Fast-Track Failure After Cardiac Surgery: Risk Factors and Outcome With Long-Term Follow-Up.

OBJECTIVES: An important cornerstone of the Enhanced Recovery After Cardiac Surgery initiative is a fast-track cardiac anesthesia management protocol. Fast-track failure has been described to have a detrimental impact on immediate postoperative outcomes. The authors here evaluated risk factors for short- and long-term effects of fast-track failure. DESIGN: A retrospective cohort study. SETTING: A single academic center. PARTICIPANTS: Adult cardiac surgery was performed on 7,064 patients between January 2013 and October 2019. INTERVENTION: The inclusion criteria for the fast-track program at the postanesthesia care unit were met by 1,097 patients. MEASUREMENTS AND MAIN RESULTS: Univariate and multivariate logistic regression analyses were used to identify independent risk factors. Fast-track failure occurred in 69 (6.3%) patients. These were associated with significant increases in the incidences of coronary revascularization, cardiac tamponade or bleeding requiring surgical intervention, new-onset atrial fibrillation, pneumonia, delirium, and sepsis. Likewise, the postoperative length of stay, and up to 5-year mortality, were significantly higher in the fast-track failure than the nonfailure group. The European System for Cardiac Operative Risk Evaluation II and transfusion of any blood product could be identified as independent risk factors for fast-track failure, with only limited discriminative ability (area under the curve = 0.676; 95% confidence interval, 0.611-0.741). CONCLUSION: Fast-track failure is associated with increases in morbidity and long-term mortality, but remains difficult to predict.

Why off-the-shelf clavicle plates rarely fit: anatomic analysis of the clavicle through statistical shape modeling.

BACKGROUND: The clavicle presents a large variability in its characterizing sigmoid shape. Prominent and nonproperly fitting fixation plates (FP) cause soft tissue irritation and lead to hardware removal. It is therefore key in FP design to account for shape variations. Statistical shape models (SSMs) have been built to analyze a cluster of complex shapes. The goal of this study was to describe the anatomic variation of the clavicle using SSMs. METHODS: Two different SSMs of the clavicle were created, and their modes of variation were described. One model contained 120 left male and female clavicles. The other model consisted of 76 left and corresponding right clavicles, 41 originating from men and 35 from women. RESULTS: The model of 120 left clavicles showed that 10 modes of variation are necessary to explain 95% of the variation. The most important modes of variation are the clavicle length, inferior-superior bow, and medial and lateral curvature. Statistically significant differences between male and female clavicles were seen in length, sigmoid shape, and medial curvature. Comparison in men between left and right revealed significant differences in length and medial curvature. For women, a statistically significant difference between left and right was only seen in the length. CONCLUSIONS: Although the operative treatment of displaced midshaft clavicular fractures has clear benefits, the variable anatomy of the clavicle often makes it challenging for the surgeon to make the plate fit adequately. Based on the identified variability in the clavicle's anatomy, it seems unlikely that a clavicle plating system can fit the entire population.

Surgery for Active Infective Endocarditis of the Aortic Valve With Infection Extending Beyond the Leaflets.

BACKGROUND: The optimal aortic substitute in extensive aortic valve active infective endocarditis (AIE) continues to be debated. To determine the surgical approach in aortic valve AIE with infection extension beyond the leaflets, we evaluated the outcome of reconstructive surgery with various valve substitutes in those patients. METHODS: During 2000-2013, 168 patients had surgery for extensive aortic valve AIE. Patients were categorised based on aortic valve substitute: Group A: Stented aortic valve replacement (AVR), Group B: Stented AVR with patch support, Group C: Stentless valve, Group D: Aortic allograft, and Group E: Composite valve graft. Outcome parameters were mortality, postoperative cardiogenic or septic shock, stroke, or reinfection. RESULTS: Stented valves with patch support were more frequently utilised in cases of native valve endocarditis (p<0.001). Postoperative complications were comparable among groups. Concomitant preoperative extension of infection in the mitral valve predicted reinfection (OR 3.6; confidence interval 1.46-8.66; p=0.005). Survival was not affected by operative group (log rank=0.6). Univariable preoperative predictors of mortality were: septic shock (hazard ratio 8.3; 95% confidence interval 3.6-19.2; p<0.001), ejection fraction (hazard ratio 0.96; 95% confidence interval 0.93-0.99; p=0.006), preoperative cardiogenic shock (hazard ratio 1.9; 95%CI 1.1-3.6, p=0.02) and concomitant mitral valve surgery (hazard ratio 1.8; 95% confidence interval 1.2-2.5; p=0.002). CONCLUSIONS: Surgical treatment of extensive aortic valve infective endocarditis remains a challenge. Outcomes were not affected by the surgical complexity of aortic reconstruction procedure or valve substitute. Surgical approach should be tailored to individual patient's characteristics.

