A lower reduction in umbilical artery pulsatility in mid-pregnancy predicts higher infant blood pressure six months after birth.

AIM: The Norwegian-based Cardiovascular Risk Reduction Diet in Pregnancy study found that a cholesterol-lowering diet during pregnancy was associated with an accentuated reduction in the umbilical artery pulsatility index. This follow-up study assessed the possible association between the index and the infants' blood pressure at six months of age. METHODS: In the original study, pregnant women consumed an anti-atherogenic or usual diet from gestational weeks 17-20 to birth and underwent Doppler velocimetry at 24, 30 and 36 gestational weeks. In this follow-up study, blood pressure was measured in 105 mother-infant pairs in the intervention group and 106 mother-infant pairs in the control group six months after birth. RESULTS: Mean systolic and diastolic blood pressures were not significantly different between both groups. When the groups were combined, multivariate linear analyses showed that a lower versus higher reduction (≥-0.17 versus <-0.17) in the umbilical artery pulsatility index between gestational weeks 24 and 30 and maternal diastolic blood pressure at six months postpartum were significant predictors of higher infant systolic blood pressure (p = 0.03, 0.01, respectively). CONCLUSION: A lower reduction in umbilical pulsatility index in mid-pregnancy was associated with higher infant blood pressure at six months of age. This suggests that fetoplacental intrauterine factors may influence future cardiovascular risk.

Impaired weight gain predicts risk of late death after surgery for congenital heart defects.

OBJECTIVES: To describe long-term somatic growth in terms of weight for age in children operated on for congenital heart defects who die late (after the first 30 postoperative days) and to study the relationship between postoperative weight gain and survival after surgery for congenital heart defects. METHODS: This was a nested case-control study of 80 children born in 1990-2002 who died late after surgery for congenital heart defects at Rikshospitalet, Norway. Weight data were obtained for 74 children, of whom 31 with no extra-cardiac anomalies were defined as cases and 31 surviving children with similar surgical complexity were defined as controls. RESULTS: In the 74 children who died late, mean weight for age converted to z scores at birth, at last operation and at last recorded weight were 0.12, -1.31 and -2.09. In the 31 children defined as cases, the same weight z scores were 0.07, -1.21 and -2.01 compared with 0.05, -1.10 and -0.99 in the 31 matched controls. The odds ratio (OR) for death was 13.5 (95% CI 3.6 to 51.0) if there was a decrease in weight z score of >0.67 after the last operation. Median follow-up time after operation was 5.7 months. CONCLUSIONS: A decrease in weight for age during the first months after surgery for congenital heart defects of more than 0.67 z scores, corresponding to a downward percentile crossing through at least one of the displayed percentile lines on standard growth charts, is strongly related to late mortality in children operated on for congenital heart defects.

The estimated number of patients with adult congenital heart defects in Norway.

An increasing survival rate for adult patients with congenital heart defects has been related to increased hospitalization and a greater risk of incidences during physical activity. The limited follow-up of these adult patients is partly due to a lack of knowledge about the number of adult patients in need of specialized care. Based on a classification into simple, moderate and severe forms of congenital heart defect, the population size was estimated for three age categories. Based on a conservative prevalence at birth of 7.0 per 1000 live births, approximately 14,000 adult patients with congenital heart defects between 16 and 64 years are alive in Norway today and in need of specialized cardiology attention. This is almost twice the number of children with a congenital heart defect. The assessment of the number of patients is important in order to reveal the risks of fatal incidence during physical activity in the adult congenital heart disease group. There is a need for knowledge and education about the potential risks during sports in coaches, teachers, health personnel, employers, parents, caretakers and in the patients themselves.

Echocardiography in adults with congenital heart disease.

Echocardiography is a valuable tool in the investigation and follow-up of adult patients with congenital heart disease. The majority of these patients have been recognised and treated in childhood, and effective investigations in adult life depend on exact knowledge of the patient history and previous treatments/operations. The major lesions are presented and important echocardiographic features briefly discussed.

Lung function, smoking and mortality in a 26-year follow-up of healthy middle-aged males.

