Prevalence, Predictors, and Outcomes of Type 2 NSTEMI in Hospitalized Patients With COVID-19.

BACKGROUND: Data on the incidence of type 2 non-ST-segment-elevation myocardial infarction (T2MI) in hospitalized patients with COVID-19 has been limited to single-center studies. Given that certain characteristics, such as obesity and type 2 diabetes, have been associated with higher mortality in COVID-19 infections, we aimed to define the incidence of T2MI in a national cohort and identify pre-hospital patient characteristics associated with T2MI in hospitalized patients with COVID-19. METHODS AND RESULTS: Using the national American Heart Association COVID-19 Cardiovascular Disease Quality Improvement Registry, we performed a retrospective 4:1 matched (age, sex, race, and body mass index) analysis of controls versus cases with T2MI. We performed (1) conditional multivariable logistic regression to identify predictive pre-hospital patient characteristics of T2MI for patients hospitalized with COVID-19 and (2) stratified proportional hazards regression to investigate the association of T2MI with morbidity and mortality. From January 2020 through May 2021, there were 709 (2.2%) out of 32 015 patients with T2MI. Five hundred seventy-nine cases with T2MI were matched to 2171 controls (mean age 70; 43% female). Known coronary artery disease, heart failure, chronic kidney disease, hypertension, payor source, and presenting heart rate were associated with higher odds of T2MI. Anti-hyperglycemic medication and anti-coagulation use before admission were associated with lower odds of T2MI. Those with T2MI had higher morbidity and mortality (hazard ratio, 1.40 [95% CI, 1.13-1.74]; P=0.002). CONCLUSIONS: In hospitalized patients with COVID-19, those with a T2MI compared with those without had higher morbidity and mortality. Outpatient anti-hyperglycemic and anti-coagulation use were the only pre-admission factors associated with reduced odds of T2MI.

The 2020 ACC/AHA Guidelines for Management of Patients With Valvular Heart Disease: Highlights and Perioperative Implications.

Valvular heart disease contributes to a large burden of morbidity and mortality in the United States. During the last decade there has been a paradigm shift in the management of valve disease, primarily driven by the emergence of novel transcatheter technologies. In this article, the latest update of the American College of Cardiology/American Heart Association valve heart disease guidelines is reviewed.

A new classification of cardio-oncology syndromes.

Increasing evidence suggests a multifaceted relationship exists between cancer and cardiovascular disease (CVD). Here, we introduce a 5-tier classification system to categorize cardio-oncology syndromes (COS) that represent the aspects of the relationship between cancer and CVD. COS Type I is characterized by mechanisms whereby the abrupt onset or progression of cancer can lead to cardiovascular dysfunction. COS Type II includes the mechanisms by which cancer therapies can result in acute or chronic CVD. COS Type III is characterized by the pro-oncogenic environment created by the release of cardiokines and high oxidative stress in patients with cardiovascular dysfunction. COS Type IV is comprised of CVD therapies and diagnostic procedures which have been associated with promoting or unmasking cancer. COS Type V is characterized by factors causing systemic and genetic predisposition to both CVD and cancer. The development of this framework may allow for an increased facilitation of cancer care while optimizing cardiovascular health through focused treatment targeting the COS type.

Modeling Precision Cardio-Oncology: Using Human-Induced Pluripotent Stem Cells for Risk Stratification and Prevention.

PURPOSE OF REVIEW: Cardiovascular toxicity is a leading cause of mortality among cancer survivors and has become increasingly prevalent due to improved cancer survival rates. In this review, we synthesize evidence illustrating how common cancer therapeutic agents, such as anthracyclines, human epidermal growth factors receptors (HER2) monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been evaluated in cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPSCs) to understand the underlying mechanisms of cardiovascular toxicity. We place this in the context of precision cardio-oncology, an emerging concept for personalizing the prevention and management of cardiovascular toxicities from cancer therapies, accounting for each individual patient's unique factors. We outline steps that will need to be addressed by multidisciplinary teams of cardiologists and oncologists in partnership with regulators to implement future applications of hiPSCs in precision cardio-oncology. RECENT FINDINGS: Current prevention of cardiovascular toxicity involves routine screenings and management of modifiable risk factors for cancer patients, as well as the initiation of cardioprotective medications. Despite recent advancements in precision cardio-oncology, knowledge gaps remain and limit our ability to appropriately predict with precision which patients will develop cardiovascular toxicity. Investigations using patient-specific CMs facilitate pharmacological discovery, mechanistic toxicity studies, and the identification of cardioprotective pathways. Studies with hiPSCs demonstrate that patients with comorbidities have more frequent adverse responses, compared to their counterparts without cardiac disease. Further studies utilizing hiPSC modeling should be considered, to evaluate the impact and mitigation of known cardiovascular risk factors, including blood pressure, body mass index (BMI), smoking status, diabetes, and physical activity in their role in cardiovascular toxicity after cancer therapy. Future real-world applications will depend on understanding the current use of hiPSC modeling in order for oncologists and cardiologists together to inform their potential to improve our clinical collaborative practice in cardio-oncology. When applying such in vitro characterization, it is hypothesized that a safety score can be assigned to each individual to determine who has a greater probability of developing cardiovascular toxicity. Using hiPSCs to create personalized models and ultimately evaluate the cardiovascular toxicity of individuals' treatments may one day lead to more patient-specific treatment plans in precision cardio-oncology while reducing cardiovascular disease (CVD) morbidity and mortality.