The Effect of a Nonpeptide Angiotensin II Type 2 Receptor Agonist, Compound 21, on Aortic Aneurysm Growth in a Mouse Model of Marfan Syndrome.

INTRODUCTION: Available evidence suggests that the renin-angiotensin-aldosterone (RAA) system is a good target for medical intervention on aortic root dilatation in Marfan syndrome (MFS). The effect of Compound 21 (C21), a nonpeptide angiotensin II type 2 receptor agonist, on aneurysm progression was tested. METHODS: Mice with a mutation in fibrillin-1 (Fbn1) and wild-type mice were treated with vehicle, losartan, C21, enalapril, or a combination. Blood pressure, aortic root diameter, and histological slides were evaluated. RESULTS: All groups had a comparable blood pressure. Echographic evaluation of the aortic root diameter revealed a protective effect of angiotensin II type 1 receptor antagonist (losartan) and no effect of C21 treatment. None of the treatments had a beneficial effect on the histological changes in MFS. DISCUSSION: This study confirms that angiotensin II type 1 receptor antagonism (losartan) decreases aortic aneurysm growth in a mouse model of MFS. A nonpeptide angiotensin II type 2 receptor agonist (C21), at the doses studied, was ineffective. Future studies are warranted to further elucidate the exact role of the RAA system in aneurysm formation in MFS and identify alternative targets for intervention.

Creation of Abdominal Aortic Aneurysms in Sheep by Extrapolation of Rodent Models: Is It Feasible?

BACKGROUND: Abdominal aortic aneurysms (AAAs) are a potentially deathly disease, needing surgical or endovascular treatment. To evaluate potentially new diagnostic tools and treatments, a large animal model, which resembles not only the morphological characteristics but also the pathophysiological background, would be useful. METHODS: Rodent animal aneurysm models were extrapolated to sheep. Four groups were created: intraluminal infusion with an elastase-collagenase solution (n = 4), infusion with elastase-collagenase solution combined with proximal stenosis (n = 7), aortic xenograft (n = 3), and elastase-collagenase-treated xenograft (n = 4). At fixed time intervals (6, 12, and 24 weeks), computer tomography and autopsy with histological evaluation were performed. RESULTS: The described models had a high perioperative mortality (45%), due to acute aortic thrombosis or fatale hemorrhage. A maximum aortic diameter increase of 30% was obtained in the protease-stenosis group. In the protease-treated groups, some histological features of human AAAs, such as inflammation, thinning of the media, and loss of elastin could be reproduced. In the xenotransplant groups, a pronounced inflammatory reaction was visible at the start. In all models, inflammation decreased and fibrosis occurred at long follow-up, 24 weeks postoperatively. CONCLUSIONS: None of the extrapolated small animal aneurysm models could produce an AAA in sheep with similar morphological features as the human disease. Some histological findings of human surgical specimens could be reproduced in the elastase-collagenase-treated groups. Long-term histological evaluation indicated stabilization and healing of the aortic wall months after the initial stimulus.

Packaging of implantable accelerometers to monitor epicardial and endocardial wall motion.

