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Background: Calcific aortic stenosis is commonly treated using surgical or transcatheter aortic valve replacement; however, many patients are not considered suitable candidates for these interventions due to severe comorbidities and limited life expectancy. As such, non-invasive therapies might offer alternative therapeutic possibilities in these patients. This study aimed to assess the safety of non-invasive ultrasound therapy and its ability to improve valvular function by softening calcified valve tissue., Methods: This prospective, multicentre, single-arm series enrolled 40 adult patients with severe symptomatic aortic valve stenosis at three hospitals in France, the Netherlands, and Serbia between March 13, 2019, and May 8, 2022. Patients were treated with transthoracically delivered non-invasive ultrasound therapy. Follow-ups were scheduled at 1, 3, 6, 12, and 24 months. The primary endpoints were procedure-related deaths within 30 days and improved valve function. We report the 6-month data. This study is registered at ClinicalTrials.gov, NCT03779620 and NCT04665596., Findings: 40 high-risk patients with a mean Society of Thoracic Surgeons score of 5·6% (SD 4·4) and multiple severe comorbidities were included. The primary endpoint, procedure-related mortality, did not occur; furthermore, no life-threatening or cerebrovascular events were reported. Improved valve function was confirmed up to 6 months, reflected by a 10% increase in mean aortic valve area from 0·58 cm 2 (SD 0·19) at baseline to 0·64 cm 2 (0·21) at follow-up (p=0·0088), and a 7% decrease in mean pressure gradient from 41·9 mm Hg (20·1) to 38·8 mm Hg (17·8; p=0·024). At 6 months, the New York Heart Association score had improved or stabilised in 24 (96%) of 25 patients, and the mean Kansas City Cardiomyopathy Questionnaire score had improved by 33%, from 48·5 (SD 22·6) to 64·5 (21·0). One serious procedure-related adverse event occurred in a patient who presented with a transient decrease in peripheral oxygen saturation. Non-serious adverse events included pain, discomfort during treatment, and transient arrhythmias., Interpretation: This novel, non-invasive ultrasound therapy for calcified aortic stenosis proved to be safe and feasible., Funding: Cardiawave., Competing Interests: Declaration of interests EM, AI, DT-Z, EP, BC, JH, RK, MvG, DT, VM, and GG are investigators of the study. EM reports being a co-founder and scientific advisory board member of, and holding shares in Cardiawave. DT-Z reports honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Pfizer, Hemofarm, and Amicus Therapeutics; support to attend meetings from and participation in data safety monitoring and advisory boards for Boehringer Ingelheim; and being the President of the Echocardiographic Society of Serbia. MT and MP are co-founders of and hold shares in Cardiawave. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Backgrounds: Patients with type 2 diabetes mellitus (T2DM) are particularly at risk of developing major adverse cardiovascular events (MACE) and peripheral artery disease (PAD) due to an acceleration of the atherosclerotic process linked to hyperglycemia and inflammation with a greater risk of local complications. We aimed to identify the predictive factors for major adverse limb events (MALE) in T2DM patients with PAD to manage modifiable factors at an early stage., Methods: This is a prospective study in which T2DM patients with PAD were included from November 2017 to May 2018 and followed over 12 months. The predictive factors for the onset of MALE, MACE, and death from all causes have been identified., Results: A total of 100 patients were included; 37% of the patients developed a MALE. After multivariate analysis, metformin was associated with a decrease of MALE (odds ratio (OR) = 0.26; 95% confidence interval (CI) [0.10; 0.68]; P = 0.007), and a history of the treatment of intravenous iloprost was associated with an increased risk of MALE (OR = 5.70; 95% CI [1.31; 31.93]; P = 0.029). Regular physical activity was associated with a decreased risk of MACE (OR = 0.07; 95% CI [0; 0.44]; P = 0.021). A history of stroke and a history of venous thromboembolism were associated with an increased all-cause mortality risk with OR = 3.68; 95% CI [1.17; 11.5]; P = 0.025 and OR = 3.78; 95% CI [1.16; 12.3]; P = 0.027., Conclusions: Metformin is protective against local complications in