Citations

Endothelial progenitor cells (EPCs) patrols the circulation and contributes to endothelial cell regeneration. Atherosclerotic renal artery stenosis (ARAS) induces microvascular loss in the stenotic kidney (STK). Low-energy shockwave therapy (SW) can induce angiogenesis and restore the STK microcirculation, but the underlying mechanism remains unclear. We tested the hypothesis that SW increases EPC homing to the swine STK, associated with capillary regeneration. Normal pigs and pigs after 3 wk of renal artery stenosis were treated with six sessions of low-energy SW (biweekly for three consecutive weeks) or left untreated. Four weeks after completion of treatment, we assessed EPC (CD34+/KDR+) numbers and levels of the homing-factor stromal cell-derived factor (SDF)-1 in the inferior vena cava and the STK vein and artery, as well as urinary levels of vascular endothelial growth factor (VEGF) and integrin-1β. Subsequently, we assessed STK morphology, capillary count, and expression of the proangiogenic growth factors angiopoietin-1, VEGF, and endothelial nitric oxide synthase ex vivo. A 3-wk low-energy SW regimen improved STK structure, capillary count, and function in ARAS+SW, and EPC numbers and gradients across the STK decreased. Plasma SDF-1 and renal expression of angiogenic factors were increased in ARAS+SW, and urinary levels of VEGF and integrin-1β tended to rise during the SW regimen. In conclusion, SW improves ischemic kidney capillary density, which is associated with, and may be at least in part mediated by, promoting EPCs mobilization and homing to the stenotic kidney.

Background The purpose of this article is to evaluate the association of voice signal analysis with adverse outcome among patients with congestive heart failure ( CHF ). Methods and Results The study cohort included 10 583 patients who were registered to a call center of patients who had chronic conditions including CHF in Israel between 2013 and 2018. A total of 223 acoustic features were extracted from 20 s of speech for each patient. A biomarker was developed based on a training cohort of non‐ CHF patients (N=8316). The biomarker was tested on a mutually exclusive CHF study cohort (N=2267) and was evaluated as a continuous and ordinal (4 quartiles) variable. Median age of the CHF study population was 77 (interquartile range 68–83) and 63% were men. During a median follow‐up of 20 months (interquartile range 9–34), 824 (36%) patients died. Kaplan–Meier survival analysis showed higher cumulative probability of death with increasing quartiles (23%, 29%, 38%, and 54%; P <0.001). Survival analysis with adjustment to known predictors of poor survival demonstrated that each SD increase in the biomarker was associated with a significant 32% increased risk of death during follow‐up (95% CI, 1.24–1.41, P <0.001) and that compared with the lowest quartile, patients in the highest quartile were 96% more likely to die (95% CI , 1.59–2.42, P <0.001). The model consistently demonstrated an independent association of the biomarker with hospitalizations during follow‐up ( P <0.001). Conclusions Noninvasive vocal biomarker is associated with adverse outcome among CHF patients, suggesting a possible role for voice analysis in telemedicine and CHF patient care.

Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells–derived extracellular vesicles (EVs). The anti-inflammatory TGF-β (transforming growth factor-β) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-β expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8 + T cells were detected in stenotic kidneys treated with Lean-EVs compared with MetS-EVs, and renal vein levels of interleukin-1β were reduced. In vitro, coculture of Lean-EVs with activated T cells led to greater TGF-β-dependent regulatory T cells induction than did MetS-EVs. Therefore, the beneficial effects of mesenchymal stem cells–derived EVs on injured kidneys might be partly mediated by their content of TGF-β signaling components, which permitting increased Treg preponderance. Modulating EV cargo and transforming their functionality might be useful for renal repair.

