摘要:

Background It has been shown that the development of coxsackievirus B3 (CB3) myocarditis is regulated by T cells and not by B cells. Interleukin-2 (IL-2) is a T-cell-derived cytokine that stimulates the growth of T cells. This study was carried out to determine the effects of IL-2 on CB3-infected BALB/c mice.Methods and Results In two separate experiments, recombinant human IL-2 (5 x 104U) was administered subcutaneously to 30 mice early (days 0 to 7) and 30 mice late (days 7 to 14) after infection with CB3. Each experiment had a control group of infected animals that did not receive IL-2. On days 7 and 10, splenic natural killer (NK) cell activity determined by Chromium-51 release assay and the distribution of myocardial lymphocyte subsets were compared in the treated and untreated groups. In the early treatment experiment, survival at 7 days was higher in treated compared with control animals, myocardial virus titers were lower, inflammatory cell infiltration was less (as was the severity of necrosis at the time the mice were killed), and NK cell activity was higher. However, in the late treatment experiment, survival at 14 days was lower in treated compared with control animals, and there was more infiltration, more severe necrosis, and more T-cell infiltration, but the NK cell activity did not differ significantly. In a third experiment similar to the late experiment described above but involving infected athymic nude mice, we confirmed the lack of effect of late in vivo administration of IL-2 on outcome.Conclusions IL-2 has the capacity to limit CB3 myocarditis by enhancing NK cell activity in the acute viremic stage, resulting in a reduction of cardiac pathology. However, in the subacute aviremic stage, in contrast, IL-2 exacerbates the course and severity of the disease by increasing the number of T cells infiltrating the myocardium. That is, IL-2 has differential effects on acute CB3 myocarditis. IL-2 is beneficial if treatment is given early but not later in murine CB3 myocarditis. (Circulation. 1994;89:2836-2842.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Increased activity of the sympathetic nervous system contributes significantly to the pathophysiology of heart failure. However, cardiac efferent sympathetic function has not been well characterized in this disorder. In this study, we evaluated cardiac sympathetic innervation using (Iodine-123)metaiodobenzylguanidine (MIBG) and compared this with left ventricular (LV) tissue norepinephrine concentration and myocardial perfusion, assessed by Thallium-201, in a canine model of heart failure.Methods and Results Planar and tomographic cardiac imaging was performed for MIBG and Thallium-201 in 23 dogs: 8 normal dogs (group 1) and 15 dogs with heart failure induced by right ventricular pacing at 250 beats per minute either continuously for 3 weeks (group 2) or intermittently for 7 weeks (group 3). Plasma and LV tissue norepinephrine concentrations were also measured. Scintigraphic studies in group 2 demonstrated reduced cardiac MIBG activity at heart failure (0.17+-0.04 versus 0.29+-0.05 counts per megabecquerel per pixel at baseline, mean+-SD; P=.0001), whereas thallium activity was unchanged from baseline. This reduction in cardiac MIBG activity with heart failure was associated with increased intraimage variability in the distribution of MIBG activity (21+-8% versus 13+-7% at baseline, mean+-SD; P=.0001). The MIBG heart-to-lung ratio was calculated for all groups to control for the inhibitory effect that plasma norepinephrine has on the neuronal uptake of MIBG. There was a positive correlation between LV tissue norepinephrine and the MIBG heart-to-lung ratio (r=.67; P<.001; n=22), for which the group 2 heart failure animals had the lowest values. No relation existed between plasma norepinephrine concentration and the MIBG heart-to-lung ratio. In addition, regional LV tissue norepinephrine concentration and MIBG activity were both lowest at the apex in normal (group 1) and heart failure (group 2) dogs. The MIBG heart-to-lung ratio also correlated inversely with cardiac filling pressure (r=-.59; P<.05) and heart rate (r=-.65; P<.01) and positively with cardiac output (r=.53; P<.05).Conclusions Heart failure is associated with severe cardiac adrenergic dysfunction manifested by reduced MIBG activity and increased heterogeneity in the LV distribution of MIBG. Furthermore, MIBG scintigraphy is a simple noninvasive method for assessing global and regional LV tissue norepinephrine levels. (Circulation. 1994;89:2843-2851.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Recent clinical trials have suggested that therapy with angiotensin-converting enzyme inhibitors in asymptomatic patients with reduced left ventricular (LV) function can significantly reduce the incidence of congestive heart failure compared with patients receiving placebo. In the present study, we examined the effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of LV systolic dysfunction and LV chamber enlargement in dogs with reduced LV ejection fraction (EF).Methods and Results LV dysfunction was produced in 28 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LVEF was 30% to 40%. Three weeks after the last embolization, dogs were randomized to 3 months of oral therapy with enalapril (10 mg twice daily, n=7), metoprolol (25 mg twice daily, n=7), digoxin (0.25 mg once daily, n=7), or no treatment (control, n=7). As expected, in untreated dogs, LVEF decreased (36+-1% versus 26+-1%, P<.001) and LV end-systolic volume (ESV) and end-diastolic volume (EDV) increased during the 3-month follow-up period (39+-4 versus 57+-6 mL, P<.001, and 61+-6 versus 78+-8 mL, P<.002, respectively). In dogs treated with enalapril or metoprolol, LVEF remained unchanged or increased after therapy compared with before therapy (35+-1% versus 38+-3% and 35+-1% versus 40+-3%, respectively, P<.05), whereas ESV and EDV remained essentially unchanged. In dogs treated with digoxin, EF remained unchanged but ESV and EDV increased significantly.Conclusions In dogs with reduced LVEF, long-term therapy with enalapril or metoprolol prevents the progression of LV systolic dysfunction and LV chamber dilation. Therapy with digoxin maintains LV systolic function but does not prevent progressive LV enlargement. (Circulation. 