Intraoperative fluorescence perfusion assessment should be corrected by a measured subject-specific arterial input function.

SIGNIFICANCE: The effects of varying the indocyanine green injection dose, injection rate, physiologic dispersion of dye, and intravenous tubing volume propagate into the shape and magnitude of the arterial input function (AIF) during intraoperative fluorescence perfusion assessment, thereby altering the observed kinetics of the fluorescence images in vivo. AIM: Numerical simulations are used to demonstrate the effect of AIF on metrics derived from tissue concentration curves such as peak fluorescence, time-to-peak (TTP), and egress slope. APPROACH: Forward models of tissue concentration were produced by convolving simulated AIFs with the adiabatic approximation to the tissue homogeneity model using input parameters representing six different tissue examples (normal brain, glioma, normal skin, ischemic skin, normal bone, and osteonecrosis). RESULTS: The results show that AIF perturbations result in variations in estimates of total intensity of up to 80% and TTP error of up to 200%, with the errors more dominant in brain, less in skin, and less in bone. Interestingly, error in ingress slope was as high as 60% across all tissue types. These are key observable parameters used in fluorescence imaging either implicitly by viewing the image or explicitly through intensity fitting algorithms. Correcting by deconvolving the image with a measured subject-specific AIF provides an intuitive means of visualizing the data while also removing the source of variance and allowing intra- and intersubject comparisons. CONCLUSIONS: These results suggest that intraoperative fluorescence perfusion assessment should be corrected by patient-specific AIFs measured by pulse dye densitometry.

Application of phiLOV2.1 as a fluorescent marker for visualization of Agrobacterium effector protein translocation.

Agrobacterium tumefaciens can genetically transform plants by translocating a piece of oncogenic DNA, called T-DNA, into host cells. Transfer is mediated by a type IV secretion system (T4SS). Besides the T-DNA, which is transferred in a single-stranded form and at its 5' end covalently bound to VirD2, several other effector proteins (VirE2, VirE3, VirD5, and VirF) are translocated into the host cells. The fate and function of the translocated proteins inside the host cell are only partly known. Therefore, several studies were conducted to visualize the translocation of the VirE2 protein. As GFP-tagged effector proteins are unable to pass the T4SS, other approaches like the split GFP system were used, but these require specific transgenic recipient cells expressing the complementary part of GFP. Here, we investigated whether use can be made of the photostable variant of LOV, phiLOV2.1, to visualize effector protein translocation from Agrobacterium to non-transgenic yeast and plant cells. We were able to visualize the translocation of all five effector proteins, both to yeast cells, and to cells in Nicotiana tabacum leaves and Arabidopsis thaliana roots. Clear signals were obtained that are easily distinguishable from the background, even in cases in which by comparison the split GFP system did not generate a signal.

Exercise-Induced Systemic Venous Hypertension in the Fontan Circulation.

Increasingly end-organ injury is being demonstrated late after institution of the Fontan circulation, particularly liver fibrosis and cirrhosis. The exact mechanisms for these late phenomena remain largely elusive. Hypothesizing that exercise induces precipitous systemic venous hypertension and insufficient cardiac output for the exercise demand, that is, a possible mechanism for end-organ injury, we sought to demonstrate the dynamic exercise responses in systemic venous perfusion (SVP) and concurrent end-organ perfusion. Ten stable Fontan patients and 9 control subjects underwent incremental cycle ergometry-based cardiopulmonary exercise testing. SVP was monitored in the right upper limb, and regional tissue oxygen saturation was monitored in the brain and kidney using near-infrared spectroscopy. SVP rose profoundly in concert with workload in the Fontan group, described by the regression equation 15.97 + 0.073 watts per mm Hg. In contrast, SVP did not change in healthy controls. Regional renal (p <0.01) and cerebral tissue saturations (p <0.001) were significantly lower and decrease more rapidly in Fontan patients. We conclude that in a stable group of adult patients with Fontan circulation, high-intensity exercise was associated with systemic venous hypertension and reduced systemic oxygen delivery. This physiological substrate has the potential to contribute to end-organ injury.

Reliability and validity of a new French-language triage algorithm: the ELISA scale.

