PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects.

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

Inherited balanced translocation t(9;17)(q33.2;q25.3) concomitant with a 16p13.1 duplication in a patient with schizophrenia.

We report two rare genetic aberrations in a schizophrenia patient that may act together to confer disease susceptibility. A previously unreported balanced t(9;17)(q33.2;q25.3) translocation was observed in two schizophrenia-affected members of a small family with diverse psychiatric disorders. The proband also carried a 1.5 Mbp microduplication at 16p13.1 that could not be investigated in other family members. The duplication has been reported to predispose to schizophrenia, autism and mental retardation, with incomplete penetrance and variable expressivity. The t(9;17) (q33.2;q25.3) translocation breakpoint occurs within the open reading frames of KIAA1618 on 17q25.3, and TTLL11 (tyrosine tubulin ligase like 11) on 9q33.2, causing no change in the expression level of KIAA1618 but leading to loss of expression of one TTLL11 allele. TTLL11 belongs to a family of enzymes catalyzing polyglutamylation, an unusual neuron-specific post-translational modification of microtubule proteins, which modulates microtubule development and dynamics. The 16p13.1 duplication resulted in increased expression of NDE1, encoding a DISC1 protein partner mediating DISC1 functions in microtubule dynamics. We hypothesize that concomitant TTLL11-NDE1 deregulation may increase mutation load, among others, also on the DISC1 pathway, which could contribute to disease pathogenesis through multiple effects on neuronal development, synaptic plasticity, and neurotransmission. Our data illustrate the difficulties in interpreting the contribution of multiple potentially pathogenic changes likely to emerge in future next-generation sequencing studies, where access to extended families will be increasingly important.

Molecular systematics of Boraginaceae tribe Boragineae based on ITS1 and trnL sequences, with special reference to Anchusa s.l.

BACKGROUND AND AIMS: Boragineae is one of the main tribes of Boraginaceae, but delimitation and intergeneric classification of this group are unclear and have not yet been studied using DNA sequences. In particular, phylogenetic relationships in Anchusa s.l. still need to be elucidated in order to assess its taxonomic boundaries with respect to the controversial segregate genera Hormuzakia, Gastrocotyle, Phyllocara and Cynoglottis. METHODS: Phylogenetic relationships among 51 taxa of tribe Boragineae were investigated by comparative sequencing of the trnL(UAA) intron of the plastid genome and of the ITS1 region of the nuclear ribosomal DNA. Exemplar taxa from 16 genera of Boragineae and all subgenera of Anchusa s.l. were included, along with two selected outgroups from tribes Lithospermeae and Cynoglosseae. KEY RESULTS: Phylogenies generated by maximum parsimony and combined ITS1-trnL sequences support the monophyly of the tribe and a split into two clades, Pentaglottis and the remainder of Boragineae. The latter contains two large monophyletic groups. The first consists of three moderately to well-supported branches, Borago-Symphytum, Pulmonaria-Nonea and Brunnera. In the Pulmonaria-Nonea subclade, the rare endemic Paraskevia cesatiana is sister to Pulmonaria, and Nonea appears to be paraphyletic with respect to Elizaldia. The second main group corresponds to the well-supported clade of Anchusa s.l., with the megaphyllic, polyploid herb Trachystemon orientalis as sister taxon, although with low support. Anchusa s.l. is highly paraphyletic to its segregate genera and falls into four subclades: (1) Phyllocara, Hormuzakia, Anchusa subgenus Buglossum and A. subgenus Buglossoides; (2) Gastrocotyle; (3) A. subgenus Buglossellum and Cynoglottis; and (4) A. subgenus Anchusa, Lycopsis and Anchusella. All species of Anchusa subg. Anchusa, including the South African A. capensis, are included in a single unresolved clade. Anchusa subgenus Limbata is also included here despite marked divergence in floral morphology. The low nucleotide variation of ITS1 suggests a recent partly adaptive radiation within this group. CONCLUSIONS: Molecular data show that nine of the usually accepted genera of the Boragineae consisting of two or more species are monophyletic: Anchusella, Borago, Brunnera, Cynoglottis, Gastrocotyle, Hormuzakia, Nonea, Pulmonaria and Symphytum. In addition, the tribe includes the four monotypic genera Paraskevia, Pentaglottis, Phyllocara and Trachystemon. The morphologically well-characterized segregate genera in Anchusa s.l. are all confirmed by DNA sequences and should be definitively accepted. Most of the traditionally recognized subgenera of Anchusa are also supported as monophyletic groups by both nuclear and plastid sequence data. In order to bring taxonomy in line with phylogeny, the institution of new, independent generic entities for subgenera Buglossum, Buglossellum and Buglossoides and a narrower but more natural concept of Anchusa are advocated.