Lung function has been associated with mortality after adjusting for other risk factors; however, few studies have adjusted for physical fitness and reported separate analyses according to smoking status. In 1972-1975, spirometry, clinical and physiological parameters were recorded in 1,623 apparently healthy males aged 40-59 yrs. After 26 yrs of follow-up, the current authors investigated the association between baseline lung function and mortality, adjusting for smoking, physical fitness and other potential factors. By 2000, 615 individuals (38%) had died, with 308 (50%) of these deaths from cardiovascular (CV) causes. Forced expiratory volume in one second was a predictor of all-cause mortality (risk ratio (RR) 1.10 per reduction of 10%) after adjusting for smoking, physical fitness, age, systolic blood pressure, body mass index and serum cholesterol. The corresponding multivariate RR was 1.07 for CV causes and 1.34 for respiratory death. In conclusion, in stratified analyses among current and former smokers, forced expiratory volume in one second % predicted was a strong independent predictor of all-cause mortality and respiratory death among current smokers. Forced expiratory volume in one second % predicted was not associated with mortality among never-smokers.

Restoration of cardiopulmonary function with 21% versus 100% oxygen after hypoxaemia in newborn pigs.

OBJECTIVE: To assess the consequences of hypoxaemia and resuscitation with room air versus 100% O(2) on cardiac troponin I (cTnI), cardiac output (CO), and pulmonary artery pressure (PAP) in newborn pigs. DESIGN: Twenty anaesthetised pigs (12-36 hours; 1.7-2.7 kg) were subjected to hypoxaemia by ventilation with 8% O(2). When mean arterial blood pressure fell to 15 mm Hg, or arterial base excess was < or = -20 mmol/l, resuscitation was performed with 21% (n = 10) or 100% (n = 10) O(2) for 30 minutes, then ventilation with 21% O(2) for 120 minutes. Blood was analysed for cTnI. Ultrasound examinations of CO and PAP (estimated from tricuspid regurgitation velocity (TR-Vmax)) were performed at baseline, during hypoxia, and at the start of and during reoxygenation. RESULTS: cTnI increased from baseline to the end point (p<0.001), confirming a serious myocardial injury, with no differences between the 21% and 100% O(2) group (p = 0.12). TR-Vmax increased during the insult and returned towards baseline values during reoxygenation, with no differences between the groups (p = 0.11) or between cTnI concentrations (p = 0.31). An inverse relation was found between increasing age and TR-Vmax during hypoxaemia (p = 0.034). CO per kg body weight increased during the early phase of hypoxaemia (p<0.001), then decreased. Changes in CO per kg were mainly due to changes in heart rate, with no differences between the groups during reoxygenation (p = 0.298). CONCLUSION: Hypoxaemia affects the myocardium and PAP. During this limited period of observation, reoxygenation with 100% O(2) showed no benefits compared with 21% O(2) in normalising myocardial function and PAP. The important issue may be resuscitation and reoxygenation without hyperoxygenation.

Increased myocardial matrix metalloproteinases in hypoxic newborn pigs during resuscitation: effects of oxygen and carbon dioxide.

BACKGROUND: Perinatal asphyxia is associated with cardiac dysfunction, and it is important to prevent further tissue injury during resuscitation. There is increasing evidence that myocardial matrix metalloproteinases (MMPs) are involved in myocardial hypoxaemia-reoxygenation injury. OBJECTIVE: To assess MMPs and antioxidant capacity in newborn pigs after global ischaemia and subsequent resuscitation with ambient air or 100% O(2) at different PaCO(2)-levels. METHODS: Newborn pigs (12-36 h of age) were resuscitated for 30 min by ventilation with 21% or 100% O(2) at different PaCO(2) levels after a hypoxic insult, and thereafter observed for 150 min. In myocardial tissue extracts, MMPs were analyzed by gelatin zymography and broad matrix-degrading capacity (total MMP). Total endogenous antioxidant capacity in myocardial tissue extracts was measured by the oxygen radical absorbance capacity (ORAC) assay. RESULTS: Matrix metalloproteinase-2 more than doubled from baseline values (P < 0.001), and was higher in piglets resuscitated with 100% O(2) than with ambient air (P = 0.012). The ORAC value was considerably decreased (P < 0.001). In piglets with elevated PaCO(2), total MMP-activity in the right ventricle was more increased than in the left ventricle (P = 0.008). In the left ventricle, total MMPactivity was higher in the piglets with low PaCO(2) than in the piglets with elevated PaCO(2) (P = 0.013). CONCLUSION: In hypoxaemia-reoxygenation injury the MMP-2 level was highly increased and was most elevated in the piglets resuscitated with 100% O(2). Antioxidant capacity was considerably decreased. Assessed by total MMP-activity, elevated PaCO(2) during resuscitation might protect the left ventricle, and probably increase right ventricle injury of the myocardium.

