APOE*3Leiden.CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome.

AIMS: This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. METHODS: Male obese, IR and dyslipidemic E3L.CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11ß-hydroxysteroid-dehydrogenase-1 (HSD-1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4-6 weeks. The effects on bw, IR and plasma and liver lipids were assessed. RESULTS: Rosiglitazone, liraglutide and HSD-1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD-1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high-density lipoprotein (HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin. CONCLUSIONS: We conclude that the E3L.CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).

A ventricular septal defect with a giant appendiform aneurysm of the membranous septum.

We report a case of a 39-year-old female with a ventricular septal defect (VSD) and a giant appendiform aneurysm of the membranous septum, illustrated by echocardiography and magnetic resonance imaging. From the literature a short review of the prevalence of spontaneous closure of VSDs together with the possible complications of persisting VSDs is presented. Since patients stay at risk in later years, follow-up at regular intervals is advised.

ST-Segment recovery adds to the assessment of TIMI 2 and 3 flow in predicting infarct wall motion after thrombolytic therapy.

BACKGROUND: Early resolution of ST-segment elevation (ST-segment recovery) is associated with an improved outcome after infarction. Whether this relation is present in patients with Thrombolysis In Myocardial Infarction (TIMI) grade 2 or 3 flow (ie, patent) infarct-related arteries is not known. METHODS AND RESULTS: To examine the associations between time to achieve stable 50% ST-segment recovery assessed by continuous ECG monitoring, infarct artery flow, and infarct zone wall motion (at 48 hours), we studied 134 patients who underwent angiography at 99 (interquartile range 92 to 110) minutes after commencing streptokinase, initiated within 12 hours of onset of symptoms of myocardial infarction. Patients with TIMI 2 or 3 flow who failed to achieve early stable ST-segment recovery (50% ST-segment recovery sustained for > or 4 hours with <100 microV change in the peak lead) by 60 or 90 minutes had a higher fraction of chords in the infarct zone >2 SD below normal wall motion (TIMI 2: 55.5% vs 15.3%, P=0.006; and 56.5% vs 26.8%, P=0.01, respectively; and TIMI 3: 48.8% vs 28.3%, P=0.07; and 51.8% vs 29.9%, P=0.03, respectively). Time to stable ST-segment recovery was a multivariate predictor of infarct zone wall motion (P=0.04) independent of TIMI flow grade and the time from symptom onset to streptokinase therapy. CONCLUSIONS: In patients with TIMI 2 or 3 flow in infarct-related artery, early stable ST-segment recovery is associated with improved infarct zone wall motion at 48 hours. ST-segment recovery may provide additional information about the degree of myocyte reperfusion achieved in patients with a patent epicardial infarct-related artery after thrombolytic therapy.

Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion.

Successful reperfusion after acute myocardial infarction (MI) has traditionally been considered to be restoration of epicardial patency, but increasing evidence suggests that disordered microvascular function and inadequate myocardial tissue perfusion are often present despite infarct vessel patency. Thus, optimal reperfusion is being redefined to include intact microvascular flow and restored myocardial perfusion, as well as sustained epicardial patency. Coronary angiography has been used as the gold standard to define failed reperfusion, according to the Thrombolysis In Myocardial Infarction (TIMI) flow grades. However, new angiographic techniques, including the corrected TIMI frame count and myocardial blush grade, have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success. Furthermore, evolving noninvasive diagnostic techniques, including measurement of infarct size with cardiac marker release patterns or technetium-99m-sestamibi single-photon emission computed tomographic imaging and analysis of ST segment resolution appear to be useful complements to angiography for the assessment of myocardial tissue reperfusion. Promising adjunctive therapies that target microvascular dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, and agents designed to improve tissue perfusion and attenuate reperfusion injury are being evaluated to further improve clinical outcomes after acute MI. To accelerate development of these new reperfusion regimens, an integrated approach to phase II clinical trials that incorporates multiple efficacy variables, including angiography and noninvasive biomarkers of microvascular dysfunction, should be considered. Thus, as the reperfusion era moves into the next millennium, the open-artery hypothesis is expected to shift downstream and guide efforts to further improve myocardial salvage and clinical outcomes after acute MI.

Repeat interventions as a long-term treatment strategy in the management of progressive coronary artery disease.

