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Background Animal studies demonstrated that serelaxin lessens fibrosis in heart failure. This study assessed its effect on myocardial deformation using cardiac magnetic resonance and elucidated its relationship to gene regulation and histology in a mouse heart failure model. Methods and Results C57 BL /6J mice were subjected to SHAM (n=4) or transverse aortic constriction ( TAC ). At week 10, TAC mice were randomized to receive either serelaxin (0.5 mg/kg per day; n=11) or vehicle (n=13) for 4 weeks. Cardiac magnetic resonance imaging was performed at baseline and repeated at the end of the study (week 14). Cine images were used to calculate left ventricular ( LV ) global longitudinal, circumferential, and radial strain. Hearts were examined for histology and gene expression. Compared with SHAM , mice 10 weeks after TAC showed increased LV mass with significant decreases in LV deformation parameters, indicating subclinical deterioration of myocardial function. At week 14, TAC mice given serelaxin demonstrated significant improvements in all LV strain parameters and no decrease in LV stroke volume and ejection fraction compared with TAC mice given vehicle. A significant positive correlation between global circumferential strain and the extent of myocardial fibrosis was found, and global circumferential strain correlated significantly with the expression of heart failure genes in serelaxin‐treated mice. Conclusions Serelaxin improved cardiac magnetic resonance–derived myocardial deformation parameters as well as histomorphometric and gene expression findings in mice with heart failure. Cardiac magnetic resonance–derived myocardial mechanics correlate with histology and gene expression, stressing its utilization in myocardial remodeling.

Background Obesity is associated with cardiovascular complications, including pulmonary hypertension (PH). Reports suggest that peroxisome proliferator-activated receptor-γ (PPARγ) has direct action in preventing vascular remodelling in PH. Here we dissected the specific role of high-fat-diet (HFD)-induced obesity and vascular smooth muscle cell (VSMC)-PPARγ for remodelling of small pulmonary arteries. Methods Wild-type (WT) and VSMC-specific PPARγ-knockout (SmPparγ −/−) mice were fed a low-fat-diet (LFD, 10% kcal from fat) or HFD (60% kcal from fat) for 24 weeks. Mice were metabolically phenotyped (e.g. weight development, insulin/glucose tolerance) at the beginning, and after 12 and 24 weeks, respectively. At 24 weeks additionally pulmonary pressure, heart structure, pulmonary vascular muscularization together with gene and protein expression in heart and lung tissues were determined. Results HFD increased right ventricular systolic pressure (RVSP) to a similar extent in WT and SmPparγ −/− mice. HFD decreased glucose tolerance and insulin sensitivity in both WT and SmPparγ −/− mice. Importantly, the increase in RVSP correlated with the degree of insulin resistance. However, VSMC-PPARγ deficiency increased pulmonary vascular muscularization independently of the diet-induced rise in RVSP. This increase was associated with elevated expression of early growth response protein 1 in heart and osteopontin in lung tissue. Conclusions Here we demonstrate a correlation of insulin resistance and pulmonary pressure. Further, deficiency of PPARγ in VSMCs diet-independently leads to increased pulmonary vascular muscularization.

Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH.

Objective: Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction. Methods: Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj−/− (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake. Results: High-fat diet fed-Ptprj−/− mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj−/− mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj−/− mice. Conclusion: Together, these data establish DEP-1 as novel negative regulator of insulin signaling.

Aims The effectiveness of stress cardiac magnetic resonance (CMR) as a gatekeeper for coronary angiography (CA) has been established. Level five HTA studies according to the hierarchical model of diagnostic test evaluation are not available. Methods This cohort study included 1,158 consecutive patients (mean age 63 ± 11 years, 42 % women) presenting at our institution between January 1, 2003 and December 31, 2004 with suspected coronary artery disease (CAD) for an elective CA. The patients were assessed for eligibility and propensity score matching was applied to address selection bias regarding the patients’ allocation to CMR or direct CA. Median patient follow-up was 7.9 years (95 % CI 7.8–8.0 years). The primary effect was calculated as relative survival difference. The cost unit calculation (per patient) at our institute was the source of costs. Results Survival was similar in CMR and CA (p = 0.139). Catheterizations ruling out CAD were significantly reduced by the CMR gate-keeper strategy. Patients with prior CMR had significantly lower costs at the initial hospital stay and at follow-up (CMR vs. CA, initial: 2,904€ vs. 3,421€, p = 0.018; follow-up: 2,045€ vs. 3,318€, p = 0.037). CMR was cost-effective in terms of a contribution of 12,466€ per life year to cover a part of the CMR costs. Conclusion Stress CMR prior to CA was saving 12,466€ of hospital costs per life year. Lower costs at follow-up suggest sustained cost-effectiveness of the CMR-guided strategy. Electronic supplementary material The online version of this article (doi:10.1007/s00392-014-0793-0) contains supplementary material, which is available to authorized users.

Aims: Subclinical diastolic dysfuntion in patients with preclinical heart failure with preserved ejection fraction (HFpEF) has been demonstrated in patients with Marfan syndrome (MFS). We investigated the relationship between diastolic dysfunction and NT-proBNP levels in patients with MFS. Methods and results: NT-proBNP, C-reactive protein (CRP) and diastolic function were assessed in 217 patients with MFS (31 ± 16 y, 110 f. and in 339 patients referred for suspected MFS in whom the diagnosis was ruled out according to the Ghent nosology (30 ± 15 y, 154 f). Assessment of cardiovascular remodeling, diastolic function in echocardiography, and NT-proBNP was analyzed with univariate analysis and multi-parameter analysis of covariance (MANCOVA). NT-proBNP was 70.6 ± 74.8 pg/ml in patients with Marfan syndrome and 58.4 ± 100.3 pg/ml in controls (p = 0.002, Kolmogorov–Smirnov). There were significant intergroup differences regarding end-diastolic left ventricular volume (p

AimTo study the effects of RD on renal artery wall function non-invasively using magnetic resonance.Methods and results32 patients undergoing RD were included. A 3.0 Tesla magnetic resonance of the renal arteries was performed before RD and after 6-month. We quantified the vessel sharpness of both renal arteries using a quantitative analysis tool (Soap-Bubble®). In 17 patients we assessed the maximal and minimal cross-sectional area of both arteries, peak velocity, mean flow, and renal artery distensibility. In a subset of patients wall shear stress was assessed with computational flow dynamics. Neither renal artery sharpness nor renal artery distensibility differed significantly. A significant increase in minimal and maximal areas (by 25.3%, p = 0.008, and 24.6%, p = 0.007, respectively), peak velocity (by 16.9%, p = 0.021), and mean flow (by 22.4%, p = 0.007) was observed after RD. Wall shear stress significantly decreased (by 25%, p = 0.029). These effects were observed in blood pressure responders and non-responders.ConclusionsRD is not associated with adverse effects at renal artery level, and leads to an increase in cross-sectional areas, velocity and flow and a decrease in wall shear stress.