Resuscitation with 100% O(2) does not protect the myocardium in hypoxic newborn piglets.

BACKGROUND: Perinatal asphyxia is associated with cardiac dysfunction secondary to myocardial ischaemia. Cardiac troponin I (cTnI) is a marker of myocardial necrosis. Raised concentrations in the blood are related to perinatal asphyxia and increased morbidity. OBJECTIVE: To assess porcine myocardial damage from enzyme release during hypoxaemia induced global ischaemia, and subsequent resuscitation with ambient air or 100% O(2). To investigate whether CO(2) level during resuscitation influences myocardial damage. DESIGN: Newborn piglets (12-36 hours) were exposed to hypoxaemia by ventilation with 8% O(2) in nitrogen. When mean arterial blood pressure had fallen to 15 mm Hg, or base excess to < -20 mmol/l, the animals were randomly resuscitated by ventilation with either 21% O(2) (group A, n = 29) or 100% O(2) (group B, n = 29) for 30 minutes. Afterwards they were observed in ambient air for another 150 minutes. During resuscitation, the two groups were further divided into three subgroups with different CO(2) levels. ANALYSIS: Blood samples were analysed for cTnI, myoglobin, and creatine kinase-myocardial band (CK-MB) at baseline and at the end of the study. RESULTS: cTnI increased more than 10-fold (p < 0.001) in all the groups. Myoglobin and CK-MB doubled in concentration. CONCLUSION: The considerable increase in cTnI indicates seriously affected myocardium. Reoxygenation with 100% oxygen offered no biochemical benefit over ambient air. CK-MB and myoglobin were not reliable markers of myocardial damage. Normoventilation tended to produce better myocardial outcome than hyperventilation or hypoventilation.

Unexpected medical coincidences require systematic and careful strategies: an example.

In a cohort of 14 children with identical cardiac xenografts, two boys developed acute myeloid leukaemia 11 and 16 months respectively after the operation. A dedicated working group designed a scheme intending to take care of all aspects of the situation. This article focuses on preferred strategies towards patients, relatives, government, and the media. We did not find any substantial evidence supporting the association between bovine xenografts and two cases of acute myeloid leukaemia.

Supine and exercise systolic blood pressure predict cardiovascular death in middle-aged men.

AIM AND METHODS: The outcome of 1999 apparently healthy men, aged 40-59 years, initially investigated in the period 1972-1975, has previously been ascertained at 7 and 16 year follow-ups. This has now been repeated after 21 years, to determine whether seated systolic blood pressure (BP) during a bicycle ergometer exercise test adds prognostic information on cardiovascular (CV) mortality beyond that of systolic BP measured after 5 min of supine rest. RESULTS: After 21 years, 41 979 years of observation, 470 patients had died, 255 from CV causes. Supine systolic BP [2 SD increase: relative risk (RR) 1.6, 95% confidence interval (CI) 1.3-2.0, P < 0.0001], 6 min exercise systolic BP (2 SD increase: RR 1.6, 95% CI 1.3-2.0, P < 0.0001) on the starting workload of 600 kpm/min (approximately 100 W, 5880 J/min) and maximal systolic BP (2 SD increase: RR 1.5, 95% CI 1.2-1.9, P = 0.0005) during work were all related to CV mortality when adjusting for a large number of variables measured in the present study including age, exercise capacity, heart rates, smoking habits, glucose tolerance and serum cholesterol. When including other systolic BPs in the continuous multivariate analysis, supine systolic BP (2 SD increase: RR 1.4, 95% CI 1.04-1.9, P = 0.029) and 6 min systolic BP at 600 kpm/min (2 SD increase: RR 1.4, 95% CI 1.06-1.9, P = 0.017) were independent predictors of CV death but not maximal systolic BP during exercise (2 SD increase: RR 1.0, 95% CI 0.7-1.2, P = 0.95). CONCLUSION: These results are different from the mortality data at 16 years, when the independent predictive effect of supine systolic BP was cancelled out by 6 min exercise systolic BP at 600 kpm/min. Twenty-one years of follow-up of 1999 apparently healthy men disclose independently predictive information on CV death, of both supine systolic BP and 6 min exercise systolic BP taken at an early moderate workload. The influence of maximal exercise systolic BP on CV death is however cancelled out by the two other systolic BPs.

