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Objective: To investigate the heterogeneous response to β blockade in patients with Marfan syndrome by non-invasive assessment of the aortic pressure-area curve. Design and patients: 25 patients with the Marfan [...]

Abstract Objective--To evaluate the role of plasma neurohormones in the diagnosis of asymptomatic or minimally symptomatic right ventricular dysfunction. Setting--Tertiary cardiovascular referral centre. Methods--Plasma brain natriuretic peptide (BNP) and atrial [...]

Marfan syndrome is a connective tissue disorder with manifestations in multiple organ systems. (1) Dilatation of the main pulmonary artery is one of the established criteria for the diagnosis of [...]

Cardiac platypnoea-orthodeoxia syndrome (POS) is a position-dependent condition of dyspnoea and hypoxaemia due to right-to-left shunting. It often remains unrecognised in clinical practice, possibly because of its complex underlying pathophysiology. We present four consecutive patients with POS and patent foramen ovale (PFO) who underwent a successful percutaneous PFO closure, describe the mechanism of their POS and provide a review of the literature.

Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-β (TGF-β) as therapeutic biomarker for effectiveness of losartan on AoDR. Baseline plasma TGF-β levels of 22 healthy controls and 99 MFS patients, and TGF-β levels after 1 month of losartan treatment in 42 MFS patients were measured. AoDR was assessed by magnetic resonance imaging at baseline and after 3 years of follow-up. Patients with MFS had higher TGF-β levels compared with healthy controls (121 pg/ml versus 54 pg/mL, p= 0.006). After 1 month of therapy, losartan normalised the TGF-β level in 15 patients (36%); the other 27 patients (64%) showed a significant increase of TGF-β. After 3 years of losartan therapy, patients with a decrease in TGF-β had significantly higher AoDR compared with patients with increased TGF-β (1.5 mm/3 years versus 0.5 mm/3 years, p= 0.04). Patients showing a decrease in TGF-β after losartan therapy had significantly elevated baseline TGF-β levels compared with patients with increased TGF-β (189 pg/ml versus 94 pg/ml, p= 0.05). Patients responding to losartan therapy with a reduction of the plasma TGF-β level had higher baseline TGF-β levels and a higher AoDR. Most likely, TGF-β levels may be considered to be a readout of the disease state of the aorta. We propose that increased angiotensin II is the initiator of aorta dilatation and is responsible for increased TGF-β levels in MFS. The concept of TGF-β as initiator of aortic dilatation in MFS patients should be nuanced.

Patients with congenital heart disease corrected in early childhood may later in life present with cardiac symptoms caused by other associated congenital anomalies that were initially not diagnosed. Nowadays, several noninvasive imaging modalities are available for the visualisation of cardiac anatomy in great detail. We describe two patients with an unroofed coronary sinus, a rare congenital anomaly which could be diagnosed using a combination of modalities including echocardiography, cardiac CT and cardiac MRI.

Communication between the aortic sinus and a cardiac chamber is a rare anomaly that can be diagnosed in children and young adults. We describe two cases with a tunnel between the aortic sinus and right atrium, discuss diagnostic modalities, and review the literature on this anomaly.Communication between the aortic sinus and a cardiac chamber is a rare anomaly that can be diagnosed in children and young adults. We describe two cases with a tunnel between the aortic sinus and right atrium, discuss diagnostic modalities, and review the literature on this anomaly.

20 % of patients with a systemic RV are pacemaker dependent, and unsuitable to undergo cardiac magnetic resonance (CMR). Multidetector row computed tomography (MDCT) could provide a reproducible alternative to CMR in these patients. The aim of this study was to compare variability of MDCT with CMR.Thirty-five patients with systemic RV underwent either MDCT (n?=?15) or CMR (n?=?20). Systemic RV volumes and ejection fraction were obtained, and intra- and interobserver variability for both modalities were assessed and compared.We found the intra- and interobserver variability of volumes and function measurements of the systemic RV obtained with MDCT to be higher compared with those obtained with CMR. However, these differences in variability were not significant, the only exception being the interobserver variability of systemic RV stroke volume.MDCT provides a reproducible alternative to CMR for volumes and function assessment in patients with a systemic RV.