people with diabetes with PAD and should be prescribed to diabetic patients with PAD at an early stage., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Tyrosine kinase inhibitors targeting the BCR-ABL1 oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 3rd generation tyrosine kinase inhibitor ponatinib is licensed for the treatment of chronic, accelerated or blast phase chronic myeloid leukaemia patients who are resistant to dasatinib or nilotinib; intolerant of dasatinib or nilotinib and for whom further treatment with imatinib is not clinically appropriate; or who express the T315I mutation. Ponatinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of ponatinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in ponatinib-treated patients., (Copyright © 2022 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objective: The aim of this study was to examine the external applicability of the COMPASS and the VOYAGER-PAD trials in patients with lower extremity artery disease (LEAD) in the real world., Methods: This was a multicentre retrospective analysis of prospectively collected COPART data, a French multicentre registry of patients hospitalised for symptomatic LEAD. The proportion of patients eligible for the combination of rivaroxaban 2.5 mg twice daily plus aspirin based on either COMPASS or VOYAGER-PAD criteria is reported. The one year cumulative incidence of outcomes between eligible and non-eligible patients, as well as eligible patients vs. control arms of the COMPASS (LEAD patient subgroup) and the VOYAGER-PAD trials were compared. Analyses were performed using Cox models., Results: Of 2 259 evaluable patients, only 679 (30.1%) were eligible for a low dose rivaroxaban plus aspirin regimen. Others were not eligible because of the need for anticoagulant (48.5% and 38.9% of patients meeting COMPASS and VOYAGER-PAD exclusion criteria, respectively) or dual antiplatelet therapy use (15.7% and 16.5%, respectively), high bleeding risk (14.4% and 11.6%, respectively), malignancy (26.1% and 21.0%, respectively), history of ischaemic/haemorrhagic stroke (21.1% and 19.8%, respectively), and severe renal failure (13.2% and 10.5%, respectively). COMPASS and VOYAGER-PAD eligible and ineligible patients were at higher risk of ischaemic events than participants in these trials. The one year cumulative incidences were 6.0% (95% CI 4.3 - 8.1) in the COMPASS eligible subset vs. 3.5% (95% CI 2.9 - 4.3) in the COMPASS control arm for major adverse cardiovascular events, and 27.9% (95% CI 19.9 - 38.3) in the VOYAGER-PAD eligible subset vs. 6.0% (95% CI 5.3 - 6.9) in the VOYAGER-PAD control arm for major adverse limb events., Conclusion: Many patients hospitalised for symptomatic LEAD in France are not eligible for the low dose rivaroxaban plus aspirin combination. In turn, those eligible may potentially have greater absolute benefit because of higher risk than those enrolled in the trials., (Copyright © 2021 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Aims: Pulsed cavitational ultrasound therapy (thombotripsy) allows the accurate fractionation of a distant thrombus. We aimed to evaluate the efficacy and safety of non-invasive thrombotripsy using a robotic assisted and high frequency ultrasound approach to recanalize proximal deep venous thrombosis (DVT) in a swine model., Methods: Occlusive thrombosis was obtained with a dual jugular and femoral endoveinous approach. The therapeutic device was composed of a 2.25 MHz focused transducer centered by a linear ultrasound probe, and a robotic arm. The feasibility, security, and efficacy (venous channel patency) assessment after thrombotripsy was performed on 13 pigs with acute occluded DVT. To assess the mid-term efficacy of this technique, 8 pigs were followed up for 14 days after thrombotripsy and compared with 8 control pigs. The primary efficacy endpoint was the venous patency. Safety was assessed by the search for local vessel wall injury and pulmonary embolism., Results: We succeeded in treating all pigs except two with no accessible femoral vein. After median treatment duration of 23 minutes of cavitation, all treated DVT were fully recanalized acutely. At 14 days, in the treated group, six of the eight pigs had a persistent patent vein and two pigs had a venous reocclusion. In the control group all pigs had a persistent venous occlusion. At sacrifice, no local vein nor arterial wall damage were observed as well as no evidence of