Hepatocyte growth factor as indicator for subclinical atherosclerosis.

Background: Hepatocyte growth factor (HGF) is a pleiotropic cytokine mainly produced by mesenchymal cells. After endothelial damage by oxidized low-density lipoprotein (LDL), HGF is produced and released into the circulation in response. Due to this mechanism HGF has been proposed as possible clinical biomarker for clinical as well as subclinical atherosclerosis. Patients and methods: The conducted study is an observational, single centre, cohort study, including 171 patients with at least one cardiovascular risk factor or already established cardiovascular disease (CVD). Each patient underwent 3D plaque volumetry of the carotid and femoral arteries as well as physical examination and record of the medical history. Additionally, plasma HGF and further laboratory parameters like high sensitivity C-reactive protein and LDL-cholesterol were determined. Results: 169 patients were available for statistical analysis. In bivariate correlation, HGF showed a highly significant correlation with total plaque volume (TPV, r=0.48; p<0.001). In receiver operating characteristic (ROC) analysis for high TPV, HGF showed an area under the curve (AUC) of 0.68 (CI 95%: 0.59-0.77, p<0.001) with a sensitivity of 78% and a specificity of 52% to predict high TPV at a cut-off of 959 ng/ml. In the ROC-analysis for the presence of CVD, HGF demonstrated an AUC of 0.65 (95% CI 0.55-0.73; p=0.01) with a sensitivity of 77% and a specificity of 52%. Conclusions: Higher plasma levels of HGF are associated with higher atherosclerotic plaque volume as measured by 3D-ultrasound.

Addendum to the German Consensus Recommendations on Ponatinib in the Treatment of Chronic Myeloid Leukemia.

BACKGROUND: Based on the new data from the primary analysis of the OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial on dose optimization of ponatinib in patients with chronic phase (CP)-CML, the German consensus paper on ponatinib published in 2020 (Saussele S et al., Acta Haematol. 2020) has been updated in this addendum. SUMMARY: Focus is on the update of efficacy and safety of ponatinib, reflecting the new data set, as well as the update of the benefit-risk assessment and recommendations for ponatinib starting dose in CP-CML - provided that the decision to use ponatinib has already been made. Furthermore, based on OPTIC and additional empirical data, the expert panel collaborated to develop a decision tree for ponatinib dosing, specifically for intolerant and resistant patients. The recommendations on cardiovascular management have also been updated based on the most recent 2021 guidelines of the European Society of Cardiology (ESC) on cardiovascular disease prevention in clinical practice. KEY MESSAGES: The OPTIC data confirm the high efficacy of ponatinib in patients with CP-CML and provide the basis for individualized dose adjustment during the course of treatment.

Increasing Soluble P-Selectin Levels Predict Higher Peripheral Atherosclerotic Plaque Progression.

BACKGROUND AND AIMS: The adhesion molecule P-selectin is expressed by endothelial cells and platelets. It is involved in platelet activation and leukocyte adhesion, both important processes in the pathogenesis of atherosclerosis. Our study was designed to assess the predictive value of soluble P-selectin (sP-selectin) on the progression of peripheral atherosclerosis. METHODS: This is an observational, single-center, cohort study that included 443 patients with established cardiovascular disease (CVD) or at least one cardiovascular risk factor. Over a period of 4 years, each patient underwent three-dimensional (3D) ultrasound to assess the plaque volume of the carotid and femoral arteries once per year. In addition, plasma sP-selectin levels were measured at each visit. The association between changes in sP-selectin and peripheral atherosclerotic plaque progression was assessed using growth curve models. RESULTS: 338 patients were available for statistical analysis. Each standard deviation increase in sP-selectin was significantly (p < 0.001) associated with a 46.09 mm3 higher plaque volume. In ROC-analysis, changes in sP-selectin over time showed an optimal cut-off value around Δ 0.0 µg/mL sP-selectin and significantly improved the predictive value of the ESC-SCORE (AUC for the combination of both parameters was 0.75 (95% CI 0.68-0.81, p < 0.001). Patients with increasing sP-selectin showed a significantly higher plaque progression compared to patients with decreasing or stable sP-selectin levels (202 mm3 vs. 110 mm3, p < 0.001). CONCLUSIONS: Increasing sP-selectin levels can predict higher atherosclerotic plaque progression as measured by 3D ultrasound. We suggest serial measurements of sP-selectin as an easily measurable biomarker for peripheral atherosclerotic plaque progression.

