Failure of cyclosporine-treated renal allograft recipients to increase glomerular filtration rate following an amino acid infusion.

Renal allograft recipients treated with cyclosporine (CsA) have increased renal vascular resistance that falls when CsA is stopped. With the aim of identifying whether CsA-treated patients with excellent renal function also have an alteration in renal vascular tone and to investigate which vessels are affected, we have studied the response of GFR and effective renal plasma flow (ERPF) to an infusion of an amino acid solution in a group of 9 CsA-treated renal transplant recipients with a normal plasma creatinine concentration (104 +/- 3.8 mumol/L [mean +/- SEM]). A similar group of 9 azathioprine-treated patients with good renal function (91 +/- 3.6 mumol/L) were used as controls. The azathioprine group had significant increases in both GFR (22%, P less than 0.05) and ERPF (19%, P less than 0.05) following a protein load, whereas there was no increase in either function in the CsA group. Amino acid infusions increase GFR and ERPF in normal kidneys--at least in part by producing afferent glomerular arteriolar dilatation. The difference we found between the two groups indicates a direct effect of cyclosporine on intrarenal vascular tone, even when renal function is considered to be normal.

Biodistribution, radiation dosimetry and pharmacokinetics of 111In-antimyosin in idiopathic inflammatory myopathies.

UNLABELLED: In view of the established role of 111In-antimyosin in the detection of heart muscle pathology, radiation dose estimates were made for this substance. Biodistribution and biokinetic data were obtained from our studies, which failed to show abnormal uptake of 111In-antimyosin in localized sites of skeletal muscle involvement in patients with idiopathic inflammatory myopathies. METHODS: After intravenous administration of 74 MBq (2 mCi) 111In-antimyosin, gamma camera scintigraphy was performed in 12 adult patients with inflammatory muscle disease and in 2 control patients. Six whole-body scans were performed over 72 h, and uptake of 111In-antimyosin in organs was quantified using an attenuation-corrected conjugate counting method. Residence times in source organs were used with MIRDOSE software to obtain radiation dose estimates. Pharmacokinetic parameters were derived from serial whole-blood and plasma 111In concentrations. RESULTS: The tracer cleared slowly from the circulation, and highest organ uptakes were found in the marrow and liver; kidneys showed the highest concentrations. Uptake was also evident in spleen, the facial image and male genitalia. CONCLUSION: For a typical administered activity of 74 MBq 111In-antimyosin, the kidneys receive the highest dose (58 mSv), and the effective dose is 11 mSv. Radioactivity was cleared from plasma at an average rate of 136 mL/h, and the mean steady-state distribution was approximately 5 L plasma.

Prognostic value of stress dobutamine technetium-99m sestamibi single-photon emission computed tomography (SPECT) in patients with suspected coronary artery disease.

Inotropic stress using graded dobutamine infusion has evolved as an alternative form of pharmacologic stress in conjunction with perfusion and functional imaging for evaluation of coronary heart disease. However, the prognostic value of technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) imaging in patients undergoing dobutamine stress testing for the detection of coronary artery disease is unclear. Accordingly, 61 patients undergoing coronary arteriography for the evaluation of chest pain on the basis of symptoms and treadmill exercise electrocardiography underwent SPECT imaging at rest and during stress. Patients were followed up for 19 +/- 11 months (2 to 33) during which 2 died, 2 had acute myocardial infarction, 13 developed unstable angina, and 3 had congestive heart failure. Univariate Cox regression analysis revealed that those with reversible defects (95%) and defects in multiple vascular territories (80%) on SPECT had a greater number of cardiac events compared to those without (59% [p = 0.02] and 34% [p = 0.002], respectively). The number of reversible (3.9 +/- 2.1) and fixed (2.3 +/- 2.0) segments (12-segment model) were greater in patients with cardiac events compared to those without, (2.3 +/- 2.5, p = 0.009 and 1.1 +/- 2.0, p = 0.02) respectively. When multivariate analysis was performed using clinical, exercise testing, and SPECT variables, the independent predictors of cardiac events were a history of myocardial infarction (p <0.001), number of reversible segments (p = 0.001), and presence of defects in multiple vascular territories (p = 0.01). In summary, dobutamine stress Tc-99m sestamibi SPECT is a powerful predictor of future cardiac events in patients undergoing coronary arteriography for evaluation of chest pain and may be used to stratify patients for further intervention.

