Ossabaw Pigs With a PCSK9 Gain-of-Function Mutation Develop Accelerated Coronary Atherosclerotic Lesions: A Novel Model for Preclinical Studies.

Background: Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp (proprotein convertase subtilisin-like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene.

Methods And Results: Ossabaw and Landrace gain-of-function founders were generated by transposition and cloning.

Targeting Murine Mesenchymal Stem Cells to Kidney Injury Molecule-1 Improves Their Therapeutic Efficacy in Chronic Ischemic Kidney Injury.

Mesenchymal stem cells (MSC) have been experimentally used for kidney repair, but modest retention limits their efficacy. Cell-surface coating allows modulating MSC homing and interaction with target cells. We coated mouse adipose tissue-derived MSC with antibodies directed against kidney injury molecule-1 (ab-KIM1), which is upregulated in injured kidneys, and tested the hypothesis that this would enhance their therapeutic effects in ischemic kidney injury.

Renal scattered tubular-like cells confer protective effects in the stenotic murine kidney mediated by release of extracellular vesicles.

To test the hypothesis that intrinsic renal scattered tubular cells (STC-like cells) contribute to repairing injured tubular epithelial cells (TEC) by releasing extracellular vesicle (EV). EV released from primary cultured pig STC-like cells were confirmed by electron microscopy. Antimycin-A (AMA)-induced injured proximal TEC (PK1 cells) were co-cultured with STC-like cells, STC-like cells-derived EV, or EV-free conditioned-medium for 3 days.

Chronic inhibition of lipoprotein-associated phospholipase A does not improve coronary endothelial function: A prospective, randomized-controlled trial.

Aims: Lipoprotein-associated phospholipase A (Lp-PLA), a novel biomarker for vascular inflammation, is associated with coronary endothelial dysfunction (CED) and independently predicts cardiovascular events. The current study aimed to determine whether darapladib, an orally administered Lp-PLA inhibitor, improved CED.

Methods And Results: Fifty-four patients with CED were enrolled in a double-blinded randomized placebo-controlled trial, and were randomized to receive oral darapladib, 160mg daily, or placebo.

Magnetic resonance elastography can monitor changes in medullary stiffness in response to treatment in the swine ischemic kidney.

Objective: Low-energy shockwave (SW) therapy attenuates damage in the stenotic kidney (STK) caused by atherosclerotic renal artery stenosis (ARAS). We hypothesized that magnetic resonance elastography (MRE) would detect attenuation of fibrosis following SW in unilateral ARAS kidneys.

Materials And Methods: Domestic pigs were randomized to control, unilateral ARAS, and ARAS treated with 6 sessions of SW over 3 consecutive weeks (n = 7 each) starting after 3 weeks of ARAS or sham.

Mitochondrial targeted peptides preserve mitochondrial organization and decrease reversible myocardial changes in early swine metabolic syndrome.

Aims: The mechanisms responsible for cardiac damage in the early stages of metabolic syndrome (MetS) remain unknown. Mitochondria are intimately associated with cellular myofibrils, with the cytoskeleton functioning as a linkage coordinator, and closely associated to the calcium release sites of the sarcoplasmic reticulum (SR). We hypothesized that early MetS is characterized by mitochondria-related myocardial damage, associated with altered cytoskeletal-mitochondria-SR interaction.

Obesity-induced mitochondrial dysfunction in porcine adipose tissue-derived mesenchymal stem cells.

Transplantation of autologous mesenchymal stem cells (MSCs) may be a viable option for treatment of several diseases. MSCs efficacy depends on adequate function of their mitochondria, which might be impaired in a noxious milieu. We hypothesized that obesity compromises MSCs mitochondrial structure and function, possibly via micro-RNA (miRNA)-based mechanisms.

Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction.

Background: MOTS-c is one of the newly identified mitochondrial-derived peptides which play a role in regulating metabolic homeostasis. The current study aimed to investigate whether circulating MOTS-c levels are also associated with endothelial dysfunction(ED) in patients without significant structural coronary lesions.

Methods: Forty patients undergoing coronary angiography and endothelial function testing for clinical indications of recurrent angina with no structural coronary lesions were included in the study.

Mesenchymal stem cell-derived extracellular vesicles for kidney repair: current status and looming challenges.

Novel therapies are urgently needed to address the rising incidence and prevalence of acute kidney injury (AKI) and chronic kidney disease (CKD). Mesenchymal stem/stromal cells (MSCs) have shown promising results in experimental AKI and CKD, and have been used in the clinic for more than a decade with an excellent safety profile. The regenerative effects of MSCs do not rely on their differentiation and ability to replace damaged tissues, but are primarily mediated by the paracrine release of factors, including extracellular vesicles (EVs), composed of microvesicles and exosomes.

Mitoprotection attenuates myocardial vascular impairment in porcine metabolic syndrome.

Metabolic syndrome (MetS) leads to cardiac vascular injury, which may reflect in increased retention of endothelial progenitor cells (EPCs). Coronary endothelial cell (EC) mitochondria partly regulate vascular function and structure. We hypothesized that chronic mitoprotection would preserve EC mitochondria and attenuate coronary vascular injury and dysfunction in swine MetS.

A rapid T mapping method for assessment of murine kidney viability using dynamic manganese-enhanced magnetic resonance imaging.

