Drop-out from cardiovascular magnetic resonance in a randomized controlled trial of ST-elevation myocardial infarction does not cause selection bias on endpoints.

BACKGROUND: The extent of selection bias due to drop-out in clinical trials of ST-elevation myocardial infarction (STEMI) using cardiovascular magnetic resonance (CMR) as surrogate endpoints is unknown. We sought to interrogate the characteristics and prognosis of patients who dropped out before acute CMR assessment compared to CMR-participants in a previously published double-blinded, placebo-controlled all-comer trial with CMR outcome as the primary endpoint. METHODS: Baseline characteristics and composite endpoint of all-cause mortality, heart failure and re-infarction after 30 days and 5 years of follow-up were assessed and compared between CMR-drop-outs and CMR-participants using the trial screening log and the Eastern Danish Heart Registry. RESULTS: The drop-out rate from acute CMR was 28% (n = 92). These patients had a significantly worse clinical risk profile upon admission as evaluated by the TIMI-risk score (3.7 (± 2.1) vs 4.0 (± 2.6), p = 0.043) and by left ventricular ejection fraction (43 (± 9) vs. 47 (± 10), p = 0.029). CMR drop-outs had a higher incidence of known hypertension (39% vs. 35%, p = 0.043), known diabetes (14% vs. 7%, p = 0.025), known cardiac disease (11% vs. 3%, p = 0.013) and known renal function disease (5% vs. 0%, p = 0.007). However, the 30-day and 5-years composite endpoint rate was not significantly higher among the CMR drop-out ((HR 1.43 (95%-CI 0.5; 3.97) (p = 0.5)) and (HR 1.31 (95%-CI 0.84; 2.05) (p = 0.24)). CONCLUSION: CMR-drop-outs had a higher incidence of cardiovascular risk factors at baseline, a worse clinical risk profile upon admission. However, no significant difference was observed in the clinical endpoints between the groups.

WITHDRAWN: Quantitative Analysis of Dobutamine-Atropine Stress Echocardiography.

The publisher regrets that this was an accidental duplication of an article that has already been published in Eur. J. Echocardiogr., 4 (2003) 169-177, . The duplicate article has therefore been withdrawn.

Combined first pass and equilibrium radionuclide cardiographic determination of stroke volume for quantitation of valvular regurgitation.

A new noninvasive procedure for quantitation of cardiac valve regurgitation was evaluated using a combination of first pass and gated equilibrium radionuclide cardiography in 38 subjects with and without cardiac valve disease. Left-sided cardiac catheterization was performed to determine the severity of mitral incompetence and aortic regurgitation semiquantitatively. In healthy subjects and in patients without valve disease, stroke volumes were nearly identical with the two methods and the correlation was high (r = 0.98 [p less than 0.001]). The mean regurgitation fraction was 13% in patients with mild mitral incompetence and 2+ aortic regurgitation, 37% in patients with moderate mitral incompetence and 3+ aortic regurgitation and 57% in patients with severe mitral incompetence and 4+ aortic regurgitation. These findings suggest that combined first pass and gated equilibrium radionuclide cardiography, being insensitive to intracardiac shunts and right-sided valve disorders, constitutes a valid noninvasive technique for quantitation of left-sided cardiac valve regurgitation.

Predictors of coronary in-stent restenosis: importance of angiotensin-converting enzyme gene polymorphism and treatment with angiotensin-converting enzyme inhibitors.