OBJECTIVE: Overcrowding in emergency departments (ED) leads to reductions in quality of care. Consequently, several different triage tools have been developed to prioritise patient intake. Differences in emergency medical services in different countries have limited the generalisation of pre-existing triage systems; for this reason, specific algorithms corresponding to local characteristics are needed. Accordingly, we developed a specific French-language triage system named Echelle Liégeoise d'Index de Sévérité à l'Admission (ELISA). This study tested its validity and efficiency. METHODS: ELISA is a five-category nursing triage algorithm. Intrarater agreement was tested by comparing triage levels attributed to the same clinical scenarios at two different times. Interrater agreement was investigated by comparing triage categories attributed to clinical cases by different triage nurses. Finally, validity was estimated by studying the correlations between the triage ranking assigned by the nurse and actual resource consumption and patient outcome. RESULTS: The distribution of the difference between nurse classification at the two times was statistically unrelated to which nurse carried out the evaluation. Regarding interrater agreement, assigned classifications were compared to the reference assignment. Cohen's κ coefficient revealed an almost perfect agreement between classification by nurses and the reference. Finally, statistical analysis revealed a strong relation between ELISA and the overall need for supplementary clinical testing. Outcomes were also significantly correlated with ELISA. CONCLUSIONS: The need for a specific, French-language triage tool in our ED led us to develop a new triage scale. This study demonstrates that the scale is a valid triage tool with high interrater and intrarater agreement and considerable efficiency.

Epidemiological profiles of human immunodeficiency virus and hepatitis C virus infections in Malian women: Risk factors and relevance of disparities.

AIM: To document the epidemiologic patterns and risk factors of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in Mali in order to develop prevention means for both diseases. METHODS: Two prospective studies were conducted in Bamako in 2009 among 1000 pregnant women (i.e., young women) who consulted six reference health centers, and in 2010, among 231 older women who attended general practice in two hospitals. Antibody tests and molecular analysis (performed only for HCV) were used to quantify the frequencies of both infections. The data were collected from patients recruited through a questionnaire. Transmission risk factors of both diseases were identified by univariate and multivariate analysis. RESULTS: HCV seroprevalence was 0.2% for young and 6.5% for older women. HIV prevalence was similar in both populations (4.1% vs 6.1%). In older women, the analysis of risk factors highlighted an association between HCV infection and episodes of hospitalization (P < 0.01). The study did not show an association between HIV infection and the variables such as hospitalization, transfusion, tattoo, dental care, and endoscopy. A significant decrease of HIV seroprevalence was detected in young women who used condoms for contraception more than for other purposes (P < 0.01). By contrast, HIV seroprevalence was significantly increased in young women using condoms mainly to prevent sexual infections rather than for contraception (P < 0.01). No HCV/HIV coinfection was detected in our study. CONCLUSION: Risk factors and epidemiologic data of HIV and HCV as well as the absence of co-infection strongly suggest epidemiological disparities between these diseases.

Prevalence of HIV and HCV infections in two populations of Malian women and serological assays performances.

AIM: To estimate the prevalence of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in women in Mali and to evaluate the performance of serological assays. METHODS: Two prospective studies were conducted in 2009 and 2010 in Mali. They concerned first, 1000 pregnant women attending six reference health centers in Bamako (Malian capital) between May 26 and June 16, 2009; and secondly, 231 women over 50 years who consulted general practitioners of two hospitals in Bamako between October 25 and December 24, 2010. Blood samples were collected and kept frozen in good condition before analysis. All samples depicted as positive using HIV/HCV enzyme immuno-assay screening assays were submitted to confirmation analysis. Molecular markers of HCV were characterized. RESULTS: The seroprevalence of HIV and HCV in the population of pregnant women was 4.1% and 0.2% respectively. Among older women the seroprevalence was higher and similar for HIV and HCV (6.1% vs 6.5%). The anti-HIV prevalence was not different in young and older women (4.1% vs 6.1%). In contrast, the anti-HCV prevalence was higher in older compared to younger women (6.5% vs 0.2%, P < 0.01). Of 2 pregnant women who were HCV seropositive, only one was polymerase chain reaction (PCR) reactive and infected by genotype 2, with a viral load of 1600 IU/mL. Regarding older women who were HCV seropositive, 13 out of 15 were PCR reactive, infected by genotype 1 or 2. Globally HCV genotype 2 was predominant. The positive predictive value (PPV) measured with VIKIA HIV test in young women was 100% therefore significantly higher than the 87.5% measured in older women (P < 0.05). Conversely, the PPV measured with Monolisa HCV assay in older women was 88.2% and higher than the 14.3% measured in younger women (P < 0.01). CONCLUSION: Whereas HIV prevalence was similar in both subpopulations HCV was more frequent among older women (P < 0.01). The PPV of screening assays varied with the age of the subjects.

ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease.

Huntington's disease (HD) is an inherited, progressive and ultimately fatal neurodegenerative disorder that is characterized by psychiatric, cognitive and motor symptoms. Among the pathways implicated in HD are those involving mitogen-activated protein kinase signaling and particularly the Ras-extracellular signal-regulated kinase (ERK) cascade. Studies in both cells and animal models suggest that ERK activation might provide a novel therapeutic target for the treatment of HD but compounds that specifically activate ERK are few. To test the hypothesis that pharmaceutical activation of ERK might be protective for HD, a polyphenol, fisetin, which was previously shown to activate the Ras-ERK cascade, was tested in three different models of HD: PC12 cells expressing mutant Httex1 under the control of an inducible promoter, Drosophila expressing mutant Httex1 and the R6/2 mouse model of HD. The results indicate that fisetin can reduce the impact of mutant huntingtin in each of these disease models. Prompted by this observation, we determined that the related polyphenol, resveratrol, also activates ERK and is protective in HD models. Notably, although more than a dozen small molecule inhibitors of ERK activation are in clinical trials, very few small molecule activators of ERK signaling are reported. Thus, fisetin, resveratrol and related compounds might be useful for the treatment of HD by virtue of their unique ability to activate ERK.

Quantitative prediction of solute strengthening in aluminium alloys.

Despite significant advances in computational materials science, a quantitative, parameter-free prediction of the mechanical properties of alloys has been difficult to achieve from first principles. Here, we present a new analytic theory that, with input from first-principles calculations, is able to predict the strengthening of aluminium by substitutional solute atoms. Solute-dislocation interaction energies in and around the dislocation core are first calculated using density functional theory and a flexible-boundary-condition method. An analytic model for the strength, or stress to move a dislocation, owing to the random field of solutes, is then presented. The theory, which has no adjustable parameters and is extendable to other metallic alloys, predicts both the energy barriers to dislocation motion and the zero-temperature flow stress, allowing for predictions of finite-temperature flow stresses. Quantitative comparisons with experimental flow stresses at temperature T=78 K are made for Al-X alloys (X=Mg, Si, Cu, Cr) and good agreement is obtained.

Deletion of host histone acetyltransferases and deacetylases strongly affects Agrobacterium-mediated transformation of Saccharomyces cerevisiae.

Agrobacterium tumefaciens is a plant pathogen that genetically transforms plant cells by transferring a part of its Ti-plasmid, the T-strand, to the host cell. Under laboratory conditions, it can also transform cells from many different nonplant organisms, including the yeast Saccharomyces cerevisiae. Collections of S. cerevisiae strains have been developed with systematic deletion of all coding sequences. Here, we used these collections to identify genes involved in the Agrobacterium-mediated transformation (AMT) of S. cerevisiae. We found that deletion of genes (GCN5, NGG1, YAF9 and EAF7) encoding subunits of the SAGA, SLIK, ADA and NuA4 histone acetyltransferase complexes highly increased the efficiency of AMT, while deletion of genes (HDA2, HDA3 and HST4) encoding subunits of histone deacetylase complexes decreased AMT. These effects are specific for AMT as the efficiency of chemical (lithium acetate) transformation was not or only slightly affected by these deletions. Our data are consistent with a positive role of host histone deacetylation in AMT.

Comparison of functional residual capacity and static compliance of the respiratory system during a positive end-expiratory pressure (PEEP) ramp procedure in an experimental model of acute respiratory distress syndrome.