Abstract: Aortic coarctation is a common congenital cardiac defect, which can be diagnosed over a wide range of ages and with varying degrees of severity. We present two cases of patients diagnosed with aortic coarctation in adulthood. Both patients were treated by an endovascular approach. These cases demonstrate the variety of indications in which percutaneous treatment is an excellent alternative for surgical treatment in adult native coarctation patients.

Abstract: After having undergone surgical correction at an early age, many patients with tetralogy of Fallot develop long-term complications including progressive pulmonary regurgitation and peripheral pulmonary stenosis. A high percentage of these patients need to undergo a second operation in their adolescence or early adulthood. If simultaneous treatment of both pulmonary regurgitation and peripheral pulmonary stenosis is warranted, a complete surgical approach has several disadvantages. We describe four cases of Fallot patients with severe pulmonary regurgitation and peripheral pulmonary stenosis who were treated using a hybrid approach involving surgical implantation of a pulmonary homograft and peroperative stenting of the pulmonary artery.

Abstract: Patent ductus arteriosus (PDA) is a rare diagnosis in adults, since symptoms and signs usually occur in infancy and most cases are treated shortly after diagnosis. We present two patients who were first diagnosed with PDA during adulthood. The first case represents a more severe form of PDA, where the need for closure of the PDA is obvious. In the second case the sequelae of the PDA are less clear. In both patients, closure of the PDA (surgically in one case, percutaneously in the other) was successful.

: Background. Patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) with the Proxis system (St. Jude Medical, St. Paul, MN, USA) achieved significantly better microvascular flow as measured by ST-segment resolution. However, no differences were observed in left ventricular ejection fraction or infarct size as obtained by cardiovascular magnetic resonance imaging. The goal of the present study was to evaluate the effect of combined proximal embolic protection and thrombus aspiration on core-lab adjudicated angiographic outcomes. Methods. In the PRoximal Embolic Protection in Acute myocardial infarction and Resolution of ST-Elevation (PREPARE) study, patients were randomised to primary PCI with the Proxis system (n=141) or primary PCI alone (n=143). An independent core laboratory re-evaluated all angiograms and adjudicated the angiographic outcomes and computerised quantitative blush evaluation (QuBE) value. Results. There were no significant differences in Thrombolysis In Myocardial Infarction (TIMI) flow grade, myocardial blush grade, or angiographic signs of distal embolisation among the two arms. QuBE values did not significantly differ between the Proxis-treated patients and control patients (15.1±5.4 vs. 15.8±5.5, respectively, p=0.34). Conclusion. Primary PCI with combined proximal embolic protection and thrombus aspiration in STEMI patients more frequently resulted in complete immediate ST resolution compared with control patients. However, there were no significant differences in core laboratory adjudicated angiographic outcomes. (Neth Heart J 2010;18:531–6.)

Abstract: Background. In patients with pulmonary hypertension, it is unknown whether the treatment effect of bosentan is dependent on the duration of pulmonary vessel changes. Therefore, we studied the response to bosentan in patients with life-long pulmonary vessel changes (pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD)) and in patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension (CTEPH)). Methods. In this open-label study, 18 patients with PAH due to CHD and 16 patients with CTEPH were treated with bosentan for at least one year. All patients were evaluated at baseline and during follow-up by means of the six-minute walk distance (6-MWD) and laboratory tests. Results. Improvement of 6-MWD was comparable in patients with PAH due to CHD (444±112 m to 471±100 m, p=0.02), and in CTEPH (376±152 m to 423±141 m, p=0.03) after three months of treatment. After this improvement, 6-MWD stabilised in both groups. Conclusion. Although duration of pulmonary vessel changes is strikingly different in patients with PAH due to CHD and CTEPH, the effect of one year of bosentan treatment was comparable. The main treatment effect appears to be disease stabilisation and decreasing the rate of deterioration. (Neth Heart J 2009;17:334–8.)