BACKGROUND Endomyocardial remodeling is characterized by progressive fibrosis and scars and may develop after heart transplantation. The role of everolimus in preventing this process has not been evaluated as yet. METHODS We prospectively studied 132 patients at baseline pretransplant and at 4 weeks, 1 year, and 3 years after heart transplantation. Fibrosis, scars (Zeiss Vision, in Sirius), and acute cellular rejection (hematoxylin-eosin) were studied in biopsy. Transplant vasculopathy was assessed by coronary angiography (focal stenoses, peripheral obliterations, negative vascular remodeling defined by peripheral obliterations, and diffusely narrowed proximal and mid vessel segments). RESULTS Patients on everolimus versus patients on mycophenolate mofetil presented with significantly less fibrosis at 4 weeks (3.8%±0.3% vs. 5.5%±0.3%, P=0.007), 1 year (4.1%±0.3% vs. 4.8%±0.3%, P=0.015), and 3 years (4.2%±0.3% vs. 5.5%±0.7%, P=0.049) posttransplant and showed less scarring at 3 years posttransplant (19.9±1.9% vs. 31.9±4.6% vs. baseline biopsy 26.0±2.8%; P=0.017). Angiographic peripheral obliterations correlated with higher amounts of endomyocardial fibrosis. The negative correlation of everolimus and the positive correlation of peripheral obliterations with fibrosis were confirmed by regression analysis. Angiographic stenoses or acute cellular rejection had no effect on the development of fibrosis. Negative vascular remodeling in 1-year follow-up tended to be less frequent in everolimus-treated patients (24% vs. 76%; P=0.053). CONCLUSIONS Everolimus prevents endomyocardial remodeling after heart transplantation and might have beneficial effects on vascular remodeling of epicardial coronary arteries too. Angiographic peripheral obliterations correlate with increased amounts of endomyocardial fibrosis, suggesting a relevant effect on microvascular perfusion.

Aims: Blood flow, vascular shape and size and local remodeling of the vascular wall are linked through wall shear stress (WSS) signaling. Inter-individual comparison of shape and WSS is hampered by large differences in size of flow and shape. We performed non-dimensional modeling to discriminate different types of coronary artery remodeling based on WSS patterns and vessel morphology. Methods and results: Blood flow was simulated in three-dimensional reconstructed right coronary artery trees from seven controls, five patients with coronary artery disease (CAD) and five patients with aneurysmatic CAD (AnCAD) classified by expert visual diagnosis. A discriminant model using low WSS area, a remodeling index, and cross-correlation of WSS in main trunks and complete trees (K) as non-dimensional parameters classified CAD and AnCAD correctly and identified three patients with high risk profile and functional disease in controls. The new model was compared with discriminant analysis of identical cases simulated without side-branches. The inclusion of K (information from side-branches) and replacement of the mean diameter by a non-dimensional remodeling index improved the model. We found significant (p < 0.005) gender differences in the remodeling index. Conclusion: The combination of non-dimensional modeling and WSS profiling should be further investigated as a novel diagnostic tool in CAD beyond local stenosis.

This study tests the correlation of coronary angiographic findings with the extent of microvascular reaction in right ventricular endomyocardial biopsies (EMBs) in transplanted hearts. In EMBs (n = 209) of 30 heart transplant patients (8 female, 22 male, mean age 48 years) microvascular reaction, i.e. endothelial cell swelling and vascular wall thickening (both grade 0-2), was graded by light microscopy at ×200. Patients' first and last coronary angiography (CA) (mean time after heart transplantation [HTx] 8 and 44 months) were graded according to the Stanford Classification and the presence of diameter irregularities was evaluated semi-quantitatively. We found a correlation of angiographic type B lesions with endothelial cell swelling during the first 5 months and vascular wall thickening during the fifth to fourteenth month after HTx (p

ObjectivesThe aim of this study was to assess the long-term value of high-dose dobutamine cardiac magnetic resonance (DCMR) for the prediction of cardiac events in a large cohort of patients with known or suspected coronary artery disease.BackgroundHigh-dose DCMR has been shown to be a useful technique for diagnosis and intermediate-term prognostic stratification.MethodsClinical data and DCMR results were analyzed in 1,463 consecutive patients undergoing DCMR between 2000 and 2004. Ninety-four patients were lost to follow-up. The remaining 1,369 patients were followed up for a mean of 44 ± 24 months. Cardiac events, defined as cardiac death and nonfatal myocardial infarction, were related to clinical and DCMR results.ResultsThree-hundred fifty-two patients underwent early revascularization (≤3 months of DCMR) and were excluded from analysis. Of the remaining 1,017 patients, 301 patients (29.6%) experienced inducible wall motion abnormalities (WMA). Forty-six cardiac events were reported. In those with and without inducible WMA, the proportion of patients with cardiac events was 8.0% versus 3.1%, respectively, p = 0.001 (hazard ratio: 3.3; 95% confidence interval: 1.8 to 5.9 for the presence of inducible WMA; p < 0.001). A DCMR without inducible WMA carried an excellent prognosis, with a 6-year cardiac event-free survival of 96.8%. In all 1,369 patients in the patient group with stress-inducible WMA, those patients with medical therapy demonstrated a trend to a higher cardiac event rate (8.0%) than those with early revascularization (5.4%) (p = 0.234). Patients with normal DCMR and medical therapy or early revascularization demonstrated similar cumulative cardiac event rates (3.1% vs. 3.2%, p = 0.964).ConclusionsIn a large cohort of patients, DCMR has an added value for predicting cardiac events during long-term follow-up, improving the differentiation between high-risk and low-risk patients. Patients with inducible WMA and following early revascularization, demonstrate lower cardiac event rates than patients with medical therapy alone.

