Lerman, Amir

Objective: To identify an efficacious intervention on treating adolescents with overweight and obesity, this might result in health benefits. Methods: Adolescents with overweight or obesity aged 10–17 years with BMI percentile ≥85th were included in this historical observational analysis. Subjects used an entirely remote weight loss program combining mobile applications, frequent self-weighing, and calorie restriction with meal replacement. Body weight changes were evaluated at 42, 60, 90, and 120 days using different metrics including absolute body weight, BMI, and BMI z-score. Chi-square or Fisher exact tests (categorical variables) and Student's t -test (continuous variables) were used to compare subjects. Results: In total, 2,825 participants, mean age 14.4 ± 2.2 years, (54.8% girls), were included from October 27, 2016, to December 31, 2017, in mainland China; 1355 (48.0%) had a baseline BMI percentile ≥97th. Mean BMI and BMI z-score were 29.20 ± 4.44 kg/m 2 and 1.89 ± 0.42, respectively. At day 120, mean reduction in body weight, BMI, and BMI z-score was 8.6 ± 0.63 kg, 3.13 ± 0.21 kg/m 2 , and 0.42 ± 0.03; 71.4% had lost ≥5% body weight, 69.4% of boys and 73.2% of girls, respectively. Compared with boys, girls achieved greater reduction on BMI z-score at all intervals ( p < 0.004 for all comparisons). Higher BMI percentile at baseline and increased frequency of use of the mobile application were directly associated with more significant weight loss. Conclusions: An entirely remote digital weight loss program is effective in facilitating weight loss in adolescents with overweight or obesity in the short term and mid term.

Background: Percutaneous transluminal renal angioplasty (PTRA) confers clinical and mortality benefits in select ‘high-risk’ patients with renovascular disease (RVD). Intra-renal-delivered extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) protect the kidney in experimental RVD, but have not been compared side-by-side to clinically applied interventions, such as PTRA. We hypothesized that MSC-derived EVs can comparably protect the post-stenotic kidney via direct tissue effects. Methods: Five groups of pigs (n = 6 each) were studied after 16 weeks of RVD, RVD treated 4 weeks earlier with either PTRA or MSC-derived EVs, and normal controls. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multi-detector CT, and renal microvascular architecture (3D micro CT) and injury pathways ex vivo. Results: Despite sustained hypertension, EVs conferred greater improvement of intra-renal microvascular and peritubular capillary density compared to PTRA, associated with attenuation of renal inflammation, oxidative stress, and tubulo-interstitial fibrosis. Nevertheless, stenotic kidney RBF and GFR similarly rose in both PTRA- and EV-treated pigs compared RVD + Sham. mRNA sequencing reveled that EVs were enriched with pro-angiogenic, anti-inflammatory, and antioxidants genes. Conclusion: MSC-derived EVs elicit a better preservation of the stenotic kidney microvasculature and greater attenuation of renal injury and fibrosis compared to PTRA, possibly partly attributed to their cargo of vasculo-protective genes. Yet, both strategies similarly improve renal hemodynamics and function. These observations shed light on diverse mechanisms implicated in improvement of post-stenotic kidney function and position EVs as a promising therapeutic intervention in RVD.

Abstract Spinal cord stimulation (SCS) is used to treat a variety of chronic pain conditions refractory to more conservative management including refractory angina pectoris. We identified 31 patients who underwent SCS implantation for the indication of refractory angina at a single institution from 2003 through 2018. Sixteen patients were male, and 15 were female. Average age was 53.9 years. Prior to SCS implantation, all patients had at least one coronary angiogram. Ten (32.3%) patients had undergone percutaneous coronary intervention, and four (12.9%) had undergone coronary artery bypass grafting. Thirty patients (96.7%) were currently using anti-angina medications. Twenty-six patients (83.9%) were on antiplatelet or anticoagulant agents at the time of SCS evaluation. Spinal cord stimulation implanters must perform a comprehensive evaluation incorporating appropriate multidisciplinary care particularly in patients with refractory angina given their cardiovascular comorbidities. It is important to have baseline data (e.g., pain scores, nitroglycerin consumption, frequency of angina episodes, and a questionnaire, such as the Seattle Angina Questionnaire) to compare with follow-up data to help define treatment success. We report a single institution’s pre-operative experience for patients undergoing SCS for refractory angina to illustrate unique pre-operative SCS considerations in this chronic pain population.