Prognostic value of predischarge exercise testing, ejection fraction, and ventricular ectopic activity in acute myocardial infarction treated with streptokinase.

The relative importance of prognostic parameters that delineate left ventricular function, myocardial ischemia, and arrhythmogenic potential after thrombolytic therapy is not clear. This study investigated 112 patients with acute myocardial infarction who were treated with thrombolysis to determine the relative prognostic value of predischarge treadmill exercise testing, radionuclide ventriculography, and ambulatory electrocardiographic monitoring for ventricular ectopic activity. During a mean follow-up period of 18 months (range 6 to 30), 42 first cardiac events were recorded, consisting of 3 deaths, 6 reinfarctions, 16 bouts of unstable angina, 16 episodes of heart failure, and 1 arrhythmic event. Univariate analysis revealed ejection fraction, exercise time, and ventricular ectopic count of > or = 10/hour to be predictive of future cardiac events. Subsequent multivariate analysis showed ejection fraction (p <0.001) and exercise time (p=0.002 to have independent prognostic value, but ventricular ectopic activity did not provide additional information. Ventricular ectopic count > or = 10/hour was additionally predictive only when combined with either ejection fraction (R2=5.4%) or exercise time (R2=2.9%). Event-free survival analysis revealed hazard ratios for ejection fraction <40% and exercise time <7 minutes of 3.63 (p=0.001) and 2.16 (p=0.01), respectively. Although ejection fraction and exercise time were able to predict future episodes of heart failure, neither could adequately identify patients at risk of recurrent ischemic events.

Influence of background correction in the estimation of myocardial uptake of 99mTc labelled perfusion imaging agents.

The effects of different corrections for background activity in the estimation of low organ uptake of radiopharmaceuticals have been examined using myocardial perfusion imaging agents. Estimates of myocardial uptake of 99mTc-labelled MIBI and tetrofosmin were made both at rest and after exercise. Patients were given one or other of the agents (12 MIBI; 17 tetrofosmin) and the measurements at rest and after exercise were made within a week of each other using a planar gamma camera method incorporating an attenuation-corrected, geometric mean technique. Myocardial uptakes were estimated using two different background corrections and also with no background subtraction. Mean values were in the range 1.3 to 3.0% and showed that, for both agents, uptakes estimated with and without background correction could differ by a factor of two. Although the study was not designed to compare myocardial uptakes of the two agents, a background correction which accounted separately for activity in tissue over- and under-lying the heart resulted in similar mean values for tetrofosmin (1.7% both at rest and after exercise) and for MIBI (1.8% rest; 1.9% exercise). For both agents, no significant difference was observed between myocardial uptakes at rest and after exercise measured at about two hours post-injection.

Effect of 2 liters of intraperitoneal dialysate on the cardiovascular system.

In 21 patients receiving continuous ambulatory peritoneal dialysis (CAPD), the effect of 2 liters of intraperitoneal dialysate on the supine and upright hemodynamics (19 patients), and the hemodynamic responses to 45 degrees head-up tilt (9 patients) were studied. Blood pressure (BP), heart rate (HR) and stroke volume (SV) (using impedance cardiography) were measured. In the supine position there was no significant difference in BP, SV, HR, derived cardiac output (CO) and peripheral resistance (PR) between "empty" (E) and "full" (F) conditions. On standing in both E and F conditions there were significant falls in systolic BP (p less than 0.001, compared with supine), SV and CO (p less than 0.05) accompanied by an increase in HR (p less than 0.001) but no significant change in peripheral resistance nor diastolic BP. The fall in systolic BP was greater in the E condition (from 149.3 +/- 4.5 mmHg to 134.6 +/- 5.9 in E, from 148.8 +/- 4 mmHg to 140.8 +/- 5.0 in F, p less than 0.001) and was accompanied by a bigger rise in HR (from 80.2 +/- 4.3 beat/min to 91.8 +/- 5.3 (E), from 79.4 +/- 4.4 to 87.7 +/- 5.2 (F, p less than 0.001). On tilting in 13 normal subjects there was an increase in diastolic BP (76.7 +/- 2.0 mmHg to 81.4 +/- 0.6, p less than 0.01), HR (63.3 +/- 2.4 beat/min to 73.6 +/- 1.0, p less than 0.01) and PR (13.4 +/- 1.0 mmHg/l/min to 21.3 +/- 0.2, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of training on the interpretation of 99Tcm-sestamibi myocardial perfusion SPET in patients with suspected coronary artery disease.