Acceleration signals, collected from the inner and the outer heart wall, offer a mean of assessing cardiac function during surgery. Accelerometric measurements can also provide detailed insights into myocardial motion during exploratory investigations. Two different implantable accelerometers to respectively record endocardial and epicardial vibrations, have been developed by packaging a commercially available capacitive transducer. The same coating materials have been deposited on the two devices to ensure biocompatibility of the implants: Parylene-C, medical epoxy and Polydimethylsiloxane (PDMS). The different position-specific requirements resulted in two very dissimilar sensor assemblies. The endocardial accelerometer, that measures accelerations from the inner surface of the heart during acute animal tests, is a 2 mm-radius hemisphere fixed on a polymethyl methacrylate (PMMA) rod to be inserted through the heart wall. The epicardial accelerometer, that monitors the motion of the outer surface of the heart, is a three-legged structure with a stretchable polytetrafluoroethylene (PTFE) reinforcement. This device can follow the continuous motion of the myocardium (the muscular tissue of the heart) during the cardiac cycle, without hindering its natural movement. Leakage currents lower than 1 µA have been measured during two weeks of continuous operation in saline. Both transducers have been used, during animal tests, to simultaneously record and compare acceleration signals from corresponding locations on the inner and the outer heart wall of a female sheep.

Remnant Epitope Autoimmunity in Human Abdominal Aortic Aneurysm: A Pilot Study with Elastin Peptides.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a prevalent disease affecting around 5% of the population aged more than 65 years. The exact etiology and physiopathology of AAA still raises questions, and elective surgery is currently the only treatment option for this often progressive disease. In this study, we hypothesized and tested a pathophysiological model that depicts AAA as an inflammation-triggered autoimmune disease with remnant vessel wall peptide fragments as the antigen. METHODS: A pilot study with male AAA patients (n = 14) and male controls (n = 8) was conducted. In both study groups, peripheral blood monocytes and plasma were separated from whole blood by centrifugation. An ELISpot test was performed on cultured white blood cells for the presence of elastin-specific T-lymphocytes. An Enzyme-linked immuno sorbent assay (ELISA) was performed on plasma for the presence of elastin-specific IgG molecules. RESULTS: ELISpot interferon-gamma secretion in AAA (7.7 ± 9.5%) and control (4.6 ± 3.5%) and ELISA anti-elastin IgG titer in AAA (77.5 ± 17.8%) and control (78.2 ± 31.5%) were not significantly different (P = 0.94 and P = 0.55, respectively). Both results are expressed as a percentage relative to the respective positive and negative control. CONCLUSIONS: The results of our pilot study did not indicate a clear and invariable autoimmune process directed against remnant elastin peptide fragments. Further research into the model mechanics and a possible antigen is still necessary. In the mean time, the model as presented here already offers a pathophysiological framework to further research into the possible remnant epitope-driven AAA etiology.

Comparative Anatomy of the Ovine and Female Pelvis.

BACKGROUND: Pelvic organ prolapse affects half of vaginally parous women. Several animal models are used to study its pathophysiology and treatment. Sheep are interesting because they develop spontaneously prolapse with similar risk factors as women and can be used for vaginal surgery. This study describes ovine pelvis anatomy and compares it to women's pelvis to provide anatomical tools for translational researchers. METHODS: MRI, pelvic dissections, and histology were used for detailed macro- and microscopic analysis of relevant anatomical structures in 6 nulliparous ewes. RESULTS: Although sheep are quadrupeds, the gross and microscopic anatomies are similar to the female pelvis. Principal differences are the shape and its orientation, the absence of the sacrospinous ligament and the internal obturator. The levator ani (except for the puborectalis) and the coccygeus muscle are present, yet the latter is more developed - coinciding with the tail. The dimensions and morphology of the ovine vagina is comparable. The retropubic and the rectovaginal space are accessible transvaginally. There is a wide expression of estrogen receptors with low or absent immunoreactivity in the urethral epithelium, bladder, anus and internal anal sphincter. CONCLUSION: The ovine pelvic floor has many anatomical and ultrastructural similarities to the female pelvic floor.

Meox2/Tcf15 heterodimers program the heart capillary endothelium for cardiac fatty acid uptake.

BACKGROUND: Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking. METHODS AND RESULTS: Using microarray profiling on freshly isolated ECs from heart, brain, and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport-related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs, in part, by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term, this combined haplodeficiency resulted in impaired cardiac contractility. CONCLUSIONS: Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.

Comparison of PCR-Electrospray Ionization Mass Spectrometry with 16S rRNA PCR and Amplicon Sequencing for Detection of Bacteria in Excised Heart Valves.