Chromosomal translocation t(18;21)(q23;q22.1) indicates novel susceptibility loci for frontotemporal dementia with ALS.

A chromosomal translocation t(18;21)(q23;q22) is reported in a patient with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We exclude the physical involvement and silencing of the ALS-linked gene for copper/zinc superoxide dismutase (SOD1) on chromosome 21q22.1. The breakpoints are assigned to sequences flanked by the markers ATA1H06, D18S462, D21S1915, and D21S1898. These critical regions may contain susceptibility loci for FTD associated with ALS.

Island colonization and evolution of the insular woody habit in Echium L. (Boraginaceae).

Numerous island-inhabiting species of predominantly herbaceous angiosperm genera are woody shrubs or trees. Such "insular woodiness" is strongly manifested in the genus Echium, in which the continental species of circummediterranean distribution are herbaceous, whereas endemic species of islands along the Atlantic coast of north Africa are woody perennial shrubs. The history of 37 Echium species was traced with 70 kb of noncoding DNA determined from both chloroplast and nuclear genomes. In all, 239 polymorphic positions with 137 informative sites, in addition to 27 informative indels, were found. Island-dwelling Echium species are shown to descend from herbaceous continental ancestors via a single island colonization event that occurred < 20 million years ago. Founding colonization appears to have taken place on the Canary Islands, from which the Madeira and Cape Verde archipelagos were invaded. Colonization of island habitats correlates with a recent origin of perennial woodiness from herbaceous habit and was furthermore accompanied by intense speciation, which brought forth remarkable diversity of forms among contemporary island endemics. We argue that the origin of insular woodiness involved response to counter-selection of inbreeding depression in founding island colonies.

Left ventricular geometry and function before and after mitral valve replacement.

Left ventricular geometry and function were assessed in 20 patients with mitral stenosis (MS) and in another 20 patients with mitral insufficiency (MI) five days before and 12 days after mitral valve replacement by transthoracic (TTE) and transesophageal (TEE) echocardiography, as well as late postoperatively (mean: 194 days) by TTE. The continuity of the subvalvular apparatus could not be preserved in any of these patients. In mitral stenosis the area ejection fraction (AEF) in the short axis of the left ventricle (LV) did not change significantly early or late postoperatively. There was a significant lengthening of the left ventricular longitudinal axis in the apical four chamber view whereas the transverse axis remained unchanged. This was likely the result of the discontinuity between the mitral valve and the papillary muscles. AEF and ejection fraction (EF) determined in the four chamber view showed a slight tendency to decrease in the postoperative phase. Patients with mitral insufficiency likewise showed a significant increase of the LV longitudinal diameter postoperatively. In the short axis of the left ventricle and in the apical four chamber view a significant reduction of the AEF was observed. Furthermore, left ventricular EF dropped significantly postoperatively. This decrease was caused by the extension of the LV longitudinal axis accompanied by an enlargement of the transverse diameter as well as by an afterload increase, and a masked impairment of left ventricular function preoperatively. Wall motion analysis of the LV in both groups documented new postoperative hypokinesis especially in the septal segments. At late postoperative examination the hypokinesis disappeared in about 50% of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Rickettsiosis of the typhus fever type. Its joint appearance with a left-ventricular thrombus and single-vessel coronary disease]. / Rickettsiose vom Fleckfiebertyp. Gemeinsames Auftreten mit einem linksventrikulären Thrombus und einer koronaren Ein-Gefäss-Krankheit.

