Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199901143400207

Atherosclerosis — An Inflammatory Disease

https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/49782/1/Yamanaka_Cell_131_5.pdf

Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

https://www.seas.upenn.edu/%7Edischer/pdfs/Cell_on_Gel-CELLpaper.pdf

Matrix elasticity directs stem cell lineage specification.

Atherosclerosis is an Inflammatory Disease

We have previously shown that a brief episode of ischemia slows the rate of ATP depletion during subsequent ischemic episodes. Additionally, intermittent reperfusion may be beneficial to the myocardium by washing out catabolites that have accumulated during ischemia. Thus, we proposed that multiple brief ischemic episodes might actually protect the heart from a subsequent sustained ischemic insult. To test this hypothesis, two sets of experiments were performed. In the first set, one group of dogs (n = 7) was preconditioned with four 5 min circumflex occlusions, each separated by 5 min of reperfusion, followed by a sustained 40 min occlusion. The control group (n = 5) received a single 40 min occlusion. In the second study, an identical preconditioning protocol was followed, and animals (n = 9) then received a sustained 3 hr occlusion. Control animals (n = 7) received a single 3 hr occlusion. Animals were allowed 4 days of reperfusion thereafter. Histologic infarct size then was measured and was related to the major baseline predictors of infarct size, including the anatomic area at risk and collateral blood flow. In the 40 min study, preconditioning with ischemia paradoxically limited infarct size to 25% of that seen in the control group (p less than .001). Collateral blood flows were not significantly different in the two groups. In the 3 hr study, there was no difference between infarct size in the preconditioned and control groups. The protective effect of preconditioning in the 40 min study may have been due to reduced ATP depletion and/or to reduced catabolite accumulation during the sustained occlusion. These results suggest that the multiple anginal episodes that often precede myocardial infarction in man may delay cell death after coronary occlusion, and thereby allow for greater salvage of myocardium through reperfusion therapy.

Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.

Despite substantial advances, bona fide regeneration of the damaged human heart is still an unmet ambition. By extracting our current knowledge from developmental biology, animal models of heart regeneration, and clinical observations, we propose five hallmarks of cardiac regeneration and suggest a holistic approach to reconstituting human heart function.

/pdf/hallmarks-of-cardiac-regeneration-57ygqlgj7h.pdf

Hallmarks of cardiac regeneration

Intramyocardial injection of therapeutic agents may enhance heart repair after infarction Incomplete retention of intramyocardial injections has been reported, but modes of loss are undefined We determined the fate of neutron-activated microspheres injected into acutely ischemic rat myocardium using saline, Pluronic F127, or Matrigel as vehicle Twenty minutes after injection in saline, 63% ± 12% of 10-μm microspheres was retained in the heart Similar retention was observed after 6 days Injection site leakage accounted for 14% ± 5% of the microspheres, whereas exit via coronary veins resulted in 112% ± 95% collecting in the lungs Microspheres distribution to other organs was minimal Retention of 40-μm microspheres was similar to that observed with the 10-μm microspheres Pluronic F127 and Matrigel reduced immediate leakage to 4% ± 1% and 2% ± 1%, respectively Surprisingly, microsphere retention in the heart was not improved at 20 min using either gelling vehicle, suggesting that leakage occurs over a prolonged period Thus, most injected particles are retained in the ischemic rat heart following direct injection, but significant fractions are lost from the injection site and through coronary veins Gelling agents reduced short-term leakage, but failed to enhance longer-term retention Hydrogels with stiffer mechanical properties might enhance retention and reduce variability © 2008 Wiley Periodicals, Inc J Biomed Mater Res, 2009

Retention and biodistribution of microspheres injected into ischemic myocardium.

Human Pluripotent Stem Cell-Derived Engineered Tissues: Clinical Considerations.

Engineered heart tissues made from human pluripotent stem cell-derived cardiomyocytes have been used for modeling cardiac pathologies, screening new therapeutics, and providing replacement cardiac tissue. Current methods measure the functional performance of engineered heart tissue by their twitch force and beating frequency, typically obtained by optical measurements. In this article, we describe a novel method for assessing twitch force and beating frequency of engineered heart tissue using magnetic field sensing, which enables multiple tissues to be measured simultaneously. The tissues are formed as thin structures suspended between two silicone posts, where one post is rigid and another is flexible and contains an embedded magnet. When the tissue contracts it causes the flexible post to bend in proportion to its twitch force. We measured the bending of the post using giant magnetoresistive (GMR) sensors located underneath a 24-well plate containing the tissues. We validated the accuracy of the readings from the GMR sensors against optical measurements. We demonstrated the utility and sensitivity of our approach by testing the effects of three concentrations of isoproterenol and verapamil on twitch force and beating frequency in real-time, parallel experiments. This system should be scalable beyond the 24-well format, enabling greater automation in assessing the contractile function of cardiomyocytes in a tissue-engineered environment.

Real-Time Force and Frequency Analysis of Engineered Human Heart Tissue Derived from Induced Pluripotent Stem Cells Using Magnetic Sensing.

The present invention generally relates to the field of cell growth and tissue engineering, in particular, tissue engineered compositions comprising a nanotextured substrate which is structurally configured for growth of cells in an anatomically correct adult phenotype in vitro. In particular, described herein are nanotextured substrates which are structurally configured for the anisotropic organization, maturation, and growth of in vitro-differentiated muscle cells, such as cardiomyocytes, and methods for the production and use thereof in varying sizes, nanotextures and substrate rigidities. In vitro-differentiated cardiomyocytes grown on the nanotextured substrates described herein are better-differentiated and more closely mimic adult cardiac tissue than the same cells grownon a non-textured substrate of the same composition. The nanotextured substrate/cell constructs provide a platform for screening to predict the effect of test agents or drugs on, for example, human cardiac tissue, including patient-derived tissue, or for the identification of agents that effect various cardiac functional parameters.

Charles E. Murry

Papers

Hallmarks of cardiac regeneration

Retention and biodistribution of microspheres injected into ischemic myocardium.

Human Pluripotent Stem Cell-Derived Engineered Tissues: Clinical Considerations.

Real-Time Force and Frequency Analysis of Engineered Human Heart Tissue Derived from Induced Pluripotent Stem Cells Using Magnetic Sensing.

Systems and method for engineering muscle tissue