1994;89:2852-2859.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Moricizine is said to have potent effects on cardiac conduction but little or no effect on cardiac refractoriness.Methods and Results The effects of moricizine (2 mg/kg IV) on induced atrial flutter were studied 2 to 4 days after the creation of sterile pericarditis in 11 dogs. Ten episodes of stable atrial flutter before and after the administration of moricizine were studied in 9 dogs in the conscious, nonsedated state, and 7 episodes were studied in 6 dogs in the anesthetized, open chest state. In the conscious state, the effects of moricizine on atrial excitability, atrial effective refractory period, and intra-atrial conduction times were studied by recording during overdrive pacing of sinus rhythm from epicardial electrodes placed at selected atrial sites. Moricizine prolonged the atrial flutter cycle length in all the episodes, from a mean of 133+-9 to 172+-27 milliseconds (P<.001), and then terminated 7 of the 10 episodes. Moricizine increased the atrial threshold of excitability from a mean of 2.3+-1.4 to 3.3+-2.2 mA (P<.01) and prolonged intra-atrial conduction times (measured from the sulcus terminalis to the posteroinferior left atrium) from a mean of 58+-6 to 64+-5 milliseconds (P<.005). Prolongation of the atrial effective refractory period from 166+-20 to 174+-24 milliseconds (P<.05) was observed only at the sulcus terminalis site. In the open chest studies, administration of moricizine prolonged the atrial flutter cycle length from a mean of 150+-15 to 216+-30 milliseconds (P<.001) and then terminated the atrial flutter in all 7 episodes. As demonstrated by simultaneous multisite mapping from 95 bipolar sites on the right atrial free wall, the atrial flutter cycle length prolongation was either due to further slowing of conduction in an area of slow conduction in the reentrant circuit of the atrial flutter (5 episodes) or further slowing of conduction in an area of slow conduction plus the development of a second area of slow conduction (2 episodes). The change in conduction times in the rest of the reentrant circuit was negligible (10.9+-8.7% of the total change). In all 7 episodes, the last circulating reentrant wave front blocked in an area of slow conduction.Conclusions Moricizine (1) prolongs the atrial flutter cycle length, primarily by slowing conduction in an area of slow conduction in the reentrant circuit, (2) terminates atrial flutter by causing block of the circulating reentrant wave front in an area of slow conduction of the reentrant circuit, and (3) effectively interrupts otherwise stable atrial flutter in this canine model. The reason for these effects of moricizine are not readily explained by its effects on global atrial conduction times and refractoriness studied during sinus rhythm. Local changes in conduction in an area(s) of slow conduction are responsible for both cycle length prolongation and atrial flutter termination rather than the traditional wavelength concept of head-tail interaction. (Circulation. 1994;89:2860-2869.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Antiarrhythmic drugs are known to have state-dependent interactions with cardiac sodium channels, and these have potentially important implications for drug effects on cardiac conduction, particularly in situations of changed resting potential and heart rate. Recent advances in theoretical approaches permit beat-to-beat changes in sodium channel block to be inferred from conduction changes in vivo and allow for an analysis of state-dependent drug action from conduction changes occurring on the onset of pacing at different rates. The purpose of the present study was to use this method to analyze the interaction between hyperkalemia and procainamide's sodium channel-blocking action in terms of resulting changes in left ventricular conduction.Methods and Results Epicardial mapping with a 56-electrode array was used to assess ventricular conduction in open chest, anesthetized mongrel dogs with Formalin-induced atrioventricular block. Procainamide was infused as a series of loading and maintenance infusions until at least 20% conduction slowing was obtained at the shortest basic cycle length (300 milliseconds). Results in a control set of normokalemic dogs were compared with results in dogs with moderate hyperkalemia produced by a loading and maintenance infusion of potassium chloride. Plasma procainamide concentration was measured by high-performance liquid chromatography, and the constancy of serum potassium concentration was verified with ion-sensitive electrode measurement. Although hyperkalemia itself (mean+-SEM potassium concentration, 6.64+-0.66 mmol/L) did not alter conduction, it resulted in substantially increased conduction slowing by procainamide despite substantially lower plasma drug concentrations (102+-10 micromole/L) compared with normokalemic dogs (potassium concentration, 3.87+-0.24 mmol/L; procainamide concentration, 277+-16 micromole/L). The onset of conduction slowing and block followed basic molecular theory, with an exponential time constant that was faster at longer cycle lengths and total block that increased as cycle length decreased. Piecewise exponential analysis of block during the rested and depolarized phases of the action potential showed that the enhancement of procainamide's action by hyperkalemia was due almost exclusively to increased rested-phase block. Hyperkalemia produced a bradycardia-dependent and slight reduction in action potential duration and antagonized the action potential-prolonging effect of procainamide, particularly at shorter cycle lengths.Conclusions Hyperkalemia strongly enhances procainamide-induced conduction slowing by increasing the interaction between the drug and sodium channels during the rested phase of the cardiac cycle. These results indicate the applicability of basic molecular theories of antiarrhythmic drug action to understanding drug-induced changes in conduction velocity in vivo and highlight the potential importance of heterogeneous magnification of sodium channel-blocking drug action by the spatially variable hyperkalemia that occurs with acute myocardial ischemia. The latter could play an important role in the known proarrhythmic potential of sodium channel-blocking drugs in patients with coronary artery disease. (Circulation. 