Estimation of central blood pressure waveform from femoral blood pressure waveform by blind sources separation.

Background: Central blood pressure (cBP) is a better indicator of cardiovascular morbidity and mortality than peripheral BP (pBP). However, direct cBP measurement requires invasive techniques and indirect cBP measurement is based on rigid and empirical transfer functions applied to pBP. Thus, development of a personalized and well-validated method for non-invasive derivation of cBP from pBP is necessary to facilitate the clinical routine. The purpose of the present study was to develop a novel blind source separation tool to separate a single recording of pBP into their pressure waveforms composing its dynamics, to identify the compounds that lead to pressure waveform distortion at the periphery, and to estimate the cBP. The approach is patient-specific and extracts the underlying blind pressure waveforms in pBP without additional brachial cuff calibration or any a priori assumption on the arterial model. Methods: The intra-arterial femoral BPfe and intra-aortic pressure BPao were anonymized digital recordings from previous routine cardiac catheterizations of eight patients at the German Heart Centre Berlin. The underlying pressure waveforms in BPfe were extracted by the single-channel independent component analysis (SCICA). The accuracy of the SCICA model to estimate the whole cBP waveform was evaluated by the mean absolute error (MAE), the root mean square error (RMSE), the relative RMSE (RRMSE), and the intraclass correlation coefficient (ICC). The agreement between the intra-aortic and estimated parameters including systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), and pulse pressure (PP) was evaluated by the regression and Bland-Altman analyses. Results: The SCICA tool estimated the cBP waveform non-invasively from the intra-arterial BPfe with an MAE of 0.159 ± 1.629, an RMSE of 5.153 ± 0.957 mmHg, an RRMSE of 5.424 ± 1.304%, and an ICC of 0.94, as well as two waveforms contributing to morphological distortion at the femoral artery. The regression analysis showed a strong linear trend between the estimated and intra-aortic SBP, DBP, MAP, and PP with high coefficient of determination R2 of 0.98, 0.99, 0.99, and 0.97 respectively. The Bland-Altman plots demonstrated good agreement between estimated and intra-aortic parameters with a mean error and a standard deviation of difference of -0.54 ± 2.42 mmHg [95% confidence interval (CI): -5.28 to 4.20] for SBP, -1.97 ± 1.62 mmHg (95% CI: -5.14 to 1.20) for DBP, -1.49 ± 1.40 mmHg (95% CI: -4.25 to 1.26) for MAP, and 1.43 ± 2.79 mmHg (95% CI: -4.03 to 6.90) for PP. Conclusions: The SCICA approach is a powerful tool that identifies sources contributing to morphological distortion at peripheral arteries and estimates cBP.

Real-World and Regulatory Perspectives of Artificial Intelligence in Cardiovascular Imaging.

Recent progress in digital health data recording, advances in computing power, and methodological approaches that extract information from data as artificial intelligence are expected to have a disruptive impact on technology in medicine. One of the potential benefits is the ability to extract new and essential insights from the vast amount of data generated during health care delivery every day. Cardiovascular imaging is boosted by new intelligent automatic methods to manage, process, segment, and analyze petabytes of image data exceeding historical manual capacities. Algorithms that learn from data raise new challenges for regulatory bodies. Partially autonomous behavior and adaptive modifications and a lack of transparency in deriving evidence from complex data pose considerable problems. Controlling new technologies requires new controlling techniques and ongoing regulatory research. All stakeholders must participate in the quest to find a fair balance between innovation and regulation. The regulatory approach to artificial intelligence must be risk-based and resilient. A focus on unknown emerging risks demands continuous surveillance and clinical evaluation during the total product life cycle. Since learning algorithms are data-driven, high-quality data is fundamental for good machine learning practice. Mining, processing, validation, governance, and data control must account for bias, error, inappropriate use, drifts, and shifts, particularly in real-world data. Regulators worldwide are tackling twenty-first century challenges raised by "learning" medical devices. Ethical concerns and regulatory approaches are presented. The paper concludes with a discussion on the future of responsible artificial intelligence.

Serelaxin Improves Regional Myocardial Function in Experimental Heart Failure: An In Vivo Cardiac Magnetic Resonance Study.

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 C57BL/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.

Pulmonary arterial remodelling by deficiency of peroxisome proliferator-activated receptor-γ in murine vascular smooth muscle cells occurs independently of obesity-related pulmonary hypertension.

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.

Inhibition of Src homology 2 domain-containing phosphatase 1 increases insulin sensitivity in high-fat diet-induced insulin-resistant mice.

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.

Clopidogrel pharmacokinetics and pharmacodynamics in out-of-hospital cardiac arrest patients with acute coronary syndrome undergoing target temperature management.

BACKGROUND: 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. PURPOSE: 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). METHODS: 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. RESULTS: Plasma concentration of clopidogrel and metabolites was lower in the TTM group after 2 and 4h, respectively (all p<0.005 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 p<0.05). Moreover, there was no significant difference in genotype and platelet function determined ex vivo at 33 or 37°C, respectively. CONCLUSION: 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.

Effects of Renal Denervation on Renal Artery Function in Humans: Preliminary Study.

AIM: To study the effects of RD on renal artery wall function non-invasively using magnetic resonance. METHODS AND RESULTS: 32 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. CONCLUSIONS: RD 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.

Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension.

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.

NT-proBNP and diastolic left ventricular function in patients with Marfan syndrome.