The angiogenic neuropeptide catestatin exerts beneficial effects on human coronary vascular cells and cardiomyocytes.

INTRODUCTION: Myocardial infarction (MI) induces irreversible tissue damage, eventually leading to heart failure. Exogenous induction of angiogenesis positively influences ventricular remodeling after MI. Recently, we could show that therapeutic angiogenesis by the neuropeptide catestatin (CST) restores perfusion in the mouse hind limb ischemia model by the induction of angio-, arterio- and vasculogenesis. Thus, we assumed that CST might exert beneficial effects on cardiac cells. METHODS/RESULTS: To test the effect of CST on cardiac angiogenesis in-vitro matrigel assays with human coronary artery endothelial cells (HCAEC) were performed. CST significantly mediated capillary like tube formation comparable to vascular endothelial growth factor (VEGF), which was used as positive control. Interestingly, blockade of bFGF resulted in abrogation of observed effects. Moreover, CST induced proliferation of HCAEC and human coronary artery smooth muscle cells (HCASMC) as determined by BrdU-incorporation. Similar to the matrigel assay blockade of bFGF attenuated the effect. Consistent with these findings western blot assays revealed a bFGF-dependent phosphorylation of extracellular-signal regulated kinase (ERK) 1/2 by CST in these cell lines. Finally, CST protected human cardiomyocytes in-vitro from apoptosis. CONCLUSION: CST might qualify as potential candidate for therapeutic angiogenesis in MI.

Inverse Correlation of Cholesterol Efflux Capacity with Peripheral Plaque Volume Measured by 3D Ultrasound.

INTRODUCTION: Cardiovascular disease (CVD) is a systemic multifocal illness called atherosclerosis that causes artery constriction and blockage. By causing cholesterol to build up in the artery wall, hypercholesterolemia is a major factor in the pathophysiology of atherosclerotic plaque development. Reverse cholesterol transport is the process of transporting cholesterol from the periphery back to the liver through cholesterol efflux mediated by high-density lipoprotein (HDL). It was suggested that the cholesterol efflux capacity (CEC), which is inversely linked with cardiovascular risk, can serve as a stand-in measure for reverse cholesterol transport. In this work, we sought to investigate a potential link between the peripheral plaque volume (PV) and CEC. METHODS: Since lipid-lowering therapy interferes with CEC, we performed a cross-sectional study of 176 patients (48.9% females) with one cardiovascular risk factor or known CVD that did not currently take lipid-lowering medication. CEC was determined using cAMP-treated 3H-cholesterol-labeled J774 cells. Cholesterol ester transfer protein (CETP)-mediated cholesterol ester transfer was measured by quantifying the transfer of cholesterol ester from radiolabeled exogenous HDL cholesterol to Apolipoprotein B-containing lipoproteins. PV in the carotid and the femoral artery, defined as the total PV, was measured using a 3D ultrasound system equipped with semi-automatic software. RESULTS: In our patients, we discovered an inverse relationship between high total PV and CEC (p = 0.027). However, there was no connection between total PV and low-density lipoprotein cholesterol, lipoprotein (a), or CETP-mediated cholesterol ester transfer. CONCLUSION: In patients not receiving lipid-lowering treatment, CEC inversely correlates with peripheral atherosclerosis, supporting its role in the pathophysiology of atherosclerosis.

Smartwatch-derived heart rate variability: a head-to-head comparison with the gold standard in cardiovascular disease.