1994;89:2870-2878.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The imaging and measurement of the proximal flow convergence region in the left ventricle have been reported to be useful for identifying the site of mitral regurgitation (MR) and for evaluating its severity. However, the application of this method has not gained general acceptance. There have been few in vivo studies with quantified reference standards for determining regurgitant volume, and those that have been reported used spectral Doppler standards and/or nonsimultaneously performed contrast ventriculography. The purpose of the present study was to evaluate the proximal flow convergence centerline velocity-distance profile method applied to chronic MR resulting from flail mitral leaflets in an animal model in which regurgitant flow rates and regurgitant volumes were determined simultaneously with electromagnetic flow probes and flowmeters.0.6 cm; the profiles for grade I regurgitation resided in a domain encompassed by velocities <0.3 m/s at distances from the orifice of <0.45 cm. The profiles for grade II regurgitations resided in a domain between them. Regression analysis for the distance at which a velocity of 0.5 m/s was first reached bore a close relation to regurgitant fraction (r=.92, P<.0001) and peak regurgitant flow rate (r=.89, P<.0001). In addition, an equation for quantitatively correlating both a and b (coefficients from the multiplicative regression fits) with the peak regurgitant flow rate (Qpeakin L/min) was derived from stepwise regression analysis: Qpeak=12a+2.7b-2.4 (r=.96, P<.0001, SEE=.45 L/min).Conclusions In this study, using quantified MR volume, we demonstrate that the proximal flow convergence axial centerline velocity-distance profile method can be used for evaluating the severity of MR without any assumption about isovelocity surface shape geometry. (Circulation. 1994;89:2879-2887.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The early termination of clinical trials, for either benefit or harm, often generates undue enthusiasm or alarm. The enhanced publicity attending early termination of a trial promotes inappropriate interpretations that are favored by the inherent difficulty of prompt and comprehensive data review. Furthermore, the process of monitoring the accumulating outcome data for early evidence of treatment benefit or harm is fraught with many statistical and methodological difficulties. This report from a task force convened by the Working Group on Arrhythmias of the European Society of Cardiology incorporates first, a series of trials terminated appropriately or inappropriately for benefit or harm and used as examples to illustrate the importance of suitable trial design and of proper stopping rules; second, a description of the committee structure of a clinical trial; third, an analysis of the general design issues; fourth, a review of the main issues in interim analysis with special reference to main strategies for reducing the rate of false-positive claims that could result from early trial termination; and finally, a series of specific recommendations concerning the design, structure, analysis, interpretation, and presentation of a clinical trial. (Circulation. 1994;89:2892-2907.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

This report describes the first long-term (505-day) application of the vented electric (VE) HeartMate left ventricular assist device (LVAD) (Thermo Cardiosystems, Inc). The device consists of an abdominally placed, battery-powered titanium blood pump that, in contrast to earlier pneumatically powered systems, allows patients untethered freedom of movement. The batteries last 5 to 8 hours and can be changed on a rotating basis indefinitely. The patient, a 33-year-old man (90 kg, blood type O) with idiopathic cardiomyopathy, experienced end-organ heart failure (New York Heart Association (NYHA) class IV) while he was awaiting heart transplantation. When his hemodynamic criteria met those outlined in the protocol, we implanted the VE-LVAD as a bridge to transplantation. The patient was supported by the device for more than 16 months. His cardiac status returned to NYHA class I, and he was eventually allowed to take day trips outside the hospital as he awaited transplantation. The VE-LVAD enabled the patient to participate in activities such as eating in restaurants, going to movies, and practicing basketball shots. Unfortunately, the patient died suddenly due to a neurological thromboembolic event that occurred on day 503 of VE-LVAD support. The VE-LVAD improved native left ventricular function by chronic unloading, and ventricular remodeling resulted in a more normal configuration anatomically, physiologically, and ultimately, histologically and pathologically. (Circulation. 1994;89:2908-2914.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background This study evaluated the relation between body iron stores and coronary artery disease. It has been suggested that total body iron stores are an independent risk factor for acute myocardial infarction (AMI).=62% had a relative risk for AMI of 1.3, which was not statistically significant.Conclusions Our observations do not support the hypothesis that coronary artery disease risk is related to iron stores. (Circulation. 1994;89:2915-2918.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID