Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease.

The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important in the development of most organs. Mutations in genes encoding components of the NOTCH signalling pathway lead to a spectrum of congenital disorders. Over the past decades, mutations in human NOTCH signalling genes have been identified in several diseases with cardiovascular involvement. NOTCH1 mutations have been described in bicuspid aortic valve disease, left-sided congenital heart disease, and Adams-Oliver syndrome. NOTCH2 mutations lead to the development of Alagille syndrome, while mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To date, mutations in NOTCH4 have not been associated with cardiovascular disease. This review focuses on the mutations described in NOTCH1, NOTCH2, and NOTCH3 and their associated cardiovascular phenotypes.

Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: a randomized controlled trial.

OBJECTIVE: To investigate the effect of oral creatine supplementation in conjunction with an exercise programme on physical fitness in patients with coronary artery disease or chronic heart failure. DESIGN: Single centre double-blind randomized placebo controlled trial. SETTING: Cardiac rehabilitation centre. SUBJECTS AND INTERVENTION: 70 (4 women) cardiac patients (age 57.5 (8.4) years) were randomized to a placebo (n = 37) or creatine (n = 33) treatment for three months. Combined aerobic endurance and resistance training (three sessions/ week) was performed during supplementation. MAIN MEASURES: Aerobic power was determined during graded bicycle testing, knee extensor peak isometric and isokinetic strength, endurance and recovery were assessed by an isokinetic dynamometer, and health related quality of life was evaluated with the SF-36 and MacNew Heart Disease questionnaires. In addition, blood samples were taken after an overnight fast and 24 hour urinary collection was performed. RESULTS: At baseline there were no significant differences between both groups. We observed main time effects for aerobic power, muscle performance, health related quality of life, high density lipoprotein cholesterol and triglycerides (pre vs post; P<0.05 for all). However, changes after training were similar between placebo group and creatine group (P>0.05). Further, no detrimental effect on renal or liver function was observed nor were there any reports of side effects. CONCLUSION: Oral creatine supplementation in combination with exercise training does not exert any additional effect on the improvement in physical performance, health related quality of life, lipid profile in patients with coronary artery disease or chronic heart failure than exercise training alone.

Oxygen uptake efficiency slope in coronary artery disease: clinical use and response to training.

The Oxygen Uptake Efficiency Slope (OUES), a new parameter derived from respiratory gas analysis, has been suggested as a submaximal index of cardiopulmonary functional reserve. We evaluated the clinical application and the effect of physical training on the OUES in patients with coronary artery disease (CAD). Maximal cycle-ergometer testing with respiratory gas analysis (breath-by-breath) was performed in 590 patients with CAD and again after three months of physical training in 425 patients. OUES was determined from the linear relation of oxygen uptake (V.O (2)) vs. the logarithm of pulmonary ventilation (V (E)) during exercise, i.e. V.O (2) = a log (10) V (E) + b, where a is the OUES. The ventilatory anaerobic threshold (VAT) and the slope of the relation of V (E) nu carbon dioxide production (V.CO (2)) (V (E)-V.CO (2) slope) were also determined. Correlation coefficients of the relation from which OUES was derived in individuals averaged 0.975 +/- 0.024 (mean +/- SD) when calculated from data up to a respiratory gas exchange ratio of 1.0. Submaximal OUES was marginally lower (5.4 +/- 7.9 %, p < 0.05) than the OUES calculated from 100 % of respiratory exercise data. Of all submaximal parameters, submaximal OUES (r = 0.837, p < 0.001) and VAT (r = 0.860, p < 0.001) correlated best with peak V.O (2), followed by V (E)-V.CO (2) slope (r = - 0.469, p < 0.001). OUES was lower in patients who underwent coronary artery bypass grafting as compared with patients after coronary angioplasty (p < 0.05). Peak V.O (2) and OUES increased significantly (p < 0.001) after training with 24 +/- 19.2 % and 20.9 +/- 19.3 %, respectively. Changes in peak V.O (2) correlated better with changes in OUES and in VAT (r = 0.61 and r = 0.55, p < 0.001, respectively) than with changes in V (E)-V.CO (2) slope (r = - 0.171, p < 0.001). The submaximal OUES is clinically useful for the quantification of exercise performance and is sensitive to physical training in patients with CAD.

Exercise performance and training in patients with implantable cardioverter-defibrillators and coronary heart disease.