Prediction of Type 2 diabetes in healthy middle-aged men with special emphasis on glucose homeostasis. Results from 22.5 years' follow-up.

AIMS: To study the glucose disappearance rate and fasting blood glucose as predictors of Type 2 diabetes in a 22.5-year prospective follow-up of 1947 healthy non-diabetic men. SUBJECTS AND METHODS: Of a cohort of 2014 Caucasian men, the 1947 who had both fasting blood glucose < 110 mg/dl and an intravenous glucose tolerance test were included. A number of other physiological parameters were also determined at baseline. Multivariate Cox regression analyses were used to investigate the possible significance of the glucose disappearance rate and fasting blood glucose as predictors of Type 2 diabetes. RESULTS: After 22.5 years' follow-up, 143 cases of Type 2 diabetes had developed. Glucose disappearance rate and fasting blood glucose were moderately correlated (r = -0.32). Men in the lowest quartile of glucose disappearance rate and highest quartile of fasting blood glucose had markedly higher diabetes rates than all other men (P < 0.0001). After adjusting for each other, age, diabetes heredity, body mass index, physical fitness, triglycerides, cholesterol and blood pressure (Cox model), both glucose disappearance rate and fasting blood glucose remained major predictors of diabetes CONCLUSIONS: Glucose disappearance rate and fasting blood glucose are, in spite of low intercorrelation, major long-term predictors of Type 2 diabetes in healthy non-diabetic Caucasian men.

Plasma levels of natriuretic peptides and hemodynamic assessment of patent ductus arteriosus in preterm infants.

UNLABELLED: The main purpose of this study was to investigate whether circulating natriuretic peptides in premature infants reflect the hemodynamic significance of a patent ductus arteriosus (PDA). The study comprises 120 examinations in 55 premature infants with a mean gestational age of 27.2 wk and a mean birthweight of 933 g. Based on clinical and echocardiographic findings, the hemodynamic influence of ductal shunting was classified as small, moderate or large. Blood samples for N-terminal proatrial natriuretic peptide (Nt-proANP) and brain natriuretic peptide (BNP) were analysed after completion of the clinical part of the study. Linear regression indicated a very strong association between Nt-proANP and BNP (adjusted R = 0.89). The mean levels of Nt-proANP and BNP increased with the size of the shunt through a PDA, and peptide values followed hemodynamic alterations. The size of PDA accounted for 50% and 47% of the total variation in the plasma values of Nt-proANP and BNP, respectively. In detecting an echocardiographically significant PDA, the area under a ROC curve was 0.94 for Nt-proANP and 0.90 for BNP. CONCLUSION: The magnitude of shunting through a PDA is the main determinant of plasma levels of natriuretic peptides in premature infants. Nt-proANP and BNP seem to have the same pattern of secretion. Our findings indicate that measurements of natriuretic peptides may provide clinically relevant information in the hemodynamic assessment of premature infants.

Aerobic capacity in adults with various congenital heart diseases.

As an increasing number of patients with congenital heart disease reach adulthood, more information is needed regarding outcomes. The first signs of impaired heart function may appear during exercise testing. The aim of the present study was to establish mean values for maximal oxygen uptake in adults with various congenital heart diseases. Patients from 6 major diagnostic groups were identified, including patients with atrial septal defect (ASD, n = 93), transposition of the great arteries corrected with the Mustard procedure (n = 84), congenitally corrected transposition of the great arteries (CCTGA, n = 41), Tetralogy of Fallot (n = 168), Ebstein's anomaly (n = 37), and Modified Fontan procedure (n = 52). Diminished maximal oxygen uptake was found in all diagnostic groups across age compared with healthy subjects. A significant decrease in maximal oxygen uptake with aging was found in those with ASD (p <0.0001), CCTGA (p = 0.01), and Tetralogy of Fallot (p <0.0001). There was no significant decline, however, in Ebstein's anomaly (p = 0.270), Fontan procedure (p = 0.182), and in the Mustard patients (p = 0.188). All patients achieved significantly lower heart rates than predicted (mean for all groups, p <0.0001). Forced vital capacity values (3.51 L, mean SD +/- 1.02) were lower than predicted values (4.10 L, mean SD +/- 0.90, p <0.0001) for all patients groups except those with ASD. Mean values, however, were within the accepted 20% range of variance. This study showed diminished aerobic capacity in all diagnostic groups when compared with a healthy population. The maximal oxygen uptake values across age groups can be used as reference values in patients with similar diagnoses and as the basis for further research.