INTRODUCTION: Functional residual capacity (FRC) measurement is now available on new ventilators as an automated procedure. We compared FRC, static thoracopulmonary compliance (Crs) and PaO2 evolution in an experimental model of acute respiratory distress syndrome (ARDS) during a reversed, sequential ramp procedure of positive end-expiratory pressure (PEEP) changes to investigate the potential interest of combined FRC and Crs measurement in such a pathologic state. METHODS: ARDS was induced by oleic acid injection in six anesthetised pigs. FRC and Crs were measured, and arterial blood samples were taken after induction of ARDS during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O. RESULTS: ARDS was responsible for significant decreases in FRC, Crs and PaO2 values. During ARDS, 20 cm H2O of PEEP was associated with FRC values that increased from 6.2 +/- 1.3 to 19.7 +/- 2.9 ml/kg and a significant improvement in PaO2. The maximal value of Crs was reached at a PEEP of 15 cm H2O, and the maximal value of FRC at a PEEP of 20 cm H2O. From a PEEP value of 15 to 0 cm H2O, FRC and Crs decreased progressively. CONCLUSION: Our results indicate that combined FRC and Crs measurements may help to identify the optimal level of PEEP. Indeed, by taking into account the value of both parameters during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O, the end of overdistension may be identified by an increase in Crs and the start of derecruitment by an abrupt decrease in FRC.

Effective arterial elastance as an index of pulmonary vascular load.

The aim of this study was to test whether the simple ratio of right ventricular (RV) end-systolic pressure (Pes) to stroke volume (SV), known as the effective arterial elastance (Ea), provides a valid assessment of pulmonary arterial load in case of pulmonary embolism- or endotoxin-induced pulmonary hypertension. Ventricular pressure-volume (PV) data (obtained with conductance catheters) and invasive pulmonary arterial pressure and flow waveforms were simultaneously recorded in two groups of six pure Pietran pigs, submitted either to pulmonary embolism (group A) or endotoxic shock (group B). Measurements were obtained at baseline and each 30 min after injection of autologous blood clots (0.3 g/kg) in the superior vena cava in group A and after endotoxin infusion in group B. Two methods of calculation of pulmonary arterial load were compared. On one hand, Ea provided by using three-element windkessel model (WK) of the pulmonary arterial system [Ea(WK)] was referred to as standard computation. On the other hand, similar to the systemic circulation, Ea was assessed as the ratio of RV Pes to SV [Ea(PV) = Pes/SV]. In both groups, although the correlation between Ea(PV) and Ea(WK) was excellent over a broad range of altered conditions, Ea(PV) systematically overestimated Ea(WK). This offset disappeared when left atrial pressure (Pla) was incorporated into Ea [Ea * (PV) = (Pes - Pla)/SV]. Thus Ea * (PV), defined as the ratio of RV Pes minus Pla to SV, provides a convenient, useful, and simple method to assess the pulmonary arterial load and its impact on the RV function.

Alteration of right ventricular-pulmonary vascular coupling in a porcine model of progressive pressure overloading.

In acute pulmonary embolism, right ventricular (RV) failure may result from exceeding myocardial contractile resources with respect to the state of vascular afterload. We investigated the adaptation of RV performance in a porcine model of progressive pulmonary embolism. Twelve anesthetized pigs were randomly divided into two groups: gradual pulmonary arterial pressure increases by three injections of autologous blood clot (n=6) or sham-operated controls (n=6). Right ventricular pressure-volume (PV) loops were recorded using a conductance catheter. Right ventricular contractility was estimated by the slope of the end-systolic PV relationship (Ees). After load was referred to as pulmonary arterial elastance (Ea) and assessed using a four-element Windkessel model. Right ventricular-arterial coupling (Ees/Ea) and efficiency of energy transfer (from PV area to external mechanical work [stroke work]) were assessed at baseline and every 30 min for 4 h. Ea increased progressively after embolization, from 0.26+/-0.04 to 2.2+/-0.7 mmHg mL(-1) (P<0.05). Ees increased from 1.01+/-0.07 to 2.35+/-0.27 mmHg mL(-1) (P<0.05) after the first two injections but failed to increase any further. As a result, Ees/Ea initially decreased to values associated with optimal SW, but the last injection was responsible for Ees/Ea values less than 1, decreased stroke volume, and RV dilation. Stroke work/PV area consistently decreased with each injection from 79%+/-3% to 39%+/-11% (P<0.05). In response to gradual increases in afterload, RV contractility reserve was recruited to a point of optimal coupling but submaximal efficiency. Further afterload increases led to RV-vascular uncoupling and failure.

Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics.