Purpose: Dynamic manganese-enhanced MRI (MEMRI) allows assessment of tissue viability by tracing manganese uptake. We aimed to develop a rapid T mapping method for dynamic MEMRI to facilitate assessments of murine kidney viability.

Methods: A multi-slice saturation recovery fast spin echo (MSRFSE) was developed, validated, and subsequently applied in dynamic MEMRI at 16.

Diagnostic imaging in the management of patients with metabolic syndrome.

Metabolic syndrome (MetS) is the constellation of metabolic risk factors that might foster development of type 2 diabetes and cardiovascular disease. Abdominal obesity and insulin resistance play a prominent role among all metabolic traits of MetS. Because intervention including weight loss can reduce these morbidity and mortality in MetS, early detection of the severity and complications of MetS could be useful.

Peripheral vascular atherosclerosis in a novel PCSK9 gain-of-function mutant Ossabaw miniature pig model.

Hypercholesterolemia is a major risk factor for atherosclerosis. Remaining challenges in the management of atherosclerosis necessitate development of animal models that mimic human pathophysiology. We characterized a novel mutant pig model with DNA transposition of D374Y gain-of-function (GOF) cDNA of chimp proprotein convertase subtilisin/kexin type-9 (PCSK9), and tested the hypothesis that it would develop peripheral vascular remodeling and target organ injury in the kidney.

Measurement of Murine Single-Kidney Glomerular Filtration Rate Using Dynamic Contrast-Enhanced MRI.

Purpose: To develop and validate a method for measuring murine single-kidney glomerular filtration rate (GFR) using dynamic contrast-enhanced MRI (DCE-MRI).

Methods: This prospective study was approved by the Institutional Animal Care and Use Committee. A fast longitudinal relaxation time (T ) measurement method was implemented to capture gadolinium dynamics (1 s/scan), and a modified two-compartment model was developed to quantify GFR as well as renal perfusion using 16.

Phase 2a Clinical Trial of Mitochondrial Protection (Elamipretide) During Stent Revascularization in Patients With Atherosclerotic Renal Artery Stenosis.

Background: Atherosclerotic renal artery stenosis reduces renal blood flow (RBF) and amplifies stenotic kidney hypoxia. Revascularization with percutaneous transluminal renal angioplasty (PTRA) and stenting often fails to recover renal function, possibly because of ischemia/reperfusion injury developing after PTRA. Elamipretide is a mitochondrial-targeted peptide that binds to cardiolipin and stabilizes mitochondrial function.

Prevalence of diastolic function and clinical impact on long-term outcome in takotsubo cardiomyopathy.

Background: Takotsubo cardiomyopathy (TTC) is a syndrome characterized by transient regional systolic dysfunction of the left ventricle (LV). However, far fewer reports focused on the prevalence of left ventricular diastolic function (DF) and its impact on an adverse prognosis in TTC.

Methods: From January 2005 to October 2014, 205 consecutive TTC patients (mean age, 70±12years; 95% female) were studied.

Porcine arteriogenesis based on vasa vasorum in a novel semi-acute occlusion model using high-resolution imaging.

Bridging collaterals (BC) develop in several chronic total artery occlusion diseases, and can prevent extensive myocardial necrosis. Yet, their origin, growth process, and histo-morphology are still unclear. Since vasa vasorum (VV) may take part in collateralization, we hypothesized that VV are the basis for BCs.

High-sensitivity C-reactive protein is an independent marker of abnormal coronary vasoreactivity in patients with non-obstructive coronary artery disease.

Background: Coronary endothelial dysfunction (CED) is an early stage of atherosclerosis and is associated with adverse cardiovascular events. Inflammation may play a role in the development of endothelial dysfunction. To date no study has evaluated the relationship between C-reactive protein and CED.

The metabolic syndrome alters the miRNA signature of porcine adipose tissue-derived mesenchymal stem cells.

Autologous transplantation of mesenchymal stem cells (MSCs) is a viable option for the treatment of several diseases. Evidence indicates that MSCs release extracellular vesicles (EVs) and that EVs shuttle miRNAs to damaged parenchymal cells to activate an endogenous repair program. We hypothesize that comorbidities may interfere with the packaging of cargo in MSC-derived EVs.

Glomerular Hyperfiltration in Obese African American Hypertensive Patients Is Associated With Elevated Urinary Mitochondrial-DNA Copy Number.

Background: Glomerular hyperfiltration may contribute to the high incidence of renal disease in Obese African Americans essential hypertensive (ObAAEH) patients, but the precise mechanisms responsible for renal injury have not been elucidated. Mitochondria are important determinants of renal injury in hypertension, and increased levels of mitochondrial DNA (mtDNA) in the urine may indicate renal mitochondrial injury. We hypothesized that urine mtDNA copy numbers would be higher in ObAAEH compared to Caucasian essential hypertensive (CEH) patients.

Single-Nephron Glomerular Filtration Rate in Healthy Adults.

Background: The glomerular filtration rate (GFR) assesses the function of all nephrons, and the single-nephron GFR assesses the function of individual nephrons. How the single-nephron GFR relates to demographic and clinical characteristics and kidney-biopsy findings in humans is unknown.

Methods: We identified 1388 living kidney donors at the Mayo Clinic and the Cleveland Clinic who underwent a computed tomographic (CT) scan of the kidney with the use of contrast material and an iothalamate-based measurement of the GFR during donor evaluation and who underwent a kidney biopsy at donation.