OBJECTIVES: This study investigates whether repeat coronary interventions, applied over an extended time period, can successfully curtail the progression of ischemic symptoms and angiographic lumen narrowing. BACKGROUND: Coronary artery disease is a chronic and generally progressive disorder, and potential treatment strategies should be examined and compared with this chronicity in mind. Percutaneous interventional revascularization procedures could theoretically be useful in controlling progression of the disease through repeated use as new coronary lesions arise. However, the outcome of this long-term management concept has not previously been subjected to detailed investigation. METHODS: From a consecutive series of 4,357 interventional cardiac procedures, 544 patients were identified who received two or more interventions during the 13-year study period. These patients were categorized into one of three groups: restenosis (repeat interventions limited to the same target segment, n = 261), new stenosis (all repeat interventions directed to stenoses not previously treated, n = 155) or both (repeat interventions directed both to the same and to different target lesions, n = 128). RESULTS: Two to five procedures were performed per patient; the time period (mean +/- SD) separating each procedure was significantly less (p < 0.0001) for the restenosis group (4.2 +/- 2.3 months) than for the new stenosis (24.2 +/- 23.5 months) or the "both" groups (11.4 +/- 11.0 months). Despite the need for repeat procedures, the severity of angina (mean New York Heart Association functional class 1.6 +/- 0.9) after 6.2 +/- 2.3 years of follow-up was substantially better than before the initial procedure (mean functional class 3.2 +/- 0.8), with a similar magnitude of change found in all three groups. This long-term functional improvement was mirrored by a corresponding anatomic improvement, with the mean number of diseased vessels remaining constant at the time of each procedure (1.5 +/- 0.7, 1.5 +/- 0.7 and 1.6 +/- 0.7, respectively, for the first, second and third procedures, p = NS). The restenosis and the new stenosis groups also demonstrated statistically similar annual rates of mortality (1.9% vs. 1.8%) and coronary surgery (2.3% vs. 2.6%), although the restenosis group had a lower rate of infarction (1.4% vs. 3.2%, p = 0.002). CONCLUSIONS: Repeat interventional treatment of newly acquired stenoses provides a rational approach for the long-term management of chronic coronary artery disease. In addition to yielding a favorable late outcome, the use of this strategy can result in sustained functional improvement and can check the progression of clinically significant stenoses.

Integrative noetic therapies as adjuncts to percutaneous intervention during unstable coronary syndromes: Monitoring and Actualization of Noetic Training (MANTRA) feasibility pilot.

BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) for unstable coronary syndromes have substantial emotional and spiritual distress that may promote procedural complications. Noetic (nonpharmacologic) therapies may reduce anxiety, pain and distress, enhance the efficacy of pharmacologic agents, or affect short- and long-term procedural outcomes. METHODS: The Monitoring and Actualization of Noetic Training (MANTRA) pilot study examined the feasibility of applying 4 noetic therapies-stress relaxation, imagery, touch therapy, and prayer-to patients in the setting of acute coronary interventions. Eligible patients had acute coronary syndromes and invasive angiography or PCI. Patients were randomized across 5 treatment groups: the 4 noetic and standard therapies. Questionnaires completed before PCI reflected patients' religious beliefs and anxiety. Index hospitalization end points included post-PCI ischemia, death, myocardial infarction, heart failure, and urgent revascularization. Mortality was followed up for 6 months after hospitalization. RESULTS: Of eligible patients, 88% gave informed consent. Of 150 patients enrolled, 120 were assigned to noetic therapy; 118 (98%) completed their therapeutic assignments. All clinical end points were available for 100% of patients. Results were not statistically significant for any outcomes comparisons. There was a 25% to 30% absolute reduction in adverse periprocedural outcomes in patients treated with any noetic therapy compared with standard therapy. The lowest absolute complication rates were observed in patients assigned to off-site prayer. All mortality by 6-month follow-up was in the noetic therapies group. In patients with questionnaire scores indicating a high level of spiritual belief, a high level of personal spiritual activity, a low level of community-based religious involvement, or a high level of anxiety, noetic therapies appeared to show greater reduction in absolute in-hospital complication rates compared with standard therapy. CONCLUSIONS: Acceptance of noetic adjuncts to invasive therapy for acute coronary syndromes was excellent, and logistics were feasible. No outcomes differences were significant; however, index hospitalization data consistently suggested a therapeutic benefit with noetic therapy. Of all noetic therapies, off-site intercessory prayer had the lowest short- and long-term absolute complication rates. Definitive demonstration of treatment effects of this magnitude would be feasible in a patient population about 4 times that of this pilot study. Absolute mortality differences make safety considerations a mandatory feature of future clinical trials in this area.

[Twelve year triage and thrombolysis treatment prior to hospitalization for myocardial infarction patients in the Rotterdam area of the Netherlands: outstanding short-term and long-term results]. / 12 jaar triage en trombolytische behandeling vóór ziekenhuisopname bij hartinfarctpatiënten in de regio Rotterdam: uitstekende korte- en langetermijnresultaten.

OBJECTIVE: To describe the results of thrombolysis prior to hospitalisation in patients with evolving myocardial infarction. DESIGN: Prospective cohort study. METHOD: The 'Reperfusion for acute infarcts Rotterdam' (Dutch acronym: REPAIR) programme aims to minimise treatment delay in patients with evolving myocardial infarction by the initiation of thrombolytic therapy prior to hospital admission. For patients with symptoms that indicate a developing myocardial infarction, treatment is initiated immediately by the ambulance personnel at the patient's home, once the diagnosis has been confirmed with the help of a portable 12-lead ECG system. The interval between the onset of symptoms and the thrombolysis infusion was recorded for all patients, as well as any complications which occurred during transportation. The long-term survival was determined using data from the municipal registration. RESULTS: In the period 1988-2000, 1487 patients were treated using the REPAIR protocol, 80% of these within two hours after the onset of symptoms. In 9 cases (0.6%) a thrombolytic treatment had been initiated, whereas the diagnosis 'myocardial infarction' was not confirmed at the hospital. During transport 40 patients (2.7%) experienced ventricle fibrillation, 25 (1.7%) severe hypotension, and 2 patients (0.1%) died. Mortality at 30 days and at one, five, and ten years was 4.9%, 7.3%, 16.2% en 30.1%, respectively. Patients treated within two hours after the onset of symptoms had lower mortality rates than those treated later: at one year 6.7% versus 9.7%, and at 5 years 14.0% versus 25.1% (Kaplan-Meier estimates; log rank test: p = 0.001). CONCLUSION: Immediate thrombolytic treatment of patients with a developing myocardial infarction which could be safely initiated by ambulance personnel, resulted in excellent short-term and long-term survival.

Ectoparasitic flies (Diptera, Streblidae) of bats (Chiroptera, Phyllostomidae) in an Atlantic Forest area, southeastern Brazil.

We studied infestation rates and parasite-host associations between streblid flies and phyllostomid bats in an Atlantic Forest area of Rio de Janeiro state, southeastern Brazil. We captured 301 individuals from seven Phyllostomidae bat species. Out of that total, 69 bats had been parasitised by nine Streblidae species; the most frequent species were Trichobius joblingi and Trichobius tiptoni. The species Paraeuctenodes longipes, associated with Anoura geoffroyi, was the most frequent species. The highest mean intensity was observed for Paraeuctenodes longipes, associated with A. geoffroyi, and Paratrichobius longicrus associated with Artibeus lituratus, both ectoparasite species with a mean intensity of five individuals per bat. Trichobius joblingi exhibited the highest mean abundance, which was over three on its host species. Streblid richness in the study area was similar to the richness found in other studies carried out in the Atlantic Forest. We observed that streblid richness in this biome depends more on inherent characteristics of each physiognomy and on the host-species than on the sampling effort.

Ectoparasitic flies (Diptera, Streblidae) of bats (Chiroptera, Phyllostomidae) in an Atlantic Forest area, southeastern Brazil / Moscas ectoparasitas (Diptera, Streblidae) de morcegos (Chiroptera, Phyllostomidae) numa área de Mata Atlântica, sudeste do Brasil

We studied infestation rates and parasite-host associations between streblid flies and phyllostomid bats in an Atlantic Forest area of Rio de Janeiro state, southeastern Brazil. We captured 301 individuals from seven Phyllostomidae bat species. Out of that total, 69 bats had been parasitised by nine Streblidae species; the most frequent species were Trichobius joblingi and Trichobius tiptoni. The species Paraeuctenodes longipes, associated with Anoura geoffroyi, was the most frequent species. The highest mean intensity was observed for Paraeuctenodes longipes, associated with A. geoffroyi, and Paratrichobius longicrus associated with Artibeus lituratus, both ectoparasite species with a mean intensity of five individuals per bat. Trichobius joblingi exhibited the highest mean abundance, which was over three on its host species. Streblid richness in the study area was similar to the richness found in other studies carried out in the Atlantic Forest. We observed that streblid richness in this biome depends more on inherent characteristics of each physiognomy and on the host-species than on the sampling effort.

Estudou-se as taxas de infestação e as associações parasita-hospedeiros de dípteros estreblídeos ectoparasitas de morcegos filostomídeos, em um fragmento de Mata Atlântica, no estado do Rio de Janeiro. Foram capturados 301 indivíduos de sete espécies de morcegos da família Phyllostomidae. Desse total, 69 morcegos encontravam-se parasitados com nove espécies de Streblidae, sendo Trichobius joblingi e Trichobius tiptoni as espécies mais freqüentes do total de estreblídeos coletados. Paraeuctenodes longipes, associada à Anoura geoffroyi foi a espécie mais prevalente. A maior intensidade média foi encontrada para Paraeuctenodes longipes, associada à A. geoffroyi e Paratrichobius longicrus associada à Artibeus lituratus, ambos com cinco ectoparasitas em média por morcego infestado. Trichobius joblingi apresentou a maior abundância média de infestação, que foi superior a três nas espécies de hospedeiros em que foi encontrada. A riqueza de estreblídeos da área de estudo é similar àquela obtida em outros estudos realizados na Mata Atlântica, e verificou-se que a riqueza de estreblídeos nesse bioma depende mais de outras características inerentes a cada fitofisionomia e à espécie hospedeira do que do esforço amostral de coleta.

Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour.

BACKGROUND: There is conclusive evidence from clinical trials that reduction of mortality by fibrinolytic therapy in acute myocardial infarction is related to the time elapsing between onset of symptoms and commencement of treatment. However, the exact pattern of this relation continues to be debated. This paper discusses whether or not appreciable additional gain can be achieved with very early treatment. METHODS: The relation between treatment delay and short-term mortality (up to 35 days) was evaluated using tabulated data from all randomised trials of at least 100 patients (n = 22; 50,246 patients) that compared fibrinolytic therapy with placebo or control, reported between 1983 and 1993. FINDINGS: Benefit of fibrinolytic therapy was 65 (SD 14), 37 (9), 26 (6) and 29 (5) lives saved per 1000 treated patients in the 0-1, 1-2, 2-3, and 3-6 h intervals, respectively. Proportional mortality reduction was significantly higher in patients treated within 2 h compared to those treated later (44% [95% CI 32, 53] vs 20% [15, 25]; p = 0.001). The relation between treatment delay and mortality reduction per 1000 treated patients was expressed significantly better by a non-linear (19.4-0.6x(+)29.3x-1) than a linear (34.7 - 1.6x) regression equation (p = 0.03). INTERPRETATION: The beneficial effect of fibrinolytic therapy is substantially higher in patients presenting within 2 h after symptom onset compared to those presenting later.

Recurrent ischemia during continuous 12-lead ECG-ischemia monitoring in patients with acute coronary syndromes treated with eptifibatide: relation with death and myocardial infarction. PURSUIT ECG-Ischemia Monitoring Substudy Investigators. Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy.

Computer-assisted continuous monitoring of the ST-segment allows detection and quantification of recurrent ischemia in patients with acute coronary syndromes. In a substudy of the PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial, this technique was used to evaluate the effects of the glycoprotein IIb/IIIa inhibitor eptifibatide on the incidence and severity of recurrent ischemia, and to investigate the relationship between recurrent ischemia and the occurrence of subsequent death or myocardial (re)infarction. A total of 258 patients with unstable angina or evolving myocardial infarction without ST elevation were monitored for 24 hours during infusion with either eptifibatide or placebo with a computer-assisted 12-lead ECG-ischemia monitoring device. Recurrent ischemic episodes were identified by an automated computer algorithm. Two hundred and sixteen patients (84%) had ECG recordings suitable for analysis. Ischemic episodes were detected in 35 (33%) of the 105 eptifibatide patients and in 32 (29%) of the 111 placebo patients (not significant). No difference in ischemic burden was apparent between both treatment groups. Patients who exhibited 2 or more episodes of recurrent ischemia more frequently died or suffered a myocardial infarction, both at 7 and 30 days, as well as through the 6-month follow-up. A greater ischemic burden was significantly related to adverse outcome during the 6-month follow-up period. Real-time computer-assisted continuous multilead ECG-ischemia monitoring may help to identify patients with unstable coronary syndromes at increased risk of adverse outcome and, thus, allow for better prognostic triage and more appropriate selection of therapeutic strategies. Integration of these systems in coronary care units and emergency wards should, therefore, be recommended.

Sustained benefit at 10-14 years follow-up after thrombolytic therapy in myocardial infarction.

AIMS: To investigate whether the benefit of thrombolytic therapy was sustained beyond the first decade. We report the 10-14 year outcome of 533 patients who were randomized to treatment with intracoronary streptokinase or to conventional therapy during the years 1980-1985. METHODS AND RESULTS: Details of survival and cardiac events were obtained from the civil registry, from medical records or from the patient's physician. At follow-up, 158 patients (59%) of the 269 patients allocated to thrombolytic treatment and only 129 patients (49%) of the 264 conventionally treated patients were alive. The cumulative 1-, 5- and 10-year survival rates were 91%, 81% and 69% in patients treated with streptokinase and 84%, 71% and 59% in the control group, respectively (P=0.02). Reinfarction during 10-years of follow-up was more frequent after thrombolytic therapy, particularly during the first year. Coronary bypass surgery and coronary angioplasty were more frequently performed after thrombolytic therapy. At 10 years approximately 30% of the patients were free from subsequent cardiac events. Independent determinants of mortality were elderly age, indicators of impaired residual left ventricular function, multivessel disease and an inability to perform an exercise test at the time of hospital discharge. CONCLUSION: Improved survival after thrombolytic therapy is maintained beyond the first decade. Age, left ventricular function, multivessel disease and an inability to perform an exercise test were independent predictors for long-term mortality, as they are predictors for early mortality.