OBJECTIVES: This study aimed to clarify the role of the angiotensin-converting enzyme (ACE) gene polymorphism in the development of in-stent restenosis. BACKGROUND: In-stent restenosis occurs after treatment of coronary artery stenosis in 12% to 32% of coronary interventions with stents. Experimental and clinical studies have suggested that the deletion/insertion (D/I) polymorphism of the ACE gene plays a role in this. METHODS: Quantitative coronary angiography before, immediately after and six months after stent implantation were compared in 369 patients, in whom D/I typing of the ACE gene was performed. RESULTS: At follow-up we found no differences between the three genotypes in minimal lumen diameter (homozygotes with two deletion alleles in the ACE gene [DD], 2.20 mm; heterozygotes with one deletion and one insertion allele in the ACE gene [DI], 2.19 mm; and homozygotes with two insertion alleles in the ACE gene [II], 2.25 mm). The corresponding diameter stenoses were: DD: 25%, DI: 27%, II: 27% (p = NS), and the frequency of restenosis (>50% diameter stenosis) was: DD: 15.7%, DI: 11.0% and II: 16.4% (p = NS). Logistic regression analysis identified diabetes (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.0 to 8.7), lesion length (OR: 1.1, 95% CI: 1.01 to 1.30) and minimal lumen diameter immediately after the intervention (OR: 0.3, 95% CI: 0.14 to 0.85) as predictors of in-stent restenosis. In a post hoc analysis of patients treated versus those not treated with an ACE-inhibitor antagonist or an angiotensin receptor antagonist, we found an increased frequency of in-stent restenosis in the DD genotypes (40% vs. 12%, p = 0.006). CONCLUSIONS: The D/I polymorphism is not an independent predictor of coronary in-stent restenosis in general, but it may be of clinical importance in patients treated with ACE inhibitors or angiotensin receptor antagonists.

Central hemodynamic changes after ingestion of a meal in patients with coronary artery disease.

Thirty-six patients with coronary artery disease participated in a controlled trial of the influence of food intake on central hemodynamic parameters determined noninvasively by radionuclide cardiography. Stroke volume increased considerably (23%) and heart rate was slightly higher (8%) half an hour after the meal, whereas the elevated cardiac output two hours postprandially could be ascribed entirely to relative tachycardia. No significant hemodynamic changes occurred in the patients who fasted. That the left ventricular ejection fraction was increased postprandially (3% to 4%) indicated that food intake had positive inotropic as well as chronotropic effects on the ischemic heart, even in heart failure. Afterload reduction and increased sympathetic nervous activity contribute to the changes, but the primary mechanism may be a change in resistance and blood flow in the intestinal vascular bed involved in digestion.

Technetium-99m labeling of red blood cells: in vitro evaluation of a new approach.

By titration of two different stannous kits for 99mTc labeling of red blood cells (RBC) we found concentrations of 1-2 micrograms tin per ml of blood to give the highest labeling yield. Using a new kit containing 2 micrograms of tin and 0.1% hypochlorite (NaOCl) as an oxidizing agent we labeled RBC with 99mTc avoiding centrifugation of cells. To evaluate this new procedure we assessed the dependency of tin incubation time, and addition of 4.4% EDTA as a chelating agent on labeling efficiency. We also measured the dependency of EDTA on the stability of the label. Optimal conditions for labeling of 1 ml of whole blood using the new stannous kit were: 5-10 min of tin incubation, 0.2 ml of 0.1% hypochlorite, and 15 min of 99mTc incubation. This procedure resulted in a labeling efficiency of at least 96%. The overall effect of EDTA was not an increased labeling efficiency, and EDTA increased the stability of the label with only a few percent. The promising results of this new labeling approach encourage to further laboratory investigations and eventual clinical evaluation of the procedure.

Technetium-99m labeling of polymorphonuclear leukocytes: preparation with two different stannous agents.

A technique for in vitro labeling of human polymorphonuclear leukocytes with Tc-99m is described. Titration of stannous fluoride and stannous pyrophosphate concentrations for pretinning was performed, and optimal amounts of the stannous agents were added to polymorphonuclear leukocytes efficiently isolated from 100 ml of blood. Labeling with 10-15 mCi Tc-99m resulted, after three washings of cell suspensions, in yields of 1.6-4.8 mCi, corresponding to 20.5-33.5% of added tracer. Cell-bound activity in the final cell suspensions was 92.3% +/- 1.9 of the added dose. Cell function was not impaired by the labeling technique. Sterility and exclusion of bacterial endotoxins in the final cell suspensions were demonstrated. The method may prove of diagnostic value in the isolation, labeling, and reinjection of autologous leukocytes for scintigraphic imaging of acute inflammatory lesions.