Cardiac surgery in a girl with trisomy 13.

We describe a profoundly retarded infant girl with multiple anomalies caused by trisomy 13. Due to heart failure, which was resistant to medical treatment, we closed successfully a ventricular septal defect at three months of age. She died at 10 months of age. Despite the short survival, we believe that the patient benefitted significantly from the surgical repair of her cardiac defect.

Erythrocyte sedimentation rate: a possible marker of atherosclerosis and a strong predictor of coronary heart disease mortality.

AIMS: Since atherosclerosis is a chronic inflammation and the erythrocyte sedimentation rate is an appropriate test for monitoring chronic inflammatory responses, we wanted to investigate whether the erythrocyte sedimentation rate might carry prognostic information on the risk of sustaining coronary heart disease events. METHOD: The erythrocyte sedimentation rate was determined in 2014 apparently healthy men aged 40-60 years during an extensive cardiovascular survey in 1972-75, and the test was repeated in an identical follow-up examination 7 years later. Cause-specific mortality and rates of non-fatal myocardial infarction were followed for 23 years. RESULTS: The erythrocyte sedimentation rate was strongly correlated with age, haemoglobin level, smoking status, total cholesterol level and systolic blood pressure. After adjusting for all these associations in multivariate Cox regression analyses, the erythrocyte sedimentation rate emerged as a strong short- and long-term predictor of coronary heart disease mortality, particularly in men who had developed angina pectoris and/or had a positive exercise ECG test at the second survey. Increases in non-coronary heart disease deaths and in non-fatal myocardial infarctions were only seen in the upper erythrocyte sedimentation rate range. CONCLUSIONS: The erythrocyte sedimentation rate is a strong predictor of coronary heart disease mortality, and appears to be a marker of aggressive forms of coronary heart disease. The erythrocyte sedimentation rate probably gives substantial information in addition to that given by fibrinogen on the risk of coronary heart disease death.

Type 2 diabetes and maternal family history: an impact beyond slow glucose removal rate and fasting hyperglycemia in low-risk individuals? Results from 22.5 years of follow-up of healthy nondiabetic men.

OBJECTIVE: Although an excess transmission of type 2 diabetes from mothers has been documented, whether this is an independent trait or whether the effect can be detected early through risk factors for type 2 diabetes remains to be elucidated. The objective of this study was to investigate the prevalence of and the possible prospective effect of family history on type 2 diabetes incidence adjusted for multiple diabetes risk factors in a 22.5-year follow-up study of healthy men. RESEARCH DESIGN AND METHODS: A total of 1,947 apparently healthy nondiabetic men with fasting blood glucose (FBG) levels <110 mg/dl at baseline, in whom an intravenous glucose tolerance test (IVGTT) was administered and several conventional risk factors were measured, were followed for 22.5 years. Family history data were obtained at the baseline examination, and morbidity data were obtained from repeated investigations, hospital records, and death certificates. RESULTS: A total of 131 men reported maternal diabetes family history only, 65 men reported paternal diabetes family history only and 10 men reported both maternal and paternal diabetes family history. Among the 1,947 men, 143 cases of type 2 diabetes developed during 22.5 years of observation. Maternal family history and combined maternal and paternal family history predisposed to future type 2 diabetes both in univariate Cox analysis and in multivariate Cox regression analysis after adjusting for glucose disappearance rate (Rd) during an IVGTT, FBG level, BMI, physical fitness, triglyceride level, and age. Maternal family history showed a relative risk (RR) of 2.51 (95% CI 1.55-4.07), combined maternal and paternal family history showed an RR of 3.96 (1.22-12.9), and paternal family history showed an RR of 1.41 (0.657-3.05) in multivariate analysis. CONCLUSIONS: Maternal family history appears to be an important risk factor for type 2 diabetes independent of prediabetic Rd, FBG, BMI, and physical fitness levels.

Results and clinical implications of the CAPARES trial.