Summary Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty-four coronary angiograms from 11 hospitals were circulated. One hundred eighty-eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa = 0.371, P

Cardiac allograft vasculopathy (CAV) in patients who have undergone heart transplantation leads to graft dysfunction and is still the major concern for long-term survival. Evaluation of coronary flow velocity reserve (CFR) has been established for diagnosis of CAV. Systemic application of adenosine vs intracoronary testing for CFR has been validated in adults; however, its accuracy in pediatric patients has not yet been proven.CFR was prospectively measured in 33 clinically asymptomatic pediatric heart transplant recipients. CFR measurements were made in the left anterior descending (LAD) artery using a 0.014-inch Doppler FloWire (Cardiometrics). CFR was defined as the ratio of hyperemic (after adenosine injection) to basal (before adenosine) average peak velocity (APV). Adenosine (Adrekar) was administered by intracoronary (15 or 30 mug bolus) and systemic (0.1 mg/kg) injection in each patient. Epicardial CAV was evaluated in coronary angiograms (Stanford criteria) and microvasculopathy was diagnosed in endomyocardial biopsies (evidence of luminal stenosis) blinded to clinical data.Thirty-three patients were included in this study. Their median age (range) was 11.9 (1.4 to 17) years and median post-transplant time 4.3 (1 to 11.7) years. Seventeen of the 33 patients had epicardial CAV (mainly peripheral obliterations or B1 and B2 lesions) and microvascular CAV. Epicardial CAV only was found in 4 patients and microvasculopathy only was present in only 1 patient. CFR was significantly reduced in patients with epicardial CAV and microvasculopathy when compared with patients without any signs of CAV: 206 +/- 53 vs 276 +/- 39 (p0.001) for the systemic application and 213 +/- 50 vs 271 +/- 45 (p = 0.004) for the intracoronary application.CFR and coronary vasoreactivity to adenosine are decreased in pediatric patients with CAV and correlate with histopathologic and angiographic evidence of microvascular disease. Measurement of CFR with intracoronary and systemic application of adenosine is comparable, while systemic application is necessary for non-invasive measurement of CFR in pediatric patients.

Background— Epicardial vasculopathy has been shown to be associated with poor outcome after heart transplantation. We demonstrate that histologically proven stenotic microvasculopathy is a novel prognostic factor for long-term survival. Methods and Results— In 9713 biopsies harvested within the first posttransplantation year from 873 patients (83% male; mean age, 49.1±0.6 years), light microscopic evaluations (×200) were performed for microvasculopathy, defined as stenotic endothelial and/or medial disease. Prevalence of severe epicardial vasculopathy was defined by presence of ≥75% luminal stenosis in coronary angiography (available in 611 of 873 patients), which was present in 118 of 611 patients (19%). For Kaplan-Meier analysis, we defined fatal cardiac events as lethal acute myocardial infarction, sudden cardiac death, and graft failure. Stenotic microvasculopathy was present in 379 of 873 patients (43%) and was due to medial (345/379; 91%) rather than endothelial disease (2/379; 1%) or a combination of both (31/379; 8%; P P =0.3329) and nonstenotic medial disease (12.44 [11.14 to 13.74] versus 12.43 years [10.51 to 14.35]; P =0.4047) did not decrease overall survival or time to fatal cardiac event. Stenotic microvasculopathy was associated with poor overall survival (10.90 [9.16 to 12.60] versus 13.40 years [11.79 to 15.07]; P =0.0374) and decreased freedom from fatal cardiac events (1, 5, 10 years, 95.6±1.4%, 86.9±2.3%, 75.5±3.1% versus 99.1±0.5%, 96.8±1.0%, 89.8±1.9%; P P =0.0031). Conclusions— Stenotic microvasculopathy is frequent in routinely processed biopsies and a new prognostic factor for long-term survival after heart transplantation.

We assessed the value of deceleration time (dt) of diastolic wave of pulmonary venous flow (PVF) (PVF_dt) as noninvasive estimation of pulmonary wedge pressure (PWP) in candidates for and recipients of heart transplantation.We prospectively recruited 51 patients with end-stage congestive heart failure (group A) and 49 recipients of heart transplantation (group B). PWP and PVF_dt were measured using a Swan-Ganz catheter and Doppler echocardiography, respectively. We performed regression analyses to assess interrelationships. Moreover, we used the area under the receiver operating characteristic curve to assess how clearly PVF_dt could discriminate between normal and elevated PWP values.In both study groups, PWP was inversely associated with PVF_dt (R(2) = 0.785 and 0.797, respectively, P.001). A cut-off value of less than 187 milliseconds was predictive of an elevated PWP value (or =12 mm Hg) in both study groups. Specificity and sensitivity were between 90% and 100%, respectively, in both study groups. The area under the receiver operating characteristic curve was 0.961 (0.908-1.013; P.001) for group A and 0.998 (0.992-1.04; P.001) for group B.In recipients of heart transplantation and patients with end-stage congestive heart failure, the noninvasive measuring of PVF_dt distinguishes between normal and elevated PWP values.

Background Previous studies in patients and in dogs with experimentally induced heart failure (HF) showed that electrical signals applied to the failing myocardium during the absolute refractory period improved left ventricular (LV) function. We examined the effects these same cardiac contractility modulating (CCM) electrical signals on myocardial oxygen consumption (MVO 2 ) in both patients and dogs with chronic HF. Methods and Results Six dogs with microembolizations-induced HF and 9 HF patients underwent CCM leads and generator (OPTIMIZER II) implantation. After baseline measurements, CCM signals were delivered continuously for 2 hours in dogs and for 30 minutes in patients. MVO 2 was measured before and after CCM therapy. In dogs, CCM therapy increased LV ejection fraction at 2 hours (26 ± 1 versus 31 ± 2 %, P = .001) without increasing MVO 2 (257 ± 41 versus 180 ± 34 μmol/min). In patients, CCM therapy increased LV peak +dP/dt by 10.1 ± 1.5 %. As with dogs, the increase in LV function after 30 minutes of CCM therapy was not associated with increased MVO 2 (13.6 ± 9.7 versus 12.5 ± 7.2 mL O 2 /min). Conclusions The study results suggest that unlike cAMP-dependent positive inotropic drugs, the increase in LV function during CCM therapy is elicited without increasing MVO 2 .