Abstract Aims There are limited contemporary data on the use of initial fibrinolysis in ST-segment elevation myocardial infarction cardiogenic shock (STEMI-CS). This study sought to compare the outcomes of STEMI-CS receiving initial fibrinolysis vs. primary percutaneous coronary intervention (PPCI). Methods Using the National (Nationwide) Inpatient Sample from 2009 to 2017, a comparative effectiveness study of adult (&gt;18 years) STEMI-CS admissions receiving pre-hospital/in-hospital fibrinolysis were compared with those receiving PPCI. Admissions with alternate indications for fibrinolysis and STEMI-CS managed medically or with surgical revascularization (without fibrinolysis) were excluded. Outcomes of interest included in-hospital mortality, development of non-cardiac organ failure, complications, hospital length of stay, hospitalization costs, use of palliative care, and do-not-resuscitate status. Results During 2009–2017, 5297 and 110 452 admissions received initial fibrinolysis and PPCI, respectively. Compared with those receiving PPCI, the fibrinolysis group was more often non-White, with lower co-morbidity, and admitted on weekends and to small rural hospitals (all P &lt; 0.001). In the fibrinolysis group, 95.3%, 77.4%, and 15.7% received angiography, PCI, and coronary artery bypass grafting, respectively. The fibrinolysis group had higher rates of haemorrhagic complications (13.5% vs. 9.9%; P &lt; 0.001). The fibrinolysis group had comparable all-cause in-hospital mortality [logistic regression analysis: 28.8% vs. 28.5%; propensity-matched analysis: 30.8% vs. 30.3%; adjusted odds ratio 0.97 (95% confidence interval 0.90–1.05); P = 0.50]. The fibrinolysis group had comparable rates of acute organ failure, hospital length of stay, rates of palliative care referrals, do-not-resuscitate status use, and lesser hospitalization costs. Conclusions The use of initial fibrinolysis had comparable in-hospital mortality than those receiving PPCI in STEMI-CS in the contemporary era in this large national observational study.

Abstract Introduction: Cardiovascular disease is the most common cause of morbidity and mortality in the United States and in the world. Patients are increasingly using internet search to find health-related information, including searches for cardiovascular diseases and risk factors. We sought to evaluate the change in the state by state correlation of cardiovascular disease and risk factors with Google Trends search volumes. Methods: Data on cardiovascular disease hospitalizations and risk factor prevalence were obtained from the publically available CDC website from 2006-2018. Google Trends data were obtained for matching conditions and time periods. Simple linear regression was performed to evaluate for an increase in correlation over time. Results: Hospitalizations for six separate cardiovascular disease conditions showed moderate to strong correlation with online search data in the last period studied (heart failure (0.58, P<0.001), atrial fibrillation (0.57, P<0.001), coronary heart disease (0.58, P<0.001), myocardial infarction (0.70, P<0.001), stroke (0.62, P<0.001), cardiac dysrhythmia (0.46, P<0.001)). All diseases studied showed a positive increase in correlation throughout the time period studied (P<0.05). All five of the cardiovascular risk factors studied showed strong correlation with online search data; diabetes (R=0.78, P<0.001), cigarette use (R=0.79, P<0.001), hypertension (R=0.81, P<0.001), high cholesterol (R=0.59, P<0.001), obesity (R=0.80, P<0.001). Three of the five showed an increasing correlation over time. Conclusion: The prevalence of and hospitalizations for cardiovascular conditions in the United States strongly correlate with online search volumes nationwide and when analyzed by state. This relationship has progressively strengthened or been strong and stable over recent years for these conditions. Google Trends represents an increasingly valuable tool for evaluating the burden of cardiovascular disease and risk factors in the United States.

Tumor necrosis factor-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of MSCs, but its ability to protect the ischemic kidney is unknown. In pigs with renal artery stenosis, we show that MSC delivery increased renal vein TSG-6, decreased kidney inflammatory macrophages, and improved renal function. In vitro, TSG-6 decreased inflammatory macrophages and tubular cell injury. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype.