First-pass radionuclide determination of cardiac output: an improved gamma camera method.

A technique for noninvasive determination of cardiac output by aid of first-pass radionuclide cardiography is described. After intravenous injection of 10-15 mCi technetium-99m-(99mTc) labeled red blood cells the method requires acquisition of a first passage time-activity curve recorded with a gamma camera over the left ventricle, the background corrected left ventricular count rate recorded after complete mixing of the tracer in the circulation, and determination of the distribution volume of the tracer. The method was applied in 14 patients with heart disease of various origins and evaluated against the conventional tracer dilution technique with arterial sampling of blood activity. Cardiac output determinations by external counting ranged from 2.30 to 8.56 l/min, mean +/- s.d. 4.50 +/- 1.66 l/min and by arterial blood sampling from 1.88 to 8.96 l/min, mean +/- s.d. 4.52 +/- 1.71 l/min. An excellent correlation was demonstrated between the two techniques, r = 0.978 (p less than 0.001). When no background subtraction was applied to the left ventricular counts at equilibrium, radionuclide cardiac output values were approximately 40% higher than those obtained by arterial sampling. The new first-pass radionuclide cardiographic technique may prove a useful tool in the noninvasive evaluation of cardiac function, especially in patients with arrhythmias and/or valvular incompetence.

Dual spillover problem in the myocardial septum with nitrogen-13-ammonia flow quantitation.

UNLABELLED: Conventional cardiac PET modeling techniques for [13N]ammonia flow determination do not fully account for the effects of spillover of activity from the right ventricle (RV) onto the activity in the myocardial septum. The purpose of this study was to investigate and to quantitatively account and correct for this effect. METHODS: Simulations were performed to determine the error introduced by conventional quantitation using septal time-activity curves, which only account for left ventricle (LV) spillover. Furthermore, we explored two separate methods to account for the dual spillover problem: direct estimation of the RV and LV spillover fractions incorporated into the [13N]ammonia model by using the LV and RV input functions in the fit and estimation of the relative dispersion and time shift between the LV and RV input functions by fitting using only the LV input function. The simulated curves were fitted using a two-compartment [13N]ammonia model. Flow estimates from the conventional model and the models including either of the two correction procedures were compared with canine microsphere data. RESULTS: The influence of RV spillover on flow estimation in the septum is determined by several parameters (e.g., dispersion between the RV and LV input function). Depending on the value of these parameters, the septal flow may be underestimated by 0%-30%. The applied methods for correction of the dual spillover problem were comparable and allow for more accurate quantitation in the septum. The canine microsphere data revealed that flow underestimation in the septum is small but significant. CONCLUSION: Dual spillover in the myocardial septum can introduce significant errors in the estimation of flow by the conventional [13N]ammonia model fitting method, which does not properly account for the RV spillover. Adjusting for the RV spillover in one of the two proposed methods allows for more accurate quantitation of myocardial septal flow with [13N]ammonia PET data.

Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse.

Ramipril 10 mg/day reduced regurgitation in chronic mitral regurgitation secondary to mitral valve prolapse in patients with sinus rhythm.

Acute effects of alcohol on left ventricular function in healthy subjects at rest and during upright exercise.