A virtual-hybrid approach to launching a cardio-oncology clinic during a pandemic.

BACKGROUND: As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic. METHODS: We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics. RESULTS: A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%). CONCLUSION: This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.

Integrating soft and hard tissues via interface tissue engineering.

The enthesis, or interface between bone and soft tissues such as ligament and tendon, is prone to injury and often does not heal, even post surgical intervention. Interface tissue engineering represents an integrative strategy for regenerating the native enthesis by functionally connecting soft and hard tissues and thereby improving clinical outcome. This review focuses on integrative and cell-instructive scaffold designs that target the healing of the two most commonly injured soft tissue-bone junctions: tendon-bone interface (e.g., rotator cuff) and ligament-bone interface (e.g., anterior cruciate ligament). The inherent connectivity between soft and hard tissues is instrumental for musculoskeletal motion and is therefore a key design criterion for soft tissue regeneration. To this end, scaffold design for soft tissue regeneration have progressed from single tissue systems to the emerging focus on pre-integrated and functional composite tissue units. Specifically, a multifaceted, bioinspired approach has been pursued wherein scaffolds are tailored to stimulate relevant cell responses using spatially patterned structural and chemical cues, growth factors, and/or mechanical stimulation. Moreover, current efforts to elucidate the essential scaffold design criteria via strategic biomimicry are emphasized as these will reduce complexity in composite tissue regeneration and ease the related burden for clinical translation. These innovative studies underscore the clinical relevance of engineering connective tissue integration and have broader impact in the formation of complex tissues and total joint regeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1069-1077, 2018.

Advances in biologic augmentation for rotator cuff repair.

Rotator cuff tear is a very common shoulder injury that often necessitates surgical intervention for repair. Despite advances in surgical techniques for rotator cuff repair, there is a high incidence of failure after surgery because of poor healing capacity attributed to many factors. The complexity of tendon-to-bone integration inherently presents a challenge for repair because of a large biomechanical mismatch between the tendon and bone and insufficient regeneration of native tissue, leading to the formation of fibrovascular scar tissue. Therefore, various biological augmentation approaches have been investigated to improve rotator cuff repair healing. This review highlights recent advances in three fundamental approaches for biological augmentation for functional and integrative tendon-bone repair. First, the exploration, application, and delivery of growth factors to improve regeneration of native tissue are discussed. Second, applications of stem cell and other cell-based therapies to replenish damaged tissue for better healing are covered. Finally, this review will highlight the development and applications of compatible biomaterials to both better recapitulate the tendon-bone interface and improve delivery of biological factors for enhanced integrative repair.

Induction of stem-cell-derived functional neurons by NanoScript-based gene repression.

Even though gene repression is a powerful approach to exogenously regulate cellular behavior, developing a platform to effectively repress targeted genes, especially for stem-cell applications, remains elusive. Herein, we introduce a nanomaterial-based platform that is capable of mimicking the function of transcription repressor proteins to downregulate gene expression at the transcriptional level for enhancing stem-cell differentiation. We developed the "NanoScript" platform by integrating multiple gene repression molecules with a nanoparticle. First, we show a proof-of-concept demonstration using a GFP-specific NanoScript to knockdown GFP expression in neural stem cells (NSCs-GFP). Then, we show that a Sox9-specific NanoScript can repress Sox9 expression to initiate enhanced differentiation of NSCs into functional neurons. Overall, the tunable properties and gene-knockdown capabilities of NanoScript enables its utilization for gene-repression applications in stem cell biology.

Inducing Stem Cell Myogenesis Using NanoScript.

Transcription factors (TFs) are multidomain proteins that play a critical role in orchestrating stem cell differentiation, but several limitations hinder the full potential of TF-based gene regulation. Here we report a unique strategy to emulate TFs and differentiate stem cells in a nonviral approach using an artificial, nanoparticle-based transcription factor called NanoScript. The NanoScript platform consists of a gold nanoparticle functionalized with small molecules that mimic the various domains of TFs. As a result, NanoScript mimics the function and structure of TF proteins. Specifically, NanoScript was designed to regulate muscle cell differentiation by targeting myogenic regulatory factors (MRFs), which play an important role in inducing myogenesis. This NanoScript-MRF is stable in physiological environments, localizes within the nucleus, induces differentiation of adipose-derived mesenchymal stem cells into mature muscle cells in 7 days, and is naturally excreted from induced muscle cells. As such, NanoScript represents a safe and powerful tool for applications requiring gene manipulation.