Identification of the causative pathogen of infective endocarditis (IE) is crucial for adequate management and therapy. A broad-range PCR-electrospray ionization mass spectrometry (PCR-ESI-MS) technique was compared with broad-spectrum 16S rRNA PCR and amplicon sequencing (16S rRNA PCR) for the detection of bacterial pathogens in 40 heart valves obtained from 34 definite infective endocarditis patients according to the modified Duke criteria and six nonendocarditis patients. Concordance between the two molecular techniques was 98% for being positive or negative, 97% for concordant identification up to the genus level, and 77% for concordant identification up to the species level. Sensitivity for detecting the causative pathogen (up to the genus level) in excised heart valves was 88% for 16S rRNA PCR and 85% for PCR-ESI-MS; the specificity was 83% for both methods. The two molecular techniques were significantly more sensitive than valve culture (18%) and accurately identified bacteria in excised heart valves. In eight patients with culture-negative IE, the following results were obtained: concordant detection of Coxiella burnetii (n = 2), Streptococcus gallolyticus (n = 1), Propionibacterium acnes (n = 1), and viridans group streptococci (n = 1) by both molecular tests, detection of P. acnes by PCR-ESI-MS whereas the 16S rRNA PCR was negative (n = 1), and a false-negative result by both molecular techniques (n = 2). In one case of IE caused by viridans streptococci, PCR-ESI-MS was positive for Enterococcus spp. The advantages of PCR-ESI-MS compared to 16S rRNA PCR are its automated workflow and shorter turnaround times.

Increased ß-adrenergic inotropy in ventricular myocardium from Trpm4-/- mice.

RATIONALE: The Trpm4 gene has recently been associated with several disorders, including cardiac conduction diseases and Brugada syndrome. Transient receptor potential member 4 (TRPM4) proteins constitute Ca2+ -activated, but Ca2+ -impermeable, nonselective cation channels and are expressed both in atrial and in ventricular cardiomyocytes. The physiological function of TRPM4 in the heart remains, however, incompletely understood. OBJECTIVE: To establish the role of TRPM4 in cardiac muscle function. METHODS AND RESULTS: We used TRPM4 knockout mice and performed patch-clamp experiments, membrane potential measurements, microfluorometry, contractility measurements, and in vivo pressure-volume loop analysis. We demonstrate that TRPM4 proteins are functionally present in mouse ventricular myocytes and are activated on Ca2+ -induced Ca2+ release. In Trpm4(-/-) mice, cardiac muscle displays an increased ß-adrenergic inotropic response both in vitro and in vivo. Measurements of action potential duration show a significantly decreased time for 50% and 90% repolarization in Trpm4(-/-) ventricular myocytes. We provide evidence that this change in action potential shape leads to an increased driving force for the L-type Ca2+ current during the action potential, which explains the altered contractility of the heart muscle. CONCLUSIONS: Our results show that functional TRPM4 proteins are novel determinants of the inotropic effect of ß-adrenergic stimulation on the ventricular heart muscle.

Aortic Regurgitation after TAVR: From Bad to Worse.

Transcatheter aortic valve replacement (TAVR) is a valuable alternative in surgical high-risk patients with symptomatic aortic valve stenosis. Here, the case is presented of very early transcatheter heart valve degeneration, probably caused by a 'Venturi effect' of a severe paravalvular regurgitant jet. This ultimately led to a leaflet being in the open position, creating severe valvular regurgitation that necessitated classical surgical revision. The occurrence of paravalvular regurgitation, and its known relationship with an adverse prognosis after TAVR, demonstrates the clear need for innovative alterations in valve design to prevent this complication. Video 1: Angiography immediately after implantation of an Edwards SAPIEN 23 mm transcatheter heart valve, showing severe paravalvular aortic valve regurgitation. The implantation position is rather low. Video 2: Transesophageal echocardiography with 2-D color imaging showing aortic valve long-axis view at 131°, three days after implantation of an Edwards SAPIEN 23 mm transcatheter heart valve. Severe eccentric paravalvular aortic valve regurgitation is shown without a significant valvular component. The implantation position is rather low. Video 3: Transesophageal echocardiography with 2-D color imaging showing aortic valve long-axis view at 120°, one month after implantation of an Edwards SAPIEN 23 mm transcatheter heart valve. Severe combined valvular and paravalvular aortic valve regurgitation (grade 4/4) is shown.

Enhanced expression of ß3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase.