Six healthy men, aged 23 to 30 years, were studied by radionuclide angiocardiography at rest and at 2 submaximal exercise levels in the upright position during increasing alcohol intoxication. At light intoxication (serum ethanol 23 mmol/liter), the median value of left ventricular (LV) ejection fraction (EF) at rest decreased by 5%. At heavy intoxication (serum ethanol 45 mmol/liter), the median LVEF decreased at rest by 11% and during 75% submaximal exercise by 6%, heart rate at rest increased (median 81 vs 62 beats/min), and systolic blood pressure decreased during 50% submaximal exercise (median 145 vs 163 mm Hg). No significant changes of plasma epinephrine concentrations were recorded, whereas plasma norepinephrine concentrations were increased by 24% at rest during light intoxication and by 30 to 38% during heavy intoxication. No changes of LVEF and plasma catecholamine levels were recorded after ingestion of isovolumic, isocaloric drinks as compared with values obtained before intake. Thus, influences of ingestion per se and repeated investigations of LV function were excluded. These findings suggest that in healthy subjects alcohol intoxication causes a dose-dependent impairment of cardiac contractility. Compensatory mechanisms may account for a reduced influence during exercise.

Left ventricular function during alcohol intoxication and autonomic nervous blockade.

Eight healthy young subjects (6 men, 2 women) entered a controlled investigation of left ventricular (LV) function during alcohol intoxication and autonomic nervous blockade. Radionuclide cardiography was performed at rest and during upright 50% submaximal bicycle exercise. During alcohol intoxication alone (serum ethanol 30 mmol/liter), heart rate at rest increased by 11% (p less than 0.05) and LV ejection fraction (EF) decreased by 6% because of end-systolic dilation. No significant alcohol-induced hemodynamic changes were observed during exercise. Plasma norepinephrine concentration increased by 29% (p less than 0.05), whereas plasma epinephrine concentration did not change. During subsequent autonomic nervous blockade with intravenous metoprolol and atropine infusion, heart rate at rest further increased and systolic blood pressure decreased. These changes were not, however, significantly different from those of a control experiment in which a nonalcoholic isocaloric drink was substituted for alcohol. Plasma norepinephrine levels at rest and during exercise were 25% and 32% higher (both p less than 0.05), respectively, than those during control conditions. Plasma epinephrine concentrations did not change. These findings suggest that alcohol intoxication has a depressant effect on LV function at rest that stimulates autonomic nervous blockade. The increased sympathetic nervous activity during exercise appears to be a toxic rather than a compensatory effect of alcohol.

Hemodynamic effects of alcohol at rest and during upright exercise in coronary artery disease.

The hemodynamic effects of acute alcohol intoxication were studied at rest and during upright exercise in 28 patients with coronary artery disease by right-sided heart catheterization and radionuclide cardiography. The mean arterial blood pressure at rest was reduced by 5% and the left ventricular ejection fraction at rest decreased 2% because of end-systolic dilation during intoxication (serum ethanol 21 mmol/liter). No changes were observed in heart rate, stroke volume, pulmonary artery pressure, pulmonary artery wedge pressure or total peripheral resistance. No significant changes occurred in plasma catecholamines, and no changes occurred in any variable during mild exercise corresponding to a 30 to 40% heart rate increase. Thus, alcohol ingested in moderate doses causes slight impairment of left ventricular emptying and a reduction in the arterial blood pressure at rest in patients with coronary artery disease. A mild exercise load can be tolerated during alcohol intoxication without hemodynamic changes.

Metoprolol abolishes exercise-induced left ventricular dysfunction in patients with silent ischemia.

Left ventricular systolic function is reduced during episodes of silent ischemia in patients with coronary artery disease (CAD). Left ventricular ejection fraction (LVEF) is increased at least 5 absolute percent during exercise in most normal subjects; however, in patients with CAD, LVEF often remains unchanged or decreases. The anti-ischemic effect of beta-adrenergic receptor blockade is well documented, including a reduction of exercise-induced electrocardiographic ST depressions; however, the effect of these drugs on left ventricular volume changes during exercise in patients with silent ischemia is unknown. The aim of this study was to evaluate the effect of a cardio-selective beta-blocking agent, metoprolol, on rest and exercise LVEF in patients with silent ischemia, using radionuclide cardiography. Fifteen patients with silent ischemia completed a double-blind, placebo-controlled crossover study at rest and during submaximal exercise. LVEF remained unchanged during exercise in the placebo phase (56% to 58%; p = NS), but even though LVEF tended to decrease 56% during rest after metoprolol versus 52% after placebo (p = NS), the LVEF increase from rest to exercise resembled a normal LVEF response, 52% to 58% (p = 0.005). Exercise-induced electrocardiographic ST depressions were also reduced during metoprolol treatment. In patients with silent ischemia, the exercise-induced change in LVEF rises significantly during metoprolol treatment. The mechanism may be a reduction in myocardial ischemia as indicated by a reduction in ischemic electrocardiographic findings.