The aim of this preliminary study was to compare exercise performance and the effect of exercise training in cardiac patients with and without an implantable cardioverter-defibrillator (ICD). There are few data on exercise performance and on the effect of exercise training in patients with an ICD. Data in patients with an ICD (n = 8) were compared with those from a matched control group (n = 16). Patients performed maximal cycle-ergometer testing before and after 3 months of exercise training. All patients had to stop the exercise test for reasons of exhaustion. The predetermined heart rate threshold in ICD patients, set at the detection rate of the ICD minus 30 beats/min, was not reached. Before training, peak oxygen uptake was not different in the ICD patients compared with the control group (21.0 +/- 6.9 vs 21.9 +/- 5.0 ml oxygen standard temperature pressure dry/min/kg). Exercise training increased peak oxygen uptake to a similar extent in both groups, 20% and 24%, respectively. One ICD patient developed uneventful ventricular tachycardia at the end of the post-training exercise test, and another during training. Thus, exercise performance and the favorable response to a 3-month exercise training program are comparable in patients with ICD and matched control patients. However, tachyarrhythmias may occur during exercise testing or training and require special attention. Selected patients with ICD can be encouraged to participate in medically supervised exercise training programs. The results of this study should be confirmed with additional studies on larger numbers of subjects.

Comparison of cardiac output measured by two automated methods of CO2 rebreathing.

PURPOSE: The aim of the present study was to investigate the reproducibility of the exponential method of CO2 rebreathing with the use of automated curve fitting and to determine whether this method is superior to the equilibrium method in terms of reproducibility and clinical practicability. METHODS: Repeated measurements of cardiac output were performed using the automated equilibrium and exponential methods. These measurements were compared in 12 healthy male subjects at rest and during incremental exercise tests. RESULTS: Estimated cardiac output was not significantly different between duplicate measurements at rest nor at any level of exercise with either method. At rest the exponential method showed a tendency toward larger variability than the equilibrium method. The exponential method produced significantly higher (P < or = 0.001) estimates at rest (averaging up to 9.8 L x min(-1)) compared with the equilibrium method (averaging up to 6.5 L x min(-1)). Reproducibility improved for both methods with increasing workloads, and a second measurement at rest also seemed more reproducible and valid than the first. During exercise, both methods produced comparable values for cardiac output, and highly significant relations between cardiac output and oxygen uptake were observed for both methods (ranging from r2 = 0.79 to r2 = 0.88, P < or = 0.001). The equilibrium method produced unpleasant side effects more frequently (75% vs 21%, P < or = 0.001) compared with the exponential method and lead more subjects to premature interruption of the exercise test because of the rebreathing maneuver (42% vs 17%, P = 0.058). CONCLUSIONS: Automated curve fitting for the exponential method gave reproducible and valid results during submaximal and maximal exercise but not at rest. The equilibrium method on the other hand interfered with exercise. Therefore, the equilibrium method is recommended at rest and at lower levels of exercise and the exponential method at higher intensities.

Effect of bisoprolol and atenolol on endurance exercise capacity in healthy men.

OBJECTIVES: To compare the effects of a highly beta1-selective adrenoceptor antagonist bisoprolol with those of atenolol and placebo on endurance exercise capacity in young, healthy male volunteers. DESIGN: Twelve subjects randomly received oral placebo, atenolol (100 mg/day) or bisoprolol (10 mg/day) for 3 weeks, following a double-blind cross-over design. METHODS: At the end of each period, the subjects performed an endurance exercise test on the bicycle ergometer at 70% of maximal aerobic power. Cardiac output was measured by means of an automated CO2-rebreathing method. Venous blood was sampled before, during and after exercise. RESULTS: Exercise duration was not significantly different between the two drugs tested. Total exercise duration was significantly reduced by bisoprolol (-19.4 +/- 6.7%, P< 0.01) (mean +/- SEM) and by atenolol (-29.8 +/- 6.6%, P< 0.001), compared with placebo. Atenolol and bisoprolol were equally effective in lowering resting plasma renin activity, heart rate and systolic blood pressure. Resting and exercise stroke volume were significantly increased by both drugs, so that cardiac output was not significantly affected. Both drugs induced significant decreases in plasma-free fatty acid concentrations during recovery and blunted the exercise-induced increase. There were no significant relationships between the reduction of exercise duration and the haemodynamic changes or the degree of impairment of the exercise-induced increase in free fatty acid release resulting from beta-blockade. CONCLUSIONS: It is concluded that both drugs affect endurance exercise capacity in young, normotensive men, with a tendency to a smaller reduction during bisoprolol treatment. Haemodynamic variables are unlikely to be involved in the reduction of endurance exercise capacity. The role of the reduced availability of plasma free fatty acids remains unclear.

Exercise performance and training in cardiac patients with atrial fibrillation.

PURPOSE: Exercise training in cardiac patients with chronic atrial fibrillation (AF) has received little attention in the literature. Therefore, this study compared exercise performance and the effect of an exercise training program over a period of 3 months in patients with and without AF. METHODS: Data in patients with AF (n = 19) were compared with a control group of patients in sinus rhythm (n = 44), drawn from a database of 2,116 patients. Patients performed a maximal exercise test on the bicycle until exhaustion before and after an ambulatory exercise training program where exercise training was offered 3 times a week for 3 months. RESULTS: Before training, peak oxygen uptake (VO2) was significantly lower in patients with AF compared with the control group (1271 +/- 368 versus 1496 +/- 414 mL/min, P < 0.05). Exercise training significantly increased peak VO2 in both groups (+31%, P < 0.001 in AF and +25%, P < 0.001 in the control group). The gain in peak VO2 did not significantly differ between both groups. A significant decrease in resting heart rate was achieved in both groups after exercise training. AF was also a significant and independent determinant of peak VO2 in the total database, but not of the change in peak VO2. CONCLUSIONS: Exercise training significantly improves exercise performance in cardiac patients with AF. AF affects exercise performance but does not impair the beneficial effects of training. Patients with chronic AF should therefore not be dissuaded from participating in exercise training after a cardiac event.