BACKGROUND: ß1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. ß3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. METHODS AND RESULTS: Mice with cardiac myocyte-specific expression of human ß3-AR (ß3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). ß3-TG and WT had similar morphometric and hemodynamic parameters at baseline. ß3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in ß3-TG mice, which also had less re-expression of fetal genes and transforming growth factor ß1. Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of ß3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, ß3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. CONCLUSIONS: Cardiac-specific overexpression of ß3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac ß3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.

Midterm clinical outcome following Edwards SAPIEN or Medtronic Corevalve transcatheter aortic valve implantation (TAVI): Results of the Belgian TAVI registry.

OBJECTIVE: To assess midterm (3 years) clinical outcomes of transcatheter aortic valve implantation (TAVI) in Belgium using the Edwards SAPIEN valve or the Medtronic CoreValve transcatheter heart valve (THV). BACKGROUND: Medium and long term follow-up data of both THVs are still relatively scarce, although of great clinical relevance for a relatively new but rapidly expanding treatment modality. Therefore, reporting mid- and long term clinical outcome data, coming from large "real world" national registries, remains contributive. METHODS: Between December 2007 and March 2012, 861 "real world" patients who were not candidates for surgical aortic valve replacement as decided by the local heart teams, underwent TAVI at 23 sites. Eleven sites exclusively used SAPIEN THV (n = 460), while 12 exclusively used CoreValve THV (n = 401). Differences in clinical outcomes by valve system were assessed, according to access route and baseline EuroSCORE risk profile (<10%: low, 10-20%: intermediate and >20%: high risk). RESULTS: Overall cumulative survival at 3 years was 51% for SAPIEN vs. 60% for CoreValve (P = 0.021). In transfemorally treated patients, SAPIEN and CoreValve had similar survival at 3 years for each of the baseline EuroSCORE cohorts (low risk: 72% vs. 76%, P = 0.45; intermediate risk: 62% vs. 59%, P = 0.94; high risk: 48% vs. 53%, P = 0.65). CONCLUSION: Cumulative midterm 3 year survival after transfemoral TAVI in "real world" patients refused for surgery with similar baseline EuroSCORE risk profile is not different between SAPIEN or CoreValve.

Aortic Annulus Rupture During TAVI: A Therapeutic Dilemma in the Inoperable Patient.

Aortic annulus rupture is a rare complication of transcatheter aortic valve implantation (TAVI), related to relative valve oversizing or eccentric calcification. A case is reported of periprocedural cardiac tamponade caused by aortic annulus rupture. Optimal management of periprocedural aortic annulus rupture and pseudoaneurysm formation in patients considered too frail for surgery should be discussed in a multidisciplinary setting.

An electro-responsive hydrogel for intravascular applications: an in vitro and in vivo evaluation.

There is a growing interest in using hydrogels for biomedical applications, because of more favourable characteristics. Some of these hydrogels can be activated by using particular stimuli, for example electrical fields. These stimuli can change the hydrogel shape in a predefined way. It could make them capable of adaptation to patient-specific anatomy even post-implantation. This is the first paper aiming to describe in vivo studies of an electro-responsive, Pluronic F127 based hydrogel, for intravascular applications. Pluronic methacrylic acid hydrogel (PF127/MANa) was in vitro tested for its haemolytic and cytotoxic effects. Minimal invasive implantation in the carotid artery of sheep was used to evaluate its medium-term biological effects, through biochemical, macroscopic, radiographic, and microscopic evaluation. Indirect and direct testing of the material gave no indication of the haemolytic effects of the material. Determination of fibroblast viability after 24 h of incubation in an extract of the hydrogel showed no cytotoxic effects. Occlusion was obtained within 1 h following in vivo implantation. Evaluation at time of autopsy showed a persistent occlusion with no systemic effects, no signs of embolization and mild effects on the arterial wall. An important proof-of-concept was obtained showing biocompatibility and effectiveness of a pluronic based electro-responsive hydrogel for obtaining an arterial occlusion with limited biological impact. So the selected pluronic-methacrylic acid based hydrogel can be used as an endovascular occlusion device. More importantly it is the first step in further development of electro-active hydrogels for a broad range of intra-vascular applications (e.g. system to prevent endoleakage in aortic aneurysm treatment, intra-vascular drug delivery).

Angiotensin-converting enzyme inhibition and food restriction restore delayed preconditioning in diabetic mice.