Target temperature management (TTM) after cardiac arrest (CA) improves outcome in patients with acute coronary syndrome (ACS). Previous data point to an interaction between hypothermia and drug metabolism, potentially impacting on platelet function in patients on antiplatelet therapy.To compare clopidogrel metabolism and platelet function in clopidogrel naïve ACS patients treated with TTM (33°C, n=15) and in ACS patients (troponin positive) without TTM (n=18).Platelet function was measured by multiple electrode platelet aggregometry (MEA), light transmittance aggregometry (LTA) and VASP analysis before and after administration of a 600mg clopidogrel loading dose. Plasma levels of clopidogrel and its metabolites were measured. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. TTM was carried out for 24h at a target temperature of 33°C using a computer feedback surface cooling device in cardiac arrest patients.Plasma concentration of clopidogrel and metabolites was lower in the TTM group after 2 and 4h, respectively (all p0.005 vs. controls), and platelet function tests revealed an attenuated response to clopidogrel with respect to baseline platelet activity in the TTM group. This was significant for MEA, LTA and VASP analysis (all p0.05). Moreover, there was no significant difference in genotype and platelet function determined ex vivo at 33 or 37°C, respectively.Inhibition of platelet function is significantly lessened in TTM at 33°C, likely due to reduced clopidogrel absorption. Patients with TTM might thus have a higher risk for further cardiovascular events despite antiplatelet therapy with clopidogrel.

Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases.

Background Mortality in severe congestive heart failure rises with the incidence of an inter- and intraventricular conduction delay and doubles if atrial fibrillation (AF) occurs. Electrical cardioversion (CV) is frequently regarded as less promising in these patients. Encouraged by first conversions during defibrillation threshold (DFT) testing we consecutively attempted electrical cardioversion in 30 patients selected for cardiac resynchronization therapy (CRT). Methods After successful CV an additional atrial electrode was placed during implantation of a CRT device (ICD or pacemaker) to ensure AV sequential biventricular pacing. Regular clinical follow-up examinations up to 2 years were performed. Results In 23 (75%) of 30 patients (onset of AF at least 6 months earlier), sinus rhythm (SR) could successfully be restored. Under antiarrhythmic medication in 21 patients SR was still present after 333±142 days. Furthermore, a significant increase of EF from 22% to 31% (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P{

AIMS The purpose of this three-dimensional intracoronary ultrasound (ICUS) study was to assess longitudinal plaque distribution patterns in patients with angiographically silent coronary artery disease (CAD) after heart transplantation (HTX). METHODS AND RESULTS Out of 334 patients without diameter stenosis >/=25% determined by coronary angiography, 321 underwent successful three-dimensional ICUS (30 MHz) of the left main coronary artery (LMCA) and all segments of the left anterior descending coronary artery (LAD). Early plaque formation was found in 296 patients (92.2%). Single (focal CAD, n = 65) or multiple (polyfocal CAD, n = 77), discrete coronary lesions were found in 142 patients and continuous plaque formation of at least one entire coronary segment (diffuse CAD) in 154 patients. Using multivariate regression analysis, male sex (P = 0.01), increasing post-transplantation time (P = 0.003) and increasing donor age (P = 0.001) were independent clinical predictors for diffuse CAD. Both focal and diffuse CAD most frequently affected the proximal LAD (88% compared with 89.6%, NS). The mean intimal index of each LAD segment was significantly higher in patients with diffuse CAD (P < 0.001) and showed a proximal-to-distal decline in patients with focal/polyfocal (LMCA, 10.1 +/- 14.3, LAD-6, 30.1 +/- 17.4%, LAD-7, 16.3 +/- 14.1%, LAD-8, 4.6 +/- 11.1%; P < 0.001) and diffuse (LMCA, 27.0 +/- 16.0, LAD-6, 47.8 +/- 16.1%, LAD-7, 41.9 +/- 14.5%, LAD-8, 24.9 +/- 23.3%; P < 0.01) CAD. CONCLUSION Evaluation of longitudinal plaque distribution after HTX by three-dimensional ICUS revealed a time-dependent increase in the incidence of diffuse CAD and a proximal-to-distal decline in frequency and magnitude of early plaque formation.

Objectives: Quantitative measurements on three-dimensional (3-D) reconstructed coronary trees permit accurate evaluation of vascular volumes, lengths and diameters. We applied this technique to investigate diffuse luminal narrowing in patients with the clinical manifestation of progressive atherosclerosis. Methods: In 13 patients who presented repeatedly for coronary angioplasty (at least 4 years of invasive follow-up), left coronary arteries were reconstructed in 3-D from biplane coronary angiograms. Mean diameter, cross-sectional areas, total length, and volume were calculated for segments and branches. Five patients without coronary artery disease served as controls. Results: Patients with progressive coronary atherosclerosis demonstrated a significant reduction of total vascular volumes, mean diameters and cross-sectional areas at the initial investigation when compared with controls. Progressive luminal shrinkage occurred during follow-up (−0.04±0.13 mm per year and per segmental diameter). The progress of luminal narrowing in patients with coronary artery disease is related to the number of coronary risk factors and the duration of follow-up. Conclusion: Quantitative measurements on 3-D reconstructed coronary trees are a useful investigative tool for the assessment of progression of coronary atherosclerosis.

Introduction: Pulmonary vein isolation (PVI) has been established as effective interventional treatment in chronic atrial fibrillation (AF). Impairment of left atrial strain is considered a surrogate parameter of fibrosis. There is considerable variance of strain among different atrial wall segments. We hypothesized that early impairment of strain affects mobile segments and thus reduces inter-segmental variance of strain. Methods: We evaluated 89 consecutive PVI patients and 28 controls (mean age 60 ± 12 y, 33 female). The longitudinal strain of the left atrium in a 4-chamber apical window was determined by speckle tracking (Philips IE33 offline analysis by QLAB™). Success was defined as maintenance of sinus rhythm until last follow-up (minimum 3 months elapsed since PVI). Follow-up comprised repeated Holter-monitoring and echocardiography. Variance was evaluated as standard deviation of segmental strain before PVI (STD). Results: Atrial fibrillation recurred in 40 of 89 patients. STD was 16.5±7.9 in controls, 8.1±5.3 in PVI with persisting success and 4.6±2.2 in late PVI failure (see also box-plot). The group differences between controls, PVI success and PVI failure were all significant (p Conclusions: Standard deviation of segmental left atrial strain is impaired in patients treated by pulmonary vein isolation with late failure and should be further evaluated as predictor for recurrence.