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 < 0.001), and aortic diameter (p < 0.001). The ratio of early diastolic mitral flow velocity (E) to early relaxation velocity in tissue Doppler (e'), E/e' (p < 0.001) was significantly higher in patients with Marfan syndrome than in controls, whereas e' (p < 0.001) and the ratio of E to inflow velocity during atrial contraction (A), E/A (p = 0.012) was significantly lower. Besides age and gender, diagnosis of MFS, diastolic function (e' and E/e'), Z-Score of aortic diameter, and left ventricular size were identified as significant independent parameters with impact on NT-proBNP levels. CONCLUSIONS: MFS patients presenting with normal ejection fraction show disturbed diastolic function and higher NT-proBNP levels, which is partly explained by aortic Z-score. Assessment of diastolic function and NT-proBNP levels may therefore detect early abnormalities and guide surveillance and prevention management of patients with MFS.

Enhanced insulin signaling in density-enhanced phosphatase-1 (DEP-1) knockout mice.

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.

Coronary CT angiography for the detection of coronary artery stenosis in patients referred for transcatheter aortic valve replacement.

BACKGROUND: Coronary CT has become the foremost noninvasive imaging modality for detecting coronary stenoses in patients with suspected coronary artery disease. Nevertheless, little is known about its performance in patients undergoing transcatheter aortic valve replacement (TAVR). OBJECTIVE: This study investigates the diagnostic performance of coronary CT angiography in patients referred for TAVR. METHODS: One hundred and fifteen consecutive patients with severe aortic stenosis underwent CT angiography with retrospective electrocardiography triggered acquisition and an iterative reconstruction algorithm, of whom 23 (20%) had prior coronary artery bypass graft (CABG) surgery. Diagnostic accuracy of CT for detecting significant coronary stenosis (≥ 50% luminal diameter stenosis in segments ≥ 2 mm) in the left main, proximal, or middle segments of coronary arteries and bypass grafts was compared with that of invasive coronary angiography. RESULTS: In the overall study population, the sensitivity, specificity, and positive and negative predictive value of CT angiography for the detection of coronary segment or bypass graft lesions were 96% (47 of 49), 73% (48 of 66), 72% (47 of 65), and 96% (48 of 50), respectively. The per-patient diagnostic yield of CT angiography was consistent among patients without prior CABG (93% [28 of 30], 73% [45 of 62], 62% [28 of 45], and 96% [45 of 47], respectively) and among patients with prior CABG (100% [19 of 19], 75% [3 of 4], 95% [19 of 20], and 100% [3 of 3], respectively). CONCLUSION: Among patients referred for TAVR, coronary CT angiography with retrospective gating and iterative reconstruction may allow detection of significant stenosis in the proximal or middle segments of coronary arteries and could permit the evaluation of patients after bypass grafts.

Incremental cost-effectiveness of dobutamine stress cardiac magnetic resonance imaging in patients at intermediate risk for coronary artery disease.

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.

Ischemic burden and clinical outcome: is one 'culprit' ischemic segment by dobutamine stress magnetic resonance predictive?

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 < 0.001) but similar to those with 2 and ≥ 3 ischemic segments (∼ 5.5% and ∼ 7%, p = NS). CONCLUSIONS: The presence of inducible ischemia even in a single 'culprit' myocardial segment during DCMR is enough to predict hard cardiac events in patients with known or suspected CAD.

Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension: data from a multi-centre cardiovascular magnetic resonance imaging trial.

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/m(1.7) vs. 43.0 ± 12.6 g/m(1.7), P < 0.001) without changes in the control group (41.9 ± 10.8 g/m(1.7) vs. 42.0 ± 9.7 g/m(1.7), P = 0.653). Ejection fraction (LVEF) in patients with impaired LVEF at baseline (<50%) significantly increased after RDN (43% vs. 50%, P < 0.001). Left ventricular circumferential strain as a surrogate of diastolic function in the subgroup of patients with reduced strain at baseline increased by 21% only in the RDN group (-14.8 vs. -17.9; P = 0.001) and not in control patients (-15.5 vs. -16.4, P = 0.508). CONCLUSIONS: Catheter-based RDN significantly reduced BP and LVMI and improved EF and circumferential strain in patients with resistant hypertension, occurring partly BP independently.

Proprotein convertase subtilisin/kexin type 3 promotes adipose tissue-driven macrophage chemotaxis and is increased in obesity.

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/m(2)) had higher furin, MT1-MMP, and resistin gene expression compared to normal weight individuals (BMI<25kg/m(2)) with significant correlations of BMI/furin and furin/MT1-MMP. In vitro, the adipocytokine resistin induced furin and MT1-MMP in mononuclear cells (MNCs), while MCP-1 had no effect. CONCLUSIONS: Acquisition of the inflammatory macrophage phenotype is characterized by an imbalance in serpinB8/furin, leading to MT1-MMP activation, thereby enhancing migration. Increases in MT1-MMP and furin are present in MNCs from obese patients. Dissecting the regulation of furin and its inhibitor serpinB8 should facilitate targeting inflammation/remodeling in cardiometabolic diseases.

Soluble P-selectin level correlates with acetylsalicylic acid but not with clopidogrel response in patients with stable coronary artery disease after a percutaneous coronary intervention.

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<0.001), LTA after stimulation with arachidonic acid (P<0.001), adenosine diphosphate (20 µmol/l, P=0.009), collagen (P<0.001), and ejection fraction (P=0.001). CONCLUSION: sP-selectin was decreased in patients receiving ASA but did not reflect a CYP2C19*2-defined clopidogrel response. This underlines that sP-selectin is a useful marker for ASA, but not for clopidogrel response, in stable coronary artery disease.

Non-HLA antibodies targeting vascular receptors enhance alloimmune response and microvasculopathy after heart transplantation.

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.