Aims: We aimed to investigate the concordance between heart rate variability (HRV) derived from the photoplethysmographic (PPG) signal of a commercially available smartwatch compared with the gold-standard high-resolution electrocardiogram (ECG)-derived HRV in patients with cardiovascular disease. Methods and results: We prospectively enrolled 104 survivors of acute ST-elevation myocardial infarction, 129 patients after an ischaemic stroke, and 30 controls. All subjects underwent simultaneous recording of a smartwatch (Garmin vivoactive 4; Garmin Ltd, Olathe, KS, USA)-derived PPG signal and a high-resolution (1000 Hz) ECG for 30 min under standardized conditions. HRV measures in time and frequency domain, non-linear measures, as well as deceleration capacity (DC) were calculated according to previously published technologies from both signals. Lin's concordance correlation coefficient (ρc) between smartwatch-derived and ECG-based HRV markers was used as a measure of diagnostic accuracy. A very high concordance within the whole study cohort was observed for the mean heart rate (ρc = 0.9998), standard deviation of the averages of normal-to-normal (NN) intervals in all 5min segments (SDANN; ρc = 0.9617), and very low frequency power (VLF power; ρc = 0.9613). In contrast, detrended fluctuation analysis (DF-α1; ρc = 0.5919) and the square mean root of the sum of squares of adjacent NN-interval differences (rMSSD; ρc = 0.6617) showed only moderate concordance. Conclusion: Smartwatch-derived HRV provides a practical alternative with excellent accuracy compared with ECG-based HRV for global markers and those characterizing lower frequency components. However, caution is warranted with HRV markers that predominantly assess short-term variability.

Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/ß receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/ß receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

Chest CT of Lung Injury 1 Year after COVID-19 Pneumonia: The CovILD Study.

Background The long-term pulmonary sequelae of COVID-19 is not well known. Purpose To characterize patterns and rates of improvement of chest CT abnormalities 1 year after COVID-19 pneumonia. Materials and Methods This was a secondary analysis of a prospective, multicenter observational cohort study conducted from April 29 to August 12, 2020, to assess pulmonary abnormalities at chest CT approximately 2, 3, and 6 months and 1 year after onset of COVID-19 symptoms. Pulmonary findings were graded for each lung lobe using a qualitative CT severity score (CTSS) ranging from 0 (normal) to 25 (all lobes involved). The association of demographic and clinical factors with CT abnormalities after 1 year was assessed with logistic regression. The rate of change of the CTSS at follow-up CT was investigated by using the Friedmann test. Results Of 142 enrolled participants, 91 underwent a 1-year follow-up CT examination and were included in the analysis (mean age, 59 years ± 13 [SD]; 35 women [38%]). In 49 of 91 (54%) participants, CT abnormalities were observed: 31 of 91 (34%) participants showed subtle subpleural reticulation, ground-glass opacities, or both, and 18 of 91 (20%) participants had extensive ground-glass opacities, reticulations, bronchial dilation, microcystic changes, or a combination thereof. At multivariable analysis, age of more than 60 years (odds ratio [OR], 5.8; 95% CI: 1.7, 24; P = .009), critical COVID-19 severity (OR, 29; 95% CI: 4.8, 280; P < .001), and male sex (OR, 8.9; 95% CI: 2.6, 36; P < .001) were associated with persistent CT abnormalities at 1-year follow-up. Reduction of CTSS was observed in participants at subsequent follow-up CT (P < .001); during the study period, 49% (69 of 142) of participants had complete resolution of CT abnormalities. Thirty-one of 49 (63%) participants with CT abnormalities showed no further improvement after 6 months. Conclusion Long-term CT abnormalities were common 1 year after COVID-19 pneumonia. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Leung in this issue.

Effect of chronic kidney disease and sex on carotid and femoral plaque volume as measured by three-dimensional ultrasound.