A 44-year-old German fell ill in Libya, where he had been living for 10 years, with high fever, rigor and a nonitching centrifugally spreading macular rash, which had spared the head, hands and soles. In addition, a systolic cardiac murmur was heard. The Weil-Felix reaction had a titre rising within 3 days from 1:160 to 1:640, confirming the diagnosis of rickettsial disease, the total clinical picture indicating typhus. On treatment with chloramphenicol (1 g three times daily i.v.) the fever subsided within 5 days. On the ninth day treatment was changed to oral doxycyclin, 200 mg daily for 3 weeks. Echocardiography surprisingly revealed a floating thrombus, about 4 x 8 cm, attached to the hypo- and even akinetic apex of the left ventricle. In addition there was single-vessel coronary disease. Since the segmental contraction abnormality persisted after the typhus had been cured, a causal connection with the rickettsial disease is unlikely. The thrombus was removed at the time of a aortocoronary bypass operation: his course has been unremarkable since then.

Non-coding chloroplast DNA for plant molecular systematics at the infrageneric level.

With primers constructed against highly conserved regions of tRNA genes (trnTUGU, trnLUAA and trnFGAA) in chloroplast DNA, we have amplified two different non-coding spacers and one intron from four species within the genus Echium L. (Boraginaceae) and from two confamilial outgroups. The trnTUGU-trnLUAA intergenic spacer contains a greater number of polymorphic sites than the trnLUAA intron or the trnLUAA-trnFGAA intergenic spacer. We analyzed a total of 11 kb of sequence data from this non-coding DNA. Total nucleotide divergence between Echium species is on the order of 1% for these regions, all of which possess infrageneric length polymorphisms. The latter two regions contain indels which occur only in the 14 Macaronesian Island endemic species of Echium studied and suggest that these may form a monophyletic group.

[Cardiopulmonary capacity in patients before and after prosthetic valve replacement]. / Kardiopulmonale Leistungsfähigkeit bei Patienten vor und nach prothetischem Klappenersatz.

In this study we wanted to investigate if noninvasive cardiopulmonary exercise testing can be securely, accurately applied in patients with acquired cardiac valve disease pre- and postoperatively with any convenience. Furthermore, we looked if the cardiopulmonary exercise capacity (anaerobic threshold, etc.) was improved postoperatively (3 and 6 months) in 15 patients suffering from severe mitral valve disease as compared to the preoperative condition. The symptom-limited cardiopulmonary exercise testing was performed on a bike in a semi-supine position using a ramp program (+20 W/min). The following parameters were continuously monitored, and the breath-by-breath gas exchange values documented: cardiocirculatory parameters (heart rate; blood pressure; surface ECG; exercise capacity in Watts); gas-exchange parameters (O2-uptake VO2; CO2-production VCO2; respiratory anaerobic threshold VO2 AT; gas-exchange ratio VCO2/VO2; O2-pulse VO2/HR; aerobic capacity delta VO2/delta WR) and ventilatory parameters (respiratory rate; tidal volume Vt; minute ventilation VE; equivalent for O2: VE/VO2 and CO2: VE/VCO2). The 155 cardio-pulmonary exercise tests in 115 patients were practicable, safe (no emergency case) and accurate. In 100 patients late postoperatively (68.3 +/- 53.0 -102.9 +/- 41.2 months) after aortic or mitral valve replacement or both without signs of significant hemolysis or prosthetic valve dysfunction the NYHA classification was too imprecise to characterize the actual exercise capacity of the patients (e.g., NYHA class II: Weber class B to E). Patients with aortic valve prosthesis had a significantly better anaerobic threshold (57.4 +/- 19.1% pred. value max. VO2) as compared to those with mitral valve replacement (mean: 35.9% pred. value max. VO2).(ABSTRACT TRUNCATED AT 250 WORDS)

[Methodologic aspects of modern, computerized ergospirometry (CPX): ramp program, constant workload test and CO2 rebreathing method]. / Methodische Aspekte der modernen, computerisierten Ergospirometrie (CPX): Rampenprogramm, konstanter Belastungstest und CO2-Rückatmungsmethode.