Continuous monitoring of global left ventricular ejection fraction during percutaneous transluminal coronary angioplasty.

Continuous monitoring of left ventricular (LV) function during percutaneous transluminal coronary angioplasty (PTCA) was performed in 40 patients (53 +/- 2 years) with a miniature, nuclear detector system after labeling the patients' red blood cells with technetium-99m. Balloon dilation (113 seconds, range 60 to 240) induced on average a 0.12 ejection fraction (EF) unit (19%) decrease in the LVEF, which was explained by a 34% increase in end-systolic counts. Balloon dilation of the left anterior descending artery (n = 23) produced a decrease in the LVEF of 0.17 +/- 0.13 EF units compared with the decrease of 0.06 +/- 0.07 EF units in patients undergoing dilation of the left circumflex artery (n = 9) and 0.05 +/- 0.04 EF units in patients treated for a stenosis of the right coronary artery (n = 8), (p = 0.02). Balloon deflation was associated with an immediate return to pre-PTCA levels. In 10 patients with 2 identical balloon occlusions, the second occlusion led to a significantly less decrease in the LVEF (0.41 +/- 0.14 vs 0.44 +/- 0.15) and electrocardiographic ST-segment deviation (88 +/- 54 microV vs 65 +/- 42 microV) than the first. We conclude that PTCA is associated with an abrupt transient decrease in the LVEF. The effect of balloon occlusion of the left anterior descending artery is more pronounced than balloon occlusion of the left circumflex and the right coronary arteries. Neither single nor multiple balloon occlusions were associated with post-PTCA global LV dysfunction, whereas the lesser degree of LV dysfunction and electrocardiographic signs of myocardial ischemia during the second of 2 identical balloon occlusions suggests that preconditioning can be induced during PTCA.

Cardiac performance in patients with asymptomatic alcoholic cirrhosis of the liver.

Twenty patients with biopsy-proved alcoholic cirrhosis of the liver and no cardiac symptoms entered a noninvasive investigation program in which cardiac performance was evaluated. One patient was excluded from the study because of a significant ethanol content in the serum at the time of investigation and 4 patients were excluded because of significant electrocardiographic ST-segment changes during exercise testing. Fifteen patients (12 men, 3 women, median age 47 years) who had abstained from alcohol drinking for at least 2 months were studied by exercise testing, echocardiography, measurement of systolic time intervals and left ventricular (LV) radionuclide ejection fraction (EF) at rest and during submaximal exercise. Twelve healthy persons of the same age served as control subjects. Heart rate at rest was significantly elevated in the patient group, median 90 beats/min (range 62 to 128) vs 73 beats/min (range 61 to 89) (p less than 0.02). No significant differences were found in physical work capacity and systolic time intervals, and echocardiographic parameters did not differ with the exception of left atrial dimension (median 36 mm [range 22 to 47] in the patient group and 31 mm [range 17 to 38] in the control subjects, p less than 0.05). No significant difference was found in LVEF at rest. During exercise, however, the median LVEF increased only 6% in the patients versus 14% in the control subjects (p less than 0.05). The results of this study suggest that patients with alcoholic liver cirrhosis, although free of cardiac symptoms, may have a latent or preclinical cardiomyopathy that is manifest during physical stress.

Doctors' requirements for reproducibility of diagnostic information.