INTRODUCTION: Previously, we reported the association between cardiovascular risk factors (CVRFs) and the presence of cardiovascular disease with peripheral atherosclerosis. In this paper, we specifically aimed to investigate the association of chronic kidney disease (CKD) and sex with carotid and femoral plaque volume. MATERIALS AND METHODS: 404 patients (median age 64; 57% men) with at least 1 CVRF or established cardiovascular disease where included into the study. 3D ultrasonography evaluated with an automated software was used to measure peripheral plaque volume. Statistical analyses were performed using SPSS Statistic. RESULTS: CKD was diagnosed in 56 patients (13.9%), with most patients in stage 3a. Total atherosclerotic plaque volume was significantly higher in patients with CKD (p < 0.001) compared to those without CKD and in men compared to women in all vascular territories (p < 0.001). CONCLUSION: Our data show that we need to be even more vigilant about the presence of atherosclerotic plaques and cardiovascular disease in these patients. Already in patients with CKD stage 3a, efficient CVRF reduction and intensive treatment is warranted.

Beneficial effects of multi-disciplinary rehabilitation in postacute COVID-19: an observational cohort study.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic increases the demand for postacute care in patients after a severe disease course. Various long-term sequelae are expected and rehabilitation medicine is challenged to support physical and cognitive recovery. AIM: We aimed to explore the dysfunctions and outcome of COVID-19 survivors after early postacute rehabilitation. DESIGN: Observational cohort study. METHODS: This study evaluated the postacute sequelae of patients hospitalized for SARS-CoV-2 infection and analyzed rehabilitative outcomes of a subgroup of patients included in the prospective observational multicenter CovILD study. RESULTS: A total of 23 subjects discharged after severe to critical COVID-19 infection underwent an individualized, multiprofessional rehabilitation. At the start of postacute rehabilitation, impairment of pulmonary function (87%), symptoms related to postintensive care syndrome, and neuropsychological dysfunction (85%) were frequently found, whereas cardiac function appeared to be largely unaffected. Of interest, multi-disciplinary rehabilitation resulted in a significant improvement in lung function, as reflected by an increase of forced vital capacity (P=0.007) and forced expiratory volume in one second (P=0.014), total lung capacity (P=0.003), and diffusion capacity for carbon monoxide (P=0.002). Accordingly, physical performance status significantly improved as reflected by a mean increase of six-minute walking distance by 176 (SD±137) meters. Contrarily, a considerable proportion of patients still had limited diffusion capacity (83%) or neurological symptoms including peripheral neuropathy at the end of rehabilitation. CONCLUSIONS: Individuals discharged after a severe course of COVID-19 frequently present with persisting physical and cognitive dysfunctions after hospital discharge. Those patients significantly benefit from multi-disciplinary inpatient rehabilitation. CLINICAL REHABILITATION IMPACT: Our data demonstrated the highly promising effects of early postacute rehabilitation in survivors of severe or critical COVID-19. This findings urge further prospective evaluations and may impact future treatment and rehabilitation strategies.

High baseline fetuin-A levels are associated with lower atherosclerotic plaque progression as measured by 3D ultrasound.

Background and aims: The glycoprotein fetuin-A has anti-inflammatory effects, increases insulin resistance and plays an important role in calcium metabolism. The aim of our study was to assess the predictive value of fetuin-A on atherosclerotic plaque progression in comparison to the established cardiovascular biomarker high sensitivity C-reactive protein (hsCRP). Methods: In this prospective, single center-, cohort study, we included 194 patients with at least one cardiovascular risk factor or established cardiovascular disease (CVD). Over a period of 4 years, each patient underwent 3D plaque volumetry of the carotid and femoral arteries on a yearly basis. To evaluate the predictive value of biomarkers in terms of plaque progression, the baseline values of fetuin-A and hsCRP were correlated with the plaque progression from baseline to the last follow up visit. Results: 171 patients were included in the final analysis. Baseline fetuin-A levels showed a significant negative correlation with plaque progression (r = -0.244; p = 0.001). In contrast, baseline hsCRP levels showed no correlation with plaque progression (r = 0.096, p = 0.20). In the ROC-analysis, fetuin-A had a significantly better predictive value than hsCRP (fetuin-A AUC 0.67; p = 0.001 vs hsCRP AUC 0.49; p = 0.88) with an optimal cut-off value at 712 µg/ml. In patients with high fetuin A levels (>712 µg/ml), a significantly lower plaque progression was observed compared to the group with low fetuin-A levels <712 µg/ml (high fetuin-A 197 mm3 vs. low fetuin-A 279 mm3; p = 0.01). Conclusions: Higher fetuin-A levels appear to predict lower atherosclerotic plaque progression in patients with or at risk of cardiovascular disease.

Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial.

BACKGROUND: After the 2002/2003 severe acute respiratory syndrome outbreak, 30% of survivors exhibited persisting structural pulmonary abnormalities. The long-term pulmonary sequelae of coronavirus disease 2019 (COVID-19) are yet unknown, and comprehensive clinical follow-up data are lacking. METHODS: In this prospective, multicentre, observational study, we systematically evaluated the cardiopulmonary damage in subjects recovering from COVID-19 at 60 and 100 days after confirmed diagnosis. We conducted a detailed questionnaire, clinical examination, laboratory testing, lung function analysis, echocardiography and thoracic low-dose computed tomography (CT). RESULTS: Data from 145 COVID-19 patients were evaluated, and 41% of all subjects exhibited persistent symptoms 100 days after COVID-19 onset, with dyspnoea being most frequent (36%). Accordingly, patients still displayed an impaired lung function, with a reduced diffusing capacity in 21% of the cohort being the most prominent finding. Cardiac impairment, including a reduced left ventricular function or signs of pulmonary hypertension, was only present in a minority of subjects. CT scans unveiled persisting lung pathologies in 63% of patients, mainly consisting of bilateral ground-glass opacities and/or reticulation in the lower lung lobes, without radiological signs of pulmonary fibrosis. Sequential follow-up evaluations at 60 and 100 days after COVID-19 onset demonstrated a vast improvement of symptoms and CT abnormalities over time. CONCLUSION: A relevant percentage of post-COVID-19 patients presented with persisting symptoms and lung function impairment along with radiological pulmonary abnormalities >100 days after the diagnosis of COVID-19. However, our results indicate a significant improvement in symptoms and cardiopulmonary status over time.

Association of Food and Alcohol Consumption with Peripheral Atherosclerotic Plaque Volume as Measured by 3D-Ultrasound.

BACKGROUND: Food patterns and alcohol consumption influence the risk for cardiovascular diseases (CVD) and a healthy nutrition is essential for the prevention of CVD. The aim of this study was to determine the influence of nutrition and alcohol consumption on peripheral atherosclerotic plaque volume (PV) using an innovative 3D ultrasound approach. METHODS: In this prospective, single centre study we included 342 patients with at least one cardiovascular risk factor or established CVD. PV in the carotid and femoral artery was measured using a semi-automatic software. Information on food and alcohol consumption of the participants was collected using an internationally acknowledged standardized questionnaire (DEGS1). RESULTS: Patients with low total PV consumed significantly more vegetables (p = 0.004) and vegetable juice (p = 0.019) per week compared to patients with high total PV. In contrast, patients with high total PV reported a higher alcohol consumption compared to patients with low total PV (p = 0.026). Patients without vascular disease, in particular cerebrovascular disease (p = 0.001) and peripheral arterial disease (p = 0.012), reported a significantly higher fish consumption per week. In the multivariate model, we found a significant negative association for vegetable consumption (p = 0.034) and female gender (p = 0.018) but a significant positive association for alcohol (p = 0.001), age (p < 0.001) the presence of vascular disease (p < 0.001) and cardiovascular risk factors (p < 0.001) with total PV. CONCLUSION: In this study we were able to show an association of food and alcohol consumption with peripheral atherosclerotic PV measured by 3D-ultrasonography. Following a healthy nutritional lifestyle (vegetable consumption, no excessive alcohol consumption) and regular fish consumption appears to be associated with less peripheral atherosclerosis and decreased prevalence of vascular diseases, respectively.

NGAL Correlates with Femoral and Carotid Plaque Volume Assessed by Sonographic 3D Plaque Volumetry.