The cardiopulmonary exercise testing (CPX) is a non-invasive method for the evaluation of the cardiopulmonary exercise capacity. Based upon the recent technical progress in gas analysers and personal computers today it is possible to perform CPX with acceptable time consumption, high practicability and high reproducibility of the results in many clinical areas. CPX is realized on a bike or on a treadmill. In bicycle CPX a ramp program (increase of x watts per minute) or a constant workload test (p.e. with 75% of the watts at anaerobic threshold) are performed. Furthermore, an estimation of the cardiac output using CO2-rebreathing method can be realized during a ramp program or a constant workload test. In this paper, also the CPX parameters of the ramp program, the constant workload test and the CO2-rebreathing method are defined and explained. The normal values of CPX are dependent of age, sex, body weight and exercise program. This should be kept in mind in interpreting the measured CPX data. Additionally, the performance of a routine CPX will be reported. Furthermore, the accuracy of the CPX parameters and the potential influences on the data will be discussed. Finally, problems during measurements and their analysis will be clarified.

[Cardiopulmonary capacity of patients with congenital heart defects in childhood, adolescence and adulthood]. / Kardiopulmonale Leistungsfähigkeit bei Patienten mit angeborenen Herzfehlern im Kindes-, Adoleszenten- und Erwachsenenalter.

Cardiopulmonary exercise capacity is a significant criterion of life quality. The evaluation of the exercise capacity is important to answer patient-questions concerning every day activity, choice of profession, sports-activity etc. We performed cardiopulmonary exercise testing in 38 patients (age 33.6 +/- 12.0 years, 18 women, 20 men) with different congenital heart disease (5 after surgical repair of tetralogy of fallot, 2 after Mustard-operation in transposition of the great arteries (TGA), 1 single ventricle, 14 atrial septal defect (ASD), 8 ventricular septal defect (VSD), 8 pulmonary valve stenosis (PS)) during outpatient routine control. All tests were performed on upright bicycle with continuous ramp program of 20 Watt increase/minute. Ventilatory values as O2-uptake, CO2-production, minute ventilation (VE) were measured breath-by-breath. Max. VO2 was reduced as average value for every patient group (tetralogy of fallot 60.2 +/- 20.3% pred., TGA 53.0 +/- 0.0% pred., single ventricle 35% pred., closed ASD 71.9 +/- 23.8% pred., ASD 62.7 +/- 30.0% pred., VSD 64.1 +/- 11.7% pred., PS 73.2 +/- 16.0% pred.). Anaerobic threshold was reduced in tetralogy of fallot (35.9 +/- 12.2% pred. max. VO2) and in single ventricle (28.3% pred. max. VO2). In comparison with clinical classification of exercise capacity we found for max. VO2 differences in 23/38 patients. 22/23 patients reported no exercise limitation but had reduced max. VO2. One patient had a normal max. VO 2 but complaints of exercise dyspnoea. For anaerobic threshold 18/38 patients had discrepancies in objective and subjective estimation of their exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiopulmonary exercise capacity in VVI stimulation in patients with high grade AV block]. / Kardiopulmonale Belastbarkeit unter VVI-Stimulation bei Patienten mit höhergradigen AV-Blockierungen.

VVI-pacemaker patients with high-grade atrioventricular block were subjected to cardiopulmonary exercise testing. An interindividual comparison was made between patients with intermittent intrinsic rhythm (n = 9) and patients with permanent VVI-stimulation (n = 15). Patients with intermittent sinus rhythm on exercise had no significant increase in exercise capacity as quantified by the O2-uptake at the anaerobic threshold. An intermittent sinus rhythm is of no relevance to therapeutic decisions, such as choosing the appropriate pacing mode. Exercise capacity is determined by multiple, partly peripheral factors.

