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Stem Cell–Based Tissue Replacement After Stroke: Factual Necessity or Notorious Fiction?
Stroke Volume 46, Issue 81 August 2015

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Abstract WMP79: Favorable Outcome of Stroke in Immunodeficient Mice is Preceded by Faster Normalization of T2 Relaxation
- Miroslaw Janowski,
- Agatha Lyczek,
- Jiadi Xu,
- Jeff W Bulte and
- Piotr Walczak
Stroke Volume 49, Issue Suppl_1

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Introduction: Despite the success of rtPA and thrombectomy stroke continues to be a major disease burden to our society. Preventing secondary brain injury after stroke, given the broad therapeutic window, has gained increasing interest. It has been hypothesized that immunological processes substantially contribute to secondary brain damage. Indeed, the outcome of stroke in immunodeficient animals is more favorable compared to that in their immunocompetent counterparts. Here, we followed the evolution of stroke in the presence vs. absence of lymphocytes using serial MRI and T2 measurements.Methods: Adult immunodeficient rag2^-/- mice (n=6) and immunocompetent BALB/c mice (n=6) were subjected to stroke by intracerebral injection of 0.5 μl of 5 mM ouabain. Brain T2 relaxation times were measured using an 11.7T scanner at 1, 5, and 16 days following stroke induction. Post-mortem analysis of tissue sections included H&E and immunohistochemical staining for myelin basic protein, neurofilament, CD8, and CD68.Results: While the increase in T2 values was identical for immunocompetent and immunodeficient animals one day post-stroke (70.88±4.58 vs. 69.88±1.78 ms, respectively, p=0.72), the normalization of the T2 relaxation time (“fogging effect”) proceeded faster in immunodeficient animals over the next few days. Over five days, T2 relaxation times decreased in both groups, but it was significantly shorter in immunodeficient animals compared to immunocompetent animals (41.88±3.68 vs. 59.91±14.95 ms, respectively; p<0.001). On day 16, the T2 relaxation time decreased further in both groups and the difference between infarcted area in immunodeficient and immunocompetent animals as well as healthy tissue was no longer observed. Post-mortem analysis revealed a better preservation of infarcted tissue in immunodeficient animals.Conclusions: In immunodeficient rag2^-/- mice, the restoration of T2 relaxation times in the brain is faster and translates into less profound destruction of brain tissue within stroke lesions. We hypothesize that T2 relaxation time can be used for assessment of immunotherapies aimed at the reduction of secondary brain injury in stroke victims.
Stretching the Spring of Endovascular Opportunity in Stroke
- Dheeraj Gandhi and
- Miroslaw Janowski
Stroke Volume 52, Issue 31 March 2021

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Intra-Arterial Delivery of Cell Therapies for Stroke
- Raphael Guzman,
- Miroslaw Janowski and
- Piotr Walczak
Stroke Volume 49, Issue 51 May 2018

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Abstract 15082: Novel Imaging/Hemodynamic Based Right Ventricular Phenotypes in Patients With Pulmonary Hypertension
- Alexandra M Janowski,
- Scott H Visovatti,
- raymond Benza and
- Rebecca Vanderpool
Circulation Volume 148, Issue Suppl_17 November 2023