pulmonary embolism in all pigs., Conclusion: High frequency thrombotripsy seems to be effective and safe for non-invasive venous recanalization of DVT., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Coronavirus disease-2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders., Objectives: To explore the coagulopathy and endothelial dysfunction in COVID-19 patients., Methods: The study analyzed clinical and biological profiles of patients with suspected COVID-19 infection at admission, including hemostasis tests and quantification of circulating endothelial cells (CECs)., Results: Among 96 consecutive COVID-19-suspected patients fulfilling criteria for hospitalization, 66 were tested positive for SARS-CoV-2. COVID-19-positive patients were more likely to present with fever (P = .02), cough (P = .03), and pneumonia at computed tomography (CT) scan (P = .002) at admission. Prevalence of D-dimer >500 ng/mL was higher in COVID-19-positive patients (74.2% versus 43.3%; P = .007). No sign of disseminated intravascular coagulation were identified. Adding D-dimers >500 ng/mL to gender and pneumonia at CT scan in receiver operating characteristic curve analysis significantly increased area under the curve for COVID-19 diagnosis. COVID-19-positive patients had significantly more CECs at admission (P = .008) than COVID-19-negative ones. COVID-19-positive patients treated with curative anticoagulant prior to admission had fewer CECs (P = .02) than those without. Interestingly, patients treated with curative anticoagulation and angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers had even fewer CECs (P = .007)., Conclusion: Curative anticoagulation could prevent COVID-19-associated coagulopathy and endothelial lesion., (© 2020 International Society on Thrombosis and Haemostasis.)

Machine learning (ML) has been increasingly used within cardiology, particularly in the domain of cardiovascular imaging. Due to the inherent complexity and flexibility of ML algorithms, inconsistencies in the model performance and interpretation may occur. Several review articles have been recently published that introduce the fundamental principles and clinical application of ML for cardiologists. This paper builds on these introductory principles and outlines a more comprehensive list of crucial responsibilities that need to be completed when developing ML models. This paper aims to serve as a scientific foundation to aid investigators, data scientists, authors, editors, and reviewers involved in machine learning research with the intent of uniform reporting of ML investigations. An independent multidisciplinary panel of ML experts, clinicians, and statisticians worked together to review the theoretical rationale underlying 7 sets of requirements that may reduce algorithmic errors and biases. Finally, the paper summarizes a list of reporting items as an itemized checklist that highlights steps for ensuring correct application of ML models and the consistent reporting of model specifications and results. It is expected that the rapid pace of research and development and the increased availability of real-world evidence may require periodic updates to the checklist., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Ultrasound techniques currently used in echocardiography are limited by conventional frame rates. Ultrafast ultrasound imaging is able to capture images at frame rates up to 100 times faster compared with conventional imaging. Specific applications of this technology have been developed and tested for clinical use in pediatric and adult cardiac imaging. These include ultrafast Doppler or vector flow imaging, shear wave imaging, electromechanical wave imaging, and backscatter tensor imaging. The principles of these applications are explained in this manuscript with illustrations on how these methods could be applied in clinical practice. Ultrafast ultrasound has great clinical potential in the assessment of cardiac function, in noninvasive hemodynamic analysis, while providing novel techniques for imaging coronary perfusion and evaluating rhythm disorders., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of our study was to investigate the potential of myocardial shear wave imaging (SWI) to quantify the diastolic myocardial stiffness (MS) (kPa) noninvasively in adult healthy volunteers (HVs) and its physiological variation with age, and in hypertrophic cardiomyopathy (HCM) populations with heart