BACKGROUND/OBJECTIVES: Inflammation represents a cornerstone in the development of atherosclerosis and early detection is essential to avoid cardiovascular events. Biomarkers like interleukin-1 beta, interleukin-6, or high sensitivity CRP (hs-CRP) have been investigated intensively in this field. Since they have several limitations, additional biomarkers are needed for cardiovascular risk stratification. The acute phase protein, neutrophil gelatinase-associated lipocalin (NGAL), modulates inflammation and is elevated in cardiovascular disease (CVD). Moreover, it contributes to plaque destabilization. METHODS: In this prospective, single-center study, we included 323 asymptomatic patients with at least one cardiovascular risk factor or established CVD. NGAL levels were measured in plasma samples using a commercially available ELISA. Carotid, femoral, and total atherosclerotic plaque volumes (PV) were measured using a 3D ultrasound system (Philips iU22). Patients were separated into a low (n = 243) and high (n = 80) total PV group. RESULTS: NGAL was significantly higher in patients with high total PV versus patients with low total PV. The NGAL amplitude for the prediction of high total PV was significantly higher when compared with hs-CRP. A high predictive value could also be observed for patients without established CVD. CONCLUSION: NGAL seems to be a promising biomarker for the identification of asymptomatic patients with atherosclerotic disease.

Early onset of menopause is associated with increased peripheral atherosclerotic plaque volume and progression.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is the leading cause of death in western countries. One risk factor unique to women is the menopausal status. The aim of this study was to analyse the influence of the onset of menopause (MP) on the extent and progression of atherosclerotic plaque volume (PV). METHODS: Postmenopausal women with at least one cardiovascular risk factor (CVRF) but without established CVD were included. Quantification of PV was performed in peripheral arteries using a three - dimensional (3D) ultrasound (US) technique. Follow-up examination to assess PV progression was performed after 19 (±8) months. RESULTS: 110 consecutive postmenopausal women (mean age 65.5) were included. Females with an earlier onset of MP (<45 years) had a significantly higher PV than those with an intermediate (45-52 years) or later onset of menopause (>52 years), irrespective of other CVRF (244 mm³ vs. 193 mm³ vs. 73 mm³, respectively, p = 0.023). In addition, women with an earlier onset of MP had a higher PV progression compared to women with an intermediate or late onset (40 mm³ vs. 35 mm³ vs. 8.5 mm³; p = 0.002, respectively). Moreover, these results were confirmed in multivariate regression, where only onset of MP (OR 0.88; 95%CI 0.81-0.96; p = 0.004) and age (OR 1.06; 95%CI 1.08-1.13; p = 0.025) were significant predictors for a higher atherosclerotic progression. CONCLUSIONS: An earlier onset of MP was associated with an increase in atherosclerotic PV and accelerated progression, independent of other CVRF.

miR-19a-3p containing exosomes improve function of ischaemic myocardium upon shock wave therapy.

AIMS: As many current approaches for heart regeneration exert unfavourable side effects, the induction of endogenous repair mechanisms in ischaemic heart disease is of particular interest. Recently, exosomes carrying angiogenic miRNAs have been described to improve heart function. However, it remains challenging to stimulate specific release of reparative exosomes in ischaemic myocardium. In the present study, we sought to test the hypothesis that the physical stimulus of shock wave therapy (SWT) causes the release of exosomes. We aimed to substantiate the pro-angiogenic impact of the released factors, to identify the nature of their cargo, and to test their efficacy in vivo supporting regeneration and recovery after myocardial ischaemia. METHODS AND RESULTS: Mechanical stimulation of ischaemic muscle via SWT caused extracellular vesicle (EV) release from endothelial cells both in vitro and in vivo. Characterization of EVs via electron microscopy, nanoparticle tracking analysis and flow cytometry revealed specific exosome morphology and size with the presence of exosome markers CD9, CD81, and CD63. Exosomes exhibited angiogenic properties activating protein kinase b (Akt) and extracellular-signal regulated kinase (ERK) resulting in enhanced endothelial tube formation and proliferation. A miRNA array and transcriptome analysis via next-generation sequencing were performed to specify exosome content. miR-19a-3p was identified as responsible cargo, antimir-19a-3p antagonized angiogenic exosome effects. Exosomes and target miRNA were injected intramyocardially in mice after left anterior descending artery ligation. Exosomes resulted in improved vascularization, decreased myocardial fibrosis, and increased left ventricular ejection fraction as shown by transthoracic echocardiography. CONCLUSION: The mechanical stimulus of SWT causes release of angiogenic exosomes. miR-19a-3p is the vesicular cargo responsible for the observed effects. Released exosomes induce angiogenesis, decrease myocardial fibrosis, and improve left ventricular function after myocardial ischaemia. Exosome release via SWT could develop an innovative approach for the regeneration of ischaemic myocardium.