BACKGROUND: Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential. METHODS: Hypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student's t-test or one-way ANOVA followed by a Fisher's LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher's LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant. RESULTS: Left ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob. CONCLUSION: Delayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome.

NO-dependent endothelial dysfunction in type II diabetes is aggravated by dyslipidemia and hypertension, but can be restored by angiotensin-converting enzyme inhibition and weight loss.

AIMS: Insulin resistance, dyslipidemia and hypertension are independent mediators of endothelial dysfunction. It is incompletely defined whether dyslipidemia and hypertension in addition to diabetes mellitus type II (DMII), as seen in the metabolic syndrome (MS), worsen diabetes-induced endothelial dysfunction. Furthermore, it is unclear whether treatment influences endothelial dysfunction similarly in MS and DMII. Therefore, we studied vascular reactivity and the effect of in vivo treatment with angiotensin-converting enzyme inhibition (ACE-I) or hypocaloric diet in LDL receptor- and leptin-deficient (ob/ob), double knockout mice (DKO), featuring MS and in ob/ob mice with DMII. METHODS AND RESULTS: Vascular reactivity was studied in isolated aortic ring segments. Maximum vasorelaxant response to acetylcholine (Ach) was more depressed in DKO than in ob/ob mice, whereas response to bradykinin (BK) was equally attenuated in both genotypes (52 ± 3 and 23 ± 9% reversal of preconstriction induced by 10(-7) M phenylephrine in DKO vs. 76 ± 3 and 23 ± 8% reversal of preconstriction in ob/ob mice, respectively). ACE-I and hypocaloric diet improved ACh-induced vasorelaxation significantly (89 ± 2 and 59 ± 2% reversal of preconstriction in DKO vs. 80 ± 3 and 84 ± 4% in ob/ob mice, respectively), but not the response to BK. CONCLUSION: These results indicate a differential impact of DMII and MS on endothelial function. ACE-I and hypocaloric diet improved ACh-, but not BK-induced vasorelaxation in these mouse models of DMII and MS.

ACE-inhibition, but not weight reduction restores cardiomyocyte response to ß-adrenergic stimulation in the metabolic syndrome.

BACKGROUND: Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling. METHODS: This study was performed in LDL-receptor (LDLR-/-) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR-/-, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during ß-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp. RESULTS: In untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and ß-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to ß-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+. CONCLUSIONS: Cardiomyocyte contractility and ß-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to ß-adrenergic stimulation in MS.

Increased pulmonary artery pressures during exercise are related to persistent tricuspid regurgitation after atrial septal defect closure.

OBJECTIVE: Although closure of an atrial septal defect type secundum often normalizes right heart dimensions and pressures, mild tricuspid insufficiency might persist. This study aimed at (1) identification of determinants explaining the persistence of tricuspid insufficiency after atrial septal defect closure, and (2) evaluation of functional capacity of patients with persistent mild tricuspid insufficiency. METHODS AND RESULTS: Twenty-five consecutive patients (age 42+17 y) were included from the outpatient clinic of congenital heart disease at the University Hospitals of Leuven. All underwent transthoracic echocardiography, semi-supine bicycle stress echocardiography and cardio-pulmonary exercise testing. Six patients (24%) had mild tricuspid insufficiency (2/4) compared to 19 patients (76%) with no or minimal tricuspid insufficiency ( 1/4) as assessed by semi-quantitative colour Doppler echocardiography. Mann-Whitney U and Fisher's exact tests were performed where applicable. Patients with persistent mild tricuspid insufficiency were significantly older than those with no or minimal tricuspid insufficiency (P = 0.042). At rest, no differences in right heart configuration, mean pulmonary artery pressure or right ventricular function were found. At peak exercise, mean pulmonary artery pressure was significantly higher in patients with mild persistent tricuspid insufficiency (P = 0.026). Peak oxygen uptake was significantly lower in patients with mild persistent tricuspid insufficiency (P = 0.019). CONCLUSIONS: Mild tricuspid insufficiency after atrial septal defect repair occurs more frequently in older patients and in patients with higher mean pulmonary artery pressure at peak exercise. In patients with mild tricuspid insufficiency, functional capacity was more reduced. Mild tricuspid insufficiency could be a marker of subclinical persistent pressure load on the right ventricle.