Importance. Obesity is a worsening epidemic worldwide. Effective and accessible weight loss programs to combat obesity on a large scale are warranted, but a need for frequent face-to-face care might impose a limitation. Objective. To evaluate whether individuals following a weight loss program based on a mobile application, wireless scale, and nutritional program but no face-to-face care can achieve clinically significant weight loss in a large cohort. Design. Retrospective observational analysis. Setting. China from October 2016 to December 2017. Participants. Mobile application users with a minimum of 2 weights (baseline and ≥35 days). Intervention. A commercial (Weijian Technologies) weight loss program consisting of a dietary replacement, self-monitoring using a wireless home scale, and frequent guidance via mobile application. Main Outcome. Mean weight change around 42, 60, 90, and 120 days after program initiation with subgroup analysis by gender, age, and frequency of use. Results. 251,718 individuals, with a mean age of 37.3 years (SD: 9.86) (79% female), were included with a mean weight loss of 4.3 kg (CI: ±0.02) and a mean follow-up of 120 days (SD: 76.8 days). Mean weight loss at 42, 60, 90, and 120 d was 4.1 kg (CI: ±0.02), 4.9 kg (CI: ±0.02), 5.6 kg (CI: ±0.03), and 5.4 kg (CI: ±0.04), respectively. At 120 d, 62.7% of participants had lost at least 5% of their initial weight. Both genders and all usage frequency tertiles showed statistically significant weight loss from baseline at each interval (P<0.001), and this loss was greater in men than in women (120 d: 6.5 vs. 5.2 kg; P<0.001). The frequency of recording (categorized as high-, medium-, or low-frequency users) was associated with greater weight loss when comparing high, medium, and low tertile use groups at all time intervals investigated (e.g., 120 d: −8.6, −5.6, and −2.2 kg, respectively; P<0.001). Conclusions. People following a commercially available hybrid weight loss program using a mobile application, wireless scale, and nutritional program without face-to-face interaction on average achieved clinically significant short- and midterm weight loss. These results support the implementation of comparable technologies for weight control in a large population.

Abstract Despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide. Progress has been challenging as half of the individuals who suffer sudden cardiac death do not experience premonitory symptoms. Furthermore, it is well-recognized that also a plaque that does not cause a haemodynamically significant stenosis can trigger a sudden cardiac event, yet the majority of ruptured or eroded plaques remain clinically silent. In the past 30 years since the term ‘vulnerable plaque’ was introduced, there have been major advances in the understanding of plaque pathogenesis and pathophysiology, shifting from pursuing features of ‘vulnerability’ of a specific lesion to the more comprehensive goal of identifying patient ‘cardiovascular vulnerability’. It has been also recognized that aside a thin-capped, lipid-rich plaque associated with plaque rupture, acute coronary syndromes (ACS) are also caused by plaque erosion underlying between 25% and 60% of ACS nowadays, by calcified nodule or by functional coronary alterations. While there have been advances in preventive strategies and in pharmacotherapy, with improved agents to reduce cholesterol, thrombosis, and inflammation, events continue to occur in patients receiving optimal medical treatment. Although at present the positive predictive value of imaging precursors of the culprit plaques remains too low for clinical relevance, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and could facilitate optimal allocation of novel, more aggressive, and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and ‘local’ diagnostics and therapies. The present state-of-the-art document aims to present and critically appraise the latest evidence, developments, and future perspectives in detection, prevention, and treatment of ‘high-risk’ plaques occurring in ‘vulnerable’ patients.

Heart failure is a common debilitating illness, associated with significant morbidity and mortality, rehospitalisation and societal costs. Current guidelines and position statements emphasise the management of patients with overt symptomatic disease, but the increasing prevalence of congestive heart failure underscores the need to identify and manage patients with early left ventricular dysfunction prior to symptom onset. Asymptomatic left ventricular systolic dysfunction (ALVSD), classified as stage B heart failure, is defined as depressed left ventricular systolic function in the absence of clinical heart failure. Early initiation of therapies in patients with presumed ALVSD has been shown to lead to better outcomes. In this article, the authors clarify issues surrounding the definition and natural history of ALVSD, outline clinical tools that may be of value in identifying patients with ALVSD and highlight potential opportunities for future investigations to better address aspects of our understanding of this complex syndrome.

Background: Heart rate variability (HRV) and pulse rate variability are indices of autonomic cardiac modulation. Increased pericardial fat is associated with worse cardiovascular outcomes. We hypothesized that progressive increases in pericardial fat volume and inflammation prospectively dampen HRV in hypercholesterolemic pigs. Methods: WT (wild type) or PCSK9 (proprotein convertase subtilisin-like/kexin type-9) gain-of-function Ossabaw mini-pigs were studied in vivo before and after 3 and 6 months of a normal diet (WT-normal diet, n=4; PCSK9-normal diet, n=6) or high-fat diet (HFD; WT-HFD, n=3; PCSK9-HFD, n=6). The arterial pulse waveform was obtained from an arterial telemetry transmitter to analyze HRV indices, including SD (SD of all pulse-to-pulse intervals over a single 5-minute period), root mean square of successive differences, proportion >50 ms of normal-to-normal R-R intervals, and the calculated ratio of low-to-high frequency distributions (low-frequency power/high-frequency power). Pericardial fat volumes were evaluated using multidetector computed tomography and its inflammation by gene expression of TNF (tumor necrosis factor)-α. Plasma lipid panel and norepinephrine level were also measured. Results: At diet completion, hypercholesterolemic PCSK9-HFD had significantly ( P <0.05 versus baseline) depressed HRV (SD of all pulse-to-pulse intervals over a single 5-minute period, root mean square of successive differences, proportion >50 ms, high-frequency power, low-frequency power), and both HFD groups had higher sympathovagal balance (SD of all pulse-to-pulse intervals over a single 5-minute period/root mean square of successive differences, low-frequency power/high-frequency power) compared with normal diet. Pericardial fat volumes and LDL (low-density lipoprotein) cholesterol concentrations correlated inversely with HRV and directly with sympathovagal balance, while sympathovagal balance correlated directly with plasma norepinephrine. Pericardial fat TNF-α expression was upregulated in PCSK9-HFD, colocalized with nerve fibers, and correlated inversely with root mean square of successive differences and proportion >50 ms. Conclusions: Progressive pericardial fat expansion and inflammation are associated with a fall in HRV in Ossabaw mini-pigs, implying aggravated autonomic imbalance. Hence, pericardial fat accumulation is associated with alterations in HRV and the autonomic nervous system. Visual Overview: A visual overview is available for this article.