Aims We sought to evaluate the impact of ischemic burden for the prediction of hard cardiac events (cardiac death or nonfatal myocardial infarction) in patients with known or suspected CAD who undergo dobutamine stress cardiac magnetic resonance imaging (DCMR) Methods We included 3166 patients (pts.), mean age 63±12 years, 27% female, who underwent DCMR in 3 tertiary cardiac centres (University Hospital Heildelberg, German Heart Institute and Kings College London). Pts. were separated in groups based on the number of ischemic segments by wall motion abnormalities (WMA) as follows: 1. no ischemic segment, 2. one ischemic segment, 3. two ischemic segments and 4. ≥three ischemic segments. Cardiac death and nonfatal myocardial infarction were registered as hard cardiac events. Pts. with an “early” revascularization procedure (in the first three months after DCMR) were not included in the final survival analysis. Results Pts. were followed for a median of 3.1 years (iqr 2–4.5 years). 187 (5.9%) pts. experienced hard cardiac events. 2349 (74.2%) had no inducible ischemia, 189 (6%) had ischemia in 1 segment, 292 (9.2%) in 2 segments and 336 (10.6%) ≥3 segments. Patients with only 1 ischemic segment showed a high rate of hard cardiac events of ∼6% annually, which was 10-fold higher compared to those without ischemia (0.6% annually, p

Aims Sympathetic stimulation induces left ventricular hypertrophy and is associated with increased cardiovascular risk. Catheter-based renal denervation (RDN) has been shown to reduce sympathetic outflow and blood pressure (BP). The present multi-centre study aimed to investigate the effect of RDN on anatomic and functional myocardial parameters, assessed by cardiac magnetic resonance (CMR), in patients with resistant hypertension. Methods and results Cardiac magnetic resonance was performed in 72 patients (mean age 66 ± 10 years) with resistant hypertension (55 patients underwent RDN, 17 served as controls) at baseline and after 6 months. Clinical data and CMR results were analysed blindly. Renal denervation significantly reduced systolic and diastolic BP by 22/8 mm Hg and left ventricular mass index (LVMI) by 7.1% (46.3 ± 13.6 g/m1.7 vs. 43.0 ± 12.6 g/m1.7, P < 0.001) without changes in the control group (41.9 ± 10.8 g/m1.7 vs. 42.0 ± 9.7 g/m1.7, P = 0.653). Ejection fraction (LVEF) in patients with impaired LVEF at baseline (

Aims: Goals of the study were the assessment of the correlation between flow-dependent and contrast-related vasodilatation, comparison of iodixanol to iopromide and evaluation of the impact of plaque on vasodilatation in coronary arteries. Methods and Results: A controlled randomized paired cross-over comparison between iodixanol (320 mg I.ml-1) and iopromide (300 mg I.ml−1) was performed in 10 consecutive patients. Vessel area (Visions Five-64 F/X™ intra-vascular ultrasound-catheter, Endosonics® and blood flow velocity measurements (0.014 inches Doppler guide wire, Cardiometrics®) were recorded simultaneously at an identical position, at baseline, after i.c. bolus injection of 10 ml physiologic saline (flow-dependent vasodilatation), and after application of contrast agent 1 and contrast agent 2 as randomized. The action of iodixanol and iopromide on the vascular wall did not differ and was equal to local flow-dependent vasodilatation induced by a saline bolus (correlation 0·95– 0·98). The increase in local luminal area after injection of saline, iodixanol and iopromide in morphologically normal vessels (∼2·5 mm2) was absent in atherosclerotic segments. Both contrast agents and saline demonstrated a nearly identical flow increase. Conclusion: If iodixanol or iopromide are used as contrast agents, contrast-related vessel area increase in vivo seems to be endothelium-dependent.

renal perfusion may result from a reduction of mean Background. Changes in renal blood flow are considered to arterial blood pressure (MABP) or decreased cardiac outplay a significant role in the induction and maintenance of put or may be due to renal vasoconstriction. The combinakidney failure, but are difficult to monitor with currently availtion of moderately reduced perfusion pressure and inable techniques. The objective was to validate renal flow measurements with Doppler guidewires and to apply this technique creased renal vascular resistance (RVR) is believed to to assess dose and time dependency of the renal vascular effects promote renal failure in patients with sepsis [2] or hepatoof norepinephrine (NE). renal syndrome [3]. The adverse effects of several “nephMethods. In 10 anesthetized pigs, flow velocity in renal arter- rotoxic” agents, including contrast media, on kidney ies (FVart) and veins (FVvein) and volumetric renal blood function are also considered to be partially due to a flow (VBF) were measured before and after intravenous bolus application of incremental doses of NE (2 to 200 mg). temporary reduction in RBF [1]. Some studies have indiResults. FVart curves exactly reflected the changes in VBF. cated that a reduction in RBF persists during the course Beat-to-beat analysis revealed a strong linear correlation over of ARF [4, 5], while others have reported that RBF is a mean VBF range of less than 0.05 to 0.35 L/min (median not an important determinant of the glomerular filtration correlation coefficient with FVart, r 5 0.998), and significant rate (GFR) depression during the maintenance phase of but less close relationships were also found between VBF and FVvein. Ten seconds after the administration of 200 mg NE, postischemic ARF [6, 7]. Therefore, in different clinical FVart dropped from 71 to 6 cm/sec and was 90% reversible situations, monitoring of renal perfusion may be releafter 48 seconds. Similarly, the renal vascular resistance tempo- vant, not only to characterize further the association rarily rose from 988 to 13711 mm Hg · min/L. In contrast, between changes in renal hemodynamics and GFR, but NE-induced increases in systemic vascular resistance were on average a maximum of 1.5-fold but persisted for more than 60 also to identify and prevent ischemic insults to the seconds. kidney. Conclusions. Doppler flow measurements in the renal artery Currently available methods for the measurement of provide an excellent surrogate of volumetric blood flow, which RBF in humans have been useful to detect RBF abnormay be useful for continuous monitoring of renal hemodynammalities in various settings, but are characterized by sevics. The renal vasculature is more sensitive when compared with the systemic vasculature, but also appears to evoke more eral methodological problems that limit their accuracy efficient counter-regulatory mechanisms in response to NE. and applicability. The urinary clearance of p-aminohippurate (PAH) [8] cannot be applied to oligo-anuric subjects, and in postischemic renal failure, PAH extraction A reduction in renal blood flow (RBF) commonly is severely impaired so that the PAH clearance markedly occurs in association with renal dysfunction and can cause underestimates renal plasma flow [6]. Dye dilution techkidney failure. In acute renal failure (ARF), renal hypo- niques require the simultaneous catheterization of the renal artery and vein and allow only bolus measurements [9]. For isotope techniques, the need for external count