The aim of this study was to examine the effect of a period of concentrated training in nuclear cardiology on the accuracy of reporting 99Tcm-sestamibi (99Tcm-MIBI) single photon emission tomographic (SPET) images. Two visiting cardiologists, with no previous experience in nuclear cardiology, were asked to report blindly 60 99Tcm-MIBI SPET scans after 2 weeks of training in nuclear cardiology. One (observer 2) reported the same scans blindly after 2 months of further training. The results were compared with the assessment made by two experienced nuclear cardiologists and by using kappa statistics. Kappa values for the overall interpretation of the scan (normal or abnormal), segmental analysis (normal, ischaemic, fixed or mixed) and the three arterial territories were 0.7, 0.58 and 0.67 respectively. Following 2 months of further intensive training of observer 2, the kappa values were 0.857, 0.78 and 0.91 respectively. The difference between the two readings of observer 2 was significantly different for the segmental analysis (P < 0.001) and arterial territories (P = 0.006) but it did not reach statistical significance for the overall interpretation (P = 0.7). Thus, cardiologists without previous interpretation skills in nuclear cardiology required about 2 months of intensive training to achieve good accuracy in the interpretation of 99Tcm-MIBI SPET images. Accordingly, these techniques can be established in centres other than tertiary sites.

First myocardial infarctions in Asian and white men.

OBJECTIVE: To compare the presentation and natural course of first myocardial infarctions in immigrant Asians and the indigenous white population in Britain and the subsequent risk states of the two groups. DESIGN: Prospective ethnic comparison of consecutive patients with first myocardial infarctions. SETTING: Secondary referrals to a coronary care unit of a district general hospital. PATIENTS: 128 Men (77 white, 54 Asian) presenting consecutively with a first myocardial infarction diagnosed on the basis of clinical, biochemical, and electrocardiographic findings. END POINT: Identification of mechanisms accounting for the increased rate of ischaemic heart disease in Asians. MEASUREMENTS AND MAIN RESULTS: Infarct size was assessed by measuring the release of creatine phosphokinase (all patients), radionuclide ventriculography (50), and contrast ventriculography (103). Risk states after infarction were assessed from the degree of ventricular dysfunction as determined by exercise electrocardiography (82 patients) and from the extent of coronary atheroma as determined by coronary arteriography (103). Glucose state was measured in fasting venous blood samples. Overall the relative rate of infarction was 4.9 times higher in Asians (95% confidence interval 3.4 to 6.9) than in the white population. Moreover, the relative rate of infarction was higher in Asians in all 10 year age groups, the greatest difference being in 30-39 year olds. The mean age of the Asian denominator population was 47.1 years compared with 49.5 years in the white population. Age at infarction was less in Asians (50.2 years) than in white patients (55.5 years; mean difference 5.5 years (95% confidence interval 2.5 to 7.1]. In Asians the mean creatine phosphokinase activity was 777 (95% confidence interval 155 to 1399) U/1 higher, radionuclide ejection fraction 8.9% (1.0% to 16.9%) lower, and left ventricular fractional shortening 4.8% (1.4% to 8.2%) lower than in white patients. The extent of coronary atheroma was significantly greater in Asians. The mean numbers of plaques in vessels not associated with infarction were 3.66 (median 3.0, range 0-10) in Asians compared with 1.97 (median 2.0, range 0-6) in white patients (p less than 0.001), and a higher proportion of Asians had three vessel coronary artery disease (p less than 0.001). Asians with diabetes or impaired glucose tolerance did not differ from those with normal blood glucose values. CONCLUSIONS: Atherogenesis arises earlier in Asians, contributing to premature first myocardial infarctions. The increased incidence of diabetes in Asians may not in itself be relevant in the greater propensity to coronary atheroma in Asians.

Technetium 99m-labeled sestamibi imaging reliably identifies retained contractile reserve in dyssynergic myocardial segments.