Probing stem cell behavior using nanoparticle-based approaches.

Stem cells hold significant clinical potential to treat numerous debilitating diseases and injures that currently have no treatment plan. While several advances have been made in developing stem cell platforms and methods to induce their differentiation, there are two critical aspects need to be addressed: (1) efficient delivery of nucleic acids and small molecules for stem cell differentiation, and (2) effective, noninvasive, and real-time tracking of transplanted stem cells. To address this, there has been a trend of utilizing various types of nanoparticles to not only deliver biomolecules to targeted site but also track the location of transplanted stem cells in real time. Over the past decade, various types of nanoparticles, including magnetic nanoparticles, silica nanoparticles, quantum dots, and gold nanoparticles, have been developed to serve as vehicles for targeted biomolecule delivery. In addition of being biocompatible without causing adverse side effect to stem cells, these nanoparticles have unique chemical and physical properties that allow tracking and imaging in real time using different imaging instruments that are commonly found in hospitals. A summary of the landmark and progressive demonstrations that utilize nanoparticles for stem cell application is described.

Integrating epigenetic modulators into NanoScript for enhanced chondrogenesis of stem cells.

N-(4-Chloro-3-(trifluoromethyl)phenyl)-2-ethoxybenzamide (CTB) is a small molecule that functions by altering the chromatin architecture to modulate gene expression. We report a new CTB derivative with increased solubility and demonstrate CTB's functionality by conjugating it on the recently established NanoScript platform to enhance gene expression and induce stem cell differentiation. NanoScript is a nanoparticle-based artificial transcription factor that emulates the structure and function of transcription factor proteins (TFs) to effectively regulate endogenous gene expression. Modifying NanoScript with CTB will more closely replicate the TF structure and enhance CTB functionality and gene expression. To this end, we first conjugated CTB onto NanoScript and initiated a time-dependent increase in histone acetyltransferase activity. Next, because CTB is known to trigger the pathway involved in regulating Sox9, a master regulator of chondrogenic differentiation, we modifed a Sox9-specific NanoScript with CTB to enhance chondrogenic gene activity and differentiation. Because NanoScript is a tunable and robust platform, it has potential for various gene-regulating applications, such as stem cell differentiation.

NanoScript: a nanoparticle-based artificial transcription factor for effective gene regulation.

Transcription factor (TF) proteins are master regulators of transcriptional activity and gene expression. TF-based gene regulation is a promising approach for many biological applications; however, several limitations hinder the full potential of TFs. Herein, we developed an artificial, nanoparticle-based transcription factor, termed NanoScript, which is designed to mimic the structure and function of TFs. NanoScript was constructed by tethering functional peptides and small molecules called synthetic transcription factors, which mimic the individual TF domains, onto gold nanoparticles. We demonstrate that NanoScript localizes within the nucleus and initiates transcription of a reporter plasmid by over 15-fold. Moreover, NanoScript can effectively transcribe targeted genes on endogenous DNA in a nonviral manner. Because NanoScript is a functional replica of TF proteins and a tunable gene-regulating platform, it has great potential for various stem cell applications.

Generation of a library of non-toxic quantum dots for cellular imaging and siRNA delivery.

The development of non-toxic quantum dots and further investigation of their composition-dependent cytotoxicity in a high-throughput manner have been critical challenges for biomedical imaging and gene delivery. Herein, we report a rapid sonochemical synthetic methodology for generating a library of highly biocompatible ZnS-AgInS(2) (ZAIS) quantum dots for cellular imaging and siRNA delivery.

Incorporation of functionalized gold nanoparticles into nanofibers for enhanced attachment and differentiation of mammalian cells.

BACKGROUND: Electrospun nanofibers have been widely used as substrata for mammalian cell culture owing to their structural similarity to natural extracellular matrices. Structurally consistent electrospun nanofibers can be produced with synthetic polymers but require chemical modification to graft cell-adhesive molecules to make the nanofibers functional. Development of a facile method of grafting functional molecules on the nanofibers will contribute to the production of diverse cell type-specific nanofiber substrata. RESULTS: Small molecules, peptides, and functionalized gold nanoparticles were successfully incorporated with polymethylglutarimide (PMGI) nanofibers through electrospinning. The PMGI nanofibers functionalized by the grafted AuNPs, which were labeled with cell-adhesive peptides, enhanced HeLa cell attachment and potentiated cardiomyocyte differentiation of human pluripotent stem cells. CONCLUSIONS: PMGI nanofibers can be functionalized simply by co-electrospinning with the grafting materials. In addition, grafting functionalized AuNPs enable high-density localization of the cell-adhesive peptides on the nanofiber. The results of the present study suggest that more cell type-specific synthetic substrata can be fabricated with molecule-doped nanofibers, in which diverse functional molecules are grafted alone or in combination with other molecules at different concentrations.