Summary: The investigation was to elucidate the role of the reduction of extravascular pulmonary fluid in the immediate symptomatic improvement and its impact on hemodynamics in patients with mitral stenosis treated by percutaneous transluminal valvuloplasty. Methods: In a prospective study of 12 patients with severe mitral stenosis extravascular pulmonary fluid volume was determined by a combined dye and thermodilution technique (COLD Z-021 TM Version 5.x, Pulsion ® ) before and after valvuloplasty. Cardiac output, left atrial pressures, atrial V-waves, diastolic transmitral gradients and their respiratory changes were measured. Dyspnea was assessed by validated questionnaires. Results: Symptomatic improvement correlated ( r =0. 808) with a decrease of extravascular lung water, but not with either an increase or a decrease of cardiac output or left atrial filling pressures. The decrease of the lung water index may be predicted from the lung water index before valvuloplasty, the final left atrial mean pressure and the cardiac index prior to intervention. The change of the mean difference between inspiratory and expiratory mitral gradient demonstrated a significant inverse correlation with the change of mean left atrial filling pressures ( r =−0.778) and with extravascular lung water after valvuloplasty ( r =−0.871). Conclusion: There is a complex relationship between left atrial filling pressures, extravascular lung water, respiratory changes of gradients, and dyspnea that need further investigation.

Background Matrix metalloproteinase (MMP)-dependent extracellular matrix (ECM) remodeling is a key feature in cardiometabolic syndrome-associated adipogenesis and atherosclerosis. Activation of membrane-tethered (MT) 1-MMP depends on furin (PCSK3). However, the regulation and function of the natural furin-inhibitor serpinB8 and thus furin/MT1-MMP-activity in obesity-related tissue inflammation/remodeling is unknown. Here we aimed to determine the role of serpinB8/furin in obesity-associated chronic inflammation. Methods and Results Monocyte → macrophage transformation was characterized by decreases in serpinB8 and increases in furin/MT1-MMP. Rescue of serpinB8 by protein overexpression inhibited furin-dependent pro-MT1-MMP activation in macrophages, supporting its role as a furin-inhibitor. Obese white adipose tissue-facilitated macrophage migration was inhibited by furin- and MMP-inhibition, stressing the importance of the furin-MMP axis in fat tissue inflammation/remodeling. Monocytes from obese patients (body mass index (BMI) >30kg/m2) had higher furin, MT1-MMP, and resistin gene expression compared to normal weight individuals (BMI

BACKGROUND Impaired response to dual antiplatelet therapy is associated with worse cardiovascular outcome. Besides antiplatelet effects, there is evidence that both clopidogrel and acetylsalicylic acid (ASA) have anti-inflammatory properties. However, little is known about the relationship between platelet function and inflammation under dual antiplatelet therapy in patients with stable coronary artery disease. PURPOSE The purpose of the study was to investigate the correlation of platelet function with soluble (s)P-selectin and soluble (s)CD40L in patients undergoing elective percutaneous coronary intervention. Poor response to ASA and clopidogrel could lead to increased levels of inflammatory markers. METHODS A total of 148 patients were included. Eighty percent of the patients were on 100 mg ASA and all patients were clopidogrel naive. They underwent percutaneous coronary intervention and received a loading dose of 600 mg clopidogrel. Platelet function was assessed by light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein analysis at baseline, 24 h after loading, and after 1 month of maintenance therapy, respectively. Plasma levels of sP-selectin and sCD40L were measured. To classify low responders to clopidogrel, patients were screened for genetic variants determining clopidogrel absorption and metabolization. RESULTS sP-selectin levels correlated with LTA findings after stimulation with arachidonic acid (P=0.012). Further, in addition to decreased platelet reactivity observed on LTA, lower sP-selectin levels were seen in patients under ASA therapy (P=0.004). CYP2C19*2 allele carriers had a higher platelet reactivity after clopidogrel loading measured by adenosine diphosphate-induced aggregation in LTA (P=0.008) and vasodilator-stimulated phosphoprotein phosphorylation (P=0.035); however, there was no difference in the inflammatory markers. Multiple regression analysis showed that variables significantly related to sP-selectin plasma levels were sCD40L (P

To the Editor: In the present study we sought to investigate the predictive value of resting and inducible wall motion abnormalities (WMA) and of late gadolinium enhancement (LGE) for hard cardiac outcomes and for revascularization procedures in 3,138 patients undergoing dobutamine cardiac magnetic

Background Non-human leukocyte antigen antibodies (Abs) targeting vascular receptors are implicated in the pathogenesis of renal allograft vascular rejection and in progressive vasculopathy in patients with systemic sclerosis. Methods We prospectively tested in 30 heart transplant recipients the impact of Abs directed against endothelin-1 type A (ET(A)R) and angiotensin II type 1 receptors (AT(1)R, cell-enzyme-linked immunosorbent assay) at time of transplantation and during the first posttransplantation year on cellular and Ab-mediated rejection (immunohistochemistry, C3d, and immunoglobulins) and microvasculopathy in endomyocardial biopsy. Results Cellular rejection, Ab-mediated rejection, and microvasculopathy was found in 40% and 13%, 57% and 18%, and 37% and 40% of biopsies at 1 month and 1 year posttransplantation, respectively. Maximum levels of AT(1)R and ET(A)R Abs were higher in patients with cellular (16.5±2.6 vs. 9.4±1.3; P=0.021 and 16.5±2.5 vs. 9.9±1.9; P=0.041) and Ab-mediated rejection (19.0±2.6 vs. 10.0±1.3; P=0.004 and 19.4±2.7 vs. 9.0±1.7; P=0.002), as compared with patients who had no rejection. Patients with elevated AT(1)R Abs (53% [16/30]) or ETAR Abs (50% [15/30]; pretransplantation prognostic rejection cutoff >16.5 U/L) presented more often with microvasculopathy (both, 67% vs. 23%; P=0.048) than patients without. Conclusions Elevated levels of AT(1)R and ET(A)R Abs are associated with cellular and Ab-mediated rejection and early onset of microvasculopathy and should be routinely monitored after heart transplantation.