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Introduction: Right ventricular function and ventricular dynamics associate with outcomes in pulmonary hypertension (PH). Measures of RV strain describe ventricular mechanics but are not included in RV function assessments. This study aimed to develop novel RV imaging-hemodynamic phenotypes using unsupervised machine learning.Methods: Participants with cardiac magnetic resonance (CMR) and right heart catheterization data were identified from The Ohio State University CMR PH registry (n=81). RV areas were segmented from CMR 4-chamber images and used to determine RV free wall (RVFW) and septal strain. K-medoids clustering was used on imaging features, RV hemodynamics, and RV function (Figure A). Correlation analysis was used to reduce collinearity. Significance was measured with Kruskal Wallis and chi-squared tests. A p-value < 0.05 was considered significant.Results: Participants were assigned to three clusters and top contributors to cluster assignment were RVEF, RVFW strain, and Ea. RV phenotypes progress from mild/no RV dysfunction (Cluster 1) to severe RV dysfunction (Cluster 3) (Figure A). Cluster 1 had normal RV function with high RVEF and PA compliance, preserved LVEF, low RVSP, and low Eed. Compared to cluster 1, cluster 2 demonstrates more RV dysfunction with reduced RVEF, stroke volume, and PA compliance with an increase in RVSP but no change in Eed. In addition to more RV dysfunction (decreased RVEF and stroke volume), cluster 3 had increased RA pressure and Eed. In terms of RV strain, (Figure B), cluster 2 had less negative RVFW and septal strain compared to cluster 1. In cluster 3, RV septal strain is similar to cluster 2 but with decreased RVFW strain.Conclusions: Imaging and hemodynamic RV variables contribute to identification of novel RV-centric phenotypes and should be included in phenotyping efforts to better describe altered ventricular dynamics contributing to RV dysfunction in PH.
Abstract 13977: Identification of Intermediate Right Ventricular Phenotypes Using Consensus Clustering in Patients With Pulmonary Hypertension
- Alexandra M Janowski,
- Keeley Ravellette,
- Joe G Garcia,
- Franz Rischard and
- Rebecca Vanderpool
Circulation Volume 144, Issue Suppl_116 November 2021

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Introduction: Current right ventricular (RV) function phenotypes in pulmonary hypertension (PH) rely on few hemodynamic parameters to quantify RV dysfunction disease severity. The aim of the study was to identify novel RV phenotypes using RV hemodynamics and unsupervised machine learning in patients with PH.Methods: Participants were identified from the UArizona PH Registry (n=190). Correlation analyses identified 9 RV variables to include in clustering analysis. Consensus clustering was used to identify an unsupervised clustering method with a large inter-cluster, and small intra-cluster distance (Fig 1A). Significance was tested with Dunn and chi-square tests.Results: K-Medoids with a Pearson distance matrix over >1000 resampling iterations identified 5 clusters (consensus range: 0.8-0.9). World Symposium PH groups were distributed across clusters (Fig 1B). Clusters 1, 2 and 5 exhibit mild RV dysfunction with low diastolic stiffness (Eed) and afterload (Ea, Fig 1C). However, RV-PA coupling (Ees/Ea) was decreased in clusters 1 and 5. Clusters 3 and 4 have moderate to severe RV dysfunction with increased Eed and Ea but cluster 4 had decreased Ees/Ea. For pulmonary hemodynamics, clusters 3 and 4 have increased mean PA pressure (mPAP), increased pulmonary vascular resistance (PVR) and decreased PA compliance (Ca) compared to clusters 1 and 2. Cluster 5 has increased mPAP and high cardiac output resulting in moderately elevated PVR and decreased Ca.Conclusions: Unsupervised clustering identified 5 unique RV phenotypes ranging from mild to severe dysfunction. Further investigations are needed to identify factors modulating intermediate phenotypes to provide insight into RV dysfunction and disease progression.
Abstract 17308: Unsupervised K-means Clustering to Identify Signatures of Right Ventricle Dysfunction in Patients With Pulmonary Hypertension
- Alexandra M Janowski,
- Keeley S Ravellette,
- Joe G Garcia,
- Franz Rischard and
- Rebecca R Vanderpool
Circulation Volume 142, Issue Suppl_317 November 2020