BACKGROUND: Recently there has been considerable controversy regarding the use of 99mTc-labeled sestamibi as an agent for the detection of viable myocardium. In this study we have used dobutamine-induced left ventricular wall thickening by echocardiography in regions with evidence of resting dyssynergy of the left ventricle as an indicator of retained contractile reserve and compared this with 99m Tc-labeled sestamibi uptake in the same regions. METHODS AND RESULTS: Twenty-seven patients with documented coronary artery disease and severe regional wall motion abnormalities underwent low-dose (5 to 15 micrograms/kg/min) dobutamine echocardiography and maximal (15 to 40 micrograms/kg/min) stress dobutamine 99mTc-labeled sestamibi single-photon emission computed tomographic imaging. Separate-day rest 99mTc-labeled sestamibi scanning was also performed. 99mTc-labeled sestamibi uptake was assessed semiquantitatively from grades from 1 to 4, from normal to absent perfusion. Regions with grade 3 or less uptake were considered viable by 99mTc-labeled sestamibi. Of the 34 regions with severe wall motion abnormalities by echocardiography, 32 showed improved wall thickening with low-dose dobutamine. Rest 99mTc-labeled sestamibi detected retained myocardial viability in 29 of these regions (91%) that were deemed to have contractile reserve by echocardiography (concordance: 91% [K = 0.53; p < 0.001]). Furthermore, stress-rest 99mTc-labeled sestamibi revealed completely reversible defects in five regions (16%), partially reversible defects in 24 regions (75%), and grade 4 uptake and fixed (nonviable) defects in three (9%) of these 32 regions with retained contractile reserve. CONCLUSION: Uptake of 99mTc-labeled sestamibi at rest accurately identifies regions of segmental dyssynergy in which recovery of function may be provoked by inotropic stimulation. Addition of stress dobutamine 99mTc-labeled sestamibi provides further proof of retained myocardial viability in these dysfunctional segments.

Superiority of nitrate-enhanced 201Tl over conventional redistribution 201Tl imaging for prognostic evaluation after myocardial infarction and thrombolysis.

BACKGROUND: 201Tl imaging has been widely used for postinfarction risk stratification. However, thrombolytic therapy and aspirin have significantly changed outcome, and there are few nuclear imaging studies that assess prognosis in such patients. Furthermore, newer techniques of 201Tl imaging, such as reinjection and nitrate-enhanced rest 201Tl imaging, have been shown to improve the detection of viable but jeopardized myocardium. METHODS AND RESULTS: We studied 100 consecutive patients, who remained event free 6 weeks after myocardial infarction and thrombolysis. Patients underwent conventional exercise and 4-hour redistribution imaging, followed on a separate day by nitrate-enhanced rest 201Tl study. Planar images were reported semiquantitatively by two experienced observers blinded to clinical data. Redistribution and rest injection images were classified as demonstrating reversible ischemia if they showed improvement in uptake by at least two grades in at least two segments in comparison with the initial exercise scintigram. Patients were followed up for 8 to 32 months (mean, 21 months); during this period, 37 patients had first cardiac events. Reversible ischemia was present in 29 patients on redistribution, of whom 14 (48%) had events; of 71 without reversible defects, 23 (32%) had events (hazard ratio, 1.5; 95% CI, 0.8 to 3.0; P=NS). Nitrate-enhanced rest 201Tl imaging detected reversible defects in 68 patients, of whom 33 (49%) had events, whereas of 32 without reversible defects, only 4 (13%) had subsequent cardiac events (hazard ratio, 8.1; 95% CI, 2.7 to 23.8; P<.001). CONCLUSIONS: Thus, after myocardial infarction and thrombolysis, even "stable" patients have a high (68%) incidence of viable but jeopardized myocardium, causing a high event rate. Those identified to be at high risk by perfusion imaging may benefit from early intervention.

Beneficial effects of intravenous and oral carvedilol treatment in acute myocardial infarction. A placebo-controlled, randomized trial.