The Coronary AngioPlasty Amlodipine REStenosis Study (CAPARES) is a multicentre, double-blind, placebo controlled restenosis trial investigating the effect of amlodipine on angiographic and clinical endpoints in patients undergoing routine percutaneous transluminal coronary angioplasty (PTCA) for stable angina pectoris. A total of 635 patients were randomized to amlodipine or placebo two weeks before PTCA and were followed for four months after PTCA. There were 451 nonstented patients who completed the study with angiographic follow-up. Quantitative coronary angiography revealed that the loss in minimal luminal diameter from immediately after PTCA to the four-month follow-up was unaffected by amlodipine treatment. However, the incidence of repeat PTCA and composite clinical events were significantly lower in patients treated with amlodipine.

[Catheter closure of open ductus arteriosus--the first 100 patients]. / Kateterbasert lukking av åpen ductus arteriosus--de første 100 pasienter.

BACKGROUND: Patent ductus arteriosus is increasingly treated with catheter based techniques. We present our results as by the end of 1998 of the first 100 patients given such treatment. MATERIAL AND METHODS: The 100 patients between 0.6 and 31.4 years were initially treated with one of these devices: The Rashkind umbrella (60 patients), Cook PDA coils (31 patients) or Amplatzer ductal occluders (ten patients). Seven umbrella patients were treated twice, one with an additional umbrella, six with coils; two coil patients twice, one with another coil and one--after embolisation--with a peg. RESULTS: The overall complete closure rate for all groups was 90% after nine patients had been treated a second time. The primary complete closure rate in pegs was 100%, after reintervention 85% in umbrella and 97% in coil patients. Neither umbrellas nor pegs have embolised. One coil embolised in the course of implantation of 40 coils (2.5%). No other complication has occurred. INTERPRETATION: The closure of the arterial duct with catheter techniques compares favorably with surgery and is now established as the method of choice. Following the investigational introduction of pegs there is no longer an upper limit in the size of ducts suitable for such treatment.

Response to changing plasma concentrations of isosorbide-bound NO2 during acute and sustained treatment with isosorbide dinitrate in patients with coronary artery disease.

BACKGROUND: The mechanisms behind development of tolerance to nitrate effects during sustained, asymmetric isosorbide dinitrate (ISDN) therapy are not fully understood. HYPOTHESIS: The study was undertaken to investigate the changes of the relationships between left ventricular (LV) function and plasma concentrations of ISDN and its vasoactive metabolites (2- and 5-ISMO) during acute and sustained, asymmetric ISDN therapy. METHODS: Left ventricular function and plasma concentrations of ISDN, 2- and 5-isosorbide mononitrates (P-ISDN, P-2- and 5-ISMO) were measured at rest and at supine exercise before and for 4 h after peroral 30 mg ISDN in 15 patients with coronary artery disease, all with initial exercise pulmonary artery wedge pressure (PAWP) > 25 mmHg. Seven patients were untreated (acute group), while eight received 30 mg ISDN b.i.d. for 2 weeks before the invasive study. P-ISDN and the concentration of available isosorbide-bound nitrate (NO2) in plasma (P-ISDN.2 + P-2-ISMO + P-5-ISMO) (P-NO2) were used as measures of the nitric oxide (NO) offer to the tissues. RESULTS: Throughout the study, after administration of medication, all plasma concentrations, in particular P-ISDN, were higher in the chronic than in the acute group. Peak P-ISDN was reached after 15 min in the chronic group and after 25 min in the acute group, while P-2- and 5-ISMO reached maximum only after 40 min in both groups. At rest, the full effect on PAWP was observed after 10 min in both groups, but at markedly higher levels of P-ISDN and P-NO2 in the chronic group. Afterward, no further changes in PAWP were observed. During exercise, 1 h after medication, PAWP and stroke index to PAWP ratio (SI/PAWP) were normal in both groups. Thereafter, at slowly declining P-NO2, PAWP rose and SI/PAWP declined toward the initial level in the chronic group, but remained unchanged in the acute group, in spite of higher P-NO2 and greater NO release in the former. CONCLUSIONS: Patients receiving sustained, asymmetric 30 mg ISDN b.i.d. dosing had the same immediate beneficial effects on LV function during exercise after a morning dose as did untreated patients. However, in spite of higher P-NO2 and higher rate of NO release during sustained treatment, the effects deteriorated gradually 2 to 3 h after medication. The changes in metabolism and/or distribution of isosorbide-bound NO2 may possibly be part of the tolerance induced by long-term treatment, even with asymmetric dosing.