Once-daily dosing almost invariably shows a slightly higher percentage of prescribed doses taken than does twice-daily dosing. Many pharmaceutical scientists, regulators, and prescribers have considered this finding to signify the therapeutic superiority of once-daily dosing. The therapeutically more relevant question, however, is not the percentage of prescribed doses taken but the comparative impact of missed doses on the pharmacologic effects of a drug under the two dosing regimens. A key point in this regard is that the pharmacokinetic equivalent of a single missed once-daily dose is 2-3 sequentially omitted twice-daily doses. Thus, an important parameter in comparing the two regimens is the probability of two or three twice-daily doses being sequentially omitted, versus the probability of missing a single once-daily dose. Our data indicate that the probability of sequential omission of 2-3 twice daily doses is half the probability of omission of a single once-daily dose. For that reason, a twice-daily regimen could prove to be superior to a once-daily regimen in maintaining drug concentrations within a therapeutically desirable range. A more important consideration, however, is to maintain not just the concentration of drug in plasma, but the drug's therapeutic action. The duration of therapeutic drug action following a last-taken dose is not only drug-specific, but also, for some drug, dependent on the pharmacodynamic properties. Judging the comparative superiority of one dosing regimen over another requires knowledge of the drug's duration action after a last-taken dose, plus knowledge of the comparative probabilities of the various patterns of dose omission. When applied to HIV protease inhibitors, a twice-daily regimen appears to be better than an once-daily regimen in maintaining therapeutically effective drug actions.

Use of the Internet by parents of children with congenital heart disease.

OBJECTIVE: We sought to document the prevalence of Internet access and usage patterns among families with children diagnosed with congenital heart disease. MATERIAL AND METHODS: A questionnaire was administered to the parents of 509 unselected children with congenital heart disease attending the outpatient cardiac clinic. RESULTS: 389 questionnaires were completed. The most common source for acquiring medical information was via the paediatric cardiologist (83%), the family doctor (53%), the general paediatrician (40%) and the Internet (15%). Among the 238 families with Internet access (62%), the most common locations for Internet access were home (74%) and work (33%), and 84 used the Internet to obtain information related to their child's cardiac diagnosis, mostly at the time of diagnosis. Two-thirds of these families considered finding information related to the cardiac diagnosis as easy or very easy, and found this information helpful or very helpful. CONCLUSION: A quarter of the families uses the Internet to find information about their child's congenital heart disease. Internet use in this patient population is expected to increase and our vigilance in providing accurate references and in identifying inaccurate information is of paramount importance.

Severe pulmonary embolism:pulmonary artery clot load scores and cardiovascular parameters as predictors of mortality.

PURPOSE: To retrospectively evaluate pulmonary artery (PA) clot load scores and computed tomographic (CT) cardiovascular parameters as predictors of mortality in patients with severe pulmonary embolism (PE). MATERIALS AND METHODS: Institutional review board approval was obtained with waiver of informed consent. A total of 82 consecutive patients (42 women, 40 men; mean age+/-standard deviation, 61 years+/-15) were admitted to the intensive care unit for PE-related conditions and were evaluated by using CT pulmonary angiography. Two independent readers who were blinded to clinical outcome quantified PA clot load by using four scoring systems. Cardiovascular measurements included right ventricular (RV) and left ventricular (LV) short-axis measurements; RV short axis to LV short axis (RV/LV) ratios; main PA, ascending aorta, azygos vein, and superior vena cava diameters; and main PA diameter to aorta diameter ratios. Reflux of contrast medium into the inferior vena cava, leftward bowing of the interventricular septum, pleural or pericardial effusion, pulmonary consolidation, infarct, platelike atelectasis, and mosaic ground-glass opacity were also recorded. Results were correlated with patient outcome during hospital stay by using the Wilcoxon rank sum and chi2 tests. RESULTS: Twelve patients died within 1-14 days. RV and LV short axis; RV/LV ratio; azygos vein, superior vena cava, and aorta diameters; and contrast medium reflux into the inferior vena cava were significantly different between survivors and nonsurvivors (P<.05). No significant relationship was found between PA clot load and mortality rate. RV/LV ratio and azygos vein diameter allowed correct prediction of survival in 89% of patients (P<.001). CONCLUSION: RV/LV ratio and azygos vein diameter are predictors of mortality in patients with severe PE.

Children with chronic conditions in a paediatric emergency department.