Abstract We evaluated the impact of standard cryopreservation on mechanical and functional properties of human aortic homografts. From 14 human heart‐valve donors, the thoracic descending aorta was obtained. Effects of cryopreservation on mechanical (elastic properties and breaking stress) and smooth muscle cell (SMC) and endothelium function were tested. Cryopreservation (cryo) did not significantly affect Young's modulus of elastin (fresh: 3.1 ± 1.0, cryo: 2.7 ± 0.9 ± 105Nm‐2), collagen recruitment pressure (fresh: 1.1 ± 0.3, cryo: 1.1 ± 0.4 ± 104Nm‐2), distensibility (fresh: 3.8 ± 1.8, cryo: 3.6 ± 1.6 ± 105N‐1m2), or breaking stress (fresh: 2.4 ± 1.0, cryo: 2.2 ± 1.0 ± 106Nm‐2). Following explantation, no endothelium‐dependent relaxation was found. SMC function and endothelium‐independent relaxation were mainly intact after explantation but significantly decreased after cryopreservation. Aortic mechanical properties are not influenced by cryopreservation. Following explantation, almost no endothelial cell function is present, and SMC contractility is strongly affected after cryopreservation.

ObjectiveTo evaluate survival and complication free survival in patients with Marfan's syndrome and to assess the possible influence of recently revised guidelines for prophylactic aortic root replacement in these patients. Methods130 patients who had been attending one institution over 14 years were evaluated. Kaplan-Meier analysis was performed in 125 patients who did not present with aortic root dissection as the first sign of Marfan's syndrome, with the end points: death, aortic root dissection, and prophylactic aortic root replacement after diagnosis. In the patients developing aortic root dissection, current guidelines for prophylactic aortic root replacement were retrospectively applied to investigate the number of dissections that could theoretically have been prevented. The guidelines were: (1) aortic root diameter ≥ 55 mm, (2) positive family history of aortic dissections and aortic root diameter ≥ 50 mm, and (3) aortic root growth ≥ 2 mm/year. Outcomes following emergency surgery (15 patients) and prophylactic surgery of the aortic root (30 patients) were compared. ResultsFive and 10 year survival after diagnosis was 95% and 88%, and the five and 10 year complication free survival was 78% and 66%, respectively. Thirteen patients developed dissection, 30 underwent prophylactic repair, and 82 had an uncomplicated course. Eleven dissections could theoretically have been prevented by application of the current guidelines. Five year survival following emergency and prophylactic repair of the aortic root was 51%, and 97%, respectively. ConclusionsSurvival in the Marfan's syndrome in the past 14 years seems satisfactory; with application of current guidelines, it has probably even improved. However, because of the high fatality rate in Marfan patients developing aortic root dissection, more extensive screening for Marfan's syndrome and a search for additional risk factors are desirable.

The third variable (V3) domain has been implicated in determining the human immunodeficiency virus (HIV) phenotype, including fusion capacity and monocytotropism. In a large set of primary HIV type 1 (HIV-1) isolates, V3 sequence analysis revealed that fast-replicating, syncytium-inducing isolates contained V3 sequences with a significantly higher positive charge than those of slow-replicating, non-syncytium-inducing monocytotropic isolates. It appeared that these differences in charge could be attributed to highly variable amino acid residues located on either side of the V3 loop, midway between the cysteine residues and the central GPG motif. In non-syncytium-inducing monocytotropic isolates, these residues were negatively charged or uncharged, whereas in syncytium-inducing nonmonocytotropic isolates, either one or both were positively charged. The substitutions at these positions result in changes in the predicted secondary structure of the V3 loop. Our data suggest that two amino acid residues in the highly variable V3 domain are responsible for phenotype differences and point to conformational differences in V3 loops from phenotypically distinct HIV-1 isolates.

The nucleotide sequences of the env genes of eight phenotypically heterogeneous human immunodeficiency virus type 1 (HIV-1) clones recovered from a single individual within a 3-week period were compared. In addition, the accessory gene sequences for four of these clones were obtained. Variation among most accessory genes was limited. In contrast, pronounced phenotype-associated sequence variation was observed in the env gene. At least three of these clones most likely resulted from genetic recombination events in vivo, indicating that this phenomenon may account for the emergence of proviruses with novel phenotypic properties. Within the env genes of the eight clones, four domains could be defined, the sequence of each of which clustered in two groups with high internal homology but 11 to 30% cluster variation. The extensive env gene variation among these eight clones could largely be explained by the unique manner in which the alleles of these four domains were combined in each clone. Experiments with chimeric proviruses demonstrated that the HIV-1 env gene determined the capacity to induce syncytia and tropism for T-cell lines. Amino acids previously shown to be involved in gp120-CD4 and gp120-gp41 interaction were completely conserved among these eight clones. The finding of identical V3 sequences in clones differing in tropism for primary monocytes and T-cell lines demonstrated the existence of determinants of tropism outside the env V3 region.