Air trapping and cardiopulmonary exercise testing in patients with mild to moderate bronchial obstruction: clinical role of trapped gas measurements.

UNLABELLED: In 14 patients with obstructive airways disease (7 atopic asthmatics, 7 COPD pts with stable disease, FEV1 < 65% pred., 11 m, 3 f, age 50.9 +/- 17.2 y) the effect of a beta mimetic agent on physical performance was studied. PROTOCOL: Inhalation of 2.5 ml normal saline (P) or salbutamol 0.1% (S) in double-blind random order on 2 successive days. Spirometry, body-plethysmography, single-breath helium dilution at rest. Spiroergometry with incremental workload to tolerance. The volume of trapped gas (D) was derived from: TLC Body-TLC Helium Single Breath. RESULTS: Base line values revealed mild to moderate airways obstruction (FEV1 2.04 +/- 0.81 L, FEV1/VC 60.2 +/- 8.5%). Subsequent to inhaling S FEV1 increased significant by 20% to 2.38 +/- 0.87 L. There was a concomitant substantial improvement of VC (3.37 +/- 1.09 L to 3.60 +/- 0.93 L). Rs declined sign. (2.37 +/- 1.43 to 1.69 +/- 0.8 kPa*s), and so did D (1.15 +/- 0.73 L to 0.55 +/- 0.89 L = -20% from base line). Despite clear-cut bronchodilation exercise performance did not improve in response to S (114.6 +/- 49.3 vs 112.5 +/- 50.0 Watt max, ns). Base line max. VO2 (19.78 +/- 6.36 ml/min/kg) and VO2 at anaerobic threshold (13.29 +/- 3.21 ml/min/kg) suggested only minimal impairment of physical performance. S induced a small but significant decrease in max. VO2 (19.78 +/- 6.36 to 18.43 +/- 6.27 ml/min/kg, p < 0.025). Gas exchange (derived from AaDO2) was impaired at rest (30.18 +/- 10.4 mmHg) and during exercise (28.07 +/- 13.03 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

[Predictive value of ergospirometry in preoperative assessment of risk factors before lung resections]. / Prädiktiver Wert der Spiroergometrie in der präoperativen Abschätzung von Risikopatienten vor Lungenresektionen.

Surgical resection for lung cancer provides the only real chance for cure. However, there is a high risk of postoperative complications including death for patients with pulmonary dysfunction. Therefore preoperative identification of patients at risk is necessary. Apart from history and physical examination three tests are currently used: 1. resting lung function (RFL), 2. invasive measurement of pulmonary vascular resistance (PVR) and 3. exercise testing with measurement of oxygen consumption (VO2). Main studies in the literature report the probability of abnormal tests for prediction of pulmonary complications (positive predictive value) and the probability of normal tests for prediction of uneventful outcome (negative predictive value) as follows: [table: see text] In conclusion, the "ideal" test predictive for morbidity and mortality after lung resection has not been found. The positive predictive values of RLF and PVR are disappointing, while the negative predictive values are acceptable. Measurement of VO2 is simple, noninvasive and might predict survivable morbidity, as suggested in the literature. Obviously, additional studies are necessary.

[Methodologic and clinical comparison of four different ergospirometry systems]. / Methodischer und klinischer Vergleich von vier verschiedenen Ergospirometriesystemen.

The clinician who uses cardio-pulmonary exercise testing (CPX) systems relies on the technical informations from the device producers. In this paper, the practicability, the accuracy and the safety of four different, available CPX systems are compared in the clinical area, using clinically orientated criteria. The exercise tests were performed in healthy subjects, in patients with cardiac and/or pulmonary disease as well as in young or old people. The comparison study showed, that there were partially large differences in device design and measurement accuracy. Furthermore, our investigation demonstrated that beneath repetitive calibrations of the CPX systems a frequent validation of the devices by means of a metabolic simulator is necessary. Problems in calibration can be caused by an inadequate performance or by unclean calibration gases. Problems in validation can be due to incompatibility of the CPX device and the validator. The comparison study of the four different systems showed that in the future standards for CPX testing should be defined.