failure and preserved ejection function (HFpEF)., Background: MS is an important prognostic and diagnostic parameter of the diastolic function. MS is affected by physiological changes but also by pathological alterations of extracellular and cellular tissues. However, the clinical assessment of MS and the diastolic function remains challenging. SWI is a novel ultrasound-based technique that has the potential to provide intrinsic MS noninvasively., Methods: We prospectively included 80 adults: 60 HV (divided into 3 groups: 20- to 39-year old patients [n = 20]; 40- to 59-year-old patients [n = 20]; and 60- to 79-year-old patients [n = 20]) and 20 HCM-HFpEF patients. Echocardiography, cardiac magnetic resonance imaging and biological explorations were achieved. MS evaluation was performed using an ultrafast ultrasound scanner with cardiac phased array. The fractional anisotropy of MS was also estimated., Results: MS increased significantly with age in the HV group (the mean MS was 2.59 ± 0.58 kPa, 4.70 ± 0.88 kPa, and 6.08 ± 1.06 kPa for the 20- to 40-year-old, 40- to 60-year-old, and 60- to 80-year-old patient groups, respectively; p < 0.01 between each group). MS was significantly higher in HCM-HFpEF patients than in HV patients (mean MS = 12.68 ± 2.91 kPa vs. 4.47 ± 1.68 kPa, respectively; p < 0.01), with a cut-off at 8 kPa (area under the curve = 0.993; sensitivity = 95%, specificity = 100%). The fractional anisotropy was lower in HCM-HFpEF (mean = 0.133 ± 0.073) than in HV (0.238 ± 0.068) (p < 0.01). Positive correlations were found between MS and diastolic parameters in echocardiography (early diastolic peak/early diastolic mitral annular velocity, r = 0.783; early diastolic peak/transmitral flow propagation velocity, r = 0.616; left atrial volume index, r = 0.623) and with fibrosis markers in cardiac magnetic resonance (late gadolinium enhancement, r = 0.804; myocardial T1 pre-contrast, r = 0.711)., Conclusions: MS was found to increase with age in healthy adults and was significantly higher in HCM-HFpEF patients. Myocardial SWI has the potential to become a clinical tool for the diagnostic of diastolic dysfunction. (Non-invasive Evaluation of Myocardial Stiffness by Elastography [Elasto-Cardio]; NCT02537041)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Various animal models of critical limb ischemia have been developed in the past. However, there is no animal model that can undergo endovascular treatment, while providing reproducible true critical limb ischemia with arterial ulcers and rest pain. We evaluated the efficacy of a new model of rabbit hindlimb ischemia created through a percutaneous approach using embolization with calibrated particles., Methods: Through a percutaneous transauricular artery approach and selective catheterization of the superficial femoral artery, embolization of distal limb vessels was performed using a mixture of 300- to 500-μm calibrated microparticles (Embosphere, Merit Medical, Salt Lake City, Utah), saline solution, and iodine contrast. Clinical and ultrasound imaging-based blood flow evaluation was performed before embolization and during follow-up. Histologic evaluation was performed at humane killing 14 days after the procedure., Results: The model was successfully created in 10 rabbits (10 limbs). One rabbit died of sudden death at 8 days after the procedure. The nine surviving rabbits developed hind ulcers. All rabbits had a higher pain score in the follow-up compared to baseline value (P < .0001). Blood flow in the saphenous artery decreased significantly after the procedure and later at 14 days follow-up (baseline value 63.4 ± 31.3 μL per cardiac cycle vs 32.0 ± 28.4 μL per cardiac cycle postprocedure [P = .0013] and 32.0 ± 28.4 μL per cardiac cycle at 14 days [P = .0015]). Pathology showed signs of severe limb ischemia in all rabbits with subacute and chronic injury patterns., Conclusions: A rabbit hind limb ischemia model created by percutaneous transauricular distal femoral artery embolization with calibrated particles may overcome some of the limitations of existing animal models. As such, this model could prove useful for assessing therapies designed to improve arterial perfusion and collateral growth., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Postoperative systemic artery to pulmonary vein fistula is very rare. In this report, we describe an exceptional condition of both intrapulmonary arteriovenous fistula and systemic