Human immunodeficiency virus type 1 (HIV-1) variants passaged in T-cell lines, often called laboratory isolates, are potently neutralized by soluble CD4 (sCD4), whereas primary HIV-1 variants are highly resistant to sCD4 neutralization. Previously, it was demonstrated that the domain from V1 to V3 of the HIV-1 gp120 molecule contains one of the major determinants of sCD4 neutralization sensitivity, and the same region has also been implicated as influencing syncytium-inducing (SI) capacity and T-cell-line tropism. To determine possible differences in sCD4 neutralization sensitivity between phenotypically distinct primary HIV-1 variants, a panel of non-syncytium-inducing (NSI) and SI HIV-1 variants was studied. Primary NSI and SI HIV-1 variants appeared to be equally resistant to sCD4 neutralization. Consistent with this observation, sCD4 did not induce gp120 shedding from either primary NSI or SI HIV-1 variants at 37 degrees C. Thus, it is not the potential of certain primary HIV-1 variants to infect T-cell lines but rather their adaptation to T-cell lines that is reflected in specific properties of the viral envelope which influence sCD4 neutralization sensitivity.

Previously, we and others have demonstrated a relation between the clinical course of human immunodeficiency virus type 1 (HIV-1) infection and biological properties of HIV-1 variants such as replication rate, syncytium-inducing (SI) capacity, and cytotropism. For the molecular analysis of the biological variability in these properties, we generated a panel of phenotypically distinct yet genetically highly homologous infectious molecular clones. These clones were derived from HIV-1 isolates, mostly recovered by direct clonal isolation, from a single individual in whom a transition from non-SI to SI isolates had been identified over time. Of 17 molecular clones tested, 8 were infectious. The clones exhibited differences in SI capacity and T-cell line tropism. Their phenotypes corresponded to those of their parental isolates, formally demonstrating that biological variability of HIV-1 isolates can be attributed to single molecular clones. With these clones we demonstrated that SI capacity and tropism for the H9 T-cell line, almost invariably coupled in primary HIV-1 isolates, are discernible properties. Also different requirements appeared to exist for H9 and Sup T1 cell line tropism. We obtained evidence that T-cell line tropism is not caused by differences in level of HIV-1 expression but most probably is restricted at the level of virus entry. Restriction mapping of four clones with divergent phenotypes revealed a high degree of nucleotide sequence homology (over 96.3%), indicating the usefulness of these clones for the tracking of genetic variability critical for differences in biological phenotype.

Elevated serum ferritin levels, especially of the H subunit, accompany many clinical malignancies. By using the subtraction-enhanced display technique, we have recently isolated several cDNA clones which are over-expressed in rat hepatocellular carcinoma induced by diethylnitrosamine. One 830-base-pair clone was 88% similar to human ferritin-H cDNA and encoded a 182 amino acid protein which is 97% homologous to human ferritin-H chain. Hepatic mRNA levels of ferritin-H were increased markedly at the early stage of diethylnitrosamine-induced hepatocarcinogenesis in the rat (6 weeks) and appeared more than 10-fold overexpressed as the tumour progressed. In contrast, hepatic ferritin-H mRNA remained constant during liver regeneration after a 70% partial hepatectomy. In situ hybridization showed that over-expression of ferritin-H was exclusively localized to preneoplastic foci, to tumour nodules and to tumour cells invading blood vessels. These findings suggest that ferritin-H is a highly conserved protein, its over-expression during tumour development is phenotypically correlated with tumour initiation and/or progression, and it is useful as an early marker for hepatocellular carcinoma.