Two radiologists independently assessed 100 leg vein phlebograms for the presence or absence of deep venous thrombosis. In a subsequent questionnaire, 66 physicians were asked to state the level of agreement they would require to use conventional phlebography in their diagnostic decisions, and whether they would reduce their requirements if the phlebographic technique were made less painful and less expensive. The responses indicated physicians' requirements for reproducibility of a well-known routine diagnostic method may be unrealistic, and that physicians do not consider the inconvenience of an examination to the patient or its cost in setting their requirements for diagnostic precision.

Reproducibility in the analysis of multigated radionuclide studies of left ventricular ejection fraction.

The authors determined the reproducibility (the standard deviation [SD]) in the analysis of multigated radionuclide studies of left ventricular ejection fraction (LVEF). Radionuclide studies from a consecutive series of 38 patients suspected of ischemic heart disease were analyzed independently by four nuclear medicine physiologists and four laboratory technicians. Each study was analyzed three times by each of the observers. Based on the analyses of the eight observers, the SD could be estimated by the use of a variance component model for LVEF determinations calculated as the average of the analyses of an arbitrary number of observers making an arbitrary number of analyses. This study presents the SDs for LVEF determinations based on the analyses of one to five observers making one to five analyses each. The SD of a LVEF determination decreased from 3.96% to 2.98% when an observer increased his number of analyses from one to five. A more pronounced decrease in the SD from 3.96% to 1.77% was obtained when the LVEF determinations were based on the average of a single analysis made by one to five observers. However, when dealing with the difference between LVEF determinations from two studies, the highest reproducibility was obtained if the LVEF determinations at both studies were based on the analyses made by the same observer. No significant difference was found in the reproducibility of analyses made by nuclear medicine physicians and laboratory technicians. Our study revealed that to increase the reproducibility of LVEF determinations, special efforts should be made to standardize the outlining of the end-systolic region interest.

Amlodipine reduces myocardial ischaemia during exercise without compromising left ventricular function in patients with silent ischaemia: a randomised, double-blind, placebo-controlled study.

BACKGROUND: Left ventricular systolic function is reduced during episodes of silent ischaemia in patients with coronary artery disease (CAD). In most normal subjects left ventricular ejection fraction (LVEF) increases at least 5% during exercise whereas LVEF often remains unchanged or decreases in patients with CAD. The anti-ischaemic effect of calcium antagonists is well documented including a capability to reduce exercise-induced electrocardiographic ST-depressions, whereas the effect of these drugs on LV volume changes during exercise in patients with silent ischaemia is unknown. AIM: The aim of this study was to evaluate the effect of amlodipine on rest and exercise LVEF in patients with silent ischaemia. METHODS: Twenty-one patients completed a double-blind placebo-controlled cross-over study. Conventional exercise test and radionuclide cardiographies during exercise were used for determining haemodynamic parameters. RESULTS: Exercise-induced electrocardiographic ST-depressions were reduced in 83% of the patients having ST-deviations during placebo even though 10 patients were already treated with a beta-blocker. Amlodipine did not affect left ventricular systolic function compared to placebo, neither at rest nor during exercise. CONCLUSION: The results indicated that amlodipine is a safe anti-ischaemic drug in patients with silent ischaemia concerning cardiac function.

Autonomic nervous control of postprandial hemodynamic changes at rest and upright exercise.

Postprandial hemodynamic changes were studied in healthy subjects at rest and during exercise in the upright position with and without autonomic blockade of the heart. At rest cardiac output increased 61% mostly because of a stroke volume increase accomplished by left ventricular end-diastolic dilation. These changes seemed to be dependent on the autonomic nervous system, whereas the postprandial heart rate increase did not. During exercise cardiac output was 23% higher after food intake due to a rise in both stroke volume and heart rate. These changes were apparently under influence of the autonomic nervous system, whereas left ventricular dilation was not. The present findings indicate that most of the postprandial changes in the central circulation are under control of the autonomic nervous system.