029 patients in the United States and 1774 patients in Canada who participated in the Coumadin/Aspirin Reinfarction Study (CARS). CARS tested the effectiveness of low dose warfarin in combination with acetylsalicylic acid (ASA) versus ASA alone in reducing cardiovascular morbidity and mortality.Before study enrollment (median day 7 to 8), 84.5% of the American patients underwent coronary angiography compared with only 7.7% in Canada (P0.01). CARS patients in the United States underwent significantly more frequent angioplasty during their hospital admission before study enrollment than their Canadian counterparts (55.8% versus 3.0%, respectively, P0.01), and there was a more frequent use of intravenous heparin among American CARS patients (96% versus 88%, respectively, P0.01) but less frequent administration of thrombolytic therapy (44% versus 49%, respectively, P0.01). For follow-up of up to 32 months, American CARS patients had significantly fewer primary events (cardiovascular deaths, nonfatal MI, nonfatal ischemic stroke) than Canadian patients. Cumulative estimate of a primary end point comparing American with Canadian patients was, respectively, 2.0% versus 3.1% at one month, 8.0% versus 11.3% at one year and 11.6% versus 15.0% at two years. Thus, time to the primary event was significantly longer in American patients (P=0.0001). All-cause mortality estimates at 12 months were 2.2% and 4.0%, respectively, for the American and Canadian CARS subgroups. When management for the index MI (ie, angiography and angioplasty) is included in the model, the risk of death for Canadian versus American subgroups of CARS is not statistically different (0.9, 95% CI 0.6 to 1.2, P=0.40).Among study participants, American patients experienced a better outcome than Canadian patients, which may be attributable to more aggressive management based on early coronary angiography and angioplasty. However, angioplasty before study enrollment in American patients may have resulted in enrollment of lower risk patients. This selection bias limits the scope of the comparison.

There is substantial clinical evidence that the incidence of depression and mortality after acute coronary events are strongly related. As mediators of coronary thrombosis, platelets may represent a link between these events, and could be possibly targeted by therapy with serotonin reuptake inhibitors.

This article is designed for primary care physicians, cardiovascular specialists, medical directors, and other managed care administrators responsible for heart failure patients.To provide the reader with a basic understanding of heart failure epidemiology, heart failure management, and different strategies for the management of this particular patient population.1. To describe the impact of heart failure on the healthcare system in the United States. 2. To briefly describe the current practice for managing heart failure. 3. To describe the evidence for care by cardiologists of heart failure patients. 4. To describe the different disease management strategies being utilized in heart failure management.

Depression occurs frequently in patients with acute myocardial infarction and is associated with increased mortality rates. It is not known whether serotonin reuptake inhibitors would be safe and effective for patients with depression after myocardial infarction and whether such treatment would reduce mortality rates.We conducted a multicenter, open-label, pilot study of sertraline treatment in patients with major depressive disorder identified 5 to 30 days after admission for acute myocardial infarction. Outcome measures included cardiovascular and hemostatic function, adverse events, and mood ratings. Twenty-six patients were enrolled in the study. During treatment there were no significant changes in heart rate, blood pressure, cardiac conduction, or left ventricular ejection fraction, and there was a trend toward reduced ventricular ectopic activity. There were no changes in coagulation measures. Bleeding time increased in 12 patients, decreased in 4 patients, and was unchanged in 2 patients. Three (12%) patients withdrew from treatment prematurely because of adverse events. Significant improvements in mood ratings occurred over the course of treatment.Sertraline treatment was associated with clinical improvement and was well tolerated in85% of the patients in this open-label treatment trial for patients with major depression after myocardial infarction. These results encourage further controlled trials to establish the effects of treatment for this high-risk population.