Objective To assess and measure the diagnostic and prognostic value of individual aortic root growth in children and adolescents with Marfan syndrome. Design From 1983 to 1996, 250 children were screened for Marfan syndrome. Serial echocardiographic aortic root measurements of 123 children (57 Marfan, 66 control) were available for evaluation of aortic root growth. Aortic root diameters were correlated with body surface area. Based on individual growth of the aortic root a discrimination formula was derived to distinguish Marfan patients from control subjects. Results Sensitivity and specificity of this method, which were dependent on the number of measurements, were 84% and 73%, respectively, for three serial measurements. The discrimination score also predicted a five year complication free survival in all patients. Conclusions In children and adolescents with Marfan syndrome, aortic root growth differs significantly from subjects in whom Marfan syndrome was definitely ruled out during screening. Measurement of individual aortic root growth may serve to establish diagnosis at an early stage and is of prognostic value for occurrence of aortic complications.

Objective To construct an adjusted nomogram for the echocardiographic screening of aortic root diameter in children with possible Marfan disease. Design In 91 children (42 boys, 49 girls, age range 3.2 to 18.4 years) undergoing Marfan screening from 1983 until 1996, the diagnosis Marfan syndrome and any other aortic pathology was definitely ruled out. These served as a control population to set appropriate reference standards. Results Compared with a standard Dutch reference population, body surface area of the control subjects (mean (SD)) was above the 50th centile (boys 0.09 (0.20) m ², range -0.28 to 0.69 m ²; girls 0.09 (0.17) m ², range -0.17 to 0.69 m ²). Echocardiographically determined aortic root diameter and body surface area showed a linear relation and a greater variability of aortic root diameter in these relatively tall subjects (n = 91, R² = 0.62) than in the standard nomogram (n = 56, R² = 0.93). In 24% of cases (n = 22), the aortic root exceeded the upper limit of normal in the standard nomogram, by 2.2 (2.0) mm. An adjusted nomogram was constructed with a higher upper limit. Conclusions A Marfan screening population differs from the unselected population in body surface area and aortic root size variability. An adjusted nomogram should therefore be used to detect a truly enlarged aortic root.

Abstract: Disturbances of rhythm and conduction in patients undergoing surgery for transposition of the great arteries have been widely reported. Some of these patients require implantation of a permanent pacemaker, especially those in whom symptomatic sick sinus syndrome is diagnosed. We present the case of a 29-year-old male corrected with a Mustard procedure, who received a pacemaker for progressive atrioventricular conduction disturbances and sinus node dysfunction, and we review the possible complications associated with transvenous pacemaker implantation in these patients. (Neth Heart J 2007;15:387-389.)

Abstract: A 59-year-old asymptomatic male was referred to our hospital for evaluation 44 years after surgical correction of a Fallot’s tetralogy. Transthoracic echocardiography showed a good surgical result with only a mild subvalvular pulmonary stenosis and mild pulmonary regurgitation. However, in the parasternal short axis a diastolic colour Doppler flow was seen in the right ventricular outflow tract with a maximum velocity over 4 m/s (figure 1). Pulmonary regurgitation seemed very unlikely because of the high velocity in the absence of elevated pulmonary artery pressure. Because a fistula was suspected, a multislice computer tomography scan was performed.

Integrated retroviral DNA is flanked by short direct repeats of the target DNA. The length of these repeats is specific for the provirus that is integrated (H.E. Varmus, in J.A. Shapiro, ed., Mobile Genetic Elements, 1983). For the human immunodeficiency virus type I (HIV-1), the length of the direct repeats in the target DNA was shown to be 5 bp in one case (Muesing et al., Nature [London] 313:450-458, 1985) and 7 bp in another (Starcich et al., Science 227:538-540, 1985). One possible explanation for this discrepancy is that the direct repeats flanking HIV-1 proviruses are variable. To investigate this, we analyzed the junctions between HIV-1 proviral DNA and human DNA from nine individual clones. In each clone the provirus was flanked by a 5-bp direct repeat of human DNA. Analysis of the proviral clone previously described as being flanked by a 7-bp direct repeat of target DNA (Starcich et al., op. cit.) revealed that this clone was flanked by a 5-bp repeat instead. Therefore, we conclude that HIV-1 proviruses are flanked by 5-bp direct repeats of human DNA. The sequences of the 5-bp duplications from the different proviral clones do not have any apparent similarity to each other or to HIV-1 DNA.