Background An artificial intelligence algorithm that detects age using the 12‐lead ECG has been suggested to signal “physiologic age.” This study aimed to investigate the association of peripheral microvascular endothelial function (PMEF) as an index of vascular aging, with accelerated physiologic aging gauged by ECG‐derived artificial intelligence–estimated age. Methods and Results This study included 531 patients who underwent ECG and a noninvasive PMEF assessment using reactive hyperemia peripheral arterial tonometry. Abnormal PMEF was defined as reactive hyperemia peripheral arterial tonometry index ≤2.0. Accelerated or delayed physiologic aging was calculated by the Δ age (ECG‐derived artificial intelligence–estimated age minus chronological age), and the association between Δ age and PMEF as well as its impact on composite major adverse cardiovascular events were investigated. Δ age was higher in patients with abnormal PMEF than in patients with normal PMEF (2.3±7.8 versus 0.5±7.7 years; P =0.01). Reactive hyperemia peripheral arterial tonometry index was negatively associated with Δ age after adjustment for cardiovascular risk factors (standardized β coefficient, –0.08; P =0.048). The highest quartile of Δ age was associated with an increased risk of major adverse cardiovascular events compared with the first quartile of Δ age in patients with abnormal PMEF, even after adjustment for cardiovascular risk factors (hazard ratio, 4.72; 95% CI, 1.24–17.91; P =0.02). Conclusions Vascular aging detected by endothelial function is associated with accelerated physiologic aging, as assessed by the artificial intelligence–ECG Δ age. Patients with endothelial dysfunction and the highest quartile of accelerated physiologic aging have a marked increase in risk for cardiovascular events.

Objective: Renovascular hypertension (RVH) induces hemodynamic and humoral aberrations that may impair cardiac function, structure and mechanics, including cardiac twist and deformation. Revascularization of a stenotic renal artery can decrease blood pressure (BP), but its ability to restore cardiac mechanics in RVH remains unclear. We hypothesized that percutaneous transluminal renal angioplasty (PTRA) would improve cardiac function and left ventricular (LV) deformation in swine RVH. Methods: Seventeen domestic pigs were studied for 16 weeks: RVH, RVH + PTRA and normal controls (n = 5–6 each). Global LV function was estimated by multidetector computed-tomography, and LV deformation by electrocardiographically triggered MRI tagging at the apical, mid, and basal LV levels. Cardiomyocyte hypertrophy, myocardial capillary density, and fibrosis were evaluated ex vivo. Results: BP and wall thickness were elevated in RVH and decreased by PTRA, yet remained higher than in controls. LV myocardial muscle mass increased in RVH pigs, which also developed diastolic dysfunction, whereas cardiac output increased. Furthermore, both apical rotation and peak torsion angle increased in RVH compared with controls. Ex vivo, RVH induced myocardial fibrosis and vascular rarefaction. PTRA restored cardiac function and alleviated hypertrophy, vascular rarefaction, and fibrosis. PTRA also normalized apical rotation and peak torsion angle, and elevated basal peak radial strain and apical peak radial strain compared with RVH. Conclusion: In addition to cardiac LV adaptive hypertrophy and diastolic dysfunction, short-term RVH causes cardiac deformation. Despite only partial improvement in BP, PTRA effectively restored cardiac function and reversed abnormal mechanics. Hence, renal revascularization may be a useful strategy to preserve cardiac function in RVH.

Scattered tubular-like cells (STCs), dedifferentiated renal tubular epithelial cells, contribute to renal self-healing, but severe injury might blunt their effectiveness. We hypothesized that ischemic renovascular disease (RVD) induces senescence in STC and impairs their reparative potency. CD24+/CD133+ STCs were isolated from swine kidneys after 16 weeks of RVD or healthy controls. To test their reparative capabilities in injured kidneys, control or RVD-STC (5×10 5 ) were prelabeled and injected into the aorta of 2 kidneys, 1-clip (2k,1c) mice 2 weeks after surgery. Murine renal function and oxygenation were studied in vivo 2 weeks after injection using micro-magnetic resonance imaging, and fibrosis, tubulointerstitial injury, capillary density, and expression of profibrotic and inflammatory genes ex vivo. STC isolated from swine RVD kidneys showed increased gene expression of senescence and senescence-associated secretory phenotype markers and positive SA-β-gal staining. Delivery of normal pig STCs in 2k,1c mice improved murine renal perfusion, blood flow, and glomerular filtration rate, and downregulated profibrotic and inflammatory gene expression. These renoprotective effects were blunted using STC harvested from RVD kidneys, which also failed to attenuate hypoxia, fibrosis, tubular injury, and capillary loss in injured mouse 2k,1c kidneys. Hence, RVD may induce senescence in endogenous STC and impair their reparative capacity. These observations implicate cellular senescence in the pathophysiology of ischemic kidney disease and support senolytic therapy to permit self-healing of senescent kidneys.

Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P =0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P =0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P =0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P =0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P =0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P =0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.