AIM: To describe the use of a paediatric emergency department by children with chronic conditions. MATERIAL AND METHODS: We prospectively indexed all the children seen in our emergency department during 1 y to describe the population of children with chronic conditions, and to compare it with the general paediatric population. RESULTS: There were 11,483 patient visits, of which 11% were by chronically ill children. Six subspeciality areas accounted for the vast majority of the chronic conditions seen: neurology (30%), cardiology (18%), pulmonology (18%), nephro-urology (16%), haemato-oncology (9%) and endocrinology (4%). Admission rate to the hospital was significantly higher for chronically ill patients (38% vs 23%). Among chief complaints, fever, respiratory distress, headache and seizures were overrepresented in chronically ill children. The chief complaint was related to the child's chronic condition in 51% of the visits. In both chronically and non-chronically ill patients, the majority of final diagnoses were related to infection (57% and 65%, respectively). Among diagnoses, bacterial infections, seizures, vasovagal syncopes and asthma were overrepresented in chronically ill children. CONCLUSION: From the analysis of our data, we conclude that children with chronic conditions account for a tenth of all visits to a paediatric emergency department. The paediatric emergency physicians provide an important service to both the children with chronic conditions and the subspecialists who care for them.

Physical activity patterns of children after neonatal arterial switch operation.

BACKGROUND: Physical inactivity is a major atherosclerosis risk factor. The exercise tolerance is usually excellent after neonatal arterial switch operation, but those patients in whom coronary anomalies remain the main late complication, risk developing atherosclerotic coronary disease owing to perceived physical activity restrictions. METHODS: We investigated physical activity patterns of 52 unselected children 7 to 14 years after neonatal arterial switch operation for transposition of the great arteries by 24-hour continuous heart rate monitoring. The percentage of heart rate reserve was used to measure the amounts of activities. Comparisons were made with 35 children with repaired atrial or ventricular septal defect and with 127 age-matched healthy children. RESULTS: Children after arterial switch operation accumulated 167.3 +/- 70.6, 25.3 +/- 12.9, and 15.7 +/- 11.3 minutes a day (mean +/- SD) of light, moderate, and vigorous physical activities, respectively. At the same activity levels, children with repaired septal defect accumulated 165.2 +/- 82.2, 26.2 +/- 11.7, and 16.2 +/- 9.1 minutes a day, and their healthy peers 164.8 +/- 74.5, 31.8 +/- 13.9, and 21.9 +/- 11.3 minutes a day. Both cardiac groups were significantly less active than the control group when considering moderate (p = 0.026) and vigorous activities (p = 0.006). Only 19% and 27% of the children after arterial switch operation engaged, respectively, in more than 30 minutes a day of moderate activity and 20 minutes a day of vigorous activity. CONCLUSIONS: Children after arterial switch operation, just like other cardiac children, do not meet the guidelines for physical activity. We should encourage regular physical activity to offset adult sedentary behavior and to prevent atherosclerotic cardiovascular disease in those patients whose long-term function of the coronary arteries remains a matter of concern.

Long-term outcome of patients with heart failure and dynamic functional mitral regurgitation.

AIMS: In patients with heart failure and chronic ischaemic mitral regurgitation (MR), the mortality risk is related to the quantified severity of MR at rest and its dynamic changes during exercise. The impact of dynamic MR on long-term mortality, hospital admission for heart failure, and major adverse cardiac events has never been investigated. METHODS AND RESULTS: We prospectively studied 161 patients with chronic ischaemic left ventricular (LV) dysfunction and at least mild MR who underwent quantitative measurement of the effective regurgitant orifice (ERO) of MR at rest and during semi-supine exercise test and who were followed up for 35+/-11 months. The 20 patients who underwent surgery were censored at the time of operation. Of the 141 patients who were treated medically, 23 died, 22 required hospitalization for heart failure, 4 had nonfatal myocardial infarction, and 11 developed unstable angina. By multivariate analysis, an exercise-induced increase in ERO by > or =13 mm(2) and a greater increase in transtricuspid pressure gradient during exercise emerged as predictors of mortality and of hospital admission for heart failure. MR severity under basal conditions (ERO> or =20 mm(2)) was an independent predictor of only cardiac death. Greater LV volumes at rest and lack of contractile reserve during exercise were additional independent markers of poor outcome. CONCLUSION: In patients with ischaemic heart disease and LV dysfunction, large exercise-induced increases in MR identify patients at high risk of morbidity and of death.