[Comparison of four different methods for respiratory determination of the anaerobic threshold in normal people, and heart- and lung patients]. / Vergleich der vier verschiedenen Methoden zur respiratorischen Bestimmung der anaeroben Schwelle bei Normalpersonen, Herz- und Lungenkranken.

We analyzed 128 cardiopulmonary exercise tests (CPX), performed in normal subjects (n = 31), in patients with coronary artery disease (n = 41), with chronic heart failure before (n = 14) and after (n = 14) application of oral PDE-inhibitors and in patients with HIV-infection on a bicycle-ergometer in semi-supine position using a ramp-program (dependent on study-population with 15, 20 or 35 Watt/min increases) with respect to the ability to determine the respiratory anaerobic threshold non-invasively, using the main criteria described by Wasserman et al.: the V-slope-method according to Beaver, the increase of the ventilatory equivalent for O2 (VE/VO2), the increase of the end-tidal PO2 (PETO2) and the increase of the respiratory quotient (RQ) during exercise. In the different study-populations we calculated the detection rates of the AT for each criteria separately. The typical changes in the end-tidal PO2 (124/128 = 96.9%) and the V-slope-method (119/128 = 92.9%) were the most reliable parameters to detect the anaerobic threshold. The characteristic changes of the ventilatory equivalent for O2 (VE/VO2) and of the respiratory quotient (RQ) we found in 100/128 (= 78.1%) and in 107/128 (= 83.6%) of the tests respectively. 86/128 tests (67.2%) showed typical changes in all four mentioned criteria. In another 24/128 tests (19.8%) three of four criteria were fulfilled. Therefore, our investigations showed that in 110/128 cases (85.9%) the AT could be determined by typical changes by means of at least three of the four described parameters. In 15/128 (11.7%) tests only two of four criteria were fulfilled.(ABSTRACT TRUNCATED AT 250 WORDS)

[Non-invasive measurement of stroke volume in steady-state and unsteady-state workload with CO2 rebreathing]. / Nichtinvasive Messung des Herzzeitvolumens während Steady-State- und Unsteady-state-Belastungen mittels CO2-Rückatmung.

During steady-state exercise the noninvasive measurement of cardiac output using CO2-rebreathing has been found to be reliable and reproducible. In contrast, reliability of cardiac output measurement during unsteady state exercise is unclear. The ability to determine cardiac output (CO) noninvasively during steady state and unsteady state exercise was assessed in nine healthy students aged 25.7 +/- 7.4 years. Two cycle ergometer exercise tests were performed, one maximal unsteady state test with 25 watts increment of workload per minute, and also one steady state test at 25, 50, and 75 percent of max. VO2. CO was measured using the equilibrium CO2-rebreathing technique during unloaded cycling in both tests, at 75 and 150 watts in the unsteady state test and at all workloads during steady state exercise. Mean max. VO2 was 31.4 +/- 5.9 ml/kg/min and mean VO2 at the anaerobic threshold 24.5 +/- 7.2 ml/kg/min, respectively. During unsteady state exercise the CO2/workload slope was linear (r = 0.973), as with steady state exercise (r = 0.976). There was no difference concerning the slopes of both curves, but the elevation of VO2 with unsteady state exercise was lower, compared to steady state (p < 0.005). The relationships of CO/VO2 during unsteady and steady state exercise were best expressed by linear equations: CO = 7.49 x VO2 + 2.35 (r = 0.866) and CO = 8.24 x VO2 + 1.4 (r = 0.852), respectively. Similar to VO2/workload, both regressions did not have different slopes, but did have different elevations (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiopulmonary capacity in patients with coronary heart disease]. / Kardiopulmonale Leistungsfähigkeit bei Patienten mit koronarer Herzkrankheit.