artery to pulmonary vein fistula, involving all right hemithoracic systemic arteries, inducing left-to-left shunt. This condition was responsible for heart failure, 24 years after a right upper lobectomy for inflammatory tumor. Investigations included computed tomographic angiography, arteriography, and four-dimensional flow magnetic resonance imaging. Differential diagnosis and management are discussed., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the potential of shear wave imaging (SWI), a novel ultrasound-based technique, to noninvasively quantify passive diastolic myocardial stiffness in an ovine model of ischemic cardiomyopathy., Background: Evaluation of diastolic left ventricular function is critical for evaluation of heart failure and ischemic cardiomyopathy. Myocardial stiffness is known to be an important property for the evaluation of the diastolic myocardial function, but this parameter cannot be measured noninvasively by existing techniques., Methods: SWI was performed in vivo in open-chest procedures in 10 sheep. Ligation of a diagonal of the left anterior descending coronary artery was performed for 15 min (stunned group, n = 5) and 2 h (infarcted group, n = 5). Each procedure was followed by a 40-min reperfusion period. Diastolic myocardial stiffness was measured at rest, during ischemia, and after reperfusion by using noninvasive shear wave imaging. Simultaneously, end-diastolic left ventricular pressure and segmental strain were measured with a pressure catheter and sonomicrometers during transient vena caval occlusions to obtain gold standard evaluation of myocardial stiffness using end-diastolic strain-stress relationship (EDSSR)., Results: In both groups, the end-systolic circumferential strain was drastically reduced during ischemia (from 14.2 ± 1.2% to 1.3 ± 1.6% in the infarcted group and from 13.5 ± 3.0% to 1.9 ± 1.8% in the stunned group; p <0.01). SWI diastolic stiffness increased after 2 h of ischemia from 1.7 ± 0.4 to 6.2 ± 2.2 kPa (p < 0.05) and even more after reperfusion (12.1 ± 4.2 kPa; p < 0.01). Diastolic myocardial stiffening was confirmed by the exponential constant coefficient of the EDSSR, which increased from 8.8 ± 2.3 to 25.7 ± 9.5 (p < 0.01). In contrast, SWI diastolic stiffness was unchanged in the stunned group (2.3 ± 0.4 kPa vs 1.8 ± 0.3 kPa, p = NS) which was confirmed also by the exponential constant of EDSSR (9.7 ± 3.1 vs 10.2 ± 2.3, p = NS)., Conclusions: Noninvasive SWI evaluation of diastolic myocardial stiffness can differentiate between stiff, noncompliant infarcted wall and softer wall containing stunned myocardium., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: The numbers of patients >85 years of age referred for abdominal aortic aneurysm (AAA) repair have increased in recent decades. With the population aging, increased screening of AAA, and introduction of less invasive surgical techniques, vascular surgeons will be treating more elderly patients. Few data are available for estimating the risks and benefits of prophylactic repair among those with such an advanced age. The aim of this single-center study was to evaluate the short-term to midterm results after AAA repair in patients >85 years of age., Methods: Between 2004 and 2012, data of patients >85 years old who required an elective AAA repair at our institution were collected prospectively. According to the current guidelines, patients underwent endovascular aneurysm repair (EVAR) each time the aortic anatomy was suitable. Open repair (OR) was performed in those patients with hostile proximal neck anatomy and/or severe iliac tortuosity. Type of repair (EVAR or OR) and perioperative and midterm outcomes were analyzed. Primary end points were 30-day mortality and midterm survival., Results: Among 1016 patients undergoing elective AAA repair during the study period, 59 (5.8%) were ≥85 years of age (54 men, mean age 87 ± 2 years), with a mean aneurysm diameter of 61.5 ± 20.3 mm. Thirty-three patients (56%) underwent EVAR and 26 (44%) had an OR. Thirty-day mortality was 6.7% (6% with EVAR and 7.6% with OR, P <0.05). Mean follow-up was 24.7 ± 18 months. Kaplan‒Meier analyses for survival were 85.5%, 64.5%, and 50% at 1, 3, and 5 years, respectively. No aneurysm-related death was observed during follow-up., Conclusion: Elective repair may be proposed in patients >85 years of age in cases of threatening AAA, showing acceptable perioperative mortality and reasonable midterm