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Introduction: Right ventricular (RV) function is a determinant of mortality in patients with pulmonary hypertension but current assessments are based on individual variables. Unsupervised k-means clustering can be used as an unbiased approach to determine distinct patient groups based on RV dysfunction. The aim of the study was to use unsupervised clustering to identify clinically meaningful RV phenotypes.Methods: Participants were identified from the University of Arizona PH registry (n=213). Patients with missing hemodynamic RV function data were excluded (n=23). Unsupervised clustering (k-means) was applied to variables of systolic and diastolic ventricular function including: max dP/dt/RVSP, Ees, Ea, Ees/Ea, max dP/dt, min dP/dt, RV EDP, β and Eed. Linear discriminant analysis (LDA) was performed to determine the weight of variables in cluster assignment.Results: Participants without PH (n=41) and World Symposium Pulmonary Hypertension (WSPH) Groups 1 (n=104), 2 (n=22), 3 (n=28), 4 (n=12), 5 (n=2) were assigned to four clusters based on the elbow method (Figure 1A). Two major determinants of cluster assignment were arterial elastance (Ea) and end systolic elastance (Ees). Participants with WSPH Group 1 were distributed across clusters (Figure 1B). Degree of RV dysfunction was highest in cluster 4 with increased Ees and Ea compared to other clusters (Figure 1C). Eed, Ees/Ea and mPAP (61 ± 22 mmHg) were increased compared to clusters 1 and 3. Sex, Ethnicity, BMI and cardiac output were not significant between clusters. Cluster 4 had increased PVR (11.1 ± 5.5 WU), and decreased PA compliance (1.2 ± 0.6 mmHg/ml) compared to other clusters.Conclusions: Unsupervised k-means clustering based on hemodynamic measures of RV function identified four distinct RV dysfunction phenotypes ranging from mild to severe.
Abstract 15151: Identification of Novel Right Ventricular Function Phenotypes in Pulmonary Arterial Hypertension Using Unbiased K-Means Clustering
- Rebecca R Vanderpool,
- Alexandra M Janowski,
- Charles Fauvel,
- Zilu Liu,
- Shili Lin,
- Priscilla Correa-Jaque,
- Amy Webb,
- Manreet Kanwar,
- Jidapa Kraisangka,
- Puneet Mathur,
- Adam Perer,
- Allen D Everett,
- Scott H Visovatti and
- Raymond L Benza
Circulation Volume 146, Issue Suppl_18 November 2022

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Introduction: Survival in pulmonary arterial hypertension (PAH) is associated with right ventricular (RV) function rather than pulmonary vascular resistance (PVR). At present, RV function is not incorporated in current risk assessment models and studies evaluating RV function are generally limited to single-center studies. The aim was to identify novel RV function phenotypes using unbiased k-means clustering in patients with PAH.Methods: Baseline clinical and hemodynamic data in patients with PAH were harmonized data from 5 PAH clinical trials (COMPASS3: n=98, EARLY: n=176, GRIPHON: n=720, MAESTRO: n=44, and SERAPHIN: n=728). Pearson correlation analysis was used to select variables that reduce the co-linearity (|r| < 0.7) between hemodynamic variables used in the models. K-means clustering methods were applied to advanced RV hemodynamics including end-systolic pressure (ESP), arterial elastance (Ea), single-beat end-diastolic elastance (Eed), Pulse pressure (PP), stroke volume (SV) and RV stroke work (RVSW). Survival analysis was used to compare all-cause mortality among each cluster group.Results: Participants in the harmonized dataset (n=1766) had a mean PAP of 53 ± 17 mmHg, a cardiac output of 4.3±1.4 L/min, a wedge pressure of 9±4 mmHg and a PVR of 11.8±7.4 WU. K-means clustering identified four distinct RV cluster phenotypes that range from mild to severe RV dysfunction (Fig. A). Participants in RV cluster 1 (RV C1) have severe RV dysfunction with increased pressure/afterload, decreased cardiac function, and increased diastolic stiffness compared to RV cluster 4 (RV C4). (Fig. A) RV C1 had decreased six-minute walk distance compared to other clusters. RVC1 and RVC2 had increased risk of mortality compared to RV C4 (Fig. B).Conclusion: Applying K-means clustering to harmonized hemodynamic data from PAH clinical trial data identified 4 unique RV function phenotypes with different clinical outcomes.
Editor’s Correspondence
- Marc Fisher
Stroke Volume 48, Issue 81 August 2017

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Liver X Receptor Activator Downregulates Angiotensin II Type 1 Receptor Expression Through Dephosphorylation of Sp1
- Ikuyo Imayama,
- Toshihiro Ichiki,
- Dan Patton,
- Keita Inanaga,
- Ryohei Miyazaki,
- Hideki Ohtsubo,
- Qingping Tian,
- Kotaro Yano and
- Kenji Sunagawa
Hypertension Volume 51, Issue 61 June 2008