Cardiopulmonary exercise testing (CPX) allows a non-invasive control of the cardiopulmonary exercise capacity. In this study, we wanted to investigate if the CPX can be securely, practicably, and accurately performed in patients with invasively documented coronary heart disease (CHD). Furthermore, we wanted to find out the clinical value of CPX in CHD diagnosis. The CPX measurements (symptom-limited; ramp program with 20 Watts increase/min; semi-supine position; continuous registration of the cardio-circulatory parameters (HR, RR, ECG), of the gas exchange parameters (O2, CO2) and of the ventilation) in 101 patients have shown that CPX is secure, accurate, and practicable. The day-to-day reproducibility is high (r > 0.8). The respiratory anaerobic threshold can be manually evaluated by means of the PET O2 criterion in 95% of the cases. The CCS-classification of angina pectoris could not accurately describe the cardiopulmonary exercise capacity as compared to the Weber-classification. The disadvantage of the Weber-classification is that it does not respect the age-, sex- and weight-dependent differences of the normal values. Our own data and results from the literature demonstrate that the anaerobic threshold, the maximum VO2 and the maximum O2-pulse are the more reduced the more coronary arteries are involved, the more reduced the left ventricular function is. But, nevertheless, the range of values shows large overlaps so that an exact differentiation, based upon these parameters, is not possible. Patients with similar functional results or degree of reduced exercise capacity have different morphological alterations. Most patients demonstrated typical ischemic cascade with anaerobic threshold, ST-segment alterations, angina pectoris and, finally, reduced max. VO2. In conclusion, CPX does not replace the traditional methods of non-invasive and invasive ischemia detection, but enables secure, practicable, and accurate measurements of the individual cardiopulmonary exercise capacity and the interaction between muscles, heart, circulation, and lungs. Possibly, CPX can be used in the near future for identifying CHD patients with low, medium or high risk.

[Dobutamine versus dipyridamole magnetic resonance tomography: safety and sensitivity in the detection of coronary stenoses]. / Dobutamin- versus Dipyridamol-Magnetresonanztomographie: Sicherheit und Sensitivität bei der Erfassung von Koronarstenosen.

Safety and sensitivity of gradient-echo magnetic resonance imaging (MRI) for the identification of significant coronary artery stenoses using pharmacologic stress testing was assessed in 61 patients with > or = 70% stenosis of a major coronary artery and a normal left ventricle. After MRI at rest 28 patients underwent dobutamine-MRI during steady-state dobutamine infusion (5, 10, 15 and 20 micrograms/kg/min) and 33 patients had dipyridamole-MRI after high-dose dipyridamole infusion (0.75 mg/kg over 10 min). All patients additionally performed standard ECG exercise stress testing (EST). Segmental wall motion analysis was performed in basal and midventricular short axis tomograms by two observers. A segment was graded pathologic if transient dobutamine or dipyridamole induced wall motion abnormalities could be detected. For comparison to coronary angiography findings, each segment was assigned to one of the coronary artery perfusion territories. There were no serious side-effects during dobutamine and dipyridamole infusion leading to termination of the study protocol. Peak double product during dobutamine infusion was significantly higher (p < 0.001) than after dipyridamole infusion (18.493 +/- 4.311 versus 12.799 +/- 2.694 mm Hg/min). Overall sensitivity of dobutamine and dipyridamole-MRI for coronary artery disease (CAD) was 85% and 84%. Regional asynergy by dobutamine and dipyridamole-MRI was observed in 73% versus 79% patients with single- and 100% versus 92% with multi-vessel disease. Individual coronary artery stenoses were correctly identified by segmental wall motion abnormalities in 87% versus 81% for left anterior descending, 62% versus 86% for left circumflex and 78% versus 92% for right coronary artery stenoses. In conclusion, dobutamine and dipyridamole-MRI are well tolerated and safe non-exercise dependent tests for detection and localization of hemodynamically significant coronary artery stenoses with a similar diagnostic accuracy but with a better control of stress intensity and duration provided by dobutamine.