Vascular abnormalities are the most important non-cystic complications in Polycystic Kidney Disease (PKD) and contribute to renal disease progression. Endothelial dysfunction and oxidative stress are evident in patients with ADPKD, preserved renal function, and controlled hypertension. The underlying biological mechanisms remain unknown. We hypothesized that in early ADPKD, the reactive oxygen species (ROS)-producing nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H)-oxidase complex-4 (NOX4), a major source of ROS in renal tubular epithelial cells (TECs) and endothelial cells (ECs), induces EC mitochondrial abnormalities, contributing to endothelial dysfunction, vascular abnormalities, and renal disease progression. Renal oxidative stress, mitochondrial morphology (electron microscopy), and NOX4 expression were assessed in 4- and 12-week-old PCK and Sprague-Dawley (wild-type, WT) control rats (n = 8 males and 8 females each). Endothelial function was assessed by renal expression of endothelial nitric oxide synthase (eNOS). Peritubular capillaries were counted in hematoxylin–eosin (H&E)-stained slides and correlated with the cystic index. The enlarged cystic kidneys of PCK rats exhibited significant accumulation of 8-hydroxyguanosine (8-OHdG) as early as 4 weeks of age, which became more pronounced at 12 weeks. Mitochondria of TECs lining cysts and ECs exhibited loss of cristae but remained preserved in non-cystic TECs. Renal expression of NOX4 was upregulated in TECs and ECs of PCK rats at 4 weeks of age and further increased at 12 weeks. Contrarily, eNOS immunoreactivity was lower in PCK vs. WT rats at 4 weeks and further decreased at 12 weeks. The peritubular capillary index was lower in PCK vs. WT rats at 12 weeks and correlated inversely with the cystic index. Early PKD is associated with NOX4-induced oxidative stress and mitochondrial abnormalities predominantly in ECs and TECs lining cysts. Endothelial dysfunction precedes capillary loss, and the latter correlates with worsening of renal disease. These observations position NOX4 and EC mitochondria as potential therapeutic targets in PKD.

Abstract BACKGROUND Mitochondria modulate endothelial cell (EC) function, but may be damaged during renal disease. We hypothesized that the ischemic and metabolic constituents of swine renovascular disease (RVD) induce mitochondrial damage and impair the function of renal artery ECs. METHODS Pigs were studied after 16 weeks of metabolic syndrome (MetS), renal artery stenosis (RAS), or MetS + RAS, and Lean pigs served as control (n = 6 each). Mitochondrial morphology, homeostasis, and function were measured in isolated primary stenotic-kidney artery ECs. EC functions were assessed in vitro, whereas vasoreactivity of renal artery segments was characterized in organ baths. RESULTS Lean + RAS and MetS + RAS ECs showed increased mitochondrial area and decreased matrix density. Mitochondrial biogenesis was impaired in MetS and MetS + RAS compared with their respective controls. Mitochondrial membrane potential similarly decreased in MetS, Lean + RAS, and MetS + RAS groups, whereas production of reactive oxygen species increased in MetS vs. Lean, but further increased in both RAS groups. EC tube formation was impaired in MetS, RAS, and MetS + RAS vs. Lean, but EC proliferation and endothelial-dependent relaxation of renal artery segments were blunted in MetS vs. Lean, but further attenuated in Lean + RAS and MetS + RAS. CONCLUSIONS MetS and RAS damage mitochondria in pig renal artery ECs, which may impair EC function. Coexisting MetS and RAS did not aggravate EC mitochondrial damage in the short time of our in vivo studies, suggesting that mitochondrial injury is associated with impaired renal artery EC function.