Comparison of maximum versus submaximum exercise testing in providing prognostic information after acute myocardial infarction and/or coronary artery bypass grafting.

Exercise testing after acute myocardial infarction (AMI) provides prognostic information. In many studies submaximum exercise tests performed until a given work load, metabolic equivalents (METs) level, or heart rate were used or patients discontinued the exercise test prematurely because of symptoms. We showed recently that peak oxygen uptake during maximum exercise provides independent prognostic information in patients with coronary artery disease. It is, however, not known whether maximum exercise testing is superior in predicting mortality than testing until a target level. Second, it is unclear which target end point best classifies patients at increased risk. Therefore, the independent relation between mortality and indexes of, respectively, maximum and submaximum exercise capacity, were analyzed in 527 patients, who were tested until exhaustion. To express submaximum exercise capacity dichotomous variables (the ability to reach a target METs level or not), and a continuous variable relative to maximum exercise capacity (the ventilatory anaerobic threshold) were used. After adjustment for significant covariates, peak oxygen uptake was significantly related to all-cause and cardiovascular mortality. The target level of 5 METs and the ventilatory anaerobic threshold, when expressed in absolute workload, were related to mortality when unadjusted, but after adjustment for age and other confounders significancy was lost. In multiple Cox regression analysis, the prognostic power of peak oxygen uptake remained significant when 5 METs or the anaerobic threshold were forced into the equations. When analyzing the relation of various METs levels with mortality, the 7 METs level was independently related to all-cause and cardiovascular mortality and yielded the highest diagnostic accuracy. We conclude that maximum exercise testing is more potent in predicting mortality than the ability to reach a predetermined level of exercise, such as the commonly used 5 METs level or the anaerobic threshold. Otherwise, the use of a higher target level of 7 METs is recommended.

Assessment of cardiorespiratory exercise function in obese children and adolescents by body mass-independent parameters.

The parameters used to assess aerobic exercise function by gas exchange are usually adjusted for body mass and are expressed as millilitres per minute per kilogram. In the case of obese children this could lead to overcorrection with an underestimation of their exercise capacity. The purpose of the present study was to assess cardiorespiratory exercise function in obese subjects using body mass-independent parameters. As both carbon dioxide output (VCO2) and oxygen uptake (VO2) are usually corrected for body mass, the slope of VCO2 versus VO2 can be considered to be independent of body mass. This slope was calculated below the ventilatory threshold (S1) and above the ventilatory threshold (S3). Exercise tests were performed on a treadmill and respiratory gas exchange was measured breath-by-breath. A group of 29 obese children [mean age 11 (SD 2.5) years] were compared to 16 normal controls of the same age range [mean age 10.8 (SD 2.2); P > 0.05]. The patients were overweight by 36 (SD 17.9)% and had a body mass index of 25.0 (SD 3.8). The results showed that S3 in the obese subjects was significantly steeper compared to the normal controls [1.30 (SD 0.20) vs 1.10 (SD 0.20); P < 0.05]. The steepest values for S3 were found in the subjects with the highest degree of obesity. This method has some limitations, since in a large proportion of the patients (48%) no ventilatory threshold could be detected, which is prerequisite for calculation of these slopes. The latter was already suppressed at the onset of exercise in 21% of the sample or could not be detected because of breathing irregularity in 27%. It is suggested from this study that cardiorespiratory exercise function in obese children is reduced, especially when assessed by parameters of aerobic exercise which cancel the confounding effect of body mass.

Serial potentiometric and conductometric detection in fast non-suppressed ion chromatography applied to the analysis of filter collected airborne particulates.

Non-suppressed ion chromatography (NSIC) has been optimized to permit the determination of chloride, nitrate and sulfate in the low mg/l concentration range within 3 min. Using conductometric detection the extraneous (positive) injection peak was found to adversely affect the early eluting chloride signal when samples with high amounts of total cations are analyzed. The serial arrangement of a downstream potentiometric detector with a chloride ion selective electrode, which does not respond to other alterations of the composition of the eluent than the change in chloride concentrations, is shown to be suitable for interference-free, sensitive and reliable chloride evaluation. Application of the proposed system to the determination of chloride in extracts of filter collected airborne particulates revealed (for those samples that could be evaluated by both detection methods) high precision and no systematic deviations between conductometric and potentiometric detection.