Investigations of calcium antagonists in patients with advanced heart failure have raised concern over an increased risk of worsening heart failure and heart failure deaths. We assessed the effect of amlodipine on cause-specific mortality in such patients enrolled in a randomized, double-blind, placebo-controlled trial. In total, 1,153 patients in New York Heart Association class IIIb or IV heart failure were randomized to receive amlodipine or placebo, along with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Over a median 14.5 months of follow-up, 413 patients died. Cardiovascular deaths accounted for 89% of fatalities, 50% of which were sudden deaths and 45% of which were due to pump failure, with fewer attributed to myocardial infarction (3.3%) or other cardiovascular causes (1.6%). Amlodipine treatment resulted in a greater relative reduction in sudden deaths (21%) than in pump failure deaths (6.6%) overall. When patients were classified by etiology of heart failure (ischemic or nonischemic), cause-specific mortality did not differ significantly between treatment groups in the ischemic stratum. In the nonischemic stratum, however, sudden deaths and pump failure deaths were reduced by 38% and 45%, respectively, with amlodipine. Thus, when added to digitalis, diuretics, and angiotensin-converting enzyme inhibitors in patients with advanced heart failure, amlodipine appears to have no effect on cause-specific mortality in ischemic cardiomyopathy, but both pump failure and sudden deaths appear to be decreased in nonischemic heart failure patients treated with amlodipine.

The widely distributed protein-L-isoaspartate(D-aspartate) O-methyltransferase (PIMT; EC 2.1.1.77) is postulated to play a role in the repair or metabolism of damaged cellular proteins containing L-isoaspartyl residues derived primarily from the spontaneous deamidation of protein asparaginyl residues. To evaluate the functional consequence of PIMT-catalyzed methylation on the stability of isoaspartyl-containing proteins in cells, Xenopus laevis oocytes were microinjected with both deamidated and nondeamidated forms of recombinant chicken calmodulin (CaM) containing a hemagglutinin (HA) epitope at its N terminus. Processing of HA-CaM was monitored by electrophoretic analysis and Western blotting of oocyte extracts. The experiments indicate that deamidated HA-CaM is degraded after microinjection, while nondeamidated HA-CaM is stable. Kinetic analysis is consistent with the entry of microinjected HA-CaM into two intracellular pools with distinct hydrolytic stabilities. The larger, more stable pool may consist of HA-CaM bound to the heterogeneous pool of oocyte CaM binding proteins detected by an overlay procedure. Enzymatic methylation of deamidated HA-CaM with purified PIMT prior to injection results in its stabilization. Conversely, inhibition of endogenous oocyte PIMT with sinefungin, a nonhydrolyzable analog of S-adenosylhomocysteine, increases the rate of deamidated HA-CaM degradation. These results are consistent with a role for PIMT-catalyzed methylation in the repair of damaged cellular proteins.

We performed a multicenter, open-label study to determine the long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia. Niaspan, 0.5 to 3.0 g once a night at bedtime, was used alone or in combination with a statin (inhibitor of hydroxymethylglutaryl coenzyme A reductase), a bile acid sequestrant, or both. Patients included 269 hypercholesterolemic male and female adults enrolled in a 96-week study, and 230 additional adults for whom short-term safety data were available. The dosages of Niaspan attained by 269 patients were 1,000 mg (95% of patients), 1,500 mg (86%), and 2,000 mg (65%). After 48 weeks of treatment, Niaspan alone (median dose 2,000 mg) reduced low-density lipaprotein (LDL) cholesterol (18%), apolipoprotein B (15%), total cholesterol (11%), triglycerides (24%), and lipoprotein(a) (36%), and increased high-density lipoprotein (HDL) cholesterol (29%). Niaspan plus a statin lowered LDL cholesterol (32%), apolipoprotein B (26%), total cholesterol (23%), triglycerides (30%), and lipoprotein(a) (19%), and increased HDL cholesterol (26%). Reversible elevations of aspartate aminotransferase or alanine aminotransferase more than twice the normal range occurred in 2.6% of patients. One patient discontinued Niaspan because of transaminase elevations. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients. The overall rate of discontinuance due to flushing in this study combined with 2 previous randomized trials was 7.3%. In the long-term treatment of hypercholesterolemia, Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy.