BACKGROUND: Evidence of efficacy and safety of beta-blockers after thrombolysis for acute myocardial infarction (AMI) is equivocal. Newer beta-blockers such as carvedilol have not been tested in this setting. METHODS AND RESULTS: This study investigated the effects of acute (intravenous) and long-term (6 months, oral) treatment with carvedilol versus placebo in 151 consecutive patients with AMI. Exercise ECG, ambulatory monitoring, and two-dimensional echocardiography were performed before hospital discharge and at 3 and 6 months. All patients were followed up and cardiovascular events recorded. The Cox proportional hazards model was used to compare time from randomization with the occurrence of a cardiovascular event, and Kaplan-Meier survival curves were calculated. Carvedilol was found to be safe, and it significantly reduced cardiac events compared with placebo (18 on carvedilol and 31 on placebo, P < .02). Fifty-four patients had heart failure at study entry; 34 received carvedilol. There were no adverse effects of carvedilol therapy and no excess events in this subgroup. Carvedilol produced significant reductions in heart rate (P < .0001), blood pressure (P < .005) at rest, and rate-pressure product at peak exercise (P < .003), but exercise capacity was unchanged. Left ventricular ejection fraction was not altered significantly by carvedilol, but stroke volume was higher at pre-hospital discharge examination (63 versus 53 mL; P < .01). Diastolic filling of the left ventricle (E/A ratio) was also improved (1.2 versus 0.9; P < .001). In a subgroup with left ventricular ejection fraction < 45% (n = 49 patients; 24 on carvedilol and 25 on placebo), carvedilol showed attenuation of remodeling. CONCLUSIONS: Carvedilol was well tolerated and safe to use in patients immediately after AMI, including those with heart failure, and significantly improved outcome.

Detection of coronary artery disease with myocardial contrast echocardiography: comparison with 99mTc-sestamibi single-photon emission computed tomography.

BACKGROUND: The purpose of this study was to determine whether myocardial contrast echocardiography (MCE) can be used to detect coronary artery disease (CAD) during rest and pharmacological stress in humans through the use of venous injections of contrast. METHODS AND RESULTS: Thirty patients with known or suspected CAD underwent MCE and 99mTc-sestamibi single-photon emission computed tomography (SPECT) at baseline and after dipyridamole (0.56 mg x kg(-1)) infusion. Ten myocardial segments (5 each in the apical two- and four-chamber views) from the two sets of images using both methods were scored for myocardial perfusion as follows: 1=normal, 0.5=mildly reduced, and 0=severely reduced. The information from baseline and postdipyridamole images was then used to determine whether an abnormal segment was irreversible (similar abnormal perfusion at baseline and after dipyridamole) or reversible (perfusion better at baseline compared with after dipyridamole). Concordance between segmental scores was 92% (kappa=.99) for both methods. Concordance between normal perfusion and reversible or irreversible segmental defects was 90% (kappa=.80). Agreem between the two methods for each of the three vascular territories in each patient was 90% (kappa=.77), while agreement for the presence or absence of CAD in each patient was 86% (kappa=.86). In the 4 patients with disagreement, the perfusion scores were 0.5 for SPECT and 1.0 for MCE. CONCLUSIONS: This study shows that MCE, with venous injection of contrast, can define the presence of CAD during rest and pharmacological stress. The location of perfusion abnormalities and their physiologic relevance (reversible or irreversible) by MCE is similar to that provided by SPECT. MCE, therefore, holds promise for the noninvasive assessment of myocardial perfusion in humans.

Effects of carvedilol on left ventricular remodelling in chronic stable heart failure: a cardiovascular magnetic resonance study.

BACKGROUND: The ability of beta blockers to improve left ventricular function has been demonstrated, but data on the effects on cardiac remodelling are limited. OBJECTIVE: To investigate, using cardiovascular magnetic resonance (CMR), the effects of carvedilol on left ventricular remodelling in patients with chronic stable heart failure and left ventricular systolic dysfunction caused by coronary artery disease. DESIGN: Randomised, double blind, placebo controlled study. SETTING: Chronic stable heart failure. PATIENTS AND INTERVENTION: 34 patients with chronic stable heart failure and left ventricular systolic function taking part in the CHRISTMAS trial (double blind carvedilol v placebo) underwent CMR before randomisation and after six months of treatment. MAIN OUTCOME MEASURE: Left ventricular remodelling at six months. RESULTS: The carvedilol and placebo groups were well balanced at baseline, with no significant intergroup differences. Over the study period, there was a significant reduction in end systolic volume index (ESV(I)) and end diastolic volume index (EDV(I)) between the carvedilol and the placebo group (carvedilol -9 v placebo +3 ml/m2, p = 0.0004; carvedilol -8 v placebo 0 ml/m2, p = 0.05). The ejection fraction increased significantly between the groups (carvedilol +3% v placebo -2%, p = 0.003). CONCLUSIONS: Treatment of chronic stable heart failure with carvedilol results in significant improvement in left ventricular volumes and function. These effects might contribute to the benefits of carvedilol on mortality and morbidity in patients with chronic heart failure.