|Year : 2002 | Volume
| Issue : 3 | Page : 1
|Date of Web Publication||22-Jun-2010|
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. Cardiovascular News. Heart Views 2002;3:1
Pepducins: New thrombin inhibitors
A new group of antithrombotic compounds could have advantages over current therapies. The new agents are peptides called pepducins and were designed to inhibit the thrombin receptors PAR1 and PAR4 on platelets. Thrombin is the most potent activator of platelets, and antagonists of these 2 receptors (PAR1 and PAR4) might be useful to prevent the thrombotic and proliferative complications of acute coronary syndromes. The pepducins work by inhibiting signaling through G-protein-coupled receptors (GPCRs), which are found throughout the body and have key roles in both normal physiology and disease. They are thus the targets for more than 50% of all prescribed drugs, but so far all GPCR agonists or antagonists act on the extracellular side of the receptors. These new pepducins are novel in that they are the first known compounds to penetrate the cell and act as intracellular inhibitors of GPCRs. These new pepducins might overcome the limitations of current antithrombotic therapies. Infusion of the anti-PAR1 and anti-PAR4 pepducins into mice extended bleeding time and protected against systemic platelet activation. New drugs targeting the thrombin PAR receptors have the potential to be both safe and efficacious. They will be efficacious because thrombin is the most potent agonist of platelet activation, and blocking the thrombin receptors PAR1 and PAR4 is safer than a direct thrombin antagonist such as heparin or hirudin because the anti-PAR drug would allow fibrin formation to be unperturbed. Anti-PAR1/4 agents should also be safer than the anti-GPIIb/IIIa drugs by allowing platelet aggregation to proceed via the other secondary agonists and the collagen receptor, which should reduce the incidence of severe hemorrhage. However, these anti-PAR1 and anti-PAR4 compounds will need to be tested further for toxicity and pharmacologic activity in animals, and if successful in these tests they will enter clinical trials, probably first in patients with acute coronary syndromes. The authors hope they will be superior to aspirin and clopidogrel in reducing complications of MI or unstable angina. The pepducins are not yet in development by any pharmaceutical company.
Proteins control size, function of heart
Researchers have discovered proteins that appear to control the size and function of the heart. A tumor-suppressor gene called PTEN was known to control the size of organs in a fly model. Experiments were carried out on mice manipulating PTEN. Suppression of PTEN caused hypertrophy in the mouse hearts as well a dramatic decrease in contractile function. PTEN and proteins called P13K have known functions in the immune system and many other tissues. PTEN works as a negative regulator of P13K in determining heart size: in these experiments, P13K unsuppressed by PTEN produced large hearts. When P13K was blocked, the mice developed hearts only half the normal size. They also demonstrated that the function of these hearts could be controlled through an interaction of PTEN with P13K. Basically, when P13K was removed, their hearts functioned normally. The researchers have been able to genetically uncouple PTEN and P13K, creating hearts in mice that are large but highly contractile or small and failing. P13K was previously known as a regulator of migration of white blood cells in the setting of infection. The authors were surprised that the same molecule that controls neutrophil migration turned out to a regulator of heart function as well. P13K acts downstream of G protein-coupled receptors, the main receptors in the heart that control contraction, including beta-adrenergic and acetylcholine receptors. It's thought that in heart failure and hypertension, pathologic changes are mediated by these receptors. Plans are under way to investigate the role of P13K in animal models of heart failure. Similarly, there may be a role for this protein in acute ischemic insult. During ischemia, contractility is dramatically reduced and begins to recover during reperfusion. Animal experiments are currently underway to see if shutting down P13K during acute myocardial infarction improves cardiac function. The hope is that manipulating the same proteins in humans may prevent pathologic cardiac problems such as hypertrophy and mechanical dysfunction.
Myoblast transfer and arrhythmia
Autologous skeletal myoblast transplantation for treatment of postinfarction heart failure is feasible and relatively safe. The procedure appears to restore contractility in some segments. Preclinical studies, have shown that myoblasts differentiate into cells that resemble myocytes and that they form fibers, induce angiogenesis to provide a blood supply, and improve function and contractility within infarcted tissue. Because the patient's own skeletal myoblasts are used, some of the problems encountered in obtaining other types of cells for myocardial regeneration are avoided with this technique. Autologous skeletal myoblasts can be easily obtained, extracted from a muscle biopsy, and then expanded in culture, and finally reinjected into an area of myocardial infarct. Siminiak and colleagues in Poland carried out autologous skeletal mypblast transfer in 10 patients with previous myocardial infarction. They injected the cells directly into scarred tissue while the patient's chest was open during bypass surgery, choosing an area of the infarction that would not be revascularized by the procedure. Injected segments had been shown to be either akinetic or dyskinetic on dobutamine stress echo. Patients at relatively low risk were purposely selected, and each received about 20 million cells. Follow-up dobutamine stress echo showed an increase in contractility in several injected segments. There was however 1 death that occurred 7 days postoperatively. Autopsy revealed a new site of infarction in a part of the left ventricle that had previously been normokinetic. Their first 2 patients experienced sustained ventricular fibrillation (VF) postoperatively. Both were treated with oral amiodarone, which was discontinued by 5 months. After these cases, prophylactic infusion of amiodarone was given in all subsequent patients, and there were no subsequent episodes of arrhythmia. Menaschι et al in France first reported their series of 10 patients at the American Heart Association Meeting in 2001 and VF was also observed in 4 patients. The possibility that arrhythmias might be related to the procedure itself raises the issue of safety. About 90% of transplanted cells die almost immediately. Such a small number of surviving cells would be unlikely to affect function. In a new phase 2 trial planned by the French group, patients are being randomized to a low dose of 400 million cells and a high dose of 800 million cells. Target enrollment for the trial is 300 patients. The forthcoming study is primarily designed to address whether or not skeletal myoblast transfer can or cannot improve function in postinfarction heart failure.
New efficient catheter-based system for myocardial gene delivery
Manipulating gene expression in the failing heart has therapeutic promise, but until now efficient and homogeneous cardiac gene delivery has required an open-chest approach. Investigators examined the hypothesis that vector delivery promoted by echo contrast microbubbles will be maximized by injection of the vectors into the aortic root with brief balloon occlusion above the sinuses, while at the same time prolonging diastole and vasodilating with acetylcholine (ACh) to maximize coronary exposure. After incubation with albumin-coated perfluorocarbon microbubbles, an adenovirus encoding a reporter gene was infused into the aortic root of rats. To maximize delivery, the aortic root was transiently occluded with a balloon catheter during a brief ACh-induced asystole. Ultrasound was used to image the delivery and disrupt the microbubbles. Aortic occlusion with concomitant ACh increased myocardial gene expression for virus + microbubbles by >2.5-fold, from 925±165 to 2358±376 relative units (RU; P<0.01). This delivery system also produced substantial expression with vector alone (1473±549 RU). All uptakes were significant compared with 433±332 RU without virus. The study concluded that an adenoviral delivery system combining echo contrast with a catheter-based technique to maximize coronary perfusion increases gene delivery compared with echo contrast alone. This novel method permits efficient percutaneous gene delivery in closed-chest animals.
Repair of infarcted myocardium by intracoronary bone marrow cell transplantation in humans
Experimental data suggest that bone marrow-derived cells may contribute to the healing of myocardial infarction (MI). 10 patients who were treated by intracoronary transplantation of autologous, mononuclear bone marrow cells (BMCs) in addition to standard therapy after MI were analyzed After standard therapy for acute MI, 10 patients were transplanted with autologous mononuclear BMCs via a balloon catheter placed into the infarct-related artery during balloon dilatation (percutaneous transluminal coronary angioplasty). Another 10 patients with acute MI were treated by standard therapy alone. After 3 months of follow-up, the infarct region (determined by left ventriculography) had decreased significantly within the cell therapy group (from 30±13 to 12±7%, P=0.005) and was also significantly smaller compared with the standard therapy group (P=0.04). Likewise, infarction wall movement velocity increased significantly only in the cell therapy group (from 2.0±1.1 to 4.0±2.6 cm/s, P=0.028). Further cardiac examinations (dobutamine stress echocardiography, radionuclide ventriculography, and catheterization of the right heart) were performed for the cell therapy group and showed significant improvement in stroke volume index, left ventricular end-systolic volume and contractility (ratio of systolic pressure and end-systolic volume), and myocardial perfusion of the infarct region. These results demonstrate for the first time that selective intracoronary transplantation of autologous, mononuclear BMCs is safe and seems to be effective under clinical conditions. The marked therapeutic effect may be attributed to BMC-associated myocardial regeneration and neovascularization.
Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs
Peripheral blood mononuclear cells (PBMNCs), platelets, and polymorphonuclear leukocytes (PMNs) contain various angiogenic factors and cytokines. Unilateral hindlimb ischemia was surgically induced in athymic nude rats, and fluorescence-labeled human blood cells (PBMNCs, platelets or PMNs) were intramuscularly implanted into the ischemic limbs. Laser Doppler imaging revealed markedly increased blood perfusion in PBMNC+platelet-implanted limbs (44% increase, P<0.001) compared with control implantation of human umbilical vein vascular endothelial cells. The addition of PMNs to PBMNCs+platelets attenuated blood perfusion (27% decrease, P<0.01). Neocapillary densities were increased by implantation of PBMNCs+platelets or platelets alone (3.5-fold and 2.4-fold, respectively; P<0.001), whereas PMNs inhibited (32%, P<0.05) PBMNC+ platelet-mediated capillary formation. There was no incorporation of implanted PBMNCs into neocapillaries, whereas PBMNCs and platelets accumulated around arterioles after implantation. Cellular extract from PBMNCs+platelets, in which vascular endothelial growth factor (VEGF), basic fibroblast growth factor, platelet-derived growth factor-AB, and transforming growth factor-ί were detected, markedly stimulated tubule formation of human umbilical vein vascular endothelial cells. Anti-VEGF neutralizing antibody markedly inhibited tubule formation and in vivo vessel formation. Neutrophil elastase inhibitor blocked the antiangiogenic action of PMNs, whereas inhibitors of oxygen metabolites had no effect. The study demonstrated that implantation of PBMNCs and platelets into ischemic limbs effectively induce collateral vessel formation by supplying angiogenic factors (mainly VEGF) and cytokines, suggesting that this cell therapy is useful as a novel strategy for therapeutic angiogenesis.
Warfarin, Aspirin, or Both after Myocardial Infarction
The potential role of oral anticoagulant therapy as secondary prevention is highlighted in the Warfarin, Aspirin, Reinfarction Study (WARIS II). In this open-label study, patients hospitalized in 20 Norwegian centers for acute myocardial infarction were randomly assigned to long-term treatment with either warfarin (at a dose targeted to achieve an international normalized ratio [INR] of 2.8 to 4.2), 160 mg of aspirin daily, or 75 mg of aspirin daily plus warfarin (INR, 2.0 to 2.5). The primary outcome-a composite of death, nonfatal reinfarction, or thromboembolic stroke-occurred in 20% of the patients in the aspirin-only group, 16.7 % of those in the warfarin-only group, and 15% of those in the combination-therapy group. The overall risk reduction was 29% in the combination-therapy group (P=0.001 for the comparison with the aspirin-only group) and 19% in the warfarin-only group (P=0.03). The incidence of nonfatal major hemorrhage among the patients receiving warfarin (either alone or in combination) was three to four times that among the patients receiving aspirin alone.
Girls have higher mortality after surgery for congenital heart disease
In a study of about 6600 cardiac surgeries performed in California hospitals, female children had 51% higher odds of death than male children. The study, which reviewed hospital discharge data between 1995 and 1997, showed that when other factors are held equal, female sex is a risk factor for higher mortality among children undergoing surgery for congenital heart disease. The surgeries were adjusted for risk, and the end-point was in-hospital death versus alive at discharge. The investigators used logistic regression analysis to evaluate the effect of sex on in-hospital mortality, controlling for age, race and ethnicity, type of insurance, home income, type of admission, date and month of surgery, hospital case volume, and the type of procedure. Among 6593 cases, there were 345 in-hospital deaths, for an overall mortality rate of 5.23%. They found that crude mortality rates did not differ significantly between the sexes, 4.98% for males and 5.54% for females. The rates were highest in neonates at 16.5%, falling to 5.57% for infants, and 1.75% for children over 1 year old. Compared with the males, though, fewer of the female children were neonates, and the females more often had lower-risk procedures such as ASD closure and fewer high-risk procedures such as the Norwood operation than the males. Multivariate logistic regression accounting for these differences showed the females actually had a higher risk of in-hospital mortality, with an odds ratio of 1.51 (P<0.01). The investigators state that the reason for this difference is unclear, but is unlikely to be due to variations in service utilization during hospitalization, since the risk-adjusted length of stay and hospital charges were similar between the groups. The authors note, however, that females in this study had a higher incidence of comorbid conditions, including Down syndrome, pulmonary hypertension, and failure to thrive. Thus, they speculate that the sex difference in surgical outcomes discovered in the present study may be due to other biological differences between young males and females that were not characterized in this administrative data set.
Early addition of carvedilol to ACE-inhibitor therapy prevents progression of mild heart failure
Data from the CARMEN trial indicate that left ventricular remodeling in patients with mild chronic heart failure (HF) can be significantly improved by the early administration of carvedilol in combination with an ACE inhibitor. The Carvedilol ACE Inhibitor Remodeling Mild CHF Evaluation (CARMEN) trial is the first large-scale study directly comparing the effects of a beta blocker with an ACE inhibitor in this condition. In 65 institutions in 13 European countries, a total of 572 patients with mild HF (ejection fraction [EF] < 39%) were randomized in a double-blind design into 3 study arms, receiving 18 months of treatment on top of their current HF therapy (diuretics, digoxin, nitrates): Carvedilol in combination with enalapril; Carvedilol alone; Enalapril alone. The objective of the trial was to evaluate the efficacy of carvedilol alone or a combination of carvedilol with enalapril vs enalapril alone, in terms of left ventricular remodeling, tolerability, and safety. The primary study end point, the change in LV-end-systolic-volume index, was assessed by echocardiogram at the initiation of treatment and at 6 and 18 months of follow-up. In patients receiving carvedilol plus ACE inhibitor and in those taking carvedilol alone the researchers found a highly significant improvement of LV-remodeling and a significant reduction in heart size. Patients on enalapril only, in contrast, did not show a benefit. All 3-treatment arms had similar safety and tolerability profiles and no significant difference in mortality and morbidity. It was pointed out that the observed effect was only seen with Carvedilol. Other beta blockers may not show the same effect. European Society of Cardiology Congress 2002. Berlin
Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population
retion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population was examined. In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deaths with known cause were recorded. We found a positive dose-response relationship between increasing UAC and mortality. A higher UAC increased the risk of both CV and non-CV death after adjustment for other well-recognized CV risk factors, with the increase being significantly higher for CV mortality than for non-CV mortality (P=0.014). A 2-fold increase in UAC was associated with a relative risk of 1.29 for CV mortality (95% CI 1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for non-CV mortality. Urinary albumin excretion is a predictor of all-cause mortality in the general population. The excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors, and the relationship was already apparent at levels of albuminuria currently considered to be normal.
Emotional and physical precipitants of ventricular arrhythmia
Observational studies have suggested that psychological stress increases the incidence of sudden cardiac death. Whether emotional or physical stressors can trigger spontaneous ventricular arrhythmias in patients at risk has not been systematically evaluated. Patients with implantable cardioverter-defibrillators (ICDs) were given diaries to record levels of defined mood states and physical activity, using a 5-point intensity scale, during 2 periods preceding spontaneously occurring ICD shocks (0 to 15 minutes and 15 minutes to 2 hours) and during control periods 1 week later. ICD-stored electrograms confirmed the rhythm at the time of shock. A total of 107 confirmed ventricular arrhythmias requiring shock were reported by 42 patients (33 men; mean age, 65 years; 78% had coronary artery disease) between August 1996 and September 1999. In the 15 minutes preceding shock, an anger level ž3 preceded 15% of events compared with 3% of control periods (P<0.04; odds ratio, 1.83; 95% confidence intervals, 1.04 to 3.16) Other mood states (anxiety, worry, sadness, happiness, challenge, feeling in control, or interest) did not differ. Patients were more physically active preceding shock than in control periods. Anger and physical activity were independently associated with the preshock period. Anger and physical activity can trigger ventricular arrhythmias in patients with ICDs. Future investigations of therapies aimed at blocking a response to these stressors may decrease ventricular arrhythmias and shocks in these patients.
Off-pump CABG reduce in-hospital mortality and morbidity in overweight patients
Off-pump coronary artery bypass surgery has been demonstrated to reduce morbidity in elective patients. However, high-risk patients might benefit the most from this surgical procedure. Investigators evaluated the effectiveness of on-pump and off-pump coronary artery bypass surgery on early clinical outcome in a consecutive series of overweight patients. From April 1996 to April 2001, data on 4321 patients undergoing coronary surgery (mortality 1.4%) were prospectively entered into the Patient Analysis and Tracking System. Data were extracted for all patients with a body mass index ž25 kg/m2. A risk-adjusted analysis was performed to assess the effect of surgical technique in the whole overweight cohort. 2844 patients were identified (2261 male, median age 63, interquartile range 56 to 68). Patients undergoing on-pump surgery (76.3%) were less likely than those undergoing off-pump surgery to have hypercholesterolemia or left main stem disease and were, on average, less obese. However, they were more likely to have unstable angina and to have had a previous myocardial infarction, and they had more extensive coronary disease and received more grafts (all P<0.05). Unadjusted analyses, taking account only of consultant team, showed significant benefits of off-pump surgery in terms of hospital deaths, arrhythmias, inotropic use, use of intra-aortic balloon pump, blood loss, transfusion requirement, postoperative hemoglobin, chest infections, neurological complications, intensive care unit and hospital stay (all P<0.05). After adjustment for confounding prognostic factors, the benefits of off-pump surgery were still significant for death in hospital, transfusion requirement, postoperative hemoglobin, neurological complications, intensive care unit and hospital stay (ORs 0.35 to 0.79, P<0.05). These results suggest that off-pump surgery is safe and effective and is associated with a reduced in-hospital mortality and morbidity in overweight patients when compared with conventional coronary surgery with cardiopulmonary bypass and cardioplegic arrest.
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