The aim of this study was to assess the prognostic value of dobutamine stress cardiovascular magnetic resonance (DCMR) in patients with previous myocardial revascularization. The role of DCMR in the risk stratification of patients with previous coronary revascularization has not been well defined.

Coronary vessel distensibility is reduced with atherosclerosis and normal aging, but direct measurements have historically required invasive measurements at cardiac catheterization. Therefore, we sought to assess coronary artery distensibility noninvasively using 3.0 Telsa coronary magnetic resonance imaging (MRI) and to test the hypothesis that this noninvasive technique can detect differences in coronary distensibility between healthy subjects and those with coronary artery disease (CAD). A total of 38 healthy, adult subjects (23 men, mean age 31 ± 10 years) and 21 patients with CAD, diagnosed using x-ray angiography (11 men, mean age 57 ± 6 years) were studied using a commercial whole-body MRI system. In each subject, the proximal segment of a coronary artery was imaged for the cross-sectional area measurements using cine spiral MRI. The distensibility (mm Hg(-1) × 10(3)) was determined as (end-systolic lumen area - end-diastolic lumen area)/(pulse pressure × end-diastolic lumen area). The pulse pressure was calculated as the difference between the systolic and diastolic brachial blood pressure. A total of 34 healthy subjects and 19 patients had adequate image quality for coronary area measurements. Coronary artery distensibility was significantly greater in the healthy subjects than in those with CAD (mean ± SD 2.4 ± 1.7 mm Hg(-1) × 10(3) vs 1.1 ± 1.1 mm Hg(-1) × 10(3), respectively, p = 0.007; median 2.2 vs 0.9 mm Hg(-1) × 10(3)). In a subgroup of 10 patients with CAD, we found a significant correlation between the coronary artery distensibility measurements assessed using MRI and x-ray coronary angiography (R = 0.65, p = 0.003). In a group of 10 healthy subjects, the repeated distensibility measurements demonstrated a significant correlation (R = 0.80, p = 0.006). In conclusion, 3.0-Tesla MRI, a reproducible noninvasive method to assess human coronary artery vessel wall distensibility, is able to detect significant differences in distensibility between healthy subjects and those with CAD.

Aims Wall shear stress (WSS) may induce local remodeling of the vascular wall and the WSS pattern in turn depends on vascular geometry. We aimed to elucidate the impact of side-branches on local WSS. Methods and results Steady numerical flow simulation studies were performed in three-dimensional reconstructed right coronary artery (RCA) trees. RCA from seven controls, five patients with coronary artery disease (CAD) and five patients with aneurysmatic CAD (AnCAD) classified by expert visual diagnosis were studied. Then three transient flow simulations were performed with cases representative for each group in order to evaluate the impact of pulsatile flow simulation. As vascular size and flow rates vary considerably between patients, non-dimensional approaches were applied for group comparison. A point-to-point comparison of the WSS in the same tree with and without side-branches revealed local differences in WSS of up to 12.0Pa. This was caused by a reduction of volume flow of up to 78.7% in the trunk. Differences are not only limited to bifurcation sites but also affect local narrowings and strongly curved segments. The point-to-point comparison of steady and transient simulations found an average increase of WSS of below 7% in transient simulations. No significant differences were found between histograms of pulsatile and steady simulations, showing a high cross-correlation of >0.97. Conclusion Side-branches must not be neglected in numerical flow simulation (steady and transient) studies. Steady simulations are valid for an assessment of time-averaged WSS distributions.

Methods Clinical data and DCMR results were analyzed in patients with peripheral arterial disease undergoing DCMR between 2000 and 2004. Peripheral arterial disease was defined as significant stenosis or occlusion of peripheral arteries of the lower and upper extremity or of the carotid artery. After an average of 35 ± 17 months, 140 patients (median age, 65 years) were contacted and medical records were reviewed. Wall motion abnormalities (WMA) at rest and the presence of stress-induced WMA (ischemia) were assessed for each patient. Cardiac events, defined as cardiac death and non-fatal myocardial infarction, were assessed.

BACKGROUND We aimed to test whether stenotic microvasculopathy affects the more beneficial course in female cardiac transplant recipients. METHODS We studied 873 patients (35/151 premenopausal women aged < or =40 years) who underwent primary heart transplantation. In 7750 biopsies harvested within the first posttransplant year endothelial disease and stenotic microvasculopathy were evaluated by light microscopy (Hematoxylin and Eosin). Kaplan-Meier and Cox regression analyses were performed for major cardiac events (MACE; lethal myocardial infarction, sudden cardiac death, graft failure, and cardiac retransplantation). RESULTS Stenotic microvasculopathy was found equally in men (38%) and women (39%). Allografts from premenopausal female-to-male transplants more frequently developed endothelial disease (78% vs. 65%; P=0.021) and stenotic microvasculopathy (46% vs. 28%, P=0.024). Beyond the first 5 posttransplant years women presented MACE less often than men, independently of donor gender and stenotic microvasculopathy (P=0.0001). Multivariate regression analysis found women to be at lower risk for MACE (Relative Risk [RR] 0.38; 95% Confidence Interval [CI] 0.17-0.81), whereas stenotic microvasculopathy (RR 2.15; 95% CI 1.42-3.26) and treated diabetes (RR 1.65; 95% CI 1.08-2.52) indicated a higher risk for MACE. CONCLUSIONS Stenotic microvasculopathy has prognostic impact on survival of male and female cardiac recipients; however, it does not affect the more beneficial course of women in the long-term follow-up.

We tested if Quilty (endocardial infiltration of lymphocytes) in routinely processed endomyocardial biopsy is associated with poor outcome after heart transplantation (HTx). Biopsies (n=9829) harvested within the first post-transplant year from 938 patients (778 men, mean age 49 years) were evaluated for Quilty and acute cellular rejection (according to the International Society for Heart and Lung Transplantation, ISHLT, classification). Transplant vasculopathy was evaluated by coronary angiography, and severe stenosis was found in 19% of patients. Survival was tested by Kaplan-Meier and Cox regression analyses for all-cause mortality and major cardiac events (lethal acute cellular rejection, graft loss or myocardial infarction). We found 1840 (19%) Quilty-positive biopsies in 487 Quilty-positive patients (52%). Quilty was more prevalent in women (p=0.038) and younger men (p=0.001), and was correlated with ISHLT grade 1R (OR 1.45, 95% CI 1.36-1.55; p0.001) and ISHLT grade 2R (OR 2.48, 95% CI 2.21-3.41; p0.001). Quilty in any biopsy was associated with a higher all-cause mortality (log rank p=0.045) due to a higher risk for major cardiac event (p=0.0001). Multivariate regression analysis showed Quilty (RR 1.69, 95%CI 1.05-2.73) and transplant vasculopathy (RR 2.78, 95%CI 1.68-4.61) as risk factors for major cardiac events and treated hyperlipidemia as lowering the risk for major cardiac events (RR 0.47, 95%CI 0.28-0.77). Quilty is associated with graft loss and poor outcome post HTx. Index biopsy during the first post-transplant year is a useful tool to identify patients at risk and is recommended during routine post-transplant management.