Aspirin therapy and platelet inhibition reduce the risk for the development of acute myocardial infarction (AMI). However, the effects of aspirin on baseline platelet activity in patients presenting with AMI are not known. We determined the effect of long-term aspirin use on baseline platelet activity in patients presenting with AMI, enrolled in the GUSTO-III Platelet Study. Platelet characteristics were investigated by aggregometry, flow cytometry and enzyme-linked immunosorbent assay in 23 patients before thrombolysis. Sixteen AMI patients were aspirin free, and 7 patients were using aspirin (81-500 mg/daily). The aspirin-treated patients exhibited a mild but consistent reduction of platelet activity which reached significance for 5 microM (p = 0.02), and 10 microM (p = 0.01) adenosine diphosphate induced aggregation. The surface expression of P-selectin (p = 0.02) and PECAM-1 (p = 0.03) and the plasma level of soluble P-selectin (p = 0.02) were also reduced. As previously observed in normal humans and patients with stable coronary artery disease, long-term aspirin therapy is also associated with diminished platelet activation in patients presenting with AMI. Long-term aspirin therapy mildly reduces baseline platelet activity; however, this degree of relative platelet inhibition does not appear to be cardioprotective.

There has been some debate regarding the benefit of parenteral magnesium (Mg) in the treatment of acute myocardial infarction (AMI), due to conflicting results from animal studies and recent clinical trials. Several different hypotheses, proposing antiplatelet, and antithrombotic properties have been advanced to explain the cardioprotective properties of Mg during AMI. Although early clinical results were promising, there were serious flaws in the design and the logistics of small trials including out of date methodology, absence of control groups, and possible observer bias due to unblinded data collection. Moreover, the latest large-scale megatrial Fourth International Study of Infarct Survival (ISIS-4) provided conflicting data and caused major controversy, which will be difficult to resolve. Proponents of Mg therapy have suggested that the potential benefit was not seen in ISIS-4 because Mg was administered too late. Further clinical trials, well-designed, and carefully conducted, should elucidate possible benefits of parenteral Mg during myocardial injury, especially in conjunction with new and aggressive reperfusion techniques. The benefits of parenteral Mg in an expanding array of clinical conditions, including AMI, may be directly related to an improved hemostatic profile. This review summarizes the latest, and often confusing data on the effects of Mg on certain hemostatic characteristics which may be directly relevant to the existing controversy.

The abstract is included in the text.

The apparent benefit of magnesium in acute myocardial infarction, and the persistently poor outcome after cardiac arrest, have led to use of magnesium in cardiopulmonary resuscitation. Because few data on its use in cardiac arrest were available, we undertook a randomised placebo-controlled trial (MAGIC trial).Patients treated for cardiac arrest by the Duke Hospital code team were randomly assigned intravenous magnesium (2 g [8 mmoles] bolus, followed by 8 g [32 mmoles] over 24 h; 76 patients) or placebo (80 patients). Only patients in intensive care or general wards were eligible; those whose cardiac arrest occurred in emergency, operating, or recovery rooms were excluded. The primary endpoint was return of spontaneous circulation, defined as attainment of any measurable blood pressure or palpable pulse for at least 1 h after cardiac arrest. The secondary endpoints were survival to 24 h, survival to hospital discharge, and neurological outcome. Analysis was by intention to treat.There were no significant differences between the magnesium and placebo groups in the proportion with return of spontaneous circulation (41 [54%] vs 48 [60%], p = 0.44), survival to 24 h (33 [43%] vs 40 [50%], p = 0.41), survival to hospital discharge (16 [21%] vs 17 [21%], p = 0.98), or Glasgow coma score (median 15 in both).Empirical magnesium supplementation did not improve the rate of successful resuscitation, survival to 24 h, or survival to hospital discharge overall or in any subpopulation of patients with in-hospital cardiac arrest.