survival results. Even if EVAR did not seem to offer significant benefits in perioperative mortality in our study, it appears reasonable to suggest this less invasive technique as first-line treatment in cases of suitable anatomy in such an advanced-age population., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Syphilitic cardiovascular disease has been described since the 19th century, mainly on autopsy series. Major clinical manifestations are aortic aneurysm, aortic insufficiency, and coronary ostial stenosis. The diagnosis of syphilitic cardiovascular disease is based mainly on positive serologic tests and overt clinical manifestations. We present here a rare and unusual clinical presentation of a tertiary syphilis with recurrent tamponade and type B aortic dissection, whose positive diagnosis was made by polymerase chain reaction on pericardial fluid analysis., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: To report the rare diagnosis and the surgical treatment of a young patient presenting a symptomatic dissection of the abdominal aorta revealing a Takayasu's arteritis (TA)., Methods and Results: A 24-year-old woman developed a painful chronic dissection of the infrarenal aorta associated with a claudication of both lower extremities. As the patient was still symptomatic despite an optimal medical treatment, a surgical revascularization was proposed. An aortobifemoral bypass was performed allowing the removal of infrarenal aorta and the histologic diagnosis of TA., Conclusion: Isolated abdominal aortic dissection is an unusual event in TA, and this is the first surgically treated case. Only few reports of aortic dissection in TA have been published so far which are commented in this article., (Copyright © 2011 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Background: It has been postulated that systemic infection with pathogens such as Porphyromonas gingivalis (Pg) elevates the inflammatory response and increases susceptibility to atherosclerosis. We hypothesized that Doxycycline would be beneficial in diet- and/or Pg-induced atherosclerosis given its role in various cell functions and matrix remodeling., Methods and Results: ApoE+/- mice were inoculated weekly with Pg and treated with either Doxycycline or saline; animals were fed either a high-fat or chow diet. Animals were euthanized at 14 or 24 weeks and histomorphometric analysis of atheromatous lesions in proximal aorta, levels of SAA and serum cytokine profiling were performed. Histomorphometric analysis demonstrated that in non-infected mice fed a high fat diet, Doxycycline treatment resulted in a reduction of mean lesions from 10.5%+/-.49 to 1.09%+/-0.102 (p<0.05) at 14 weeks and a reduction from 21.5%+/-6.49 to 8.26%+/-0.162 (p=0.106) at 24 weeks. Chow-fed Pg mice treated with Doxyclycline also resulted in a reduction from 0.62%+/-0.128 to 0.0%+/-0.0 (p<0.05) at 14 weeks and a reduction from 0.92%+/-0.23 to 0.0%+/-0.0 (p<0.05) at 24 weeks. Administration of Doxycycline to mice fed a high fat diet and Pg-inoculated resulted in a reduction of mean percentage of atheromatous lesions from 16.46%+/-1.69 to 1.141%+/-0.23 (p<0.05) at 14 weeks and a reduction from 25.27%+/-1.734 to 0.428%+/-0.033 (p<0.05) at 24 weeks. At this timepoint, SAA levels in Pg-infected animals were reduced by five-fold and three-fold in Doxycycline-treated chow and high fat-diet groups, respectively. Cytokine antibody arrays revealed a marked reduction in the levels of pro-inflammatory cytokines in Doxycycline-treated groups whether Pg-infected or fed a high fat diet while anti-inflammatory cytokines were not affected. Consistent with the role of Doxycycline on matrix proteases, at 24 weeks MMP-9 Serum levels were markedly reduced by 60% (p<0.05) and 30% (p<0.05) with Doxycycline treatment in Pg-infected high fat and chow diet groups, respectively., Conclusions: Doxycycline decreases pro-inflammatory cytokines and results in reduction of atherosclerosis in ApoE+/-Pg-inoculated and/or high fat diet fed mice.

Background: Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model., Methods: We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation., Findings: Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9.9% (range -20 to 0.3) relative to baseline (p=0.011) whereas in the treated group it improved by 6.6% (-5.7 to 50.8; comparison between groups p=0.002)., Interpretation: These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.