Background Local wall shear stress (WSS) has an impact on local remodelling of the vessel wall. WSS in turn strongly depends on local geometry. Our aim was to characterize patterns of local wall shear stress associated with distinct types of remodelling in coronary arteries. Vessel size and flow rates are different between patients, however. To compare distribution patterns of WSS in analogy to fluid-dynamic modelling, non-dimensional WSS/area functions are calculated. Methods Right coronary arteries from seven controls, five patients with coronary artery disease (CAD) and five patients with aneurysmatic CAD (AnCAD) were analyzed. Flow simulations were performed in three-dimensionally reconstructed coronary vessels from biplane angiographic projections. Local WSS was normalized as percentage of maximum value in a histogram (100 classes) and corresponding area was expressed as percentage of total area. Results The normalized WSS distribution was characterized by a single peak with a large lower tie in controls, a loss of the single peak and a stochastic distribution in AnCAD and a narrowing of the lower tie in CAD. Correct classification of 16/17 coronary arteries was feasible by Fisher's discriminant functions based on median WSS, mean diameter, percentage of area with WSS ≤0.4Pa and with WSS ≥15Pa. Conclusion Normalized WSS distribution might be an efficient tool in comparing wall shear stress between different patient groups. Whether normalized WSS distribution curves are apt to grade severity of disease remains to be investigated.

The impact of Quilty (sub-endocardial infiltration of lymphocytes) on the development of stenotic microvasculopathy and outcome after heart transplantation has not yet been evaluated.Biopsies (n = 9,713) obtained within the first post-transplant year from 873 patients (722 men, age 49.3 +/- 0.3 years) were evaluated by light microscopy (hematoxylin-eosin) for Quilty and cellular rejection (ISHLT), stenotic microvasculopathy (luminal radius:medial thickness ratio1) and endothelial disease (core diameter:cell diameter ratioor =1). Risk factors for stenotic microvasculopathy were analyzed by logistic regression. Overall survival and freedom from graft failure (cardiac re-transplantation, myocardial infarction and sudden cardiac death) were estimated by the Kaplan-Meier method and tested using a Cox proportional hazard model.We found 1,830 (19%) Quilty-positive biopsies in 481 (55%) Quilty-formers and stenotic microvasculopathy in 866 (9%) biopsies of 379 (43%) patients. Evidence of Quilty (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.26 to 2.57) and endothelial disease (OR 4.98; 95% 95% CI 3.31 to 7.49) indicated higher risk, whereas post-transplant statin therapy was associated with lower risk for stenotic microvasculopathy (OR 0.68; 95% CI 0.48 to 0.97). Freedom from graft failure was lower in Quilty-formers (p = 0.0060) and even worse if patients suffered from both Quilty and stenotic microvasculopathy (p = 0.0017). Both factors were confirmed in multivariate regression analysis (stenotic microvasculopathy risk ratio [RR] 1.90, 95% CI 1.23 to 2.95; Quilty RR 1.77, 95% CI 1.11 to 2.82, p = 0.0430).Presence of Quilty indicates increased risk for stenotic microvasculopathy in biopsy early after heart transplantation. Both are associated with poor outcome due to graft failure.

The study tested the prevalence of graft vessel disease (GVD) in 54 paediatric heart transplant (HTx) patients (32 male, age 0-17 years) who underwent coronary angiographic investigations (N=117). These were evaluated according to the Stanford classification and additional criteria (peripheral obliterations, diameter fluctuations, pathologic tapering) were applied for risk assessment (no GVD/minimal lesions, GVD without Stanford lesions, accelerated GVD). In H&E stainings from right ventricular endomyocardial biopsies (EMB=169) diagnosis of acute cellular rejection (ACR, ISHLT) and microvasculopathy were performed. Mild rejection was found in 43% (N=44) and severe rejection in 7% (N=7) of EMB early (1st year) and mild rejection in 31% (N=32) and severe in 8% (N=9) late (>3 years) after HTx. Microvasculopathy was present in 22% of EMB. Risk assessment of coronary angiographies showed no GVD/minimal disease in 25% (N=29), GVD without Stanford lesions in 12% (N=14) and different grades of accelerated GVD in 74% (N=74) of studies. All patients dying due to cardiac related causes of death (N=6, 3-12 years after HTx) had evidence of GVD. The data show GVD to be an important cause of late cardiac related deaths in this population.

Background Transplant vasculopathy is a long-term complication of cardiac transplantation. Percutaneous transluminal coronary angioplasty (PCI) is a method of choice for local revascularization that is also increasingly used in heart transplant patients. Methods Between October 1989 and November 2006, 160 adult cardiac transplant recipients (19 women) with mean age at heart transplantation of 47 ± 12 years underwent PCI in 502 coronary segments during 319 catheterizations (balloon only, 209; bare metal stents, 227, drug-eluting stents, 66). Concomitant medical therapy, procedural data, primary success, recurrence of stenosis, and cardiac events (cardiac death or repeat transplantation) were analyzed retrospectively. Multivariate Cox proportional hazards analysis was performed. Results Stents reduced early and mid-term recurrence of stenosis but had no impact on graft survival. Drug-eluting stents did not improve the restenosis rate. Immunosuppression with mycophenolate mofetil and concomitant treatment with statins and clopidogrel were significantly associated with reduced recurrence of stenosis and prolonged graft survival. Low steroid dosage was associated with a positive impact on graft survival. Conclusions Stenting in heart transplant patients has no impact on graft survival despite high primary success and deferred recurrence of stenosis. Early reduction of steroids, immunosuppression by mycophenolate mofetil, and concomitant treatment with statins are likely to reduce recurrent stenosis and to improve graft survival in heart transplant patients needing PCI. Long-term treatment with clopidogrel deserves further assessment.