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Atherosclerosis is considered to be a combined disorder of lipid metabolism and chronic inflammation. Recent studies have reported that liver X receptors (LXRs) are involved in lipid metabolism and inflammation and that LXR agonists inhibit atherogenesis. In contrast, angiotensin II is well known to accelerate atherogenesis through activation of the angiotensin II type 1 receptor (AT1R). To better understand the mechanism of LXR on the prevention of atherogenesis, we examined whether activation of LXR affects AT1R expression in vascular smooth muscle cells. T0901317, a synthetic LXR ligand, decreased AT1R mRNA and protein expression with a peak reduction at 6 hours and 12 hours of incubation, respectively. A well-established ligand of LXR, 22-(R)-hydroxycholesterol, also suppressed AT1R expression. The downregulation of AT1R by T0901317 required de novo protein synthesis. AT1R gene promoter activity measured by luciferase assay revealed that the DNA segment between −61 bp and +25 bp was sufficient for downregulation. Luciferase construct with a mutation in Sp1 binding site located in this segment lost its response to T0901317. T0901317 decreased Sp1 serine phosphorylation. Although preincubation of vascular smooth muscle cells with T0901317 for 30 minutes had no effect on angiotensin II–induced extracellular signal–regulated kinase phosphorylation, phosphorylation of extracellular signal–regulated kinase by angiotensin II was markedly suppressed after 6 hours of preincubation. These results indicate that the suppression of AT1R may be one of the important mechanisms by which LXR ligands exert antiatherogenic effects.
Dual-Modality Monitoring of Targeted Intraarterial Delivery of Mesenchymal Stem Cells After Transient Ischemia
- Piotr Walczak,
- Jian Zhang,
- Assaf A. Gilad,
- Dorota A. Kedziorek,
- Jesus Ruiz-Cabello,
- Randell G. Young,
- Mark F. Pittenger,
- Peter C.M. van Zijl,
- Judy Huang and
- Jeff W.M. Bulte
Stroke Volume 39, Issue 51 May 2008

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Background and Purpose— In animal models of stroke, functional improvement has been obtained after stem cell transplantation. Successful therapy depends largely on achieving a robust and targeted cell engraftment, with intraarterial (IA) injection being a potentially attractive route of administration. We assessed the suitability of laser Doppler flow (LDF) signal measurements and magnetic resonance (MR) imaging for noninvasive dual monitoring of targeted IA cell delivery.Methods— Transient cerebral ischemia was induced in adult Wistar rats (n=25) followed by IA or intravenous (IV) injection of mesenchymal stem cells (MSCs) labeled with superparamagnetic iron oxide. Cell infusion was monitored in real time with transcranial laser Doppler flowmetry while cellular delivery was assessed with MRI in vivo (4.7T) and ex vivo (9.4T).Results— Successful delivery of magnetically labeled MSCs could be readily visualized with MRI after IA but not IV injection. IA stem cell injection during acute stroke resulted in a high variability of cerebral engraftment. The amount of LDF reduction during cell infusion (up to 80%) was found to correlate well with the degree of intracerebral engraftment, with low LDF values being associated with significant morbidity.Conclusions— High cerebral engraftment rates are associated with impeded cerebral blood flow. Noninvasive dual-modality imaging enables monitoring of targeted cell delivery, and through interactive adjustment may improve the safety and efficacy of stem cell therapy.

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Stem Cell–Based Tissue Replacement After Stroke: Factual Necessity or Notorious Fiction?

Abstract

Abstract WMP79: Favorable Outcome of Stroke in Immunodeficient Mice is Preceded by Faster Normalization of T2 Relaxation

Abstract

Stretching the Spring of Endovascular Opportunity in Stroke

Abstract

Intra-Arterial Delivery of Cell Therapies for Stroke

Abstract

Abstract 15082: Novel Imaging/Hemodynamic Based Right Ventricular Phenotypes in Patients With Pulmonary Hypertension

Abstract

Abstract 13977: Identification of Intermediate Right Ventricular Phenotypes Using Consensus Clustering in Patients With Pulmonary Hypertension

Abstract

Abstract 17308: Unsupervised K-means Clustering to Identify Signatures of Right Ventricle Dysfunction in Patients With Pulmonary Hypertension

Abstract

Abstract 15151: Identification of Novel Right Ventricular Function Phenotypes in Pulmonary Arterial Hypertension Using Unbiased K-Means Clustering

Abstract

Editor’s Correspondence

Abstract

Liver X Receptor Activator Downregulates Angiotensin II Type 1 Receptor Expression Through Dephosphorylation of Sp1

Abstract

Dual-Modality Monitoring of Targeted Intraarterial Delivery of Mesenchymal Stem Cells After Transient Ischemia

Abstract