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management.

Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib's safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit-risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib's efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.

Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix.

Background Mechanical stimulation of acute ischemic myocardium by shock wave therapy ( SWT ) is known to improve cardiac function by induction of angiogenesis. However, SWT in chronic heart failure is poorly understood. We aimed to study whether mechanical stimulation upon SWT improves heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis and to dissect underlying mechanisms. Methods and Results SWT was applied in a mouse model of chronic myocardial ischemia. To study effects of SWT on postnatal vasculogenesis, wild-type mice received bone marrow transplantation from green fluorescence protein donor mice. Underlying mechanisms were elucidated in vitro in endothelial cells and murine aortic rings. Echocardiography and pressure/volume measurements revealed improved left ventricular ejection fraction, myocardial contractility, and diastolic function and decreased myocardial fibrosis after treatment. Concomitantly, numbers of capillaries and arterioles were increased. SWT resulted in enhanced expression of the chemoattractant stromal cell-derived factor 1 in ischemic myocardium and serum. Treatment induced recruitment of bone marrow-derived endothelial cells to the site of injury. In vitro, SWT resulted in endothelial cell proliferation, enhanced survival, and capillary sprouting. The effects were vascular endothelial growth factor receptor 2 and heparan sulfate proteoglycan dependent. Conclusions SWT positively affects heart function in chronic ischemic heart failure by induction of angiogenesis and postnatal vasculogenesis. SWT upregulated pivotal angiogenic and vasculogenic factors in the myocardium in vivo and induced proliferative and anti-apoptotic effects on endothelial cells in vitro. Mechanistically, these effects depend on vascular endothelial growth factor signaling and heparan sulfate proteoglycans. SWT is a promising treatment option for regeneration of ischemic myocardium.

Gene therapy with the angiogenic neuropeptide secretoneurin ameliorates experimental diabetic neuropathy.

The pathogenesis of diabetic neuropathy remains enigmatic. Damage to the vasa nervorum may be responsible for this disorder. Recently, we showed that secretoneurin (SN) induces angiogenesis in hindlimb and myocardial ischemia. Moreover, beneficial effects were observed in wound healing. We therefore hypothesized that SN therapy may ameliorate diabetic neuropathy. We used db/db mice as animal model for neuropathy. Gene therapy was accomplished by intramuscular injection of SN plasmid along the sciatic nerve. Sciatic nerve motor and sensory conduction velocities were then measured for 9 wk. Nerve conduction velocities showed normal values in heterozygous mice for the observational period, but were severely reduced in homozygous mice in which velocities were significantly improved by SN, but not by control plasmid gene therapy. The reaction time in the tail-flick test improved significantly in SN-treated animals. The induction of growth of vasa nervorum seems to be part of the underlying mechanism. In addition, SN positively affected Schwann cell function in vitro and induced activation of important signaling pathways. Our observations suggest that SN exerts beneficial effects on nerve function in vivo and on Schwann cells in vitro. It therefore may be a promising treatment option for diabetic neuropathy.-Theurl, M., Lener, D., Albrecht-Schgoer, K., Beer, A., Schgoer, W., Liu, Y., Stanzl, U., Fischer-Colbrie, R., Kirchmair, R. Gene therapy with the angiogenic neuropeptide secretoneurin ameliorates experimental diabetic neuropathy.