OBJECTIVES: To test the "Gardner hypothesis" that childhood leukaemia and non-Hodgkin lymphoma can be caused by fathers' exposure to ionising radiation before the conception of the child, and, more generally, to investigate whether such radiation exposure of either parent is a cause of childhood cancer. DESIGN: Case-control study. SETTING: Great Britain. SUBJECTS: 35,949 children diagnosed as having cancer, together with matched controls. MAIN OUTCOME MEASURES: Parental employment as radiation worker as defined by inclusion in the National Registry for Radiation Workers and being monitored for external radiation before conception of child; cumulative dose of external ionising radiation for various periods of employment before conception; dose during pregnancy. RESULTS: After cases studied by Gardner and colleagues were excluded, fathers of children with leukaemia or non-Hodgkin lymphoma were significantly more likely than fathers of controls to have been radiation workers (relative risk 1.77, 95% confidence interval 1.05 to 3.03) but there was no dose-response relation for any of the exposure periods studied; indeed, the association was greatest for those with doses below the level of detection. No increased risk was found for fathers with a lifetime preconception dose of 100 mSv or more, or with a dose in the 6 months before conception of 10 mSv or more. There was no increased risk for the group of other childhood cancers. Mothers' radiation work was associated with a significant increase of childhood cancer (relative risk 5.00, 1.42 to 26.94; based on 15 cases and 3 controls). Only four of the case mothers and no controls were radiation workers during pregnancy. CONCLUSIONS: These results do not support the hypothesis that paternal preconception irradiation is a cause of childhood leukaemia and non-Hodgkin lymphoma; the observed associations may be chance findings or results from exposure to infective or other agents. If there is any increased risk for the children of fathers who are radiation workers, it is small in absolute terms: in Britain the average risk by age 15 years is 6.5 per 10,000; our best estimate, using all available data, is that the increase is 5.4 per 10,000. For mothers, the numbers are too small for reliable estimates of the risk, if any, to be made.

To determine the relative risk of myocardial ischemia triggered by specific emotions during daily life.Relative risk was calculated by the recently developed case-crossover method, in which the frequency of a presumed trigger during nonischemic, or control, hours is compared with the trigger's frequency during ischemic, or case, hours. Outpatients at Duke University Medical Center, Durham, NC, underwent 48 hours of ambulatory electrocardiographic (ECG) monitoring with concurrent self-report measures of activities and emotions. Occurrences of negative emotions in the hour before the onset of myocardial ischemia were compared with their usual frequency based on all hours in which ischemia did not occur.From a sample of 132 patients with coronary artery disease and recent evidence of exercise-induced ischemia who underwent 48 hours of ambulatory ECG monitoring, 58 patients exhibited ambulatory ischemia and were included in the analysis.Myocardial ischemia during 48-hour ECG monitoring was defined as horizontal or downsloping ST-segment depression of 1 mm (0.1 mV) or more for 1 minute or longer compared with resting baseline. The ECG data were cross-tabulated with subjects' concurrent diary ratings of 3 negative emotions-tension, sadness, and frustration-and 2 positive emotions-happiness and feeling in contro-on a 5-point scale of intensity.The unadjusted relative risk of occurrence of myocardial ischemia in the hour following high levels of negative emotions was 3.0 (95% confidence interval [CI], 1.5-5.9; P.01) for tension, 2.9 (95% CI, 1.0-8.0; P.05) for sadness, and 2.6 (95% CI, 1.3-5.1; P.01) for frustration. The corresponding risk ratios adjusted for physical activity and time of day were 2.2 (95% CI, 1.1 -4.5; P.05) for tension, 2.2 (95% CI, 0.7-6.4; P=.16) for sadness, and 2.2 (95% CI, 1.1-4.3; P.05) for frustration.Mental stress during daily life, including reported feelings of tension, frustration, and sadness, can more than double the risk of myocardial ischemia in the subsequent hour. The clinical significance of mental stress-induced ischemia during daily life needs to be further evaluated.

Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure.We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events.Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P0.001).Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

Previous research has established that patients with coronary artery disease (CAD) have an increased risk of death if they are depressed at the time of hospitalization. Follow-up periods have been short in these studies; therefore, the present investigation examined this phenomenon over an extended period of time. Patients with established CAD (n = 1,250) were assessed for depression with the Zung Self-Rating Depression Scale (SDS) and followed for subsequent mortality. Follow-up ranged up to 19.4 years. SDS scores were associated with increased risk of subsequent cardiac death (p = 0.002) and total mortality (p0.001) after controlling for initial disease severity and treatment. Patients with moderate to severe depression had a 69% greater odds of cardiac death and a 78% greater odds of mortality from all causes than nondepressed patients. Increased risk was not confined to the initial months after hospitalization. Patients with high SDS scores at baseline still had a higher risk of cardiac death5 years later (p0.005). Compared with the nondepressed, patients with moderate to severe depression had an 84% greater risk 5 to 10 years later and a 72% greater risk after10 years. Patients with mild depression had intermediate levels of risk in all models. The heightened long-term risk of depressed patients suggests that depression may be persistent or frequently recurrent in CAD patients and is associated with CAD progression, triggering of acute events, or both.

The focus of new research efforts to improve the morbidity and mortality associated with acute myocardial infarction (AMI) has turned to adjuvant agents that show promise of improving outcomes following coronary thrombolysis. We enrolled 162 patients with AMI in a randomized trial comparing front-loaded tissue-plasminogen activator (t-PA) plus weight-adjusted heparin with anisoylated plasminogen streptokinase activator complex (APSAC) without heparin as well as standard-dose (325 mg) and low-dose (81 mg) aspirin. The primary end point was an in-hospital morbidity profile; secondary end points were clinical and angiographic potency and hemorrhagic events. Selected sites performed an electrocardiographic substudy to determine the time to 50% ST-segment recovery and the time to steady state. Although the trial was terminated when the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I trial showed that t-PA had a significant mortality advantage over streptokinase, important trends were evident. Patients given t-PA and heparin were better anticoagulated (p = 0.001), yet AP-SAC-treated patients had more bleeding complications. The primary end point favored t-PA (25.4% vs 31.3%), and the secondary end points were similar in both groups. In the electrocardiographic substudy, the t-PA group achieved both 50% ST-segment recovery and steady-state recovery sooner than the APSAC group. Patients taking low-dose aspirin had lower in-hospital mortality and less recurrent ischemia but more strokes than the standard-dose aspirin group. Thus, this trial demonstrated trends favoring front-loaded t-PA with weight-adjusted heparin over APSAC without heparin in the treatment of AMI. The use of low-dose aspirin did not appear to impose a loss of protection from adverse events, nor did standard-dose aspirin increase serious bleeding.

Depression is more prevalent in patients with coronary artery disease (CAD) than in the general elderly population. Although CAD patients with depression have higher mortality rates, depression is often not recognized and treated in these patients. We administered structured psychiatric diagnostic interviews to 99 inpatients with CAD and diagnosed 23% with a major depressive episode (MDE) by DSM-IV criteria. Severity of medical illness and family history of psychopathology were indicators for increased risk for MDE. These findings may facilitate the recognition of CAD patients at greater risk for MDE.

Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.

A protein methyltransferase which recognizes racemized and isomerized aspartyl residues in proteins has been identified in both the cytoplasm and nucleus of Xenopus laevis oocytes by enzymatic and immunochemical assays. The methyltransferase activity is maintained at a constant concentration of approximately 0.2 microM throughout vitellogenesis. Two forms of the enzyme can be identified on immunoblots by their cross-reactivity with an antibody prepared against the purified enzyme from bovine brain. Although both forms, with molecular weights of 27,000 and 34,000, are present in the cytoplasm, only the smaller form is found in the oocyte nucleus. A heterogeneous group of endogenous methyl-accepting proteins has been identified following the addition of S-adenosyl-L-[methyl-3H]methionine to oocyte extracts. The subcellular distribution of these methyl-accepting proteins, i.e. those proteins with unmodified or unmetabolized D- and L-isoaspartyl residues, is complementary to that of the methyltransferase. Very low levels of methyl-accepting activity are associated with nuclear proteins, which are actively methylated by the methyltransferase in vivo (O'Connor, C. M., and Germain, B. J. (1987) J. Biol. Chem. 262, 10404-10411). Yolk platelet proteins, which are inaccessible to the methyltransferase in vivo, are readily methylated by the enzyme in vitro. The specific methyl-accepting activity of the yolk proteins increases severalfold during the months required for the development of an early-to-late vitellogenic oocyte, suggesting that derivatized aspartyl residues accumulate with time in proteins which are inaccessible to the methyltransferase. The results support the hypothesis that the methyltransferase initiates either the repair or metabolism of cellular proteins which have been damaged by spontaneous racemization and deamidation processes (Clarke, S. (1985) Annu. Rev. Biochem. 54, 479-506).